WO2016022936A1 - Système d'administration de forme dosifiée gastro-intestinale orale améliorée de cannabinoïdes et/ou d'extraits de marijuana standardisés - Google Patents

Système d'administration de forme dosifiée gastro-intestinale orale améliorée de cannabinoïdes et/ou d'extraits de marijuana standardisés Download PDF

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WO2016022936A1
WO2016022936A1 PCT/US2015/044248 US2015044248W WO2016022936A1 WO 2016022936 A1 WO2016022936 A1 WO 2016022936A1 US 2015044248 W US2015044248 W US 2015044248W WO 2016022936 A1 WO2016022936 A1 WO 2016022936A1
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peg
thc
esters
glyceryl
oil
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PCT/US2015/044248
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English (en)
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Santos B. Murty
Ram B. Murty
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Murty Pharmaceuticals, Inc.
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Priority claimed from US14/454,145 external-priority patent/US20140357708A1/en
Application filed by Murty Pharmaceuticals, Inc. filed Critical Murty Pharmaceuticals, Inc.
Publication of WO2016022936A1 publication Critical patent/WO2016022936A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • This disclosure relates generally to a delivery system to improve administration of cannabinoids and standardized marijuana extracts to patients and, more particularly, through a self-emulsifying drug delivery system, which optimizes cannabinoid dissolution properties and avoids hepatic first-pass metabolism, thereby enhancing bioavailability through the gastrointestinal tract.
  • Cannabinoids are compounds derived from the cannabis sativa plant commonly known as marijuana.
  • the plant contains more than 400 chemicals and approximately 60 cannabinoids.
  • the most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly ⁇ 9 -THC.
  • ⁇ 9 -tetrahydrocannabinol also known as dronabinol
  • Marinol soft gelatin capsules which have been approved by the Food and Drug Administration (FDA) for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of AIDS patients suffering from the wasting syndrome.
  • FDA Food and Drug Administration
  • ⁇ 9 - tetrahydrocannabinol shows other biological activities, which lend themselves to possible therapeutic applications, such as in the treatment of glaucoma, migraine headaches, spasticity, anxiety, analgesia, and drug addiction.
  • ⁇ 9 -THC is dissolved in sesame oil and encapsulated in gelatin capsules for oral administration.
  • Dronabinol After oral administration, Dronabinol has an onset of action of approximately 0.5 to 1 hour, with a peak effect of 2-4 hours. The duration of action for psychoactive effects is 4-6 hours, but the appetite stimulant effect may continue for 24 hours or longer after administration.
  • the maximal plasma levels after oral dosing of 20 mg ⁇ 9 -THC in a sesame oil formulation are around 10 ng/ml.
  • ⁇ 9 -THC or dronabinol When administered orally, ⁇ 9 -THC or dronabinol is almost completely absorbed (90- 95%) after a single oral dose. However, due to the combined effect of first pass hepatic metabolism and high lipid solubility, only about 10-20% of an administered dose reaches systemic circulation with highly variable maximal concentrations. It has been found that fasting or food deprivation may decrease the rate of absorption of ⁇ 9 -THC from the sesame oil capsules currently available in the market. Previous studies have reported that another limitation of orally administered ⁇ 9 -THC is the large inter-subject variability in absorption.
  • Both sublingual and buccal formulations depend on the efficient transfer of medicament from a hydrophilic vehicle to the mucous membrane of the sublingual or buccal mucosa. Transfer of medicament through the interstices between or through epithelial cells is governed principally by the lipid solubility of the medicament. When a drug is water insoluble as in the case with cannabinoids, this presents a further barrier to absorption from the sublingual area.
  • This solid lipid composition involves a method for delivering a non-psychoactive cannabinoid (i.e. dexanabinol) in a dry lipid mixture to greatly enhance oral bioavailability when compared to known formulations.
  • a non-psychoactive cannabinoid i.e. dexanabinol
  • the patentees anticipated that treatment could be directed towards brain damage associated with stroke, head trauma, and cardiac arrest. This, however, required sufficient bioavailability of the drug compound.
  • Oral ⁇ 9 -THC or dronabinol therapy would be greatly benefited by improved bioavailability for treating a variety of conditions described above.
  • Oral gastrointestinal dosage forms are designed to enable sufficient availability of the active compound at its site of action.
  • the bioavailability of a drug depends on several parameters, i.e., the physicochemical nature of the active compound, the dosage form, as well as physiological factors.
  • the cannabinoid compounds being hydrophobic by nature, show wetting difficulties and poor dissolution in the gastrointestinal region.
  • ⁇ 9 -THC or dronabinol undergo extensive hepatic first-pass metabolism. These properties represent barriers to drug absorption from oral gastrointestinal dosage forms. These barriers in turn cause a subsequent reduction in the bioavailability.
  • a pharmaceutical formulation may utilize or take advantage of one or more mechanisms to increase the rate and/or the extent to which the administered drug is absorbed.
  • Dronabinol or ⁇ 9 -THC belongs to Class II (low aqueous solubility and high permeability) of the biopharmaceutical classification system (BCS).
  • BCS biopharmaceutical classification system
  • SEDDS self-emulsifying lipid based delivery system
  • Patents demonstrating the potential use of SEDDS or lipid delivery systems for lipophilic drugs are U.S. Patent Nos.: 5,484,801; 5,798,333; 5,965,160; 6,008,228; 6,730,330. See also U.S. Patent Application No. 20050209345, and International Application No. PCT/EP96/02431 (WO 96/39142)).
  • one of the objects of the present disclosure is to provide a more optimized and improved delivery system for ⁇ 9 -THC as well as other cannabinoids and/or standardized marijuana extracts to meet the desired needs of the patients.
  • It is another object of the present disclosure is to provide a pharmaceutical formulation for ⁇ 9 -THC as well as other cannabinoids and/or standardized marijuana extracts which does not cause gastrointestinal irritation.
  • Another object of the present disclosure is to promote drug absorption through alternate gastrointestinal pathways, outside the conventional hepatic portal vein transport mechanism, which results in a high first-pass effect.
  • the present disclosure provides an isotropic phased and chemically stabilized oral delivery system of dronabinol or other cannabinoids.
  • the drug compound(s) are dissolved in an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated fatty acids) with at least one surfactant to promote self- emulsification.
  • an oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated fatty acids
  • This formulation was unexpectedly found to promote targeted chylomicron/lipoprotein delivery, and optimal bioavailability after administration through the mammalian intestinal tract where endogenous bile salts reside.
  • the SEDDS formulation of the present disclosure preferably falls under one of the three categories, Type I, Type II, and Type III, which are defined as isotropic mixtures. These mixtures contain the following types of ingredients: (1) natural or synthetic oily mediums, (2) solid or liquid surfactants, and (3) one or more hydrophilic solvents and co-solvents/surfactants.
