[go: up one dir, main page]

WO2025099099A1 - Nouvelles formulations orales de cannabinoïdes - Google Patents

Nouvelles formulations orales de cannabinoïdes Download PDF

Info

Publication number
WO2025099099A1
WO2025099099A1 PCT/EP2024/081400 EP2024081400W WO2025099099A1 WO 2025099099 A1 WO2025099099 A1 WO 2025099099A1 EP 2024081400 W EP2024081400 W EP 2024081400W WO 2025099099 A1 WO2025099099 A1 WO 2025099099A1
Authority
WO
WIPO (PCT)
Prior art keywords
cbd
dosage form
poloxamer
solid
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/081400
Other languages
English (en)
Inventor
Hardin JACKSON
Devin MACHIN
Jinhee OH
Andrew SAICH
Venkat GOSKONDA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Esolate Pharmaceuticals Ltd
Original Assignee
Esolate Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB2316995.6A external-priority patent/GB202316995D0/en
Application filed by Esolate Pharmaceuticals Ltd filed Critical Esolate Pharmaceuticals Ltd
Publication of WO2025099099A1 publication Critical patent/WO2025099099A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin

Definitions

  • NOVEL ORAL CANNABINOID FORMULATIONS [0001] The present disclosure is related to and claims benefit of GB2316995.6 filed on 6 November 2023, GB2400238.8 filed on 5 January 2024, and GB2410075.2 filed on 11 July 2024 the contents of which are hereby incorporated by reference in their entirety.
  • FIELD OF THE DISCLOSURE [0002] The present disclosure relates to novel pharmaceutical formulations, including solid oral dosage forms comprising the non-psychoactive cannabinoid cannabidiol (CBD). The disclosure further relates to methods of manufacture of the pharmaceutical formulations and the use of the formulations to treat diseases and conditions.
  • CBD non-psychoactive cannabinoid cannabidiol
  • Cannabinoids in the form of botanical, plant-based cannabis have been used in medicine for millennia, with evidence of its first use around 400AD. Cannabinoids are highly lipophilic and as such present a problem with their formulation. Early use of cannabis as medicine involved the preparation of tinctures where the cannabis is extracted and concentrated in an alcohol which is then administered in drop form. [0003] In recent times, cannabinoids have been more thoroughly researched and have evidenced efficacy as medicaments, which has necessitated finding more effective ways of drug delivery. [0004] There are currently four approved drugs which contain cannabinoids.
  • Dronabinol comprises synthetically produced tetrahydrocannabinol (THC) which is formulated in sesame oil and administered orally as capsules. Dronabinol is indicated as an appetite stimulant in patients with HIV/AIDS and cancer and it is additionally approved to treat chemotherapy-induced nausea and vomiting.
  • THC tetrahydrocannabinol
  • Another drug derived from THC is nabilone which comprises an analogue of THC. Nabilone is formulated with povidone and corn starch and again is delivered orally as capsules. Nabilone is indicated for similar treatments as dronabinol.
  • the medication nabiximols is a botanical extract comprising a high-THC and a high- CBD extract in approximately equal amounts.
  • the drug is formulated with ethanol, propylene glycol and peppermint flavouring and is delivered as an oromucosal spray which is sprayed into the cheek of the user.
  • Nabiximols was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in 2010 to treat neuropathic pain, spasticity, and overactive bladder in patients with multiple sclerosis.
  • MHRA Medicines and Healthcare products Regulatory Agency
  • the cannabinoid CBD is approved as the medication Epidiolex for the treatment of seizures associated with the rare epilepsy syndromes Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex.
  • the CBD is formulated as 100mg/ml in sesame seed oil and further comprises the sweetener sucralose, strawberry flavouring and up to 10% v/v ethanol which is administered as an oral solution.
  • Epidiolex is dosed at 5mg/kg/day for a week, titrating up to a maximum dose of 25mg/kg/day, therefore meaning a 50kg child would be required to take 12.6ml of Epidiolex per day.
  • adults taking Epidiolex would need to take a considerable amount more than a child, given that the doses are calculated based on weight. In this situation the adult would be taking a large volume of oil on a daily basis which can lead to pernicious side effects.
  • Cannabinoids are highly lipophilic and as such cause difficulties during their formulation, particularly where a substantial dose of cannabinoids are required, for example in the case of CBD. Due to the poor water solubility of cannabinoids, they are often formulated in oils or alcohols or a combination of the two which leads to problems particularly where large doses are required. A high intake of oils can cause gastrointestinal problems such as vomiting, or diarrhoea and are contraindicated in subjects with an allergy to the nut/oil. Also, a high alcohol content is contraindicated in children and adults with alcohol sensitivities.
  • CBD is approximately 6% in humans due to extensive first- pass metabolism, while its bioavailability via inhalation is 11 to 45% (mean 31%).
  • CBD was found to be rapidly absorbed, with mean peak plasma concentrations of 114 to 181ng/mL being attained at about 2.5 to 3 hours at steady state (Devinsky et al., 2014).
  • the patent application WO 2015/184127 describes several cannabinoid oral formulations such as an alcohol-free formulation where a cannabinoid is formulated in a mixture of polyethylene glycol and propylene glycol.
  • the application additionally describes formulations where the cannabinoid is dissolved in lipids and another comprising alcohol.
  • the patent applications WO 2021/081138 and WO 2021/081140 describe compositions and methods of preparing said compositions whereby a lipophilic active pharmaceutical ingredient (API) is encapsulated using cyclodextrins.
  • the compositions produced are described as having a 200% increase in bioavailability compared to non-cyclodextrin-encapsulated APIs and utilise highly purified, 99.9% pure API.
  • the patent application EP4252745 describes cannabinoid formulations with varying components.
  • Cannabidiol (10 or 20%), a combination of three different cyclodextrins (30 or 55%) and non-specific poloxamers (26 or 35%), plus 8 other excipients including PEG, EDTA, and citric acid which are used to produce a formulation.
