WO2022013854A1 - Oral cannabinoid compositions - Google Patents

Oral cannabinoid compositions Download PDF

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Publication number
WO2022013854A1
WO2022013854A1 PCT/IL2021/050788 IL2021050788W WO2022013854A1 WO 2022013854 A1 WO2022013854 A1 WO 2022013854A1 IL 2021050788 W IL2021050788 W IL 2021050788W WO 2022013854 A1 WO2022013854 A1 WO 2022013854A1
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Prior art keywords
composition according
composition
amount
cannabinoid
compositions
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PCT/IL2021/050788
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French (fr)
Inventor
Hadel ONALLAH SAAD
Shimon Amselem
Esmira Naftali
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Cannassure Ltd.
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Publication of WO2022013854A1 publication Critical patent/WO2022013854A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • 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
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/40—Cyclodextrins; Derivatives 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • compositions for oral administration comprising at least one cannabinoid.
  • Cannabis is a genus of plants comprising the species Cannabis sativa, C. indica, and C. ruderalis. Cannabis plants have been cultivated for a variety of uses including making fibers (hemp), medicinal use and recreational drug use. Cannabis is also commonly known as marijuana.
  • Cannabis is used for medicinal use in many countries (also known as medical marijuana) is through smoking.
  • Smoking cannabis is typically performed by using a pipe, by using a water-pipe (also known as a bong) which filters the smoke through water before inhalation or by rolling in paper to form marijuana cigarettes, also known colloquially as "joints.”
  • the part of the plant typically used for smoking is the whole flower and budding leaf.
  • CBD cannabidiolic acid
  • CBD cannabidiolic acid
  • Cannabinoid a compound having a cannabinoid structure.
  • a phytocannabinoid may be produced synthetically, for example, through a chemical synthetic process or by using a biological organism such as a yeast or a bacteria modified to produce the cannabinoid.
  • a cannabinoid may originate from a cannabis plant.
  • a cannabinoid may be isolated, in pure form, or in combination with other cannabinoids.
  • Cannabis a plant from the family Cannabaceae, optionally cannabis sativa, indica and ruderalis and fiber-type hemp.
  • a plant comprising a cannabinoid Preferably a plant comprising a cannabinoid.
  • Cannabis oil A concentrated cannabis plant extract prepared using cannabis inflorescence extracted using a solvent (preferably alcohol, most preferably ethanol). After extraction, the solvent is removed, for example, by evaporation, leaving behind an oil.
  • a solvent preferably alcohol, most preferably ethanol.
  • the oil is high in cannabinoids, having over 50% cannabinoids preferably between 50% and 90%, and low in residual solvent, preferably lower than 500 ppm.
  • Cannabis oil may further comprise at least one terpene.
  • CBD cannabidiol.
  • Sulfobutylether beta cyclodextrin A macrocyclic ring of 7 glucose subunits.
  • the Sulfobutylether beta cyclodextrin sodium salt has the following structure: wherein R(la-f), R(2a-f), R(3a-f) is independently -OH or -0-CH2 -CH2 -CH2 -CH2 -S03Na.
  • the average number of -0-CH2 -CH2 -CH2 -CH2 -S03Na substitutions per cyclodextrin molecule is between 6 and 7, preferably 6.5.
  • THC tetrahydrocannabinol.
  • a cannabinoid having the structure:
  • Vitamin E TPGS also known as d-a-tocopherol polyethylene glycol 1000 succinate. It is a water-soluble derivative of the natural form of vitamin E, d-a-tocopherol. It is produced by the esterification of crystalline d-a-tocopheryl succinate by polyethylene glycol 1000. Used as an emulsifier. It has an amphiphilic molecular structure with a polar hydrophilic head (consisting of polyethylene glycol) and a non-polar lipophilic tail (consisting of the phytyl chain of d-a- tocopherol). This makes it soluble in both water and oil.
  • the chemical structure of Vitamin E TPGS is: wherein n is about 22.5.
  • compositions comprising at least one cannabinoid and having enhanced physical and biological characteristics when compared to known cannabinoid compositions.
  • the cannabinoid used is a phyto-cannabinoid.
  • it is a phyto- cannabinoid present in cannabis plant.
  • the cannabinoid may be plant extract.
  • the cannabinoid is CBD or THC.
  • the THC may be delta9-THC or delta8-THC.
  • cannabinoids which can be used in compositions described herein include but are not limited to one or a combination of: cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenic acid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCVA), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C (CBN-C4), cannabinol C2 (CBN-C2), cannabinol Ci (CBN-Ci), cannabinodiol (CBND), cannabinovarinic acid (CBNVA), cannabinovarin (CB
  • Plant inflorescence rich in a specific cannabinoid may be used.
  • inflorescence having high levels of CBD may be used to form extracts with high levels of CBD.
  • plant inflorescence high levels of THC may be used to form extracts with high levels of THC.
  • Various extracts having various ratios of cannabinoids may be used to form compositions described herein.
  • the composition may be administered in the form of a dosage form.
  • the dosage form is selected from the group consisting of a soft gelatin capsule, a hard gelatin capsule, an oral fluid, a semifluid, a semi-solid, on oral liquid suspension, an oral dispersions, an oral gel, an oral spray, a sublingual spray, a candy, and a gummy.
  • a capsule may be prepared having an enteric coating which can be formulated for extended release or delayed release.
  • An oral capsule may be prepared by using the compositions such as those described in the examples. To formulate the compositions that are semi-solid, they may be heated to form a flowable liquid, and capsules may then be filled, and then sealed.
  • compositions described herein comprise high concentrations of cannabis oil.
  • concentration (by weight) of cannabis oil in the compositions is 50% or above. Preferably it is 54.5%.
  • compositions described herein comprise sulfobutylether beta cyclodextrin (SBEpCD).
  • SBEpCD sulfobutylether beta cyclodextrin
  • SBEpCD in an amount (by weight) of between 5% and 10%.
  • compositions described herein comprise Vitamin E TPGS in an amount (by weight) between 15% and 20%.