  • Types I, II, & III may be categorized as follows:
  • Type I formulations consist of an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids); whereas the oily medium may also be polyfunctional with potential surfactant characteristics to promote self-emulsification.
  • Oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids
  • the oily medium may also be polyfunctional with potential surfactant characteristics to promote self-emulsification.
  • Mixed glycerides are defined herein as glycerols which have been esterified with fatty acids at one or two hydroxyl groups on the glycerol to form mono or diglycerides.
  • Type II consist of an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids) and at least one surfactant component to promote self-emulsification.
  • oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids
  • Type III consist of an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids) and at least one surfactant component to promote self-emulsification, and at least one hydrophilic cosolvent.
  • oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids
  • the dosage form can include co-solvents, anti-oxidants, viscosity modifying agents, cytochrome P450 metabolic inhibitors, P-GP efflux inhibitors, and finally amphiphilic/non-amphiphilic solutes to induce semi-solid formation for targeted release rates.
  • the contents Upon administration as an isotropic liquid, semi-solid, or waxy solid phase and upon initial dilution in the gastric region of a mammal, the contents immediately form dispersion for protection against acid catalyzed degradation of cannabinoids.
  • gastric emptying of the dispersion into the intestinal lumen further solubilization with bile salts and downstream processing promote the selective discriminative transport of drug into lipid absorption pathways, particularly chylomicron/lipoprotein assembly in the endoplasmic reticulum of the intracellular environment of enterocytes, thereby promoting lymphatic transport and thus avoiding hepatic first-pass metabolism.
  • An isotropic semi-solid or waxy solid phase is prepared by dissolving a high concentration of ascorbyl palmitate (or other amphiphilic / non-amphiphilic solutes) as well as colloidal silicon dioxide, granulated fumed silicas, precipitated silicas, amorphous silica gel, magnesium aluminum silicates, sodium magnesium aluminum silicates, microcrystalline cellulose, talc, dicalcium phosphate anhydrous, and isomaltose into the oily liquid state as described above.
  • the self-emulsifying formulations of the present disclosure for cannabinoids and/or standardized marijuana extracts may be categorized as follows:
  • Type I formulations consist of an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids); whereas the oily medium may also be polyfunctional with potential surfactant characteristics to promote self-emulsification.
  • oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids
  • the oily medium may also be polyfunctional with potential surfactant characteristics to promote self-emulsification.
  • Type II consists of an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids), and at least one surfactant component to promote self-emulsification.
  • oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids
  • Type III consist of an oily medium (e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids) and at least one surfactant component to promote self-emulsification, and at least one hydrophilic cosolvent.
  • oily medium e.g. triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated free fatty acids
  • an oral gastrointestinal dosage form of cannabinoids and/or standardized marijuana extracts in a self-emulsifying system operable to avoid hepatic first pass metabolism via targeted chylomicron/lipoprotein delivery, thereby promoting lymphatic transport is disclosed.
  • the oral gastrointestinal dosage form includes: (a) a pharmacologically active form of cannabinoids and/or standardized marijuana extracts; (b) an oily medium consisting of: (i) one or more triglycerides formed from long chain fatty having from C 13 to C24 carbon atoms; and (ii) one or more mixed glycerides formed from long chain fatty having from C 13 to C24 carbon atoms; and (iii) one or more free fatty acids formed from un- esterified long chain fatty acids having from C 13 to C 24 carbon atoms; and (c) about 10-60 wt% of a surfactant which promotes self-emulsification.
  • the oral gastrointestinal dosage form includes about 1 to 70 wt% of free long chain fatty acids having from C 13 to C 24 carbon atoms.
  • the oral gastrointestinal dosage form may include a semi- solid inducer selected from the group consisting of colloidal silicon dioxide, granulated fumed silicas, precipitated silicas, amorphous silica gel, magnesium aluminum silicates, sodium magnesium aluminum silicates, microcrystalline cellulose, talc, dicalcium phosphate anhydrous, isomaltose and mixtures thereof.
  • the semi-solid inducer may be present in an amount of about 1 to 70 wt%.
  • the pharmacologically active cannabinoid may be selected from the group consisting of tetrahydrocannabinol, ⁇ 9 -tetrahydrocannabinol(THC), ⁇ 8 - tetrahydrocannabinol, standardized marijuana extracts, ⁇ 8 -tetrahydrocannabinol-DMH, ⁇ 9 - tetrahydrocannabinol propyl analogue (THCV), 11 -hydroxy- tetrahydrocannabinol, l l-nor-9- carboxy-tetrahydrocannabinol, 5'-azido- ⁇ 8 -tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, AM919, AM926, AM938, cannabidiol(CBD), cannabidiol propyl analogue(CBDV), cannabinol (CBN), cannabin
  • the one or more triglycerides may be selected from the group consisting of borage oil, coconut oil, cottonseed oil, soybean oil, safflower oil, sesame oil sunflower oil, castor oil, corn oil, olive oil, palm oil, peanut oil, poppy seed oil, canola oil, hydrogenated soybean oil, hydrogenated sesame oil, hydrogenated vegetable oils, triolein, trilinolein, and trilinolenin.
  • the one or more mixed glycendes may be selected from the group consisting of mixed glycerides esterified with long chain fatty acids, glyceryl behenate, glyceryl distearate, glyceryl isostearate, glyceryl laurate, glyceryl monooleate, glyceryl monolinoleate, glyceryl palmitate, glyceryl palmitostearate, glyceryl ricinoleate, glyceryl stearate, polyglyceryl 10-oleate, polyglyceryl 3-oleate, polyglyceryl 4-oleate, and polyglyceryl 10-tetralinoleate.
  • the one or more mixed glycerides may be formed from fatty acids having from C13 to C24 carbon atoms, with about 10 to 90 wt% of the fatty acids in the mixed glycerides being esterified within monoglycerides, and about 10 to 90 wt% of the fatty acids in the mixed glycerides being esterified within diesters.
  • the one or more free fatty acids may be selected from the group consisting of, behenic acid, lauric acid, linoleic acid, linolenic acid, myristic acid, palmitic acid, palmitoleic acid, palmitostearic acid, ricinoleic acid, stearic acid, soy fatty acids, oleic acid, and mixtures thereof.
  • the surfactant may be one or more selected from the group consisting of polyglycolized glycerides, polyoxyethylene glycerides, polyoxyethylene castor oil derivatives, polyethylene glycol-fatty acid esters, polyethylene glycol glycerol fatty acid esters, transesterfication products of oils and alcohols, polyglycerized fatty acids, glycerol fatty acid esters, polyglycerol fatty acid esters, propylene glycol fatty acid esters, mono and diglycerides, polyethylene glycol sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, d- ⁇ - tocopheryl polyethylene glycol 1000 succinate, polyoxyethyleneglycol 660 12-hydroxystearate, polyoxyl 15 hydroxystearate, polysorbates, sodium lauryl sulfate, and mixtures thereof.