  • the data presented in the application demonstrates that they are able to produce an effervescent tablet with either 15mg or 30mg of CBD.
  • Another cannabinoid formulation is described in CN112891310. Here a full spectrum cannabinoid oil which comprises 50-83% CBD. This is used to prepare a formulation comprising an emulsifier (which can be poloxamer-188), and a carrier (which can be a cyclodextrin).
  • Example 1 details a combination of poloxamer-188 and HP- ⁇ -CD, the CBD content of the formulation is 6.05%.
  • the application US2023/0000770 describes a method of preparing a cannabinoid nano- micelle powder.
  • the cannabinoid CBD is present with an amphiphilic polymer (which can be a poloxamer) and a freeze-drying agent (which can be a cyclodextrin, including HP- ⁇ -CD).
  • Table 1 details CBD (10-60%), poloxamer-188 (0, 10 or 50%), HP- ⁇ -CD (0 or 5%) and up to 17 additional excipients.
  • the effervescent tablets prepared in Example 4 comprise either 20, 40 or 60mg of CBD.
  • the application US2021/0393784 describes a method for treating pain comprising injecting a subject with a cannabinoid solubilized in SBE-7-B-cyclodextrin and optionally a solubility enhancer (which can be poloxamer-188).
  • the cannabinoid can be CBD and is present at 1-5mg/ml.
  • the buccal or sublingual dosage form described in US2011/0028431 comprises a non- ionic polymeric solubility enhancer (which can be a poloxamer), a pharmaceutically active agent (which is a water-soluble complex of a cannabinoid and a cyclodextrin) in addition to a mucoadhesive polymer, a disintegrant and a filler.
  • a non- ionic polymeric solubility enhancer which can be a poloxamer
  • a pharmaceutically active agent which is a water-soluble complex of a cannabinoid and a cyclodextrin
  • the cannabinoid-cyclodextrin complex is present at 5-65%.
  • the amount of cannabinoid used to make the CB-CD complex are between 0.01-10 (THC, Example 1) and 1-20% (CBD, Example 2).
  • the maximum percentage of CBD in the final formulation will be 13% (20% CBD in 65% CB-CD complex).
  • the bioavailability is generally very poor as most of the cannabinoids are lost to primary metabolism called the first-pass effect, whereby the active cannabinoid is quickly metabolised by the liver into inactive metabolites.
  • the present disclosure provides novel oral cannabinoid formulations which have been shown to produce a higher bioavailability than currently available formulations without side effects. Such formulations solve the problems associated with administering high doses of cannabinoids in oil and / or alcoholic solutions.
  • the novel formulation of the disclosure provides the ability to dose the cannabinoid in a solid oral dosage form such as a pill, capsule or tablet which enables a more pleasant experience for the patient and greater patient compliance.
  • a solid oral dosage form such as a pill, capsule or tablet which enables a more pleasant experience for the patient and greater patient compliance.
  • CBD used to treat epilepsy is dosed at 20-25mg/kg/day which for a 70kg person would amount to 1,400-1,750mg of CBD per day.
  • the pill burden for these doses would therefore mean patients needing to take greater than 10 capsules / tablets per day.
  • a solid, oral pharmaceutical dosage form comprising cannabidiol, hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD), poloxamer-188, and poloxamer-407, wherein the cannabidiol is present in an amount from 100- 300mg per unit dose.
  • the cannabidiol is present in an amount of between 20% (w/w) to 50% (w/w) of the total composition.
  • the hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD) is present in an amount of between 15% (w/w) and 35% (w/w).
  • the poloxamer-188 is present in an amount of between 20% (w/w) to 40% (w/w).
  • the poloxamer-407 is present in an amount of between 5% (w/w) to 15% (w/w).
  • the formulation further comprises one or more pharmaceutically acceptable emulsifiers and / or surfactants.
  • pharmaceutically acceptable emulsifier and / or surfactant is taken from the group consisting of: lecithin, glyceryl monostearate, methylcellulose, sodium lauryl sulfate, sodium oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, tragacanth, triethanolamine oleate, polyethylene sorbitan monolaurate, polyethylene glycol (PEG), macrogol 3350, macrogol 4000, macrogol 6000, detergents, polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 20 (polyoxyethylene sorbitan monolaurate), cetearyl glucoside, polyglucosides, sorbitan monooleate (Span 80), sorbitan monolaurate (Span 20), polyoxyethylene
  • the pharmaceutically acceptable emulsifier and / or surfactant is present in an amount of between 0.1% (w/w) to 35% (w/w) of the total composition.
  • the solid, oral pharmaceutical dosage is formulated for administration as a dosage form selected from the group consisting of: tablet, pill, pellet, capsule, powder, lozenge, granule, and sustained-release formulation.
  • the solid, oral pharmaceutical dosage is formulated for administration before food, with food or after food.
  • the cannabidiol is present in an amount of about 250mg per unit dose.
  • the dosage form produces an AUC0-t which is between 80% and 125% of the AUC0-t of a reference compound Epidiolex (RTM) following administration of the dosage form to a subject.
  • the dosage form produces a Cmax which is between 80% and 125% of the C max of a reference compound Epidiolex (RTM) following administration of the dosage form to a subject.
  • a method of treatment comprising administering to a subject a therapeutically effective amount of the solid oral dosage form.
  • a process for preparing the solid, oral pharmaceutical dosage form of the disclosure comprising the steps of: a) Mixing the cannabidiol, hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD), poloxamer-188, and poloxamer-407 under supercritical CO2 conditions of 2,000-3,000 psi and 30-50 o C for 20 to 60 minutes; b) depressurising the reactor and collecting the material; heating the material collected in step (b) to 40-50oC; and filling capsules with material whilst warm using an injection filling technique.
  • a pharmaceutical composition comprising one or more cannabinoids, one or more cyclodextrins or cyclodextrin derivatives, and one or more poloxamers and optionally one or more pharmaceutically acceptable emulsifiers and / or surfactants.
