WO2025073997A1 - Extrudat de cannabinoïde - Google Patents

Extrudat de cannabinoïde Download PDF

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Publication number
WO2025073997A1
WO2025073997A1 PCT/EP2024/078139 EP2024078139W WO2025073997A1 WO 2025073997 A1 WO2025073997 A1 WO 2025073997A1 EP 2024078139 W EP2024078139 W EP 2024078139W WO 2025073997 A1 WO2025073997 A1 WO 2025073997A1
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Prior art keywords
extrudate
solid
solid extrudate
cannabinoid
acid
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English (en)
Inventor
Martin Thomas Kuentz
Susanne HERZIG
Renata ABREU-VILLELA
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DSM IP Assets BV
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DSM IP Assets BV
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the disclosed inventions pertain to solid extrudates for human oral consumption, such as for pharmaceutical use.
  • the solid extrudates comprise at least one cannabinoid isolate.
  • Cannabinoid isolates are several structural classes of compounds found in the cannabis plant, primarily. They may exist as natural or synthetic compounds. At least 113 different cannabinoids have been isolated from the cannabis plant, some of which have been linked to beneficial pharmacological activity and others which are being investigated for pharmacological activity. Some health benefits associated with cannabinoids are lowering blood pressure, reducing inflammation, preventing relapse in drug and alcohol addiction, treating anxiety disorders, treating gastrointestinal (Gl) disorders, and preventing seizures.
  • Gl gastrointestinal
  • Cannabinoid isolates can be delivered in multiple ways, such as by inhalation, oral consumables, or sprays.
  • a delivery format that is not pleasing to a consumer may affect use and compliance.
  • existing pharmaceutical products comprising cannabinoids are delivered in formats that require multiple steps or are otherwise displeasing to the patient.
  • EPIDIOLEX® the first and only FDA-approved prescription cannabidiol (CBD)
  • CBD cannabidiol
  • the dose may vary, one or more administrations of varying syringe sizes or liquid amounts may be required.
  • the syringe must be washed, rinsed, and dried prior to the next dose. This method is cumbersome and may introduce errors in dosing.
  • cannabinoid isolate administration could be reduced or eliminated with a solid product that could be consumed orally, for example, as a tablet.
  • solid products possess challenges in achieving sufficient stability and bioavailability of the cannabinoid. Improving the bioavailability of cannabinoid-containing products is challenging due to the poor water solubility of cannabinoids and the limited solubility of cannabinoids in various oils. The poor solubility leads to poor resorption to the body, followed by extensive first-pass metabolism and elimination.
  • a solid, orally consumable cannabinoid product with improved bioavailability would therefore be desirable.
  • such product should preferably not exhibit discoloration.
  • the complicated process used to administer EPIDIOLEX® is essential because today a liquid formulation is required to deliver the CBD in a solubilized form to assure sufficient bioavailability. Excipients used for the liquid formulation are ethanol, sesame oil as well as benzyl alcohol. Bioavailability of crystalline CBD is known to be poor and administration of the solubilised CBD greatly improves bioavailability. However, ethanol is not desirable for all patients.
  • a common technical approach to increase bioavailability of poorly soluble compounds is to formulate them as amorphous solid dispersions (ASDs) to circumvent a slow dissolution rate and limiting solubility of an otherwise crystalline compound.
  • ASDs amorphous solid dispersions
  • solid compositions/ products and associated methods of manufacturing thereof comprising cannabinoid isolates in the form of ASDs containing high amounts of cannabinoid isolate(s) with improved bioavailability.
  • solid compositions/ product should preferably not exhibit extensive discoloration and provide good storage stability such as color stability and no crystallization of CBD over time.
  • the inventors have discovered solid extrudates, and compositions and methods for producing such solid extrudates, that evidence a surprising improvement in the bioavailability of a cannabinoid isolate that may be utilized in a desirable, orally consumable format.
  • the solid extrudates may be produced by hot melt extrusion (HME), a solvent-free process with a low production footprint.
  • HME hot melt extrusion
  • the disclosed compositions and methods may yield advantages for efficient process development and scale-up while enabling a continuous manufacturing process. Said compositions in addition did not show discoloration as well as (re-)crystallization of the cannabinoid isolate.
  • a solid extrudate comprises: a. 20-40 wt% of a cannabinoid isolate, b. 20-40 wt% of a hydroxypropyl methylcellulose, c. 5-15 wt% of a monounsaturated fatty acid, and d. 10-30 wt% of a surfactant.
  • the solid extrudate may be manufactured by a hot melt extrusion process.
