US 20070 104741A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0104741 A1 Murty et al. (43) Pub. Date: May 10, 2007
(54) DELIVERY OF TETRAHYDROCANNABINOL Publication Classification (51) Int. Cl. (75) Inventors: Ram B. Murty, Lexington, KY (US); A6II 3 L/353 (2006.01) Santos B. Murty, Lexington, KY (US) A6IR 9/00 (2006.01) A6II 3 L/655 (2006.01) Correspondence Address: (52) U.S. Cl...... 424/400: 514/454: 514/151 TOWNSEND & BANTA (57) ABSTRACT fo PORTFOLIO P A self-emulsifying drug delivery system to improve disso PO BOX S2OSO lution, stability, and bioavailability of drug compounds of MINNEAPOLIS, MN 55402 (US) dronabinol or other cannabinoids. The drug compound(s) are dissolved in an oily medium (e.g. triglycerides and/or (73) Assignee: Murty Pharmaceuticals, Inc., Lexing mixed glycerides and/or free fatty acids containing medium ton, KY and/or long chain Saturated, mono-unsaturated, and/or poly Appl. No.: 11/592,393 unsaturated free fatty acids) together with at least one (21) Surfactant. The Surfactant promotes self-emulsification, (22) Filed: Nov. 3, 2006 thereby promoting targeted chylomicron delivery and opti mal bioavailability to a mammalian intestinal lumen. A dosage form can optionally include co-solvents, anti-oxi Related U.S. Application Data dants, viscosity modifying agents, cytochrome P450 meta bolic inhibitors, P-GP efflux inhibitors, and amphiphilic/ (60) Provisional application No. 60/734,160, filed on Nov. non-amphiphilic solutes to induce semi-solid formation for 7, 2005. targeted release rates.
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DELIVERY OF TETRAHYDROCANNABINOL reported that another limitation of orally administered THC is the large inter-Subject variability in absorption. RELATED APPLICATION DATA 0008. Other postulated mechanisms for the biopharma 0001) This application claims the benefit of U.S. Provi ceutical anomalies can be attributed to the physical-chemical sional application No. 60/734,160, filed on Nov. 7, 2005. properties of A-THC. This compound is highly lipophilic, essentially water insoluble, and potentially acid labile within FIELD OF THE INVENTION the stomach. This compound is also sensitive to environ 0002 The present invention relates in general to a deliv mental storage and stress conditions. For instance, this ery system to improve administration of cannabinoids compound is thermolabile and photolabile, and long-term (THC) to patients and, more particularly, to a self-emulsi storage can lead to a cumulative decrease in A-THC content fying drug delivery system. The drug delivery system of the by an oxidation reaction forming cannabinol (CBN). present invention optimizes THC dissolution properties and 0009. It is well known that in mammals certain areas of avoids hepatic first-pass metabolism, thereby enhancing the alimentary canal have a venous drainage, which does not bioavailability through the gastrointestinal tract. The deliv involve a first pass through the liver. The avoidance of the ery system of the present invention can be administered as first pass effect is the rationale for the use of rectal, buccal, either a liquid or semi-solid matrix within a capsule shell for nasal, and Sublingual formulations. A A-THC and canna immediate or Sustained release rates. bidiol combination have been formulated as a buccal spray. Some of the disadvantages associated with nasal, Sublingual BACKGROUND OF THE INVENTION and buccal routes of administration are that the nasal mucosa 0003 Cannabinoids are compounds derived from the may cause pain or reflex Sneezing and, in extreme cases, cannabis sativa plant commonly known as marijuana. The may cause irritation and damage to the nasal mucosa. plant contains more than 400 chemicals and approximately Sublingual formulations may stimulate the flow of saliva, 60 cannabinoids. The most active chemical compound of the making it difficult for patients to avoid Swallowing when naturally occurring cannabinoids is tetrahydrocannabinol Substantial amounts of saliva are produced. Also, buccal formulations may be subject to the same limitations as (THC), particularly A-THC. Sublingual formulations. 0004 Currently, A-tetrahydrocannabinol, also known as dronabinol, is available commercially in MarinolR soft 0010 Both sublingual and buccal formulations depend gelatin capsules which have been approved by the Food and on the efficient transfer of medicament from a hydrophilic Drug Administration (FDA) for the control of nausea and vehicle to the mucous membrane of the sublingual or buccal Vomiting associated with chemotherapy and for appetite mucosa. Transfer of medicament through the interstices stimulation of AIDS patients suffering from the wasting between or through epithelial cells is governed principally syndrome. A-tetrahydrocannabinol shows other biological by the lipid solubility of the medicament. When a drug is activities, which lend themselves to possible therapeutic water insoluble as in the case with cannabinoids, this pre applications, such as in the treatment of glaucoma, migraine sents a further barrier to absorption from the sublingual area. headaches, spasticity, anxiety, analgesia, and drug addiction. 0011. In an effort to improve local drug delivery of THC, 0005. In Marinol R, A-THC is dissolved in sesame oil researchers have tried to develop a transdermal delivery and encapsulated in gelatin capsules for oral administration. system. The bioactive material administered dermally, how After oral administration, Dronabinol has an onset of action ever, may show erratic and irregular absorption. Hence, the of approximately 0.5 to 1 hour, with a peak effect of 2-4 need exists for the addition of absorption enhancers which in hours. The duration of action for psychoactive effects is 4-6 Some cases may be detrimental to the skin due to local side hours, but the appetite stimulant effect may continue for 24 effects. hours or longer after administration. The maximal plasma 0012. Other delivery systems for THC or cannabinoids levels after oral dosing of 20 mg THC in a sesame oil described in the patent literature, include: Metered dose formulation are around 10 ng/ml. inhaler using non-CFC propellants (U.S. Pat. Nos. 6,509, 0006. At the present time, some cancer patients manage 005 and 6,713,048); Pump action spray (U.S. Pat. No. to obtain prescriptions for marijuana in order to alleviate 6,946,150); Microsphere nasal delivery system (U.S. Pat. pain as well as nausea and vomiting due to chemotherapy. No. 6,383,513); Water soluble prodrugs for intranasal This latter situation arises due to poor or partial response administration (U.S. Patent No.: 6,380,175); Topical lini from oral therapy, which often requires oral administration ment (U.S. Pat. No. 6,949.582); Cyclodextrin complexes two to three times a day to obtain equivalent acute psycho with cannabinoids (U.S. Patent Application No. logical and physiological effects obtained from Smoking 20050153931); and Solid lipid compositions for oral admin marijuana. istration (U.S. Pat. Nos. 5,891, 469 and 5,989,583). 0007 When administered orally, THC or dronabinol is 0013 This solid lipid composition involves a method for almost completely absorbed (90-95%) after a single oral delivering a non-psychoactive cannabinoid (i.e. dexanab dose. However, due to the combined effect of first pass inol) in a dry lipid mixture to greatly enhance oral bioavail hepatic metabolism and high lipid solubility, only about ability when compared to known formulations. With 10-20% of an administered dose reaches systemic circula enhanced absorption characteristics of oral delivery systems, tion with highly variable maximal concentrations. It has the patentees anticipated that treatment could be directed been found that fasting or food deprivation may decrease the towards brain damage associated with stroke, head trauma, rate of absorption of THC from the sesame oil capsules and cardiac arrest. This, however, required sufficient bio currently available in the market. Previous studies have availability of the drug compound. Oral THC or dronabinol US 2007/01 04741 A1 May 10, 2007 therapy would be greatly benefited by improved bioavail 0020. Another object of the present invention is to pro ability for treating a variety of conditions described above. mote drug absorption through alternate gastrointestinal path Oral dosage forms are designed to enable sufficient avail ways, outside the conventional hepatic portal vein transport ability of the active compound at its site of action. The mechanism, which results in a high first-pass effect. bioavailability of a drug depends on several parameters, i.e., the physicochemical nature of the active compound, the SUMMARY OF THE INVENTION dosage form, as well as physiological factors. The cannab inoid compounds, being hydrophobic by nature, show wet 0021. The inventors herein, after extensive investigation ting difficulties and poor dissolution in the gastrointestinal and research, unexpectedly discovered an oral dosage form region. In addition, THC or dronabinol undergo extensive of cannabinoids which achieve the above objectives of the hepatic first-pass metabolism. These properties represent present invention. barriers to drug absorption from oral dosage forms. These 0022. The present invention provides an isotropic phased barriers in turn cause a Subsequent reduction in the bioavail and chemically stabilized oral delivery system of dronabinol ability. To compensate for the poor absorption displayed by or other cannabinoids. The drug compound(s) are dissolved many drugs, a pharmaceutical formulation may utilize or in an oily medium (e.g. triglycerides and/or mixed glycer take advantage of one or more mechanisms to increase the ides and/or medium/long chain Saturated, mono-unsaturated, rate and/or the extent to which the administered drug is and poly-unsaturated fatty acids) with at least one Surfactant absorbed. to promote self-emulsification. This formulation was unex 0014) Dronabinol or A-THC belongs to Class 11 (low pectedly found to promote targeted chylomicron delivery, aqueous solubility and high permeability) of the biophar and optimal bioavailability upon administration to the mam maceutical classification system (BCS). Hence, there may be malian intestinal lumen where endogenous bile salts reside. an advantage associated with a self-emulsifying (SEDDS) 0023 The SEDDS formulation of the present invention lipid based delivery system to enhance the dissolution of a preferably falls under one of the three categories. Type I, drug system in an aqueous environment. Patents demon Type II, and Type III, which are defined as isotropic mix strating the potential use of SEDDS or lipid delivery systems tures. These mixtures contain the following types of ingre for lipophilic drugs are U.S. Pat. Nos.: 5,484.801; 5,798, dients: (1) natural or synthetic oily mediums, (2) Solid or 333; 5,965,160; 6,008,228: 6,730,330. See also U.S. Patent liquid Surfactants, and (3) one or more hydrophilic solvents Application No. 20050209345, and International Applica and co-solvent/surfactants. tion No. PCT/EP96/02431 (WO 96/39142)). There are no known reports disclosing the oral delivery of THC based on 0024 Preferably, for A9-THC SEDDS, Types I, II, & III SEDDS technology to improve the dissolution characteris may be categorized as follows: tics and increase the oral bioavailability through chylomi 0025 (i) Type I formulations consist of an oily medium cron/lymphatic system. THC dosage forms intended for (e.g. triglycerides and/or mixed glycerides and/or other routes of administration are subjected to high intra and medium/long chain Saturated, mono-unsaturated, and inter patient variability. poly-unsaturated free fatty acids); whereas the oily 0015. However, SEDDS systems have not been used with medium may also be polyfunctional with potential cannabinoids for a number of reasons; first, due to the Surfactant characteristics to promote self-emulsifica possibility that the SEDDS system may undergo gastric tion. emptying while in a colloidal state; second, or the emulsi 0026 (ii) Type II consist of an oily medium (e.g. fying system may result in rapid absorption and higher peak triglycerides and/or mixed glycerides and/or medium/ concentrations of the drug; third, large concentrations of long chain Saturated, mono-unsaturated, and poly-un surfactant in the SEDDS system may cause gastrointestinal Saturated free fatty acids) and at least one Surfactant irritation. component to promote self-emulsification. 0016. Therefore, one of the objects of the present inven 0027 (iii) Type III consist of an oily medium (e.g. tion is to provide a more optimized and improved delivery triglycerides and/or mixed glycerides and/or medium/ system for THC to meet the desired needs of the patients. It long chain Saturated, mono-unsaturated, and poly-un is still another object of the present invention to provide an Saturated free fatty acids) and at least one Surfactant oral dosage form of THC or dronabinol, which provides component to promote self-emulsification, and at least sufficient bioavailability of this drug for the treatment of one hydrophilic cosolvent. numerous medical complications for which the drug can be therapeutically beneficial (e.g. brain damage associated with 0028 Optionally, the dosage form can include co-sol stroke, heat trauma, and cardiac arrest). vents, anti-oxidants, viscosity modifying agents, cyto chrome P450 metabolic inhibitors, P-GP efflux inhibitors, 0017. It is another object of the present invention to and finally amphiphilic/non-amphiphilic Solutes to induce provide a pharmaceutical formulation which compensates semi-solid formation for targeted release rates. for poor absorption displayed by THC or dronabinol. 