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WO2020252284A1 - Composition pharmaceutique cannabinoïde compressible - Google Patents

Composition pharmaceutique cannabinoïde compressible Download PDF

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Publication number
WO2020252284A1
WO2020252284A1 PCT/US2020/037464 US2020037464W WO2020252284A1 WO 2020252284 A1 WO2020252284 A1 WO 2020252284A1 US 2020037464 W US2020037464 W US 2020037464W WO 2020252284 A1 WO2020252284 A1 WO 2020252284A1
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cannabinoid
composition
doi
granulate
cbd
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Leo MENDEZ
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Imbucanna Inc
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Imbucanna Inc
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Priority to CA3140813A priority Critical patent/CA3140813A1/fr
Publication of WO2020252284A1 publication Critical patent/WO2020252284A1/fr
Priority to US17/127,186 priority patent/US20210196637A1/en
Priority to US17/446,663 priority patent/US20210401795A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • a compressible pharmaceutical composition comprising a cannabinoid and at least one excipient is disclosed.
  • the composition may be used in the manufacture of compressible dosage forms of cannabinoids such as tablets.
  • CBD cannabidiol
  • Cannabis is a genus of flowering plants that includes three different species, Cannabis sativa, Cannabis indica and Cannabis ruderalis.
  • the term“Cannabis plant(s)” encompasses wild type Cannabis and also variants thereof, including Cannabis chemovars which naturally contain different amounts of the individual cannabinoids.
  • Cannabis chemovars which naturally contain different amounts of the individual cannabinoids.
  • some Cannabis strains have been bred to produce minimal levels of THC, the principal psychoactive constituent responsible for the high associated with it and other strains have been selectively bred to produce high levels of THC and other psychoactive cannabinoids.
  • Hemp is a strain of Cannabis sativa and produces almost exclusively CBD and little or no THC.
  • Cannabis plants produce a unique family of terpeno-phenolic compounds called cannabinoids, which produce the intoxication effect from consuming marijuana, which is orally active or can be smoked.
  • cannabinoids There are 483 identifiable chemical constituents known to exist in the cannabis plant, and at least 85 different cannabinoids have been isolated from the plant.
  • the two cannabinoids usually produced in greatest abundance are cannabidiol (CBD) and D9- tetrahydrocannabinol (THC), but only THC is psychoactive.
  • CBD cannabidiol
  • THC D9- tetrahydrocannabinol
  • the best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).
  • cannabinoids include for example, cannabichromene (CBC), cannabigerol (CBG) cannabinidiol (CBND), Cannabicyclol (CBL), Cannabivarin (CBV), Tetrahydrocannabivarin (THCV), Cannabidivarin (CBDV), Cannabichromevarin (CBCV) Cannabigerovarin (CBGV), Cannabigerol Monomethyl Ether (CBGM).
  • CBC cannabichromene
  • CBG cannabigerol
  • CBDND cannabinidiol
  • CBL Cannabicyclol
  • CBV Cannabivarin
  • THC Tetrahydrocannabivarin
  • THCV Cannabidivarin
  • CBDV Cannabichromevarin
  • CBDV Cannabigerovarin
  • CBGV Cannabigerol Monomethyl Ether
  • CBD cannabidiol
  • THC delta-9-tetrahydrocannabinol
  • Synthetic cannabinoids encompass a variety of distinct chemical classes: the cannabinoids structurally related to THC, the cannabinoids not related to THC, such as (cannabimimetics) including the aminoalkyl indoles, 1 ,5-diarylpyrazoles, quinolines, and arylsulfonamides, and eicosanoids related to the endocannabinoids. Any or all of these cannabinoids can be used in the present invention.
  • THC more formally (-)-trans-A 9 -tetrahydrocannabinol, approved as a drug in many countries with the INN“Dronabinol,” is a naturally occurring compound and is the primary active ingredient in marijuana.
  • Marijuana is dried hemp plant Cannabis Sativa. The leaves and stems of the plant contain cannabinoid compounds (including dronabinol). Dronabinol has been approved by the Food and Drug Administration for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of patients suffering from wasting syndrome.
  • Synthetic dronabinol is a recognized pharmaceutically active ingredient (API), but natural botanical sources of Cannabis rather than synthetic THC are also known in the art. Any or all of these cannabinoids can be used in the present invention.
  • Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000: 1 at pH 7. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.
  • CBD does not have the clinically undesirable (but recreationally desirable) psychotropic effects but is capable of inhibiting many effects of receptor ligands in the endocannabinoid system, which are responsible for the expression of THC's angiogenic and psychotogenic properties (Zuardi AW,“Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action,” Rev Bras Psiquiatr, 2008, 30, 271-280, doi: 10.1590/S1516-44462008000300015).
  • CBD shares many beneficial effects, including the capacity to act as an immunomodulator, with classic psychocannabinoids (Kozela E et al.,“Cannabidiol has been shown to inhibit pathogenic T cells,” Br J Pharmacol, 2011 , 163(7), 1507-1519, doi: 10.1111/j.1476-5381.2011.01379.x).
  • Cannabis extracts and several cannabinoids have been shown to exert broad anti inflammatory activities in experimental models of inflammatory central nervous system (CNS) degenerative diseases. While clinical use of many cannabinoids is limited by their psychotropic effects, phytocannabinoids like CBD, which are devoid of psychoactive activity, are potentially safe and therapeutically effective alternatives for the alleviation of neuroinflammation and neurodegeneration (Kozela E, Lev N, et al.“Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice,” Br J Pharmacol, 2011 ,163,1507-1519, doi: 10.1111/j.1476-5381.2011.01379.x).