  • a pharmaceutical composition according to claim 1 wherein the said composition exhibits an AUC 0-t which is between 80% and 125% of the reference compound following administration of the composition to a subject.
  • a pharmaceutical composition according to claim 1 or claim 2 wherein the said composition exhibits a Cmax which is between 80% and 125% of the reference compound following administration of the composition to a subject.
  • cannabinoids are taken from the group consisting of: cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA).
  • CBC cannabichromene
  • CBCV cannabichromenic acid
  • CBDD cannabidiol
  • CBDA cannabidiolic acid
  • CBDDV cannabidivari
  • a pharmaceutical composition according to claim 1 wherein the one or more poloxamers are taken 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. 11.
  • a pharmaceutical composition according to any of the preceding claims comprising cannabidiol, hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD), poloxamer-188, poloxamer-407 and optionally macrogol 6000 and polysorbate 80. 17.
  • a dosage form selected from the group consisting of: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intramuscular
  • compositions according to any of the preceding claims wherein the composition is formulated for administration as a dosage form selected from the group consisting of: tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays. 22.
  • a pharmaceutical composition according to any of the preceding claims wherein the composition is administered before food.
  • the composition is administered after food.
  • composition is formulated as a capsule.
  • the composition comprises cannabidiol. 26.
  • Figure 2 details the mean 7-OH-CBD plasma concentration (0-96h) of Epidiolex (red diamond), Formulation T1 (blue circle) and Formulation T2 (green triangle).
  • Figure 3 details the mean 7-COOH-CBD plasma concentration (0-96h) of Epidiolex (red diamond), Formulation T1 (blue circle) and Formulation T2 (green triangle).
  • Figure 4 details the mean CBD plasma concentration (0-24h) of Formulation T1 under fed conditions (blue circle) and Formulation T1 under fasted conditions (red diamond).
  • Figure 5 details the mean 7-OH-CBD plasma concentration (0-96h) of Formulation T1 under fed conditions (blue circle) and Formulation T1 under fasted conditions (red diamond).
  • Figure 6 details the mean 7-COOH-CBD plasma concentration (0-96h) of Formulation T1 under fed conditions (blue circle) and Formulation T1 under fasted conditions (red diamond).
  • “About” refers to all values having substantially the same effect, or providing substantially the same result, as the reference value. Thus, the range encompassed by the term “about” will vary depending on the context in which the term is used, for instance the parameter that the reference value is associated with. Thus, depending on context, "about” can mean, for example: ⁇ 0.10%; ⁇ 0.25%; ⁇ 0.5%; ⁇ 1.0%; ⁇ 2.5%; ⁇ 5.0%; or ⁇ 10.0%.
  • administering includes any mode of administration, such as oral, subcutaneous, sublingual, transmucosal, parenteral, intravenous, intra-arterial, buccal, sublingual, topical, vaginal, rectal, ophthalmic, otic, nasal, inhaled, and transdermal.
  • administration method can be oral administration.
  • Bioequivalence means the absence of a significant difference in the rate and extent to which the active agent or surrogate marker for the active agent in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action when administered in an appropriately designed study.
  • Co-administration refers to administration of two or more different active agents together in a coordinated manner. Co-administration includes administration of two or more different active agents simultaneously, sequentially, or separately. Thus, “co-administration” includes administration in the same or different dosage forms, concurrent administration, as well as administration that is not concurrent, such as administration of a first active agent followed or alternated with administration of a second active agent as part of a coordinated plan for treatment.
  • a "composition” is a collection of materials containing the specified components.
  • One or more dosage forms may constitute a composition, so long as those dosage forms are associated and designed for use together.
  • Enteric polymer refers to a polymer that is poorly soluble in aqueous medium at a pH of about 4.5 or less but becomes soluble in aqueous medium at a pH of greater than about 5.
  • an enteric polymer is poorly soluble in gastric juice but is soluble in the lower GI tract environment.
  • “Pharmaceutical composition” refers to a formulation of a compound of the disclosure, such as cannabidiol, and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • the pharmaceutical composition may be in various dosage forms or contain one or more unit dose formulations.
  • "Pharmaceutically acceptable” means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use within the scope of sound medical judgment.
  • a "reference composition of cannabidiol” is a composition comprising cannabidiol that an AUC0-t in the fasted state that is about 35% or more lower than the AUC0-t in the fed state; and/or has an intra-subject variability of about 30% or greater.
  • the term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, 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, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • Solidvate means a complex formed by solvation (the combination of solvent molecules with molecules or ions of the active agent of the present disclosure), or an aggregate that consists of a solute ion or molecule (the active agent of the present disclosure) with one or more solvent molecules.
  • a solvate where the solvent molecule or molecules are water is called a hydrate. Hydrates are particularly contemplated as solvates of the materials described herein.
  • Solid dispersion relates to a solid system comprising a nearly homogeneous or homogeneous dispersion of an active ingredient in an inert carrier or matrix.
  • Prodrug refers to a precursor of the active agent wherein the precursor itself may or may not be pharmaceutically active but, upon administration, will be converted, either metabolically or otherwise, into the active agent or drug of interest.
  • prodrug includes an ester or an ether form of an active agent.
