WO2017183011A1 - Water soluble cannabinoid inclusion complexes - Google Patents

Water soluble cannabinoid inclusion complexes Download PDF

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Publication number
WO2017183011A1
WO2017183011A1 PCT/IB2017/052346 IB2017052346W WO2017183011A1 WO 2017183011 A1 WO2017183011 A1 WO 2017183011A1 IB 2017052346 W IB2017052346 W IB 2017052346W WO 2017183011 A1 WO2017183011 A1 WO 2017183011A1
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WIPO (PCT)
Prior art keywords
cyclodextrin
cannabinoid
beta
inclusion complex
water
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PCT/IB2017/052346
Other languages
French (fr)
Inventor
David M. DEGEETER
Liani JOHNSON
Original Assignee
Degeeter David M
Johnson Liani
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Publication date
Application filed by Degeeter David M, Johnson Liani filed Critical Degeeter David M
Publication of WO2017183011A1 publication Critical patent/WO2017183011A1/en

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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
    • A61K31/33—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to water-soluble inclusion complexes of cannabinoid compounds.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Dronabinol is a synthetic analog of THC which is dissolved in sesame oil and administered orally as a capsule containing 5 or 10 mg of THC.
  • the major problem of THC in oral administration is its low bioavailability due to its poor dissolution properties and high first-pass metabolism.
  • the bioavailability of orally ingested THC ranges from only 6% to approximately 20% depending on the drug vehicle employed.
  • cannabinoids which are the essential active ingredients which constitute the medicinal properties of the Cannabis sativa L. species, are all lipid based and present obstacles for not only complexation and formulations, along with human
  • cannabinoids like THC and CBD are more readily available to the more lipid tolerant structures of the CNS when inhaled as smoke or vapor, oral dosing of cannabinoids adds many complexities to the equation. Both THC (in both acid and delta nine forms) and CBD require additional processing with liver and pancreas enzymes for metabolism of the essential cannabinoids.
  • CBD-7-oic acid (7-COOH-CBD) 7-COOH-CBD
  • Vapor producing devices or vaporizers are battery- powered devices which accept cartridges containing so-called e-liquid or e-juice. An atomizer heats the e-liquid and creates vapor that the user inhales. E-liquids are aqueous liquids infused with nicotine or another active substance, with or without flavoring.
  • Vegetable glycerine diluted with water is the main ingredient in e-liquids, while propylene glycol is typically used to carry flavorings. These ingredients are heated to their boiling points, which creates large plumes of water based vapors.
  • the cannabis industry has relied on using oils in the cartridge mechanism to supply the vaping market. Since oils have a much higher boiling point, battery manufacturers have increased wattage and voltage to accommodate reaching flash point, which is the easiest way to vaporize an oil. Other oil optimization modifications made these devices unsafe for operation, adding harmful effects from carbonization of the wicking material (usually a cotton/polyester blend) from the high temperatures that were never meant to be reached with these devices.
  • aspects of the present invention may allow for the use of cannabinoid in water-based vaporizers and/or the advancement of cannabinoid based product development to pharmacological standards.
  • Embodiments of the present invention display hydrophilic properties, which may allow use in a wide array of formulations and pharmaceutical preparations.
  • Embodiments of the invention may be used in pharmacological, dietary supplement, food and beverage, vapor, cosmetic and legal cannabis industries, amongst others, without restriction.
  • Water-soluble cannabinoid inclusion complex compounds may be used to formulate stable cannabinoid formulations or medications with more predictable bioavailability, results and side effects.
  • Cannabidiol (CBD) and tetrahydrocannabinol (THC) are exemplary cannabinoids used in examples of the present invention.
  • the present invention relates to water-soluble complexes of a water-insoluble cannabinoid compound and a cyclodextrin, and formulations, medicaments, and other compositions made therefrom. Aspects of the invention also include methods of preparation of such complexes and formulations, and methods of using such complexes and formulations.
  • Cannabinoids are compounds which act on cannabinoid receptors in cells, which can alter neurotransmitter release in the brain. Cannabinoids were originally found in Cannabis saliva L., the origin of marijuana and hashish. Marijuana or its components have been reported in the scientific literature to alleviate the symptoms of a broad range of conditions including multiple sclerosis and forms of muscular spasm, including uterine and bowel cramps; movement disorders; pain, including migraine headache; glaucoma, asthma, inflammation, insomnia, and high blood pressure. There may also be utility for cannabinoids as an oxytoxic, anxiolytic, anti-convulsive, anti-depressant and anti-psychotic agent, or anticancer agent, as well as an appetite stimulant.
  • cannabinoids Many chemically related compounds, collectively classified as cannabinoids, have been isolated from Cannabis saliva L., Cannabis indica and Cannabis ruderalis, including tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • CBN cannabinol
  • various synthetic ligands for cannabinoid receptors have been developed.
  • the cannabinoids usually divided in the groups of classical cannabinoids, non-classical cannabinoids, aminoalkyhndol derivatives and eicosanoids.
  • Classical cannabinoids are isolated from Cannabis saliva L. or they can comprise synthetic analogs of these compounds.
  • Non-classical cannabinoids are bi- or tricyclic analogs of tetrahydrocannabinol (THC) while aminoalkylindols form a group which differs structurally substantially from classical and non-classical cannabinoids.
  • the present invention comprises a cannabinoid component, comprising a cannabinoid, which may be classical, non-classical or a synthetic analog, which is insoluble or sparingly soluble in water, and which may provide a medicinal, nutritional or recreational benefit to a user.
  • a cannabinoid component comprising a cannabinoid, which may be classical, non-classical or a synthetic analog, which is insoluble or sparingly soluble in water, and which may provide a medicinal, nutritional or recreational benefit to a user.
  • insoluble means that not more than 0.1 g will dissolve in 100 ml of water, while “sparingly soluble” means than not more than 3.3 g will dissolve in 100 ml of water.
  • the cannabinoid component may comprise a single cannabinoid compound or a plurality of cannabinoid compounds, either in substantially pure form, or mixed with various other compounds.
  • the cannabinoid component may be isolated or purified from a natural source such as a cannabis plant, or a chemically- synthesized cannabinoid compound.
  • the cannabinoid component can include, but is not limited to, cannabinoid compounds that may naturally occur in different combinations and relative quantities in the plant tissues of various species, subspecies, hybrids, strains, chemovars, and other genetic variants of the genus Cannabis, including material that may variously be classified as “marijuana” and "hemp” in accordance with various legal or technical definitions and standards.
  • a cannabinoid component can comprise a cannabinoid molecular distillate comprising a plurality of cannabinoid compounds.
  • a cannabinoid molecular distillate can comprise at least about 80% cannabinoid compounds by weight, or more.
  • An exemplary water-insoluble cannabinoid comprises THC, having the formula (I):
  • the cannabinoid component may also include various other cannibinoids such as tetrahydrocannabinolic acid (THCA), delta-8- tetrahydrocannabinol (D8THC),), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), tetrahydrocannabinovann (THCV), tetrahydrocannabinovarinic acid (THCVA), cannabidivarin (CBDV), cannabidivarin acid (CBDVA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabinodiol (CBND), and cannabinodiolic acid (CBNDA).
