Novel oral cannabinoid preparations

Abstract

This invention relates to novel pharmaceutical formulations, including solid oral dosage forms containing the non-psychoactive cannabidiol (CBD). The invention also relates to methods for preparing the pharmaceutical formulation and its application in treating diseases and conditions.

Description

[0001] Cross Reference to Related Applications

[0002] The present disclosure is related to UK patent applications GB2316995.6, filed on 6 November 2023, GB2400238.8, filed on 5 January 2024, and GB2410075.2, filed on 11 July 2024, and claims priority from the three applications, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present invention relates to a novel pharmaceutical formulation comprising a solid oral dosage form containing the non-psychoactive cannabinoid cannabidiol (CBD). The present invention also relates to a process for the preparation of the pharmaceutical formulation and to the use of the formulation in the treatment of diseases and conditions. BACKGROUND

[0004] Plant cannabinoids (i.e. cannabinoids derived from the plant Cannabis) have been used in medicine for thousands of years, with the earliest records dating back to around 400 AD. Cannabinoids are highly lipophilic, and therefore their formulation development has been challenging. Early medicinal use of cannabis was in the form of tinctures, i.e. cannabis was extracted and concentrated in alcohol, which was then taken as drops.

[0005] In recent years, cannabinoids have been studied more intensively and their effectiveness as medicines has been confirmed, and therefore more effective ways of administering them are required.

[0006] There are currently four approved medicines containing cannabinoids. Dronabinol is a synthetic tetrahydrocannabinol (THC) in sesame oil, taken orally in capsule form. Dronabinol is indicated for use in patients with AIDS and cancer, as an appetite stimulant, and is also approved for the treatment of chemotherapy-induced nausea and vomiting.

[0007] Another medicine derived from tetrahydrocannabinol (THC) is Nabilone, which contains a THC analogue. Nabilone is formulated with povidone and corn starch, and is also taken orally in capsule form. Nabilone is indicated for similar conditions as dronabinol.

[0008] Nabiximols is a plant extract, consisting of a high-THC and high-CBD extract, in approximately equal amounts. Due to the highly lipophilic nature of the plant extract, the medicine is formulated with ethanol, propylene glycol and peppermint flavouring, and is administered as an oromucosal spray, sprayed into the inner side of the user’s cheeks. Nabiximols was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in 2010 for the treatment of neuropathic pain, spasticity and overactive bladder in patients with multiple sclerosis.

[0009] CBD, a cannabinoid, is used in the drug Epidiolex. ® The form of Epidiolex is approved for the treatment of seizures associated with rare epilepsy syndromes such as Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis. This CBD formulation is dissolved in sesame oil at a concentration of 100 mg / ml and contains the sweetener sucralose, strawberry flavoring, and up to 10% (v / v) ethanol, and is administered as an oral solution. ® The initial dose is 5 mg / kg / day for one week, then gradually increased to a maximum dose of 25 mg / kg / day. This means a 50 kg child would need to take 12.6 ml of Epidiolex daily. ® Furthermore, because the dosage is calculated based on body weight, adults taking Epidiolex... ® The required dosage would be much higher than for children. In this case, adults would need to take large amounts of oil daily, which could lead to serious side effects.

[0010] Cannabinoids are highly lipophilic, making formulation difficult, especially when large doses are required, such as CBD. Due to their poor water solubility, cannabinoids are typically formulated as oils, alcohols, or a mixture of both, which can cause problems, particularly with large doses. Large intakes of oils can lead to gastrointestinal issues such as vomiting or diarrhea, and are contraindicated for those with nut / oil allergies. Furthermore, products with high alcohol content are contraindicated for children and adults with alcohol sensitivity.

[0011] Due to extensive first-pass metabolism, the oral bioavailability of CBD in humans is approximately 6%, while the bioavailability via inhalation is 11% to 45% (average 31%).

[0012] In healthy subjects, a single oral dose of 400 mg of CBD in gelatin capsules was administered, and it was found that CBD was rapidly absorbed, reaching a mean peak plasma concentration of 114 to 181 ng / mL in about 2.5 to 3 hours under steady state (Devinsky et al., 2014).

[0013] Patent application WO2015 / 184127A2 describes several oral cannabinoid formulations, such as an alcohol-free formulation in which the cannabinoids are formulated in a mixture of polyethylene glycol and propylene glycol. The application also describes formulations in which cannabinoids are dissolved in lipids and formulations containing alcohol.

[0014] Patent applications WO2021 / 081138A1 and WO2021 / 081140A1 describe compositions and methods for their preparation, wherein a lipophilic active pharmaceutical ingredient (API) is encapsulated with cyclodextrin. The prepared compositions exhibit 200% higher bioavailability compared to APIs not encapsulated with cyclodextrin, and utilize high-purity (99.9%) APIs.

[0015] Patent application EP4252745A1 describes cannabinoid formulations with different ingredients. These formulations contain a combination of 10% or 20% cannabidiol (CBD), three different cyclodextrins (30% or 55%), and nonspecific poloxamer (26% or 35%), along with eight other excipients, including polyethylene glycol (PEG), ethylenediaminetetraacetic acid (EDTA), and citric acid. Data provided in the application indicates that they are able to produce effervescent tablets containing 15 mg or 30 mg of CBD.

[0016] Patent application CN112891310A describes another cannabinoid formulation. This formulation is a full-spectrum cannabinoid oil with a CBD content of 50-83%. This oil is used to prepare formulations containing an emulsifier (e.g., poloxamer-188) and a carrier (e.g., cyclodextrin). Example 1 details a combination of poloxamer-188 and HP-β-CD, in which the CBD content is 6.05%.

[0017] Patent application US2023 / 0000770A1 describes a method for preparing cannabinoid nanomicelle powder. The cannabinoid CBD is coexisting with an amphiphilic polymer (e.g., poloxamer) and a lyophilizing agent (e.g., cyclodextrin, including HP-β-CD). Table 1 of Example 1 details CBD (10–60%), poloxamer-188 (0, 10%, or 50%), HP-β-CD (0 or 5%), and up to 17 other excipients. The effervescent tablets prepared in Example 4 contain 20, 40, or 60 mg of CBD.

[0018] US2021 / 0393784A1 describes a method for treating pain, comprising injecting a subject with a cannabinoid dissolved in SBE-7-β-cyclodextrin, and optionally a solubilizer (e.g., poloxamer-188). The cannabinoid may be CBD at a concentration of 1–5 mg / ml.

[0019] The buccal or sublingual formulation described in patent application US2011 / 0028431A1 comprises a nonionic polymeric solubilizer (which may be poloxamer), a pharmaceutically active ingredient (a water-soluble complex of cannabinoids and cyclodextrin), a mucosal adhesive polymer, a disintegrant, and a filler. The cannabinoid-cyclodextrin complex content is 5% to 65%. The cannabinoid content used to prepare the CB-CD complex is between 0.01% and 10% (THC, Example 1) and 1% and 20% (CBD, Example 2). Therefore, the maximum percentage of CBD in the final formulation is 13% (65% CB-CD complex contains 20% CBD).

[0020] When cannabinoids are taken orally, their bioavailability is usually very low because most of them are lost in the primary metabolic process known as the first-pass effect, where active cannabinoids are rapidly metabolized into inactive metabolites in the liver.

[0021] This invention discloses a novel oral cannabinoid formulation that has been shown to have higher bioavailability and no side effects compared to existing formulations. This type of formulation addresses the problems associated with high doses of cannabinoids when administered in oil and / or alcoholic solutions.

[0022] The novel formulation disclosed in this invention can be administered in solid oral dosage forms (such as pills, capsules or tablets), thereby providing patients with a more pleasant experience and improving patient compliance.

[0023] Furthermore, as outlined in the prior art above, the amount of cannabinoids that can dissolve in solid oral dosage forms is quite low. Therefore, patients requiring high doses of cannabinoids, such as CBD used to treat epilepsy, would typically take 20–25 mg / kg / day, which equates to 1400–1750 mg of CBD daily for a 70 kg person. Such a high dose means that a patient would need to take more than 10 capsules / tablets daily. This is generally unacceptable for medications that require daily administration.

[0024] This application can increase the CBD content in each capsule, thereby reducing the burden of medication for patients. Summary of the Invention

[0025] According to a first aspect of this disclosure, a solid oral pharmaceutical dosage form is provided, comprising cannabidiol, hydroxypropyl-β-cyclodextrin (HPβCD), poloxamer-188, and poloxamer-407, wherein the cannabidiol content is 100 to 300 mg per unit dose.