  • “Therapeutically effective amount” or “effective amount” refers the amount of a pharmaceutically active agent, that, when administered to a patient for treating a disease according to the dosing regimen as described herein, is sufficient to affect such treatment for the disease.
  • composition or dosage form is “therapeutically equivalent” to a reference composition or dosage form if it has a therapeutic effect that is substantially like the therapeutic effect of the reference composition or dosage form, for example, therapeutically equivalent dosage forms can have substantially similar efficacy towards a particular disease or condition when administered over a substantially similar time period.
  • patient or “subject” refers to a mammal, e.g., a human, in need of medical treatment.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • “Cyclodextrin/s” or “CD” are cyclic oligosaccharides consisting of alpha 1-4 linked D- glucopyranose units. The number of glucopyranosides which are linked refers to the category of cyclodextrin.
  • cyclodextrin alpha ( ⁇ ) cyclodextrins have 6 glucose subunits, beta ( ⁇ ) cyclodextrins have 7 glucose subunits, and gamma ( ⁇ ) cyclodextrins have 8 glucose subunits are the most commonly used natural cyclodextrins although larger cyclodextrins have been reported.
  • Cyclodextrins can be used as pharmaceutical excipients and are deemed generally recognised as safe (GRAS) by the FDA for human use.
  • GRAS deemed generally recognised as safe
  • Cyclodextrin derivatives the hydroxyl group of cyclodextrins can be modified producing cyclodextrin derivatives.
  • propylene oxide produces hydroxypropyl-cyclodextrin derivatives.
  • Cyclodextrin derivatives often have superior properties for example, ⁇ -cyclodextrin and M ⁇ CD remove cholesterol from cultured cells, however the methylated form M ⁇ CD was found to be more efficient than ⁇ -cyclodextrin.
  • Certain cyclodextrins are approved by the FDA and EMA for inclusion in drugs.
  • cyclodextrin derivative refers to any in known cyclodextrin derivative.
  • Poly(propylene oxide) poly(propylene oxide)
  • poly(ethylene oxide) poly(ethylene oxide)
  • Poloxamers have surfactant properties and are often used to increase the water solubility of pharmaceuticals.
  • poloxamer refers to any in known poloxamer.
  • DETAILED DESCRIPTION [0067] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure. [0068] The following Examples describe novel oral cannabinoid formulations.
  • the novel formulation of the disclosure provides the ability to dose the cannabinoid in a solid oral dosage form such as a pill, capsule or tablet which enables a more pleasant experience for the patient and greater patient compliance.
  • Active pharmaceutical ingredient (API) [0069]
  • the API used for the present application is one or more cannabinoid selected from those disclosed in Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3 to 15.
  • the preferred cannabinoids of the disclosure are cannabidiol (CBD) and / or tetrahydrocannabinol (THC).
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • the cannabinoid is present in an amount of from about 5 to 80 wt%, based on the total composition, preferably from about 10 to 50 wt%, more preferably from about 15 to 25 wt%.
  • the cannabinoid is synthetic or highly purified from its natural source (for example, plant derived recrystallized form). When a highly purified source is used, it is purified such that the cannabinoid is present at greater than 95% of the total extract (w/w).
  • the unit dose of cannabinoid in the oral pharmaceutical formulation may be in the range of from 0.001 to 1000 mg, preferably 1 to 500 mg, more preferably 150 to 350 mg.
  • the amount of cannabinoid present may be about 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, 1000 mg.
  • test articles Preparation of test articles [0074] The procedure for preparing the formulations of the disclosure were as follows: [0075] The ingredients were weighed using a calibrated balance and transferred to a clean and dry wide mouth glass jar. [0076] The glass jar was closed with a SureTight lid and shaken well for 2-3 minutes to mix and seal it with parafilm. [0077] The powder mix was prepared in a 150 ml stainless-steel high-pressure reactor. All ingredients were added, and the reactor was sealed prior to the addition of the solvent. CO 2 was added and pressure and temperature were increased to reach the supercritical phase. Reactor was held between 2000 and 3000 psi with a temperature between 30 and 50 o C and the contents were vigorously mixed for between 20 and 60 minutes.
  • EXAMPLE 1 EVALUATION OF THE PHARMACOKINETICS OF CANNABIDIOL (CBD) IN PLASMA FOLLOWING ORAL ADMINISTRATION OF TWO CBD FORMULATIONS TO MALE SPRAGUE-DAWLEY RATS
  • PK pharmacokinetics
  • CBD-1 cannabidiol
  • CBD MCT oil tincture Catheters were placed in the carotid artery of 8 rats for blood collection. Each formulation was administered to a group of 4 catheterized rats and blood plasma was serially collected at 12 time-points over 24 hours following dosing.
  • CBD-1 was formulated with cyclodextrin
  • CBD-2 was formulated with a medium chain triglyceride oil. Details of the test articles are described in Table 1 below. Table 1.
  • Test article details Test Article Route of THC Dose (mg) Inactive Administration per Administration Ingredients/Excipients C BD-1 oral gavage 10 Poloxamer-407, ⁇ - cyclodextrin C BD-2 oral gavage 10 Medium chain triglyceride Preparation of test article: [0088] The procedure for preparing the CBD-1 was as described previously. Table 2. Composition of CBD-1 formulation Ingredient Composition Quantity per batch (% w/w) (grams) C annabidiol 16.7% 2 Poloxamer-407 66.6% 8 ⁇ -cyclodextrin 16.7% 2 TOTAL 100% 12 Results [0089] The in vivo PK parameters for CBD following 10 mg/kg per os (“p.o.” i.e.
  • CBD PK plasma parameters comparison (fold change) between CBD-1 formulation versus CBD MCT tincture Parameter CBD-1 vs CBD in MCT tmax (min) 0.125 Cmax/Dose (kg*ng/ml/mg) 14.2 AUC0-tlast/Dose (min*kg*ng/ml/mg) 4.16
  • the dose-normalised maximum plasma concentration (Cmax/Dose) attained following administration of the CBD-1 formulation was 16.7 kg*ng/ml/mg and was significantly higher (14- fold P ⁇ 0.0001) than that following administration of the CBD MCT tincture (1.17 kg*ng/ml/mg).
  • EXAMPLE 2 EVALUATION OF THE PHARMACOKINETICS OF CANNABIDIOL (CBD) IN PLASMA FOLLOWING ORAL ADMINISTRATION OF FOUR CBD FORMULATIONS TO MALE SPRAGUE-DAWLEY RATS [0095]