  • CBD exerts a wide range of anti-inflammatory properties and regulates cell cycle and function of various immune cells. These effects include suppression of humoral responses, such as release of cytokines, chemokines, growth factors, as well as suppression of immune cell proliferation, activation, maturation, migration, and antigen presentation (Raphel Mechoulam et al.,“Cannabidiol - Recent Advances,” Chem Biodivers, 2007, vol.4, 1678-1692, doi: 10.1002/cbdv.200790147)
  • MS multiple sclerosis
  • MS is a demyelinating disease which causes cytotoxic, degenerative processes, including inflammation, demyelination, oligodendrocyte cell death, and axonal degeneration.
  • cytotoxic, degenerative processes including inflammation, demyelination, oligodendrocyte cell death, and axonal degeneration.
  • Sativex® (GW Pharmaceuticals), the world's first pharmaceutical prescription medicine derived from the Cannabis plant, was launched in April 2005 for neuropathic pain relief in multiple sclerosis. It is a mixture of CBD and donabinol, and was most recently formulated as an oromucosal spray for the treatment of symptoms of spasticity associated with multiple sclerosis (G.W. Pharmaceuticals: Products and Pipeline, accessed at: https://www.gwpharm.com/products-pipeline/sativex, checked on July 3, 2017).
  • the endocannabinoid system could provide a rescue mechanism, particularly for patients suffering from late-stage MS.
  • THC-like cannabinoids possess ameliorating, neuroprotective activity in this respect, and that cannabinoid- mediated neuroprotection, rather than immunosuppression, is relevant for the recovery process at the later, proficientsive stages of MS (Croxford JL et al.,“Cannabinoid- mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis,” J Neuroimmunol, 2008, 193, 120- 129, doi: 10.1016/j.jneuroim.2007.10.024; Maresz K et al., “Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells”, Nat Med, 2007,13, 492-497, doi: 10.1038/nm1561).
  • Cannabinoids may have two roles in the treatment of cancer. First, there is evidence of anticancer effects from several mechanisms. Second, cannabinoids may have a role in the palliative care for sequelae of cancer.
  • cannabinoids exert an inhibitory action on the proliferation of various cancer cell lines and are able to slow down or arrest the growth of different models of tumor xenograft in experimental animals (Oesch S, Gertsch J.,“Cannabinoid receptor ligands as potential anticancer agents--high hopes for new therapies?,” J Pharm Pharmacol.
  • cannabinoids have been shown to exert anti-proliferative and pro-apoptotic effects in various cancer types (lung, glioma, thyroid, lymphoma, skin, pancreas, uterus, breast, prostate, and colorectal carcinoma) (D. Wade et al.,“A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms,” Clin. Reha, 2003 ,17, 21-29, doi: 10.1191/0269215503cr581oa; T.J.
  • phytocannabinoids such as CBD
  • CBD phytocannabinoids
  • CBD also possesses antitumor properties in gliomas, tumors of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemo-therapy (Massi P et al.,“Cannabidiol as potential anticancer drug,” Br J Clin
  • cannabinoids can affect other important processes in tumorigenesis, in particular, angiogenesis, or the formation of new blood vessels from pre-existing ones - an essential step in tumor growth, invasion, and metastasis and a major therapeutic target for cancer therapy (Solinas M et al..’’Cannabidiol inhibits angiogenesis by multiple mechanisms,” Brit J Pharmacol, 2012, 167, 1218-31 , doi: 10.1111/j.1476-5381.2012.02050.x).
  • CBD non- psychotropic cannabinoids
  • the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumors and may also exert anti-migratory, anti- invasive, anti-metastatic, and perhaps anti-angiogenic properties.
  • CBD is a potent and selective inhibitor of cancer cell growth and spread (Massi P et al.,“Cannabidiol as potential anticancer drug,” Br J Clin Pharmacol ,2013, 75(2), 303-312, doi: 10.1111/j.1365-2125.2012.04298.x).
  • CBD is worthy of clinical consideration in an appropriate formulation for cancer therapy.
  • Cannabinoids are currently used in cancer patients to palliate wasting, emesis, and pain that often accompany cancer (Massi P et al.,“Cannabidiol as potential anticancer drug,” Br J Clin Pharmacol, 2013, 75(2), 303-312, doi: 10.1111/j.1365-2125.2012.04298.x); J.R. Johnson et al.,“Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain,” J. Pain Symptom Manag., 2010, 39, 167-799 doi:
  • Cannabinoids exert their pharmacological effects via cannabinoid receptors which are widely distributed in the central nervous system (Mackie K,“Cannabinoid receptors: where they are and what they do,” J Neuroendocrinol. 2008, 1 , 10-4. doi: 10.1111/j.1365- 2826.2008.01671.x).
  • CBD reduces subjective anxiety, achieving clinically significant reductions in anxiety, cognitive impairment, and discomfort.
  • Epilepsy is a prevalent and devastating disorder of the CNS, which may be defined as a brain condition causing spontaneous recurrent seizures. These seizures are sometimes both progressively severe and accompanied by cognitive and behavioral comorbidities (Goldberg EM et al.,“Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction,” Nat. Rev. Neurosci. 2013,14, 337-49, doi: 10.1038/nrn3482).
  • Epileptogenesis refers to a scantily understood cascade of events that generally transmute a non-epileptic brain into one that triggers spontaneous seizures; these events occur in a specific time window included between a brain-damaging insult such as stroke, infection, or genetic predisposition, and the onset of unprovoked and unpredictable seizures Ibid.)