[0026] In one embodiment, the content of cannabidiol is 20% (w / w) to 50% (w / w) of the total composition.

[0027] In another embodiment, the content of hydroxypropyl-β-cyclodextrin (HPβCD) is from 15% (w / w) to 35% (w / w).

[0028] In another embodiment, the content of poloxamer-188 is 20% (w / w) to 40% (w / w).

[0029] In another embodiment, the content of poloxamer-407 is 5% (w / w) to 15% (w / w).

[0030] In one embodiment, the formulation further comprises one or more pharmaceutically acceptable emulsifiers and / or surfactants.

[0031] In another embodiment, the pharmaceutically acceptable emulsifier and / or surfactant is selected from the following components: lecithin, glyceryl monostearate, methylcellulose, sodium lauryl sulfate, sodium oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, tragacanth gum, triethanolamine oleate, polyethylene glycol monolaurate (PEG), polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, detergent, polysorbate 80 (polyoxyethylene monooleate), polysorbate 20 (polyoxyethylene monolaurate), cetearyl glucoside, polysaccharide glycoside, sorbitan monooleate (Span 80), sorbitan monolaurate (Span 20), polyoxyethylene monostearate (Myrj 45) Polyoxyethylene vegetable oil (Emulphor), cetyl chlorinated pyridine, polysaccharide gum, xanthan gum, tragacanth gum, gum arabic, and acacia gum.

[0032] In one embodiment, the pharmaceutically acceptable emulsifier and / or surfactant content is from 0.1% (w / w) to 35% (w / w) of the total composition.

[0033] In another embodiment, the solid oral medication dosage is formulated into one of the following dosage forms: tablets, pills, granules, capsules, powders, lozenges, granules, and sustained-release formulations.

[0034] In another embodiment, the solid oral medication dosage is formulated to be taken before, during, or after meals.

[0035] In one embodiment, each unit dose contains approximately 250 mg of cannabidiol.

[0036] In another embodiment, the dosage form, after being administered to a subject, has an AUC of 0-t For reference compound Epidiolex ® AUC 0-t 80% to 125%.

[0037] In another embodiment, after administration of this dosage form to a subject, its C max For reference compound Epidiolex ® C max 80% to 125%.

[0038] In another embodiment, a treatment method is provided, comprising administering a therapeutically effective amount of a solid oral dosage form to a subject.

[0039] This disclosure discloses a method for producing a solid oral drug dosage form, the method comprising the following steps:

[0040] a) Mix cannabidiol, hydroxypropyl-β-cyclodextrin (HPβCD), poloxamer-188, and poloxamer-407 for 20 to 60 minutes under supercritical CO2 conditions of 2,000–3,000 psi and 30–50°C; b) reduce the pressure in the reactor and collect the material; heat the material collected in step (b) to 40–50°C; while hot, fill the material into capsules using injection filling technology.

[0041] The following paragraphs are based on previous priority claims:

[0042] 1. A pharmaceutical composition comprising one or more cannabinoids, one or more cyclodextrins or cyclodextrin derivatives, one or more poloxamers, and optionally one or more pharmaceutical emulsifiers and / or surfactants.

[0043] 2. The pharmaceutical composition according to claim 1, wherein the composition, after being administered to a subject, has an AUC of 0-t This represents 80% to 125% of the reference compound.

[0044] 3. The pharmaceutical composition according to claim 1 or 2, wherein the composition, after being administered to a subject, has a C max This represents 80% to 125% of the reference compound.

[0045] 4. The pharmaceutical composition according to any one of the preceding claims, wherein one or more cannabinoids are derived from the group consisting of: cannabinoid (CBC), cannabinoid acid (CBCV), cannabidiol (CBD), cannabidiol acid (CBDA), cannabidiol acid (CBDV), cannabidiol (CBG), cannabidiol propyl variant (CBGV), cannacyclophenol (CBL), cannabinol (CBN), cannabidiol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinolic acid (THCV), and tetrahydrocannabinolic acid (THCVA).

[0046] 5. The pharmaceutical composition according to claim 4, wherein the content of one or more cannabinoids is from 15% (w / w) to 25% (w / w) of the total composition.

[0047] 6. The pharmaceutical composition according to claim 4 or 5, wherein one or more cannabinoids are cannabidiol (CBD).

[0048] 7. The pharmaceutical composition according to claim 1, wherein the one or more cyclodextrins or cyclodextrin derivatives are selected from the group consisting of: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, α-cyclodextrin hexadecyl acetate (AACD), β-cyclodextrin dodecyl acetate (ABCD), γ-cyclodextrin octadecyl acetate (AGCD), hydroxypropyl-α-cyclodextrin (HPαCD), hydroxypropyl-β-cyclodextrin (HPβCD), hydroxypropyl-γ-cyclodextrin (HPγCD), methyl-α-cyclodextrin (MαCD), methyl-β-cyclodextrin (MβCD), methyl-γ-cyclodextrin (MγCD), sulfobutyl ether-α-cyclodextrin (SBEαCD), sulfobutyl ether-β-cyclodextrin (SBEβCD), and sulfobutyl ether-γ-cyclodextrin (SBEγCD).

[0049] 8. The pharmaceutical composition according to claim 7, wherein the content of one or more cyclodextrins or cyclodextrin derivatives is from 25% (w / w) to 50% (w / w) of the total composition.

[0050] 9. The pharmaceutical composition according to claim 7 or 8, wherein one or more cyclodextrins or cyclodextrin derivatives are hydroxypropyl-β-cyclodextrin (HPβCD).

[0051] 10. The pharmaceutical composition according to claim 1, wherein the one or more poloxamers are selected from the group consisting of: poloxamer-182, poloxamer-183, poloxamer-184, poloxamer-185, poloxamer-188, poloxamer-212, poloxamer-215, poloxamer-217, poloxamer-234, poloxamer-235, poloxamer-237, poloxamer-238, poloxamer-288, poloxamer-333, poloxamer-334, poloxamer-335, poloxamer-338, poloxamer-402, poloxamer-403, and poloxamer-407.

[0052] 11. The pharmaceutical composition according to claim 10, wherein the content of one or more poloxamers is from 10% (w / w) to 70% (w / w) of the total composition.

[0053] 12. The pharmaceutical composition according to claim 10 or 11, wherein one or more poloxamers are poloxamer-188 and / or poloxamer-407.

[0054] 13. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable emulsifiers and / or surfactants are selected from the group consisting of: lecithin, glyceryl monostearate, methylcellulose, sodium lauryl sulfate, sodium oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, tragacanth gum, triethanolamine oleate, polysorbitan monolaurate, polyethylene glycol (PEG), polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, detergent, polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 20 (polyoxyethylene sorbitan monolaurate), cetearyl glucoside, polyglucoside, sorbitan monooleate (Span 80), sorbitan monolaurate (Span 20), and polyoxyethylene monostearate (Myrj 45). Polyoxyethylene vegetable oil (emulsifier), cetyl chlorinated pyridine, polysaccharide gum, xanthan gum, tragacanth gum, gum arabic, acacia gum.

[0055] 14. The pharmaceutical composition of claim 13, wherein the content of one or more pharmaceutically acceptable emulsifiers and / or surfactants is from 0% (w / w) to 35% (w / w) of the total composition.

[0056] 15. The pharmaceutical composition according to claim 13 or 14, wherein one or more pharmaceutically acceptable emulsifiers and / or surfactants are polyethylene glycol 6000 and / or polysorbate 80.

[0057] 16. The pharmaceutical composition according to any one of the preceding claims, comprising cannabidiol, hydroxypropyl-β-cyclodextrin (HPβCD), poloxamer-188, poloxamer-407, and optionally polyethylene glycol 6000 and polysorbate 80.

[0058] 17. The pharmaceutical composition according to claim 16, wherein the content of cannabidiol is 15% (w / w) to 25% (w / w) of the total composition, the content of hydroxypropyl-β-cyclodextrin (HPβCD) is 25% (w / w) to 50% (w / w) of the total composition, the content of poloxamer-188 and poloxamer-407 is 10% (w / w) to 70% (w / w) of the total composition, and the content of polyethylene glycol 6000 and polysorbate 80 is 0% (w / w) to 35% (w / w) of the total composition.