0029. Upon administration as an isotropic liquid, semi 0018. It is yet another object of the present invention to Solid, or waxy Solid phase and upon initial dilution in the provide a pharmaceutical formulation for THC or dronab gastric region of a mammal, the contents immediately form inol which does not result in gastric emptying while in a a solid dispersion or coarse colloidal dispersion for protec colloidal state. tion against acid catalyzed degradation of cannabinoids. 0019. It is another object of the present invention is to With gastric emptying of the dispersion into the intestinal provide a pharmaceutical formulation for THC or dronab lumen, further solubilization with bile salts and downstream inol which does not cause gastrointestinal irritation. fatty acid processing promote the selective discriminative US 2007/01 04741 A1 May 10, 2007 transport of drug into lipid absorption pathways, particularly oily medium is selected from the group consisting of trig chylomicron synthesis in the endoplasmic reticulum of the lycerides formed from fatty acids having from C to C. intracellular environment of enterocytes, thereby avoiding carbon atoms with at least 75% of the fatty acids having hepatic first-pass metabolism. from C to C. carbon atoms, mixed glycerides formed from 0030. An isotropic semi-solid or waxy solid phase is fatty acids having from C to C. carbon atoms with at least prepared by dissolving a high concentration of ascorbyl 75% of the fatty acids having from C to C. carbon atoms, palmitate (or other amphiphilic/non-amphiphilic Solutes) in free fatty acids having from C to C2 carbon atoms with at an oily liquid State as described above. Upon administration least 75% of the fatty acids having from C to C. carbon as an isotropic semi-solid phase and upon initial dilution in atoms, and mixtures thereof. the gastric region of a mammal, the contents immediately 0038. In a fourth preferred embodiment, applicants dis form a solid dispersion or coarse colloidal dispersion for covered an oral dosage form of cannabinoids wherein the protection against acid catalyzed degradation of cannab oily medium is selected from the group consisting of borage inoids. oil, coconut oil, cottonseed oil, soybean oil, safflower oil, Sunflower oil, castor oil, corn oil, olive oil, palm oil, peanut 0031. With gastric emptying of the dispersion into the oil, peppermint oil, poppy seed oil, canola oil, hydrogenated intestinal lumen, further solubilization with bile salts and Soybean oil, hydrogenated vegetable oils, glyceryl esters of downstream fatty acid processing promote the selective saturated fatty acids, glyceryl behenate, glyceryl distearate, discriminative transport of drug into lipid absorption path glyceryl isostearate, glyceryl laurate, glyceryl monooleate, ways, particularly chylomicron synthesis in the endoplasmic glyceryl, monolinoleate, glyceryl palmitate, glyceryl palmi reticulum of the intracellular environment of enterocytes, to Stearate, glyceryl ricinoleate, glyceryl Stearate, polyglyc thereby avoiding hepatic first-pass metabolism. eryl 10-oleate, polyglyceryl 3-oleate, polyglyceryl 4-oleate, 0032. The self-emulsifying formulations of the present polyglyceryl 10-tetralinoleate, behenic acid, caprylyic/ca invention for A9-THC may be categorized as follows: pric glycerides, lauric acid, linoleic acid, linolenic acid, 0033 (i) Type I formulations consist of an oily medium myristic acid, palmitic acid, palmitoleic acid, palmitostearic (e.g. triglycerides and/or mixed glycerides and/or acid, ricinoleic acid, Stearic acid, soy fatty acids, oleic acid, medium/long chain Saturated, mono-unsaturated, and C-tocopherol, Y-tocopherol, Vitamin E, and vitamin A, and poly-unsaturated free fatty acids); whereas the oily mixtures thereof. medium may also be polyfunctional with potential 0039. In a fifth preferred embodiment, applicants discov Surfactant characteristics to promote self-emulsifica ered an oral dosage form of cannabinoids wherein the tion. triglycerides and mixed glycerides contain at least 75% of 0034 (ii) Type II consists of an oily medium (e.g. trig fatty acids having from C to C. carbon atoms. lycerides and/or mixed glycerides and/or mediumaong chain 0040. In a sixth preferred embodiment, applicants dis saturated, mono-unsaturated, and poly-unsaturated free fatty covered an oral dosage form of cannabinoids in which the oil acids), and at least one Surfactant component to promote is selected from the group consisting of synthetic oils, self-emulsification. semi-synthetic oils, naturally occurring oils, and mixtures 0035) In a first preferred embodiment, applicants discov thereof. ered an oral dosage form of cannabinoids comprising a 0041. In a seventh preferred embodiment, applicants dis pharmacologically active form of cannabinoids in a self covered an oral dosage form of cannabinoids in which the emulsifying system comprising an oily medium selected Surfactant is selected from the group consisting of polygly from the group consisting of triglycerides, glycerides, mixed colized glycerides, polyoxyethylene glycerides, polyethyl glycerides, free fatty acids having from C to C. carbon ene glycol-fatty acid esters, polyethylene glycol glycerol atoms, and mixtures thereof, and a surfactant which pro fatty acid esters, transesterfication products of oils and motes self-emulsification. alcohols, polyglycerized fatty acids, glycerol fatty acid 0036). In a second preferred embodiment, applicants dis esters, polyglycerol fatty acid esters, propylene glycol fatty covered an oral dose form of cannabinoids wherein the acid esters, mono and diglycerides, polyethylene glycol pharmacologically active cannabinoid is selected from the Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy group consisting of tetrahydrocannabinol, A-tetrahydrocan lene block copolymers, Sorbitan fatty acid esters, d-C.- nabinol(THC), A-tetrahydrocannabinol, A-tetrahydrocan tocopheryl polyethylene glycol 1000 succinate, polyoxyeth nabinol-DMH, A-tetrahydrocannabinol propyl analogue yleneglycol 660 12-hydroxy Stearate, polysorbates, and (THCV), 11-hydroxy-tetrahydrocannabinol, 11-nor-9-car mixtures thereof. boxy-tetrahydrocannabinol, 5'-azido-A-tetrahydrocannab 0042. In an eighth preferred embodiment, applicants dis inol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, covered an oral dosage form of cannabinoids in which the AM919, AM926, AM938, cannabidiol(CBD), cannabidiol Surfactant is selected from the group consisting of almond propyl analogue(CBDV), cannabinol (CBN), cannab oil PEG-6 esters, almond oil PEG-60 esters, apricot kernel ichromene, cannabichromene propyl analogue, cannabig oil PEG-6 esters, caprylic/capric triglycerides PEG-4 esters, erol, CP 47497, CP 55940, CP 55244, CP 50556, CT-3 caprylic/capric triglycerides PEG-4 complex, caprylic/ca (ajulemic acid), dimethylheptyl HHC, HU-210, HU-211, pric glycerides PEG-6 esters, caprylic?capric glycerides HU-308, WIN 55212-2, desacetyl-L-nantradol, dexanab PEG-8 esters, castor oil PEG-50 esters, hydrogenated castor inol, JWH-051, levonantradol, L-759633, nabilone, O-1184, oil PEG-5 esters, hydrogenated castor oil PEG-7 esters, 9 and mixtures thereof. hydrogenated castor oil PEG-9 esters, corn oil PEG-6 esters, 0037. In a third preferred embodiment, applicants dis corn oil PEG-8 esters, corn glycerides PEG-60 esters, olive covered an oral dosage form of cannabinoids wherein the oil PEG-6 esters, hydrogenated palm/palm kernel oil PEG-6 US 2007/01 04741 A1 May 10, 2007 esters, hydrogenated palm? palm kernel oil PEG-6 esters 0046. In a twelfth preferred embodiment, applicants dis with palm kernel oil and PEG-6 and palm oil, palm kernel covered an oral dosage form of cannabinoids comprising oil PEG-40 esters, peanut oil PEG-6 esters, glycerol esters of from about 1-80 wt % of a pharmacologically active form of saturated C8-C 18 fatty acids, glyceryl esters of saturated cannabinoids in a self-emulsifying system comprising from C12-C18 fatty acids, glyceryl laurate/PEG-32 laurate, glyc about 10-80 wt % of oily medium, from about 10-80 wt % eryl laurate glyceryl/PEG 20 laurate, glyceryl laurate glyc of surfactant, optionally from about 5-50 wt % of solubi eryl/PEG 32 laurate, glyceryl, laurate glyceryl/PEG 40 lau lizing co-solvent, and optionally from about 0.01-12.5 wt % rate, glyceryl oleate/PEG-20 glyceryl, glyceryl oleate/PEG of antioxidant. 30 oleate, glyceryl palmitostearate/PEG-32 palmitostearate, 0047. In a thirteenth preferred embodiment, applicants glyceryl Stearate/PEG stearate, glyceryl Stearate/PEG-32 discovered an oral dosage form of cannabinoids in which the Stearate, Saturated polyglycolized glycerides, trisoStearin pharmacologically active cannabinoid is selected from the PEG-6 esters, triolein PEG-6 esters, trioleate PEG-25 esters, group consisting of tetrahydrocannabinol, A-tetrahydrocan polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, nabinol(THC), A-tetrahydrocannabinol, A-tetrahydrocan polyoxyl 60 hydrogenated castor oil, PEG-8 caproate, nabinol-DMH, A-tetrahydrocannabinol propyl analogue PEG-8 caprylate, PEG-8 caprate PEG-8 laurate, PEG-8 (THCV), 11-hydroxy-tetrahydrocannabinol, 11-nor-9-car oleate, PEG-8 stearate, PEG-9 caproate, PEG-9 caprylate, boxy-tetrahydrocannabinol, 5'-azido-A-tetrahydrocannab PEG-9 caprate PEG-9 laurate, PEG-9 oleate, PEG-9 stear inol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, ate, PEG-10 caproate, PEG-10 caprylate, PEG-10 caprate AM919, AM926, AM938, cannabidiol(CBD), cannabidiol PEG-10 laurate, PEG-10 oleate, PEG-10 stearate, PEG-10 propyl analogue(CBDV), cannabinol (CBN), cannab laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, ichromene, cannabichromene propyl analogue, cannabig PEG-20 oleate, caprylate/caprate diglycerides, glyceryl erol, CP 47,497, CP 55940, CP 55244, CP 50556, CT-3 monooleate, glyceryl ricinoleate, glyceryl laurate, glyceryl (ajulemic acid), dimethylheptyl HHC, HU-210, HU-211, dilaurate, glyceryl dioleate, glyceryl mono/dioleate, glyceryl HU-308, WIN 55212-2, desacetyl-L-nantradol, dexanab caprylate/caprate, medium chain (C8/C10) mono- and dig inol, JWH-051, levonantradol, L-759633, nabilone, O-1184, lycerides, mono-and diacetylated monoglycerides, polyg and mixtures thereof. lyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 tri oleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, 0048. In a fourteenth preferred embodiment, applicants polyglyceryl-10 mono dioleate, propylene glycol caprylate/ discovered an oral dosage form of cannabinoids in which the caprate, propylene glycol dicaprylate? dicaprate, propylene oily medium is selected from the group consisting of trig glycol monolaurate, propylene glycol ricinoleate, propylene lycerides formed from fatty acids having from Cs to Ca glycol monooleate, propylene glycol dicaprylate/dicaprate, carbon atoms with at least 75% of the fatty acids having propylene glycol dioctanoate, PEG-20 sorbitan monolau from C8 to C. carbon atoms, mixed glycerides formed from rate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan fatty acids having from Cs to C. carbon atoms with at least monostearate, PEG-20 sorbitan monooleate, poloxamers 75% of the fatty acids having from Cs to C. carbon atoms, (108, 124, 182, 183, 188,212, 217, 238,288,331,338,335, free fatty acids having from Cs to C carbon atoms with at 407), Sorbitan monolaurate, Sorbitan monopalmitate, Sorbi least 75% of the free fatty acids having from Cs to Ca tan monoleate, Sorbitan monostearate, Sorbitan tristearate, carbon atoms; and mixtures thereof. d-C.- tocopheryl polyethylene glycol 1000 succinate, 0049. In a fifteenth preferred embodiment, applicants polysorbate 20, polysorbate, polyethyleneglycol 660 12-hy discovered an oral dosage form of cannabinoids in which the droxyStearate, and mixtures thereof. oily medium is selected from the group consisting of trig lyceride formed from fatty acids having from C8 to Cs 0043. In a ninth preferred embodiment, applicants dis carbon atoms with at least 75% of the fatty acids having covered an oral dosage form of cannabinoids incorporating from Cs to Cs carbon atoms, mixed glycerides formed from optional cosolvents, solubilizing agents and antioxidants fatty acids having from C8 to Cs carbon atoms with at least selected from the group consisting of ethanol, polyethylene 75% formed from fatty acids having from Cs to Cs carbon glycol 300, polyethylene glycol 400, propylene glycol, atoms, free fatty acids having from Cs to Cs carbon atoms propylene carbonate, N-methyl-2- pyrrolidones, dimethy with at least 75% of the fatty acids having from Cs to Cs lacetamide, dimethyl sulfoxide, hydroxypropyl-3-cyclodex trins, Sulfobutylether-B-cyclodextrin, C.-cyclodextrin, phos carbon atoms; and mixtures thereof. pholipids (HSPC, DSPG, DMPC, DMPG), ascorbyl 0050. In a sixteenth preferred embodiment, applicants palmitate, butylated hydroxy anisole, butylated hydroxy ani discovered an oral dosage form of cannabinoids in which the sole, propyl gallate, C.