  • Vitamin E TPGS is present in an amount of 18%.
  • Compositions according to an embodiment may further comprise water.
  • the water may be present in an amount of up to 20%, preferably between 10% and 20%.
  • Compositions according to an embodiment may further comprise propylene glycol, in an amount of between 5% and 10%.
  • compositions described herein may be made using the following method: A solution of SBEpCD in water is prepared, preferably at a concentration of 30% SBEpCD by weight. Cannabis oil, and Vitamin E-TPGS, are co-melted, optionally, at 60°C and stirred. Optionally, propylene glycol is added to the cannabis oil and Vitamin E-TPGS mixture. Cyclodextrin solution is combined with the cannabis oil and Vitamin E-TPGS mixture, and stirred further, and optionally homogenized. The mixtures are then encapsulated.
  • Novel compositions described herein are advantageous relative to other cannabis oil- based compositions in that they are dispersible in aqueous solutions and are expected to have an enhanced pharmacokinetic profile, enhanced bioavailability, increased C max , shorter t max , higher AUC in comparison to known cannabis oil-containing compositions. In addition, they are advantageous in that more than 50% cannabis oil, and/or more than 50% cannabinoid, and can be included in compositions which are stable and dispersible.
  • Some embodiments relate to methods for treating a disease comprising administering to a patient in need thereof, a therapeutically effective amount of a composition comprising a at least one cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS.
  • the therapeutically effective amount may be an amount, which upon administration to a patient, ameliorates a symptom associated with the disease or modifies the level of a biological marker associated with the disease in the patient.
  • the disease is selected from the group consisting of: post trauma syndrome disorder (PTSD), anxiety, depression, psychosis syndromes, autism, Alzheimer's disease, Parkinson disease, inflammation , spasticity and muscle tension, pain, epilepsy, stroke, traumatic brain injury, bronchial disorders, cancer, drug abuse, Huntington's disease, Dystonia, Amyotrophic lateral sclerosis (ALS), Tourette syndrome, Myasthenia gravis, sleep disorders, skin related syndromes and inflammatory bowel disease, cachexia, nausea, vomiting, endometriosis, and rheumatic arthritis.
  • PTSD post trauma syndrome disorder
  • anxiety anxiety
  • depression psychosis syndromes
  • autism Alzheimer's disease
  • Parkinson disease Parkinson disease
  • inflammation spasticity and muscle tension
  • pain epilepsy
  • stroke traumatic brain injury
  • bronchial disorders cancer
  • drug abuse Huntington's disease
  • Dystonia Dystonia
  • Tourette syndrome Myasthenia gravis
  • sleep disorders
  • the method of treatment comprises treating a patient in need thereof with a cannabinoid, optionally, THC or CBD.
  • a cannabinoid optionally, THC or CBD.
  • the amount of THC is optionally between 0.1 and 25 mg per dose, 1 to 10 mg per dose, or 1 to 5 mg per dose.
  • the amount of CBD is optionally between 0.1-500 mg/dose, 1-10 mg per dose, 10-25 mg per dose, 15-50 mg per dose, 100-500 mg per dose, 200-500 mg per dose, or 400-500 mg per dose.
  • a dose may be administered once daily, twice daily, three times daily, or four times daily. Alternatively the dose may be administered between 1 and 3 times weekly.
  • the method for administration is through an oral route (per- os).
  • Cannabis oil was prepared from dried cannabis inflorescence using ethanolic extraction followed by evaporation of the ethanol to achieve a brown sticky extract containing primarily 90% ⁇ API ⁇ 50% of either THC or CBD, and ⁇ 1.5% of CBN. Trace amounts of additional cannabinoids can be found at ⁇ 5%.
  • Example 2A Preparation of Cannabis Oil-based Compositions with Cyclodextrins and TPGS for Oral Delivery
  • compositions were prepared using excipients, in the amounts disclosed in Table 1. Table 1:
  • Vitamin E-TPGS (abbreviated in table as TPGS, obtained from Antares Health Products Inc., Jonesborough Tennessee, USA) was used in many of the compositions, as was a cyclodextrin (CD, obtained from Cylcolab, Budapest, Hungary).
  • the CD used was either sulfobutylether beta cyclodextrin (SBEpCD), gamma- cyclodextrin (g- CD), or hydroxypropyl beta- cyclodextrin (HRb-CD).
  • SBEpCD sulfobutylether beta cyclodextrin
  • g- CD gamma- cyclodextrin
  • HRb-CD hydroxypropyl beta- cyclodextrin
  • compositions were prepared using the following general method:
  • TPGS and cannabis oil extract and propylene glycol were co-melted for 2 hours at 60°C on a hot plate while stirring.
  • Cyclodextrin solutions having 30% cyclodextrin were prepared by stirring water with cyclodextrin at room temperature for 3 hours. The cyclodextrin solution was then added to the TPGS and cannabis extract mixture. Stirring proceeded for an additional 2 hours.
  • a Heidolph homogenizer (Diax 100) was used for a few pulses to homogenize the mixtures in compositions 6-12.
  • compositions 1-4, 6, 8, 10 and 12 were turbid upon preparation.
  • compositions may be prepared using pure, synthetic or biosynthetic cannabinoids as described in this example, by substituting the cannabinoid in place of cannabis oil.
  • cannabinoids which may be used are CBD, THC, or combinations thereof.
  • Example 2B Stability of SBEpCD and TPGS Based Cannabis Oil Compositions
  • compositions prepared in Example 2A were maintained at room temperature in closed containers for one week. After one week they were checked to determine phase separation, precipitation of solids and color change. None of the compositions changed color, but phase separation and/or precipitation were present in a number of compositions, as detailed in Table 2 below. Phase separation were visually determined and graded on a scale of 0 to 5, with 0 being no phase separation/ precipitation, 1 being slight phase separation/ precipitation and 5 being total phase separation/ precipitation.
  • Table 2 The two most stable compositions which maintained a thick, creamy, fluid semi-solid consistency showed no phase separation and no precipitation were compositions 6 and 12. They were maintained at the same conditions and analyzed again at 2 weeks, 1 month and 2 months from preparation, and all were found to maintain the same texture with no phase separation and no precipitation at all time points.