  • Potential advantages of the invention are higher bioavailability, improved patient compliance, easier or more efficient manufacturing, improved appearance (reduced discoloration), no crystallization of the cannabinoid isolate and improvements with respect to shipping and storage.
  • Fig. 1 is a series of DSC measurements associated with Example 2-1.
  • Fig. 2 is a series of DSC measurements associated with Example 2-2.
  • Fig. 3 and 4 show extrudates associated with examples 10 and CE5
  • the solid extrudate comprises a cannabinoid isolate.
  • Cannabinoids are chemical substances regardless of structure or origin, that join the cannabinoid receptors of the body and brain and that have similar effects to those produced by the cannabis plant.
  • the two main cannabinoids found in the cannabis plant are delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • Cannabinoids found in the cannabis plant are generally referred to as cannabinoid isolates and are a unique family of terpeno-phenolic compounds.
  • cannabinoid isolate refers to cannabinoids found in the cannabis plant.
  • the cannabinoid isolate used according to the present invention may be natural (i.e. isolated from cannabis plant) or synthetic.
  • the cannabinoid isolate is synthetic, such as cannabinoid isolate produced by fermentation of recombinant yeast.
  • the cannabinoid isolate comprises cannabigerolic acid (CBGA), cannbigerol (CBG), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidivarinic acid (CBDVA), or cannabidivarin (CBDV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabinolic acid (CBNA), cannabinol (CBN), cannabidivarinic acid, cannabichromevarinic acid (CVCVA), cannabichromevarin (CBCV), cannabigerovarinic acid (CBGVA), cannabigerovarin CBGV), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabielsoinic acid (CBEA), cannabielsoin (CBE), cannabicitranic acid (CBTCA), or cannabicitran (CBTC) as well as
  • the cannabinoid isolate comprises cannabigerolic acid (CBGA), cannbigerol (CBG), cannabidiolic acid (CBDA), or cannabidiol (CBD) as well as any mixtures thereof.
  • the cannabinoid isolate is cannabidiol (CBD).
  • CBD is oxidation labile and has a molecular weight of 314.5 g/mol with a melting point between 66 and 67 °C.
  • CBD is e.g. commercially available from BSPG Laboratories Ltd (Kent, Great Britain).
  • CBD is extracted from industrial hemp (Cannabis sativa L.).
  • the CBD has a purity of at least 95%, more preferably of at least 96%, even more preferably of at least 97%, most preferably of at least 98% (HPLC). Even more preferably, the CBD does not contain any detectable (0.000006% limit of detection) tetrahydrocannabinol (THC) or any other controlled cannabinoid.
  • the solid extrudate or the melt used to form the solid extrudate comprises from 20- 40 wt% of a cannabinoid isolate, preferably from 25-35 wt% of the cannabinoid isolate. In an embodiment the solid extrudate or the melt used to form the solid extrudate comprises from 25, 26, 27, 28, 29 or 30 wt% to 35, 34, 33, 32, 31, or 30 wt% of a cannabinoid isolate.
  • the solid extrudate comprises hydroxypropyl methylcellulose (HPMC), also known as hypromellose.
  • HPMC hydroxypropyl methylcellulose
  • Various grades of HPMC are commercially available. These grades can be split into pH sensitive grades and pH insensitive grades. Examples of pH sensitive HPMC grades are hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and hydroxypropyl methylcellulose phthalate (HPMC-P).
  • pH sensitive it is meant that the release of the cannabinoid isolate from the solid extrudate will vary significantly based on the pH of the environment within the body. It is preferred that the hydroxypropyl methylcellulose is pH insensitive.
  • HPMC hydroxypropyl methylcellulose
  • the Tg of the hydroxypropyl methylcellulose is from 130 to 200 °C as measured by DSC (Differential scanning calorimetry: sample amounts between 3 and 8 mg are filled in an aluminum pan with a pierced lid. The measurements are conducted at a heating rate of 10°C/min from 10 to 220°C. The measurement cell is purged with nitrogen at 200 mL/min).
  • DSC Different scanning calorimetry: sample amounts between 3 and 8 mg are filled in an aluminum pan with a pierced lid. The measurements are conducted at a heating rate of 10°C/min from 10 to 220°C. The measurement cell is purged with nitrogen at 200 mL/min).
  • the solid extrudate or the melt used to form the solid extrudate comprises from 20 to 40 wt% of a hydroxypropyl methylcellulose. In an embodiment, the solid extrudate or the melt used to form the solid extrudate comprises from 25 to 35 wt% of the hydroxypropyl methylcellulose. In an embodiment, the solid extrudate or the melt used to form the solid extrudate comprises from 20, 21 , 22, 23, 24, 25, 26, 27, 28, or 29 wt% to 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 wt% of the hydroxypropyl methylcellulose.