-tocopherol, and Y-tocopherol, and oily medium is selected from the group consisting of Syn mixtures thereof. thetic oils, semi-synthetic oils, naturally occurring oils, and mixtures thereof. 0044) In a tenth preferred embodiment, applicants dis covered an oral dosage form of cannabinoids in which the 0051. In a seventeenth preferred embodiment, applicants cannabinoids comprise from about 1-90 wt %, the oily discovered an oral dosage form of cannabinoids in which the medium comprises from about 5-90 wt %, and the surfactant Surfactant is selected from the group consisting of polygly comprises from about 5-90 wt %. colized glycerides, polyoxyethylene glycerides, polyethyl ene glycol-fatty acid esters, polyethylene glycol glycerol 0045. In an eleventh preferred embodiment, applicants fatty acid esters, transesterfication products of oils and discovered an oral dosage form of cannabinoids which alcohols, polyglycerized fatty acids, glycerol fatty acid further include optional Solubilizing co-solvents comprising esters, polyglycerol fatty acid esters, propylene glycol fatty from about 1-80 wt %, and the optional antioxidants com acid esters, mono and diglycerides, polyethylene glycol prising from about 0.01-15 wt %. Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy US 2007/01 04741 A1 May 10, 2007 lene block copolymers, Sorbitan fatty acid esters, d-C.- polyglyceryl 10-tetralinoleate, behenic acid, caprylyic/ca tocopheryl polyethylene glycol 1000 succinate, polyoxyeth pric glycerides, lauric acid, linoleic acid, linolenic acid, yleneglycol 660 1 2-hydroxyStearate, polysorbates, and mix myristic acid, palmitic acid, palmitoleic acid, palmitostearic tures thereof. acid, ricinoleic acid, Stearic acid, soy fatty acids, oleic-acid, 0.052 In an eighteenth preferred embodiment, applicants C-tocopherol, Y-tocopherol, Vitamin E, and vitamin A, and discovered an oral dosage form of cannabinoids comprising mixtures thereof. from about 1 to 60wt % of a pharmacologically active form of cannabinoids in a self-emulsifying system comprising BRIEF DESCRIPTION OF THE DRAWINGS from about 20 to 80 wt % of oily medium, from about 20 to 0055 FIG. 1 is a graph showing dissolution profiles of 60 wt % of surfactant, optionally from about 10 to 50 wt % cannabinoid containing formulations of the present inven of solubilizing co-solvent, and optionally from about 0.5 to tion, and a dissolution profile of a conventional cannabinoid 12.5 wt % of an antioxidant; the pharmacologically active containing formulation; cannabinoid being selected from the group consisting of tetrahydrocannabinol, A-tetrahydrocannabinol(THC), 0056 FIG. 2 is a graph showing the dissolution profile of A-tetrahydrocannabinol, A-tetrahydrocannabinol-DMH, a cannabinoid containing formulation of the present inven A-tetrahydrocannabinol propyl analogue (THCV), 11-hy tion illustrating, in particular, the peak concentration and droxy-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydro plateau region of the dissolution profile; and cannabinol, 5'-azido-A-tetrahydrocannabinol, AMG-1, 0057 FIG. 3 is a graph showing the dissolution profile of AMG-3, AM411, AM708, AM836, AM855, AM919, a cannabinoid containing formulation of the present inven AM926, AM938, cannabidiol(CBD), cannabidiol propyl tion illustrating, in particular, the Sustained drug release analogue(CBDV), cannabinol (CBN), cannabichromene, pattern over a four to six-hour period. cannabichromene propyl analogue, cannabigerol, CP 47497. CP 55940, CP 55244, CP 50556, CT-3 (ajulemic acid), DETAILED DESCRIPTION OF THE dimethylheptyl HHC, HU-210, HU-211, HU-308, WIN 55212-2, desacetyl-L-nantradol, dexanabinol, JWH-051. INVENTION levonantradol, L-759633, nabilone, 0-1184, and mixtures 0058 According to the present invention, improved dis thereof, and the oily medium being selected from the group solution, stability, and bioavailability of A9-THC is achieved consisting of triglycerides formed from fatty acids and/or by dissolving the A9-THC in an oily medium comprising mixed glycerides and/or medium/long chain free fatty acids, triglycerides and/or mixed glycerides and/or medium/long the triglycerides formed from fatty acids having from Cs to chain Saturated, mono-unsaturated, and poly-unsaturated Cs carbon atoms with at least 75% of the fatty acids having fatty acids containing at least one Surfactant component. from Cs to Cs carbon atoms, the mixed glycerides formed This composition promotes self-emulsification, thereby pro from fatty acids having from Cs to Cs carbon atoms with at moting targeted chylomicron delivery and optimal bioavail least 75% of the -fatty acids having from Cs to Cs carbon ability upon administration to the mammalian intestinal atoms, and free fatty acids having from Cs to Cs carbon lumen where endogenous bile salts reside. atoms with at least 75% of the free fatty acids having from 0059 Optionally, a preferred dosage form can include Cs to Cls carbon atoms. co-solvents, anti-oxidants, viscosity modifying agents, cyto 0053. In a nineteenth preferred embodiment, applicants chrome P450 metabolic inhibitors, P-GP efflux inhibitors, discovered an oral dosage form of cannabinoids wherein the and amphiphilic/non-amphiphilic solutes to induce semi Surfactant is selected from the group consisting of polygly Solid formation for targeted release rates. colized glycerides, polyoxyethylene glycerides, polyethyl ene glycol-fatty acid esters, polyethylene glycol glycerol 0060. In a preferred embodiment, to improve the solu fatty acid esters, transesterfication products of oils and bility of the lipophilic drug, the oily medium of thc formu alcohols, polyglycerized fatty acids, glycerol fatty acid lation can be selected from the group consisting of one or esters, polyglycerol fatty acid esters, propylene glycol fatty more of long-chain chain triglycerides or mixed glycerides acid esters, mono and diglycerides, polyethylene glycol including polyglycolized glycerides and polyoxyethylene Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy glycerides, such as, anise oil, apricot kernel oil, apricot lene block copolymers, Sorbitan fatty acid esters, d-C.- kernel oil PEG-6 esters, beeswax, borage oil, canola oil, tocopheryl polyethylene glycol 1000 succinate, polyoxyeth castor oil, castor oil polyoxyl 35, castor oil polyoxyl 40, yleneglycol 660 12-hydroxy Stearate, polysorbates, and mix castor oil polyoxyl 40 hydrogenated, castor oil polyoxyl 60, tures thereof. castor oil polyoxyl 60 hydrogenated castor oilhydrogenated, cinnamon oil, clove oil, coconut oil, coconut oil-lecithin, 0054. In a twentieth preferred embodiment, applicants coconut oil fractioned, coriander oil, corn oil, corn oil discovered an oral dosage form of cannabinoids wherein the PEG-6 esters, corn oil PEG-8 esters, cottonseed oil, cotton oily medium is selected from the group consisting of borage seed oil hydrogenated, kernel oil, kernel oil PEG-6 esters, oil, coconut oil, cottonseed oil, soybean oil, safflower oil, lemon oil, mineral oil, mineral oil (light), neutral oil, nutmeg Sunflower oil, castor oil, corn oil, olive oil, palm oil, peanut oil, olive oil, olive oil PEG-6 esters, orange oil, palm kernel oil, peppermint oil, poppy seed oil, canola oil, hydrogenated oil, palm kernel oil/hydrogenated, palm kernel oil PEG-6 Soybean oil, hydrogenated vegetable oils, glyceryl esters of esters, peanut oil, peanut oil PEG-6 esters, peppermint oil, saturated fatty acids, glyceryl behenate, glyceryl distearate, poppy seed oil, safflower oil, Sunflower oil, Soybean oil, glyceryl isostearate, glyceryl laurate, glyceryl monooleate, Soybean oil hydrogenated, soybean oil refined, trisoStearin glyceryl, monolinoleate, glyceryl palmitate, glyceryl palmi PEG-6 esters, vegetable oil, vegetable oil hydrogenated, to Stearate, glyceryl ricinoleate, glyceryl Stearate, polyglyc vegetable oils glyceride hydrogenated, vegetable oil PEG eryl 10-oleate, polyglyceryl 3-oleate, polyglyceryl 4-oleate, esters, and mixtures thereof. US 2007/01 04741 A1 May 10, 2007
0061. Other preferred oily mediums are long chain CS), hydrogenated palm/palm kernel oil PEG-6 esters mono-, or di-, glycerides, and/or polyglycolized glycerides (Labrafil RM 2130 BS), hydrogenated palm? palm kernel oil and polyoxyethylene glycerides, including glycerol esters of PEG-6 esters with palm kernel oil, PEG-6, palm oil (Labra saturated C8-C18 fatty acids (Gelucire R 33/01), glyceryl filR M 2130 CS), palm kernel oil PEG-40 esters, peanut oil esters of saturated C12-C18 fatty acids (Geluciree 39/01 and PEG-6 esters (Labrafil R. M. 1969 CS), glycerol esters of 43/01), glyceryl behenate, glyceryl distearate, glyceryl isos saturated C8-C18 fatty acids (Gelucire R 33/01), glyceryl tearate, glyceryl laurate, glyceryl laurate/PEG-32 laurate esters of saturated C12-C18 fatty acids (Gelucire R 39/01 (Gelucire R 44/14), glyceryl monooleate (Peceol(R) and and 43/01), glyceryl laurate/PEG-32 laurate (GelucireR) glyceryl monolinoleate (Maisine.R.), glyceryl palmitate, 44/14), glyceryl laurate glyceryl/PEG 20 laurate, glyceryl glyceryl palmitostearate, glyceryl palmitostearate/PEG-32 laurate glyceryl/PEG 32 laurate, glyceryl, laurate glyceryl/ (Gelucire R 50/13) palmitostearate glyceryl ricinoleate, PEG 40 laurate, glyceryl oleate/PEG-20 glyceryl, glyceryl glyceryl Stearate, glyceryl Stearate/PEG stearate, glyceryl oleate/PEG-30 oleate, glyceryl palmitostearate/PEG-32 stearate/PEG-32 stearate (Gelucire R 53/10), glyceryl Stear palmitostearate (Geluciree 50/13), glyceryl Stearate/PEG ate/PEG-40 stearate, glyceryl Stearate/PEG-75 stearate, stearate, glyceryl Stearate/PEG-32 stearate (GelucireR glyceryl Stearate/PEG-100 stearate, polyglyceryl 10-oleate, 53/10), saturated polyglycolized glycerides (GelucireR polyglyceryl 3-oleate, polyglyceryl 4-oleate, polyglyceryl 37/02 and Gelucire(R) 50/02), triisostearin PEG-6 esters (i.e. 10-tetralinoleate, polyoxyl 100 glyceryl Stearate, and satu Labrafil R. Isostearique), triolein PEG-6 esters, trioleate rated polyglycolized glycerides (Geluciree 37/02 and Gelu PEG-25 esters, polyoxyl 35 castor oil (Cremophor R EL), cireR 50/02), and mixtures thereof. polyoxyl 40 hydrogenated castor oil (Cremophor(R) RH 40), 0062). Other preferred oily mediums are long chain satu polyoxyl 60 hydrogenated castor oil (Cremophor R. RH60), rated fatty acids such as arachidic acid, behenic acid, 3-hy and mixtures thereof. droxymyristic acid, lauric acid, lignoceric acid, mycoceranic 0067 Preferred polyglycolized derivatives and polyoxy acid, myristic acid, palmitic acid, phytanic acid, Stearic acid, ethylene derivatives of medium to long chain fatty acids, tuberculoStearic acid, etc. Preferred long chain unsaturated which can be used in the present invention include PEG-8 fatty acids include arachidonic acid, linoleic acid, (C. or Y caproate, PEG-8 caprylate, PEG-8 caprate PEG-8 laurate, type), nervonic acid, oleic acid, palmitoleic acid, Soy fatty PEG-8 oleate, PEG-8 stearate, PEG-9 caproate, PEG-9 acids, and mixtures thereof. caprylate, PEG-9 caprate PEG-9 laurate, PEG-9 oleate, 0063 Preferred medium-chain mono-, di-, or tri-glycer PEG-9 stearate, PEG-10 caproate, PEG-10 caprylate, PEG ides, including polyglycolized glyceride derivatives and 10 caprate PEG-10 laurate, PEG-10 oleate, PEG-10 stearate, polyoxyethylene glycerides, include caprylic/capric glycer PEG-10 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 ides, caprylic/capric glycerides derived from coconut oil or laurate, PEG-20 oleate, and mixtures thereof. palm seed oil (e.g. LabrafacR, Miglyole 810, 812, Crodamol 0068 Preferred glycerol, polyglycerol, and propylene GTCC-PN, Softison R. 378), propylene glycol caprylate/ glycol esters of medium to long chain fatty acids, which can caprate (LabrafacR. PC), propylene glycol dicaprylate/dica be used in the present invention include caprylate/caprate prate (Miglyole 840), medium chain (C8/C10) mono- and diglycerides, glyceryl monooleate, glyceryl ricinoleate, diglycerides (CapmulR MCM, CapmulR MCM (L)), and glyceryl laurate, glyceryl dilaurate, glyceryl dioleate, glyc glycerol esters of saturated C8-C18 fatty acids (GelucireR) eryl mono/dioleate, glyceryl caprylate/caprate, medium 33/01), and mixtures thereof. chain (C8/C10) mono- and diglycerides (CapmulR MCM, CapmulR MCM (L)), mono-and diacetylated monoglycer 0064 Preferred medium chain fatty acids include caproic ides, polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyc acid, caprylic acid, capric acid, and mixtures thereof. eryl-10 trioleate, polyglyceryl-10 laurate, polyglyceryl-10 0065 Preferred fat-soluble vitamins and derivatives oleate, and polyglyceryl-10 monodioleate, propylene glycol include vitamin A, vitamin E (C. or Y tocopherol), vitamin E caprylate/caprate (Labrafac(R) PC), propylene glycol dica PEG 1000 succinate (d-C.