  • THCA tetrahydrocannabinolic acid
  • D8THC delta-8- tetrahydroc
  • CBD Cannabidiol
  • IUPAC 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]- 5-pentylbenzene-l,3-diol, having the formula (II): is one preferred cannabinoid of the present invention.
  • CBD is not known to have the psychotropic effects of THC, it is still considered to have a wide scope of potential medical and therapeutic applications. CBD may be derived from industrial hemp which has negligible amounts of THC, and may be legally grown and consumed in Canada and the United States.
  • the cannabinoid component can comprise both decarboxylated cannabinoid compounds as well as the corresponding carboxylic acid forms, such as, for example, both THC and THCA.
  • a cannabis extract or cannabinoid component can be decarboxylated, such as by heating, and in various embodiments, a cannabinoid component can be substantially devoid of acid forms of cannabinoid compounds.
  • substantially devoid means having an undetectable amount of a substance, or less than about 0.1% of a composition by weight.
  • the cannabinoid component may comprise isomers, stereoisomers, homologues, salts, or other forms or variants of the cannabinoid compounds disclosed herein.
  • the cannabinoid component is complexed with a water-soluble cyclodextrin to produce the water-soluble inclusion complexes of the present invention.
  • water-soluble means that at least 3.3 g of the substance may be completely dissolved in 100 ml of water at 20° C.
  • the cyclodextrin comprises a beta cyclodextrin.
  • Cyclodextrin molecules have ring structure formed of sugar moieties, forming a lipophilic cavity and a hydrophilic outer shell.
  • Beta-cyclodextrins have 7-member rings and 2- hydroxypropyl beta-cyclodextrin (HPbCD) is an esterification of beta-cyclodextrins, as shown below in formula III.
  • HPbCD 2- hydroxypropyl beta-cyclodextrin
  • the cannabinoids are complexed within the cyclodextrin ring structure.
  • the complex is water-soluble due to the externally facing hydroxyl units, while retaining the biological activity of the cannabinoid retained within the ring.
  • Beta-cyclodextrins are preferred because, without restriction to a theory, it is believed that the relative size of the cannabinoids and the cyclodextrin ring are closely matched.
  • beta-cyclodextrins, and particularly HPbCD are among the safer cyclodextrins for human ingestion or application, allowing for greater active ingredient loading per tolerable dosage, thus making HPbCD a superior complexation agent.
  • HPBbCD is the only cyclodextrin approved for ocular formulations, and is the only water-soluble cyclodextrin recommended for rectal dosing.
  • the inclusion complex may have a 1 : 1 molar ratio between the cannabinoid and a cyclodextrin.
  • the inclusion complex may be formed by mixing a molar excess of cyclodextrin to the cannabinoid.
  • Examples of the inclusion complex described herein are a white semi-opaque fine powder (at room temperature) that is water soluble, and can be used in stabilized water based formulations at high dosages.
  • the inclusion complex product may be used directly, or mixed or dissolved in other carriers.
  • the invention may provide compositions or formulations suitable for recreational, nutritional or medicinal purposes. If intended for medicinal purposes, the invention may comprise pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the water-soluble inclusion complexes described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • pharmaceutical carriers suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • pharmaceutical carriers suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • pharmaceutical carriers suit
  • the water-soluble inclusion complexes of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, micro suspensions, spray- dried dispersions), syrups, and emulsions; sublingually; parenterally, such as by
  • subcutaneous, intravenous, intramuscular injection, or infusion techniques e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions
  • nasally or by inhalation including administration to the nasal membranes, such as by inhalation spray or vaping;
  • topically such as in the form of a cream or ointment; or rectally such as in the form of suppositories.
  • They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject water soluble inclusion complex from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject water soluble inclusion complex from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Pharmaceutically acceptable carriers may include, for example, an adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • an adjuvant such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • diluents such as lactose and calcium bicarbonate may be added.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day.
  • the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • the inclusion complexes of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the water soluble inclusion complexes of the present invention, alone or in combination with a pharmaceutical carrier.
  • inclusion complexes of the present invention can be used alone, in combination with other inclusion complexes of the invention, or in combination with one or more other therapeutic agent.
  • the water-soluble inclusion complexes of the present invention and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.
  • a pharmaceutical composition can comprise a cannabinoid composition formulated to provide a particular therapeutic benefit.
  • a composition can be configured to provide a pharmacologically effective amount and/or a therapeutically effective amount of one or more specific cannabinoid compounds.
  • a pharmaceutical composition can be formulated with a cannabinoid composition comprising a pharmacologically effective amount and/or a therapeutically effective amount of at least one of the cannabinoid compounds selected from the group consisting of THC, CBD, CBC, and CBN to provide a therapeutic benefit.
  • Other substances may be added to produce particular products. This might include phospholipids such as phosphatidylcholine or sphingomyelin for oral tablets, and/or methylcellulose for liquid based food product (soft drinks, juices and fortified waters). Or the active ingredient might be pre-complexed into a salt for targeted delivery to receptor sites and easier dissolution in liquid preparations.
  • the water-soluble inclusion complex may be used in formulations intended for vapour production and inhalation (vaping) or in a topical application.
  • an amount of the water-soluble inclusion complex may be completely dissolved in propylene glycol (PG), for example, at a rate of at least 4.5g per 1 fl. Ounce (150 mg/ml)), which provides a PG solution with no cloudiness or separation whatsoever.
  • PG propylene glycol
  • This PG solution may be mixed with flavoured or unflavoured glycerine to form e-liquids suitable for vaping.
  • a concentrated or saturated PG solution may be used as a concentrated base.
  • about 320 mg of the inclusion complex in dry powder form may provide about 80mg active cannabinoids per ml of PG.
  • the water-soluble inclusion complex may be added directly to topical formulations such as balms, salves, creams, lotions and gels, or first dissolved in a carrier such as propylene glycol.
  • a topical lotion may be made with concentrated or saturated PG and the formulation stabilized. When used by test subjects, the results were consistent with those of a topical lotion comprising uncomplexed CBD or THC.
  • a topical formulation may comprise a surfactant, which may decomplex the cannabinoids from the HPBCD at the dermal layer, which may increase penetration through the outer epithelial cells.
  • the water-soluble inclusion complex may be formulated into liquids, tablets or capsules for oral administration, using any acceptable carrier, excipient, diluent or additive.
  • Pharmaceutically acceptable carriers, excipients or additives are well-known and suitable for this purpose.
  • the inclusion complex may be combined with liposomes or phospholipids, such as phosphatidylcholine, to form a type of self-emulsifying drug delivery system (SEDDS).
  • SEDDS self-emulsifying drug delivery system
  • liposomes and/or phospholipids as drug delivery carriers or vehicles is well known and need not be further described here.
  • Phospholipids/liposomes may assist getting the cannabinoids to better permeate the mucus membrane and help drive the inclusion complex cannabinoids into the bloodstream to their targeted receptor sites.
  • the water-soluble inclusion complexes may be spray coated, or micro- or
  • nanoencapsulated such as with nanoemulsions or microemulsions to help further increase bioavailability and targeted receptor site agonism.
  • the water-soluble inclusion complexes may be formulated for intranasal or pulmonary delivery with a fine mist nasal spray or nebulizer.
