WO2020183436A1 - Formes posologiques pour administration orale de cannabinoïdes, procédé de préparation et utilisations de celles-ci - Google Patents

Formes posologiques pour administration orale de cannabinoïdes, procédé de préparation et utilisations de celles-ci Download PDF

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Publication number
WO2020183436A1
WO2020183436A1 PCT/IB2020/052334 IB2020052334W WO2020183436A1 WO 2020183436 A1 WO2020183436 A1 WO 2020183436A1 IB 2020052334 W IB2020052334 W IB 2020052334W WO 2020183436 A1 WO2020183436 A1 WO 2020183436A1
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Prior art keywords
dosage form
solid dosage
acid
cannabinoids
amount
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PCT/IB2020/052334
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English (en)
Inventor
Alon SINAI
Yehuda Baruch
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One World Cannabis Ltd.
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Publication of WO2020183436A1 publication Critical patent/WO2020183436A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present disclosure relates to dosage forms for delivery of cannabinoids to the oral cavity.
  • Cannabis contains various cannabinoids, two of which have been extensively studied: A9-Tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • THC A9-Tetrahydrocannabinol
  • CBD cannabidiol
  • Oral dosage forms comprising CBD and/or THC have been described.
  • WO 02/064109 describes a pharmaceutical formulation for use in administration of, inter alia, THC and mixtures of THC and CBD via a mucosal surface.
  • the formulation may be in the form of a gel or a compressed tablet for administration via the sublingual and/or buccal mucosa.
  • the pharmaceutical formulations are intended for the treatment of a variety of diseases among which are multiple sclerosis, spinal cord injury, peripheral neuropathy and other neurogenic pain.
  • WO16/014454 describes solid dosage forms of cannabinoids comprising a solvated cannabinoid (THC or CBD) for buccal or sublingual administration, and methods of making and using the same.
  • the solvent may comprise ethanol and the solvated cannabinoid is absorbed onto an adsorbent comprising, for example, silica.
  • compositions which deliver therapeutically effective amounts of cannabinoids to a subject in need thereof.
  • the oral compositions comprise chewing gum, lozenges and fast-dissolving lozenges.
  • International Patent Application Publication No. W016/084075 describes pharmaceutical compositions comprising CBD and THC, or a derivative thereof, in a predefined ratio, for use in the treatment of multiple myeloma (MM).
  • the composition comprises cannabis oil.
  • the solid formulations are formulated as sublingual tablets containing THC and CBD combinations.
  • U.S. Patent No. 9,308,175 describes an oral pharmaceutical dosage unit comprising microgranulate particles distributed throughout a solid hydrophilic matrix, the microgranulate particles consisting of one or more cannabinoids, sugar and fatty acid esters that, together, represent at least 80 w% of the microgranulate.
  • the pharmaceutical dosage unit forms a micro-emulsion upon contact with saliva or water.
  • U.S. Patent No. 9,943,491 describes compressed tablet containing cannabidiol, method for its manufacture and use of such tablet in oral treatment of psychosis or anxiety disorders.
  • the compressed tablets contain, inter alia, ascorbic acid as an anti-oxidant and other tablet excipients, such as disintegrants (e.g. croscarmellose sodium).
  • U.S. Patent No. 8,735,374 describes oral mucoadhesive dosage forms obtained by direct compression. Specifically, formulation suitable for buccal and/or sublingual are described that comprise a cannabinoid-cyclodextrin complexes.
  • the present disclosure relates, in accordance with a first aspect, to a solid dosage form, preferably a tablet, for release of at least one cannabinoid to the oral cavity, the dosage form comprises the at least one cannabinoid and at least one organic acid.
  • the dosage form has a disintegration rate sufficient to allow at least one of buccal or sublingual absorption of the released cannabinoids.
  • a contemplated solid dosage form may comprise a mixture of at least 4 organic acids, at least one being a C3-C8 dicarboxylic acid.
  • the organic acids include succinic acid, malic acid, maleic acid, tartaric acid, fumaric acid, glutaric acid, glutamic acid, aspartic acid, ascorbic acid, alginic acid, citric acid, adipic acid and acetic acid.
  • the dosage form is a tablet comprising one or more organic acid in an amount of at least 1 wt% out of the total weight of the tablet, for example, an amount of between 10 wt% to 95 wt%.
  • a disclosed solid dosage form may comprise one or more cannabinoids, particularly, but not exclusively, at least one cannabinoid comprises cannabidiol (CBD) and/or tetrahydrocannabinol (THC).
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • a contemplated solid dosage form may comprise CBD in an amount of between 0.5 wt% to 50 wt%, for example, between 1.0 wt% to 20 wt% out of the total weight of the tablet, and/or THC in an amount of between 0.5 wt% to 50 wt%, for example, between 1.0 wt% to 20 wt% out of the total weight of the tablet.
  • a disclosed solid dosage form comprises a mixture of CBD and THC
  • the amount of CBD and THC may be the same or different, and their w/w ratio may be between 1: 1-10 and 1-10: 1.
  • These and optional additional cannabinoids comprised in the solid dosage form may constitute up to 50 wt% of the total weight of the dosage form, for example, between 1 wt% and 40 wt% out of the total weight of a contemplated tablet;
  • the solid dosage form of any one of claims 1 to 14 disclosed herein is characterized as having a hardness of between 30 N to 65 N, and disintegration rate (defined by full disintegration of the solid dosage form when placed in water) which is, within a time period of between 60 seconds and 240 seconds, for example, between 120 seconds and 180 seconds.
  • the present disclosure relates to a method of preparing a solid dosage form, for example, a tablet, comprising at least one cannabinoid and at least one organic acid, the method comprises:
  • the particulate matter comprises at least a glidant material, a sweetener and a superdisintegrant;
  • the present disclosure relates to a method of treatment of a disease, disorder or condition for which cannabinoids have therapeutic properties, the method comprising:
  • the solid dosage form e.g., a tablet
  • the solid dosage form is held for a time period of at least 60 seconds for example, for a time period of between 60 seconds and 240 seconds.
  • the solid dosage form is held by the subject in any one of the buccal regions of the oral cavity and sublingual region of the oral cavity.
  • Non-limiting examples of diseases, disorders or conditions for which cannabinoids have therapeutic properties include cancer and metastasis, neurodegeneration, pain, inflammation, autoimmunity, neurological and psychiatric disorders.
  • the present disclosure is based on the development, by the inventors, of solid dosage forms suitable for oral delivery of cannabinoids.