[0059] 18. The pharmaceutical composition according to any one of the preceding claims, wherein the object is a mammal.

[0060] 19. The pharmaceutical composition according to any one of the preceding claims, wherein the subject is a human.

[0061] 20. The pharmaceutical composition according to any one of the preceding claims, wherein the dosage form of the composition is selected from the group consisting of: oral single-dose dosage forms, intravenous single-dose dosage forms, intranasal single-dose dosage forms, suppository single-dose dosage forms, intradermal single-dose dosage forms, intramuscular single-dose dosage forms, intraperitoneal single-dose dosage forms, subcutaneous single-dose dosage forms, epidural single-dose dosage forms, sublingual single-dose dosage forms, liquids, tablets, rapidly disintegrating tablets, lyophilized preparations, films, sprays (including nasal sprays, oral sprays, or topical sprays) or mucosal adhesives.

[0062] 21. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated for administration in a manner selected from the following dosage forms: tablets, pills, granules, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays.

[0063] 22. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is taken before food intake.

[0064] 23. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is taken after a meal.

[0065] 24. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated into a capsule.

[0066] 25. The pharmaceutical composition of claim 24, wherein the composition comprises cannabidiol.

[0067] 26. The pharmaceutical composition according to claim 25, wherein each capsule contains 127.5 mg to 172.5 mg of cannabidiol.

[0068] 27. The pharmaceutical composition according to claim 26, wherein each capsule contains about 150 mg of cannabidiol.

[0069] 28. A treatment method comprising administering a therapeutically effective amount of the composition to a subject according to any of the preceding claims. Attached Figure Description

[0070] The following describes the contents of this disclosure and refers to the following data:

[0071] Figure 1 shows Epidiolex in detail. ® Mean CBD plasma concentrations (0-24 hours) for formulations T1 (red diamond), T2 (blue circle), and T2 (green triangle).

[0072] Figure 2 shows Epidiolex in detail. ®Mean 7-OH-CBD plasma concentrations (0-96 hours) for formulations T1 (red diamond), T2 (blue circle), and T3 (green triangle).

[0073] Figure 3 shows Epidiolex in detail. ® Mean 7-COOH-CBD plasma concentrations (0-96 hours) for formulations T1 (red diamond), T2 (blue circle), and T3 (green triangle).

[0074] Figure 4 shows in detail the mean CBD plasma concentrations (0-24 hours) of the T1 formulation in the fed state (blue circle) and the T1 formulation in the fasting state (red diamond).

[0075] Figure 5 shows in detail the mean 7-OH-CBD plasma concentrations of formulation T1 in the fed state (blue circle) and the fasting state (red diamond) (0-96 hours).

[0076] Figure 6 shows in detail the mean 7-COOH-CBD plasma concentrations of formulation T1 in the fed state (blue circle) and the fasting state (red diamond) (0-96 hours).

[0077] Definitions

[0078] "Approximately" refers to all values ​​that have a substantially similar effect or provide substantially the same result as the reference value. Therefore, the meaning of "approximately" varies depending on the context in which it is used, such as the parameter associated with the reference value. Thus, depending on the context, "approximately" could refer to: ±0.10%; ±0.25%; ±0.5%; ±1.0%; ±2.5%; ±5.0%; or ±10.0%. All expressions that preface a reference value with "approximately" refer to the reference value itself alone.

[0079] When used to describe pharmacokinetic parameters (such as AUC; AUC 0-t AUC 0-inf C max ;T max When referring to the reference parameter, the word "about" indicates 80% to 125%.

[0080] C max Data analysis (including its curves) is used to determine the rate and extent of drug exposure.

[0081] "Administration" includes any route of administration, such as oral, subcutaneous, sublingual, mucosal, parenteral, intravenous, arterial, buccal, sublingual, local, vaginal, rectal, ocular, ear, nasal, inhalation, and transdermal. It should be particularly noted that oral administration is a possible route of administration.

[0082] "Bioequivalence" refers to the absence of significant differences in the rate and extent to which two drugs or alternative drugs achieve the same concentration of active ingredient or its alternative biomarker at the site of action in a well-designed clinical trial. When safety and efficacy factors are fully considered, the logarithmic transformation C0 of the two products or methods... max The 90% confidence interval for the ratio of geometric means can be wider.

[0083] "Combined therapy" refers to the simultaneous use of two or more different active ingredients in a coordinated manner. Combined therapy includes the simultaneous, sequential, or separate use of two or more different active ingredients. Therefore, "combined therapy" includes the use of the same or different dosage forms, simultaneous administration, and non-simultaneous administration, such as the use of one active ingredient first, followed by or alternating with another active ingredient as part of a coordinated treatment regimen.

[0084] A “composition” is a collection of substances that contains specific ingredients. One or more dosage forms can constitute a composition, provided that these dosage forms are related to each other and designed for use together.

[0085] "Enteric-coated polymers" are polymers that have very low solubility in aqueous media with a pH of about 4.5 or lower, but high solubility in aqueous media with a pH greater than about 5. For example, enteric-coated polymers have low solubility in gastric juice, but can dissolve in the lower digestive tract environment.

[0086] "Pharmaceutical composition" refers to a formulation of a compound disclosed herein (e.g., cannabidiol) with a medium generally accepted in the art for delivering the bioactive compound to mammals (e.g., humans). This medium includes all pharmaceutically acceptable carriers, diluents, or excipients. The pharmaceutical composition may be in various dosage forms or comprise one or more single-dose formulations.

[0087] "Pharmaceutical acceptable" means that it is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., has a reasonable benefit / risk ratio, and is effective for its intended use within the limits of reasonable medical judgment.

[0088] "Cannabidiol reference composition" (reference composition) refers to the AUC in a fasting state. 0-t AUC compared to the feeding state 0-t Cannabidiol compositions with a content of approximately 35% or more; and / or an intra-subject variability of approximately 30% or more.

[0089] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Examples of inorganic bases that can be used to prepare salts include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases that can be used to produce salts include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Specifically, examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In the examples, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0090] "Solvate" refers to a complex formed by solvation (the binding of solvent molecules with molecules or ions of the active ingredient disclosed herein), or an aggregate composed of solute ions or molecules (the active ingredient disclosed herein) and one or more solvent molecules. For example, a solvate whose solvent molecule is water is called a hydrate. Hydrates particularly refer to solvates of the materials described herein.

[0091] "Solid dispersion" refers to a solid system in which the active ingredient is nearly uniformly or uniformly dispersed in an inert carrier or matrix.

[0092] "Substantially similar" means that it has a high degree of similarity or similarity with the reference item, terminology, quantity, etc.

[0093] "Prodrugs" are precursors to active ingredients. These precursors may or may not have pharmacological activity, but after administration, they are converted into the target active ingredient or drug through metabolism or other pathways. For example, prodrugs include ester or ether forms of the active ingredient.

[0094] "Therapeutic effective dose" or "effective dose" refers to the dosage of the active ingredient in a drug that is sufficient to achieve a therapeutic effect when administered to a patient according to the dosing regimen described herein. Therapeutic effective doses can vary depending on the type and severity of the disease, as well as the patient's age, weight, and other conditions.

[0095] A composition or dosage form is said to be "therapeuticly equivalent" to a reference composition or dosage form if it has a therapeutic effect substantially similar to that of the reference composition or dosage form. For example, therapeutically equivalent dosage forms, when administered over substantially similar time periods, can have substantially similar efficacy against a specific disease or condition.

[0096] "Patient" or "subject" refers to a mammal, such as a human, that needs to receive medical treatment.

[0097] As used herein, the terms "treatment" or "treatment" refer to methods employed to achieve a beneficial or anticipated outcome in relation to a disease, symptom, or medical condition, including but not limited to therapeutic and / or preventative effects. Therapeutic effects may include, for example, eradicating or improving the underlying disease being treated. Furthermore, therapeutic effects may also include eradicating or improving one or more physiological symptoms associated with the underlying disease, thereby improving the condition of the subject, even if the subject may still have the underlying disease. In some embodiments, to achieve a preventative effect, the composition may be administered to subjects at risk of developing a specific disease, or to subjects who report the presence of one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0098] Cyclodextrins (CDs) are cyclic oligosaccharides composed of α-1,4-linked D-glucanose units. The number of linked D-glucanose units determines the type of cyclodextrin. There are three main types of cyclodextrins: α-cyclodextrin (containing 6 glucose subunits), β-cyclodextrin (containing 7 glucose subunits), and γ-cyclodextrin (containing 8 glucose subunits). These three are the most commonly used natural cyclodextrins, although larger cyclodextrins have been reported. Cyclodextrins are used as pharmaceutical excipients and are recognized as generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA) for human use. In this disclosure, the term "cyclodextrin" refers to any known cyclodextrin.