  • the solid extrudate comprises a monounsaturated fatty acid.
  • the monounsaturated fatty acid comprises palmitoleic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, and erucic acid.
  • the monounsaturated fatty acid has from 16 to 18 carbons.
  • the monounsaturated fatty acid has 19 carbons.
  • the monounsaturated fatty acid comprises oleic acid.
  • the monounsaturated fatty acid comprises at least 50 wt% of oleic acid, based on the total monounstaturated fatty acid content.
  • the monounsaturated fatty acid comprises at least 50, 60, 70, 80, 90, 95 or 100 wt% of oleic acid, based on the total monounstaturated fatty acid content.
  • the solid extrudate comprises solely oleic acid as monounsaturated fatty acid, i.e. the extrudate comprises no (i.e. is free of) other mono-unsaturated fatty acid.
  • the solid extrudate or the melt used to form the solid extrudate comprises from 5 to 15 wt% of a monounsaturated fatty acid. In an embodiment, the solid extrudate or the melt used to form the solid extrudate comprises from 5, 6, 7, 8, 9, or 10 wt% to 15, 14, 13, 12, 11 , or 10 wt% of monounsaturated fatty acid.
  • the ratio of cannabinoid isolate to monounsaturated fatty acid, by weight, in the solid extrudate or the melt used to form the solid extrudate is from 4, 3.5, 3, or 2.5 to 1. In an embodiment, the ratio of cannabinoid isolate to monounsaturated fatty acid, by weight, in the solid extrudate or the melt used to form the solid extrudate is 4:1 to 2.5:1, more preferably from 3.5:1 to 2.5:1.
  • the solid extrudate comprises oleic acid having a purity of at least 65 w.-% (assay), preferably from 65 to 88 % (assay) which is e.g. commercially available from PanReac AppliChem (ITW Reagents) / Assay Ph. Eur. (G.C.): 65.0 - 88.0 %.
  • the solid extrudate comprises oleic acid having a purity of at least 90%, more preferably of at least 95%, most preferably of at least 97% such as >99% (GC).
  • GC e.g. commercially available at Sigma Aldrich or Hanseler AG.
  • the solid extrudate does not comprise a natural oil comprising oleic acid such as in particular sesame oil or macadamia oil, as this leads to discoloration of the solid extrudate, in particular upon storage.
  • a natural oil comprising oleic acid such as in particular sesame oil or macadamia oil
  • the solid extrudate or the melt used to form the solid extrudate comprises a surfactant.
  • the surfactant comprises sodium lauryl sulphate, lecithin, polyethylene glycol, a polyoxylethylene stearates, a polyoxyethylene glyceride, a poly(ethylene glycol)/poly(propylene glycol) block copolymer, such as a poly(ethylene glycol)-block- poly(propylene glycol)-block-poly(ethylene glycol) (i.e.
  • a polysorbate for example polysorbate 20, 40, 60, or 80.
  • Preferred is a polysorbate, more preferably polysorbate 80 (e.g. commercially available as Tween® 80 from Sigma Aldrich) or a poly(ethylene glycol)/poly(propylene glycol) block copolymer wherein a is selected in the range from 70-110 and b is selected in the range from 25 to 60 (e.g.
  • At least 40 wt%, more preferably at least 50 wt%, more preferably at least 60 wt%, more preferably at least 70 wt%, more preferably at least 80 wt%, more preferably at least 90 wt%, more preferably 100 wt% of the surfactant comprises a polysorbate, based on the total weight of the surfactant. Most preferred polysorbate 80 is used as the sole surfactant in the solid extrudate.
  • the solid extrudate or the melt used to form the solid extrudate comprises from 10- 30 wt% of a surfactant, preferably from 15-25 wt% of a surfactant.
  • the solid extrudate or the melt used to form the solid extrudate comprises from 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 wt% to 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 wt% of a surfactant.
  • the solid extrudate or the melt used to form the solid extrudate further comprises a porous inorganic carrier.
  • Porous inorganic carriers decrease the density of the extrudate and may improve flowability and processability of the melt in the extrusion process.
  • the porous inorganic carrier comprises silica, calcium carbonate, calcium phosphate, polypropylene powders (Accurel®), porous calcium silicate (Florite®), or magnesium aluminometasilicate.
  • a preferred porous inorganic carrier is a porous calcium silicate.
  • the solid extrudate or the melt used to form the solid extrudate comprises from 5 to 25 wt%, more preferably from 5 to 20 wt%, more preferably from 8 to 15 wt% of a porous inorganic carrier.
  • a preferred porous inorganic carrier is a calcium silicate, such as Florite® R.