  • Example 2C Water Dispersion of SBEpCD and TPGS Based Cannabis Oil Compositions
  • Cannabis oil-based compositions with RH40 and/or with RAMEBCD were prepared using the excipients described in Table 3 below.
  • compositions in Table 3 are in grams.
  • the cyclodextrins (where applicable) were added in form of a solution prepared with water, having 30% cyclodextrin.
  • the amounts in table 3 refer to weight of cyclodextrin solution.
  • water was added in the amounts listed in the column entitled “water”.
  • Compositions in Table 3 were prepared using the following general method:
  • TPGS, or RH40 and cannabis oil extract were co-melted for 2 hours at 60°C on a hot plate while stirring.
  • Cyclodextrin solutions having 30% cyclodextrin were prepared by stirring water with cyclodextrin at room temperature for 3 hours. The cyclodextrin solution was then added to the TPGS and cannabis extract mixture or to the RH40 and cannabis extract mixture. Stirring proceeded for an additional 2 hours.
  • a Heidolph homogenizer (Diax 100) was used for a few pulses to homogenize the mixtures. All compositions were turbid upon preparation.
  • compositions 13, 14, 15 and 18 were maintained at room temperature in closed containers for one week. After one-week phase separation was evident in all of compositions 13, 14, 15 and 18.
  • This example illustrates the superiority of compositions comprising combinations of cannabis oil, SBEpCD and TPGS.
  • Composition 14 is identical to composition 6, with the modification that it uses RH40 instead of TPGS.
  • the combination of RH40 with SBEpCD in composition 14 was not effective in making a stable composition with cannabis oil, as evidenced by phase separation within one week of preparation.
  • Composition 18 is identical to composition 6, with the modification that it uses RAMEBCD instead of SBEpCD. Although used in the same amounts as SBEpCD, RAMEBCD was ineffective in composition 18, as evidenced by phase separation within one week of preparation.
  • Composition 15, which comprises RAMEBCD and RH40 in the same amounts as SBEpCD and TPGS respectively in composition 6 was similarly not stable as evidenced by phase separation within 1 week.
  • Gelatin or hydroxypropylmethyl (HPMC) capsules are filled with the compositions of the present invention by preheating the formulations to approximately 60 C to allow fluidity of the compositions during the filling into the lower part of the capsules with the desired amount of the compositions and active material using corresponding capsule size.
  • the capsules can be sealed with a gelatin spray to provide hermetic seal of the capsules.
  • the capsules can be filled using manual or automatic filling devices.
  • composition 33 precipitation of the composition was observed shortly after preparation.
  • Compositions 34 and 35 remained stable and no precipitation was evident after preparation. Without being bound by theory it is suggested that the low content of CD and TPGS in composition 33 contributed to its lack of stability.
  • Compositions 34 and 35 having CD concentration of 5% and TPGS concentration of between 10% and 20%, were more stable.
  • the addition of phospholipid and propylene glycol improved workability of compositions 34 and 35 while maintaining the stability.
  • compositions 34 and 35 were used to fill hard gelatin capsules by syringe. Capsules filled with composition 34 deformed shortly after formation, but composition 35 was stable in capsules, which maintained proper appearance. Although other capsule formulations have not been tested, it is probable that composition 34 can be used in other capsules, or other types of pharmaceutical compositions.
  • the composition further comprises water.
  • water is present in an amount between 10% and 20% of the composition, by weight.
  • the composition comprises 5-6% sulfobutylether beta cyclodextrin.
  • the composition comprises 8-9% sulfobutylether beta cyclodextrin.
  • the composition comprises 18-19% vitamin E TPGS.
  • the composition comprises 12-13% water, optionally 19-20% water.
  • the composition comprises propylene glycol in an amount between 5%-10% by weight.
  • the composition comprises one or more than one cannabinoid selected from the group consisting of: cannabidiol (CBD), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenic acid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCVA), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C4 (CBN- C4), cannabinol C2 (CBN-C2), cannabinol Cl (CBN-C1), cannabinodiol (CBND), can
  • the cannabinoid present in an amount of more than 50% of the cannabis oil is CBD.
  • the cannabinoid present in an amount of more than 50% of the cannabis oil is THC.
  • the cannabis oil is prepared by: extracting dried cannabis inflorescence in an alcohol, and removing the alcohol to form cannabis oil.
  • cannabis oil is present in an amount of greater than 25% by weight.
  • the composition further comprises a phospholipid.
  • the phospholipid is phosphatidylcholine.
  • the phosophatidylcholine is present in an amount of between 15% and 25% by weight.
  • the composition further comprises propylene glycol.
  • propylene glycol is present in an amount between 20% and 40% by weight.
  • the composition is for use in treating a disorder selected from the group consisting of: post trauma syndrome disorder (PTSD), anxiety, depression, psychosis syndromes, autism, Alzheimer's disease, Parkinson disease, inflammation , spasticity and muscle tension, pain, epilepsy, stroke, traumatic brain injury, bronchial disorders, cancer, drug abuse, Huntington's disease, Dystonia, Amyotrophic lateral sclerosis (ALS), Tourette syndrome, Myasthenia gravis, sleep disorders, skin related syndromes and inflammatory bowel disease, cachexia, nausea, vomiting, endometriosis, and rheumatic arthritis.
  • PTSD post trauma syndrome disorder
  • anxiety depression
  • psychosis syndromes autism
  • Alzheimer's disease Parkinson disease
  • inflammation spasticity and muscle tension
  • pain epilepsy
  • stroke traumatic brain injury
  • bronchial disorders cancer
  • drug abuse Huntington's disease
  • Dystonia Dystonia
  • Tourette syndrome Myasthenia gravis
  • compositions as described herein comprising admixing cannabis oil with Vitamin E-TPGS, while heating; and combining with an aqueous cyclodextrin solution.
  • the method further comprises homogenizing the mixture after combining.