[0099] "Cyclodextrin derivatives" refer to derivatives formed by modifying the hydroxyl groups of cyclodextrin. For example, propylene oxide can generate hydroxypropyl cyclodextrin derivatives. Cyclodextrin derivatives generally exhibit superior properties; for example, β-cyclodextrin and methylated β-cyclodextrin (MβCD) can remove cholesterol from cultured cells, but the methylated form of MβCD is more effective than β-cyclodextrin. Some cyclodextrins have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in pharmaceuticals. For example, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is used in the antifungal active pharmaceutical ingredient itraconazole, which is available in both intravenous and oral formulations. In this disclosure, the term "cyclodextrin derivative" refers to any known cyclodextrin derivative.

[0100] "Poloxamer / s" is a nonionic triblock copolymer consisting of a hydrophobic polyoxypropylene (polypropylene oxide) central chain and two hydrophilic polyoxyethylene (polyethylene oxide) chains on either side. By varying the length of the polymer blocks, various poloxamers can be formed, resulting in slightly different properties. Poloxamers possess surfactant properties and are commonly used to improve the water solubility of drugs. In this disclosure, the term "poloxamer" refers to any known poloxamer. Detailed Implementation

[0101] This disclosure references numerous patents, patent applications, and publications. To provide a more comprehensive description of the prior art known to those skilled in the art as of the date of this disclosure, the entire contents of these patents, patent applications, and publications are incorporated herein by reference. In the event of any discrepancy between the referenced patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0102] The following examples describe novel oral cannabinoid formulations. These formulations have been tested and confirmed to have higher bioavailability and no side effects compared to existing formulations. Such formulations address the problems associated with high doses of cannabinoids when administered in oil and / or alcoholic solutions. The novel formulations disclosed herein can be administered in solid oral dosage forms (e.g., pills, capsules, or tablets), thereby providing a more comfortable experience for patients and improving patient adherence.

[0103] Active pharmaceutical ingredient (API)

[0104] The API used in this application is selected from one or more cannabinoids disclosed in Chapter 1, pages 3 to 15 of Roger Pertwee's "The Cannabis Handbook".

[0105] The preferred cannabinoids disclosed are cannabidiol (CBD) and / or tetrahydrocannabinol (THC).

[0106] The cannabinoid content is preferably about 5 to 80 wt% of the total composition, preferably about 10 to 50 wt%, and more preferably about 15 to 25 wt%.

[0107] Ideally, cannabinoids should be synthetic or highly purified from their natural sources (e.g., recrystallized forms from plant sources). When using highly purified sources, the degree of purification should result in a cannabinoid content (w / w) of over 95% in the total extract. The advantage of using synthetic or highly purified cannabinoids is that they contain relatively less wax. This helps prevent the formation of oily formulations, thus improving the physical stability of the formulation.

[0108] The unit dose range of cannabinoids in oral pharmaceutical preparations is 0.001 to 1000 mg, preferably 1 to 500 mg, and more preferably 150 to 350 mg. For example, when present in single-dose tablet or capsule form, the amount of cannabinoids contained therein is expected to be approximately 0.5, 1, 2, 5, 10, 25, 50, 100, 125, 150, 175, 200, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0109] Preparation of test samples

[0110] The steps for preparing the formula disclosed in this invention are as follows:

[0111] Weigh the ingredients using a calibrated balance, then transfer them to a clean, dry, wide-mouthed glass jar.

[0112] Cover the glass jar with a SureTight lid, shake for 2-3 minutes to mix thoroughly, and then seal with sealing film.

[0113] The powder mixture was prepared in a 150 mL stainless steel high-pressure reactor. After adding all raw materials, the reactor was sealed before adding solvent. CO2 was introduced, and the pressure and temperature were increased to reach a supercritical state. The reactor pressure was maintained between 2000 and 3000 psi, the temperature between 30 and 50°C, and vigorous stirring was performed for 20 to 60 minutes. After depressurizing the reactor for 1 hour, the resulting inclusion complex powder was collected.

[0114] The use of CO2 was solely for the preparation of the formulations disclosed in this invention and was not for the extraction of cannabinoids or other components.

[0115] This formulation can also be prepared using the method described in WO2021 / 081138A1, which is incorporated herein by reference.

[0116] Example

[0117] Example 1: Evaluation of the pharmacokinetics of cannabidiol (CBD) in plasma following oral administration of two CBD formulations to male Sprague-Dawley rats Example 2: Evaluation of the pharmacokinetics of cannabidiol (CBD) in plasma following oral administration of four CBD formulations to male SD rats

[0118] This study determined the plasma pharmacokinetics (PK) of CBD at a dose of 10 mg / kg after oral administration of two different CBD formulations (CBD-1 and CBD MCT tincture) to male Sprague-Dawley rats. Blood samples were collected from the carotid arteries of eight rats via catheter placement. Each formulation was administered to four rats with implanted catheters, and plasma samples were collected at 12 consecutive time points within 24 hours post-administration.

[0119] The average maximum CBD plasma concentrations for the two formulations and the time required to reach these concentrations were calculated.

[0120] Materials and Methods

[0121] This study used eight male SD rats (weighing 250–325 g; Charles River Laboratory). These animals were acclimatized to the experimental environment for at least five days prior to surgery.

[0122] A catheter was implanted in the carotid artery of all animals for continuous blood collection and replenishment. The catheter was implanted at least one day before the start of the drug administration procedure.

[0123] The animals were divided into two treatment groups, with four animals in each group, and the test substance was administered by gavage.

[0124] Blood samples were collected at the following time points: 3, 5, 10, 20, 30, 45, 60, 90, 120, 240, 480, and 1440 minutes, and CBD content was tested in the samples using quantitative bioanalytical methods.

[0125] To determine the CBD plasma exposure (C) of the three formulations max To determine whether there is a statistically significant difference between AUC and GraphPad Prism, use GraphPad Prism. ® One-way ANOVA was performed using software 9.1, and Tukey's multiple comparison test was used. A p-value <0.05 was considered statistically significant.

[0126] test product

[0127] This study used two different CBD-containing test samples. CBD-1 was formulated from cyclodextrin, and CBD-2 was formulated from medium-chain triglyceride oil. Detailed information about the test samples is shown in Table 1 below.

[0128] Table 1. Test Sample Details

[0129]

[0130] Preparation of test samples:

[0131] The preparation method of CBD-1 is as described above.

[0132] Table 2. Composition of CBD-1 formulations

[0133]

[0134] result

[0135] Table 3 summarizes the in vivo PK parameters of CBD after oral administration (po) of 10 mg / kg for two different formulations, and Table 4 summarizes the comparison of the pharmacokinetic (PK) plasma parameters (fold change) of the two formulations.

[0136] Table 3. Summary of Mean Pharmacokinetic Parameters

[0137]

[0138] Note: a – Dosage = Measured concentration of the dosing solution multiplied by the volume of the dosing solution

[0139] b – There was a significant difference compared to the CBD-1 group (p < 0.05)

[0140] n / c – This cannot be calculated because the terminator is not well-defined.

[0141] As shown in the table, the CBD-1 formulation takes effect significantly faster than CBD in MCT oil, with its t max The duration of action was 52.5 minutes, while that of CBD in MCT oil was 7 hours. Furthermore, the blood glucose level of the CBD-1 formulation was [not specified]. max It was also significantly higher than CBD in MCT oil, with average values ​​of 195 ng / ml and 15 ng / ml, respectively.

[0142] Table 4 below provides a detailed comparison of the PK parameters.

[0143] Table 4. Comparison of CBD PK plasma parameters (fold change) between CBD-1 formulation and CBD MCT tincture

[0144]

[0145] The dose-normalized maximum plasma concentration (CBD-1) achieved after administration of a CBD-1 formulation (C max The dose was 16.7 kg. * The concentration was ng / ml / mg, significantly higher than other formulations (14 times higher; P < 0.0001), and the concentration was 1.17 kg compared to the concentration after administration of CBD MCT tincture. * ng / ml / mg.