  • a specific treatment may stop or modify the epileptogenic process and thereby positively influence the quality of life of an epileptogenic subject (White HS, Loscher W. Searching for the ideal epileptogenic agent in experimental models: single treatment versus combinatorial treatment strategies.
  • CBD or THC formulations may offer significant advantages over and above existing antiepileptic drugs (AEDs), accompanied by a superior pharmacokinetic, pharmacodynamic, and side effects profile.
  • AEDs antiepileptic drugs
  • CBD or formulations may have the additive value of simultaneously managing psychiatric comorbidities associated with epilepsy, which are often more harmful to patients than seizures themselves (Dos Santos RG et al., “Phytocannabinoids and epilepsy” J Clin Pharm Ther, 2015, 40, 135-43, doi:
  • CBD or THC formulations may also be of additional value for drug-resistant epilepsies which are non- responsive to conventional AEDs (Leo A et al.,“Cannabidiol and epilepsy: rationale and therapeutic potential,” Pharma Res, 2016, 107, 85-92, doi: 10.1016/j.phrs.2016.03.005,).
  • CBD or THC formulations may have the advantage of an intentional dosage of synthetic or natural preparations with ideal pharmacology, to the exclusion of other cannabinoids and their respective pharmacokinetic and pharmacodynamics influences.
  • CBD achieves characteristic effects of induced anti-psychotic and anxiolytic activity in subjects, and also attenuates the development of stress-induced behavior al consequences, raising the possibility that CBD could be useful for treating psychiatric disorders thought to involve impairment of stress-coping mechanisms, such as depression (Guimaraes FS et al.,“Antianxiety effect of cannabidiol in the elevated plus-maze.
  • CBD has a favorable profile in a model predictive of antidepressant like activity in comparison to prototype antidepressants, but that such effects are only attainable at precise dosages, with smaller or higher doses producing no effect (Zanelati TV et al., “Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT 1 A receptors,” Br J Pharmacol, 2010, 159, 122-28, doi: 10.1111/j.1476-5381.2009.00521.x).
  • the present invention can be the basis for formulations capable of providing dosages in accordance with the most clinically appropriate pharmacokinetic and pharmacodynamic profile in order to achieve desired therapeutic effects in a patient presenting with a specific pathophysiology, such as major depressive disorder.
  • CBD central nervous system
  • CBD improves sleep in individuals suffering from insomnia (Carlini EA et al.,“Hypnotic and antiepileptic effects of cannabidiol,” J. Clin.
  • CBD appears to increase total sleep time in subjects, in addition to increasing sleep latency in the light period of the day of administration (Chagas M et al.,“Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats” J. Psychopharmacol, 2013, 27(3), 312-16, doi: 10.1177/0269881112474524).
  • Drug addiction is a chronic, relapsing disease characterized by the compulsion to seek and take a drug, loss of control in limiting intake and emergence of negative emotional states when access to the drug is prevented (koob et al.,“Drug abuse: hedonic homeostatic dysregulation,” Science, 1997, 278, 52-58, doi: 10.1126/science.278.5335.52) It is a chronic disorder involving persistent changes in the central nervous system.
  • Prototypical examples of those changes include tolerance, dependence, and/or sensitization after repeated drug exposure with corresponding neurochemical changes in the brain (Chao and Nestler, Molecular neurobiology of drug addiction (2004) Annu Rev Med. 55: 1 13-132; Nestler, Molecular mechanisms of drug addiction (2004) Neuropharm. 47:24-32; Ron and Jurd, The 'ups and downs' of signaling cascades in addiction (2005) Sci STKE 309:rel4). It is these neuropharmacological and neuroadaptive mechanisms that mediate the transition from occasional, controlled drug use to the loss of behavioral control over drug-seeking and drug taking that defines addiction.
  • the endocannabinoid system is the major player and a neurobiological mechanism underlying drug reward (Onaivi,“An endocannabinoid hypothesis of drug reward and addiction “,Acad sci ,2008,1139: 412-21 , doi: 10.1196/annals.1432.056 ).
  • the endocannabinoid system is a modulator of dopaminergic activity in the basal ganglia, elucidating its participation in the primary rewarding effects of alcohol, opioids, nicotine, cocaine, amphetamine, cannabinoids, and benzodiazepines through the release of endocannabinoids that act as retrograde messengers to inhibit classical transmitters, including dopamine, serotonin, GABA, glutamate, acetylcholine, and norepinephrine (Onaivi,“An endocannabinoid hypothesis of drug reward and addiction”, Acad sci,2008, 1139: 412-21 , doi: 10.1196/annals.1432.056).
  • the endocannabinoid system is further involved in the common mechanisms underlying relapse to drug-seeking behavior by mediating the motivational effects of drug-related environmental stimuli and drug re exposure (Maldonado et al.,“Involvement of the endocannabinoid system in drug addiction” Trends Neurosci,2006, 29, 225-232, doi: 10.1016/j.
  • the endocannabinoid system triggers or prevents reinstatement of drug-seeking behavior (Fattore et al.,“An endocannabinoid mechanism in relapse to drug seeking: a review of animal studies and clinical perspectives”, Brain Res Rev, 2007, 53, 1 -16, doi: 10.1016/j.brainresrev.2006.05.003).
  • the perturbation of the endocannabinoid system by drugs of abuse can be ameliorated byrestoring the perturbed system using cannabinoid receptor ligands.
  • Cannabinoid receptor antagonists are useful in the reduction of drug use, in smoking cessation, and reduction in alcohol consumption, and rimonabant has been demonstrated to have antagonistic activity against disruption of cognition or reward-enhancing properties of morphine, amphetamine, cocaine, (Poncelet, Blockade of CB1 receptors by 141716 selectively antagonizes drug-induced reinstatement of exploratory behavior in gerbils (1999) Psychopharmacology 144: 144-50) ethanol, and diazepam.