- tocopheryl polyethylene glycol prylate? dicaprate (Miglyol(R) 840), propylene glycol mono 1000 succinate or TPGS), and mixtures thereof. laurate, propylene glycol ricinoleate, propylene glycol monooleate, propylene glycol dicaprylate/dicaprate, propy 0.066 The surfactant component of the formulation can lene glycol dioctanoate, and mixtures thereof. be used either alone or in combination with another surfac tant to improve the self-emulsifying properties of the for 0069 Preferred polyethylene glycol sorbitan fatty acid mulation. Preferred surfactant components are selected from esters, which can be used include PEG-20 sorbitan mono the goup consisting of polyglycolized glycerides and poly laurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan oxyethylene glycerides of medium to long chain mono-, di-, monostearate, and PEG-20 sorbitan monooleate, and mix and triglycerides, such as: almond oil PEG-6 esters, almond tures thereof. oil PEG-60 esters, apricot kernel oil PEG-6 esters (Labrafil.R. 0070 Preferred polyoxyethylene-polyoxypropylene M1944CS), caprylic/capric triglycerides PEG-4 esters block copolymers, which can be used include poloxamers (LabrafacR. Hydro WL 1219), caprylic/capric triglycerides (108, 124, 182, 183, 188,212, 217, 238,288,331, 338,335, PEG-4 complex (LabrafacR. Hydrophile), caprylic/capric and 407), and mixtures thereof. glycerides PEG-6 esters (SoftigenR 767), caprylic/capric glycerides PEG-8 esters (Labrasol(R), castor oil PEG-50 0071 Preferred sorbitan fatty acid esters, which can be esters, hydrogenated castor oil PEG-5 esters, hydrogenated used include Sorbitan monolaurate, Sorbitan monopalmitate, castor oil PEG-7 esters, 9 hydrogenated castor oil PEG-9 Sorbitan monoleate (Spane 20), Sorbitan monostearate and esters, corn oil PEG-6 esters (Labrafil R5 M 2125 CS), corn sorbitan tristearate and mixtures thereof. oil PEG-8 esters (Labrafile WL 2609 BS), corn glycerides 0072 Other preferred surfactants, which can be used PEG-60 esters, olive oil PEG-6 esters (Labrafil.R M1980 include TPGS (d-C.- tocopheryl polyethylene glycol 1000 US 2007/01 04741 A1 May 10, 2007 succinate), polysorbate 20 (Tweene.R. 20), polysorbate into a commercially available proprietary blend of excipi (Tween R. 80), polyethyleneglycol 660 12-hydroxystearate ents, Surfactants, coSurfactants, and a lipid phase. These (Solutol R HS-15), and mixtures thereof. proprietary blends known as SMEDDSR) (available from 0073. In a preferred embodiment, optional components of Gattefosse Corporation) are self-emulsifying matrixes the formulation can include co-solvents, antioxidants, vis which achieve improved dissolution and bioavailability of cosity modifying agents, cytochrome P450 metabolic inhibi lipophilic compounds. Optional components can also be tors, P-GP efflux inhibitors, and finally amphiphilic/non added such as co-solvents, antioxidants, viscosity modifying amphiphilic Solutes. These optional components can be used agents, cytochrome P450 metabolic inhibitors, P-GP efflux either alone or in combination with other ingredients to inhibitors, and amphiphilic/non-amphiphilic Solutes. improve the chemical and physical properties of the self 0081. In a preferred embodiment, the proportions of the emulsifying drug delivery systems. ingredients in the composition of the present invention 0074 Preferred co-solvents or solubilizers include agents include from about 1-90 wt %, preferably from about 1-80 such as ethanol, polyethylene glycol 300, polyethylene wt %, and more preferably from about 1-60 wt % of an glycol 400, propylene glycol, propylene carbonate, N-me active cannabinoid; thyl-2- pyrrolidones, dimethylacetamide, dimethyl sulfox 0082 from about 5-90 wt %, preferably from about 10-80 ide, hydroxypropyl-f-cyclodextrins, sulfobutylether -f-cy wt %, more preferably from about 20-80 wt % of an oily clodextrin, C.-cyclodextrin, glycerin, and various medium; and phospholipids (HSPC, DSPG, DMPC, & DMPG), and mix tures thereof. 0.083 from about 5-90 wt %, preferably from about 10-80 wt %, more preferably from about 20 to 60 wt % of the 0075 Preferred antioxidants include ascorbyl palmitate, Surfactant component; butylated hydroxy anisole, butylated hydroxy toluene, pro pyl gallate, C.-tocopherol, and finally Y-tocopherol, etc. The 0084. The optional solubilizing and co-solvent amounts antioxidants that can be chosen include combinations of two vary from about 1-80 wt %, preferably from about 5-50 wt or more agents described above, whereby ascorbyl palmitate %: more preferably from about 10-50 wt %. and tocopherol provide optimal Synergistic effects. 0085. The optional antioxidants may vary from about 0.076 Preferred viscosity modifying agents that can be 0.01-15 wt %, preferably from about 0.5 to 12.5 wt %. used include unmodified Starches, pregelatinized starches, crosslinked starches, guar gum, Xanthan gum, acacia, traga 0086). In a preferred embodiment, the semi-solid inducer canth, carrageenans, alginates, chitosan, polyvinyl pyrroli amount, which transforms the liquid SEDDS matrix to a done (PVP, e.g. Kollidon R, Povidone(R), polyethylene oxide semi-solid SEDDS matrix, varies from about 2.5-15 wt %, (e.g. PolyoxR), polyethylene glycols (PEGs, e.g. Carbo preferably from about 5-10 wt %, more preferably from wax(R), polycarbophils (e.g. CarbopolR), Eudragit(R) series about 7.5 to 10 wt %. polymers (E. L. S. RL, RS, NE), hydroxymethylpropyl 0087 Direct filling of hot melt matrices into hard gelatin cellulose (HPMC), hydroxyethylcellulose (HEC), hydrox capsules can be performed in the case of self-emulsifying ypropylmethylcelluose (HPC), carboxymethylcellose drug delivery systems. The vehicles act as dispersing or sodium (Na-CMC), ethylcellulose (e.g. Ethocel(R), cellulose emulsifying agents for the liberated drug in a finely divided acetate, and cellulose acetate phthalate, polyvinylacetate/ state. The higher Surface area of a drug produced in this way polyvinylpyrrolidone (PVA/PVP, e.g. Kollidon SRR), PVA/ facilitates dissolution in the gastrointestinal fluid, especially PEG graft copolymer (e.g. Kollidon IRR), hydrogenated in the presence of bile salts, lecithin, and lipid digestion vegetable oils, polyglycolized esters of fatty acids, carnauba mixtures. wax, Stearyl alcohol, and beeswax, and mixtures thereof. 0088 For ease of manufacturing, the carrier must be 0077 Preferred cytochrome P450 inhibitors include any amenable to liquid filling into hard gelatin capsules as hot agent incorporated into the SEDDS matrix that inhibits melt matrixed. The melting temperatures of carriers solu pre-systemic hepatic first pass metabolism (i.e. first pass tions preferably do not exceed above 80° C., which is the metabolism), such as d-C.- tocopheryl polyethylene glycol maximum acceptable temperature for hard gelatin capsule 1000 Succinate, anise oil, cinnamon oil, coriander oil, grape shells. This preferred approach has been followed in filling fruit oil, lemon oil, orange oil, peppermint oil, ascorbyl preferred formulations of the present invention. palmitate, propyl gallate, and various combinations thereof. 0089 Appropriate in vitro dissolution testing can be used 0078 Preferred PGP efflux inhibitors include any agent to predict therapeutic performance of any liquid, and semi incorporated into the SEDDS matrix that inhibits PGP Solid oral dosage forms in order to ensure product quality induced cellular efflux mechanisms (i.e. MDR), such as and batch-to-batch consistency. Optimal dissolution testing polyethoxylated castor oil derivatives, polyoxyethylene Sor methodologies clarify dissolution testing of self-emulsifying bitan monooleate, polyoxyethylene glycerides, and various drug delivery formulations intended for gastrointestinal combinations thereof. delivery. Thermal and textural properties, as well as Viscos 0079 Preferred amphiphilic/non-amphiphilic solutes ity and consistency of the dosage form, can be used to include any agent incorporated into the SEDDS matrix that influence drug release from lipid-based formulations. induces semi-solid formation from a liquid state. Preferably, 0090. In addition, it has been shown that changes in these agents would be pharmaceutical grade powder mate dissolution rate on aging do not always correlate with rials, which. are water insoluble (e.g. Ascorbyl Palmitate). changes in bioavailability from lipid-based formulations. 0080. In a preferred embodiment, A9-THC or any other Consequently, in order to achieve more meaningful results cannabinoid class compound can be directly incorporated during dissolution testing, SEDDS are analyzed under simu US 2007/01 04741 A1 May 10, 2007
lated gastric and intestinal conditions under fed and fasted cardiac inotropics, corticosteroids, diuretics, antiparkinso states. This is in addition to conventional dissolution testing nian, gastrointestinal, antihistamines, keratolytics, lipid in aqueous media with the presence of various Surfactants. regulating agents, muscle relaxants, antianginal, nutritional, 0091. In the present invention, the compositions are sex hormones, and stimulants. initially tested under various dissolution media having dif EXAMPLES ferent surfactant concentrations (1-5% w/w of sodium lauryl sulfate, TritonX-100, and Polysorbate 80) in order to iden 0095 The following examples illustrate formulations, tify ideal conditions for routine analysis. These composi dissolution methodology, and physical-chemical stability tions are also evaluated against the commercial product to evaluations. However, the following examples are intended predict better in vivo release profile. Thereafter, stability to be exemplary only and in no way limit the scope of the testing for SEDDS formulations is peculiar due to the present invention. The listed ingredients can be suitably presence of lipophilic compounds and lipid excipients are replaced with similar excipients known in the art. carried out. Thus, monitoring the stability of excipients is important in addition to the active ingredient. 0096] A list of materials used in the Examples and the source of these materials is as follows: 0092 Capsule leakage is a common problem and sophis ticated detection systems are often employed to monitor 0097 (i) A9-THC (National Institute on Drug Abuse, Such leakage. In order to maintain the product integrity and Rockville, Md.) closure from the Surrounding environment, the capsule dosage form resulting from the use of SEDDS in the present 0.098 (ii) Oleic Acid, Super Refined (Croda, USA) invention is anticipated to be in either a soft gelatin form, 0099 (iii) Peppermint Oil hard gelatin with band-sealed, hard gelatin with solvent sealing (e.g. Capsugel's Licaps). Band sealing, for instance, 0100 (iv) Sesame Oil, Super Refined (Croda, USA) utilizes a sealing Solution containing gelatin. This compo 0101 (v) Soybean Oil, Super Refined (Croda, USA) sition is preferably maintained at 45-48° C. for a nice band formation around a capsule to prevent any leakage or 0102 (vi) Capmul MCM (L) (Abitec Corp., USA) (vii) accidental opening of the product. Cremophor EL (BASF, Germany) 0093. In the present invention various cannabinoids can 0103 (viii) Cremophor RH 40 (BASF, Germany) be used alone or in combination to achieve Synergestic effects. Suitable cannabinoid compounds which can be used 0.104 (ix) Labrasol (Gattefosse, USA) either alone or in combination include tetrahydrocannabinol, A-tetrahydrocannabinol(THC), A-tetrahydrocannabinol, 0105 (x) Labrafil M1944 CS (Gattefosse, USA) A-tetrahydrocannabinol-DMH, A-tetrahydrocannabinol 0106 (xi) Ascorbyl Palmitate (Spectrum Chemicals, propyl analogue (THCV), 11-hydroxy-tetrahydrocannab USA) inol, 11-nor-9-carboxy-tetrahydrocannabinol, 5'-azido-A- 0107 (xii) Vitamin E, FCC (Spectrum Chemicals, tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM708, USA) AM836, AM855, AM919, AM926, AM938, cannabidiol (CBD), cannabidiol propyl analogue(CBDV), cannabinol 0108 (xiii) Povidone K-30 BASF, Germany) (CBN), cannabichromene, cannabichromene propyl ana logue, cannabigerol, CP 47,497, CP 55940, CP 55244, CP Example 1 50556, CT-3 (ajulemic acid), dimethylheptyl HHC, HU-210, 0.109 Tests were conducted to determine the feasibility of HU-211, HU-308, WIN 55212-2, desacetyl-L-nantradol, applying Type I and Type II self-emulsifying drug delivery dexanabinol, JWH-051, levonantradol, L-759633, nabilone, systems for THC, as well as for improving dissolution 0-1184. This invention also extends to other agents with testing over the existing sesame oil based compositions (i.e. homologous structural characteristics common with the can Marinol R). Based on initial results, it was found that Type nabinoid class of compounds. III self-emulsifying drug delivery systems could be used 0094. The proposed SEDDS compositions of the present with the addition of hydrophilic co-solvents (e.g. ethanol). invention are also useful to improve the dissolution, bio The formulations tested to improve the dissolution of THC availability, and stability of various lipophilic drugs having are shown in Table 1. The required amounts of excipients poor aqueous solubility. These agents can belong to drugs included therein along with THC (resin from) were trans categories such as analgesics, antihelminthics, antiarrhyth ferred to the test tube and were sonicated for 30-45 min mic, antiasthma, antibacterial, antiviral, anticoagulants, anti (temperature not more than 50° C.) until a clear solution was depressants, antidiabetics, antiepileptics, antifungal, anti obtained. The solutions of respective formulations were gout, antihypertensitive, antimalarials. antimigraine, filled into size “1” capsules. It was later found that heat antimuscuranic, antineoplastic, antiprotozoal, antithyroid, could be applied to the formulation processing steps to antitussives, anxiolytics, sedatives, hypnotics, neuroleptics, improve formulation content uniformity and homogeneity.