  • the surfactant may be selected from the group consisting of almond oil PEG-6 esters, almond oil PEG-60 esters, apricot kernel oil PEG-6 esters, caprylic/capric triglycerides PEG-4 esters, caprylic/capric triglycerides PEG-4 complex, caprylic/capric glycerides PEG-6 esters, caprylic/capric glycerides PEG-8 esters, castor oil PEG-50 esters, hydrogenated castor oil PEG-5 esters, hydrogenated castor oil PEG-7 esters, 9 hydrogenated castor oil PEG-9 esters, corn oil PEG-6 esters, corn oil PEG-8 esters, corn glycerides PEG-60 esters, olive oil PEG-6 esters, hydrogenated palm/palm kernel oil PEG-6 esters, hydrogenated palm/ palm kernel oil PEG-6 esters with palm kernel oil and PEG-6 and palm oil, palm kernel oil PEG-40 esters, peanut oil PEG-6 esters, glycerol esters, g
  • the oral gastrointestinal dosage form may include cosolvents, solubilizing agents and antioxidants selected from the group consisting of ethanol, polyethylene glycol 300, polyethylene glycol 400, propylene glycol, propylene carbonate, N-methyl-2- pyrrolidones, dimethylacetamide, dimethyl sulfoxide, hydroxypropyl-P-cyclodextrins, sulfobutylether - ⁇ - cyclodextrin, ⁇ -cyclodextrin, HSPC phospholipid, DSPG phospholipid, DMPC phospholipid, DMPG phospholipid, ascorbyl palmitate, butylated hydroxy anisole, butylatedhydroxy anisole, propyl gallate, ⁇ - tocopherol, and ⁇ -tocopherol, and mixtures thereof.
  • the oral gastrointestinal dosage form may also include about 1 to 70 wt% of solubilizing co-solvents and about 0.01 to 15 wt% of antioxidants.
  • the oral gastrointestinal dosage form may include viscosity modifying agents for supersaturable systems selected from the group consisting of unmodified starches, pregelatinized starches, crosslinked starches, guar gum, xanthan gum, acacia, tragacanth, carrageenans, alginates, chitosan, polyvinyl pyrrolidone (PVP, e.g. Kollidon®, Povidone®), polyethylene oxide (e.g. Polyox®), polyethylene glycols (PEGs, e.g.Carbowax®), polycarbophils (e.g.
  • viscosity modifying agents for supersaturable systems selected from the group consisting of unmodified starches, pregelatinized starches, crosslinked starches, guar gum, xanthan gum, acacia, tragacanth, carrageenans, alginates, chitosan, polyvinyl pyrrolidone (PVP, e.g. Kollid
  • Carbopol® Eudragit® series polymers (E, L, S, RL, RS, NE), hydroxymethylpropyl cellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylmethylcelluose (HPC), carboxymethylcellose sodium (Na-CMC), ethylcellulose (e.g. Ethocel®), cellulose acetate, and cellulose acetate phthalate, polyvinylacetate /polyvinylpyrrolidone (PVA/PVP, e.g. Kollidon SR®), PV A/PEG graft copolymer (e.g.
  • PVA/PVP polyvinylacetate /polyvinylpyrrolidone
  • PV A/PEG graft copolymer e.g.
  • the oral gastrointestinal dosage form may include about 1 to 70 wt% of viscosity modifying agents.
  • the standardized marijuana extracts may include defined concentrations of ⁇ 9 -tetrahydrocannabinol(THC) with subsequent varying ratios of cannabigerol (CBG), cannabichromeme (CBC), cannabidiol (CBD), ⁇ 9 -tetrahydrocannabinol(THC), ⁇ 8 - tetrahydrocannabinol(THC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBDL), and cannabitriol (CBTL), and mixtures thereof.
  • an oral gastrointestinal dosage form of cannabinoids and/or standardized marijuana extracts in a self-emulsifying system operable to avoid hepatic first pass metabolism via targeted chylomicron/lipoprotein delivery, thereby promoting lymphatic transport is disclosed.
  • the oral gastrointestinal dosage form includes: (a) about 1 to 60 wt% of a pharmacologically active form of cannabinoids and/or standardized marijuana extract; (b) about 15 to 44 wt% of one or more triglycerides formed from long chain fatty acids having from C 13 to C24 carbon atoms; and (c) about 15 to 44 wt% of one or more mixed glycerides formed from long chain fatty acids having from C 13 to C 24 carbon atoms; and (d) about 1 to 70 wt% of one or more free fatty acids formed from un-esterified long chain fatty acids having from C 13 to C 24 carbon atoms; and mixtures thereof; and (e) about 10 to 60 wt% of a surfactant which promotes self-emulsification.
  • the standardized marijuana extracts may include defined concentrations of ⁇ 9 -tetrahydrocannabinol(THC) with subsequent varying ratios of cannabigerol (CBG), cannabichromeme (CBC), cannabidiol (CBD), ⁇ 9 - tetrahydrocannabinol(THC), ⁇ 8 -tetrahydrocannabinol(THC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBDL), and cannabitriol (CBTL), and mixtures thereof.
  • an oral gastrointestinal dosage form of cannabinoids and/or standardized marijuana extracts in a self-emulsifying system operable to avoid hepatic first pass metabolism via targeted chylomicron/lipoprotein delivery, thereby promoting lymphatic transport is disclosed.
  • the oral gastrointestinal dosage form includes: (a) about 1 to 60 wt% of a pharmacologically active form of cannabinoids selected from the group consisting of tetrahydrocannabinol, ⁇ 9 -tetrahydrocannabinol(THC), ⁇ 8 -tetrahydrocannabinol, standardized marijuana extracts, ⁇ 8 -tetrahydrocannabinol-DMH, ⁇ 9 -tetrahydrocannabinol propyl analogue (THCV), 11 -hydroxy- tetrahydrocannabinol, l l-nor-9-carboxy-tetrahydrocannabinol, 5'-azido- ⁇ 8 -tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, AM919, AM926, AM938, cannabidiol(CBD), cannabidiol propyl ana
  • Fig. 1 is a graph showing dissolution profiles of cannabinoid containing formulations of the present disclosure, and a dissolution profile of a conventional cannabinoid containing formulation;
  • Fig. 2 is a graph showing the dissolution profile of a cannabinoid containing formulation of the present disclosure illustrating, in particular, the peak concentration and plateau region of the dissolution profile
  • Fig. 3 is a graph showing the dissolution profile of a cannabinoid containing formulation of the present disclosure illustrating, in particular, the sustained drug release pattern over a four to six -hour period.