  • the solid extrudate or the melt used to form the solid extrudate comprises from 5, 6, 7, 8, 9, 10, 11 , or 12 wt% to 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, or 12 wt% of a porous inorganic carrier.
  • the solid extrudate or the melt used to form the solid extrudate consists essentially of of a cannabinoid isolate, a hydroxypropyl methylcellulose, a monounsaturated fatty acid, and a surfactant with all the definitions and preferences as given herein.
  • the solid extrudate or the melt used to form the solid extrudate consists essentially of a cannabinoid isolate, a hydroxypropyl methylcellulose, a monounsaturated fatty acid, a surfactant, and a porous inorganic carrier with all the definitions and preferences as given herein.
  • the cannabinoid isolate is present as an amorphous solid within the solid extrudate, i.e. in the form of a so-called amorphous solid dispersion.
  • at least 90 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in a non-crystalline form.
  • at least 95 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in a non-crystalline form.
  • at least 98 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in a non-crystalline form.
  • At least 99 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in a non-crystalline form. Even more preferred, 100 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in a non-crystalline form.
  • the content of the crystalline form of the cannabinoid isolate can be measured using commonly known methods, such as differential scanning calorimetry (DSC).
  • DSC is used to determine the amount of crystalline form of the cannabinoid isolate.
  • the DSC method to determine the crystallinity of the cannabinoid isolate is carried out as follows: Liquid or powder (solid) formulations (ca. 8-10 mg) are placed in aluminum pans and hermetically sealed. Empty pans are used as a reference samples. For the investigation of the cannabinoid bulk material (i.e. the non-formulated, crystalline cannabinoid), about 5-8 mg of sample is used. Each sample is heated from 10 °C at 10 °C/min to 90-220°C and then cooled down to 10 °C at 10 °C/min.
  • a thermal transition peak is determined, which for CBD is approx. 68°C, which is attributed to the melting of cannabinoid crystals.
  • CBD is approx. 68°C, which is attributed to the melting of cannabinoid crystals.
  • the degree of crystallinity of a formulated sample can be determined, as the height of the DSC peak corresponds to the amount of heat released during crystallization/heat consumed during melting and is proportional to the degree of crystallinity of the sample. Accordingly, to determine the % of crystallinity, the peak areas of the samples are referenced against the peak area of the crystalline cannabinoid.
  • the amount of crystalline cannabinoid present in a sample can be calculated, which is then used to determine the degree of crystallinity (%), based on known total amount of cannabinoid present in the sample. If no peak is observable in the range of the melting point of the cannabinoid (approx. 70°C), the cannabinoid in the formulated sample is in an amorphous, non-crystalline form.
  • Vitamin E is a group of eight fat soluble compounds that include four tocopherols ((a)-tocopherol, (P)-tocopherol, (y)-tocopherol and (8)-tocopherol) and four tocotrienols ((a)-tocotrienol, (P)-tocotrienol, (y)-tocotrienol and (S)-tocotrienol).
  • mixtures of these compounds can be used such as (all-rac)-a-tocopherol.
  • (all-rac)-a-tocopherol is preferred.
  • the solid extrudate or the melt used to form the solid extrudate further comprises an emulsifier.
  • the solid extrudate or the melt used to form the solid extrudate further comprises an auxiliary agent chosen from the group consisting of dyestuffs, thickeners (such as maltodextrin, glucose syrup), fillers, binders, flavours, antioxidants (other than vitamin E), a pH buffer, and mixtures thereof.
  • an auxiliary agent chosen from the group consisting of dyestuffs, thickeners (such as maltodextrin, glucose syrup), fillers, binders, flavours, antioxidants (other than vitamin E), a pH buffer, and mixtures thereof.
  • the amount of the solid extrudate to be incorporated into such an oral dosage form is preferably selected in the range from 10 mg to 500 mg.
  • the solid extrudate according to the present invention may be admixed with excipients known in the art such as
  • diluents like lactose, starch, microcrystalline cellulose, sorbitol, mannitol, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate, sucrose-based diluents and mixtures thereof;
  • binders like acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrollidone, starch, sucrose, sorbitol, tragacanth, sodium alginate and mixtures thereof; • disintegrants, like microcrystalline cellulose and cellulose derivatives, starch and its derivatives, alginic acid and its derivatives, ion-exchange resins, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone and formaldehyde-caseine;
  • the present invention relates to a method to improve the bioavailability of a cannabinoid isolate, preferably of CBD, said method comprising the step of formulating the cannabinoid isolate into an extrudate comprising from 5-15 wt% of a monounsaturated fatty acid, preferably oleic acid (compared to an extrudate comprising less than 5 wt% of the monounsaturated acid).