TABLE 1. mg of ingredient per formulation (% per caps Composition (i) (ii) (iii) (iv) (v) (vi) (vii) A9-THC (in resin form) 10 (3.85) 10 (3.85) 10 (3.85) 10 (3.85) 10 (3.65) 10 (3.71) 10 (4.1) Oleic acid 125 (48.1) 125 (48.1) 62 (24) 235 (95.95) Capmul MCM (L) 250 (96.15) – US 2007/01 04741 A1 May 10, 2007
TABLE 1-continued
mg of ingredient per formulation (% Composition (i) (ii) (iii) (iv) (v) (vi) (vii) Labrasol 125 (48.1) — 131.5 (48.88) – Labrafi M1944CS 125 (48.1) 188 (72.16) 139 (50.70) Sesame Oil 125 (45.65) Soybean Oil 127.5 (47.41) – Total 260 (100) 260 (100) 260 (100) 260 (100) 274 (100) 269 (100) 245 (100)
0110 FIG. 1 shows that the tested formulations proved to SEDDS formulations. Additional media such as simulated be more optimal than commercial formulations. These dis gastric and intestinal media may be required for further solution studies where conducted using 2% SLS in water evaluation. In particular, fasted State simulated intestinal media (Paddle Apparatus, 75 rpm). These tests also estab media (FaSSIF) and fed state simulated intestinal media lished that it was possible to enhance the dissolution of THC (FeSSIF) are preferably used. using self-emulsifying drug delivery systems. 0112 The data in Table 2 also establishes that SEDDS Example 2 systems have a protective effect for A9-THC against acid catalyzed degradation in the stomach environment. This is 0111. The above prepared formulation vii (Table 1), due to the fact that the drug is retained within the SEDDS which was categorized as a Type I SEDDS system, was matrix upon initial dilution in aqueous media and is unavail evaluated in various dissolution medium at 37° C. (Paddle, able for release into the Surrounding media. Upon perform 75 RPM) in order to determine the most appropriate testing ing aqueous dilution tests for placebo formulations conditions. The percentage release obtained in each of the described below (Examples 3 & 4), the formation of coarse tested dissolution medium is set forth in Table 2. solid dispersions or cloudy dispersions further show that SEDDS systems protect active cannabinoids against acid TABLE 2 catalyzed degradation in the stomach (Example 5). Percentage release (nin Example 3 0113 Preferred Type I, Type II, and Type III SEDDS Dissolution medium 15 30 60 120 240 systems are isotropic in nature with uniform phase behavior Water O O O O.3 1.1 2% SLS in Water 2100.O 21 OO.O 21 OO.O 21 OO.O 2100.0 before dilution in aqueous media. Phase separated SEDDS 5% TritonX-100 67.5 21 OO.O 21 OO.O 21 OO.O 2100.0 formulae, are not isotropic in nature and demonstrate crack Acetate buffer, pH 4.5 O.O O.O O.O O.O O.O ing or poor matrix uniformity in the case of semi-solids. Borate buffer, pH 9.5 39.8 67.3 21 OO.O 21 OO.O 2100.0 O.1N HC O.O O.O O.O O.O O.O 0114 Table 3 below shows the results of phase behavior examinations for select SEDDS, placebo formulations uti lizing combinations of an oily carrier medium with Cremo It is evident from the above results in Table 2 that 2% SLS phor EL. Examinations were macroscopic (i.e. visual) as or 5% TritonX-100 is an ideal choice for evaluating the THC well as microscopic (OlympusTM Stereomicroscope).
TABLE 3
Ingredient
(a) (b) (c) (d) mg (%) mg (%) mg (%) mg (%) PHYSICAL STATE
Fluidic Semi- Semi Liquid Liquid Solid Solid
Active Agent () (3.85) () (3.85) () (3.85) () (3.85) Oil Component Fatty Acid 120.0 (46.15) 121.75 (46.8) 158.0 (60.8) 112.5 (43.1) Carrier (e.g. Oleic Acid) Surfactant Component (e.g. 120.0 (46.15) 121.75 (46.8) 79.0 (30.4) 112.5 (43.1) Cremophor EL) US 2007/01 04741 A1 May 10, 2007
TABLE 3-continued Ingredient (a) (b) (c) (d) mg (%) mg (%) mg (%) mg (%) PHYSICAL STATE
Fluidic Semi Semi Liquid Liquid Solid Solid Vitamin E, FCC 5.0 (1925) Ascorbyl Palmitate 5.0 (1925) 6.5 (2.5) 13.0 (5.0) 26.0 (10.0) Total 250 (100) 250 (100) 250 (100) 251 (100) *Percentages in “( ) are based on the fill weight of ~260 mg for all drug loaded formulations
0115 Table 3 shows that with increasing ascorbyl palmi tate concentrations, the SEDDS matrix changes from liquid TABLE 4 state to a fluidic semi-solid state or semi-solid State. Thus, ascorbyl palmitate, an amphiphilic solute, serves as a semi Ingredient Solid inducer when present in excess concentrations in the (e) (f) (g) SEDDS formulation matrix. mg (%) mg (%) mg (%) 0116. In the present example, the oily carrier medium is PHYSICAL STATE replaced by various “oils”. The surfactant component is Fluidic replaced by various ingredients. Additional ingredients in Semi- Semi the SEDDS matrix include viscosity modifiers, antioxidants, Liquid Solid Solid and metabolic/PGP inhibitors. When SEDDS matrices are Active Agent () (3.85) () (3.85) () (3.85) administered with or without a capsule shell to a mammalian Oil Component 121.75 (46.8) 158.0 (60.8) 112.5 (43.1) gastrointestinal system (see Example 5), the following Fatty Acid Carrier (e.g. Oleic Acid) apply: Surfactant 121.75 (46.8) 79.0 (30.4) 112.5 (43.1) Component 0117 (i) The initial aqueous dispersion of the SEDDS (e.g. Labrasol) systems in the acidic stomach contents result in a Ascorbyl Palmitate 6.5 (2.5) 13.0 (5.0) 26.0 (10.0) coarse dispersion or Solid dispersion for protection against the acidic climate. Total 250 (100) 250 (100) 251 (100) 0118 (ii) With the presence of bile salts in the upper *Percentages in “( ) are based on the fill weight of ~260 mg for all drug duodenum, the SEDDS dosage form is incorporated loaded formulations into mammalian lipid absorption pathways, thereby bypassing hepatic first pass metabolism. 0123. It can be seen from Table 3 that with increasing ascorbyl palmitate concentrations, the SEDDS matrix 0119 (iii) When comparing the liquid SEDDS versus the semi-solid SEDDS compositions due to higher changes from a liquid State to a fluidic semi-solid state or a concentration of amphiphilic/non-amphiphilic, the semi-solid state, etc. Thus, ascorbyl palmitate, an former system provides faster drug dissolution profiles, amphiphilic Solute, serves as a semi-solid inducer when whereas the latter system provides more prolonged present in excess concentrations in the SEDDS formulation dissolution profiles, respectively. matrix. 0120 (iv) Liquid SEDDS systems immediately release 0.124. In the present example, the oily carrier medium is dosage forms, whereas semi-solid SEDDS systems replaced by various “oils” and the surfactant component Sustain release dosage forms. replaced by various ingredients as previously described above. Additional optional ingredients are present in the Example 4 SEDDS matrix (e.g. viscosity modifiers, antioxidants, meta 0121 Preferred Type I, Type II, and Type III SEDDS bolic/PGP inhibitors, etc.) The following conditions apply systems are isotropic in nature with uniform phase behavior when SEDDS matrices are administered with or without a before dilution in aqueous media. Phase separated SEDDS capsule shell to a mammalian gastrointestinal system (see formulae, which are not isotropic in nature, demonstrate Example 5): cracking or poor matrix uniformity in the case of semi Solids. 0125 (i) The initial aqueous dispersion of the SEDDS systems in the acidic stomach contents result in a 0122 Table 4 below provides the results of phase behav coarse dispersion or Solid dispersion for protection ior examinations for select SEDDS, placebo formulations utilizing combinations of an oily carrier medium with Labra against the acidic climate. Sol. Examinations were macroscopic (i.e. visual) as well as 0.126 (ii) With the presence of bile salts in the upper microscopic (OlympusTM Stereomicroscope). duodenum, the SEDDS dosage form contents are incor US 2007/01 04741 A1 May 10, 2007 11
porated into mammalian lipid absorption pathways, 0.133 (i) The initial aqueous dispersion of the SEDDS thereby bypassing hepatic first pass metabolism. systems in the acidic stomach contents result in a 0127 (iii) When comparing the liquid SEDDS versus coarse dispersion or Solid dispersion for protection the semi-solid SEDDS compositions due to higher against the acidic climate, and concentration of amphiphilic/non-amphiphilic, the 0.134 (ii) In the presence of bile salts in the upper former System would provide faster drug dissolution duodenum, the SEDDS dosage form contents are incor profiles whereas the latter system would provide more porated into mammalian lipid absorption pathways, prolonged dissolution profiles, respectively. thereby bypassing hepatic first pass metabolism. 0.128 (iv) Liquid SEDDS systems are immediately The results illustrated in Examples 1-5 provide encour released and semi-solid SEDDS systems undergo sus aging results of optimization of THC SEDDS compo sitions. Further efforts demonstrated in subsequent tained release. examples emphasize the modulation of drug release Example 5 rates by excipient selection as well as chemical stabi lization of SEDDS compositions by incorporating syn 0129. The present invention provides THC SEDDS com ergistic antioxidant combinations. positions (i.e. Types I, II, & III) that form coarse or solid dispersions upon initial dilution in an aqueous environment. Example 6 With the presence of bile salts in the upper intestinal lumen, 0.135 Based on initial compositions (Table 1) as well as the dispersion components resulting from the disintegration information in U.S. Pat. No. 6,232, 333, additional THC of the dosage form are incorporated into lipid absorption SEDDS compositions are tested to evaluate the effect of pathways (i.e chylomicron synthesis to avoid hepatic first changing oil:Surfactant ratios on dissolution properties in pass metabolism). 2% SLS media (see Example 2). The resultant formulation matrices are evaluated to ascertain if they perform as imme 0130. To test these possible outcomes, dispersion tests diate release products. Table 6 Summarizes the compositions were conducted in both aqueous and Surfactant media. Table evaluated in Example 6. The basic procedures to be 5 below provides the results of aqueous dispersion tests of employed for the preparation of these SEDDS combinations placebo formulations previously described in Examples 3 include: and 4. In addition, dispersion tests were conducted on select placebo compositions based on the original SEDDS formu 0.136 (i) Transfer Oil and Surfactant components into lae presented in Example 1. a clean beaker and heating the ingredients to 50° C.; 0131) Approximately 25 mg of each placebo formulation 0137 (ii) Slowly adding Ascorbyl Palmitate to the was added to 90 mL of selected media in a beaker with stir mixture; bar at 37°C. This procedure was designed to simulate USP 0.138 (iii) Stirring the contents well to form a homo Type II dissolution testing conditions employed in Example geneous mixture and continuing to maintain Solution at 1. 50-550 C.