[0146] With CBD MCT tincture (528 min) * kg *Compared to (ng / mL / mg), administration of the CBD-1 formulation resulted in dose-normalized CBD exposure (2200 min). * kg * The concentration of ng / mL / mg was significantly higher (4-fold; P = 0.0027).

[0147] in conclusion

[0148] This invention discloses a novel CBD-1 formulation, wherein the CBD is solubilized with α-cyclodextrin and poloxamer-407, and exhibits favorable pharmacokinetic parameters after administration to rats. It demonstrates a significantly faster time to peak concentration (ts). max This indicates that the formulation has a faster onset of action compared to MCT oil formulations. Furthermore, this novel formulation exhibits a higher peak concentration (C0). max Compared to the other two formulations, it requires a lower dosage to achieve the same effect. This brings many advantages, including lower cost and fewer side effects.

[0149] Example 3: Evaluation of the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) in plasma following oral administration of three THC formulations to male SD rats.

[0150] This study aimed to investigate the plasma pharmacokinetic (PK) changes of four different CBD formulations (CBD-1, CBD-2, CBD-3, and CBD-4) at a dose of 10 mg / kg in male SD rats. Blood samples were collected from the carotid arteries of sixteen rats via catheter implantation. Each formulation was administered to four rats with implanted catheters, and plasma samples were collected at 12 consecutive time points within 24 hours post-administration.

[0151] The average maximum CBD plasma concentrations for the four formulations and the time required to reach these concentrations were calculated.

[0152] Materials and Methods

[0153] This study used sixteen male SD rats (weighing 250–325 g) (Charles River Laboratory). These animals were acclimatized to their environment for at least five days prior to surgery.

[0154] A catheter was implanted in the carotid artery of all animals for continuous blood collection and replenishment. The catheter was implanted at least one day before the start of the drug administration procedure.

[0155] The animals were divided into two treatment groups, with four animals in each group, and the test substance was administered by gavage.

[0156] Blood samples were collected at the following time points: 3, 5, 10, 20, 30, 45, 60, 90, 120, 240, 480, and 1440 minutes, and CBD content was tested in the samples using quantitative bioanalytical methods.

[0157] To determine the CBD plasma exposure (C) of the three formulations max To determine whether there is a statistically significant difference between AUC and GraphPad Prism, use GraphPad Prism. ® 9.1 One-way ANOVA was performed using the software, and Tukey's multiple comparison test was used. A p-value <0.05 was considered statistically significant.

[0158] test product

[0159] This study used four different CBD-containing test samples. CBD-1 was formulated with α-cyclodextrin and poloxamer-407, the same formulation used in Example 1. The remaining formulations used hydroxypropyl-β-cyclodextrin (HPβCD) and various other excipients as described in Table 5 below.

[0160] Table 5. Test Item Details

[0161]

[0162] Preparation of test sample:

[0163] The steps for preparing CBD formulations using the ingredients detailed in Tables 6 to 9 are the same as those previously described.

[0164] Table 6. Composition of CBD-1 formulations

[0165]

[0166] Table 7. Composition of CBD-2 formulations

[0167]

[0168] Table 8. Composition of CBD-3 formulations

[0169]

[0170] Table 9. Composition of CBD-4 formulations

[0171]

[0172] result

[0173] Table 10 summarizes the in vivo pharmacokinetic parameters of CBD after oral administration of four different formulations at 10 mg / kg, and Table 11 summarizes the comparison of plasma pharmacokinetic parameters (fold change) among the four formulations.

[0174] Table 10. Summary of Mean Pharmacokinetic Parameters

[0175]

[0176] Note: a – Dosage = Measured concentration of the dosing solution multiplied by the volume of the dosing solution

[0177] b – There was a significant difference compared to the THC-1 group (p<0.05)

[0178] As shown in the table, the CBD-1 formulation has a significantly faster onset of action than CBD in MCT oil, with a peak time (t) max The peak plasma concentration (CPD) of the CBD-1 formulation was 52.5 minutes, while that of CBD in MCT oil was 7 hours. Furthermore, the peak plasma concentration of the CBD-1 formulation was [not specified]. max The levels of CBD in the oil were also significantly higher than those in MCT oil, with average values ​​of 195 ng / ml and 15 ng / ml, respectively.

[0179] Table 11 below provides a detailed comparison of the PK parameters.

[0180] Table 11. Comparison of CBD PK plasma parameters (fold change) among different formulations

[0181] Following administration of the CBD-1 formulation, within 30 to 60 minutes (mean t) after administration, max = 41 minutes) to reach maximum CBD plasma concentration (C max = 91 ng / mL).

[0182] After administration of CBD-2 preparations, C max It was 135 ng / mL (1.4 times higher than the CBD-1 formulation), t max It lasted 56 minutes.

[0183] Following administration of CBD-3 and CBD-4 formulations, CBD levels peaked between 30 and 240 minutes, with corresponding C... max The values ​​were 52.8 ng / mL and 102 ng / mL, respectively (0.56 times and 1.1 times that of the CBD-1 formulation, respectively).

[0184] The apparent half-life (t) of CBD 1 / 2 The CBD half-life was similar in formulations 8A, SP-14, and SP-24 (271, 277, and 251 minutes, respectively), while the CBD half-life of formulation P-25 was slightly longer (324 minutes, Table 1).

[0185] Total plasma exposure to CBD in animals (AUC) 0-inf The highest and least variable (18500 min) * The plasma exposures of formulations 8A and SP-25 were comparable (14200 ng / mL and 14700 min, respectively). *The plasma exposure of SP-24 formulation (Table 1) was the lowest (12300 min / mL), while that of SP-24 formulation (Table 1) was the lowest (12300 min / mL). * (ng / mL).

[0186] in conclusion

[0187] This invention discloses a novel CBD-1 formulation, wherein CBD is solubilized with α-cyclodextrin and poloxamer-407, and its pharmacokinetic parameters have been confirmed to be favorable after administration to rats. Significantly faster time to peak concentration (ts) is observed. max This indicates that, compared to the MCT oil formulation (Example 1), this formulation has a faster onset of action. Furthermore, this novel formulation exhibits higher bioavailability and C... max Compared to the other two formulations, it requires a lower dosage to achieve the same effect. This brings many advantages, including lower cost and fewer side effects.

[0188] Example 4: A phase 1, two-part, open-label pilot study in healthy adult male subjects to assess the relative bioavailability of three cannabidiol (CBD) formulations under fasting (Part A) and fed (Part B) conditions. Part A:

[0189] This study investigated the plasma pharmacokinetics (PK) of three different oral formulations of Δ9-tetrahydrocannabinol (THC) (at a dose of 10 mg / kg). The formulations tested included a cyclodextrin formulation, a THC tincture (THC dissolved in medium-chain triglyceride oil), and a commercially available THC emulsion.

[0190] The average maximum THC plasma concentration of the formulation and the time required to reach these concentrations were calculated.

[0191] Materials and Methods

[0192] This study used twelve male SD rats (weighing 250 g to 325 g) (Charles River Laboratory). These animals were acclimatized to their environment for at least five days prior to surgery.

[0193] A catheter was implanted in the carotid artery of all animals for continuous blood collection and replenishment. The catheter was implanted at least one day before the start of the drug administration procedure.

[0194] The animals were divided into three treatment groups, with four animals in each group, and the test substance was administered by gavage.

[0195] Blood samples were collected at the following time points: 3, 5, 10, 20, 30, 45, 60, 90, 120, 240, 480, and 1140 minutes, and the THC content of the samples was tested using quantitative bioanalytical methods.

[0196] To determine the THC plasma exposure (C) among the three formulations max To determine whether there is a statistically significant difference between AUC and GraphPad Prism, use GraphPad Prism. ®9.1 One-way ANOVA was performed using the software, and Tukey's multiple comparison test was used. A p-value < 0.05 was considered statistically significant.

[0197] test product

[0198] This study used three different THC-containing test samples. THC-1 was formulated from cyclodextrin, THC-2 from medium-chain triglyceride oil, and THC-3 was a commercially available THC preparation. Detailed information on the test samples is shown in Table 12 below.