  • improved dissolution, stability, and bioavailability of ⁇ 9 -THC is achieved by dissolving the ⁇ 9 -THC in an oily medium comprising triglycerides and/or mixed glycerides and/or medium/long chain saturated, mono-unsaturated, and poly-unsaturated fatty acids containing at least one surfactant component.
  • This composition promotes self- emulsification, thereby promoting targeted chylomicron/lipoprotein delivery and optimal bioavailability after administration through the mammalian intestinal tract where endogenous bile salts reside.
  • a preferred dosage form can include co-solvents, anti- oxidants, viscosity modifying agents, cytochrome P450 metabolic inhibitors, P-GP efflux inhibitors, and amphiphilic/non-amphiphilic solutes to induce semi-solid formation for targeted release rates.
  • the oily medium of the formulation can be selected from the group consisting of one or more of long- chain chain triglycerides or mixed glycerides including polyglycolized glycerides and polyoxyethylene glycerides, such as, anise oil, apricot kernel oil, apricot kernel oil PEG-6 esters, beeswax, borage oil, canola oil, castor oil, castor oil polyoxyl 35, castor oil polyoxyl 40, castor oil polyoxyl 40 hydrogenated, castor oil polyoxyl 60, castor oil polyoxyl 60 hydrogenated castor oil hydrogenated, cinnamon oil, clove oil, coconut oil, coconut oil-lecithin, coconut oil fractioned, coriander oil, corn oil, corn oil PEG-6 esters, corn oil PEG- 8 esters, cottonseed oil, cottonseed oil hydrogenated, kernel oil, kernel oil PEG-6 esters, lemon oil, mineral oil, mineral oil (light),
  • Other preferred oily mediums are long chain mono-, or di-, glycerides, and/or polyglycolized glycerides and polyoxyethylene glycerides, including glycerol esters of saturated C8-C18 fatty acids (Gelucire ® 33/01), glyceryl esters of saturated C12-C18 fatty acids (Gelucire 39/01 and 43/01), glyceryl behenate, glyceryl distearate, glyceryl isostearate, glyceryl laurate, glyceryl laurate/PEG-32 laurate (Gelucire ® 44/14), glyceryl monooleate (Peceol ® ) and glyceryl monolinoleate (Maisine ® ), glyceryl palmitate, glyceryl palmitostearate, glyceryl palmitostearate/PEG-32 (Gelucire 50/13) palmitostearate
  • long chain saturated fatty acids such as arachidic acid, behenic acid, 3-hydroxymyristic acid, lauric acid, lignoceric acid, mycoceranic acid, myristic acid, palmitic acid, phytanic acid, stearic acid, tuberculostearic acid, etc.
  • Preferred long chain unsaturated fatty acids include arachidonic acid, linoleic acid, (a or y type), nervonic acid, oleic acid, palmitoleic acid, soy fatty acids, and mixtures thereof.
  • Preferred medium-chain mono-, di-, or tri- glycerides include caprylic/capric glycerides, caprylic/capric glycerides derived from coconut oil or palm seed oil (e.g.
  • Labrafac ® Miglyol ® 810, 812, Crodamol GTCC-PN, Softison ® 378
  • propylene glycol caprylate/caprate Labrafac® PC
  • propylene glycol dicaprylate/dicaprate Miglyol 840
  • medium chain C8/C10 mono- and diglycerides
  • Capmul ® MCM Capmul ® MCM (L)
  • glycerol esters of saturated C8-C18 fatty acids (Gelucire 33/01), and mixtures thereof.
  • Preferred medium chain fatty acids include caproic acid, caprylic acid, capric acid, and mixtures thereof.
  • Preferred fat-soluble vitamins and derivatives include vitamin A, vitamin E (a or ⁇ tocopherol), vitamin E PEG 1000 succinate (d- ⁇ - tocopheryl polyethylene glycol 1000 succinate or TPGS), and mixtures thereof.
  • the surfactant component of the formulation can be used either alone or in combination with another surfactant to improve the self-emulsifying properties of the formulation.
  • Preferred surfactant components are selected from the group consisting of polyglycolized glycerides and polyoxyethylene glycerides of medium to long chain mono-, di-, and triglycerides, such as: almond oil PEG-6 esters, almond oil PEG-60 esters, apricot kernel oil PEG-6 esters (Labrafil M1944CS), caprylic/capric triglycerides PEG-4 esters (Labrafac® Hydro WL 1219), caprylic/capric triglycerides PEG-4 complex (Labrafac® Hydrophile), caprylic/capric glycerides PEG-6 esters (Softigen ® 767), caprylic/capric glycerides PEG-8 esters (Labrasol ® ), castor oil PEG-50 esters, hydrogenated castor oil PEG-5 esters, hydrogen
  • Labrafil ® Isostearique triolein PEG-6 esters, trioleate PEG-25 esters, polyoxyl 35 castor oil (Cremophor ® EL or Kolliphor ® EL), polyoxyl 40 hydrogenated castor oil (Cremophor ® RH 40 or Kolliphor ® RH40), polyoxyl 60 hydrogenated castor oil (Cremophor ® RH60), and mixtures thereof.
  • Preferred polyglycolized derivatives and polyoxyethylene derivatives of medium to long chain fatty acids which can be used in the present disclosure include PEG-8 caproate, PEG-8 caprylate, PEG-8 caprate PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 caproate, PEG-9 caprylate, PEG-9 caprate PEG-9 laurate, PEG-9 oleate, PEG-9 stearate, PEG- 10 caproate, PEG- 10 caprylate, PEG- 10 caprate PEG- 10 laurate, PEG- 10 oleate, PEG- 10 stearate, PEG- 10 laurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 laurate, PEG-20 oleate, and mixtures thereof.
  • Preferred glycerol, poly glycerol, and propylene glycol esters of medium to long chain fatty acids which can be used in the present disclosure include caprylate/caprate diglycerides, glyceryl monooleate, glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate, glyceryl dioleate, glyceryl mono/dioleate, glyceryl caprylate/caprate, medium chain (C8/C10) mono- and diglycerides (Capmul ® MCM, Capmul ® MCM (L)), mono-and diacetylated monoglycerides, polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, and polyglyceryl-10 mono dioleate, propylene glycol caprylate/caprate (La
  • Preferred polyethylene glycol sorbitan fatty acid esters can be used including PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, and PEG-20 sorbitan monooleate, and mixtures thereof.
  • Preferred polyoxyethylene-polyoxypropylene block copolymers which can be used include poloxamers (108, 124, 182, 183, 188, 212, 217, 238, 288, 331, 338, 335, and 407), and mixtures thereof.