  • the solid dosage forms disclosed herein are defined by a controlled disintegration rate, thereby allowing the controlled release of the cannabinoids from the solid dosage form and, consequently, the controlled absorption of the cannabinoids through the oral cavity (e.g., buccal, sublingual).
  • the solid dosage forms comprise, in accordance with one aspect of the present disclosure, the cannabinoids and at least one organic acid and have a disintegration rate sufficient to allow oral absorption of the released cannabinoids.
  • the cannabinoids comprise at least one of cannabidiol (CBD) and tetrahydrocannabinol (THC).
  • solid dosage form it is to be understood as referring to any form suitable for sublingual delivery, buccal delivery and oral local delivery.
  • the solid dosage form may be in the form of tablets including adhesive tablets, patches, films, and powders http://www.imedpub.com/articles/a-comprehensive- review-on-buccal-drug-delivery-system.pdf.
  • the solid dosage form is in the form of a tablet.
  • cannabinoid includes any member and any combination of naturally occurring and synthetic cannabinoids and related compounds, and extracts from any Cannabis species and varieties.
  • the cannabinoid may be natural, semisynthetic, or synthetic. It may be included in its natural (pure) form, or in the form of a prodrug such as a cannabinoid derivative, e.g., an amide derivative, a pharmaceutically acceptable salt such as an acid addition salt of an ester, an enantiomer, an isomer or a tautomer.
  • the cannabinoid may be in different isomeric forms (for example, enantiomers and diastereoisomers), both in pure form and in admixture, including racemic mixtures.
  • Cannabinoids include compounds (such as THC) that have high affinity for a certain cannabinoid receptor, i.e., CB 1 (for example, Ki ⁇ 250 nM), and compounds that have significant affinity for another cannabinoid receptor, CB2, (such as cannabidiol (CBD)).
  • cannabinoids also include compounds that have a characteristic dibenzopyran ring structure (of the type seen in THC) and cannabinoids which do not possess a pyran ring (such as cannabidiol).
  • cannabinoid is also meant to encompass derivatives that are produced from another compound of similar structure by the replacement of, e.g., substitution of one atom, molecule or group by another, for example, delta-8-tetrahydrocannabinol and delta-9-tetrahydrocannabinol (THC) and their respective 11-hydroxy metabolites: l l-hydroxy-delta-8-tetrahydrocannabinol and l l-hydroxy-delta-9- tetrahy droc annabinol .
  • delta-8-tetrahydrocannabinol and delta-9-tetrahydrocannabinol THC
  • cannabinoids include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabicyclol (CBL), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol (CDB), cannabitriol (CBO), cannabinol propyl variant (CBNV), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidiorcol (CBD-C1), delta-9-tetrahydrocannabinolic acid
  • cannabinoid also includes complexes of cannabinoids.
  • cannabinoids it is to be understood as referring to any one or more cannabinoids as defined herein.
  • the cannabinoid comprises at least CBD and/or THC.
  • the cannabinoids comprise at least CBD.
  • the cannabinoids comprise at least THC.
  • the cannabinoids comprise a mixture of CBD and
  • the cannabinoids may be from any source, be it a cannabis plant extract, cannabis oil or isolated cannabinoid compounds, including isolated CBD and/or isolated THC.
  • the cannabis extract or the cannabinoids are oil-free.
  • the extract if such is used as the cannabinoid source, is other than an oil extract of a cannabis plant.
  • a contemplated solid dosage form comprises CBD in an amount of between 0.5 wt% and 50 wt% out of the total weight of the solid dosage form, for example, between 1 wt% and 20 wt%, or between 2 wt% and 10 wt% out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the solid dosage form comprises THC in an amount of between 0.5 wt% and 50 wt% out of the total weight of the solid dosage for, for example, between 1 wt% and 20 wt% or between 2 wt% and 10 wt% out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • a contemplated solid dosage form comprises a combination of CBD and THC.
  • the relative amounts of CBD and THC e.g., the CBD:THC w/w ratio of such solid dosage form, may be between 1: 10 and 10: 1.
  • CBD:THC w/w ratio is between 1:2-10 and 2-10: 1, for example, 1:2.5, 1:3, 1:4, 1:5, 1:6.5, 1:8, 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1, 6.5: 1, 7: 1, 8: 1, or 9: 1.
  • CBD:THC w/w is between 1:4 and 4: 1.
  • CBD:THC w/w is about 1: 1.
  • the solid dosage form comprises a combination of CBD and THC at a CBD:THC w/w ratio of about 1: 1, about defining a deviation of ⁇ 10% from the ratio.
  • the solid dosage form comprises a combination of CBD and THC at a CBD:THC w/w ratio of about 1:4, about defining a deviation of 10% from the ratio.
  • the solid dosage form comprises cannabinoids at a total amount of between 0.5 wt% and 50 wt%, for example, between 1 wt% and 20 wt%, or between 2 wt% and 10 wt% out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of CBD and THC in the solid dosage form is essentially the same (essentially defining a deviation of 5 wt% between one amount and the other).
  • the amounts of CBD and THC in the solid dosage form are different.
  • the solid dosage form disclosed herein comprises at least one organic acid.
  • organic acid denotes an edible organic compound comprising one or more carboxylic functional groups.
  • the organic acid is a C3-C8 compound, at times, C3-C5 compound, namely a compound comprising 3 to 8 or 3 to 5 carbon atoms, respectively.
  • the organic acid comprises or is a monocarboxylic acid.
  • the organic acid comprises or is a dicarboxylic acid.
  • the organic acid comprises or is a tricarboxylic acid.
  • the organic acid comprises or is alpha-hydroxy acid, such as, but not limited to, tartaric acid and lactic acid.
  • the organic acid comprises or is acidic amino acid, such as, but not limited to, aspartic acid and glutamic acid.
  • a non-limiting list of edible monocarboxylic acids include acetic acid, alginic acid, propionic acid, each constituting a separate example of the present disclosure.
  • a non-limiting list of edible dicarboxylic acids include succinic acid, malic acid, maleic acid, fumaric acid, glutaric acid, glutamic acid, aspartic acid, adipic acid, oxalic acid, each constituting a separate example of the present disclosure.
  • a non-limiting example of edible tricarboxylic acid include citric acid.
  • the solid dosage form is comprised of two or more organic acids.
  • the solid dosage form is comprised of at least one dicarboxylic acid.
  • the solid dosage form comprises between 2 and 7 organic acids, for example, between 4 and 5 or between 3 and 6 organic acids.
  • the solid dosage form comprises between 5 and 6 organic acids.