  • PK pharmacokinetics
  • CBD-1, CBD-2, CBD-3 and CBD-4 were placed in the carotid artery of 16 rats for blood collection.
  • Each formulation was administered to a group of 4 catheterized rats and blood plasma was serially collected at 12 time-points over 24 hours following dosing.
  • the mean maximum CBD plasma concentrations of the four formulations were calculated along with the times in which these were achieved.
  • Materials and Methods [0097] Sixteen male Sprague-Dawley rate (250g-325g) (Charles River) were used for the study. The animals were acclimatised to their environment for a minimum of 5 days prior to surgery. [0098] Catheters were implanted in the carotid artery in all animals for serial blood collection and blood sample volume replacement. Catheters were implanted at least one day prior to the start of the dosing procedures.
  • CBD-1 was formulated with ⁇ -cyclodextrin and poloxamer-407 and was the same formulation used in Example 1. The remainder of the formulations used hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD) along with various additional excipients as described in Table 5 below. Table 5.
  • HP ⁇ CD hydroxypropyl- ⁇ -cyclodextrin
  • Test article details Test Article Route of THC Dose (mg) Inactive Administration per Administration Ingredients/Excipients C BD-1 oral gavage 10 ⁇ -cyclodextrin Poloxamer-407 C BD-2 oral gavage 10 HP ⁇ CD Poloxamer-407 Poloxamer-188 C BD-3 oral gavage 10 HP ⁇ CD Poloxamer-407 Poloxamer-188 Polysorbate 80 PEG-6000 C BD-4 oral gavage 10 HP ⁇ CD Poloxamer-407 Poloxamer-188 Polysorbate 80 PEG-1500 Preparation of test article: [00103] The procedure for preparing the CBD formulations using the ingredients detailed in Tables 6 to 9 were as previously described. Table 6.
  • composition of CBD-1 formulation Ingredient Composition Quantity per batch (% w/w) (grams) C annabidiol 16.7% 2 Poloxamer-407 66.6% 8 ⁇ -cyclodextrin 16.7% 2 TOTAL 100% 12 Table 7.
  • Composition of CBD-2 formulation Composition Quantity per batch Ingredient (% w/w) (grams) C annabidiol 22.2% 2 Poloxamer-407 11.1% 1 Poloxamer-188 33.3% 3 hydroxypropyl- ⁇ -cyclodextrin 33.3% 3 TOTAL 100% 9 Table 8.
  • composition of CBD-3 formulation Ingredient Composition Quantity per batch (% w/w) (grams) C annabidiol 16.7% 2 Poloxamer-407 4.2% 0.5 Poloxamer-188 12.5% 1.5 hydroxypropyl- ⁇ -cyclodextrin 33.3% 4 Polysorbate 80 16.7% 2 PEG-6000 16.7% 2 TOTAL 100% 12 Table 9.
  • composition of CBD-4 formulation Ingredient Composition Quantity per batch (% w/w) (grams) C annabidiol 16.7% 2 Poloxamer-407 4.2% 0.5 Poloxamer-188 12.5% 1.5 hydroxypropyl- ⁇ -cyclodextrin 33.3% 4 Polysorbate 80 16.7% 2 PEG-1500 16.7% 2 TOTAL 100% 12 Results [00104] The in vivo PK parameters for CBD following 10 mg/kg p.o. administration of four different formulations are summarised in Table 10, and PK plasma parameters comparisons (fold change) between the four formulations are summarised in Table 11. Table 10.
  • CBD PK plasma parameters comparison (fold change) between the various formulations Formulation Parameter CBD-2 vs CBD-3 vs CBD-4 vs CBD-4 vs CBD-1 CBD-1 CBD-3 t max (min) 1.36 2.55 2.36 0.929 Cmax (ng/ml) 1.42 0.555 1.07 1.93 Apparent t1/2 (min) 1.02 0.926 1.20 1.29 AUC0-inf (min*ng/ml) 1.31 0.872 1.04 1.19
  • CBD-2 Administration of the CBD-2 formulation resulted in a Cmax of 135 ng/mL (1.4-fold higher than formulation CBD-1) and t max of 56 min.
  • CBD levels peaked between 30- and 240-minutes following administration of both CBD-3 and CBD-4 formulations with corresponding C max values of 52.8 ng/mL and 102 ng/mL (0.56 and 1.1-fold that of formulation CBD-1), respectively.
  • the apparent half-life (t1/2) of CBD was similar among the 8A, SP-14 and SP-24 formulations (271, 277 and 251 min, respectively), whereas the estimated CBD t1/2 was slightly longer for the P-25 formulation (324 min, Table 1).
  • EXAMPLE 3 EVALUATION OF THE PHARMACOKINETICS OF ⁇ 9- TETRAHYDROCANNABINOL ( ⁇ 9-THC) IN PLASMA FOLLOWING ORAL ADMINISTRATION OF THREE THC FORMULATIONS TO MALE SPRAGUE-DAWLEY RATS.
  • PK plasma pharmacokinetics
  • THC ⁇ 9-tetrahydrocannabinol
  • a cyclodextrin formulation was tested alongside a THC tincture in which the THC was dissolved in a medium chain triglyceride oil and a commercial THC emulsion.
  • the mean maximum THC plasma concentrations of the formulations were calculated along with the times in which these were achieved.
  • the animals were acclimatised to their environment for a minimum of 5 days prior to surgery.
  • Catheters were implanted in the carotid artery in all animals for serial blood collection and blood sample volume replacement. Catheters were implanted at least one day prior to the start of the dosing procedures.
  • Animals were separated into three treatment groups, four per group, and were dosed by oral gavage with test article.
  • Blood samples were taken at time points: 3, 5, 10, 20, 30, 45, 60, 90, 120, 240, 480, and 1140 minutes and the samples were tested using a quantified bioanalytical method for the amount of THC.
  • THC-1 was formulated with cyclodextrin
  • THC-2 was formulated with a medium chain triglyceride oil
  • THC-3 was a commercially available THC formulation. Details of the test articles is described in Table 12 below. Table 12.
  • Test article details Test Article Route of THC Dose (mg) Inactive Administration per Administration Ingredients/Excipients T HC-1 oral gavage 10 Poloxamer-407, ⁇ - cyclodextrin T HC-2 oral gavage 10 Medium chain triglyceride THC-3 oral gavage 10 Unknown (commercial formulation) Preparation of test article: [00121] The procedure for preparing the THC-1 formulations using the ingredients detailed in Table 13 was as previously described. Table 13.
  • composition of THC-1 formulation Ingredient Composition Quantity per batch (% w/w) (grams) T etrahydrocannabinol 16.7% 2 Poloxamer-407 66.6% 8 ⁇ -cyclodextrin 16.7% 2 TOTAL 100% 12 Results [00122] The in vivo PK parameters for THC following 10 mg/kg p.o. administration of three different formulations are summarised in Table 14, and PK plasma parameters comparisons (fold change) between the three formulations are summarised in Table 15. Table 14.
  • the Cmax was also more favourable in the THC- 1 formulation with a mean of 66 ng/ml compared to 12 and 32 for the THC in MCT and the commercial THC respectively.
  • Table 15 below details the PK parameters in comparison to each other. Table 15.