  • mice treated with CB1 antagonists showed a significant reduction in self- administered alcohol consumption (Colombo et al.,“Suppressing effect of the cannabinoid CB1 receptor antagonist, SR 141716, on alcohol's motivational properties in alcohol- preferring rats,” Eur J Pharmacol , 2004,498,119-123, doi: 10.1016/j.ejphar.2004.07.069), cocaine-related locomotor activity (Gerdeman et al.,“Context- specific reversal of cocaine sensitization by the CB1 cannabinoid receptor antagonist rimonabant,” Neuropsychopharmacology, 2008, 33, 2747-2759, doi: 10.1038/sj.npp.1301648), and a reduction in the reward effects of nicotine (Cohen et al. ,“SRI 41716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats”,Be
  • the endocannabinoid physiological control system is a directly important natural regulatory mechanism for reward in the brain, and also contributes to reduction in aversive consequences of abused substances, such that manipulating the endocannabinoid system can be exploited in order to treat alcohol and drug dependency, and to reduce the behavioral consequences associated with withdrawal (Onaivi,“An endocannabinoid hypothesis of drug reward and addiction,” Acad scie,2008, 1139, 412-21 , doi: 10.1196/annals.1432.056).
  • the classes of prescription drugs that are commonly abused include oral narcotics such as hydrocodone (Vicodin), oxycodone (OxyContin), propoxyphene (Darvon), hydromorphone (Dilaudid), meperidine (Demerol) and diphenoxylate (Lomotil), and their non-medical use has increased dramatically in recent years.
  • oral narcotics such as hydrocodone (Vicodin), oxycodone (OxyContin), propoxyphene (Darvon), hydromorphone (Dilaudid), meperidine (Demerol) and diphenoxylate (Lomotil)
  • Opioids such as heroin and morphine
  • opioid receptors Kieffer, Opioids: first lessons from knockout mice,” Trends Pharmacol Sci,1999, 20, 19-26, doi: 10.1016/S0165-6147(98)01279-6; Matthes et al.,“Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene,” Nature, 1996, 383,819-823, doi: 10.1038/383819a0)
  • CB1 and m-receptors are similarly expressed in many brain areas involved in reward processes (Herkenham et al.,“Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study,” J Neurosci,1991 , 11 ,563-583, doi:
  • cannabis use can be associated with positive treatment prognosis among opioid-dependent cohorts.
  • Epstein and Preston found that cannabis abuse and dependence were predictive of decreased heroin and cocaine use during treatment (Epsteinet al.,“Does cannabis use predict poor outcome for heroin- dependent patients on maintenance treatment? Past findings and more evidence against,” Addiction, 2003, 98,269-279, doi: 10.1046/j.1360-0443.2003.00310.x).
  • CB1 receptors influence the rewarding effects of opiates.
  • CB1 receptor anatagonists block the development of morphine-induced conditioned place preference in rats and mice (Chaperon et al., Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats (1998).
  • mice lacking CB1 receptors display reduced morphine-induced CPP (Rice et al.,“Conditioned place preference to morphine in cannabinoid CB1 receptor knockout mice”, Brain Res, 2002, 945(1), 135-138, doi: 10.1016/s0006-8993(02)02890-1) CB1 receptor knockout mice do not acquire heroin self-administration.
  • SR141716A dose-dependently reduces heroin self-administration in rats (Navarro et al. ,“Functional interaction between opioid and cannabinoid receptors in drug self- administration”, J Neurosci,2001 , 21(14), 5344-5350, doi: 10.1523/JNEUROSCI.21-14- 05344.2001).
  • CB1 antagonists can be used to selectively treat conditioned place preference and prevent the genesis of opioid dependency (Manzanedo et al.,“Cannabinoid agonist-induced sensitisation to morphine place preference in mice,” NeuroReport, 2004,15, 1373-1377, doi: 10.1097/01. wnr.0000126217.87116.8c).
  • the CB1 receptor antagonist AM251 significantly attenuates the motivation for cocaine self- administration under a progressive ratio schedule of reinforcement (Xi et al.,“Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: experiments with self- administration and brain-stimulation reward in rats,” Neuropsychopharmacology, 2008, 33(7), 1735-1745, doi: 10.1038/sj.npp.1301552), reduces methamphetamine self- administration (Vinklerova et al.,“Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251 ,” J Psychopharmacol,2002, 16, 139-143, doi:
  • Alcohol is a habit-forming drug that has been extensively studied for its relationships with the endocannabinoid signaling system (Hungund et al.,“Are anandamide and cannabinoid receptors involved in ethanol tolerance?
  • mice treated with CB I antagonists showed a significant reduction in self- administered alcohol consumption (Colombo et al.,“Suppressing effect of the cannabinoid CB1 receptor antagonist, SR 141716, on alcohol's motivational properties in alcohol- preferring rats,” Eur J Pharmacol, 2004, 498, 19-123, doi: 10.1016/j.ejphar.2004.07.069).
  • the instant invention provides for the administration of unique dosage forms of cannabinoids, including CB1 receptor antagonists like SR 141716 and other CBD antagonists, in the treatment of alcohol dependence.