  • the solid dosage form comprises more than two organic acids
  • at least one of the organic acids is a dicarboxylic acid.
  • the solid dosage form comprises 2, 3, 4, 5, or 6 dicarboxylic acids.
  • the amount of the acids may be the same or different.
  • the solid dosage form comprises total organic acids that amounts to at least 1 wt%, yet often the total amount of the organic acids is at least 10 wt% or even at least 20 wt%, for example, at least 25 wt%, at least 30 wt%, at least 35 wt%, at least 40 wt%, at least 50 wt%, or at least 75 wt%, out of the total weight of the solid dosage form, and any values therebetween.
  • the wt% of the total organic acids in the solid dosage form is in the range of between 10 wt% and 95 wt%, for example, between 20 wt% and 75 wt%, between 20 wt% and 40 wt%, between 30 wt% and 50 wt%, or between 35 wt% and 60 wt%, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least succinic acid.
  • the amount of succinic acid ranges between 1 wt% and 60 wt%, for example, between 10 wt% and 30 wt%, between 13 wt% and 50 wt%, between 20 wt% and 40 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween. In some exemplary embodiments, the amount of succinic acid ranges between 1 mg and 100 mg, for example, between 30 mg and 80 mg, between 2 mg and 10 mg, between 3 mg and 15 mg, between 5 mg and 20 mg, or between 10 mg and 65 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least malic acid.
  • the amount of malic acid ranges between 0.1 wt% and 60 wt%, for example, between 1 wt% and 10 wt%, between 4 wt% and 7 wt%, between 2 wt% and 10 wt%, between 5 wt% and 9 wt%, between 10 wt% and 20 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of malic acid ranges between 1 mg and 150 mg, for example, between 5 mg and 25 mg, between 1 mg and 10 mg, between 15 mg and 35 mg, between 2 mg and 8 mg, or between 2.5 mg and 20 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least maleic acid.
  • the amount of maleic acid ranges between 0.1 wt% and 10 wt%, for example, between 1 wt% and 5 wt%, between 0.5 wt% and 2.5 wt%, between 1 wt% and 3 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of maleic acid ranges between 1 mg and 10 mg, for example, between 2.5 mg and 5 mg, or between 3 mg and 5 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least tartaric acid.
  • the amount of tartaric acid ranges between 0.1 wt% and 20 wt%, for example, between 0.2 wt% and 1 wt%, between 1 wt% and 10 wt%, between 2.5 wt% and 10 wt%, between 4 wt% and 12 wt%, or between 8 wt% and 15 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of tartaric acid ranges between 1 mg and 100 mg, for example, between 5 mg and 50 mg, between 5 mg and 10 mg, or between 1 mg and 20 mg and any individual values or subranges therebetween.
  • the solid dosage form comprises at least fumaric acid.
  • the amount of fumaric acid ranges between 0.1 wt% and 60 wt%, at times, between 1 wt% and 20 wt%, at times between 5 wt% and 15 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween. In some examples, the amount of fumaric acid ranges between 1 mg and 150 mg, for example, between 1 mg and 10 mg, between 5 mg and 50 mg, or between 5 mg and 25 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least glutamic acid.
  • the amount of glutamic acid ranges between 1 wt% and 10 wt%, at times, between 0.1 wt% and 5 wt%, between 5 wt% and 10 wt%, or between 1 wt% and 15 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of glutamic acid ranges between 1 mg and 10 mg, for example, between 1 mg and 3 mg, between 2 mg and 6 mg, or between 5 mg and 10 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least ascorbic acid.
  • the amount of ascorbic acid ranges between 0.1 wt% and 5 wt%, and at times, between 0.1 wt% and 1 wt% out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of ascorbic acid ranges between 1 mg and 5 mg, for example, between 0.5 mg and 1 mg, or between 0.5 mg and 5 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least alginic acid.
  • the amount of alginic acid ranges between 0.1 wt% and 60 wt%, at times, between 1 wt% and 20 wt%, between 1 wt% and 15 wt%, or between 10 wt% and 30 wt% out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of alginic acid ranges between 1 mg and 150 mg, for example, between 5 mg and 50 mg, between 5 mg and 25 mg or, or between 10 mg and 40 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least citric acid.
  • the amount of citric acid ranges between 0.1 wt% and 60 wt%, at times, between 0.2 wt% and 5 wt%, between 1 wt% and 25 wt%, between 5 wt% and 30 wt%, or between 10 wt% and 40 wt%, out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the amount of citric acid ranges between 1 mg and 150 mg, for example, between 5 mg and 75 mg, between 1 mg and 15 mg, between 10 mg and 50 mg, or between 15 mg and 60 mg, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least 0.01% acetic acid.
  • the amount of acetic acid ranges between 0.1-2 mg out of the total weight of the solid dosage form.
  • the solid dosage form comprises at least one of a disintegrant or superdisintegrant substance.
  • disintegrant and “superdisintegrant” are to be understood as encompassing any substance that aids in the break-up of the solid dosage form when in aqueous containing environment (including body fluids).
  • the disintegrant or superdisintegrant can be water soluble or water insoluble.
  • Water soluble disintegrants/superdisintegrants include, without being limited thereto, sodium citrate or citric acid, or a pyrollidone, for example the polyvinylpyrrolidone (also commonly known as polyvidone, povidone, or PVP, e.g., the commercially available product having the brand name Kollidon® 25, herein, for convenience, designated“PVP K25”), or vinylpyrrolidone-vinyl acetate copolymer (such as the commercially available product Kollidon® VA64).
  • polyvinylpyrrolidone also commonly known as polyvidone, povidone, or PVP, e.g., the commercially available product having the brand name Kollidon® 25, herein, for convenience, designated“PVP K25”
  • PVP K25 the commercially available product having the brand name Kollidon® 25, herein, for convenience, designated“PVP K25”
  • vinylpyrrolidone-vinyl acetate copolymer such as the commercially available product Kollid
  • Water insoluble, or poorly soluble disintegrants/superdisintegrants include, without being limited thereto, hydroxypropyl cellulose (HPC), especially low substituted hydroxypropyl cellulose (L-HPC) as defined in United States Pharmacopeia (USP) reference standard, sodium starch glycollate, carboxymethyl cellulose (the sodium salt of carboxymethyl ether), croscarmellose sodium (internally cross-linked sodium carboxymethylcellulose (NaCMC)), crospovidone (cross-linked PVP), calcium silicate and starch, and derivatives thereof.