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Abstract

Described herein are novel compositions comprising at least one cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS. These compositions are suitable for oral administration and have high concentrations of cannabinoids, while maintaining stability and favorable physical and biological characteristics. Also described herein are methods of treatment of diseases comprising administering to a patient in need thereof an oral composition comprising at least one cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS.

Description

ORAL CANNABINOID COMPOSITIONS
CROSS REFERENCE TO RELATED APPLICATIONS
Benefit is claimed to Israel Patent Application 276051 filed July 14, 2020; the content of which is incorporated by reference herein in its entirety.
FIELD
Provided herein are compositions for oral administration comprising at least one cannabinoid.
BACKGROUND
Cannabis is a genus of plants comprising the species Cannabis sativa, C. indica, and C. ruderalis. Cannabis plants have been cultivated for a variety of uses including making fibers (hemp), medicinal use and recreational drug use. Cannabis is also commonly known as marijuana.
One of the most common ways that cannabis is used for medicinal use in many countries (also known as medical marijuana) is through smoking. Smoking cannabis is typically performed by using a pipe, by using a water-pipe (also known as a bong) which filters the smoke through water before inhalation or by rolling in paper to form marijuana cigarettes, also known colloquially as "joints." The part of the plant typically used for smoking is the whole flower and budding leaf.
Cannabinoids are compounds active on cannabinoid receptors in humans. Cannabinoids of plant origin, also known as phyto-cannabinoids, are abundant in plants of the Cannabis genus. Two known cannabinoids which are present in relatively high concentrations in Cannabis sativa are tetrahydracannabinol-acid (THCA) or its decarboxylated product tetrahydracannabinol (THC) and cannabidiolic acid (CBDA) or its decarboxylated product cannabidiol (CBD). Psychoactive and other medical effects of many of the cannabinoids have been studied.
SUMMARY
Described herein are novel compositions comprising at least one cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS. These compositions are suitable for oral administration and have high concentrations of cannabinoids, while maintaining stability and favorable physical and biological characteristics. Also described herein are methods of treatment of diseases comprising administering to a patient in need thereof an oral composition comprising at least one cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS.
DETAILED DESCRIPTION
Terms
Unless otherwise noted, technical terms are used according to conventional usage. Definitions of common terms in molecular biology can be found in Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology , published by Blackwell Science Ltd., 1994 (ISBN 0-632- 02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).
Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. It is further to be understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides or peptides or proteins or portions or fractions thereof are approximate, and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term “comprises” means “includes.” The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.”
In case of conflict, the present specification, including explanations of terms, will control. In addition, all the materials, methods, and examples are illustrative and not intended to be limiting.
Cannabinoid: a compound having a cannabinoid structure. Preferably, a phytocannabinoid. A cannabinoid may be produced synthetically, for example, through a chemical synthetic process or by using a biological organism such as a yeast or a bacteria modified to produce the cannabinoid. Alternatively, a cannabinoid may originate from a cannabis plant. A cannabinoid may be isolated, in pure form, or in combination with other cannabinoids. Cannabis: a plant from the family Cannabaceae, optionally cannabis sativa, indica and ruderalis and fiber-type hemp. Preferably a plant comprising a cannabinoid.
Cannabis oil: A concentrated cannabis plant extract prepared using cannabis inflorescence extracted using a solvent (preferably alcohol, most preferably ethanol). After extraction, the solvent is removed, for example, by evaporation, leaving behind an oil. Preferably, the oil is high in cannabinoids, having over 50% cannabinoids preferably between 50% and 90%, and low in residual solvent, preferably lower than 500 ppm. Cannabis oil may further comprise at least one terpene.
CBD: cannabidiol. A cannabinoid having the structure:
Figure imgf000004_0001
Sulfobutylether beta cyclodextrin (SBEpCD): A macrocyclic ring of 7 glucose subunits. The Sulfobutylether beta cyclodextrin sodium salt has the following structure:
Figure imgf000004_0002
wherein R(la-f), R(2a-f), R(3a-f) is independently -OH or -0-CH2 -CH2 -CH2 -CH2 -S03Na. The average number of -0-CH2 -CH2 -CH2 -CH2 -S03Na substitutions per cyclodextrin molecule is between 6 and 7, preferably 6.5.
THC: tetrahydrocannabinol. A cannabinoid having the structure:
Figure imgf000005_0001
Vitamin E TPGS: also known as d-a-tocopherol polyethylene glycol 1000 succinate. It is a water-soluble derivative of the natural form of vitamin E, d-a-tocopherol. It is produced by the esterification of crystalline d-a-tocopheryl succinate by polyethylene glycol 1000. Used as an emulsifier. It has an amphiphilic molecular structure with a polar hydrophilic head (consisting of polyethylene glycol) and a non-polar lipophilic tail (consisting of the phytyl chain of d-a- tocopherol). This makes it soluble in both water and oil. The chemical structure of Vitamin E TPGS is:
Figure imgf000005_0002
wherein n is about 22.5.
II. Overview of Several Embodiments
As mentioned above, provided herein are compositions comprising at least one cannabinoid and having enhanced physical and biological characteristics when compared to known cannabinoid compositions. Preferably, the cannabinoid used is a phyto-cannabinoid. Preferably, it is a phyto- cannabinoid present in cannabis plant. The cannabinoid may be plant extract. Preferably the cannabinoid is CBD or THC. The THC may be delta9-THC or delta8-THC.
Other cannabinoids which can be used in compositions described herein include but are not limited to one or a combination of: cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenic acid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCVA), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C (CBN-C4), cannabinol C2 (CBN-C2), cannabinol Ci (CBN-Ci), cannabinodiol (CBND), cannabinovarinic acid (CBNVA), cannabinovarin (CBNV), cannabielsoin (CBE), cannabielsoic acid A (CBEA- A), Cannabielsoic acid B (CBEA-B), cannabicyclol (CBL), cannabicycloic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol (CBT), cannabitriolvarin (CBTV), ethoxy- cannabitriolvarin (CBTVE), cannabivarin (CBV), cannabinodivarin (CBVD), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabifuran (CBF), dehydrocannabifuran (DCBF), cannabirispol (CBR).