  • CB1 knockout mice indicate a critical role of CB1 receptors in the rewarding effects of nicotine (Valjent et al.,“Behavior al and biochemical evidence for interactions between Delta 9- tetrahydrocannabinol and nicotine,” Br J Pharmacol, 2002, 135(2), 564-578, doi:
  • SR141716A have been successful in blocking the acquisition of nicotine-induced conditioned place preference in rats (Le Foil et al.,“Rimonabant, a CB1 antagonist, blocks nicotine- conditioned place preferences,” Neuroreport, 2004, 15(13), 2139-2143, doi: 10.1097/00001756- 200409150-00028; Forget et al.,“Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats,” Psychopharmacology (Berl), 2005, 181(4), 722-734); Cohen et al., “SR141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats,” Behav Pharmacol, 2002, 13, 451— 463).
  • SRI 41 76A dose-dependently reduces nicotine self-administration by rats (Cohen et al.,“SR141716, a central cannabinoid (CB(1 )) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats,” Behav Pharmacol, 2002, 13, 451-463).
  • the instant invention provides a measured dosage form capable of predictably administering precise, therapeutically effective amounts of cannabinoids, including, but not limited to, CB I receptor antagonists as a means of reducing nicotine dependency.
  • High CBD intake relative to THC has been associated with lower scores on the positive dimensions of the CAPE (Community Assessment of Psychic Experiences) Scale, inhibition of psychotic symptoms, and reduced deficiencies in episodic memory (Englund et al. ,“Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment,” J Psychopharmacol,” Jan27(1), 2013,19-27, doi: 10.1177/0269881112460109.).
  • the present formulations present the advantage of an intentional dosage of synthetic or natural preparations with ideal pharmacology, to the exclusion of other cannabinoids, if desired, and their respective pharmacokinetic and pharmacodynamics influences.
  • the "protective effects" afforded by extended or sustained release formulations can be harnessed by virtue of the present invention, along with the desired therapeutic effects of cannabidiols, either alone or in concert with therapeutically effective amounts of other cannabinoids.
  • CBD achieves characteristic effects of induced anti-psychotic and anxiolytic activity in subjects, and also attenuates the development of stress-induced behavior al consequences (Guimaraes et al.,“Antianxiety effect of cannabidiol in the elevated plus-maze,” Psychopharmacology, 1990, 100, 558-559; Resstel et al.,“Effects of cannabidiol and diazepam on behavior al and cardiovascular responses induced by contextual conditioned fear in rats,” Behav Brain Res, 2006, 172(2), 294-98, doi: 10.1016/j.bbr.2006.05.016; Resstel et al.,“5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavior al and cardiovascular- induced attenuation of behavior al and cardiovascular responses to acute restraint stress in rats,” Br J Pharmacol, 2009, 156(1), 181-88, doi: 10.1111/j.1476-5381
  • the instant invention is important and useful because CBD has a favorable profile in a model predictive of antidepressant-like activity in comparison to antidepressants, but such effects are only attainable at precise dosages, with smaller or higher doses producing no effect (Porsolt et al.,“Depression: a new animal model sensitive to antidepressant treatment,” Nature ,1977, 266,730-32, doi: 10.1038/266730a0; Zanelati et al. ,“Antidepressant-like effects of cannabidiol in mice: possible involvement of 5- HT1A receptors,” Br J Pharmacol, 2010, 159, 122-28, doi: 10.1111/j.1476-5381.2009.00521.x).
  • the present invention provides formulations which are capable of administering dosages in accordance with the most clinically appropriate pharmacokinetic and pharmacodynamic profile in order to achieve desired therapeutic effects in a patient presenting with a specific pathophysiology, such as major depressive disorder.
  • CBD central nervous system
  • cannabinoids the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol,” Med. Hypotheses, 2006, 66,234-246, doi: 10.1016/j.mehy.2005.08.026).
  • CBD improves sleep in individuals suffering from insomnia (Carlini et al.,“Hypnotic and antiepileptic effects of cannabidiol,” J. Clin. Pharmacol, 1981 , 21 (suppl 8-9), 417S-427S, doi: 10.1002/j.1552-4604.1981 tb02622.x). It has been successfully employed to block anxiety-induced REM sleep alteration via its anxiolytic effects (Hsiao et al., “Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats,” Neuropharmacol (2012) 62: 373-84).
  • CB1 R blockade attenuates relapse-like behavior in rats, thus paving the way for numerous studies demonstrating a potent influence of CB1 R signalling on relapse-like behavior induced both by drug exposure and by drug-paired conditioned cues across multiple classes of abused drugs (Fattore et al.,“An endocannabinoid mechanism in relapse to drug seeking: a review of animal studies and clinical perspectives,” Brain Res, 2007, Rev. 53, 1-16, doi:
  • CB1 receptor antagonism attenuates drug-primed, cue- induced and some forms of stress-induced reinstatement of cocaine- and methamphetamine-seeking behavior in rats (Serrano et al.,’’Endocannabinoid influence in drug reinforcement, dependence and addiction- related behaviors,” Pharmacol, Ther. 2011 , 132, 215-241 , doi:
  • CB1 R signaling modulates drug-seeking for various pharmacologically distinct drugs.
  • CB1 receptor antagonism blocks both cue- and priming-induced reinstatement of seeking behavior for non-drug rewards, such as sucrose and corn oil (De Vries et al.,“Suppression of conditioned nicotine and sucrose seeking by the cannabinoid- 1 receptor antagonist SR141716A,” Behav. Brain, 2005, Res. 161 , 164-168, doi: 10.1016/j.bbr.2005.02.021
  • CBD and THC in the pure state are solids.
  • Pure CBD has a reported melting point of 62- 66°C (Chemspider).
  • Pure THC has a predicting melting point of 160°C (Chemspider).