  • a saturated PG solution may be diluted with water to create a mistable or sprayable composition.
  • the water-soluble inclusion complexes may be formulated for rectal delivery, for example by forming a water based suppository using a concentrated or saturated PG solution or directly solubilizing the inclusion complex into a water based formulation for
  • the water-soluble inclusion complexes may be formulated for ocular delivery or for parenteral injection using suitably formulated liquids.
  • the inclusion complexes of the present invention can be produced using the methods described below, together with known methods in the art of chemistry and product formulation, or by variations thereon as appreciated by those skilled in the art. Preferred methods may include, but are not limited to, those described below. It will be understood by those skilled in the art of chemistry that the functionality present on the product should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of steps or to select one particular process scheme over another in order to obtain a desired complex or product of the invention.
  • the cannabinoid is melted and the cyclodextrin added in liquid form, and the two components mixed until the inclusion complex forms. Gradual cooling will result in solidification into a dry powder.
  • This method can also be performed with industrial gas driers, and spray drier systems for larger volume production requirements. There is a multitude of industrial equipment that can be expertly modified to reproduce these results.
  • the mixing step may include water or an alcohol as a solvent to encourage mixing.
  • processing for pilot and production scales may be performed using water/ethanol solutions for the mixture, followed by a spray drying or lyophilization step. Less preferred are evaporation steps using heat, which may adversely affect the photosensitivity of the cannabinoid component.
  • an excess of cyclodextrin may be added on a molar basis to assist in complexing all of the available cannabinoid component.
  • the ratio of cannabinoid compnent to cyclodextrin may be between about 1: 1 to about 1 :3, on a mass basis.
  • Indications of use may encompass every recognized ailment that cannabis/THC/CBD has been used to treat.
  • One particularly promising aspect seems to lie in the pain management sector, where opiate based medicines have created abuse and addiction problems. It has become apparent that existing pain management medicine may benefit from new alternatives for treatment.
  • the inclusion complexes of the present invention may offer a non-addictive approach to pain management.
  • the pharmacokinetics that the invented complexation compound has displayed will help bring natural phyto-cannabinoids into the mainstream pharmaceutical markets where it can assist with many symptoms, ailments, diseases or disorders that has been alleviated by Cannabis products in previous studies.
  • a non-exhaustive list of such indications may include inflammatory diseases and disorders, arthritis, mild to moderate pain, gout, rash, boils and skin infections, lupus, desensitization of nerve endings, glaucoma or other ocular issues, Crohns, irritable bowel syndrome, lower GI disorders and pain, abdominal and lower GI pain, chronic pain, cancer, traumatic injury and other symptoms and disorders have also been found to be alleviated by cannabis use.
  • capsules were prepared at a comparable strength of 30mg CBD per capsule.
  • the capsule were found to alleviate pain and inflammation in an initial test subject, (one 30mg CBD capsule (3x) daily (morning, afternoon and before sleep) for a three day period) who suffers from chronic pain associated with various orthopedic and neuropathic pain associated from multiple surgeries on lumbar and cervical spine.
  • a substantial reduction in overall inflammation was observed.
  • the amount of pain that was reduced was quite significant and noticeable. The effects did not impair cognitive ability whatsoever, although an upbeat and energetic feeling was noted.
  • a water-soluble inclusion complex powder form in similar steps in Experiment A ( 1.4 g of CBD and 4.2 g of HPbCD) was dissolved in propylene glycol (PG) to a concentration of 160mg of the complex (equivalent to 40 mg CBD) per ml of PG, with no dropout or cloudiness.
  • PG propylene glycol
  • the solution maintained stabilization through multiple phase temperature fluctuations, with only a slight decrease in viscosity of the solution in comparison to straight PG at the same temperatures.
  • CBD/HPbCD complex from Experiment A added incrementally until the solution ran clear.
  • This e-liquid was vaporized and inhaled by 10 different individuals at random. Each milliliter provides approximately 160 plumes (inhales) which amounts to approx. 1.25 micrograms CBD per inhale. Subjects tried to take between 10-20 "puffs" (inhales) in a 15 minute session. Bad flavors and aftertastes have been a big obstacle in the formulation of cannabinoid e-liquids, however, the inclusion complex had no detectable effect on the taste of the liquid. Importantly, it appeared that the CBD had psychoactive effects on the test subjects, despite the consensus view that CBD does not provide the same psychoactive effects that other cannabinoids, such as THC offer. The subjects described feeling an immediate relaxation and anti-anxiety type of effect.
  • Experiment D-1 is identical to Experiment A-1, except that the mixture was processed using ethanol, followed by drying in a vacuum oven to evaporate the alcohol.
  • THC sample from Experiment E was made a PG solution at the similar dissolution rate of 80mg THC/ml PG.
  • the PG complex solution was then mixed into the same vapor matrix as Experiment A-l (60/40 VG/PG with 20mg THC per ml).
  • Experiment F CBD (Cannabidiol) isolate + ChoP ( Phosphatidylcholine) + HPbCD (2-Hydroxypropyl beta Cyclodextrin) and Experiment G - D'9 THC (Delta 9 - Tetrahydrocannabinol) isolate + ChoP ( Phosphatidylcholine) + HPbCD (2-Hydroxypropyl beta Cyclodextrin)
  • a SEDDS (self emulsifying drug delivery systems) formulation was then tested using phosphatidylcholine, which is known to be a safe and effective drug delivery agent.
  • Lecithin and phospholipids are being used in greater frequency in the art to help create a more water soluble drug complexation that can still effectively penetrate membranes.
  • the phospholipid augmented formulation appeared to provided extend relief. The onset was quick and resulted in substantial elimination of chronic lower back pain associated with lumbar fusion surgery at L4/5 and L5/S 1 and the subsequent removal of hardware instrumentation due to complications.
  • references in the specification to "one embodiment”, “an embodiment”, etc., indicate that the embodiment described may include a particular aspect, feature, structure, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to combine, affect or connect such aspect, feature, structure, or characteristic with other embodiments, whether or not such connection or combination is explicitly described. In other words, any element or feature may be combined with any other element or feature in different embodiments, unless there is an obvious or inherent incompatibility between the two, or it is specifically excluded.
  • ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values.
  • a recited range e.g., weight percents or carbon groups
  • Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • Cyclodextrins in eye drop formulations enhanced topical delivery of corticosteroids to the eye. Thorsteinn Loftsson, Einar Stefansson Acta Ophthalmologica. First published: April 2002. Full publication history DOI: 10.1034/j.1600-0420.2002.800205.
  • Drug salts and solubilization modeling the influence of cyclodextrins on oral absorption.
  • Gamsiz ED 1 Thombre AG, Ahmed I, Carrier RL.

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Abstract

A water-soluble inclusion complex is formed from a cannabinoid component and a beta- cyclodextrin. The cannabinoid component may be cannabidiol or tetrahydrocannabinol. The beta-cyclodextrin may comprise 2-hydroxypropyl-beta-cyclodextrin.

Description

WATER SOLUBLE CANNABINOID INCLUSION COMPLEXES
Field of the Invention
[0001] The present invention relates to water-soluble inclusion complexes of cannabinoid compounds.