According to an embodiment, the composition comprises an oil prepared by extraction from the cannabis plant. The plant extract may be prepared from extracting dried cannabis inflorescence in an alcohol, preferably ethanol. The plant matter may then be removed, and the alcoholic solvent dried to form a plant extract. The plant extract may comprise between 50% and 90% by weight of cannabinoids.
Plant inflorescence rich in a specific cannabinoid may be used. For example, inflorescence having high levels of CBD may be used to form extracts with high levels of CBD. Alternatively, plant inflorescence high levels of THC may be used to form extracts with high levels of THC. Various extracts having various ratios of cannabinoids may be used to form compositions described herein.
The composition may be administered in the form of a dosage form. Optionally, the dosage form is selected from the group consisting of a soft gelatin capsule, a hard gelatin capsule, an oral fluid, a semifluid, a semi-solid, on oral liquid suspension, an oral dispersions, an oral gel, an oral spray, a sublingual spray, a candy, and a gummy.
Optionally, a capsule may be prepared having an enteric coating which can be formulated for extended release or delayed release. An oral capsule may be prepared by using the compositions such as those described in the examples. To formulate the compositions that are semi-solid, they may be heated to form a flowable liquid, and capsules may then be filled, and then sealed.
According to an embodiment, compositions described herein comprise high concentrations of cannabis oil. Optionally, the concentration (by weight) of cannabis oil in the compositions is 50% or above. Preferably it is 54.5%.
According to an embodiment, compositions described herein comprise sulfobutylether beta cyclodextrin (SBEpCD). Optionally SBEpCD in an amount (by weight) of between 5% and 10%.
According to an embodiment, compositions described herein comprise Vitamin E TPGS in an amount (by weight) between 15% and 20%. Preferably Vitamin E TPGS is present in an amount of 18%.
Compositions according to an embodiment may further comprise water. The water may be present in an amount of up to 20%, preferably between 10% and 20%.
Compositions according to an embodiment may further comprise propylene glycol, in an amount of between 5% and 10%.
Methods for manufacture:
Compositions described herein may be made using the following method: A solution of SBEpCD in water is prepared, preferably at a concentration of 30% SBEpCD by weight. Cannabis oil, and Vitamin E-TPGS, are co-melted, optionally, at 60°C and stirred. Optionally, propylene glycol is added to the cannabis oil and Vitamin E-TPGS mixture. Cyclodextrin solution is combined with the cannabis oil and Vitamin E-TPGS mixture, and stirred further, and optionally homogenized. The mixtures are then encapsulated.
Figure imgf000007_0001
Novel compositions described herein are advantageous relative to other cannabis oil- based compositions in that they are dispersible in aqueous solutions and are expected to have an enhanced pharmacokinetic profile, enhanced bioavailability, increased Cmax, shorter tmax, higher AUC in comparison to known cannabis oil-containing compositions. In addition, they are advantageous in that more than 50% cannabis oil, and/or more than 50% cannabinoid, and can be included in compositions which are stable and dispersible. Methods for Treatment:
Some embodiments relate to methods for treating a disease comprising administering to a patient in need thereof, a therapeutically effective amount of a composition comprising a at least one cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS. The therapeutically effective amount may be an amount, which upon administration to a patient, ameliorates a symptom associated with the disease or modifies the level of a biological marker associated with the disease in the patient.
According to an embodiment, the disease is selected from the group consisting of: post trauma syndrome disorder (PTSD), anxiety, depression, psychosis syndromes, autism, Alzheimer's disease, Parkinson disease, inflammation , spasticity and muscle tension, pain, epilepsy, stroke, traumatic brain injury, bronchial disorders, cancer, drug abuse, Huntington's disease, Dystonia, Amyotrophic lateral sclerosis (ALS), Tourette syndrome, Myasthenia gravis, sleep disorders, skin related syndromes and inflammatory bowel disease, cachexia, nausea, vomiting, endometriosis, and rheumatic arthritis.
According to an embodiment, the method of treatment comprises treating a patient in need thereof with a cannabinoid, optionally, THC or CBD. The amount of THC is optionally between 0.1 and 25 mg per dose, 1 to 10 mg per dose, or 1 to 5 mg per dose. The amount of CBD is optionally between 0.1-500 mg/dose, 1-10 mg per dose, 10-25 mg per dose, 15-50 mg per dose, 100-500 mg per dose, 200-500 mg per dose, or 400-500 mg per dose. A dose may be administered once daily, twice daily, three times daily, or four times daily. Alternatively the dose may be administered between 1 and 3 times weekly.
According to an embodiment, the method for administration is through an oral route (per- os).
The following examples are provided to illustrate certain particular features and/or embodiments. These examples should not be construed to limit the disclosure to the particular features or embodiments described.
EXAMPLES
Example 1: Preparation of Cannabis Oil
Cannabis oil was prepared from dried cannabis inflorescence using ethanolic extraction followed by evaporation of the ethanol to achieve a brown sticky extract containing primarily 90%<API <50% of either THC or CBD, and < 1.5% of CBN. Trace amounts of additional cannabinoids can be found at < 5%. Example 2A: Preparation of Cannabis Oil-based Compositions with Cyclodextrins and TPGS for Oral Delivery
Compositions were prepared using excipients, in the amounts disclosed in Table 1. Table 1:
Figure imgf000009_0001
Attempts were made to form liquid compositions in which cannabis oil was stable at high concentrations of greater than 25%. To achieve this, Vitamin E-TPGS (abbreviated in table as TPGS, obtained from Antares Health Products Inc., Jonesborough Tennessee, USA) was used in many of the compositions, as was a cyclodextrin (CD, obtained from Cylcolab, Budapest, Hungary). The CD used was either sulfobutylether beta cyclodextrin (SBEpCD), gamma- cyclodextrin (g- CD), or hydroxypropyl beta- cyclodextrin (HRb-CD). The amounts in each composition in Table 1 are in grams. The cyclodextrins (where applicable) were added in form of a solution prepared with water, having 30% cyclodextrin. The amounts in table 1 refer to weight of cyclodextrin solution. In the compositions without cyclodextrin, water was added in the amounts listed in the column entitled “water”.