TABLE 5
Dispersion Media
Observations of Dilution of Aqueous Dispersion Testing after 290 SLS Water Dispersion into 2% SLS 1 Hour (Surfactant Dispersion) (Aqueous Dispersion) Surfactant Bath (5x) (a) from Table 3 Clear Solution with No Cloudy Dispersion with Cloudy Dispersion Visible Particulates Particulates Visible Previously Observed Becomes Clear Solution (e) from Table 4 Clear Solution with No Cloudy Dispersion with Cloudy Dispersion Visible Particulates Particulates Visible Previously Observed Becomes Clear Solution (i) from Table 1 Clear Solution with No Fine Cloudy Dispersion Cloudy Dispersion Visible Particulates with Particulates Visible Previously Observed Becomes Clear Solution
0132) The dispersion testing results further support 0.139 (iv) Adding the required quantity of A9-THC anticipated results when THC SEDDS compositions are into the above melt matrix slowly under stirring and administered to a mammalian gastrointestinal system. Based continue heating at 50–55°C. until it dissolves/melts to on Table 5, the following outcomes apply: form a homogeneous formulation matrix; and US 2007/01 04741 A1 May 10, 2007 12
0140 (V) Filling the formulation matrix with the help of 0.144 (i) Transferring Capmul MCM (L) and Povidone a pipette into a capsule size “1 as per the target weight, and K-30 into a clean beaker and heating the ingredients to allowing to cool to room temperature. 50° C.
TABLE 6 mg of ingredient per formulations 20 per caps
Composition #1 #2 #3 hia A9-THC (in resin form) 10 (3.85) 10 (3.85) 10 (3.85) 10 (3.85) Oil Component (Oleic acid) 121.75 (46.8) 181.75 (69.9) 121.75 (46.8) 181.75 (69.9) Surfactant (Cremophor RH40) 121.75 (46.8) 61.75 (23.75) Surfactant (Labrasol) 121.75 (46.8) 61.75 (23.75) Ascorbyl Palmitate 6.5 (2.5) 6.5 (2.5) 6.5 (2.5) 6.5 (2.5) Total 260 (100) 260 (100) 260 (100) 260 (100
0141. The variations in oil to surfactant ratios do not 0145 (ii) Slowly adding Ascorbyl Palmitate or DL-C.- adversely impact the dissolution test results. For, Formula Tocopherol to the preceding mixture; tion is 1, 2, 3, & 4 as shown in Table 6, dissolution of the active agent in 2% SLS is nearly complete within 1 hour 0146 (iii) Stirring the contents well to form a homo (paddle, 75 RPM). These results are similar to the SEDDS geneous mixture and continuing to maintain Solution at compositions described in Table 1 and FIG.1. It is noted that 50-550 C. formulations prepared under Example 6 are characterized as 0147 (iv) Adding the required quantity of A9-THC liquid SEDDS compositions. into the above melt matrix slowly under stirring and continue heating at 50–55°C. until it dissolves/melts to Example 7 form a homogeneous formulation matrix; and 0142 Based on initial compositions (Table 1) as well as 0.148 (V) Filling the formulation matrix with the help of information obtained from U.S. Pat. No. 6,008,228, addi a pipette into a capsule size “1” as per the target weight and tional compositions are tested to evaluate the efficacy of allowing to cool to room temperature to form a semi-solid supersaturable SEDDS systems with the addition of viscos matrix.
TABLE 7 mg of ingredient per formulation 20 per caps
Composition #5 i11 #6 #12 A9-THC (in resin form) 10 (3.85) 10 (3.85) 10 (3.85) 10 (3.85) Oil Surfactant Component 223.5 (85.95) 223.5 (85.95) 217.0 (83.45) 217.0 (83.45) (Capmul MCM (L)) PVP K-30 (Povidone) 20 (7.70) 20 (7.70) 20 (7.70) 20 (7.70) DL-C-Tocopherol 6.5 (2.5) 13.0 (5.0) Ascorbyl Palmitate 6.5 (2.5) 13.0 (5.0) Total 260 (100) 260 (100) 260 (100) 260 (100) * Capmul based compositions based on commercial Saquinivir (Fortovase) formulae as described in U.S. Patent # 6,008,228 ity modifying agents. These supersaturable SEDDS systems 0.149 The variations in antioxidant type or concentra are evaluated for improvements in THC dissolution profiles tions (i.e. Ascorbyl Palmitate or DL-C.- Tocopherol) do not in 2% SLS media when compared to Marinol R) dissolution drastically alter the dissolution testing profiles for these (FIG. 1). It is noted that Capmul MCM (L) serves as both the superstaturable SEDDS formulation (i.e. is 5, 6, 11 & 12 as oil and surfactant components of the SEDDS systems. This shown in Table 7). The profiles for these formulations in 2% polyfunctional pharmaceutical excipient contains multiple SLS were, however, peculiarly different from profiles for the ingredients, especially medium chain mono and diglycer initial compositions (i.e. FIG. 1). ides. The resultant formulation matrices performed as imme 0150. As for Formulation #5 as presented in Table 7, the diate release products. dissolution results are illustrated in FIG. 2, whereby the initial dispersion provides a Supersaturable peak concentra 0143 Table 7 summarizes the compositions listed in tion. This is analogous to a situation observed with amor Example 7. The basic procedures to be employed for the phous drug dissolution profiles. In either case, a plateau preparation of these SEDDS combinations include: region occurs after initial Supersaturation. US 2007/01 04741 A1 May 10, 2007
Example 8 0158. The variations in oily medium do not alter the 0151. Based on initial compositions (Table 1), additional release profile pattern as previously described with the THC SEDDS compositions are tested to evaluate the effect original compositions. The dissolution process is nearly of varying the oily medium (i.e. from oleic acid to Soybcan complete within 1 hour in 2% SLS media (paddle, 75 RPM). oil) on dissolution properties in 2% SLS media (see Example 2). The resultant formulation matrices perform as Example 9 immediate release products. 0152 Table 8 summarizes the compositions in Example 0159 Based on initial compositions (Table 1) as well as 8. The basic procedures to be employed for the preparation information obtained from Examples 3 and 4, additional of these SEDDS combinations include: THC SEDDS compositions are tested with high ascorbyl 0.153 (i) Transferring Oil and Surfactant components palmitate. content loading for semi-solid formation. The into a clean beaker and heating the ingredients to 50° C.; resultant formulation matrices perform as Sustained release products. Table 9 Summarizes the compositions evaluated in 0154 (ii) Slowly adding Ascorbyl Palmitate to the mixture; Example 9. The basic procedures to be employed for the preparation of these SEDDS combinations include: 0.155 (iii) Stirring the contents well to form a homo geneous mixture and continuing to maintain Solution at 0.160 (i) Transferring A9-THC into a clean beaker and 50-550 C. heating the ingredients to 65-70° C: 0156 (iv) Adding the required quantity of A9-THC into the above melt matrix slowly under stirring and 0.161 (ii) Slowly adding the oil component to the continuing heating at 50–55°C. until it dissolves/melts beaker; to form a homogeneous formulation matrix; and 0157 (v) Filling the formulation matrix with the help of 0162 (iii) Adding surfactant component to the clear a pipette into a capsule size “1 as per the target weight and mixture; allowing to cool to room temperature. 0163 (iv) Stirring9. the contents well to form a homo TABLE 8 geneous mixture and continuing to maintain the clear mixture at 65-70° C.; mg of ingredient per formulation 20 per caps 0.164 (v) Adding the required quantity of Ascorbyl Palmitate into the above melt matrix slowly under Composition # 7 # 8 stirring and continuing heating at 65-70° C. until it A9-THC (in resin form) 10 (3.85) 10 (3.85) dissolves/melts to form a homogeneous formulation Oil Component (Soybean Oil) 121.75 (46.8) 181.75 (69.9) Surfactant Component 121.75 (46.8) 61.75 (23.75) matrix; and (Cremophor RH40) Ascorbyl Palmitate 6.5 (2.5) 6.5 (2.5) 0.165 (vi) Filling the formulation matrix with the help of a pipette into a capsule size “1 as per the target weight and Total 260 (100) 260 (100) allowing to cool to room temperature to form a semi-solid matrix or liquid.
TABLE 9
mg of ingredient per placebo formulation (% per caps)
Composition #13 #14 #15 i16
Active Agent 10 (3.85) 10 (3.85) 10 (3.85) () (3.85) Oil Component (Oleic acid) 150.0 (57.47) 150.0 (57.47) Oil Component (Soybean Oil) 150.0 (57.47) 150.0 (57.47) Surfantant Component 75.0 (28.74) 75.0 (28.74) (Cremophor RH40) Surfantant Component 75.0 (28.74) 75.0 (28.74) (Labrasol) Ascorbyl Palmitate 26.0 (9.96) 26.0 (9.96) 26.0 (9.96) 26.0 (9.96)
Total 261 (100) 261 (100) 261 (100) 261 (100) US 2007/01 04741 A1 May 10, 2007
0166 The incorporation of high ascorbyl palmitate con centrations results in Sustained drug release pattern over a 4 TABLE 10-continued to 6 hour period in 2% SLS media (paddle, 75 RPM). The mg of ingredient per placebo prolonged drug release rates is attributed to the formation of formulation a semi-solid matrix. The semi-solid matrix induced by the 20 per caps ascorbyl palmitate serves as a stabilizing mechanism for a compound such as A9-THC, which demonstrates a high Composition # 17 # 18 ii. 19 oxidation potential. Finally, it is realized during formulation Vitamin E, FCC 5.0 (1925) 5.0 (1925) 5.0 (1925) preparation that processing temperatures can reach as high Ascorbyl Palmitate 5.0 (1925) 5.0 (1925) 13.0 (5.0) as 65-70° C. This does not adversely impact the chemical and physical characteristics of the A9-THC SEDDS matri Total 260 (100) 260 (100) 260 (100) CCS. Example 10 0.175. The variations in surfactant component does not 0167 Based on initial compositions (Table 1) as well as alter the release profile pattern as with the original compo information obtained from Example 6, additional THC sitions. The dissolution process is nearly complete within 1 SEDDS compositions are evaluated with different surfactant hour in 2% SLS media (paddle, 75 RPM). Furthermore, components (i.e. Cremophor EL, Labrafil M1944CS). In additional examples can substitute a multitude of different addition, combinations of Surfactants are tested in order to Surfactant components. Finally, it was realized that during obtain a composite HLB value of approximately between formulation preparation, processing temperatures can reach 11-12 for optimal performance of a Type II SEDDS system. as high as 65-70° C. This does not adversely impact the Finally, combination of antioxidants are tested in order to chemical and physical characteristics of the A9-THC optimize Synergistic protection for the drug compound and SEDDS matrices. SEDDS matrix. The resultant formulation matrices perform as immediate release products. 0176 Example 11 0168 Table 10 Summarizes the compositions evaluated 0.177 Based on initial compositions (Table I) as well as in Example 10. The basic procedures to be employed for the information from Example 10, additional THC SEDDS preparation of these SEDDS combinations include: compositions are tested with different surfactant compo 0.169 (i) Transferring A9-THC into a clean beaker and nents (i.e. Labrasol, Labrafil M1944CS). In addition, com heating the ingredients to 65-70° C: binations of surfactants are tested in order to obtain a composite HLB value of approximately between 11-12 for 0170 (ii) Slowly adding the oil component to the optimal performance of a Type II SEDDS system. Finally, beaker; combination of antioxidants are tested in order to optimize 0171 (iii) Add surfactant component to the clear mix synergistic protection for the drug compound and SEDDS ture; matrix. The resultant formulation matrices perform as immediate release products. 0172 (iv) Stirring9. the contents well to form a homo geneous mixture and continuing to maintain the clear 0.178 Table 11 summarizes the compositions evaluated in mixture at 65-70° C.; Example 11. The basic procedures to be employed for the 0173 (v) Adding the required quantity of Ascorbyl preparation of these SEDDS combinations include: Palmitate into the above melt matrix slowly under stirring and continuing heating at 65-70° C. until it 0.179 (i) Transferring A9-THC into a clean beaker and dissolves/melts to form a homogeneous formulation heating the ingredients to 65-70° C.; matrix; and 0180 (ii) Slowly adding the oil component to the 0174 (vi) Filling the formulation matrix with the help of beaker; a pipette into capsule size '1' (hypromellose or hard gelatin) as per the target weight and allow to cool to room tempera 0181 (iii) Adding surfactant component to the clear ture to form a semi-solid matrix or liquid. mixture; 0182 (iv) Stirring9. the contents well to form a homo TABLE 10 geneous mixture and continuing to maintain the clear mg of ingredient per placebo mixture at 65-70° C.; formulation 20 per caps 0183 (v) Adding the required quantity of Ascorbyl Palmitate into the above melt matrix slowly under Composition # 17 # 18 ii. 19 stirring and continue heating at 65-70° C. until it Active Agent 10.0 (3.85) 10.0 (3.85) 10.0 (3.85) dissolves/melts to form a homogeneous formulation Oil Component 120.0 (46.15) 120.0 (46.2) 155.0 (59.62) matrix; and (Oleic Acid) Surfantant Component 120.0 (46.15) 95.0 (36.5) 57.0 (21.92) (Cremophor EL) 0.184 (vi) Filling the formulation matrix with the help of Surfantant Component 25.0 (9.61) 20.0 (7.69) a pipette into a capsule size “1 (hypromellose or hard (Labrafil M1944CS) gelatin) as per the target weight and allowing to cool to room temperature to form a semi-solid matrix or liquid US 2007/01 04741 A1 May 10, 2007 15