  • HPC hydroxypropyl cellulose
  • L-HPC low substituted hydroxypropyl cellulose
  • USP United States Pharmacopeia
  • sodium starch glycollate sodium starch glycollate
  • carboxymethyl cellulose the sodium salt of carboxymethyl ether
  • croscarmellose sodium internally cross-linked sodium carboxymethylcellulose (NaCMC)
  • crospovidone cross-linked PVP
  • Water insoluble or poorly soluble disintegrants/superdisintegrants typically absorb water and swell (promote water up-take into the solid dosage form).
  • the disintegrant/superdisintegrant is a water soluble or poorly soluble substance.
  • a disintegrant and superdisintegrant The distinction between a disintegrant and superdisintegrant is known in the art. Generally, a superdisintegrant can be distinguished from a disintegrant by its greater effectiveness even at low concentrations. The superdisintegrants are also effective intragranularly. Superdisintegrants function principally by swelling on absorbing water. In some embodiments, the superdisintegrants can be distinguished from disintegrants by their swelling index (swelling index being the volume in milliliters that is occupied by 1 gr of material after it has swollen in an aqueous liquid for 3-4 hours).
  • swelling index being the volume in milliliters that is occupied by 1 gr of material after it has swollen in an aqueous liquid for 3-4 hours).
  • the superdisintegrants can also be divided into synthetic superdisintegrants and natural superdisintegrants such as, without being limited thereto, mucilage (a thick, gluey substance) produced from the plant Isapghula Husk (a member of the plant genus Plantago ovata ), chitosan, Guar Gums (a galactomannan polysaccharide extracted from guar beans), Agar and soy polysaccharides such as the commercially available product having the brand name EMCOSOY®, an all-natural tablet disintegrant manufactured from soy that has not been genetically modified.
  • mucilage a thick, gluey substance
  • chitosan a galactomannan polysaccharide extracted from guar beans
  • EMCOSOY® an all-natural tablet disintegrant manufactured from soy that has not been genetically modified.
  • Representing synthetic superdisintegrants suitable for incorporation in solid dosage form contemplated herein, each representing a separate example of the present disclosure, include: crospovidone (e.g., the commercially available products sold under the brand names Kollidon® CL, Kollidon® CL-SF, Kollidon® CL-M, PolyplasdoneTM XL) or derivatives thereof; Croscarmellose sodium (NaCMC), in which the cross-linking reduces water solubility while still allowing the material to swell (like a sponge) and absorb many times its weight in water.
  • crospovidone e.g., the commercially available products sold under the brand names Kollidon® CL, Kollidon® CL-SF, Kollidon® CL-M, PolyplasdoneTM XL
  • Croscarmellose sodium (NaCMC) Croscarmellose sodium (NaCMC), in which the cross-linking reduces water solubility while still allowing the material to swell (like a sponge) and absorb
  • Non-limiting examples of commercially available croscarmellose sodium products include, e.g., products sold under the brand names Ac-Di-sol®, Primellose®, or VIVASOL®, or derivatives thereof; sodium starch glycollate, a superdisintegrant made of potato starch by carboxymethylation and crosslinking, provides rapid water penetration into the tablets (up more than 20 times its own weight) and powerful swelling that results in rapid disintegration.
  • Non-limiting examples of commercially available sodium starch glycollate are products having the brand names VIVASTAR® and EXPLOTAB® (produced by JRS Pharma), GLYCOLYS® and EXPLOSOL® (manufactured by Roquettes Fre'res), Primojel® (manufactured by DMV- Fonterra Excipients), or derivatives thereof.
  • Sodium starch glycolate is available in a number of speciality grades, e.g.
  • GLYCOLYS® LM calcium silicate, (Ca 2 Si0 4 ), also known as calcium silicon oxide, a product derived from limestone and diatomaceous earth, used in the pharmaceutical industry as an anticaking agent. Anti-caking agents absorb moisture and allow products to flow freely during the manufacturing process. Silicon dioxide and various silicates occur abundantly in the earth's crust, are present in practically all natural waters, animals, and plants, and are part of the normal human diet.
  • L-HPC low-substituted hydroxypropyl cellulose
  • a disintegrant commercially available, e.g., under brand name Nisso HPC (manufactured by SEPPICTM); alginic acid (synonyms: E 400, L-gulo-D- mannoglycuronan, polymannuronic acid), a linear glycuronan polymer consisting of a mixture of b-(1 4)-D-mannosyluronic acid and a-(l 4)-L-gulosyluronic acid residues, of general formula (CeHxO),
  • Non-limiting alginic acid disintegrant products are commercially available under brand names Satialgine® H8, Protacid® AR-1112 (Kelacid NF) and Protacid® F120NM.
  • the solid dosage form comprises a superdisintegrant in a weight percent of between 0.5 wt% and 10 wt%, at times between 2 wt% and 6 wt%, between 0.5 wt% and 2 wt%, or between 1 wt% and 5 wt% out of the total weight of the solid dosage form, and any individual values or subranges therebetween.
  • the superdisintegrant is croscarmellose sodium.
  • the croscarmellose sodium is in an amount of between 1 wt% and 5 wt% out of the total weight of the solid dosage form, or between 1 mg and 20 mg in a dosage form weighting about 200 mg.
  • the superdisintegrant is PVP K25.
  • the PVP K25 is in an amount of between 1 wt% and 5 wt% out of the total weight of the solid dosage form, or between 1 mg and 20 mg in a dosage form weighting between about 100 mg and about 500 mg, preferably about 200 mg.
  • disintegrants/superdisintegrants are mainly of three types:
  • the incorporation of superdisintegrant is intra- and extra- granularly.
  • the solid dosage form described herein also comprises, in accordance with some examples, at least one sweetener.
  • the amount of the sweetener may vary depending on the type of sweetener used.
  • the sweetener is a naturally occurring sweetener, a modified sugar or a sugar alcohol, for example, a saccharide-based sweetener.
  • sugar based sweeteners that can be used in a dosage form according to the present disclosure include fructose, xylitol, trehalose, sucrose, lactose, maltose, galactose, dextrose (glucose), erythritol from natural sweeteners (e.g., maple syrup, honey, stevia, molasses, coconut sugar, date sugar, agave nectar, xylitol)
  • the sweetener is an artificial sweetener.
  • artificial sweeteners include mannitol, aspartame, maltitol, saccharin, acesulfame, neotame, adventame, alitame, cyclamate, sucralose.
  • the dosage form disclosed herein may include a single sweetener or a mixture of two or more sweeteners (be it a natural sweetener, a modified sweetener, a sugar alcohol and/or artificial sweetener).