  • the substantially faster tmax denotes that this formulation provides a faster onset than both commercial THC and THC in MCT oil.
  • the higher Cmax demonstrated by the novel formulation provides the ability to administer lower doses to achieve the same effect in comparison to the other two formulations tested. This provides many advantages including a lower cost of goods and a lower side effect profile.
  • EXAMPLE 4 A HUMAN PHASE 1, 2-PART, OPEN-LABEL, PILOT TRIAL TO ASSESS THE RELATIVE BIOAVAILABILITY OF THREE FORMULATIONS OF CANNABIDIOL (CBD) UNDER FASTED (PART A) AND FED (PART B) CONDITIONS IN HEALTHY ADULT MALE SUBJECTS [00129] A clinical study was undertaken to assess the relative bioavailability of two novel CBD formulations (T1 and T2) compared to a reference formulation (Epidiolex®) under fasting conditions in healthy adult male subjects.
  • Part A included a screening visit from Day -28 to Day -2. Eligible subjects were admitted to the clinical site on Day -1, with dosing occurring on Day 1 following at least 10 hours of fasting. Subjects were confined until the completion of the assessments on Day 3 and returned to the clinical site for outpatient follow-up (FU) visits on Days 4 and 5. [00135] Subjects were re-admitted to the clinical site on Days 7 and 14 and received the second and third allocated treatment on Days 8 and 15, respectively.
  • Subjects were confined until completion of the assessments on Days 10 and 17 for treatment periods 2 and 3, respectively and returned to the clinical site for FU visits on Days 11 and 12 in treatment Period 2 and Days 18 and 19 in treatment period 3. [00136] Following at least 2 weeks washout period following last dose administration in Part A, subjects returned to the clinical site on Day 28 at earliest to continue in study Part B. [00137] All subjects received a single dose of one test CBD formulation (T1), thirty minutes after the start of the high-fat, high-calorie breakfast. Subjects were confined until completion of the assessments on Day 31 and returned to the clinical site for follow up “FU” visits on Days 32 and 33.
  • T1 test CBD formulation
  • Treatment A 350 mg CBD (100 mg/mL CBD solution) Epidiolex® administered orally under fasting conditions.
  • Treatment B 350 mg CBD (87.5 mg capsules) administered orally under fasting conditions.
  • Treatment C 350 mg CBD (87.5 mg capsules) administered orally under fasting conditions.
  • Part B Treatment D (T1): 350 mg CBD based on the PK and safety data from study Part A administered orally after a standard high-fat diet.
  • Investigational product details Investigational Dose Route of CBD Dose Inactive Product Form Administration (mg) per Ingredients/Excipients Administration
  • Preparation of investigational products [00140] The procedure for preparing the T1 and T2 formulations using the ingredients detailed in Tables 17 and 18 were as previously described.
  • Formulation T1 I ngredient Source Composition Quantity per (% w/w) batch (grams) C annabidiol Purisys 22.6% 98 Poloxamer-407 Spectrum Chemicals 11.1% 48 Poloxamer-188 Spectrum Chemicals 33.2% 144 Hydroxypropyl- ⁇ -cyclodextrin Sigma-Aldrich 33.2% 144 TOTAL 100% 434 Table 18.
  • Formulation T2 I ngredient Source Composition Quantity per (% w/w) batch (grams) C annabidiol Purisys 17.1% 98 Poloxamer-407 Spectrum Chemicals 4.2% 24 Poloxamer-188 Spectrum Chemicals 12.6% 72 Hydroxypropyl- ⁇ - cyclodextrin Sigma-Aldrich 33.6% 192 Polysorbate 80 Spectrum Chemicals 15.7% 90 Polyethylene glycol 6000 Millipore Sigma 16.8% 96 TOTAL 100% 572 Blood Sample Collection for PK Analysis: [00141] In each treatment period, a total of 19 blood samples were collected to analyse the blood for levels of CBD and its metabolites (7-OH-CBD and 7-COOH-CBD) plasma concentrations and PK analysis at the following time points: pre-dose, 5 min, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24-, 48-, 72- and 96-hours post-dose.
  • PK analysis [00143] Analysis of CBD, 7-OH-CBD and 7-COOH-CBD plasma concentration data are listed individually and summarized by each timepoint by treatment. Such data enable the ratios of CBD to the metabolites to be calculated. [00144] PK parameters Cmax, Tmax, AUC0-t, AUC0- ⁇ were determined using noncompartmental methods and summarized by treatment using descriptive statistics.
  • formulation T1 was chosen for dosing under Part B whereby the formulation was dosed 30 minutes after a high-fat meal.
  • the mean plasma concentrations of CBD, 7-OH-CBD and 7-COOH-CBD for the T1 formulation after dosing under fed conditions are detailed by each timepoint in Table 20A.
  • Figures 4 to 6 detail the mean plasma concentrations of CBD, 7-OH CBD and 7-COOH CBD respectively which were recorded for formulation T1 after fed and fasted conditions. Table 20A.
  • CBD is a hydrophobic molecule which is virtually insoluble in aqueous systems. Once ingested CBD is primarily absorbed through passive diffusion in the gastrointestinal tract.
  • Various different methods have been employed by scientists wishing to enhance the solubility of CBD formulations including use of lipid formulations, encapsulation of the CBD to form micelles, and the preparation of nanoemulsions of CBD. [00168] These technologies result in low drug loading and poor stability. They are complex processes with a high cost.
  • the aim of the current example was to enhance the drug loading of CBD in the present formulations.
  • the formulation used in the present example is that of SP-14, which comprises CBD at approximately 22% (w/w), poloxamer-407 at approximately 11% (w/w), poloxamer-188 at approximately 33% (w/w) and hydroxypropyl-beta-cyclodextrin at approximately 33% (w/w).
  • SP-14 which comprises CBD at approximately 22% (w/w), poloxamer-407 at approximately 11% (w/w), poloxamer-188 at approximately 33% (w/w) and hydroxypropyl-beta-cyclodextrin at approximately 33% (w/w).
  • any of the exemplified formulations of the disclosure would be suitable to be used for the improved filling technique to achieve enhanced drug loading of cannabinoid.