Background
[0002] The inherent insolubility of cannabinoids such as cannabidiol (CBD) and
tetrahydrocannabinol (THC) in water is associated with inefficient and unpredictable bioavailability. The pharmacological and toxicological studies of cannabinoids have been focused mainly on THC, which has been approved for the treatment of chemotherapy associated nausea and vomiting, and for AIDS-associated wasting and anorexia. Dronabinol is a synthetic analog of THC which is dissolved in sesame oil and administered orally as a capsule containing 5 or 10 mg of THC. The major problem of THC in oral administration is its low bioavailability due to its poor dissolution properties and high first-pass metabolism. The bioavailability of orally ingested THC ranges from only 6% to approximately 20% depending on the drug vehicle employed.
[0003] One of the biggest challenges faced in the emerging medical cannabinoid and hemp supplement markets is that the cannabinoids, which are the essential active ingredients which constitute the medicinal properties of the Cannabis sativa L. species, are all lipid based and present obstacles for not only complexation and formulations, along with human
bioavailability. [0004] Although cannabinoids like THC and CBD are more readily available to the more lipid tolerant structures of the CNS when inhaled as smoke or vapor, oral dosing of cannabinoids adds many complexities to the equation. Both THC (in both acid and delta nine forms) and CBD require additional processing with liver and pancreas enzymes for metabolism of the essential cannabinoids.
[0005] The metabolization of CBD in vivo has not been fully elucidated. Although studies have shown that further processing of CBD through hepatic channels, the number and type of CBD metabolites is quite extensive. It is believed that CBD undergoes extensive
hydroxylation at multiple sites and further oxidations result in a complex metabolic pattern, as it is a good substrate of CYP450 mixed function oxidases. Altogether, some 100 CBD metabolites have been identified. In general, the major metabolites of CBD were derivatives of CBD-7-oic acid (7-COOH-CBD) further oxidized at the side chain (Istvan et al.).
[0006] Electronic cigarettes or vapor producing ("vaping") devices are becoming increasing popular, however, water-insoluble cannabinoids have not easily been utilized in electronic cigarette devices or vaping devices. Vapor producing devices or vaporizers are battery- powered devices which accept cartridges containing so-called e-liquid or e-juice. An atomizer heats the e-liquid and creates vapor that the user inhales. E-liquids are aqueous liquids infused with nicotine or another active substance, with or without flavoring.
Vegetable glycerine diluted with water is the main ingredient in e-liquids, while propylene glycol is typically used to carry flavorings. These ingredients are heated to their boiling points, which creates large plumes of water based vapors. [0007] The cannabis industry has relied on using oils in the cartridge mechanism to supply the vaping market. Since oils have a much higher boiling point, battery manufacturers have increased wattage and voltage to accommodate reaching flash point, which is the easiest way to vaporize an oil. Other oil optimization modifications made these devices unsafe for operation, adding harmful effects from carbonization of the wicking material (usually a cotton/polyester blend) from the high temperatures that were never meant to be reached with these devices.
[0008] In addition there have been issues with batteries exploding due to abnormal heat exposure to the lithium batteries, as well as highly unregulated lithium batteries from unverifiable sources, which sometimes malfunction in these high heat settings. In addition, the mismatch of low and zero resistance atomizers adds to the overheating of these batteries.
Summary of the Invention
[0009] Aspects of the present invention may allow for the use of cannabinoid in water-based vaporizers and/or the advancement of cannabinoid based product development to pharmacological standards. Embodiments of the present invention display hydrophilic properties, which may allow use in a wide array of formulations and pharmaceutical preparations.
[0010] Embodiments of the invention may be used in pharmacological, dietary supplement, food and beverage, vapor, cosmetic and legal cannabis industries, amongst others, without restriction. Water-soluble cannabinoid inclusion complex compounds may be used to formulate stable cannabinoid formulations or medications with more predictable bioavailability, results and side effects. Cannabidiol (CBD) and tetrahydrocannabinol (THC) are exemplary cannabinoids used in examples of the present invention.
Detailed Description
[0011] The present invention relates to water-soluble complexes of a water-insoluble cannabinoid compound and a cyclodextrin, and formulations, medicaments, and other compositions made therefrom. Aspects of the invention also include methods of preparation of such complexes and formulations, and methods of using such complexes and formulations.
A. Cannabinoids
[0012] Cannabinoids are compounds which act on cannabinoid receptors in cells, which can alter neurotransmitter release in the brain. Cannabinoids were originally found in Cannabis saliva L., the origin of marijuana and hashish. Marijuana or its components have been reported in the scientific literature to alleviate the symptoms of a broad range of conditions including multiple sclerosis and forms of muscular spasm, including uterine and bowel cramps; movement disorders; pain, including migraine headache; glaucoma, asthma, inflammation, insomnia, and high blood pressure. There may also be utility for cannabinoids as an oxytoxic, anxiolytic, anti-convulsive, anti-depressant and anti-psychotic agent, or anticancer agent, as well as an appetite stimulant.
[0013] Many chemically related compounds, collectively classified as cannabinoids, have been isolated from Cannabis saliva L., Cannabis indica and Cannabis ruderalis, including tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN). In addition, various synthetic ligands for cannabinoid receptors have been developed. The cannabinoids usually divided in the groups of classical cannabinoids, non-classical cannabinoids, aminoalkyhndol derivatives and eicosanoids. Classical cannabinoids are isolated from Cannabis saliva L. or they can comprise synthetic analogs of these compounds. Non-classical cannabinoids are bi- or tricyclic analogs of tetrahydrocannabinol (THC) while aminoalkylindols form a group which differs structurally substantially from classical and non-classical cannabinoids.
[0014] The present invention comprises a cannabinoid component, comprising a cannabinoid, which may be classical, non-classical or a synthetic analog, which is insoluble or sparingly soluble in water, and which may provide a medicinal, nutritional or recreational benefit to a user. As used herein, "insoluble" means that not more than 0.1 g will dissolve in 100 ml of water, while "sparingly soluble" means than not more than 3.3 g will dissolve in 100 ml of water.
[0015] In accordance with various embodiments, the cannabinoid component may comprise a single cannabinoid compound or a plurality of cannabinoid compounds, either in substantially pure form, or mixed with various other compounds. The cannabinoid component may be isolated or purified from a natural source such as a cannabis plant, or a chemically- synthesized cannabinoid compound. The cannabinoid component can include, but is not limited to, cannabinoid compounds that may naturally occur in different combinations and relative quantities in the plant tissues of various species, subspecies, hybrids, strains, chemovars, and other genetic variants of the genus Cannabis, including material that may variously be classified as "marijuana" and "hemp" in accordance with various legal or technical definitions and standards. [0016] In some embodiments, a cannabinoid component can comprise a cannabinoid molecular distillate comprising a plurality of cannabinoid compounds. In various
embodiments, a cannabinoid molecular distillate can comprise at least about 80% cannabinoid compounds by weight, or more.
[0017] An exemplary water-insoluble cannabinoid comprises THC, having the formula (I):
Figure imgf000007_0001
which includes delta-9-tetrahydrocannabinol (D9THC), which is acknowledged to be the main psychoactive compound in marijuana. The cannabinoid component may also include various other cannibinoids such as tetrahydrocannabinolic acid (THCA), delta-8- tetrahydrocannabinol (D8THC),), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), tetrahydrocannabinovann (THCV), tetrahydrocannabinovarinic acid (THCVA), cannabidivarin (CBDV), cannabidivarin acid (CBDVA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabinodiol (CBND), and cannabinodiolic acid (CBNDA).