  • Preferred sorbitan fatty acid esters can be used including sorbitan monolaurate, sorbitan monopalmitate, sorbitan monoleate (Span ® 20), sorbitan monostearate and sorbitan tristearate, and mixtures thereof.
  • TPGS d- ⁇ - tocopheryl polyethylene glycol 1000 succinate
  • polysorbate 20 Tween ® 20
  • polysorbate Tween ® 80
  • polyethyleneglycol 660 12-hydroxystearate Solutol HS-15 or Kolliphor® HS15
  • polyoxyl 15 hydroxystearate sodium lauryl sulfate, and mixtures thereof.
  • optional components of the formulation can include co- solvents, antioxidants, viscosity modifying agents, cytochrome P450 metabolic inhibitors, P-GP efflux inhibitors, and finally amphiphilic/non-amphiphilic solutes. These optional components can be used either alone or in combination with other ingredients to improve the chemical and physical properties of the self-emulsifying drug delivery systems.
  • Preferred co-solvents or solubilizers include agents such as ethanol, polyethylene glycol 300, polyethylene glycol 400, propylene glycol, propylene carbonate, N-methyl-2- pyrrolidones, dimethylacetamide, dimethyl sulfoxide, hydroxypropyl- -cyclodextrins, sulfobutylether - ⁇ - cyclodextrin, ⁇ -cyclodextrin, glycerin, and various phospholipids (HSPC, DSPG, DMPC, & DMPG), and mixtures thereof.
  • agents such as ethanol, polyethylene glycol 300, polyethylene glycol 400, propylene glycol, propylene carbonate, N-methyl-2- pyrrolidones, dimethylacetamide, dimethyl sulfoxide, hydroxypropyl- -cyclodextrins, sulfobutylether - ⁇ - cyclodextrin, ⁇ -cyclo
  • Preferred antioxidants include ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toluene, propyl gallate, ⁇ - tocopherol, and finally ⁇ - tocopherol, etc.
  • the antioxidants that can be chosen include combinations of two or more agents described above, whereby ascorbyl palmitate and tocopherol provide optimal synergistic effects.
  • Preferred viscosity modifying agents that can be used include unmodified starches, pregelatinized starches, crosslinked starches, guar gum, xanthan gum, acacia, tragacanth, carrageenans, alginates, chitosan, polyvinyl pyrrolidone (PVP, e.g. Kollidon®, Povidone®), polyethylene oxide (e.g. Polyox®), polyethylene glycols (PEGs, e.g.Carbowax®), polycarbophils (e.g.
  • Carbopol® Eudragit® series polymers (E, L, S, RL, RS, NE), hydroxymethylpropyl cellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylmethylcelluose (HPC), carboxymethylcellose sodium (Na-CMC), ethylcellulose (e.g. Ethocel®), cellulose acetate, and cellulose acetate phthalate, polyvinylacetate /polyvinylpyrrolidone (PVA/PVP, e.g. Kollidon SR®), PV A/PEG graft copolymer (e.g.
  • PVA/PVP polyvinylacetate /polyvinylpyrrolidone
  • PV A/PEG graft copolymer e.g.
  • Kollidon IR® hydrogenated vegetable oils, polyglycolized esters of fatty acids, carnauba wax, stearyl alcohol, and beeswax, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ® ), and mixtures thereof.
  • Preferred cytochrome P450 inhibitors include any agent incorporated into the SEDDS matrix that inhibits pre-systemic hepatic first pass metabolism (i.e. first pass metabolism), such as d- ⁇ - tocopheryl polyethylene glycol 1000 succinate, anise oil, cinnamon oil, coriander oil, grapefruit oil, lemon oil, orange oil, peppermint oil, ascorbyl palmitate, propyl gallate, and various combinations thereof.
  • pre-systemic hepatic first pass metabolism i.e. first pass metabolism
  • first pass metabolism such as d- ⁇ - tocopheryl polyethylene glycol 1000 succinate, anise oil, cinnamon oil, coriander oil, grapefruit oil, lemon oil, orange oil, peppermint oil, ascorbyl palmitate, propyl gallate, and various combinations thereof.
  • Preferred PGP efflux inhibitors include any agent incorporated into the SEDDS matrix that inhibits PGP induced cellular efflux mechanisms (i.e. MDR), such as polyethoxylated castor oil derivatives, polyoxyethylene sorbitan monooleate, polyoxyethylene glycerides, and various combinations thereof.
  • MDR PGP induced cellular efflux mechanisms
  • Preferred amphiphilic/non-amphiphilic solutes include any agent incorporated into the SEDDS matrix that induces semi-solid formation from a liquid state.
  • these agents would be pharmaceutical grade powder materials, which are either water soluble or insoluble (e.g. Ascorbyl Palmitate).
  • Other semi-solid inducers include colloidal silicon dioxide, granulated fumed silicas, precipitated silicas, amorphous silica gel, magnesium aluminum silicates, sodium magnesium aluminum silicates, microcrystalline cellulose, talc, dicalcium phosphate anhydrous, and isomaltose.
  • ⁇ 9 -THC or any other cannabinoid class compound can be directly incorporated into a commercially available proprietary blend of excipients, surfactants, cosurfactants, and a lipid phase.
  • SMEDDS® available from Gattefosse Corporation
  • Optional components can also be added such as co- solvents, antioxidants, viscosity modifying agents, cytochrome P450 metabolic inhibitors, P-GP efflux inhibitors, and amphiphilic/non-amphiphilic solutes.
  • the proportions of the ingredients in the composition of the present disclosure include from about 1 - 90 wt%, preferably from about 1 - 80 wt%, and more preferably from about 1 - 60 wt% of an active cannabinoid; from about 5 - 90 wt%, preferably from about 10 - 80 wt%, more preferably from about 20 - 80 wt% of an oily medium; and from about 5 - 90 wt%, preferably from about 10 - 80 wt%, more preferably from about 20 to 60 wt% of the surfactant component;
  • the optional solubilizing and co-solvent amounts vary from about 1 - 80 wt%, preferably from about 5 - 50 wt%; more preferably from about 10 - 50 wt%.
  • the optional antioxidants may vary from about 0.01 - 15 wt%, preferably from about 0.5 to 12.5 wt%.
  • the semi- solid inducer amount which transforms the liquid SEDDS matrix to a semi-solid SEDDS matrix, varies from about 2.5 - 15 wt%, preferably from about 5 - 10 wt%, more preferably from about 7.5 to 10 wt%.
  • Direct filling of hot melt matrices into hard gelatin capsules, soft gelatin capsules, pullulan capsules, and hypromellose can be performed in the case of self- emulsifying drug delivery systems.