[0199] Table 12. Test Item Details

[0200]

[0201] Preparation of test sample:

[0202] The steps for preparing THC-1 formulations using the ingredients detailed in Table 13 are the same as those described previously.

[0203] Table 13. Composition of THC-1 formulations

[0204]

[0205] result

[0206] Table 14 summarizes the in vivo PK parameters of THC after oral administration of 10 mg / kg for three different formulations, and Table 15 summarizes the comparison of plasma PK parameters (fold change) of the three formulations.

[0207] Table 14. Summary of Mean Pharmacokinetic Parameters

[0208]

[0209] Note: a – Dosage = Measured concentration of the dosing solution multiplied by the volume of the dosing solution

[0210] b – There was a significant difference compared to the THC-1 group (p < 0.05)

[0211] c – There was a significant difference in THC compared to the MCT group (p<0.05)

[0212] n / c – This cannot be calculated because the terminator phase is not well-defined.

[0213] It can be seen that the THC-1 formulation has a faster onset of action, and its peak time (t) is shorter. max The peak plasma concentration (C) of THC-1 formulations was 35 minutes, while commercial THC formulations took over 1 hour, and THC in MCT oil took 6 hours. maxThe concentration of THC in MCT oil is also more ideal, with an average of 66 ng / ml, while the concentration of THC in commercially available THC is lower than that in MCT oil. max The concentrations were 12 ng / ml and 32 ng / ml, respectively.

[0214] Since the AUC of the THC MCT tincture group cannot be extrapolated to infinity, it is not possible to directly compare the dose-normalized total plasma exposure (AUC) of different formulations. 0-∞ Instead of comparing the concentration from 0 to the last measurable concentration (t), the comparison was made from the dose (t). last The dose-normalized AUC (=1440 minutes) is calculated.

[0215] Table 15 below provides a detailed comparison of the PK parameters.

[0216] Table 15. Comparison of plasma pharmacokinetic parameters (fold change) between THC-1 formulation, THC MCT tincture, and commercial THC.

[0217]

[0218] Dosage-standardized maximum plasma concentration (C max The dose was 7.08 kg. * The concentration was ng / ml / mg, significantly higher than the concentration achieved after taking THCMCT tincture (1.27 kg). * The concentration was 5.57 times higher than that achieved after taking THC drops (3.81 ng / mL / μg; P = 0.0448), which was also higher than that achieved after taking THC drops (1.86 times higher than that achieved after taking THC drops (3.81 ng / mL / μg; P = 0.2916).

[0219] AUC 0-tlast Exposure (1440 min) * kg * The ng / ml / mg level was significantly higher (2.96-fold), but comparable to the exposure level of commercial THC (1100 min). * kg * (ng / ml / mg, P = 0.3698).

[0220] in conclusion

[0221] The novel THC-1 formulation disclosed in this invention, wherein THC is solubilized with α-cyclodextrin and poloxamer-407, exhibits favorable pharmacokinetic parameters after administration to rats. Significantly faster t max This indicates that the formulation has a faster onset of action than THC in commercially available THC and MCT oils. Furthermore, this novel formulation has a higher C60 content. max Compared to the other two formulations, it requires a lower dosage to achieve the same effect. This brings many advantages, including lower cost and fewer side effects.

[0222] Part B: Pharmacokinetic analysis:

[0223] A clinical study aims to evaluate two novel CBD formulations (T1 and T2) compared to a reference formulation (Epidiolex). ® Relative bioavailability in healthy adult male subjects under fasting conditions.

[0224] As part of the study, the effects of a high-fat, high-calorie diet on the bioavailability of the active ingredient CBD and its major metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-carboxycannabidiol (7-COOH-CBD) after a single dose of T1 or T2 in healthy adult male subjects were investigated.

[0225] Research Design

[0226] A single-center, phase 1, randomized, open-label, three-treatment, four-cycle, three-sequence crossover study aims to compare two novel CBD formulations (T1 and T2) with a reference formulation (Epidiolex). ® The relative bioavailability under fasting conditions was assessed, and the effect of food on T1 or T2 bioavailability in healthy male subjects was evaluated.

[0227] Part A consisted of three treatment phases. A total of fifteen participants were recruited and randomly assigned to one of three sequences, with five participants in each sequence (n=5).

[0228] According to the randomization protocol, subjects received a single dose of one of three CBD formulations in each cycle. There was a washout period of at least seven days (not exceeding fourteen days) between the two doses.

[0229] Part A includes screening visits from day -28 to day -2. Eligible subjects were admitted on day -1 and administered medication on day 1, after fasting for at least 10 hours prior to administration. Subjects completed assessments during their hospital stay (day 3) and returned to the clinical center for outpatient follow-up on days 4 and 5.

[0230] Subjects were readmitted on days 7 and 14, and received their second and third doses of treatment on days 8 and 15, respectively. Subjects were able to return to the clinical center after completing assessments on days 10 and 17 of treatment cycles 2 and 3, respectively, and returned to the clinical center for follow-up on days 11 and 12 of treatment cycle 2 and days 18 and 19 of treatment cycle 3.

[0231] After a washout period of at least 2 weeks following the last dose of Part A, subjects may return to the clinical trial site as early as day 28 to continue Part B of the study.

[0232] All participants received a single dose of the test CBD formulation (T1) 30 minutes after consuming a high-fat, high-calorie breakfast. Participants were restricted from physical activity until the assessment was completed on day 31, and returned to the clinical trial center for follow-up on days 32 and 33 (FU / follow-up).

[0233] Research on treatment

[0234] During each treatment cycle, the subject receives a single dose of one of the following treatment regimens:

[0235] Bioequivalence acceptance criteria:

[0236] Treatment A (Reference): Oral administration of Epidiolex on an empty stomach ® 350 mg CBD (100 mg / mL CBD solution).

[0237] Treatment of B (T1): 350 mg CBD (87.5 mg capsules) orally on an empty stomach.

[0238] Treatment of C (T2): 350 mg CBD (87.5 mg capsules) orally on an empty stomach.

[0239] Safety and tolerability analysis:

[0240] Treatment of D (T1): Based on PK and safety data from Part A of the study, 350 mg of CBD was administered orally after a standard high-fat diet.

[0241] Table 16 below provides detailed information on the research products used.

[0242] Table 16. Details of the Research Products

[0243]

[0244] Product preparation:

[0245] The steps for preparing formulations T1 and T2 using the ingredients detailed in Tables 17 and 18 are the same as those previously described.

[0246] Table 17. Formula T1

[0247]

[0248] Table 18. Formula T2

[0249]

[0250] Blood sample collection for pharmacokinetic analysis:

[0251] During each treatment cycle, a total of 19 blood samples were collected to analyze the plasma concentrations and pharmacokinetic analysis of CBD and its metabolites (7-OH-CBD and 7-COOH-CBD) in the blood at the following time points: before administration, 5 minutes after administration, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours after administration.

[0252] Total bile acid samples were collected only prior to administration at each treatment period. Plasma levels of CBD, 7-OH-CBD, and 7-COOH-CBD in all subjects were analyzed using a validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS / MS) bioanalytical method.

[0253] Statistical analysis

[0254] Example 5: Investigation of various excipient combinations

[0255] Plasma concentration data for CBD, 7-OH-CBD, and 7-COOH-CBD are listed separately and summarized by treatment time point. These data can be used to calculate the ratio of CBD to its metabolites.

[0256] PK parameter C max T max AUC 0-t AUC 0-∞ The results were summarized using descriptive statistical methods based on the treatment outcomes.

[0257] By analyzing the key exposure PK parameter AUC 0-t AUC 0-∞ and C max A linear fixed-effects model was used to study the exposure comparison between different treatment regimens ([Test 1] and [Test 2] with Epidiolex) based on logarithmically transformed values. ® [Reference] (compared to the geometric mean Frel treatment ratio), α level 0.05, for each treatment regimen.

[0258] The ratio of geometric least squares (LS) means (in test / reference terms) and the corresponding 90% confidence interval (CI) are also given.

[0259] T max Nonparametric analysis was performed. The table lists the T values ​​for each treatment. max The median and its approximate 90% confidence interval.

[0260] Analysis of variance (ANOVA) or nonparametric methods were used to analyze the untransformed K. el and T ½elAdditional modeling is performed. The paper presents the geometric least squares (LS) mean ratios (expressed as experimental / reference values) and their corresponding 90% confidence intervals (CIs). These ratios are for AUC. 0-t AUC 0-∞ and C max Calculated. In addition, the C of the sum of CBD and 7-OH-CBD was also calculated. max AUC and Frel (if applicable), and using WinNonLin or similar software, extrapolated from single-dose data to steady state over a 12-hour dosing interval.