0188 (i) Transferring A9-THC into a clean beaker and TABLE 11 heating the ingredients to 65-70° C.;
mg of ingredient per placebo 0189 (ii) Slowly adding the oil component to the formulation beaker; (% per caps) 0.190 (iii) Adding surfactant component to the clear Composition # 20 # 21 # 22 mixture; 0191 (iv) Stirring9. the contents well to form a homo Active Agent 10.0 (3.85) 10.0 (3.85) 10.0 (3.85) geneous mixture and continuing to maintain the clear Oil Component (Oleic 120.0 (46.15) 120.0 (46.2) 155.0 (59.62) mixture at 65-70° C.; Acid) Surfantant Component 120.0 (46.15) 95.0 (36.5) 57.0 (21.92) 0.192 (v) Adding the required quantity of Ascorbyl (Labrasol) Palmitate into the above melt matrix slowly under Surfantant Component 25.0 (9.61) 20.0 (7.69) stirring and continuing heating at 65-70° C. until it (Labrafil M1944CS) dissolves/melts to form a homogeneous formulation Vitamin E, FCC 5.0 (1925) 5.0 (1925) 5.0 (1925) matrix; and Ascorbyl Palmitate 5.0 (1925) 5.0 (1925) 13.0 (5.0) 0193 (vi) Filling the formulation matrix with the help Total 260 (100) 260 (100) 260 (100) of a pipette into a capsule size “1 (hypromellose or hard gelatin) as per the target weight and allow to cool to room temperature to form a semi-solid matrix or liquid
TABLE 12 mg of ingredient per placebo formulation 20 per caps
Composition # 23 ii. 24 # 25 # 26 Active Agent 10.0 (3.85) 10.0 (3.85) 10.0 (3.85) 10.0 (3.85) Oil Component (Oleic Acid) 109.5 (42.12) 109.5 (42.12) 150.0 (57.69) 150.0 (57.69) Surfactant Component 87.5 (33.65) 55.0 (21.15) (Cremophor EL) Surfactant Component 87.5 (33.65) 55.0 (21.15) (Labrasol) Surfactant Component (Labrafil 22.0 (8.46) 22.0 (8.46). 20.0 (7.69) 20.0 (7.69) M1944CS) Vitamin E, FCC 5.0 (1925) 5.0 (1925) 5.0 (1925) 5.0 (1.925) Ascorbyl Palmitate 26.0 (10.00) 26.0 (10.00) 20.0 (7.69) 20.0 (7.69)
0185. The variations in surfactant component do not alter 0194 The use of high ascorbyl palmitate concentrations the release profile pattern as with the original compositions. can result in Sustained drug release pattern over a 4 to 6 hour The dissolution process is nearly complete within 1 hour in period in 2% SLS media (paddle, 75 RPM), as illustrated in 2% SLS media (paddle, 75 RPM). Furthermore, additional FIG. 3 (Dissolution Profiles for Formulation # 25 in Hard examples may be performed by Substituting a multitude of Gelatin and Hypromellose Capsule Shells). different Surfactant components. During formulation prepa 0.195 The prolonged drug release rates are attributed to ration, processing temperatures can reach as high as 65-70 the formation of a semi-solid matrix. It is found that the semi-solid matrix induced by the ascorbyl palmitate serves C. This does not adversely influence the chemical and as a stabilizing mechanism for a compound such as A9-THC, physical characteristics of the A9-THC SEDDS matrices. which illustrates a high oxidation potential. It is realized during formulation preparation that processing temperatures Example 12 can reach as high as 65-70° C. This does not adversely 0186 Based on initial compositions (Table 1) as well as impact the chemical and physical characteristics of the information obtained from Example 9, additional THC A9-THC SEDDS matrices. SEDDS compositions are tested to optimize dissolution Example 13 parameters for semi-solid formulations with high ascorbyl 0.196 Based on initial compositions (Table 1) as well as palmitate content loading. Furthermore, the resultant formu information obtained from Examples 6, 10, & 11, additional lation matrices perform as Sustained release products. THC SEDDS compositions are evaluated to determine the effect of additional oily components (i.e. Peppermint Oil) on 0187 Table 12 Summarizes the compositions evaluated dissolution properties in 2% SLS media (see Example 2). in Example 12. The basic procedures to be employed for the The resultant formulation matrices perform as immediate preparation of these SEDDS combinations include: release products. US 2007/01 04741 A1 May 10, 2007 16
0197) Table 13 Summarizes the compositions evaluated zation effects for both the drug compound as well as the in Example 13. The basic procedures to be employed for the SEDDS matrix. Table 14 below provides the evaluation preparation of these SEDDS combinations include: results, which show the efficacy of antioxidants in maintain 0198 (i) Transferring A9-THC into a clean beaker and ing the stability of the drug compound as well as the heating the ingredients to 65-70° C.; integrity of the capsule shell. 0199 (ii) Slowly adding the oil component to the beaker; TABLE 1.4 Related and 0200 (iii) Adding surfactant component to the clear Degradation mixture; Substances 0201 (iv) Stirring9. the contents well to form a homo Capsule Delta-8 geneous mixture and continuing to maintain the clear Conditions Time (Months) Description Assay CBN THC mixture at 65-70° C.; NA Initial No Deformity 99.3% 2.3% NA 0202 (v) Adding the required quantity of Ascorbyl 2° 8° C. 1 No Deformity 97.1% 1.9% 1.0% 2 No Deformity 98.6% 1.7% 1.0% Palmitate into the above melt matrix slowly under 3 No Deformity 97.7% 2.2% 1.1% stirring and continue heating at 65-70° C. until it 25° C.60% 1 No Deformity 99.0% 2.8% 1.5% dissolves/melts to form a homogeneous formulation RH 2 No Deformity 99.0% 1.8% 0.9% matrix; and 3 No Deformity 98.7% 2.2% 0.9% 40° C.75% 1 No Deformity 95.3% 2.4% 1.5% 0203 (vi) Filling the formulation matrix with the help of RH 2 No Deformity 96.5% 1.9% 0.8% a pipette into a capsule size “1 as per the target weight and 3 No Deformity 96.2% 2.2% 1.1% allow to cool to room temperature to form a semi-solid matrix or liquid.
TABLE 13 mg of ingredient per formulation 20 per caps
Composition # 27 # 28 # 29 if 30 Active Agent 10 (3.85) 10 (3.85) 10 (3.85) 10 (3.85) Oil Component (Oleic Acid) 95.0 (36.54) 120.0 (46.15) 95.0 (36.54) 120.0 (46.15) Oil Component (Peppermint Oil, USP-NF) 25.0 (9.615) 25.0 (9.615) 25.0 (9.615) 25.0 (9.615) Surfactant Component 95.0 (36.54) 75.0 (28.85) (Cremophor EL) Surfactant Component 95.0 (36.54) 75.0 (28.85) (Labrasol) Surfactant Component (Labrafil M1944CS) 25.0 (9.615) 20.0 (7.692) 25.0 (9.615) 20.0 (7.692) Vitamin E, FCC 5.0 (1925) 5.0 (1925) 5.0 (1925) 5.0 (1925) Ascorbyl Palmitate 5.0 (1925) 5.0 (1925) 5.0 (1925) 5.0 (1925) Total 260 (100) 260 (100) 260 (100) 260 (100)
0204 The additional oil component does not alter the What we claim is: release profile pattern as with the original compositions 1. An oral dosage form of cannabinoids comprising a (Table 1). The dissolution process is nearly complete within pharmacologically active form of cannabinoids in a self 1 hour in 2% SLS media (paddle, 75 RPM). Furthermore, emulsifying system comprising an oily medium selected additional examples may be evaluated by Substituting a from the group consisting of triglycerides, mixed glycerides, multitude of different oil components. Finally, it is realized free fatty acids having from C to C. carbon atoms, and during formulation preparation, that processing tempera mixtures thereof, and a surfactant which promotes self tures can reach as high as 65-70°C. This does not adversely emulsification. influence the chemical and physical characteristics of the 2. The oral dosage form of cannabinoids of claim 1, A9-THC SEDDS matrices. wherein the pharmacologically active cannabinoid is selected from the group consisting of tetrahydrocannabinol, Example 14 A9-tetrahydrocannabinol(THC), A-tetrahydrocannabinol, 0205 Based on the information provided in Example 10, A-tetrahydrocannabinol-DMH, A-tetrahydrocannabinol Formulation # 18 is evaluated under ICH stability testing propyl analogue (THCV), 11-hydroxy-tetrahydrocannab conditions (i.e. 2-8° C., 25° C. /60% RH., & 40° C. /75% inol, 11-nor-9-carboxy-tetrahydrocannabinol, 5'-azido-A- RH). After storing hard gelatin filled capsules and bulk tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, AM919, AM926, AM938, cannabidiol formulation solutions from Formulation # 18 for three (CBD), cannabidiol propyl analogue(CBDV), cannabinol months, parameters are evaluated as described in Table 14. (CBN), cannabichromene, cannabichromene propyl ana 0206. The combination of Vitamin E, FCC (DL-C-Toco logue, cannabigerol, CP 47,497, CP 55940, CP 55244, CP pherol) and Ascorbyl Palmitate provides synergistic stabili 50556, CT-3 (ajulemic acid), dimethylheptyl HHC, HU-210, US 2007/01 04741 A1 May 10, 2007
HU-211, HU-308, WIN 55212-2, desacetyl-L-nantradol, esters, glycerol esters of saturated C8-C18 fatty acids, dexanabinol, JWH-051, levonantradol, L-759633, nabilone, glyceryl esters of saturated C12-C 18 fatty acids, glyceryl O-1184, and mixtures thereof. laurate/PEG-32 laurate, glyceryl laurate glyceryl/PEG 20 3. The oral dosage form of cannabinoids of claim 1, laurate, glyceryl laurate glyceryl/PEG 32 laurate, glyceryl, wherein the oily medium is selected from the group con laurate glyceryl/PEG 40 laurate, glyceryl oleate/PEG-20 sisting of triglycerides formed from fatty acids having from glyceryl, glyceryl oleate/PEG-30 oleate, glyceryl palmito C to C. carbon atoms with at least 75% of these fatty acids stearate/PEG-32 palmitostearate, glyceryl Stearate/PEG having from C to C. carbon atoms, mixed glycerides Stearate, glyceryl Stearate/PEG-32 Stearate, Saturated polyg formed from fatty acids having from C to C. carbon atoms lycolized glycerides, triisostearin PEG-6 esters, triolein with at least 75% of the fatty aids having from C to C. PEG-6 esters, trioleate PEG-25 esters, polyoxyl 35 castor carbon atoms, free fatty acids having from C to C. carbon oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydro atoms with at least 75% of the free fatty acids having from genated castor oil, PEG-8 caproate, PEG-8 caprylate, PEG-8 C to C2 carbon atoms; and mixtures thereof. caprate PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, 4. The oral dosage form of cannabinoids of claim 1, PEG-9 caproate, PEG-9 caprylate, PEG-9 caprate PEG-9 wherein the oily medium is selected from the group con laurate, PEG-9 oleate, PEG-9 stearate, PEG-10 caproate, sisting of borage oil, coconut oil, cottonseed oil, Soybean oil, PEG-10 caprylate, PEG-10 caprate