  • the vehicles hard gelatin capsules
  • the higher surface area of a drug produced in this way facilitates dissolution in the gastrointestinal fluid, especially in the presence of bile salts, lecithin, and lipid digestion mixtures.
  • liquid based SEDDS may be administered directly to the patient after dilution in sufficient water or other compatible aqueous/liquid media.
  • the carrier For ease of manufacturing, the carrier must be amenable to liquid filling into hard gelatin capsules soft gelatin capsules, pullulan capsules, and hypromellose (HPMC) capsules as hot melt matrices.
  • the melting temperatures of carrier solutions preferably do not exceed above 80°C, which is the maximum acceptable temperature for gelatin capsule shells. This preferred approach has been followed in filling preferred formulations of the present disclosure.
  • liquid based SEDDS may be administered directly to the patient after dilution in sufficient water or other compatible aqueous/liquid media.
  • Appropriate in vitro dissolution testing can be used to predict therapeutic performance of any liquid, and semisolid oral gastrointestinal dosage forms in order to ensure product quality and batch-to-batch consistency.
  • Optimal dissolution testing methodologies clarify dissolution testing of self-emulsifying drug delivery formulations intended for gastrointestinal delivery. Thermal and textural properties, as well as viscosity and consistency of the dosage form, can be used to influence drug release from lipid-based formulations.
  • compositions are initially tested under various dissolution media having different surfactant concentrations (1-5% w/w of sodium lauryl sulfate, TritonX- 100, and Polysorbate 80) in order to identify ideal conditions for routine analysis. These compositions are also evaluated against the commercial product to predict better in vivo release profile. Thereafter, stability testing for SEDDS formulations is peculiar due to the presence of lipophilic compounds and lipid excipients are carried out. Thus, monitoring the stability of excipients is important in addition to the active ingredient.
  • Capsule leakage is a common problem and sophisticated detection systems are often employed to monitor such leakage.
  • the capsule dosage form resulting from the use of SEDDS in the present disclosure is anticipated to be in soft gelatin form, hard gelatin with band-sealed, hard gelatin with solvent sealing (e.g. Capsugel's Licaps), pullulan form, and hypromellose (HPMC) form.
  • Band sealing for instance, utilizes a sealing solution containing gelatin. This composition is preferably maintained at 45-48°C for a nice band formation around a capsule to prevent any leakage or accidental opening of the product.
  • liquid based SEDDS may be administered directly to the patient after dilution in sufficient water or other compatible aqueous/liquid media.
  • cannabinoids can be used alone or in combination to achieve synergistic effects.
  • Suitable cannabinoid compounds which can be used either alone or in combination include tetrahydrocannabinol, ⁇ 9 -tetrahydrocannabinol(THC), ⁇ 8 -tetrahydrocannabinol, standardized marijuana extracts, ⁇ 8 -tetrahydrocannabinol-DMH, ⁇ 9 -tetrahydrocannabinol propyl analogue (THCV), 11 -hydroxy-tetrahydrocannabinol, l l-nor-9-carboxy- tetrahydrocannabinol, 5'-azido- ⁇ 8 -tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, AM919, AM926, AM938, cannabidiol(CBD), cannabidiol propyl analogue
  • This disclosure also extends to other agents with homologous structural characteristics common with the cannabinoid class of compounds.
  • the prevent disclosure is not inclusive of cannabinoid receptor antagonists which do not possess homologous structural characteristics common with the cannabinoid class of compounds.
  • the present disclosure does not include the cannabinoid receptor antagonists as described in the chemical literature as substituted amides possessing common functional and chemical structural groups as found with the compound described in U.S. Patent Publication No. 2007/0298099 to Peresypkin et al.
  • Additional specific examples of cannabinoid receptor antagonists include SR 141716A and SR 144528. These additional compounds again bear the name cannabinoid antagonist; however, these agents have no chemical structure resemblance or homology with the known cannabinoid class compounds.
  • the proposed SEDDS compositions of the present disclosure are also useful to improve the dissolution, bioavailability, and stability of various lipophilic drugs having poor aqueous solubility.
  • These agents can belong to drugs categories such as analgesics, antihelminthics, antiarrhythmic, antiasthma, antibacterial, antiviral, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifungal, antigout, antihypertensive, antimalarials, antimigraine, antimuscarinic, antineoplastic, antiprotozoal, antithyroid, antitussives, anxiolytics, sedatives, hypnotics, neuroleptics, cardiac inotropics, corticosteroids, diuretics, antiparkinsonian, gastrointestinal, antihistamines, keratolytics, lipid regulating agents, muscle relaxants, antianginal, nutritional, sex hormones, and stimulants.
  • Type II self-emulsifying drug delivery systems for ⁇ 9 -THC, as well as for improving dissolution testing over the existing sesame oil based compositions (i.e. Marinol®). Based on initial results, it was found that Type III self-emulsifying drug delivery systems could be used with the addition of hydrophilic co-solvents (e.g. ethanol).
  • hydrophilic co-solvents e.g. ethanol
  • the formulations tested to improve the dissolution of ⁇ 9 - THC are shown in Table 1 below.
  • the solutions of the respective formulations were filled into size "1" hard gelatin capsules. It was later found that heat could be applied to the formulation processing steps to improve formulation content uniformity and homogeneity.
  • Figure 1 shows that the tested formulations proved to be more optimal than commercial formulations. These dissolution studies were conducted using 2% SLS in water media (Paddle Apparatus, 75 rpm). These tests also established that it was possible to enhance the dissolution of ⁇ 9 -THC using self-emulsifying drug delivery systems.
  • TritonX- 100 is an ideal choice for evaluating the ⁇ 9 -THC SEDDS formulations. Additional media such as simulated gastric and intestinal media may be required for further evaluation. In particular, fasted state simulated intestinal media (FaSSIF) and fed state simulated intestinal media (FeSSIF) are preferably used.
  • FaSSIF fasted state simulated intestinal media
  • FeSSIF fed state simulated intestinal media
  • Type I, Type II, and Type III SEDDS systems are isotropic in nature with uniform phase behavior before dilution in aqueous media.
  • Phase separated SEDDS formulae are not isotropic in nature and demonstrate cracking or poor matrix uniformity in the case of semisolids.
  • Table 3 shows the results of phase behavior examinations for select SEDDS, placebo formulations utilizing combinations of an oily carrier medium with Cremophor EL. Examinations were macroscopic (i.e. visual) as well as microscopic (Olympus ' Stereomicroscope).
  • the oily carrier medium is replaced by various "oils".
  • the surfactant component is replaced by various ingredients. Additional ingredients in the SEDDS matrix include viscosity modifiers, antioxidants, and metabolic/PGP inhibitors.