[0261] Example 6: Stability study

[0262] AUC based on logarithmic transformation 0-∞ The 90% confidence interval for the least squares mean and geometric mean ratio (experimental formulation / reference formulation) of the analysis of variance must be between 80.00% and 125.00%.

[0263] Example 7: Increasing the drug load of the CBD formulation

[0264] Epidiolex was evaluated by assessing adverse events (i.e., severity, degree of severity, relationship to the study drug, outcome, duration, and management), vital signs, 12-lead electrocardiogram, clinical laboratory tests, and physical examination. ® Safety and tolerability of T1 and T2 formulations.

[0265] Medical history and adverse event terms are coded using the MedDRA (Medical Terminology Reference Intake). Previous medications and concomitant medications are coded using the World Health Organization Drug Dictionary (WHO-DD).

[0266] Individual adverse events, clinical laboratory data (if outside the normal reference range, this should be noted), and physical examination results (including changes compared to baseline) are listed. In addition, descriptive information on clinical laboratory data, vital signs, and electrocardiogram parameters is provided (if applicable).

[0267] result

[0268] Mean plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD. Figures 1 through 3 detail the mean plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD during the study period.

[0269] Table 19A. Part A (fasting) of taking Epidiolex ® The average concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD in post-concentration plasma

[0270]

[0271] Table 19B. Part A (Fasting) Average plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD after administration of T1 formulation.

[0272]

[0273] Table 19C. Part A (Fasting) Average plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD after administration of T2 formulation.

[0274]

[0275] Epidiolex ® The mean PK parameter T of two different CBD formulations after administration in Part A (fasting condition). lag T max C max AUC 0-last AUC 0-∞ 、Kel、t ½ For details on CI / F and Vz / F, please refer to Table 19D.

[0276] Table 19D. Epidiolex ® Mean p-values ​​of formulations T1 and T2 in Part A (fasting)

[0277]

[0278] As shown above, under the fasting conditions in Part A, both formulations T1 and T2 were superior to Epidiolex. ® Producing higher C max And AUC.

[0279] Following Part A, formulation T1 was selected as the dosing regimen for Part B, administered 30 minutes after a high-fat meal. Table 20A details the mean plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD at various time points after administration of formulation T1 in a fed state. Figures 4 to 6 detail the mean plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD recorded for formulation T1 in both fed and fasting states, respectively.

[0280] Table 20A. Mean plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD after administration of formulation T1 in Part B (dietary intake).

[0281]

[0282] Epidiolex ®The mean PK parameter T of two different CBD formulations after administration in Part A (fasting condition). lag T max C max AUC 0-last AUC 0-∞ 、Kel、t ½ For details on CI / F and Vz / F, please refer to Table 20B.

[0283] Table 20B. Average pharmacokinetic parameters of formulation T1 in Part B (feeding)

[0284]

[0285] As can be seen from the table, under the conditions of intake in part B, the C produced by the T1 CBD preparation is... max The AUC is much higher than that under fasting conditions.

[0286] in conclusion

[0287] The use of this novel CBD formulation produces better results than Epidiolex. ® These formulations have more favorable plasma concentrations and PK parameters, making them suitable for development for commercial use.

[0288] Example 8: Maximizing the effective delivery dose of CBD

[0289] To determine the various excipients and their proportions, we prepared different CBD-containing formulations using the methods detailed earlier. The excipient combinations are detailed in Table 21 below.

[0290] Table 21. Combination of excipients used

[0291]

[0292]

[0293]

[0294] As shown above, CBD is successfully formulated by combining one or more cyclodextrins or cyclodextrin derivatives, and one or more poloxamers, with the optional addition of one or more pharmaceutically acceptable emulsifiers and / or surfactants.

[0295] Dissolution tests were performed on the formulation to assess its disintegration time and dissolution characteristics.

[0296] All formulations have suitable solubility properties.

[0297] ​

[0298] The capsules prepared for Phase I human studies were tested to determine their stability characteristics and ensure their suitability for use.

[0299] Tables 22 to 25 detail the stability data obtained for the two formulations.

[0300] Table 22. Stability data of formulation T1 at 25℃ / 60% relative humidity

[0301]

[0302] Table 23. Stability data of formulation T1 at 40℃ / 75% relative humidity

[0303]

[0304] Table 24. Stability data of formulation T2 at 25℃ / 60% relative humidity

[0305]

[0306] Table 25. Stability data of formulation T2 at 40℃ / 75% relative humidity

[0307]

[0308] As can be seen from the table above, both formulations are considered stable in both normal stability and accelerated stability tests.

[0309] ​

[0310] CBD is a hydrophobic molecule that is almost insoluble in aqueous systems. After ingestion, CBD is mainly absorbed through passive diffusion in the gastrointestinal tract. To improve the solubility of CBD formulations, scientists have employed various methods, including using lipid formulations, encapsulating CBD into micelles, and preparing CBD nanoemulsions.

[0311] These technologies result in low drug loading, poor stability, and complex and costly processes.

[0312] The aim of this example is to increase the CBD loading in existing formulations.

[0313] The formulation used in this example is SP-14, which contains approximately 22% (w / w) CBD, approximately 11% (w / w) poloxamer-407, approximately 33% (w / w) poloxamer-188 and approximately 33% (w / w) hydroxypropyl-β-cyclodextrin.

[0314] Any of the exemplary formulations disclosed are applicable to improved filling techniques to achieve enhanced cannabinoid drug loading.

[0315] method

[0316] Formula SP-14 in Table 21 is prepared as follows:

[0317] Weigh the ingredients using a calibrated balance, then transfer them to a clean, dry, wide-mouthed glass jar.

[0318] Cover the glass jar with a SureTight lid, shake for 2-3 minutes to mix thoroughly, and then seal with sealing film.

[0319] The powder mixture was prepared in a 150 mL stainless steel high-pressure reactor. After adding all raw materials, the reactor was sealed before adding solvent. CO2 was introduced, and the pressure and temperature were increased to reach a supercritical state. The reactor pressure was maintained between 2000 and 3000 psi, the temperature between 30 and 50 °C, and vigorous stirring was maintained for 20 to 60 minutes. After depressurizing the reactor for 1 hour, the resulting inclusion complex powder was non-flowing and viscous. The powder was collected in a sealed, waterproof container and placed in a 50 °C water bath.

[0320] Upon heating, the material becomes semi-liquid with a consistency similar to toothpaste. While still hot, transfer the material into a syringe.

[0321] The material is injected into the larger side of the two-piece size 0 capsule using a syringe, and then the two pieces of the capsule are put together.

[0322] Then store the capsules at room temperature away from light.

[0323] The CBD content was then analyzed to determine the drug loading of the capsules using this enhanced filling method.

[0324] result

[0325] Analysis of the filled capsules showed that each No. 0 capsule contained 680 mg of the formulation.

[0326] This is equivalent to a drug dose of 150 mg (22%) CBD.

[0327] For example, the CBD content of capsule #00 can be increased by 15%, with each capsule containing 172.5 mg of CBD. Smaller capsules can also be used, but the CBD content will be reduced by 15%, with each capsule containing 127.5 mg of CBD.

[0328] in conclusion

[0329] Each capsule contains 150 mg of CBD, significantly increasing the drug loading. Previous literature has reported that solid oral dosage forms have not yet achieved such a high drug loading.

[0330] This capsule formulation can reduce the burden on patients who need to take capsules. For example, Epidiolex. ® The approved dose of CBD is 20–25 mg / kg / day. For an adult weighing 70 kg, this is equivalent to 1400–1750 mg of CBD per day.

[0331] Standard filling processes typically produce capsules containing a maximum of 80 mg of CBD, but more commonly around 50 mg. Patients need to take 17 to 28 capsules daily.

[0332] Using the high-drug-content CBD formula shown in this example will greatly reduce the burden on patients taking capsules daily, requiring only about 9 to 11 capsules.

[0333] This filling method is cost-effective and scalable, and reducing capsule burden ensures an improved patient experience.