  • Both of these cannabinoids are poorly soluble in water and most formulations to date have been liquid or oil formulations, including tinctures and gelcaps. In view of the intense interest in these drugs, and the likely legalization and rescheduling of cannabis, new formulations of cannabinoids are urgently needed.
  • This invention involves dry granulations of cannabinoids.
  • Granulation is the process of particle enlargement by agglomeration.
  • Granulation is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules.
  • Granulation transforms fine powders into free-flowing, dust-free granules that are easy to compress.
  • this invention involves dry granulation methods, i.e. , granulates formed without the use of a solvent in the granulation process.
  • Compressible dosage forms made by dry granulation are known in the art, from e.g., WO 2009/135948A2 and US 4,439,453.
  • Cannabinoid formulations in oral dosage forms are disclosed in e.g., US 2018/0221332A1 , US 2016/0143972 A1 , and US 20180271827A1.
  • None of these references disclose dry granulations of cannabinoids and high drug loadings as provided by the instant invention.
  • this invention discloses a compressible pharmaceutical composition
  • a compressible pharmaceutical composition comprising a cannabinoid and at least one excipient, wherein the cannabinoid comprises 5%- 90% w/w of the composition, and wherein the excipient is a compressible pharmaceutical binder, and wherein the composition is a dry powder of 20 mesh or smaller particle size.
  • the cannabinoid may be selected from CBD, THC, or another solid cannabinoid.
  • the compressible pharmaceutical binder is selected from microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SiMCC), hydroxypropyl cellulose (HPC), a glycol, a polaxamer, lactose, mannitol, polyvinyl pyrrolidone (PVP), a starch, or a matrix-forming polymer such as a polyvinylpyrrolidone-vinyl acetate copolymer; a polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000 copolymer; or an ethylene oxide and propylene oxide copolymer.
  • MCC microcrystalline cellulose
  • SiMCC silicified microcrystalline cellulose
  • HPC hydroxypropyl cellulose
  • a glycol a polaxamer
  • lactose lactose
  • mannitol polyvinyl pyrrolidone
  • PVP polyvinyl pyrrolidone
  • starch
  • the composition may include a compressible pharmaceutical disintegrant is selected from a starch, croscarmellose sodium, cross-linked polyvinyl pyrrolidone (crospovidone), or a cellulose.
  • a compressible pharmaceutical lubricant is selected from magnesium stearate, stearic acid or a natural gum.
  • this invention provides a process for the preparation of a compressible pharmaceutical composition, comprising the steps of mixing a dry powdered cannabinoid with magnesium stearate and a binding excipient in a twin shell blender to form a uniform mixed blend; slugging the uniformly mixed blend in a tablet press to form slugs, breaking the slugs with an oscillating mill and passing the granulation through a 20-mesh screen to obtain a 20-mesh granulate.
  • this invention provides a process for the preparation of a
  • compressible pharmaceutical composition comprising the steps of mixing a dry powdered cannabinoid with magnesium stearate and a binding excipient in a twin shell blender to form a uniform mixed blend, and compacting the uniformly mixed blend in a rotary compaction press to form a ribbon, and pulverizing the ribbon with an oscillating mill and passing the pulverized material through a 20-mesh screen to obtain a 20-mesh granulate.
  • this invention provides a process for the preparation of a
  • compressible pharmaceutical composition comprising the steps of feeding a dry powdered cannabinoid and a matrix-forming polymer and optionally additional excipients into a hot-melt extrusion machine, wherein the hot-melt extrusion machine has at least one Archimedes screw in a zone heated to a sufficient temperature to melt the matrix forming polymer, wherein the screw in the hot zone mixes the cannabinoid, matrix- forming polymer, and optional additional excipients into a uniformly blended plastic mixture, and forcing the plastic mixture through an orifice to form an extrudate.
  • the extrudate is cooled and formed into a granulate by milling the extrudate to a desired particle size.
  • a compressible pharmaceutical composition comprising a cannabinoid and a compressible excipient formed by a dry granulation method, and suitable for compression into tablets.
  • dry granulation it is meant that no solvent is used in the granulation process, such as water, ethanol, or another solvent or solvent blend.
  • the composition is a pharmaceutical intermediate suitable for further processing into oral dosage forms, such as immediate release, controlled release formulations or orally dissolving formulations.
  • Cannabinoids include CBD, THC, or synthetic variants that have medical or recreational pharmaceutical value.
  • Compressible excipients include microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SiMCC), hydroxypropyl cellulose (HPC), lactose, mannitol, or a starch.
  • MCC microcrystalline cellulose
  • SiMCC silicified microcrystalline cellulose
  • HPC hydroxypropyl cellulose
  • lactose lactose
  • mannitol or a starch.
  • the composition is 70%-90% by weight of the cannabinoid.
  • additional ingredients may be included, such as magnesium stearate. In an embodiment, this material has a particle size of 20 mesh or less.
  • a matrix-forming agent for hot-melt extrusion may be used.
  • matrix forming agents include various co-polymers, for example Kollidon® VA 64, a polyvinylpyrrolidone-vinyl acetate copolymer; Soluplus®, a co-polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, available from BASF; and Kolliphor® P 188, a poloxamer (BASF). Other Kolliphor grades are available also and are within the scope of this invention. Poloxamers are copolymers of ethylene oxide and propylene oxide. All of these matrix forming agents are compressible and are supplied as free flowing powders.
  • this material is intended to be mixed with other materials that can be formed into tablets by a compression method.
  • the inventive intermediate can be blended with diluents, controlled release agents, fillers, disintegrants, and the like known in the art of tablet formulations.
  • a very high concentration of cannabinoid is desirable, such as 70% to 90% by weight.