  • the solid extrudate with the improved bioavailability comprises a. 20-40 wt% of a cannabinoid isolate, b. 20-40 wt% of a hydroxypropyl methylcellulose, c. 5-15 wt% of a monounsaturated fatty acid, and d. 10-30 wt% of a surfactant, and with all the definitions and preferences as given herein.
  • CBD was from BSPG Laboratories Ltd (Kent, Great Britain).
  • BSPG s CBD is extracted from industrial hemp (Cannabis sativa L.) before being purified and crystallised to produce the final ingredient, which is highly pure (minimum purity of 98%) and does not contain any detectable (0.000006% limit of detection) tetrahydrocannabinol (THC) or any other controlled cannabinoid.
  • THC tetrahydrocannabinol
  • HPMC Hydroproply methylcellulose
  • Croscarmellose was from Sigma Aldrich
  • Tween® 80 polysorbate 80
  • glycerin monostearate were from Sigma Aldrich
  • Lutrol® F68 and F127 Poly(ethylene glycol)-block-poly(propylene glycol)-block- poly(ethylene glycol) were from BASF (Ludwigshafen, Germany).
  • Gelucire® 48/16 and Gelucire® 50/13 were from Gattefosse pic. (Lucerne, Switzerland)
  • Nicotinamide was from Sigma Aldrich (Bruchs, Switzerland) • Florite® R (Calcium Silicate) was from Tomita Pharmaceuticals (Tokushima, Japan).
  • Alpha-Tocopherol was from BASF (Ludwigshafen, Germany).
  • Example 1 - Hot Melt Extrusion Feasibility Extrudates were prepared as follows to determine feasibility of extruding compositions comprising CBD. All extrudates were produced with the co-rotating twin-screw extruder ZE9 ECO from Three-Tec (Birren, Switzerland) equipped with a pair of screws with a diameter of 9 mm, a length of 180 mm. The three heating zones were heated 20 minutes before adding the powder mix to the extruder and the screw speed was set to 45 rpm. Prior to extrusion, all ingredients were pre-mixed with mortar and pestle and the blend (minimum 5g) was then given manually in small portions to the extruder. The extrudates were cooled to room temperature and stored in the fridge at 4°C. Performance in the hot melt extrusion process and a description of the resulting extrudate for various formulations is shown in Fig. 1.
  • CBD amorphous form of CBD is known to present better bioavailability. Samples were tested to determine whether CBD is present in an amorphous during storage.
  • compositions were formed and extrudates obtained in the same manner of Example 1. Samples were tested either in the extrudate form or a milled form of the extrudate.
  • Milled samples of extrudates were produced as follows. The extrudates were cut into small pieces and grinded by a cryogenic grinder Freezer/Mill® from Spex SamplePrep (Metuchen, USA). The setting was 10 min precooling and a rate of 10 CPS for 2 cycles with 2 minutes. The resulting powder was purged with inert gas, packed airtight and stored in the fridge at 4°C.
  • Samples stored according to condition B were stored for four weeks in closed aluminum bags at 25 °C, 60% rH.
  • Samples stored according to condition C were stored for four weeks in closed aluminum bags 40 °C, 75% rH for the stated amount of time.
  • Table 2 The storage conditions are summarized in Table 2.
  • the crystallization behavior of the extrudates or milled samples thereof was determined by using a differential scanning calorimeter DSC 3 (Mettler Toledo, Gsammlungsee, Switzerland). The measurements were conducted at a heating rate of 10°C/min from 10 to 220°C. The measurement cell was purged with nitrogen at 200 mL/min. Sample amounts between 3 and 8 mg were filled in an aluminum pan with a pierced lid. Extrudates were cut into small pieces. The thermal events were analyzed with the STARe Evaluation-Software Version 16 (Mettler Toledo, Gsammlungsee, Switzerland). For sample evaluation mainly the first heating curve was used.
  • crystalline CBD As reference crystalline CBD was used (5-8mg). The crystalline CBD exhibited a thermal transition peak (melting point) at ca. 68°C.
  • compositions shown in Table 2-1 have the compositions shown in Table 2-1. Compositions in the below table are expressed as parts by weight. Table 2-1 - Example 2-1 Compositions
  • Results of the DSC are shown in Fig. 1.
  • the notation used in Fig. 1 and 2 is composition/form/condition.
  • an extrudate of composition Comparative Example 2- 1 stored according to condition C is notated as CE2-1/E/C.
  • a milled powder of composition 2-1 stored according to condition A is notated as 2-1/P/A.
  • CBD has a melting point of approximately 70 °C. None of the samples show a peak at 70°C. Therefore, it was concluded that the CBD is amorphous throughout the experiment, whether in extrudate or powder form.