Compositions were prepared using the following general method:
TPGS and cannabis oil extract and propylene glycol (abbreviated PG, where applicable) were co-melted for 2 hours at 60°C on a hot plate while stirring. Cyclodextrin solutions having 30% cyclodextrin were prepared by stirring water with cyclodextrin at room temperature for 3 hours. The cyclodextrin solution was then added to the TPGS and cannabis extract mixture. Stirring proceeded for an additional 2 hours. A Heidolph homogenizer (Diax 100) was used for a few pulses to homogenize the mixtures in compositions 6-12.
Compositions 1-4, 6, 8, 10 and 12 were turbid upon preparation. Similarly, compositions may be prepared using pure, synthetic or biosynthetic cannabinoids as described in this example, by substituting the cannabinoid in place of cannabis oil. Preferable cannabinoids which may be used are CBD, THC, or combinations thereof.
Example 2B: Stability of SBEpCD and TPGS Based Cannabis Oil Compositions
Compositions prepared in Example 2A were maintained at room temperature in closed containers for one week. After one week they were checked to determine phase separation, precipitation of solids and color change. None of the compositions changed color, but phase separation and/or precipitation were present in a number of compositions, as detailed in Table 2 below. Phase separation were visually determined and graded on a scale of 0 to 5, with 0 being no phase separation/ precipitation, 1 being slight phase separation/ precipitation and 5 being total phase separation/ precipitation.
Table 2:
Figure imgf000010_0001
The two most stable compositions which maintained a thick, creamy, fluid semi-solid consistency showed no phase separation and no precipitation were compositions 6 and 12. They were maintained at the same conditions and analyzed again at 2 weeks, 1 month and 2 months from preparation, and all were found to maintain the same texture with no phase separation and no precipitation at all time points.
Example 2C: Water Dispersion of SBEpCD and TPGS Based Cannabis Oil Compositions
Samples of compositions 6 and 12, each weighing 0.5 g, were weighted into a glass container to which 250 ml of water were added at 37°C. The water and the compositions were mixed for 20 minutes at low speed using a Heidolph homogenizer. Both samples demonstrated excellent water dispersion, and the water became very turbid.
As a control, 0.2725 g of cannabis oil (the amount of cannabis oil present in 0.5 g of composition 6 and composition 12) was added to a glass container to which 250 ml of water were added at 37°C, and were homogenized at the same conditions as described for the compositions 6 and 12. After homogenizing, the water remained clear, and the cannabis oil was visible as a separate phase.
This example illustrates that the combination of SBEpCD and TPGS acts as an emulsifier, making compositions 6 and 12 self-emulsify when contacting water. It appears that stable compositions can be prepared with both of these excipients, as compositions without CD (2 and 4) were shown not to be stable, as were compositions without TPGS (7, 9 and 11). Without being bound by theory, it is suggested that upon ingestion by a human patient, compositions 6 and 12 form micelles upon dilution with the gastric and intestinal fluids through self emulsification, which are then readily absorbed by the human, through oral administration. It is suggested that oral absorption in a human patient of compositions 6 and 12 is higher than oral absorption in a human patient to whom an equivalent amount of cannabis oil (formulated without SBEpCD and TPGS) is administered.
Compositions 8 and 10 are similar to composition 12, but composition 8 was prepared with g-CD while composition 10 was prepared with HRb-CD. Although SBEpCD is structurally similar to g-CD and to HRb-CD, surprisingly composition 12 had much greater stability than compositions 8 and 12. Out of all of the CD tested, only 8BEbOϋ (in combination with TPGS) was successful to make stable compositions having more than 50% cannabis oil. Example 3: Preparation of Cannabis Oil-based Compositions with Alternate Cyclodextrins and/or RH40 for Oral Delivery
Kolliphor® RH40 (RH40) is an excipient also known as polyoxyl castor oil, prepared from hydrogenated castor oil and ethylene oxide. RH40 is used as a non-ionic oil-in-water solubilizer and emulsifying agent. It is particularly suitable for fat-soluble vitamins. Kolliphor® RH40 is widely used in self-emulsifying drug delivery systems (SEDDS) or microemulsifying systems (SMDDS) in combination with a co- solubilizer and/or co-solvent.
Randomly methylated cyclodextrin (RAMBECD) is a beta cyclodextrin in which some of the hydroxyl groups are substituted with methyl groups. The average number of substitutions of hydroxyl groups with methyl groups is 12 per molecule.
Cannabis oil-based compositions with RH40 and/or with RAMEBCD were prepared using the excipients described in Table 3 below.
Table 3:
Figure imgf000012_0001
The amounts in each composition in Table 3 are in grams. The cyclodextrins (where applicable) were added in form of a solution prepared with water, having 30% cyclodextrin. The amounts in table 3 refer to weight of cyclodextrin solution. In the compositions without cyclodextrin, water was added in the amounts listed in the column entitled “water”. Compositions in Table 3 were prepared using the following general method:
TPGS, or RH40 and cannabis oil extract were co-melted for 2 hours at 60°C on a hot plate while stirring. Cyclodextrin solutions having 30% cyclodextrin were prepared by stirring water with cyclodextrin at room temperature for 3 hours. The cyclodextrin solution was then added to the TPGS and cannabis extract mixture or to the RH40 and cannabis extract mixture. Stirring proceeded for an additional 2 hours. A Heidolph homogenizer (Diax 100) was used for a few pulses to homogenize the mixtures. All compositions were turbid upon preparation.