  • This type of intermediate (composition) may give maximal flexibility to formulators to blend the inventive intermediate with other materials to achieve a desired effect, for example a controlled-release formulation or a quick-release formulation, such as a sublingual orally dissolving tablet.
  • the cannabinoid concentration may be lower.
  • a concentration as low as 5% is envisioned by this invention.
  • an embodiment may have 5% to 30% by weight of cannabinoid, or 30% to 50% by weight of cannabinoid, or 50% to 90% by weight of cannabinoid, wherein any of the embodiments mentioned in this paragraph are made by the dry granulation of this invention.
  • low concentration compositions may also be desirable, allowing tablet manufacturers to minimize additional processing by directly using a low concentration material having e.g., 5-10% w/w of a cannabinoid.
  • a low concentration material having e.g., 5-10% w/w of a cannabinoid.
  • CBD doses are typically in the 1 mg to 10 mg per dose range, so a 100 mg tablet (total tablet weight) made from the inventive mixture having 10% w/w CBD would provide a tablet with a 10 mg dose.
  • the cannabinoid may be any pharmaceutically active agent extracted from cannabis plant material, or a chemically related synthetic variant thereof.
  • the cannabinoid may be cannabidiol, also termed herein CBD, or (-)-trans-A 9 -tetrahydrocannabinol, referred to herein as THC.
  • this invention provides a process for manufacturing the compressible pharmaceutical composition.
  • the inventive intermediate is formed by a dry granulation method.
  • dry granulation methods are known in the art, for example slugging, roller compaction, and hot-melt extrusion.
  • slugging and roller compaction methods two or more ingredients are subjected to a compression force (also termed“compaction”), so the ingredients form an intimate uniformly distributed mixture of the ingredients without the use of a solvent.
  • hot- melt extrusion method ingredients with a meltable polymer are mixed in a hot zone in a machine with an Archimedes screw and extruded and milled to a desired particle size.
  • hot-melt extrusion does not involve the use of a solvent and can be termed a dry-granulation method.
  • Dry granulation methods do not use a solvent such as water, alcohol, or some other solvent to assist in the uniform blending of ingredients. For this reason, dry granulation may have the advantage of lower costs of not requiring a solvent that must be safely disposed of.
  • the slugging dry granulation method employs a tablet press to compact a mixture into crude tablets called“slugs” that are then broken apart to a desired size by milling.
  • a mixture of a cannabinoid such as pure CBD in a solid powdered form is blended in a V-blender with a compressible excipient and any other ingredients, such as a disintegrant or lubricant such as magnesium stearate.
  • the blend is then compressed into tablets on a tablet press. These tablets are not intended for consumption.
  • the tablet press may use any of several available punches, such as a flat face punch, and be anywhere from 7-20 mm along the longest dimension.
  • the compression force is not highly critical at this stage, and may be from about 5-30 KN.
  • the resulting tablets are termed“slugs.”
  • the slugs are then milled and sieved. In an embodiment, there may be sequential milling and sieving steps.
  • roller compaction may be used to form the granulate of this invention.
  • Roller compaction processes employ a roller compaction machine.
  • Leading manufacturers are Gerteis, Komareck, and others. These devices typically have settings for the gap and roller speed, which determine the compaction force.
  • the method is usually used to produce a ribbon or briquets of the compressed material. Either product may be milled to a desired particle size.
  • Roller compaction is a dry-granulation method employing two counter-rotating rollers that compact a mixture forcing a feed between the rollers.
  • roller compaction employs the following steps: powdered material is conveyed to the compaction area, e.g. with a screw feeder. The powder is compacted between two counter-rotating rollers with applied forces and milling the resulting compact to a desired particle size distribution.
  • the powdered material is transported by gravity forces or screws into a gap between two counter rotating rolls. Within the gap the material is densified to a compact by the force transmitted from the rolls.
  • different types of compacts may be generated (e.g. ribbons, briquettes). Using knurled or smooth surfaces of the rolls a compact band is produced, which is called ribbon.
  • the produced compacts may be grinded through a sieve to produce granules.
  • hot-melt extrusion may be used to manufacture the inventive compositions (Rina Chokshi et al.,“Hot-Melt Extrusion Technique: A Review,” Egyptian J. Pharm, 2004, 3, 3-16).
  • a hot-melt process also referred to in the literature as a“melt process”
  • the active agent is mixed with a matrix-forming polymer that melts at elevated temperature, which typically ranges from about 60°C to 160°C.
  • the active agent and polymer are fed into a hot-melt extruder which comprises one or two Archimedes screws in a hot zone that mixes the materials and melts the matrix-forming polymer to form a plastic mixture.
  • a barrel section in the extruder houses the screw and is heated to the desired temperature as the screw conveys and mixes the material.
  • a variety of screws with different pitches may be selected to achieve the desired mixing and conveyance.
  • Some extruders have twin screws in the mixing process.
  • the melt is forced by the screw(s) through an orifice that may make a ribbon, rod, or other extruded shape.
  • the extrudate is then cooled and milled to a desired mesh size to provide a granulate according to this invention.
  • a particular advantage to hot-melt extrusion is that the percentage of active agent (active pharmaceutical ingredient, or API) may be fairly high, with 40-60% of active agent can be used, with about 60-40%% of matrix forming polymer.
  • active agent active pharmaceutical ingredient, or API
  • matrix forming polymer This gives the kind of concentrated product that is desirable in many embodiments of this invention, that can be used in blends for tableting and other formulations as discussed in this disclosure.
  • CBD and THC can easily withstand the elevated temperatures in hot-melt extrusion without degradation. Appropriate temperatures and matrix-forming polymers should be selected to prevent thermal degradation in the hot-melt apparatus.