  • Formulation SP-14 from Table 21 was prepared as follows: [00173] The ingredients were weighed using a calibrated balance and transferred to a clean and dry wide mouth glass jar. [00174] The glass jar was closed with a SureTight lid and shaken well for 2-3 minutes to mix and seal it with parafilm. [00175] The powder mix was prepared in a 150 ml stainless-steel high-pressure reactor. All ingredients were added, and the reactor was sealed prior to the addition of the solvent. CO 2 was added and pressure and temperature were increased to reach the supercritical phase. Reactor was held between 2000 and 3000 psi with a temperature between 30 and 50 o C and the contents were vigorously mixed for between 20 and 60 minutes.
  • the reactor was depressurized over 1 hour and the resultant inclusion complex powder was un-flowable and tacky in consistency.
  • This material was collected into an airtight and waterproof container and placed in a water bath heated to 50 o C.
  • This material was transferred into a syringe whilst still warm.
  • the material was dispensed via the syringe into the larger side of a two-piece size 0 capsule and the two pieces of the capsule joined.
  • Capsules were then stored at room temperature in the dark.
  • Analysis of the quantity of CBD was then undertaken to determine the drug loading of the capsule using this enhanced filling method.
  • results [00180] Analysis of the filled capsule resulted in a fill of 680mg of formulation per size 0 capsule. [00181] This equates to a drug loading of 150mg (22%) CBD. [00182] In the case of a size 00 capsule a 15% higher loading of CBD could be achieved resulting in 172.5mg of CBD per capsule. Smaller capsules can also be filled resulting in a 15% lower CBD loading of 127.5mg of CBD per capsule. Conclusion [00183] The enhanced drug loading of 150mg of CBD per capsule is very significant. Such a high drug loading has not heretofore been achieved in the literature for a solid oral dosage form. [00184] The resultant capsule enables the capsule burden for patients to be lessened.
  • the approved dose of CBD in Epidiolex is 20-25 mg/kg/day. In a 70kg adult this equates to 1,400-1,750 mg of CBD per day.
  • Standard filling techniques usually produce capsules comprising a maximum of 80mg of CBD, but more commonly around 50mg of CBD. The patient would need to take between 17 to 28 capsules per day.
  • the use of the higher drug loading CBD formulation exemplified in this example would result in a far lower capsule burden for the patient of around 9 to 11 capsules per day.
  • the filling methodology is cost effective and scalable and the reduction in capsule burden ensures an enhanced patient experience.
  • EXAMPLE 8 MAXIMISING DELIVERABLE DOSE OF CBD
  • Example 7 above describes the use of an innovative filling methodology whereby the capsules can be loaded with a larger quantity of formulation resulting in a higher drug loading of CBD and a reduced capsule burden to the patient.
  • the present example details experiments undertaken whereby the amounts of the various excipients in formulation SP-14 were altered in order to determine whether a higher concentration of CBD could be loaded into the capsule, thereby increasing the deliverable dose of CBD per capsule.
  • Excipients poloxamer-407 (p407), poloxamer-188 (P188) and hydroxypropyl- beta-cyclodextrin (HP-b-CD) and active cannabidiol (CBD) were mixed in the percentages detailed in Table 26 below.
  • Formulations were prepared and loaded into a size 0 HPMC capsule as detailed in Example 7.
  • Capsules were accurately weighed and the amount of API and excipients loaded were recorded. The potency of the CBD was measured in ppm and converted into percentage and recorded.
  • Dissolution testing of formulations AVT-121 to AVT-128 was then undertaken using industry standard dissolution testing methodologies.
  • CBD amount (%) (mg) (mg) A VT-103 35.6 725 258.0 AVT-104 42.7 725 310.0 AVT-107 33.8 725 245.0 AVT-121 30.4 759 230.5 AVT-122 33.0 775 255.6 AVT-123 32.3 783 252.9 AVT-124 32.1 759 243.4 AVT-125 32.2 794 255.4 AVT-126 33.4 805 268.8 AVT-127 33.4 795 265.8 AVT-128 33.0 791 261.3 SP-14 22.5% 675 152.0 [00199] The dissolution characteristics of formulations AVT-121 to AVT-128 were tested and results are detailed in Table 28 below. Table 28.
  • the dissolution characteristics of the formulations AVT-121 to AVT-128 demonstrate improved properties with a high percentage of CBD recovered in almost all cases.
  • Stability testing of the injection capsule filling method detailed in Example 7 with the formulations of the present example show excellent stability at all experimentally tested conditions.
  • the application details the various challenges associated with the development of a cannabinoid formulation and how the inventors have overcome these challenges.
  • the first challenge was the preparation of a solid dosage form of cannabinoids, in the case illustrated, CBD.
  • CBD is only available to be prescribed as Epidiolex (RTM) which is formulated in sesame oil.
  • RTM Epidiolex
  • RTM Epidiolex
  • cannabinoids can be formulated into a solid dosage form. This dosage form has been shown to be stable and not produce side effects in a Phase 1 clinical trial. The data from the clinical trial also showed that the bioavailability of the CBD was commensurate with the reference compound Epidiolex (RTM).
  • the final challenge presented by the preparation of solid dose formulations of cannabinoids was the regulatory challenge presented by the excipients which all have a maximum daily allowance defined by the FDA.
  • the FDA details the maximum daily amount of poloxamer-407 to be 495mg; poloxamer-188 to be 1,800mg; and HP- ⁇ -CD to be 8,000mg.
  • the FDA details the maximum daily amount of poloxamer-407 to be 495mg; poloxamer-188 to be 1,800mg; and HP- ⁇ -CD to be 8,000mg.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente divulgation concerne de nouvelles formulations pharmaceutiques, notamment des formes posologiques orales solides comprenant le cannabinoïde non psychoactif cannabidiol (CBD). L'invention concerne en outre des procédés de fabrication des formulations pharmaceutiques et l'utilisation desdites formulations pour traiter des maladies et des états pathologiques.
PCT/EP2024/081400 2023-11-06 2024-11-06 Nouvelles formulations orales de cannabinoïdes Pending WO2025099099A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB2316995.6 2023-11-06
GBGB2316995.6A GB202316995D0 (en) 2023-11-06 2023-11-06 Novel oral cannabinoid formulations
GB2400238.8 2024-01-08
GBGB2400238.8A GB202400238D0 (en) 2023-11-06 2024-01-08 Novel oral cannabinoid formulations
GB2410075.2 2024-07-11
GB2410075.2A GB2635260A (en) 2023-11-06 2024-07-11 Novel oral cannabinoid formulations