[0018] Cannabidiol (CBD) IUPAC: 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]- 5-pentylbenzene-l,3-diol, having the formula (II):
Figure imgf000008_0001
is one preferred cannabinoid of the present invention. Although CBD is not known to have the psychotropic effects of THC, it is still considered to have a wide scope of potential medical and therapeutic applications. CBD may be derived from industrial hemp which has negligible amounts of THC, and may be legally grown and consumed in Canada and the United States.
[0019] In some embodiments, the cannabinoid component can comprise both decarboxylated cannabinoid compounds as well as the corresponding carboxylic acid forms, such as, for example, both THC and THCA. A cannabis extract or cannabinoid component can be decarboxylated, such as by heating, and in various embodiments, a cannabinoid component can be substantially devoid of acid forms of cannabinoid compounds. As used herein, the term "substantially devoid" means having an undetectable amount of a substance, or less than about 0.1% of a composition by weight.
[0020] In some embodiments, the cannabinoid component may comprise isomers, stereoisomers, homologues, salts, or other forms or variants of the cannabinoid compounds disclosed herein.
B. Cyclodextrin [0021] The cannabinoid component is complexed with a water-soluble cyclodextrin to produce the water-soluble inclusion complexes of the present invention. As used herein, "water-soluble" means that at least 3.3 g of the substance may be completely dissolved in 100 ml of water at 20° C.
[0022] In one preferred embodiment, the cyclodextrin comprises a beta cyclodextrin.
Cyclodextrin molecules have ring structure formed of sugar moieties, forming a lipophilic cavity and a hydrophilic outer shell. Beta-cyclodextrins have 7-member rings and 2- hydroxypropyl beta-cyclodextrin (HPbCD) is an esterification of beta-cyclodextrins, as shown below in formula III.
Figure imgf000009_0001
[0023] The cannabinoids are complexed within the cyclodextrin ring structure. As a result, the complex is water-soluble due to the externally facing hydroxyl units, while retaining the biological activity of the cannabinoid retained within the ring. Beta-cyclodextrins are preferred because, without restriction to a theory, it is believed that the relative size of the cannabinoids and the cyclodextrin ring are closely matched. Furthermore, beta-cyclodextrins, and particularly HPbCD, are among the safer cyclodextrins for human ingestion or application, allowing for greater active ingredient loading per tolerable dosage, thus making HPbCD a superior complexation agent. HPBbCD is the only cyclodextrin approved for ocular formulations, and is the only water-soluble cyclodextrin recommended for rectal dosing.
[0024] At a molecular level, the inclusion complex may have a 1 : 1 molar ratio between the cannabinoid and a cyclodextrin. As a composition, the inclusion complex may be formed by mixing a molar excess of cyclodextrin to the cannabinoid.
[0025] Examples of the inclusion complex described herein are a white semi-opaque fine powder (at room temperature) that is water soluble, and can be used in stabilized water based formulations at high dosages.
C. COMPOSITIONS AND DOSING
[0026] The inclusion complex product may be used directly, or mixed or dissolved in other carriers. In one aspect, the invention may provide compositions or formulations suitable for recreational, nutritional or medicinal purposes. If intended for medicinal purposes, the invention may comprise pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the water-soluble inclusion complexes described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices. Optionally, one or more additional therapeutic agents may be added. The term "pharmaceutical composition" means a composition comprising a water soluble inclusion complex of the invention in combination with at least one additional pharmaceutically acceptable carrier.
[0027] The water-soluble inclusion complexes of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, micro suspensions, spray- dried dispersions), syrups, and emulsions; sublingually; parenterally, such as by
subcutaneous, intravenous, intramuscular injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally or by inhalation, including administration to the nasal membranes, such as by inhalation spray or vaping;
topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
[0028] The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject water soluble inclusion complex from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Pharmaceutically acceptable carriers may include, for example, an adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. For tableting, fillers and excipients such as lactose and calcium bicarbonate may be added.
[0029] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
[0030] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion. The inclusion complexes of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
[0031] The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the water soluble inclusion complexes of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, inclusion complexes of the present invention can be used alone, in combination with other inclusion complexes of the invention, or in combination with one or more other therapeutic agent.
[0032] Regardless of the route of administration selected, the water-soluble inclusion complexes of the present invention and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
[0033] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
[0034] A physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
[0035] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
[0036] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.
[0037] In various embodiments, a pharmaceutical composition can comprise a cannabinoid composition formulated to provide a particular therapeutic benefit. Such a composition can be configured to provide a pharmacologically effective amount and/or a therapeutically effective amount of one or more specific cannabinoid compounds. For example, in various
embodiments, a pharmaceutical composition can be formulated with a cannabinoid composition comprising a pharmacologically effective amount and/or a therapeutically effective amount of at least one of the cannabinoid compounds selected from the group consisting of THC, CBD, CBC, and CBN to provide a therapeutic benefit. [0038] Other substances may be added to produce particular products. This might include phospholipids such as phosphatidylcholine or sphingomyelin for oral tablets, and/or methylcellulose for liquid based food product (soft drinks, juices and fortified waters). Or the active ingredient might be pre-complexed into a salt for targeted delivery to receptor sites and easier dissolution in liquid preparations.
[0039] The water-soluble inclusion complex may be used in formulations intended for vapour production and inhalation (vaping) or in a topical application. In one embodiment, an amount of the water-soluble inclusion complex may be completely dissolved in propylene glycol (PG), for example, at a rate of at least 4.5g per 1 fl. Ounce (150 mg/ml)), which provides a PG solution with no cloudiness or separation whatsoever. This PG solution may be mixed with flavoured or unflavoured glycerine to form e-liquids suitable for vaping. A concentrated or saturated PG solution may be used as a concentrated base. For example, about 320 mg of the inclusion complex in dry powder form may provide about 80mg active cannabinoids per ml of PG.
[0040] For topical applications, the water-soluble inclusion complex may be added directly to topical formulations such as balms, salves, creams, lotions and gels, or first dissolved in a carrier such as propylene glycol. A topical lotion may be made with concentrated or saturated PG and the formulation stabilized. When used by test subjects, the results were consistent with those of a topical lotion comprising uncomplexed CBD or THC. In one embodiment, a topical formulation may comprise a surfactant, which may decomplex the cannabinoids from the HPBCD at the dermal layer, which may increase penetration through the outer epithelial cells. (Loftsson et al, 2001) [0041] The water-soluble inclusion complex may be formulated into liquids, tablets or capsules for oral administration, using any acceptable carrier, excipient, diluent or additive. Pharmaceutically acceptable carriers, excipients or additives are well-known and suitable for this purpose.
[0042] In one embodiment, the inclusion complex may be combined with liposomes or phospholipids, such as phosphatidylcholine, to form a type of self-emulsifying drug delivery system (SEDDS). The use of liposomes and/or phospholipids as drug delivery carriers or vehicles is well known and need not be further described here. Phospholipids/liposomes may assist getting the cannabinoids to better permeate the mucus membrane and help drive the inclusion complex cannabinoids into the bloodstream to their targeted receptor sites.