  • Some common matrix-forming polymers that may be useful in this invention include Kollidon® VA 64, a polyvinylpyrrolidone-vinyl acetate copolymer (BASF); Soluplus®, a co polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, available from BASF; and Kolliphor® P 188, a poloxamer (BASF).
  • Kolliphor grades are available also and are within the scope of this invention. These materials all act as matrix forming agents and binders and are compressible.
  • melt granulation Another process that may be used is melt granulation. See Desai, et al.,“Melt granulation: An alternative to traditional granulation techniques,” Indian Drugs. 2013. 50. 5-13; see also T. Listro, https://www.pharmasalmanac.com/articles/twin-screw-melt-granulation-as-a- platform-technology-for-continuous-manufacturing.
  • Melt granulation is a size enlargement process in which the addition of a binder that melts or softens at relatively low temperatures (about 60°C) is used to achieve agglomeration of solid particles in the formulation.
  • the process utilizes materials that are effective as granulating agents when they are in the softened or molten state. This process is particularly useful for formulations of lipophilic drug products. This technique can produce cannabinoid drug loadings as high as 80-90%.
  • a combination of a dry powdered cannabinoid and a matrix-forming polymer and optionally additional excipients into a hot-melt extrusion machine, wherein the hot zone of the extruder is kept at a temperature of 60-120°C, which is sufficient to soften but not melt the polymer.
  • a granulate is formed that is forced through the orifice of the extruder.
  • the granulate can then be milled to a desired particle size, for example 20 mesh.
  • the approximately 20 mesh particles of any of these methods may be used in a tablet formulation to produce cannabinoid tablets.
  • CBD, Cellulose and Mg Stearate were blended in a twin shell mixer for 5 minutes.
  • the blend was slugged blend using 10 mm flat face punches with 20 kN pressure.
  • the granulate was milled further with an oscillating mill and passed through a 20-mesh screen to give a 20-mesh granulate.
  • This example employs a roller-compactor method to make the inventive dry granulate.
  • the following ingredients are used.
  • the blend is compressed on a Gerteis Mini-Pactor® pilot scale roller compactor to form a ribbon, using the following parameters:
  • Gap 1 - 6 mm 3 The ribbon is broken up with an oscillating mill equipped with a 20-mesh screen, to give the granulate.
  • This experiment yields a 20 mesh or less granulate that can be compressed into tablets.
  • This example employs hot-melt extrusion to form a dry granulate.
  • Soluplus is a co-polymer of polyvinylcaprolactam, polyvinyl acetate, and polyethylene glycol 6000, in a ratio of 57/30/13, available from BASF
  • Soluplus exhibits both matrix-forming and solubilization properties.
  • This material may be blended with active ingredient (e.g., CBD) and any other excipient such as magnesium stearate.
  • active ingredient e.g., CBD
  • any other excipient such as magnesium stearate.
  • the blended powder is fed through a hot-melt extrusion apparatus at 120°C, at a rate of 1 kg/h, with a 1 kneading block with 5x0.25 D kneading elements at 90°, screw speed 200 rpm, and torque 0.5 Nm.
  • the method produces an extrudate that can be milled to a desired size such as 20 mesh with an oscillating sieve.
  • This example employs hot-melt extrusion to form a dry granulate of THC.
  • Soluplus may be blended with THC ((-)-trans-A 9 -tetrahydrocannabinol) as the active ingredient and any other excipient such as magnesium stearate.
  • the blended powder is fed through a hot-melt extrusion apparatus at 120°C, at a rate of 1 kg/h, with a 1 kneading block with 5x0.25 D kneading elements at 90°, screw speed 200 rpm, and torque 0.5 Nm.
  • the method produces an extrudate that can be milled to a desired size such as 20 mesh with an oscillating sieve. This material can be formulated into pharmaceutical compositions with recreational or medical value.
  • EXAMPLE 5 [0111] This example employs the melt granulation technique to form a dry granulate of a cannabinoid. This example can be used with THC or CBD, or a combination of the two, or include another cannabinoid.
  • Soluplus may be blended with THC or CBD, or a combination thereof, as the active ingredient and any other excipient such as magnesium stearate.
  • the blended powder is fed through a hot-melt extrusion apparatus at 80°C, at a rate of 1 kg/h, screw speed 100 rpm, and torque 0.5 Nm.
  • the method produces a granulate that can be milled to a desired size such as 20 mesh with an oscillating sieve. This material can be formulated into compressible pharmaceutical compositions with recreational or medical value.

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Abstract

L'invention concerne une composition pharmaceutique compressible comprenant un cannabinoïde et au moins un excipient. La composition peut être un intermédiaire utilisé dans la fabrication de formes posologiques compressibles de cannabinoïdes tels que des comprimés. Le cannabinoïde peut être du CBD ou du THC. L'excipient compressible peut être un matériau tel que la cellulose microcristalline ou le lactose, ou un polymère formant une matrice tel qu'un copolymère de polyvinylpyrrolidone-acétate de vinyle ; un polyvinylcaprolactame, de l'acétate de polyvinyle et un copolymère de polyéthylène glycol 6000 ; et un copolymère d'oxyde d'éthylène et d'oxyde de propylène. L'invention concerne également des procédés de granulation par voie sèche pour la fabrication de la composition de l'invention, comprenant le briquetage, le compactage à rouleaux, l'extrusion à chaud et la granulation à l'état fondu.
PCT/US2020/037464 2019-06-13 2020-06-12 Composition pharmaceutique cannabinoïde compressible Ceased WO2020252284A1 (fr)

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