  • compositions shown in Table 2-2 have the compositions shown in Table 2-2. Compositions in the below table are expressed as parts by weight.
  • Caco-2 ECACC 86010202 (European Collection of Cell Cultures, Salisbury, UK) were cultured at 37 °C, in atmosphere of 5% CO2 in DMEM medium supplemented with 4.5 g/L D- Glucose, 4 mM L-Glutamine, 1 mM Sodium Pyruvate, 1% MEM Non-Essential Amino Acids, 50 pg/mL Gentamicin (Life Technologies Europe B.V., Switzerland) and 10% heat-inactivated FBS (Sigma-Aldrich, Buchs, Switzerland). Sub-confluent cells were tryptinized using 0.25% Trypsin/EDTA (Life Technologies Europe B.V., Switzerland).
  • TEER transepithelial electrical resistance
  • HBSS solution HBSS pH 7.4 with Ca2+ and Mg2+, containing 5.5 mM D-(+)-glucose, Sodium Bicarbonate, and supplemented with 4 mM L-glutamine and 20 mM HEPES, Life Technologies Europe B.V., Switzerland
  • the different prototypes were prepared in HBSS solution at a concentration of 15 pM.
  • the prototype solution was applied on the apical chamber (200 pL) and 1.5 mL of 4% BSA in HBSS solution were added to the basolateral chamber.
  • the plate was then incubated for 3 h at 37 °C in the CO2 incubator on an orbital shaker (80 rpm).
  • the buffer solutions from the basolateral (BL) and the apical (API) compartments were collected and diluted in acetonitrile for analysis.
  • the cell layers (CL) were washed once with HBSS solution, then 500 pL acetonitrile were added to the apical part.
  • the cells were scraped off from the membrane using a pipet tip, and then collected for analysis.
  • Cannabidiol was quantitated by a stable isotope dilution LC-MS method using an Agilent 1290 Infinity II UHPLC connected to a Bruker Impact II Q-TOF mass spectrometer.
  • Eight cannabidiol calibration solutions covering a concentration range of 2.5 ng/ml to 2000 ng/ml were prepared in acetonitrile.
  • a 500 ng/ml solution of deuterium labelled d3-Cannabidiol (CAS No. 1435783-16-6) in acetonitrile served as internal standard.
  • 250 ml of calibration solution was mixed with 25 ml of internal standard.
  • 250 ml of the centrifuged CaCo2 compartment samples were combined with 25 ml internal standard.
  • the analytical column was a Raptor ARC C18 column (2.1 x 150 mm).
  • the mobile phase was water/acetonitrile 24:76 (v/v) containing 5 mM ammonium formate and 0.1 % v/v formic acid.
  • the chromatogram was developed isocratically at a flow rate of 0.4 ml/min and a column temperature of 30°C.
  • the injection volume was 1.5 ml.
  • the column effluent was introduced into a VIP-HESI source (Bruker Daltonik GmbH) operating in positive ionization mode.
  • the mass spectrometer was operating in full-scan mode scanning the range m/z 100-1000 with a spectrum rate of 4 Hz.
  • CBD measured as a percent of the original CBD content from the apical compartment (API), basolateral (BL) compartment, and the cell layer (CL) are shown in Table 3.
  • Cell permeability of CBD is determined by the sum of the amounts measured in the basolateral compartment and the cell layer (BL+CL). Higher recovery indicates higher cell permeability of CBD.
  • CE3-1 (CBD in DMSO) is included to determine the theoretical maximum recovery, being 68.4%.
  • Sesame oil comprises about 39 wt% of monounsaturated fatty acid (oleic acid), about 41 wt% polyunsaturated fatty acid (linoleic acid), and about 13 wt% saturated fatty acids (palmitic acid and stearic acid).
  • oleic acid monounsaturated fatty acid
  • lainoleic acid polyunsaturated fatty acid
  • saturated fatty acids palmitic acid and stearic acid
  • Samples 3-1 and 3-2 have the same composition but Sample 3-2 uses a different extruder design than the other samples in Example 3. High recovery is demonstrated also with this alternative extruder design, indicated the robustness of the compositions.
  • a solid extrudate or composition for forming an extrudate via a hot melt extrusion process comprising: a. 20-40 wt% of a cannabinoid isolate, b. 20-40 wt% of a hydroxypropyl methylcellulose, c. 5-15 wt% of a monounsaturated fatty acid, and d. 10-30 wt% of a surfactant.