[0043] The water-soluble inclusion complexes may be spray coated, or micro- or
nanoencapsulated, such as with nanoemulsions or microemulsions to help further increase bioavailability and targeted receptor site agonism.
[0044] The water-soluble inclusion complexes may be formulated for intranasal or pulmonary delivery with a fine mist nasal spray or nebulizer. For example, a saturated PG solution may be diluted with water to create a mistable or sprayable composition.
[0045] The water-soluble inclusion complexes may be formulated for rectal delivery, for example by forming a water based suppository using a concentrated or saturated PG solution or directly solubilizing the inclusion complex into a water based formulation for
suppositories.. [0046] The water-soluble inclusion complexes may be formulated for ocular delivery or for parenteral injection using suitably formulated liquids.
D. METHODS OF PREPARATION
[0047] The inclusion complexes of the present invention can be produced using the methods described below, together with known methods in the art of chemistry and product formulation, or by variations thereon as appreciated by those skilled in the art. Preferred methods may include, but are not limited to, those described below. It will be understood by those skilled in the art of chemistry that the functionality present on the product should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of steps or to select one particular process scheme over another in order to obtain a desired complex or product of the invention.
[0048] In one process, the cannabinoid is melted and the cyclodextrin added in liquid form, and the two components mixed until the inclusion complex forms. Gradual cooling will result in solidification into a dry powder. This method can also be performed with industrial gas driers, and spray drier systems for larger volume production requirements. There is a multitude of industrial equipment that can be expertly modified to reproduce these results. The mixing step may include water or an alcohol as a solvent to encourage mixing.
[0049] In one embodiment, processing for pilot and production scales may be performed using water/ethanol solutions for the mixture, followed by a spray drying or lyophilization step. Less preferred are evaporation steps using heat, which may adversely affect the photosensitivity of the cannabinoid component. [0050] In one embodiment, an excess of cyclodextrin may be added on a molar basis to assist in complexing all of the available cannabinoid component. In one example, the ratio of cannabinoid compnent to cyclodextrin may be between about 1: 1 to about 1 :3, on a mass basis.
E. THERAPEUTIC APPLICATIONS
[0051] Indications of use may encompass every recognized ailment that cannabis/THC/CBD has been used to treat. One particularly promising aspect seems to lie in the pain management sector, where opiate based medicines have created abuse and addiction problems. It has become apparent that existing pain management medicine may benefit from new alternatives for treatment.
[0052] The inclusion complexes of the present invention may offer a non-addictive approach to pain management. The pharmacokinetics that the invented complexation compound has displayed will help bring natural phyto-cannabinoids into the mainstream pharmaceutical markets where it can assist with many symptoms, ailments, diseases or disorders that has been alleviated by Cannabis products in previous studies.
[0053] A non-exhaustive list of such indications may include inflammatory diseases and disorders, arthritis, mild to moderate pain, gout, rash, boils and skin infections, lupus, desensitization of nerve endings, glaucoma or other ocular issues, Crohns, irritable bowel syndrome, lower GI disorders and pain, abdominal and lower GI pain, chronic pain, cancer, traumatic injury and other symptoms and disorders have also been found to be alleviated by cannabis use. EXAMPLES
[0054] The following Examples are provided for the purpose of illustration only.
[0055] Experiment A - CBD (Cannabidiol) + HPbCD (2-Hydroxypropyl beta Cyclodextrin)
[0056] Using a Pyrex glass 400ml beaker in water bath (approx. 70° C) over a probe driven magnetic spinning hotplate, 1.4 g of 99.5% CBD isolate was melted in the preheated beaker. Once the CBD melted, 2.8g of HPbCD was slowly added to the liquefied CBD. Another trial uses 1.4 g of CBD and 4.2 g of HPbCD. The mixture became a liquid slurry and become drier until a non clumpy dry powder is achieved. The beaker was removed from the hot water bath and place in a cooling bath until the dry powder reaches room temperature.
[0057] Once the precipitate was brought to dry powder form, capsules were prepared at a comparable strength of 30mg CBD per capsule. The capsule were found to alleviate pain and inflammation in an initial test subject, (one 30mg CBD capsule (3x) daily (morning, afternoon and before sleep) for a three day period) who suffers from chronic pain associated with various orthopedic and neuropathic pain associated from multiple surgeries on lumbar and cervical spine. A substantial reduction in overall inflammation was observed. The amount of pain that was reduced was quite significant and noticeable. The effects did not impair cognitive ability whatsoever, although an upbeat and energetic feeling was noted.
[0058] Experiment Al - CBD isolate + HPbCD (2-Hydroxypropyl beta Cyclodextrin) + Propylene Glycol (PG)
[0059] A water-soluble inclusion complex powder form in similar steps in Experiment A ( 1.4 g of CBD and 4.2 g of HPbCD) was dissolved in propylene glycol (PG) to a concentration of 160mg of the complex (equivalent to 40 mg CBD) per ml of PG, with no dropout or cloudiness. The solution maintained stabilization through multiple phase temperature fluctuations, with only a slight decrease in viscosity of the solution in comparison to straight PG at the same temperatures.
[0060] In another test, a sample of 30ml PG was heated and small amounts of the
CBD/HPbCD complex from Experiment A added incrementally until the solution ran clear. We were able to get the comparative dosage to 80mg CBD/ml PG, which was mixed in with a flavored VG/PG blend so that the concentration of VG/PG ratio was 60%/40% and a CBD concentration of 20mg per ml of e-liquid vapor solution.
[0061] This e-liquid was vaporized and inhaled by 10 different individuals at random. Each milliliter provides approximately 160 plumes (inhales) which amounts to approx. 1.25 micrograms CBD per inhale. Subjects tried to take between 10-20 "puffs" (inhales) in a 15 minute session. Bad flavors and aftertastes have been a big obstacle in the formulation of cannabinoid e-liquids, however, the inclusion complex had no detectable effect on the taste of the liquid. Importantly, it appeared that the CBD had psychoactive effects on the test subjects, despite the consensus view that CBD does not provide the same psychoactive effects that other cannabinoids, such as THC offer. The subjects described feeling an immediate relaxation and anti-anxiety type of effect. Further use resulted in reports of a "day dream" type feeling with lightness in extremities. Other effects included headache relief, muscle relaxation, reduced inflammation and mild pain relief. These effects appeared to subside within 15 minutes of stopping usage. All of the test subjects reported an uplifting feeling with increased focus when used sparingly. Although psychoactive effects were experienced, functionality did not appear to negatively affected at any level. The effects were close to vitamin B12 or mildly caffeinated teas, and made the individuals very social and mildly energetic. Tobacco and/or nicotine use cessation was noted by some individuals.
[0062] Experiment B - HCO extracted High D9THC (Delta 9 - tetrahydrocannabinol/Linoleic Acid) Oleoresin + HPbCD
[0063] Following the successful complexation with CBD/HPbCD (experiment A), a similar test was attempted with delta-(9)-tetrahydrocannabinol (D9 THC) complexed with HPbCD. For this experiment, the same setup as with the CBD complexation wa sused. A lg sample of an oleoresin oil (71.5% D9THC) was heated along with 0.5ml of 99% ethanol
(pharmaceutical grade) in a water bath 90° C. 3g of HPbCD was added to the heated mixture and stirred vigorously to shear the complexation until it reached a uniform texture and color hue. The beaker with the complexation was placed in a vacuum oven to fully evaporate any residual ethanol. The result was a fine, dry powder which held together somewhat. This complex displayed poorer aqueous solubility than other examples.