PEG-10 laurate, PEG-10 safflower oil, Sunflower oil, castor oil, corn oil, olive oil, oleate, PEG-10 stearate, PEG-10 laurate, PEG-12 oleate, palm oil, peanut oil, peppermint oil, poppy seed oil, canola PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, caprylate/ oil, hydrogenated Soybean oil, hydrogenated vegetable oils, caprate diglycerides, glycceryl monooleate, glyceryl, rici glyceryl esters of Saturated fatty acids, glyceryl behenate, noleate, glyceryl laurate, glyceryl dilaurate, glyceryl glyceryl distearate, glyceryl isostearate, glyceryl laurate, dioleate, glyceryl mono/dioleate, glyceryl caprylate/caprate, glyceryl monooleate, glyceryl, monolinoleate, glyceryl medium chain C8/C10 mono- and diglycerides, mono-and palmitate, glyceryl palmitostearate, glyceryl ricinoleate, diacetylated monoglycerides, polyglyceryl oleate, polyglyc glyceryl Stearate, polyglyceryl 10-oleate, polyglyceryl eryl-2 dioleate, polyglyceryl-10 trioleate, polyglyceryl-10 3-oleate, polyglyceryl 4-oleate, polyglyceryl 10-tetrali laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono noleate, behenic acid, caprylyic/capric glycerides, lauric dioleate, propylene glycol caprylate/caprate, propylene gly acid, linoleic acid, linolenic acid, myristic acid, palmitic col dicaprylate? dicaprate, propylene glycol monolaurate, acid, palmitoleic acid, palmitostearic acid, ricinoleic acid, propylene glycol ricinoleate, propylene glycol monooleate, Stearic acid, soy fatty acids, oleic acid, C-tocopherol, Y-to propylene glycol dicaprylate/dicaprate, propylene glycol copherol, Vitamin E, and vitamin A, and mixtures thereof. dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan 5. The oral dosage form of cannabinoids of claim 1, monopalmitate. PEG-20 sorbitan monostearate, PEG-20 wherein the triglycerides and mixed glycerides contain at Sorbitan monooleate, poloxamer 108, poloxamer 124, poloX least 75% of fatty acids having from C to C. carbon atoms. amer 182, poloxamer 183, poloxamer 188, poloxamer 212, 6. The oral dosage form of cannabinoids of claim 1, poloxamer 217, poloxamer 238, poloxamer 288, poloxamer wherein the oil is selected from the group consisting of 331, poloxamer 338, poloxamer 335, poloxamer 407, sor synthetic oils, semi-synthetic oils, naturally occurring oils, bitan monolaurate, Sorbitan monopalmitate, Sorbitan mono leate, Sorbitan monostearate, Sorbitan tristearate, d-C-toco and mixtures thereof. pheryl polyethylene glycol 1000 succinate, polysorbate 20, 7. The oral dosage form of cannabinoids of claim 1, polysorbate, polyethyleneglycol 660 12-hydroxystearate, wherein the Surfactant is selected from the group consisting of polyglycolized glycerides, polyoxyethylene glycerides, and mixtures thereof. polyethylene glycol-fatty acid esters, polyethylene glycol 9. The oral dosage form of cannabinoids of claim 1, glycerol fatty acid esters, transesterfication products of oils further comprising optional cosolvents, Solubilizing agents and alcohols, polyglycerized fatty acids, glycerol fatty acid and antioxidants selected from the group consisting of esters, polyglycerol fatty acid esters, propylene glycol fatty ethanol, polyethylene glycol 300, polyethylene glycol 400, acid esters, mono and diglycerides, polyethylene glycol propylene glycol, propylene carbonate, N-methyl-2-pyrroli Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy dones, dimethylacetamide, dimethyl Sulfoxide, hydroxypro lene block copolymers, Sorbitan fatty acid esters, d-C.- pyl-3-cyclodextrins, Sulfobutylether -3-cyclodextrin, C.-cy tocopheryl polyethylene glycol 1000 succinate, polyoxyeth clodextrin, HSPC phospholipid, DSPG phospholipid, yleneglycol 660 12-hydroxy Stearate, polysorbates, and mix DMPC phospholipid, DMPG phospholipid, ascorbyl palmi tures thereof. tate, butylated hydroxy anisole, butylated hydroxy anisole, 8. The oral dosage form of cannabinoids of claim 1, propyl gallate, C.-tocopherol, and Y-tocopherol, and mixtures wherein the Surfactant is selected from the group consisting thereof. of almond oil PEG-6 esters, almond oil PEG-60 esters, 10. The oral dosage form of cannabinoids of claim 1, apricot kernel oil PEG-6 esters, caprylic/capric triglycerides wherein the cannabinoid comprises from about 1-90 wt %, PEG-4 esters, caprylic/capric triglycerides PEG-4 complex, the oily medium comprises from about 5-90 wt %, and the caprylic?capric glycerides PEG-6 esters, caprylic/capric surfactant comprises from about 5-90 wt %. glycerides PEG-8 esters, castor oil PEG-50 esters, hydro 11. The oral dosage form of cannabinoid of claim 1, genated castor oil PEG-5 esters, hydrogenated castor oil further comprising optional Solubilizing co-solvents com PEG-7 esters, 9 hydrogenated castor oil PEG-9 esters, corn prising from about 1-80 wt %, and the optional antioxidants oil PEG-6 esters, corn oil PEG-8 esters, corn glycerides comprising from about 0.01-15 wt %. PEG-60 esters, olive oil PEG-6 esters, hydrogenated palm/ 12. An oral dosage form of cannabinoids comprising from palm kernel oil PEG-6 esters, hydrogenated palm? palm about 1-80 wt % of a pharmacologically active form of kernel oil PEG-6 esters with palm kernel oil and PEG-6 and cannabinoids in a self-emulsifying system comprising from palm oil, palm kernel oil PEG-40 esters, peanut oil PEG-6 about 10-80 wt % of oily medium, from about 10-80 wt % US 2007/01 04741 A1 May 10, 2007
of surfactant, optionally from about 5-50 wt % of solubi wt % of surfactant, optionally from about 10 to 50 wt % of lizing co-solvent, and optionally from about 0.01-12.5 wt % solubilizing co-solvent, and optionally from about 0.5 to of antioxidant. 12.5 wt % of an antioxidant, the pharmacologically active 13. The oral dosage form of cannabinoids of claim 12, cannabinoid being selected from the group consisting of wherein the pharmacologically active cannabinoid is tetrahydrocannabinol, A-tetrahydrocannabinol, A-tetrahy selected from the group consisting of tetrahydrocannabinol, drocannabinol, A-tetrahydrocannabinol-DMH, A-tetrahy A-tetrahydrocannabinol, A-tetrahydrocannabinol, A-tet drocannabinol propyl analogue, 11-hydroxy-tetrahydrocan rahydrocannabinol-DMH, A-tetrahydrocannabinol propyl nabinol, 11-nor-9-carboxy-tetrahydrocannabinol, 5'-azido analogue, 11-hydroxy-tetrahydrocannabinol. 1-nor-9-car A-tetrahydrocannabinol, AMG-1, AMG-3, AM41 1, boxy-tetrahydrocannabinol, 5'-azido-A-tetrahydrocannab AM708, AM836, AM855, AM919, AM926, AM938, can inol, AMG-1, AMG-3, AM41 1, AM708, AM836, AM855, nabidiol, cannabidiol propyl analogue, cannabinol, cannab AM919, AM926, AM938, cannabidiol, cannabidiol propyl ichromene, cannabichromene propyl analogue, cannabig analogue, cannabinol, cannabichromene, cannabichromene erol, CP 47497, CP 55940, CP 55244, CP 50556, CT-3, propyl analogue, cannabigerol, CP 47,497, CP 55940, CP dimethylheptyl HHC, HU-210, HU-21 1, HU-308, WIN 55244, CP 50556, CT-3, dimethylheptyl HHC, HU-210, 55212-2, desacetyl-L-nantradol, dexanabinol, JWH-051. HU-211, HU-308, WIN 55212-2, desacetyl-L-nantradol, levonantradol, L-759633, nabilone. 0-1184, and mixtures dexanabinol, JWH-051, levonantradol, L-759633, nabilone, thereof, and the oily medium is selected from the group 0-1184, and mixtures thereof. consisting of triglycerides and/or mixed glycerides and/or 14. The oral dosage form of cannabinoids of claim 12, medium/long chain free fatty acids, the triglycerides formed wherein the oily. medium is selected from the group con from fatty acids having from Cs to Cs carbon atoms with at sisting of triglycerides formed from fatty acids having from least 75% of the fatty acids having from Cs to Cs carbon Cs to C. carbon atoms with at least 75% of the fatty acids having from Cs to C. carbon atoms, mixed glycerides atoms, the mixed glycerides formed from fatty acids having formed from fatty acids having from Cs to C. carbon atoms from Cs to Cs carbon atoms with at least 75% of the fatty with at least 75% formed from fatty acids having from Cs to acids having from Cs to Cs carbon atoms, and free fatty C. carbon atoms, free fatty acids having from Cs to Ca acids having from Cs to Cs carbon atoms with at least 75% carbon atoms with at least 75% of the free fatty acids having of the free fatty acids having from Cs to Cs carbon atoms. from Cs to C. carbon atoms; and mixtures thereof. 19. The oral dosage form of cannabinoids of claim 18, 15. The oral dosage form of cannabinoids of claim 12, wherein the Surfactant is selected from the group consisting wherein the oily medium is selected from the group con of polyglycolized glycerides, polyoxyethylene glycerides, sisting of triglyceride formed from fatty. acids having from polyethylene glycol-fatty acid esters, polyethylene glycol Cs to Cs carbon atoms with at least 75% of the fatty acids glycerol fatty acid esters, transesterfication products of oils having from Cs to Cs carbon atoms, mixed glycerides and alcohols, polyglycerized fatty acids, glycerol fatty acid formed from fatty acids having from Cs to Cs carbon atoms esters, polyglycerol fatty acid esters, propylene glycol fatty with at least 75% formed from fatty acids having from Cs to acid esters, mono and diglycerides, polyethylene glycol Cs carbon atoms, free fatty acids having from Cs to Cs Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy carbon atoms with at least 75% of the fatty acids having lene block copolymers, Sorbitan fatty acid esters, d-C.- from Cs to Cs carbon atoms; and mixtures thereof. tocopheryl polyethylene glycol 1000 succinate, polyoxyeth 16. The oral dosage form of cannabinoids of claim 12, yleneglycol 660 12-hydroxy Stearate, polysorbates, and mix wherein the oily medium is selected from the group con tures thereof. sisting of synthetic oils, semi-synthetic oils, naturally occur 20. The oral dosage form of cannabinoids of claim 18, ring oils, and mixtures thereof. wherein the oily medium is selected from the group con 17. The oral dosage form of cannabinoids of claim 12, sisting of borage oil, coconut oil, cottonseed oil, Soybean oil, wherein the Surfactant is selected from the group consisting safflower oil, Sunflower oil, castor oil, corn oil, olive oil, of polyglycolized glycerides, polyoxyethylene glycerides, palm oil, peanut oil, peppermint oil, poppy seed oil, canola polyethylene glycol-fatty acid esters, polyethylene glycol oil, hydrogenated Soybean oil, hydrogenated vegetable oils, glycerol fatty acid esters, transesterfication products of oils glyceryl esters of Saturated fatty acids, glyceryl behenate, and alcohols, polyglycerized fatty acids, glycerol fatty acid glyceryl distearate, glyceryl isostearate, glyceryl laurate, esters, polyglycerol fatty acid esters, propylene glycol fatty glyceryl monooleate, glyceryl, monolinoleate, glyceryl acid esters, mono and diglycerides, polyethylene glycol palmitate, glyceryl palmitostearate, glyceryl ricinoleate, Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy glyceryl Stearate, polyglyceryl 10-oleate, polyglyceryl lene block copolymers, Sorbitan fatty acid esters, d-C.- 3-oleate, polyglyceryl 4-oleate, polyglyceryl 10-tetrali tocopheryl polyethylene glycol 1000 succinate, polyoxyeth noleate, behenic acid, caprylyic/capric glycerides, lauric yleneglycol 660 12-hydroxy Stearate, polysorbates, and mix acid, linoleic acid, linolenic acid, myristic acid, palmitic tures thereof. acid, palmitoleic acid, palmitostearic acid, ricinoleic acid, 18. An oral dosage form of cannabinoids comprising from Stearic acid, soy fatty acids, oleic acid, C.-tocopherol, Y-to about 1 to 60 wt % of a pharmacologically active form of copherol, Vitamin E, and vitamin A, and mixtures thereof. cannabinoids in a self-emulsifying system comprising from about 20 to 80 wt % of oily medium, from about 20 to 60