WO2017183011A1 - Complexes d'inclusion hydrosolubles à base de cannabinoïdes - Google Patents

Complexes d'inclusion hydrosolubles à base de cannabinoïdes Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
cyclodextrin
cannabinoid
beta
inclusion complex
water
Prior art date
Application number
PCT/IB2017/052346
Other languages
English (en)
Inventor
David M. DEGEETER
Liani JOHNSON
Original Assignee
Degeeter David M
Johnson Liani
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Degeeter David M, Johnson Liani filed Critical Degeeter David M
Publication of WO2017183011A1 publication Critical patent/WO2017183011A1/fr

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un complexe d'inclusion hydrosoluble formé à partir d'un composant cannabinoïde et d'une bêta-cyclodextrine. Le composant cannabinoïde peut être le cannabidiol ou le tétrahydrocannabinol. La beta-cyclodextrine peut comprendre la 2-hydroxypropyl-bêta-cyclodextrine.
PCT/IB2017/052346 2016-04-22 2017-04-24 Complexes d'inclusion hydrosolubles à base de cannabinoïdes WO2017183011A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662326529P 2016-04-22 2016-04-22
US62/326,529 2016-04-22

Publications (1)

Publication Number Publication Date
WO2017183011A1 true WO2017183011A1 (fr) 2017-10-26

Family

ID=60115804

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/052346 WO2017183011A1 (fr) 2016-04-22 2017-04-24 Complexes d'inclusion hydrosolubles à base de cannabinoïdes

Country Status (1)

Country Link
WO (1) WO2017183011A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019140145A1 (fr) * 2018-01-13 2019-07-18 Pure Green Transformation de cannabinol et d'huiles terpéniques en poudres sèches solubles dans l'eau pour administration sublinguale sous forme solide
CN110204426A (zh) * 2019-07-02 2019-09-06 黑龙江康源生物科技有限公司 一种水溶性cbd的制备方法及水溶性cbd
WO2020018453A1 (fr) * 2018-07-16 2020-01-23 Orochem Technologies, Inc. Cannabidiol soluble dans l'eau
WO2020028897A1 (fr) * 2018-08-03 2020-02-06 Lilu's Garden, Ltd. CONSTRUCTION DE COMPLEXE INVITÉ DE β-CYCLODEXTRINE ET DE CANNABINOÏDE ET PROCÉDÉS DE PRODUCTION D'UNE PÂTE LA COMPRENANT
WO2020214220A3 (fr) * 2019-01-15 2020-11-26 Gustin John C Systèmes cannabinoïdes et procédés : solubilité dans l'eau, ciblage et augmentation
WO2020238642A1 (fr) * 2019-05-30 2020-12-03 汉义生物科技（北京）有限公司 Composé d'inclusion contenant un cannabinoïde non psychoactif et son procédé de préparation
US10925853B2 (en) 2019-04-17 2021-02-23 Nordiccan A/S Oral cannabinoid tablet
WO2021077061A1 (fr) * 2019-10-18 2021-04-22 Quicksilver Scientific, Inc. Systèmes multi-livrables auto-microémulsifiants
WO2021081010A1 (fr) * 2019-10-20 2021-04-29 Respira Technologies, Inc. Liquides pour aérosolisation et inhalation à l'aide de dispositifs électroniques
US11097206B2 (en) 2016-12-09 2021-08-24 Orochem Technologies Inc. Method for producing purified steviol product using simulated moving bed chromatography
WO2022016060A1 (fr) * 2020-07-17 2022-01-20 Canna Chemistries Llc Compositions solides de δ9-tétrahydrocannabinol (δ9-thc)
US11241413B2 (en) 2019-04-17 2022-02-08 Nordiccan A/S Cannabinoid lozenge formulation
CN114748429A (zh) * 2020-12-29 2022-07-15 汉义生物科技（北京）有限公司 一种水溶性大麻素制剂及其制备方法
EP3897732A4 (fr) * 2018-12-19 2022-08-17 Joyn Botanicals Ltd. Composition contenant des cannabinoïdes
US11517685B2 (en) 2019-01-18 2022-12-06 Qnovia, Inc. Electronic device for producing an aerosol for inhalation by a person
US11633351B2 (en) 2019-12-13 2023-04-25 Nordiccan A/S Fast disintegrating cannabinoid tablets
US11690963B2 (en) 2018-08-22 2023-07-04 Qnovia, Inc. Electronic device for producing an aerosol for inhalation by a person
LU501323B1 (en) 2022-01-25 2023-07-25 Kemijski Inst Cannabinoid complexes with improved properties
JP7421027B2 (ja) 2019-12-06 2024-01-24 漢義生物科技（北京）有限公司 カンナビノイドナノミセル製剤及びその製造方法
US11975098B2 (en) 2020-05-22 2024-05-07 Colorado School Of Mines Nanosuspensions of cannabidiol for developing water-dispersible formulations
WO2024097327A1 (fr) * 2022-11-02 2024-05-10 Progressive Therapeutics, Inc. Formulations de cannabinoïdes et utilisation pour le traitement de troubles émotionnels et d'un dysfonctionnement sexuel