  • the SEDDS dosage form contents are incorporated into mammalian lipid absorption pathways (i.e., lymphatic transport), thereby bypassing hepatic first-pass metabolism.
  • mammalian lipid absorption pathways i.e., lymphatic transport
  • Type I, Type II, and Type III SEDDS systems are isotropic in nature with uniform phase behavior before dilution in aqueous media.
  • Table 4 below provides the results of phase behavior examinations for select SEDDS, placebo formulations utilizing combinations of an oily carrier medium with Labrasol. Examinations were macroscopic (i.e. visual) as well as microscopic (OlympusTM Stereomicroscope).
  • Carrier e.g. Oleic Acid (46.8) (60.8) (43.1 )
  • Surfactant Component e.g. 121 .75 79.0 1 12.5
  • oily carrier medium is replaced by various "oils” and the surfactant component replaced by various ingredients as previously described above.
  • Additional optional ingredients are present in the SEDDS matrix (e.g. viscosity modifiers, antioxidants, metabolic/PGP inhibitors, etc.)
  • the present disclosure provides ⁇ 9 -THC SEDDS compositions (i.e. Types I, II, & III) that form dispersions upon initial dilution in an aqueous environment.
  • ⁇ 9 -THC SEDDS compositions i.e. Types I, II, & III
  • the dispersion components resulting from the disintegration of the dosage form are incorporated into lipid absorption pathways ⁇ i.e. chylomicron/lipoprotein assembly to promote lymphatic transport and to avoid hepatic first-pass metabolism).
  • Example 1 Approximately 25 mg of each placebo formulation was added to 90 mL of selected media in a beaker with stir bar at 37°C. This procedure was designed to simulate USP Type II dissolution testing conditions employed in Example 1.
  • the dispersion testing results further support anticipated results when ⁇ 9 -THC SEDDS compositions are administered to a mammalian gastrointestinal system. Based on Table 5, the following outcomes apply:
  • the SEDDS dosage form contents are incorporated into mammalian lipid absorption pathways (i.e., lymphatic transport), thereby bypassing hepatic first-pass metabolism.
  • mammalian lipid absorption pathways i.e., lymphatic transport
  • Table 7 summarizes the compositions listed in Example 7.
  • the basic procedures to be employed for the preparation of these SEDDS combinations include:
  • antioxidant type or concentrations i.e. Ascorbyl Palmitate or DL- ⁇ - Tocopherol
  • dissolution testing profiles for these supers aturable SEDDS formulation i.e. #s 5, 6, 11 & 12 as shown in Table 7.
  • the profiles for these formulations in 2 % SLS were, however, peculiarly different from profiles for the initial compositions (i.e. Figure 1).
  • Table 8 summarizes the compositions in Example 8.
  • the basic procedures to be employed for the preparation of these SEDDS combinations include:
  • Table 10 summarizes the compositions evaluated in Example 10.
  • the basic procedures to be employed for the preparation of these SEDDS combinations include:
  • Table 11 summarizes the compositions evaluated in Example 11.
  • the basic procedures to be employed for the preparation of these SEDDS combinations include:
  • Table 12 summarizes the compositions evaluated in Example 12.
  • the basic procedures to be employed for the preparation of these SEDDS combinations include:
  • Table 13 summarizes the compositions evaluated in Example 13.
  • the basic procedures to be employed for the preparation of these SEDDS combinations include:
  • Formulation # 18 is evaluated under ICH stability testing conditions (i.e. 2-8°C, 25°C / 60% RH, & 40°C / 75% RH). After storing hard gelatin filled capsules and bulk formulation solutions from Formulation # 18 for three months, parameters are evaluated as described in Table 14.
  • Vitamin E Vitamin E
  • FCC DL- ⁇ - Tocopherol
  • Ascorbyl Palmitate provides synergistic stabilization effects for both the drug compound as well as the SEDDS matrix.
  • Table 14 below provides the evaluation results, which show the efficacy of antioxidants in maintaining the stability of the drug compound as well as the integrity of the capsule shell.
  • Example 15 Additional ⁇ 9 -THC SEDDS compositions are evaluated to determine the effect of additional oily components (e.g., Maisine 35-1) as well as co-solvents (e.g. , ethanol) on dissolution properties in 2 % SLS media (see Example 2).
  • additional oily components e.g., Maisine 35-1
  • co-solvents e.g. , ethanol
  • the resultant formulation matrices perform as immediate release products.
  • Table 15 summarizes the compositions evaluated in Example 15.
  • the basic procedures to be employed for the preparation of these Type III SEDDS combinations include:
  • Type III SEDDS compositions are evaluated to determine the effect of adding standardized marijuana extract (i.e., Cannabis sativa extract) on dissolution properties in 2 % SLS media (see Example 2).
  • standardized marijuana extract i.e., Cannabis sativa extract
  • the resultant formulation matrices also perform as immediate release products.
  • Table 16 summarizes the compositions evaluated in Example 16.
  • the basic procedures to be employed for the preparation of these Type III SEDDS combinations include:
  • CBD cannabigerol
  • cannabichromeme cannabidiol
  • CBD cannabidiol
  • delta-9-tetrahydrocannabinol delta-8-tetrahydrocannabinol
  • cannabicyclol CBL
  • cannabielsoin CBE
  • cannabinol CBN
  • CBDL cannabinodiol
  • CBTL cannabitriol
  • Gastrointestinal absorption for instance, involves hepatic (liver) first-pass whereas mucosal absorption does not.
  • the USP 35 th edition describes dissolution testing as a comparative test for ⁇ 9 - Tetrahydrocannabinol capsules intended for gastro-intestinal delivery only. The procedure is described below:
  • compositions are evaluated to determine the effect of additional oily components (e.g. , Maisine 35- 1) as well as co-solvents (e.g. , ethanol) on dissolution properties in 2 % SLS media (see Example 2).
  • additional oily components e.g. , Maisine 35- 1
  • co-solvents e.g. , ethanol
  • Table 18 summarizes the compositions evaluated in Example 18.
  • the basic procedures ployed for the preparation of these Type III SEDDS combinations include:
  • Type III SEDDS compositions are evaluated to determine the effect of adding standardized marijuana extract (i.e., Cannabis sativa extract) on dissolution properties in 2 % SLS media (see Example 2).
  • standardized marijuana extract i.e., Cannabis sativa extract
  • the resultant formulation matrices perform as immediate release products when administered as solutions after dilution in sufficient water or other compatible aqueous/liquid media.
  • Table 19 summarizes the compositions evaluated in Example 19.
  • the basic procedures to be employed for the preparation of these Type III SEDDS combinations include:
  • cannabinoid class phyto chemicals including cannabigerol ( CBG), cannabichromeme ( CBC), cannabidiol ( CBD), delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabicyclol ( CBL), cannabielsoin ( CBE), cannabinol ( CBN), cannabinodiol ( CBDL), and cannabitriol ( CBTL), etc.