  • the cannabinoid isolate comprises cannabigerolic acid (CBGA), cannbigerol (CBG), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidivarinic acid (CBDVA), or cannabidivarin (CBDV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabinolic acid (CBNA), cannabinol (CBN), cannabidivarinic acid, cannabichromevarinic acid (CVCVA), cannabichromevarin (CBCV), cannabigerovarinic acid (CBGVA), cannabigerovarin CBGV), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabielsoinic acid (CBEA), cannabielsoin (CBE), cannabicitranic acid (CBTCA), or cannabigerolic acid (CBGA), cannbigerol
  • the cannabinoid isolate comprises cannabigerolic acid (CBGA), cannbigerol (CBG), cannabidiolic acid (CBDA), or cannabidiol (CBD).
  • CBD cannabidiol
  • CBD cannabidiol
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition comprises from 20-40 wt% of a cannabinoid isolate, preferably from 25-35 wt% of the cannabinoid isolate.
  • extrudate or composition according to any one of the previous exemplary embodiments wherein the extrudate or composition comprises from 25, 26, 27, 28, 29 or 30 wt% to 35, 34, 33, 32, 31 , or 30 wt% of a cannabinoid isolate.
  • the extrudate or composition according to any one of the previous exemplary embodiments wherein the extrudate or composition comprises from 25 to 35 wt% of the hydroxypropyl methylcellulose.
  • Tg of the hydroxypropyl methylcellulose is from 130 to 200 °C measured by DSC.
  • extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition comprises from 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 wt% to 40, 39, 38, 37, 36, 35, 34, 33, 32, 31 , or 30 wt% of the hydroxypropyl methylcellulose.
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the monounsaturated fatty acid is selected from the group consisting of palmitoleic acid, oleic, elaidic acid, vaccenic, gadoleic acid, eicosenoic acid, and erucic acid, and mixtures thereof.
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the monounsaturated fatty acid has from 16 to 18 carbons.
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the monounsaturated fatty acid comprises oleic acid.
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the monounsaturated fatty acid consists essentially of oleic acid.
  • extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition comprises from 5 to 15 wt% of a monounsaturated fatty acid.
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition comprises solely oleic acid as monounsaturated fatty acid (i.e. does not comprise any other monounsaturated fatty acid).
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the ratio of cannabinoid isolate to monounsaturated fatty acid in the extrudate or composition is from 4, 3.5, 3, or 2.5 to 1 by weight.
  • the extrudate or composition according to any one of the previous exemplary embodiments, wherein the ratio of cannabinoid isolate to monounsaturated fatty acid in the extrudate or composition is 4:1 to 2.5:1 , more preferably from 3.5:1 to 2.5:1 , by weight.
  • the surfactant comprises polysorbate 20, 40, 60, or 80 preferably polysorbate 80.
  • the surfactant comprises a poly(ethylene glycol)/poly(propylene glycol) block copolymer HO-[CH2-CH2-O] a -[CH2CH(CH3)-O]b-[CH2-CH2-O] a -H wherein a is selected in the range from 70-110 and b is selected in the range from 25 to 60, preferably wherein a is 80 and b is 27 or a is 101 and b is 56.
  • the surfactant comprises a polyoxylethylene stearate, preferably PEG-32 stearate.
  • the surfactant comprises polyoxyethylene glycerides, preferably PEG-32 Hydrogenated palm glycerides.
  • the surfactant is selected from the group consisting of polysorbate 80, a poly(ethylene glycol)/poly(propylene glycol) block copolymer HO-[CH2-CH2-O] a - [CH2CH(CH3)-O]b-[CH2-CH2-O] a -H wherein a is 80 and b is 27 or a is 101 and b is 56, PEG- 32 stearate or PEG-32 Hydrogenated palm glycerides as well as mixtures thereof, preferably in the absence of any other surfactant.
  • the surfactant is selected from the group consisting of polysorbate 80, a poly(ethylene glycol)/poly(propylene glycol) block copolymer HO-[CH2-CH2-O] a - [CH2CH(CH3)-O]b-[CH2-CH2-O] a -H wherein a is 80 and b is 27 or a is 101 and b is 56, PEG- 32 stearate or PEG
  • the extrudate or composition according to any one of the previous exemplary embodiments wherein at least 40 wt%, more preferably at least 50 wt%, more preferably at least 60 wt%, more preferably at least 70 wt%, more preferably at least 80 wt%, more preferably at least 90 wt%, more preferably 100 wt% of the surfactant comprises a polysorbate, based on the total weight of the surfactant.
  • extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition comprises from 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 wt% to 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 , or 20 wt% of the surfactant.
  • extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition further comprises a porous inorganic carrier.