[0064] Experiment C - HCO extracted High D9THC (Delta 9 -Tetrahydrocannabinol/Linoleic Acid) Oleoresin + HPbCD (2-Hydroxypropyl beta Cyclodextrin) - Slurry Prep/evap step added (standard for all following powder preps)
[0065] To remedy the poor solubility of Experiment B, the experiment was repeated but with the addition of 15ml of ethanol to create the mixture. It was thought that this would increase the shear mixing and better complex the THC into the cavity. A heated vacuum oven was used to evaporate the alcohol. When it got to the final precipitated amount, there was extraneous lipid that pulled into the center that would not evaporate. After removing the extraneous lipid matter, the finished complex was a more crystalline powder, which after pulverization, produced superior aqueous solubility in water to that of Experiment B.
[0066] The extraneous lipid matter was most likely linoleic acid, which is the main triglyceride chain present in the oleoresin. The long chain triglycerides likely do not complex with HPbCD due to the size of the beta cavity being too small.
[0067] A test base of 10 patients ingested capsules made with the resulting powder (20mg D9THCpe capsule), with positive results being reported for mild to severe chronic pain, a sharp decline in bodily inflammation, relaxation, anti-anxiety with very mild euphoria for THC versions being noted for no longer than 3 hours after ingestion.
[0068] Experiment D - CBD (Cannabidiol) isolate + HPbCD (2-Hydroxypropyl beta
Cyclodextrin) -Slurry Prep/evap added
[0069] As a control measure, the same experiment as Experiment C was performed with CBD isolate replacing the THC oleoresin . The same amount of CBD isolate (lg) was used with the same amount of HPbCD. After evaporating off the ethanol, the same condition (extraneous lipid) did not occur. The final result was a more crystalline white powder, which after pulverisation, was more soluble in water than the powder of Experiment C.
[0070] *Experiment D-1 - CBD (Cannabidiol) isolate + HPbCD (2-Hydroxypropyl beta Cyclodextrin) »Propylene Glycol
[0071] Experiment D-1 is identical to Experiment A-1, except that the mixture was processed using ethanol, followed by drying in a vacuum oven to evaporate the alcohol. [0072] Experiment E - D'9 THC (Delta 9 - Tetrahydrocannabinol) isolate + HPbCD (2- Hydroxypropyl beta Cyclodextrin)
[0073] Due to the extraneous lipid from the oleoresin, the experiment was repeated using a pure 99.2% THCA sample (lg used for the experiment). Sample was made from a wiped film distillation of extracted oleoresin which was further filtered for purity over 99%.. The sample was converted to delta 9 THC by means of exposing to the required heat to successfully decarboxylate the sample. We performed the decarboxylization using a probed magnetic spinning hotplate, while observing the heat signature of the reaction to confirm its conversion to D9 THC. The same parameters of Experiments C and D were performed, substituting the pure isolated D9THC as the cannabinoid component.
[0074] The results were consistent with experiment D , with no noted extraneous matter being noted.
[0075] Larger samples of the powder of Experiments D and E were made for the purpose of placing in capsules to test the efficacy for mild to moderate pain and inflammation. 5 test subjects who volunteered for trials all exhibited chronic pain from varying symptoms, of varying severity. Although the trials were successful in that all five patient/volunteers reported very quick onset, the effects were mild, and did not last longer than 2 hours. All patients felt no change whatsoever in their normal pain after 2 hours.
[0076] Experiment E-l - D'9 THC (Delta 9 - Tetrahydrocannabinol) isolate + HPbCD (2- Hydroxypropyl beta Cyclodextrin) » Propylene Glycol [0077] We performed the same experiment with the THC sample from Experiment E and made a PG solution at the similar dissolution rate of 80mg THC/ml PG. The PG complex solution was then mixed into the same vapor matrix as Experiment A-l (60/40 VG/PG with 20mg THC per ml).
[0078] The results and effects of this e-liquid were not as positive as with CBD (Experiment A-l). This product produced similar effects to straight oleoresin cartridges that are rated at 600mg THC/ml.
[0079] Experiment F - CBD (Cannabidiol) isolate + ChoP ( Phosphatidylcholine) + HPbCD (2-Hydroxypropyl beta Cyclodextrin) and Experiment G - D'9 THC (Delta 9 - Tetrahydrocannabinol) isolate + ChoP ( Phosphatidylcholine) + HPbCD (2-Hydroxypropyl beta Cyclodextrin)
[0080] It appears that the more water soluble a cyclodextrin is, the more difficulty it has penetrating membranes in the upper gastrointestinal tract. As the pharmacology of the powder of both Experiments D & E, although quicker acting than D9THC on its own, appeared to be only absorbed in less significant amounts before being excreted.
[0081] A SEDDS (self emulsifying drug delivery systems) formulation was then tested using phosphatidylcholine, which is known to be a safe and effective drug delivery agent. Lecithin and phospholipids are being used in greater frequency in the art to help create a more water soluble drug complexation that can still effectively penetrate membranes.
[0082] Experiments D and E were repeated with the addition of 1 g phosphatidylcholine, to a 2 gram sample of CBD (Experiment F) and D9THC (Experiment G) isolate and 0.5ml of ethanol to increase shear. 9g of HPbCD were added, stirred into the complex, and then diluted with 30ml of ethanol to produce a mixture. Ethanol was heat evaporated under vacuum returning into crystalline powders. These powders were then pulverized and added to capsules. Dissolution of both samples seemed somewhat consistent with the other
Experiments D-G although the phospholipid/cannabinoid complexed HPbCD displayed somewhat increased water solubility. We were able to easily get both (F) & (G) samples dissolved in water at a rate of lOmg active cannabinoids (CBD or D9THC) per ml of water.
[0083] A test subject ingested 4 oz. (120 ml) of the above concentration level of sample (G) , and experienced a very quick onset with very noticeable cognitive effects. The duration of effect seemed to last much longer than the capsuled samples of (E). Samples of both in capsule form at an average concentration level of 15mg CBD (F) and 15mg D9THC (G) per capsule were also tested with similar results (a single 15mg capsule 3x daily, for a duration of 10 days).
[0084] The phospholipid augmented formulation appeared to provided extend relief. The onset was quick and resulted in substantial elimination of chronic lower back pain associated with lumbar fusion surgery at L4/5 and L5/S 1 and the subsequent removal of hardware instrumentation due to complications.
[0085] Both (G) and (F) samples were also sampled with a patient who suffers from fibromyalgia, and another patient who has arthritic knees and joints due to advanced age. Both had similar results from the medication, and remarked on the efficiacy of the medication for pain. [0086] Surprisingly, the THC capsule didn't provide a hazy "stoned" effect, and had a somewhat uplifting effect (most likely from sharp reduction of pain triggering other bodily responses), although doubling up on the dose (30mg) did provide some cognitive effects, but effects that seemed somewhat unique and unlike the effects of smoking or ingesting cannabis.