Publications (1)

Publication Number Publication Date
WO2025099099A1 true WO2025099099A1 (fr) 2025-05-15

Family

ID=93521759

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/081400 Pending WO2025099099A1 (fr) 2023-11-06 2024-11-06 Nouvelles formulations orales de cannabinoïdes

Country Status (1)

Country Link
WO (1) WO2025099099A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110028431A1 (en) 2009-07-31 2011-02-03 Zerbe Horst G Oral mucoadhesive dosage form
WO2015184127A2 (fr) 2014-05-29 2015-12-03 Insys Pharma, Inc. Formulations de cannabinoïdes stables
CN110433133A (zh) * 2019-08-19 2019-11-12 中国人民解放军军事科学院军事医学研究院 治疗创伤后应激障碍的大麻二酚鼻用制剂
WO2021081140A1 (fr) 2019-10-21 2021-04-29 Esolate Ltd Composés superfins et production associée
CN112891310A (zh) 2019-12-03 2021-06-04 晨光生物科技集团股份有限公司 一种大麻二酚粉末的制备方法、制备得到的大麻二酚粉末及其用途
CN111956641B (zh) * 2019-12-30 2021-11-02 云南汉盟制药有限公司 一种黄酮类化合物的组合物及其制备方法
US20210393784A1 (en) 2016-05-10 2021-12-23 Resurgent Biosciences, Inc. Injectable cannabinoid formulations for treating pain
WO2022141823A1 (fr) * 2020-12-29 2022-07-07 汉义生物科技（北京）有限公司 Préparation effervescente de cannabinoïdes et son procédé de préparation
US20230000770A1 (en) 2019-12-06 2023-01-05 Hanyi Biotechnology (Beijing) Co., Ltd Cannabinoid nanomicelle preparation and method for preparing same
EP4252745A1 (fr) 2020-12-29 2023-10-04 Hanyi Biotechnology (Beijing) Co., Ltd. Formulation de cannabinoïde soluble dans l'eau et sa méthode de préparation

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110028431A1 (en) 2009-07-31 2011-02-03 Zerbe Horst G Oral mucoadhesive dosage form
WO2015184127A2 (fr) 2014-05-29 2015-12-03 Insys Pharma, Inc. Formulations de cannabinoïdes stables
US20210393784A1 (en) 2016-05-10 2021-12-23 Resurgent Biosciences, Inc. Injectable cannabinoid formulations for treating pain
CN110433133A (zh) * 2019-08-19 2019-11-12 中国人民解放军军事科学院军事医学研究院 治疗创伤后应激障碍的大麻二酚鼻用制剂
WO2021081140A1 (fr) 2019-10-21 2021-04-29 Esolate Ltd Composés superfins et production associée
WO2021081138A1 (fr) 2019-10-21 2021-04-29 Esolate Ltd Compositions comprenant des composés superfins et leur production
CN112891310A (zh) 2019-12-03 2021-06-04 晨光生物科技集团股份有限公司 一种大麻二酚粉末的制备方法、制备得到的大麻二酚粉末及其用途
US20230000770A1 (en) 2019-12-06 2023-01-05 Hanyi Biotechnology (Beijing) Co., Ltd Cannabinoid nanomicelle preparation and method for preparing same
CN111956641B (zh) * 2019-12-30 2021-11-02 云南汉盟制药有限公司 一种黄酮类化合物的组合物及其制备方法
WO2022141823A1 (fr) * 2020-12-29 2022-07-07 汉义生物科技（北京）有限公司 Préparation effervescente de cannabinoïdes et son procédé de préparation
EP4252745A1 (fr) 2020-12-29 2023-10-04 Hanyi Biotechnology (Beijing) Co., Ltd. Formulation de cannabinoïde soluble dans l'eau et sa méthode de préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Handbook of Cannabis", ROGER PERTWEE

Similar Documents

Publication Publication Date Title
US9095555B2 (en) Cannabinoid formulations
US20230172844A1 (en) Cannabidiol orally disintegrating tablets
AU2017334283A1 (en) Sustained release cannabinoid formulations
US20160058866A1 (en) Alternative solutions for the administration of cannabis derived botanical products
CN108778342B (zh) 基于环糊精和三氯蔗糖的高生物利用度口腔粘膜药物制剂
US20250360176A1 (en) Chewing gum containing synergistic medicinal compounds
JP2024500552A (ja) 水溶性カンナビノイド製剤及びその製造方法
US20180263953A1 (en) Sustained Release Cannabinoid Formulations
CA2817177A1 (fr) Compositions a delitement rapide comprenant de la nabilone et de la beta-cyclodextrine methylee de maniere aleatoire
WO2025099099A1 (fr) Nouvelles formulations orales de cannabinoïdes
US20180263954A1 (en) Sustained Release Cannabinoid Formulations
GB2635260A (en) Novel oral cannabinoid formulations
US20240139217A1 (en) Formulations of cannabinoids
KR20210018165A (ko) 대마의 오일 추출물 또는 파우더 추출물을 제제의 원료로 함유하는 구강 내 속붕해 제제
US20240139101A1 (en) Advanced oral film formulations
CA3005885A1 (fr) Pastilles de cannabinoide a liberation continue
CN117715626A (zh) 大麻素的制剂
WO2025202951A1 (fr) Composition de film vaginal à base de clotrimazole et son procédé de préparation
Shah Formulation, Optimization And Characterization Of Sublingual Dosage Forms Of Promethazine Hydrochloride
EP4667001A2 (fr) Formulations de cannabinoïdes
WO2021195540A1 (fr) Composition à base de cannabinoïdes pour l'atténuation d'effets viraux
JP2023551954A (ja) トコトリエノールの経粘膜送達
EP4074307A1 (fr) Formulations de cannabinoïdes
Eliphaz Formulation of a natural intraoral dispersible film (IDF) for intraoral delivery of various natural drugs using edible rice paper film as the carrier vehicle
TARTRATE EUROPEAN JOURNAL OF PHARMACEUTICAL AND MEDICAL RESEARCH

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24805769

Country of ref document: EP

Kind code of ref document: A1