  • the total amount of the sweetener is in the range of between 5 wt% and 50 wt%, at times between 10 wt% and 50 wt%, between 10 wt% and 50 wt%, or between 5 wt% and 40 wt%, and any individual values or subranges therebetween.
  • the solid dosage form comprises at least sucralose.
  • the dosage form when it comprises sucralose, it may be present in an amount of between 0.1 wt% and 10 wt%, at times between 0.1 wt% and 5 wt%, between 1 wt% and 15 wt%, or between 1 wt% and 2 wt%, and any individual values or subranges therebetween.
  • sucralose may be present in an amount of between 1 mg and 30 mg, for example, in an amount of from 1 mg to 10 mg, or from 2 mg and 5 mg.
  • the solid dosage form comprises at least mannitol. In some embodiments, when the dosage form comprises mannitol, it may be present in an amount of between 0.1 wt% and 75 wt%, at times between 1 wt% and 5 wt%, between 5 wt% and 12 wt%, between 10 wt% and 75 wt%, between 10 wt% and 50 wt%, or between 20 wt% and 75 wt%, and any individual values or subranges therebetween.
  • mannitol may be present in an amount of between 0.1 mg and 150 mg, for example, an amount of 10 mg to 120 mg, further at times in an amount of between 20 mg and 110 mg.
  • the sweetener comprises a mixture of sweeteners, such as a combination of two or more sweeteners from the group of sucralose, mannitol, aspartame (e.g., in an amount of about 40 mg, or up to 20 wt%), maltitol (e.g., in an amount of about 200 mg, or up to 95 wt%), saccharin (e.g., in an amount of about 7.5 mg, or up to 5 wt%), dextrose (e.g.
  • a mixture of sweeteners such as a combination of two or more sweeteners from the group of sucralose, mannitol, aspartame (e.g., in an amount of about 40 mg, or up to 20 wt%), maltitol (e.g., in an amount of about 200 mg, or up to 95 wt%), saccharin (e.g., in an amount of about 7.5 mg, or up to 5 wt%), dextrose (e.
  • acesulfame e.g., in an amount of about 10 mg, or up to 5 wt%)
  • sorbitol e.g., in an amount of about 150 mg, or up to 75 wt%
  • fructose e.g., in an amount of about 150 mg, or up to 75 wt%)
  • the dosage form disclosed herein may be characterized by its hardness/firmness (friability).
  • the solid dosage form disclosed herein may be characterized by hardness using any hardness tester (like Erweka hardness tester (e.g., TBH 325), Electro lab hardness tester, Monsanto hardness tester) being greater than > 30 N, at times, between 40 N and 65 N (i.e., the tablets should be resistance to breakage under storage conditions).
  • any hardness tester like Erweka hardness tester (e.g., TBH 325), Electro lab hardness tester, Monsanto hardness tester) being greater than > 30 N, at times, between 40 N and 65 N (i.e., the tablets should be resistance to breakage under storage conditions).
  • the solid dosage form disclosed herein may be characterized by disintegration rate.
  • An aim of the present disclosure is to provide a dosage form that does not rapidly disintegrate. In other words, it is desired that the solid dosage form remains at least partially intact within the first 60 seconds and yet fully disintegrate after about 250 seconds.
  • the solid dosage form disclosed herein reaches full disintegration in a time period of between 60 seconds and 240 seconds, for example, between 60 seconds and 120 seconds, between 100 seconds and 200 seconds, between 120 seconds and 200 seconds, between 120 seconds and 180 seconds, or between 200 seconds and 240 seconds.
  • full disintegration may be determined by placing the solid dosage form within water and measuring the time until the dosage form is at least visually, completely dissolved (disappears).
  • full disintegration is determined by known techniques, as described, for example, by the United States Pharmacopeial Convention (Disintegration August 1, 2008)
  • the present disclosure relates to processes for manufacturing of contemplated tablets described herein.
  • Embodiments herein relate to a method for preparing the solid dosage form, the method comprises at least the following steps:
  • the cannabinoids comprise at least one of cannabidiol (CBD) and/or tetrahydrocannabinol (THC) to obtain cannabinoids granules;
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • wet granulation is a well-known technique and is generally used to form agglomerates of a certain particle size from single powder ingredients. Processes like wet granulation are used in order to achieve a homogenous and compressible "mixture" of the single components of a solid oral dosage form.
  • wet granulation involves wetting of powder ingredients with a volatile solvent typically carrying the active pharmaceutical ingredient (API).
  • a suitable sieve e.g. 1 mm
  • dried by removing the volatile solvent to obtain dried granules
  • the dried granules are screened through the same or different sieve.
  • the granules may be subjected to one or more milling stages, before and/or after removal of the solvent.
  • the particulate matter may comprise any material commonly used in solid dosage forms, e.g., in tablets.
  • the particulate matter is selected from filler material, bulking agent, glidant, binder material, lubricants, disintegrants, superdisintegrant and any combination of same.
  • the particulate matter comprises at least a glidant.
  • Glidants are typically used to improve the flow of powders during tablets manufacturing by reducing friction and adhesion between particles.
  • the glidant comprises silica.
  • silicon encompasses materials that contain silicon dioxide including, but not limited to, amorphous silica, hydrated silicon dioxide, fumed silica, silica gel, colloidal silicon dioxide, magnesium aluminum silicate, magnesium silicate, calcium silicate, and/or mixtures thereof.
  • the glidant is colloidal silica.
  • colloidal silica includes products having the brand names ZEOPHARM® 5170, AEROSIL® 200, CAB-O- SIL® MP5, AEROPERL® 300, SYLOID® 244FP, SYLOID® 63FP, SYLOID® 72 FP, SIPERNAT® 160PQ, SIPERNAT® 50, SIPERNAT® 50S, SYLOID® 3050, SYLOID® 3150, SIPERNAT® 500LS, SIPERNAT® 2200, SIDENT® 8, SIDENT® 9, SIDENT® 10, or SIDENT® 22S, all being commercially available products, e.g. from Evonik Resource Efficiency GmbH, BL Silica.
  • the colloidal silica can be defined by their surface area.
  • AEROSIL® 200 (CAS No. 112 945-52-5 or 7631-86-9) is a hydrophilic fumed silica with a specific surface area of 175 - 225 m 2 /g or about 200 m 2 /g
  • AEROSIL® 300 is a hydrophilic fumed silica with a specific surface area of 275 - 325 m 2 /g or about 300 m 2 /g
  • AEROSIL® R972 (CAS-No. 68 611 44 9) has a specific surface area of 90 - 130 m 2 /g.