[0334] ​

[0335] Example 7 above describes an innovative filling method that can pack more formulation into the capsule, thereby increasing the drug loading of CBD and reducing the capsule burden on the patient.

[0336] This example details the experiments conducted to determine whether higher concentrations of CBD could be encapsulated, thereby increasing the delivery dose of CBD per capsule, by altering the amounts of various excipients in formulation SP-14.

[0337] method

[0338] The excipients poloxamer-407 (p407), poloxamer-188 (p188) and hydroxypropyl-β-cyclodextrin (HP-b-CD) were mixed with active cannabidiol (CBD) in the percentages detailed in Table 26 below.

[0339] Prepare the formulation and fill it into HPMC capsules of size 0.

[0340] After precise weighing, the amounts of the active pharmaceutical ingredient (API) and excipients contained in the capsules are recorded. The potency of CBD is determined in ppm and converted to a percentage for recording.

[0341] Then, the dissolution of formulations AVT-121 to AVT-128 was tested using industry-standard dissolution testing methods.

[0342] The thermal stability of formulations AVT-121 to AVT-124 was tested at various processing temperatures to determine whether CBD would be lost during capsule loading.

[0343] Table 26. Percentage of CBD and excipients

[0344]

[0345] result

[0346] Table 27 below details the measured potency of CBD in the various formulations prepared. All formulations showed higher CBD potency than the baseline formulation SP-14.

[0347] All new formulations have increased the filler content of size 0 capsules from the baseline (SP-14 formulation) of 675 mg to 725 mg to 805 mg.

[0348] In all new formulations, the CBD content per capsule has been increased. The basic formulation (SP-14) contains 152 mg of CBD per capsule.

[0349] The improved formula contains 230 mg to 310 mg of CBD per capsule, a significant increase in CBD content per unit dose.

[0350] Table 27. Efficacy, Capsule Filling Weight, and CBD Content per Capsule

[0351]

[0352] The solubility characteristics of formulations AVT-121 to AVT-128 were tested, and the results are detailed in Table 28 below.

[0353] Table 28. Dissolution characteristics of the formulation

[0354]

[0355] Table 29 below details the thermal stability of CBD during the loading of AVT-121 to AVT-124 formulation capsules.

[0356] Table 29. Thermal stability of CBD during capsule loading process

[0357]

[0358] in conclusion

[0359] This example demonstrates that by altering the proportions of excipients in the formulation and employing novel injection capsule filling technology, the CBD content per capsule can be significantly increased. This allows for the delivery of more active ingredient in fewer dosage units, offering a clear advantage.

[0360] Formulations AVT-121 to AVT-128 exhibited improved solubility characteristics, with high CBD recovery rates in almost all cases.

[0361] Stability tests on the injection capsule filling method described in detail in Example 7 and the formulation of this embodiment showed that it had excellent stability under all experimental test conditions.

[0362] Overall Conclusions and Summary

[0363] The application details the various challenges associated with cannabinoid formulation development and how the inventors overcame them.

[0364] The primary challenge is preparing a solid dosage form of cannabinoids (in this case, CBD). Currently, CBD is only available through Epidiolex. ® The form is approved for prescription use, while Epidiolex ® The solvent in the formula is sesame oil.

[0365] This leads to some adults who are heavier than children needing to consume large amounts of sesame oil daily, resulting in gastrointestinal side effects. Furthermore, children and adults allergic to sesame cannot take Epidiolex. ® .

[0366] The above examples demonstrate that cannabinoids can be formulated into solid dosage forms. This dosage form has been proven stable and without side effects in Phase I clinical trials. Clinical trial data also show that the bioavailability of CBD is comparable to that of the reference compound Epidiolex. ® quite.

[0367] The second challenge facing the inventors was increasing the cannabinoid content in single-dose formulations. Previously, solid dosage forms were unsuitable due to their limited CBD content. Effective CBD formulations require relatively high doses, meaning patients would need to take a large number of tablets daily to achieve the desired effect.

[0368] As shown in the example above, by combining specific excipients with specific processing methods, a high CBD drug loading can be achieved per unit of product.

[0369] The final challenge in preparing cannabinoid solid dosage forms is the regulatory challenge of excipients, as all excipients have maximum daily allowable dosages (MADs) set by the U.S. Food and Drug Administration (FDA). For example, the FDA specifies a maximum daily dosage of 495 mg for poloxamer-407, 1800 mg for poloxamer-188, and 8000 mg for HP-β-CD.

[0370] When considering the content of these excipients per unit dose, the challenge is to ensure that the content of the excipients is within the limits while still providing an effective dose of CBD.

[0371] As can be seen from the examples above and Table 30 below, the inventors have obtained a solid dosage form of CBD, and its excipients comply with the FDA's restrictions on excipients.

[0372] Table 30. Cannabinoid / Excipient Content in Each Unit Dosage Formulation

[0373]

Claims

1. A solid oral medication dosage form, comprising: Cannabidiol; Hydroxypropyl-β-cyclodextrin (HPβCD); Polosham-188; and Polosham-407, of which: The content of cannabidiol is 100-300 mg per unit dose.

2. The solid oral medication dosage form according to claim 1, wherein: The content of cannabidiol is 20% (w / w) to 50% (w / w) of the total composition.

3. The solid oral medication dosage form according to claim 1 or 2, wherein: The content of the hydroxypropyl-β-cyclodextrin (HPβCD) is 15% (w / w) to 35% (w / w).

4. The solid oral medication dosage form according to any one of the preceding claims, wherein: The content of poloxamer-188 is 20% (w / w) to 40% (w / w).

5. The solid oral dosage form according to any one of the preceding claims, wherein: The content of poloxamer-407 is 5% (w / w) to 15% (w / w).

6. The solid oral dosage form according to any one of the preceding claims, wherein: The formulation also contains one or more pharmaceutically acceptable emulsifiers and / or surfactants.

7. The solid oral dosage form according to claim 6, wherein the pharmaceutically acceptable emulsifier and / or surfactant is selected from the group consisting of: lecithin, glyceryl monostearate, methylcellulose, sodium lauryl sulfate, sodium oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, tragacanth gum, triethanolamine oleate, polysorbitan monolaurate, polyethylene glycol (PEG), polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, detergent, polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 20 (polyoxyethylene sorbitan monolaurate), cetearyl glucoside, polyglucoside, sorbitan monooleate (Span 80), sorbitan monolaurate (Span 20), and polyoxyethylene monostearate (Myrj 45). Polyoxyethylene vegetable oil (emulsifier), cetyl chlorinated pyridine, polysaccharide gum, xanthan gum, tragacanth gum, gum arabic, and acacia gum.

8. The solid oral medication dosage form according to claim 6 or 7, wherein: The pharmaceutically acceptable content of emulsifiers and / or surfactants is 0.1% (w / w) to 35% (w / w) of the total composition.

9. The solid oral pharmaceutical dosage form according to any one of the preceding claims, wherein the dosage form is formulated into a dosage form selected from the following dosage forms: tablets, pills, granules, capsules, powders, lozenges, granules and sustained-release formulations.

10. The solid oral dosage form according to any one of the preceding claims, wherein: This dosage form is formulated to be taken before, during, or after meals.

11. The solid oral dosage form according to any one of the preceding claims, wherein: Each unit dose contains 250 mg of cannabidiol.

12. The solid oral dosage form according to any one of the preceding claims, wherein: After administration to subjects, the AUC of this dosage form... 0-t For reference compound Epidiolex ® AUC 0-t 80% to 125% of that.

13. The solid oral dosage form according to any one of the preceding claims, wherein: After administration to subjects, the maximum plasma concentration (C) of this dosage form was achieved. max (Referring to the compound Epidiolex) ® Maximum blood concentration (C max 80% to 125% of ).

14. A treatment method comprising administering to a subject a therapeutically effective amount of a solid oral dosage form, according to any of the preceding claims.

15. A method for preparing a solid oral pharmaceutical dosage form according to any one of the preceding claims, comprising the following steps: a) Under supercritical CO2 conditions of 2,000–3,000 PSI and 30–50 °C, the cannabidiol, the hydroxypropyl-β-cyclodextrin (HPβCD), the poloxamer-188 and the poloxamer-407 were mixed for 20–60 minutes. b) Reduce the pressure in the reactor and collect the material; c) Heat the material collected in step (b) to 40–50°C; and d) Using injection filling technology, the material is filled into the capsule while it is still hot.

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