  • CBG cannabigerol
  • CBC cannabichromeme
  • CBD cannabidiol
  • delta-9-tetrahydrocannabinol delta-8-tetrahydrocannabinol
  • cannabicyclol CBL
  • cannabielsoin CBE
  • cannabinol CBN
  • CBDL cannabinodiol
  • CBDL cannabitriol
  • additional ⁇ 9 -THC SEDDS compositions are evaluated to determine the effect of additional oily components (e.g. , Sesame Oil & Maisine 35- 1) as well as co-solvents (e.g. , ethanol) on dissolution properties in 2 % SLS media (see Example 2).
  • additional oily components e.g. , Sesame Oil & Maisine 35- 1
  • co-solvents e.g. , ethanol
  • Table 20 summarizes the compositions evaluated in Example 20.
  • the basic procedures to be employed for the preparation of these Type III SEDDS combinations include:
  • Type III SEDDS compositions are evaluated to determine the effect of adding standardized marijuana extract (i.e., Cannabis sativa extract) on dissolution properties in 2 % SLS media (see Example 2).
  • standardized marijuana extract i.e., Cannabis sativa extract
  • the resultant formulation matrices perform as immediate release products when administered as liquid solutions after dilution in sufficient water or other compatible aqueous/liquid media.
  • Table 21 summarizes the compositions evaluated in Example 21.
  • the basic procedures to be employed for the preparation of these Type III SEDDS combinations include:
  • CBD cannabigerol
  • cannabi hromeme cannabidiol
  • CBD cannabidiol
  • delta-9 -tetrahydrocannabinol delta-8-tetrahydrocannabinol
  • cannabicyclol CBL
  • cannabielsoin CBE
  • cannabinol CBN
  • CBDL cannabinodiol
  • CBTL cannabitriol
  • Example 22 In lieu of incorporating a synthetic cannabinoid or pure cannabinoid into dosage forms, Standardized Marijuana Extracts were incorporated into formulations as demonstrated in Example 19 and Example 21 above.
  • the Standardized Marijuana Extracts comprise of defined concentrations of ⁇ 9 -tetrahydrocannabinol(THC) with subsequent varying ratios of cannabigerol (CBG), cannabichromeme (CBC), cannabidiol (CBD), ⁇ 9 -tetrahydrocannabinol(THC), ⁇ 8 - tetrahydrocannabinol(THC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBDL), and cannabitriol (CBTL), and mixtures thereof.
  • CBG cannabigerol
  • CBC cannabichromeme
  • CBD cannabidiol
  • Standardized Marijuana Extracts were prepared with the addition of ethanol as a co- solvent, whereby extraction efficiencies were further enhanced with near zero content of ⁇ 9 -THC in the resultant raffinate (Marijuana plant leaf residue).
  • ethanol extracts were analyzed by a gas chromatographic (GC) analytical procedure.
  • cannabinoids present in the same Standardized Marijuana Extracts (e.g., cannabigerol (CBG), cannabichromeme (CBC), cannabidiol (CBD), ⁇ 9 -tetrahydrocannabinol (THC), ⁇ 8 - tetrahydrocannabinol (THC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBDL), and cannabitriol (CBTL), and mixtures thereof).
  • CBG cannabigerol
  • CBC cannabichromeme
  • CBD cannabidiol
  • THC cannabidiol
  • THC cannabidiol
  • THC cannabicyclol
  • CBE cannabielsoin
  • CBN cannabinol
  • CBDL cannabinodiol
  • CBTL canna
  • cannabinoids may be present including cannabigerol (CBG), cannabichromeme (CBC), cannabidiol (CBD), ⁇ 9 -tetrahydrocannabinol (THC), ⁇ 8 -tetrahydrocannabinol(THC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBDL), and cannabitriol (CBTL).

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Abstract

L'invention concerne une forme dosifiée gastro-intestinale orale de cannabinoïdes et/ou d'extraits de marijuana standardisés dans un système auto-émulsifiant conçu pour éviter un métabolisme de premier passage hépatique par l'intermédiaire de l'administration de chylomicron/lipoprotéine ciblée pour favoriser le transport lymphatique. La forme dosifiée gastro-intestinale orale comprend : (a) une forme pharmacologiquement active de cannabinoïdes et/ou d'extraits de marijuana standardisés ; et (b) un milieu huileux constitué de : (i) un ou plusieurs triglycérides formés à partir de gras à chaîne longue ayant des atomes de carbone C13 à C24 ; (ii) un ou plusieurs glycérides mélangés formés à partir de gras à chaîne longue ayant des atomes de carbone C13 à C24 ; et (iii) un ou plusieurs acides gras libres formés à partir d'acides gras à chaîne longue non estérifiés ayant des atomes de carbone C13 à C24 ; et (c) d'environ 10 à 60 % en poids d'un tensioactif qui favorise l'auto-émulsification.
PCT/US2015/044248 2014-08-07 2015-08-07 Système d'administration de forme dosifiée gastro-intestinale orale améliorée de cannabinoïdes et/ou d'extraits de marijuana standardisés WO2016022936A1 (fr)

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US14/454,145 US20140357708A1 (en) 2005-11-07 2014-08-07 Oral dosage form of tetrahydrocannabinol and a method of avoiding and/or suppressing hepatic first pass metabolism via targeted chylomicron/lipoprotein delivery
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WO2017180954A1 (fr) * 2016-04-15 2017-10-19 Ronald Silver Procédé de fabrication d'huile de cannabis hydrophilisée à l'aide d'émulsifiants, et compositions de cannabinoïdes associées
WO2017180953A1 (fr) * 2016-04-15 2017-10-19 Ronald Silver Édulcorants et élixirs imprégnés de cannabis
WO2017185038A1 (fr) 2016-04-22 2017-10-26 Receptor Life Sciences Composés médicinaux à base de plantes à action rapide, et suppléments nutritionnels
GB2551985A (en) * 2016-07-01 2018-01-10 Gw Res Ltd Novel formulation
WO2018061007A1 (fr) * 2016-09-29 2018-04-05 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Formulations diluables de cannabinoïdes et leurs procédés de préparation
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US20230075007A1 (en) * 2021-08-09 2023-03-09 Impact Naturals, Inc. Pharmaceutical formulations of cannabidiol
US20240082187A1 (en) * 2021-12-30 2024-03-14 Neuropro Therapeutics, Inc. Pharmaceutical composition
US20230390230A1 (en) * 2021-12-30 2023-12-07 Neuropro Therapeutics, Inc. Pharmaceutical composition

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