  • the colloidal silica can be defined by the treatment it received, for example, AEROSIL® 972 is a fumed silica after being treated with dimethyldichloro silane (DDS) or AEROSIL® 202 is fumed silica after treatment with polydimethylsiloxane.
  • DDS dimethyldichloro silane
  • AEROSIL® 202 is fumed silica after treatment with polydimethylsiloxane.
  • the particulate matter may also comprise a sweetener, as defined hereinabove.
  • the wet cannabinoid granules are free of organic acids (i.e., no organic acid added).
  • the particulate matter is brought into contact with a solvent solution of cannabinoids to obtain the cannabinoids granules.
  • the solvent(s) is a pharmaceutically acceptable organic solvent that vaporizes at room temperature (> 40 ⁇ 5 hPa).
  • the solvent is a pharmaceutically acceptable organic solvent.
  • the organic solvent is a hydrophilic organic solvent.
  • the solvent is an alcohol
  • the solvent is selected from methanol, ethanol, 1 -propanol, or acetic acid.
  • the solvent is ethanol.
  • the concentration of the at least one cannabinoid in the extract is between about 1 %w/v to 60 %w/v, for example, 5 %w/v, 8 %w/v 10 %w/v, 15 %w/v, 20 %w/v, 25 %w/v, 30 %w/v, 35 %w/v, 40 %w/v, 45 %w/v, 50 %w/v or 55 %w/v, and any value therebetween.
  • Cannabinoid extracts e.g., alcoholic extract of cannabinoids and particularly ethanolic extract can be prepared or obtained commercially. Such solutions are available, for example, from Panaxia (Israel).
  • the wet cannabinoid granules are free of organic acids.
  • the wet cannabinoid granules obtained can be subjected to milling or sieving to obtain granules of a desired size, and then the solvent is removed.
  • Removal of the solvent may be by any means of evaporation. Typically, but not exclusively, removal of the solvent is by heating the wet mass at moderate temperatures, e.g., of not more than 80°C. In some examples, heating is at a temperature of at least 20°C, at times between 40°C and 60°C, or at a temperature of about 50°C ⁇ 5°C.
  • Heating can be for minutes or hours, as can be determined by the practitioner, for example, based on the type of solvent used. Removal of the solvent results in dry granules.
  • dry granules or “dried granules” it is to be understood as granules comprising not more than 5 wt% remaining solvent, for example, not more than 4 wt%, 3 wt%, 2 wt% or even not more than 1 wt% of the solvent.
  • dry granules refer to granules with only trace amount or no traceable amount of the solvent.
  • the dried granules are then mixed with a carrier material to form the formulation mixture which will then be compressed onto the solid dosage form.
  • the carrier material comprises at least one organic acid, as defined hereinabove.
  • the carrier material may comprise other excipients.
  • the carrier material may comprise in addition to the at least one organic acid, at least one of a bulking agent (filler), a lubricant, a binder, a disintegrant, a superdisintegrant (as defined above), a sweetener (as defined above), lubricant, a diluent, bile salts, azones, surfactants, complexing agents, co-solvents, terpenes, an antioxidant (e.g. vitamin E, cysteine) and/or a penetration enhancer, each constituting a separate embodiment of the present disclosure.
  • buccal penetration enhancement typically results from agents being able to (a) increase the partitioning of drugs into the buccal epithelium; (b) extract (and not disrupt) intercellular lipids; (c) interact with epithelial protein domains; and/or (d) increase the retention of drugs at the buccal mucosal surface.
  • the penetration enhancer must be safe and effective, pharmacologically inactive and chemically inert. Exemplary penetration enhancers and other excipients employed in buccal delivery formulation are disclosed, e.g., in:
  • Non-limiting examples for penetration enhancers include fatty acids, salts and esters thereof as well as fatty acid alcohols.
  • diluents are used to provide bulk, and these may include lactose, dextrin, glucose, sucrose, sorbitol or inorganic compounds such as calcium and magnesium salts, sodium or potassium chloride;
  • binders also known as compression aids
  • these may include natural or synthetic polymers, such as starches, sugars, sugar alcohols, and cellulose derivatives; and
  • lubricants are used for slowing disintegration and dissolutions, and these may include stearic acid and its salts (e.g. magnesium stearate).
  • the carrier material comprises a mixture of two or more organic acids, a sweetener, a superdisintegrant, a lubricant and a binder.
  • the carrier material also comprises an antioxidant.
  • the amounts of dried granules and of the carrier material may vary depending on the desired eventual weight of the solid dosage form and/or the desired amount of the cannabinoids in a single unit of the solid dosage form.
  • the mixing of the dried granules and the carrier material is such as to provide a total weight of the solid dosage form of between 10 mg and 1,000 mg, for example, between 100 mg and 500 mg, at times, between 150 mg and 250 mg, or about 200 mg.
  • the mixing of the dried granules and the carrier material is such as to provide a total cannabinoid weight of between 1 mg and 100 mg, at times, between 2.5 mg and 40 mg, between 2.5 mg and 5 mg, between 5 mg and 10 mg, between 5 mg and 20 mg, between 20 mg and 55 mg, or between 25 mg and 80 mg, per unit of the solid dosage form and any subranges and individual values therebetween.
  • This formulation mixture comprises all ingredients of the final solid dosage form, and is subjected to processing, including compression into a dosage form, using any of the compression techniques known to those versed in the art.
  • tablets contemplated herein are produced by a direct compression technique as known to those versed in the art. From the term “direct compression”, this method can be defined as basically mixing and processing of formulation ingredients then compressing into tablets. The tablets are obtained directly from the powder API or other excipients. This technique affords reduction in units of operation, less machinery involvement and minimized processing time.
  • Tablet manufacturing by direct compression offers advantages over the other manufacturing processes for tablets, such as wet granulation, and provides high efficiency as direct compression is more economic, reducing the cycle time and straight forward in terms of good manufacturing practice requirements.
  • Direct compression overcomes certain limitations imposed by thermolability and moisture sensitivity of the active. For example, tablets produced by direct compression method give lower microbial levels than those prepared by the wet granulation method. The compaction process exerts lethal effect on the survival of microorganisms.
  • the tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with the dissolution fluid and exhibit a comparatively faster dissolution. Thus, tablets prepared by the direct compression method are less suitable for sustained drug release protocols.