Compositions 13, 14, 15 and 18 were maintained at room temperature in closed containers for one week. After one-week phase separation was evident in all of compositions 13, 14, 15 and 18. This example illustrates the superiority of compositions comprising combinations of cannabis oil, SBEpCD and TPGS. Composition 14 is identical to composition 6, with the modification that it uses RH40 instead of TPGS. The combination of RH40 with SBEpCD in composition 14 was not effective in making a stable composition with cannabis oil, as evidenced by phase separation within one week of preparation. Composition 18 is identical to composition 6, with the modification that it uses RAMEBCD instead of SBEpCD. Although used in the same amounts as SBEpCD, RAMEBCD was ineffective in composition 18, as evidenced by phase separation within one week of preparation. Composition 15, which comprises RAMEBCD and RH40, in the same amounts as SBEpCD and TPGS respectively in composition 6 was similarly not stable as evidenced by phase separation within 1 week.
Example 4: Preparation of Capsules Filled with SBEpCD and TPGS Based Cannabis Oil Compositions
Gelatin or hydroxypropylmethyl (HPMC) capsules are filled with the compositions of the present invention by preheating the formulations to approximately 60 C to allow fluidity of the compositions during the filling into the lower part of the capsules with the desired amount of the compositions and active material using corresponding capsule size. Optionally the capsules can be sealed with a gelatin spray to provide hermetic seal of the capsules. The capsules can be filled using manual or automatic filling devices.
Capsules used may be size #2, #1, #0, #00, or #000. Capsules, according to an embodiment, may each contain between 0.1 ml of composition and 1.3 ml of composition. Accordingly, the amount of cannabinoid per capsule may be between 20 mg and 700 mg of cannabinoid per capsule.
Example 5: Additional Compositions with Cannabis Oil, SBEpCD and TPGS
Compositions were prepared with additional solvents such as phospholipid Lipoid S 100 and propylene glycol, to improve the flowability of the composition at room temperature and to allow for easier filling of syringes and capsule filling equipment. The excipients and amounts (in grams) used are described in Table 4 below. Lipoid S-100 is a soybean phosphatidylcholine. Phosphatidylcholine is a phospholipid which serves as a solubilizing agent. PG stands for propylene glycol, which acts as a cosolvent and diluting agent. The cyclodextrin (CD) used was SBEpCD. Table 4:
Figure imgf000014_0001
Composition 33 was prepared by mixing the phospholipid with propylene glycol at 60°C, then adding synthetic CBD, and mixing well. A clear solution was obtained. Cyclodextrin was added and stirred until dissolved at 60°C for one hour. Then TPGS was added and mixed. At first the solution had bubbles, but then a clear, viscous solution was obtained.
Compositions 34 and 35 were prepared by mixing the phospholipid with PG and cyclodextrin at 60°C, then CBD was added and further mixed. A clear solution was obtained. Then, vitamin E TPGS was added. At first the solution had bubbles, but then a clear, viscous solution was obtained.
In composition 33, precipitation of the composition was observed shortly after preparation. Compositions 34 and 35 remained stable and no precipitation was evident after preparation. Without being bound by theory it is suggested that the low content of CD and TPGS in composition 33 contributed to its lack of stability. Compositions 34 and 35, having CD concentration of 5% and TPGS concentration of between 10% and 20%, were more stable. The addition of phospholipid and propylene glycol improved workability of compositions 34 and 35 while maintaining the stability.
Each of compositions 34 and 35 was used to fill hard gelatin capsules by syringe. Capsules filled with composition 34 deformed shortly after formation, but composition 35 was stable in capsules, which maintained proper appearance. Although other capsule formulations have not been tested, it is probable that composition 34 can be used in other capsules, or other types of pharmaceutical compositions.
Embodiments described herein relate to a composition comprising a cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS; wherein the cannabinoid is present in an amount of at least 12.5% by weight of the composition. Optionally, the composition comprises a cannabinoid which is in the form of cannabis oil. Optionally, the cannabis oil is present in an amount of 50% or more by weight of the composition. Optionally, the sulfobutylether beta cyclodextrin is present in an amount of between 5% and 10% by weight of the composition. Optionally, the vitamin E TPGS is present in an amount of between 15% and 20% of the composition. Optionally, the composition further comprises propylene glycol. Optionally, the composition further comprises water. Optionally, water is present in an amount between 10% and 20% of the composition, by weight. Optionally, the composition comprises 5-6% sulfobutylether beta cyclodextrin. Optionally, the composition comprises 8-9% sulfobutylether beta cyclodextrin. Optionally, the composition comprises 18-19% vitamin E TPGS. Optionally, the composition comprises 12-13% water, optionally 19-20% water. Optionally, the composition comprises propylene glycol in an amount between 5%-10% by weight.
Optionally, the composition comprises one or more than one cannabinoid selected from the group consisting of: cannabidiol (CBD), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenic acid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCVA), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C4 (CBN- C4), cannabinol C2 (CBN-C2), cannabinol Cl (CBN-C1), cannabinodiol (CBND), cannabinovarinic acid (CBNVA), cannabinovarin (CBNV), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), Cannabielsoic acid B (CBEA-B), cannabicyclol (CBL), cannabicycloic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol (CBT), cannabitriolvarin (CBTV), ethoxy- cannabitriolvarin (CBTVE), cannabivarin (CBV), cannabinodivarin (CBVD), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabirispol (CBR). Optionally, the cannabinoid present in an amount of more than 50% of the cannabis oil is CBD. Optionally, the cannabinoid present in an amount of more than 50% of the cannabis oil is THC. Optionally, the cannabis oil is prepared by: extracting dried cannabis inflorescence in an alcohol, and removing the alcohol to form cannabis oil. Optionally, cannabis oil is present in an amount of greater than 25% by weight. Optionally, the composition further comprises a phospholipid. Optionally, the phospholipid is phosphatidylcholine. Optionally, the phosophatidylcholine is present in an amount of between 15% and 25% by weight. Optionally, the composition further comprises propylene glycol. Optionally, propylene glycol is present in an amount between 20% and 40% by weight.