[0087] Experiment F-1 - CBD (Cannabidiol) isolate + ChoP ( Phosphatidylcholine) + HPbCD (2-Hydroxypropyl beta Cyclodextrin) » Propylene Glycol
[0088] We experimented with using the cannabidiol-phosphatidylcholine-HPbCD for vaporization (F- 1 ) at the same rates and procedure as with experiment (D- 1 ) . Although the complexation and dissolution performance was consistent with that of (D-1) , (F-1) produced a slightly altered taste (although no aftertaste) that was less desirable than that of (D- 1 ) .
Definitions and Interpretation
[0089] The description of the present invention has been presented for purposes of illustration and description, but it is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. Embodiments were chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated. To the extent that the following description is of a specific embodiment or a particular use of the invention, it is intended to be illustrative only, and not limiting of the claimed invention. [0090] References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to combine, affect or connect such aspect, feature, structure, or characteristic with other embodiments, whether or not such connection or combination is explicitly described. In other words, any element or feature may be combined with any other element or feature in different embodiments, unless there is an obvious or inherent incompatibility between the two, or it is specifically excluded.
[0091] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with the recitation of claim elements or use of a "negative" limitation. The terms "preferably," "preferred," "prefer," "optionally," "may," and similar terms are used to indicate that an item, condition or step being referred to is an optional (not required) feature of the invention.
[0092] The singular forms "a," "an," and "the" include the plural reference unless the context clearly dictates otherwise. The term "and/or" means any one of the items, any combination of the items, or all of the items with which this term is associated.
[0093] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percents or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
[0094] As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited, and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio.
References:
[0095] The following references are provided as being indicative of the level of skill of those skilled in the art, and are incorporated by reference in their entirety for all purposes (where permitted):
Enhancement of Naringenin Bioavailability by Complexation with Hydroxypropyl-β- Cyclodextrin. Maria Shulman, Merav Cohen, Alejandro Soto-Gutierrez, Hiroshi Yagi, Hongyun Wang, Jonathan Goldwasser, Carolyn W. Lee-Parsons, Ofra Benny-Ratsaby, Martin L. Yarmush, Yaakov Nahmias Published: April 6, 2011
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http://doi .org/10.1016/S0378-5173(00)00365-3 Pharmaceutical applications of cyclodextrins: basic science and product development Thorsteinn Loftsson, Marcus E. Brewster Journal of Pharmacy and Pharmacology
First published: 20 July 2010 Full publication history DOI: 10.1 11 l/j.2042- 7158.2010.01030.x
Role of cyclodextrins in improving oral drug delivery. American Journal of Drug Delivery Loftsson, T., Brewster, M.E. & Masson, M. Am J Drug Deliv (2004) 2: 261.
doi: 10.2165/00137696-200402040-00006
An intravenous toxicity study of 2-hydroxypropyl-P-cyclodextrin, a useful drug solubilizer, in rats and monkeys Marcus E. Brewster, Kerry S. Estes, Nicholas Bodor. International Journal of Pharmaceutics Volume 59, Issue 3, 30 March 1990, Pages 231-243
Medicinal applications of cyclodextrins. Szejtli Jl . Medicinal Research Review. 1994
May; 14(3):353-86.
Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye. Thorsteinn Loftsson, Einar Stefansson Acta Ophthalmologica. First published: April 2002. Full publication history DOI: 10.1034/j.1600-0420.2002.800205.
Investigation into the Mechanism by Which Cyclodextrins Influence Transdermal Drug Delivery Clifford L. Kear, Jing Yang, Donald A. Godwin & Linda A. Felton Drug
Development and Industrial Pharmacy Volume 34, 2008 - Issue 7, pages 692-697 I Published online: 25 Sep 2008
Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy Ujvary Istvan and Hanus Lumir. Cannabis and Cannabinoid Research. March 2016, 1(1): 90- 101. doi: 10.1089/can.2015.0012. Published in Volume: 1 Issue 1 : March 23, 2016. htip://onlmeJiebertpubx'oin/doi/pdf/l(3.1089/can.2015.(){312
Biotechnology and Bioengineering 2013 Sep;l 10(9):2536-47. doi: 10.1002/bit.24932. Epub 2013 Jul 10. Model predicting impact of complexation with cyclodextrins on oral absorption. Gamsiz ED 1 , Thombre AG, Ahmed I, Carrier RL.
hitps://www.ncbi.nh'n.«ih.gov/pubmed/20960062. Annals of Biomedical Engineering 201 1 Jan;39(l):455-68. doi: 10.1007/sl0439-010-0169- l. Epub 2010 Oct 20.
Drug salts and solubilization: modeling the influence of cyclodextrins on oral absorption. Gamsiz ED 1 , Thombre AG, Ahmed I, Carrier RL.
http://^^yw.scieiicedirectxoni/science/article pii/$03785 i73()l(K)761 X
Cyclodextrins in topical drug formulations: theory and practice Review Article International Journal of Pharmaceutics, Volume 225, Issues 1-2, 28 August 2001 , Pages 15-30 Thorsteinn Loftsson, , Mar Masson

Claims

Claims:
1. A water-soluble inclusion complex comprising a cannabinoid component and a beta- cyclodextrin.
2. The inclusion complex of claim 1 wherein the cannabinoid component comprises CBD or THC.
3. The inclusion complex of claim 1 or 2 where the beta-cyclodextrin comprises 2- hydroxypropyl-beta-cyclodextrin.
4. The inclusion complex of claim 1, 2 or 3 which is soluble greater than 150 mg/ml in propylene glycol.
5. The inclusion complex of claim 4 which is soluble greater than 300 mg/ml in propylene glycol.
6. The inclusion complex of one of claims 1 -5 having a mass ratio between the beta- cyclodextrin and the cannabinoid component of between about 1: 1 to about 5: 1.
7. A composition comprising an inclusion complex comprising a cannabinoid component and a beta-cyclodextrin, and a pharmaceutically acceptable carrier.
8. The composition of claim 7 wherein the pharmaceutically acceptable carrier comprises propylene glycol.
9. The composition of claim 8 further comprising glycerine.
10. The composition of claim 7 or 8 formulated as a liquid, tablet or capsule.
11. The composition of claim 7 or 8 further comprising a surfactant, lecithin or a
phospholipid.
12. The composition of claim 11 comprising a phospholipid comprising phosphatidylcholine.
13. A method of producing an inclusion complex comprising a cannabinoid component and a beta-cyclodextrin, comprising the steps of mixing the cannabinoid component and a beta- cyclodextrin as liquids to form a liquid mixture, and cooling or drying the liquid mixture to form a powder.
14. The method of claim 13 wherein the cannabinoid component and beta-cyclodextrin are mixed with water or an alcohol, or both.
15. The method of claim 14 wherein the water or alcohol is evaporated by spray draying or by lyophilization.
16. A method treating a disease, disorder or condition in a human, comprising the step of administering an effective amount of a composition comprising an inclusion complex comprising a cannabinoid component and a beta-cyclodextrin, and a pharmaceutically acceptable carrier.
17. The method of claim 16 wherein a symptom of the disease, disorder or condition in a human include chronic or acute pain.
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