  • Manufacturing of tablets using direct compression method involves processes that can be condensed to three. The order of following these processes first involves using induced die feeders, dry binders and lastly by using direct compression excipients.
  • a special feeding device is used that prevents segregation and complements the powders to flow down the die cavity of the tablet compression machine from the hopper.
  • Employing the induced die feeder usually minimizes entrapment of air thereby increasing the density of the filling powder and its susceptibility to compaction.
  • Microcrystalline cellulose and polyethylene glycol are some examples of dry binders that are commonly used to manufacture tablets using the direct compression technique.
  • the functional components which are to be compressed in the formulation mix must exhibit good flowability and compressibility.
  • Flowability and compressibility factors are increasingly important when the amount of functional excipient in the formulation is reduced, e.g., due to a required high drug load, or the API itself demonstrates poor flowability and/or compressibility.
  • the formulation mixture is compressed in a conventional tablet pressing apparatus employing a compression force of, for example, about 20 - 28 kN to form the desired solid oral dosage forms for administration to the oral cavity.
  • the solid dosage form is designed to release the cannabinoids within the oral cavity, at a controlled release mode, which may be a slow release mode or a rapid release mode. To this end, the solid dosage form is placed and held within the oral cavity.
  • the solid dosage form is a tablet and delivery of the tablet comprises placing the tablet within the buccal region.
  • the solid dosage form is a tablet and delivery of the tablet comprises placing the tablet in the sublingual region and leaving it undisturbed until it at least partially, and preferably fully, disintegrates.
  • the dosage form is held within the selected region for a time sufficient to allow release of at least part of the cannabinoids to the oral cavity and leaving it undisturbed until it at least partially, and preferably fully disintegrates.
  • the holding is for at least 60 seconds, at least 80 seconds, at least 100 seconds, at least 120 seconds, at least 140 seconds, at least 160, or at least 180 seconds.
  • the holding is for a time period of between 60 seconds and 240 seconds or any subrange between 60 seconds and 240 seconds.
  • the present disclosure relates to methods of treatment of diseases, conditions or disorders, comprising orally administering to a subject in need thereof a solid dosage form as disclosed herein, wherein the solid dosage form is held within a subject’s oral cavity to allow it to disintegrates within the oral cavity.
  • a contemplated method of treatment may be for various diseases, disorders and/or conditions for which cannabinoids have therapeutic properties.
  • Non-limiting examples of such diseases and conditions include AIDS; neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS)); cancer and malignant tumors, which are often accompanied with a lack of appetite, nausea, and vomiting, chronic pain (especially neuropathic pain); spasticity (e.g., in multiple sclerosis and spinal cord injury); dystonia; and intractable pediatric epilepsy.
  • Other conditions treatable with the solid dosage form disclosed herein include oxidation- associated disease such as myocardial infarction, stroke (motor or sensory abnormalities), and cerebral infarct, or a neurovascular thromboembolic event.
  • Still other conditions treatable with the solid dosage form disclosed herein includes pain (e.g., neuropathic, nociceptive, chronic, acute), migraine, psychiatric indications (PTSD), neurological, and autoimmune diseases.
  • pain e.g., neuropathic, nociceptive, chronic, acute
  • migraine e.g., migraine, psychiatric indications (PTSD), neurological, and autoimmune diseases.
  • PTSD psychiatric indications
  • the solid dosage form is for treating cancer.
  • the solid dosage form is for treating metastatic cancer.
  • cancer and metastatic cancer include without being limited thereto, hematological cancer such as multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia and solid tumors.
  • the solid dosage form is for treating neurodegenerative diseases. Examples include, without being limited thereto, Alzheimer's diseases, Parkinson's disease, ALS and Huntington's disease. In some embodiments, the solid dosage form is for treating pain. Examples include, without being limited thereto, fibromyalgia, interstitial cystitis, low back pain.
  • the solid dosage form is for treating inflammation, such as colitis.
  • the solid dosage form is for treating autoimmune disorders.
  • autoimmune disorders include, without being limited thereto, psoriasis, Crohn’s, rheumatoid arthritis, lupus, multiple sclerosis (MS).
  • the solid dosage form is for treating psychiatric disorders.
  • examples include, without being limited thereto, posttraumatic stress disorder (PTSD), depression, nicotine/opioid addiction, and post- menopausal symptoms.
  • the solid dosage form can be administered in combination with other therapeutic drugs.
  • the amount and manner of treatment comprising administration of the solid dosage form according to the present disclosure is determined by a medical professional.
  • the term“about” refers to ⁇ 10%. It is understood by the skilled artisan, that use of the term “about” includes the range as stated, is within what is normally acceptable in the pharmaceutical industry.
  • the US Pharmacopeia allows a plus and minus range of 10 percent in the assay for the active ingredient in most solid dosage forms.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • THC/CBD oil extract was purchased from Canndoc Ltd.
  • THC/CBD ethanol extract was purchased from Panaxia.
  • Hardness was determined by conventional hardness tester (like Erweka hardness tester, Electro lab hardness tester, Monsanto hardness tester).
  • a disintegration test is one provided to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions presented below. Compliance with the limits on Disintegration stated in the individual monographs is required except where the label states that the tablets or capsules are intended for use as troches, or are to be chewed, or are designed as extended-release dosage forms or delayed-release dosage forms.
  • the type of units under test is determined from the labeling and from observation, and the appropriate procedure is applied to 6 or more dosage units. For the purposes of this test, disintegration does not imply complete solution of the unit or even of its active constituent.
  • Complete disintegration is defined as that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core.
  • the dissolution test was performed in water.
  • the tablets are aimed for use as buccal disintegrating tablets, their target dissolution rate is determined to be satisfactory if it is within a time period of between 60 seconds and 240 seconds, preferably, at least 120 seconds.
  • disintegration within less than 60 seconds is considered to be a too rapid (undesirable) disintegration rate and any disintegration above 240 seconds is considered to be a too slow (undesirable) disintegration.
  • THC/CBD tablets were prepared for exemplifying the present disclosure. For this purpose, the materials and methods detailed above were employed.
  • the active pharmaceutical ingredient was a canola oil extract of cannabis containing 40% THC and 10% CBD obtained from Canndoc Ltd. This API was diluted with ethanol to allow homogenous distribution of the API in the blend of ingredients as detailed in Table 1A below. After homogenous blending, the mixture was dried at 80°C and sieved through 1.2 mm screen sieves. Before wet granulation, the ethanol was evaporated.
  • wet granulation was needed to dispense the API equally with the rest of the ingredients.
  • the tableting included a first stage of wet granulation and a second stage of compression.