Optionally, the composition is for use in treating a disorder selected from the group consisting of: post trauma syndrome disorder (PTSD), anxiety, depression, psychosis syndromes, autism, Alzheimer's disease, Parkinson disease, inflammation , spasticity and muscle tension, pain, epilepsy, stroke, traumatic brain injury, bronchial disorders, cancer, drug abuse, Huntington's disease, Dystonia, Amyotrophic lateral sclerosis (ALS), Tourette syndrome, Myasthenia gravis, sleep disorders, skin related syndromes and inflammatory bowel disease, cachexia, nausea, vomiting, endometriosis, and rheumatic arthritis. Optionally, when the composition is stored at room temperature for two months from preparation, no phase separation is visible.
Another embodiment relates to a dosage form comprising a composition as described above. Optionally, the dosage form may be in the form of a soft gelatin capsule, a hard gelatin capsule, an oral fluid, a semifluid, a semi-solid, on oral liquid suspension, an oral dispersion, an oral gel, an oral spray, a sublingual spray, a candy, and a gummy. Optionally, the dosage form is in the form of a capsule. Optionally, the dosage form comprises between 10 and 1300 mg of the composition. Optionally, the capusule comprises an enteric coating. Further embodiments relate to methods for preparing a composition as described herein, comprising admixing cannabis oil with Vitamin E-TPGS, while heating; and combining with an aqueous cyclodextrin solution. Optionally, the method further comprises homogenizing the mixture after combining.
In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

Claims:
1. A composition comprising a cannabinoid, sulfobutylether beta cyclodextrin, and vitamin E TPGS; wherein the cannabinoid is present in an amount of at least 12.5% by weight of the composition.
2. The composition according to claim 1 wherein the composition comprises a cannabinoid which is in the form of cannabis oil.
3. The composition according to claim 2 wherein the cannabis oil is present in an amount of 50% or more by weight of the composition.
4. The composition according to any one of the previous claims wherein the sulfobutylether beta cyclodextrin is present in an amount of between 5% and 10% by weight of the composition.
5. The composition according to any one of the previous claims wherein the vitamin E TPGS is present in an amount of between 15% and 20% of the composition.
6. The composition according to any one of the previous claims, further comprising propylene glycol.
7. The composition according to any one of the previous claims, further comprising water.
8. The composition according to claim 7 wherein the water is present in an amount between 10% and 20% of the composition, by weight.
9. The composition according to any one of the previous claims, comprising 5-6% sulfobutylether beta cyclodextrin.
10. The composition according to any one of claims 1-8, comprising 8-9% sulfobutylether beta cyclodextrin.
11. The composition according to any one of the previous claims, comprising 18-19% vitamin E TPGS.
12. The composition according to any one of the previous claims, comprising 12-13% water.
13. The composition according to any one of claims 1-11, comprising 19-20% water.
14. The composition according to any one of the previous claims, comprising propylene glycol in an amount between 5%-10% by weight.
15. The composition according to any one of claims 1 to 14 for use in treating a disorder selected from the group consisting of: post trauma syndrome disorder (PTSD), anxiety, depression, psychosis syndromes, autism, Alzheimer's disease, Parkinson disease, inflammation , spasticity and muscle tension, pain, epilepsy, stroke, traumatic brain injury, bronchial disorders, cancer, drug abuse, Huntington's disease, Dystonia, Amyotrophic lateral sclerosis (ALS), Tourette syndrome, Myasthenia gravis, sleep disorders, skin related syndromes and inflammatory bowel disease, cachexia, nausea, vomiting, endometriosis, and rheumatic arthritis.
16. The composition according to any one of claims 1 to 15 wherein when the composition is stored at room temperature for two months from preparation, no phase separation is visible.
17. A dosage form comprising a composition according to any one of the previous claims.
18. The dosage form according to claim 17, in the form of a soft gelatin capsule, a hard gelatin capsule, an oral fluid, a semifluid, a semi-solid, on oral liquid suspension, an oral dispersion, an oral gel, an oral spray, a sublingual spray, a candy, and a gummy.
19. The dosage form according to claim 18 in the form of a capsule.
20. The capsule according to claim 19, comprising between 10 and 1300 mg of the composition.
21. The capsule according to claim 20, comprising an enteric coating.
22. A method for preparing a composition according to any one of claims 1 to 16 comprising admixing cannabis oil with Vitamin E-TPGS, while heating; and combining with an aqueous cyclodextrin solution.
23. The method according to claim 22, further comprising homogenizing the mixture after combining.
24. The composition according to any one of claims 1-16 wherein the composition comprises one or more than one cannabinoid selected from the group consisting of: cannabidiol (CBD), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerol monomethyl ether (CBGM), cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenic acid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCVA), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C4 (CBN-C4), cannabinol C2 (CBN-C2), cannabinol Ci (CBN-Ci), cannabinodiol (CBND), cannabinovarinic acid (CBNVA), cannabinovarin (CBNV), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), Cannabielsoic acid B (CBEA-B), cannabicyclol (CBL), cannabicycloic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol (CBT), cannabitriolvarin (CBTV), ethoxy-cannabitriolvarin (CBTVE), cannabivarin (CBV), cannabinodivarin (CBVD), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabirispol (CBR).
25. The composition according to claim 24 wherein the cannabinoid present in an amount of more than 50% of the cannabis oil is CBD.
26. The composition according to claim 24 wherein the cannabinoid present in an amount of more than 50% of the cannabis oil is THC.
27. The composition according to any one of claims 1-16 or 24-26 wherein the cannabis oil is prepared by: extracting dried cannabis inflorescence in an alcohol, and removing the alcohol to form cannabis oil.
28. The composition according to claim 1 wherein cannabis oil is present in an amount of greater than 25% by weight.
29. A composition according to any one of claims 1 to 16 or 24 to 28 further comprising a phospholipid.
30. The composition according to claim 29 wherein the phospholipid is phosphatidylcholine.
31. The composition according to claim 30 wherein the phosophatidylcholine is present in an amount of between 15% and 25% by weight.
32. A composition according to any one of claims 1 to 16 or 24 to 31 further comprising propylene glycol.
33. The composition according to claim 32 wherein propylene glycol is present in an amount between 20% and 40% by weight.
PCT/IL2021/050788 2020-07-14 2021-06-28 Oral cannabinoid compositions WO2022013854A1 (en)

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