  • extrudate or composition according to any one of the previous exemplary embodiments wherein the extrudate or composition further comprises a porous inorganic carrier comprising silica, calcium carbonate, calcium phosphate, polypropylene powders (Accurel®), porous calcium silicate (Florite®), or magnesium aluminometasilicate.
  • a porous inorganic carrier comprising a calcium silicate, preferably as sole porous inorganic carrier.
  • a porous inorganic carrier which is calcium silicate, preferably as sole porous inorganic carrier.
  • extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate or composition further comprises from 5 to 25 wt%, more preferably from 5 to 20 wt%, more preferably from 8 to 15 wt% of a porous inorganic carrier.
  • extrudate or composition according to any one of the previous exemplary embodiments, wherein the extrudate comprises the cannabinoid isolate in the form of an amorphous solid dispersion.
  • the extrudate or composition according to any one of the previous exemplary embodiments wherein at least 90, more preferably 95, more preferably 98, more preferably 99, more preferably 100 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in a non-crystalline form.
  • the extrudate or composition according to any one of the previous exemplary embodiments wherein at least 90, more preferably 95, more preferably 98, more preferably 99, more preferably 100 wt%, based on the total weight of the cannabinoid isolate, of the cannabinoid isolate is in an amorphous form.
  • a solid dosage form suitable for oral application comprising a solid extrudate or composition according to any one of the previous exemplary embodiments, wherein the solid dosage form is in the form of a tablet (orally dispersible tablet, chewable tablet, film coated tablet, immediate release tablet, extended or sustained release tablet and similar), a capsule, an orally dispersible film, or a gummy.
  • a pharmaceutical product comprising a solid extrudate or composition according to any one of the previous exemplary embodiments, wherein the pharmaceutical product is preferably in the form of a tablet (orally dispersible tablet, chewable tablet, film coated tablet, immediate release tablet, extended or sustained release tablet and similar), a capsule, an orally dispersible film, or a gummy.
  • a method of forming a solid extrudate comprising the steps of: a. forming a melt comprising the composition of any one of the previous exemplary embodiments; b. pushing the melt through a die, c. hardening the melt to form a solid extrudate.
  • a pharmaceutical product comprising the solid extrudate of any one of the previous exemplary embodiments.
  • a pharmaceutical product comprising at least one solid extrudate formed from the method of any one of the previous exemplary embodiments.
  • the term ‘consisting essentially of’ as used in the context of the invention means that the addition of the wt- percent of the ingredients add up to 100 wt.- percent. However, it cannot be excluded that small amounts of impurities may be present such as e.g. in amounts of less than 5 wt.- percent, preferably less than 3 wt.- percent which are introduced via the respective raw materials or processes used.

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Abstract

La présente invention concerne des extrudats solides à usage pharmaceutique. Les extrudats solides comprennent au moins un isolat de cannabinoïde et peuvent être produits par extrusion à chaud. Dans un mode de réalisation, un extrudat solide comprend de 20 à 40 % en poids d'un isolat de cannabinoïde, de 20 à 40 % en poids d'une hydroxypropylméthylcellulose, de 5 à 15 % en poids d'un acide gras mono-insaturé, et de 10 à 30 % en poids d'un tensioactif.
PCT/EP2024/078139 2023-10-06 2024-10-07 Extrudat de cannabinoïde Pending WO2025073997A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120231083A1 (en) * 2010-11-18 2012-09-13 The Board Of Trustees Of The University Of Illinois Sustained release cannabinoid medicaments
WO2021119844A1 (fr) * 2019-12-20 2021-06-24 Organigram Inc. Formulations émulsifiantes de cannabinoïdes et/ou d'extraits de cannabinoïdes
WO2023015378A1 (fr) * 2021-08-09 2023-02-16 CannTab Therapeutics Limited Stabilisation de résine de cannabis et formulations orales solides de cannabinoïdes
WO2023055648A1 (fr) * 2021-09-28 2023-04-06 Latitude Pharmaceuticals Inc. Formulation de cannabidiol à dissolution améliorée

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120231083A1 (en) * 2010-11-18 2012-09-13 The Board Of Trustees Of The University Of Illinois Sustained release cannabinoid medicaments
WO2021119844A1 (fr) * 2019-12-20 2021-06-24 Organigram Inc. Formulations émulsifiantes de cannabinoïdes et/ou d'extraits de cannabinoïdes
WO2023015378A1 (fr) * 2021-08-09 2023-02-16 CannTab Therapeutics Limited Stabilisation de résine de cannabis et formulations orales solides de cannabinoïdes
WO2023055648A1 (fr) * 2021-09-28 2023-04-06 Latitude Pharmaceuticals Inc. Formulation de cannabidiol à dissolution améliorée

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
no. 1435783-16-6

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