  • AEROSIL® colloidal silicon dioxide is known for use as a glidant to optimize the flow of powders.
  • AEROSIL® 200 or AEROSIL® R 972 were added for flowability.
  • AEROSIL® 200 is a hydrophilic fumed silica with specific surface area of 200 m 2 /g.
  • AEROSIL® R 972 is a fumed silica aftertreated with dimethyldichloro silane (DDS). Both are applicable as adhesives and used for improvement of free flow and anticaking characteristics of powders. In embodiments described herein, they are used as glidants.
  • DDS dimethyldichloro silane
  • silicon dioxide (silica)-based excipient serving as glidant/binder/ab sorbent used in embodiments described herein is a Parteck® SLC silica drug carrier, more particularly, the excipient Parteck® SLC 500.
  • Parteck® SLC has a surface structure that provides high loadability for APIs in oral dosage forms. Tableting was with an 8.5 mm or 7 mm punch, as indicated. Each tablet contained 10 mg THC and 2.5 mg CBD.
  • This orally disintegrating tablet had an unpleasant flavor and brittle with hardness of 20 N.
  • a hydrophobic binder was used instead of, or in addition to, mannitol.
  • a BenecelTM hydroxypropyl methylcellulose (HPMC) binder which is a water soluble, non-ionic cellulose ether.
  • BenecelTM HPMC binders also function as thickeners, water-binders, and co-suspending and co-emulsifying agents.
  • BenecelTM HPMC E5 (herein“Benecel E5”), is one of the most widely used hydrophilic matrix materials that can significantly affect the release kinetics of the API due to its high swellability.
  • Carnauba wax is a further binder used in preparation of contemplated tablets. This is a natural wax originating from the leaves of the Copernicia prunifera palm grown only in Brazil. Carnauba wax consists of fatty acid esters (80-85%), fatty alcohols (10-16%), acids (3-6%) and hydrocarbons (1-3%).
  • Tablet #1 Further modifications of Tablet #1 included use of sodium stearyl fumarate as the lubricant, which is more hydrophilic than magnesium stearate.
  • AEROSIL® 200 and AEROSIL® R 972 were added for flowability. The ingredients are summarized in Table IB: Table IB. Oil based Tablet #2 ingredients and characteristics
  • ETHOCELTM premium ethylcellulose polymers more particularly ETHOCELTM 100 PF, were used as binders.
  • ETHOCELTM polymers are water-insoluble polymers used in extended release solid dosage formulations, as taste-masking of bitter actives, extended release binder in inert matrix systems and as solvent and extrusion granulation.
  • Ethanol based Tablet #4 is exemplified in Table 2: Table 2. Ethanol based Tablet #4 ingredients and characteristics
  • This hydrophilic tablet had all targeted properties including good hardness and firmness (lacked the brittleness of Tablets #1, #2 and #3), however had a rapid disintegration rate and a bitter taste.
  • a tablet comprising the ethanol without cannabinoids was then prepared, the ingredients being detailed in Table 3A (Tablet #5). Notably, there was no need in wet granulation separate phase. Ethanol was added to all the ingredients, the mass was dried, milled and compressed.
  • Ethanolic extract of cannabis (THC/CBD 10 mg/10 mg) was purchased from Panaxia. This solution was much more diluted than the THC/CBD 40/10 %w/v (20% of solids in solution vs 50% of solids).
  • mannitol and silicon dioxide were increased in the ethanolic APIs phase.
  • more croscarmellose sodium and PVP K25 were added to enhance the disintegration.
  • Further cannabinoids from the ethanol extract were also added.
  • Table 4A summarizes the ingredients and characteristics of the resulting Tablet.
  • This formulation had good disintegration properties (fully disintegrated in water within 2-3 min) and was sufficiently hard.
  • the compression punch was changed to a 9 mm (instead of the 7 mm) to provide a thinner tablet, which indeed increased disintegration.

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Abstract

L'invention concerne une forme posologique solide pour la libération de cannabinoïdes dans la cavité buccale, la forme posologique solide comprenant un mélange d'au moins un cannabinoïde, par exemple, le cannabidiol (CBD) et/ou le tétrahydrocannabinol (THC), et au moins un acide organique. La forme posologique solide a un taux de désintégration suffisant pour permettre l'absorption buccale ou sublinguale des cannabinoïdes libérés. L'invention concerne également un procédé de préparation d'une forme posologique solide, par exemple, un comprimé.
PCT/IB2020/052334 2019-03-13 2020-03-13 Formes posologiques pour administration orale de cannabinoïdes, procédé de préparation et utilisations de celles-ci WO2020183436A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023250274A1 (fr) * 2022-06-22 2023-12-28 Ilera Therapeutics Llc Matrice de capture et de dissolution améliorée pour cannabinoïdes et leurs procédés de fabrication

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US8980940B2 (en) * 2006-11-10 2015-03-17 Johnson Matthey Public Limited Company Stable cannabinoid compositions and methods for making and storing them
US20150132400A1 (en) * 2012-05-07 2015-05-14 Echo Pharmaceuticals B.V. Granulate containing cannabinoid, method for its manufacture and oral dosage unit comprising such granulate
WO2016014454A1 (fr) * 2014-07-21 2016-01-28 Pharmaceutical Productions, Inc. Composition de forme galénique solide pour une administration par voie buccale ou sublinguale de cannabinoïdes
WO2018211388A1 (fr) * 2017-05-13 2018-11-22 Alvit Lcs Pharma Ltd. Compositions de cannabinoïdes sublinguales

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Publication number Priority date Publication date Assignee Title
US8980940B2 (en) * 2006-11-10 2015-03-17 Johnson Matthey Public Limited Company Stable cannabinoid compositions and methods for making and storing them
US20150132400A1 (en) * 2012-05-07 2015-05-14 Echo Pharmaceuticals B.V. Granulate containing cannabinoid, method for its manufacture and oral dosage unit comprising such granulate
WO2016014454A1 (fr) * 2014-07-21 2016-01-28 Pharmaceutical Productions, Inc. Composition de forme galénique solide pour une administration par voie buccale ou sublinguale de cannabinoïdes
WO2018211388A1 (fr) * 2017-05-13 2018-11-22 Alvit Lcs Pharma Ltd. Compositions de cannabinoïdes sublinguales

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023250274A1 (fr) * 2022-06-22 2023-12-28 Ilera Therapeutics Llc Matrice de capture et de dissolution améliorée pour cannabinoïdes et leurs procédés de fabrication

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