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090298929A1 (en) * 2002-02-20 2009-12-03 Pedipharm Oy Novel natural cyclodextrin complexes
US20140209109A1 (en) * 2013-01-30 2014-07-31 Raymond Louis Larson Smokeless THC and Administration Method Thereof
US8808734B2 (en) * 2011-07-11 2014-08-19 Full Spectrum Laboratories Limited Cannabinoid formulations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090298929A1 (en) * 2002-02-20 2009-12-03 Pedipharm Oy Novel natural cyclodextrin complexes
US8808734B2 (en) * 2011-07-11 2014-08-19 Full Spectrum Laboratories Limited Cannabinoid formulations
US20140209109A1 (en) * 2013-01-30 2014-07-31 Raymond Louis Larson Smokeless THC and Administration Method Thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HAZEKAMP, A. ET AL.: "Structure elucidation of the tetrahydrocannabinol complex with randomly methylated beta-cyclodextrin", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 29, 2006, pages 340 - 347, XP025137176, DOI: doi:10.1016/j.ejps.2006.07.001 *
JARHO, P. ET AL.: "Hydroxypropyl-beta-cyclodextrin and its combination with hydroxypropyl-methylcellulose increases aqueous solubility of DELTA9-tetrahydrocannabinol", LIFE SCIENCES, vol. 63, no. 26, 1998, pages PL 381 - PL 384, XP002963822 *
MANNILA, J. ET AL.: "Precipitation complexation method produces cannabidiol/13-cyclodextrin inclusion complex suitable for sublingual administration of cannabidiol", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 96, no. 2, 2007, pages 312 - 319 *
MANNILA, J. ET AL.: "Sublingual administration of DELTA9-tetrahydrocannabinol/ beta-cyclodextrin complex increases the bioavailability of DELTA9-tetrahydrocannabinol in rabbits", LIFE SCIENCES, vol. 78, no. 17, 2006, pages 1911 - 1914, XP028050620, Retrieved from the Internet <URL:doi:10.1016/j.lfs.2005.08.025> *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11813550B2 (en) 2016-12-09 2023-11-14 Orochem Technologies Inc. Method for producing purified steviol product using simulated moving bed chromatography
US11097206B2 (en) 2016-12-09 2021-08-24 Orochem Technologies Inc. Method for producing purified steviol product using simulated moving bed chromatography
WO2019140145A1 (fr) * 2018-01-13 2019-07-18 Pure Green Transformation de cannabinol et d'huiles terpéniques en poudres sèches solubles dans l'eau pour administration sublinguale sous forme solide
US20210077454A1 (en) * 2018-01-13 2021-03-18 Pure Green Pharmaceuticals, Inc. Transformation of cannabinol and terpene oils into water soluble dry powders for solid form sublingual delivery
WO2020018453A1 (fr) * 2018-07-16 2020-01-23 Orochem Technologies, Inc. Cannabidiol soluble dans l'eau
WO2020028897A1 (fr) * 2018-08-03 2020-02-06 Lilu's Garden, Ltd. CONSTRUCTION DE COMPLEXE INVITÉ DE β-CYCLODEXTRINE ET DE CANNABINOÏDE ET PROCÉDÉS DE PRODUCTION D'UNE PÂTE LA COMPRENANT
US11690963B2 (en) 2018-08-22 2023-07-04 Qnovia, Inc. Electronic device for producing an aerosol for inhalation by a person
US11660283B2 (en) 2018-12-19 2023-05-30 Joyn Botanicals Ltd. Cannabinoid-containing composition
EP3897732A4 (fr) * 2018-12-19 2022-08-17 Joyn Botanicals Ltd. Composition contenant des cannabinoïdes
WO2020214220A3 (fr) * 2019-01-15 2020-11-26 Gustin John C Systèmes cannabinoïdes et procédés : solubilité dans l'eau, ciblage et augmentation
US11517685B2 (en) 2019-01-18 2022-12-06 Qnovia, Inc. Electronic device for producing an aerosol for inhalation by a person
US11241413B2 (en) 2019-04-17 2022-02-08 Nordiccan A/S Cannabinoid lozenge formulation
US10925853B2 (en) 2019-04-17 2021-02-23 Nordiccan A/S Oral cannabinoid tablet
US11903919B2 (en) 2019-04-17 2024-02-20 Nordiccan A/S Oral cannabinoid tablet
JP7408045B2 (ja) 2019-05-30 2024-01-05 漢義生物科技（北京）有限公司 非向精神性カンナビノイドを含有する包接物及びその調製方法
JP2022531510A (ja) * 2019-05-30 2022-07-06 漢義生物科技（北京）有限公司 非向精神性カンナビノイドを含有する包接物及びその調製方法
WO2020238642A1 (fr) * 2019-05-30 2020-12-03 汉义生物科技（北京）有限公司 Composé d'inclusion contenant un cannabinoïde non psychoactif et son procédé de préparation
CN110204426B (zh) * 2019-07-02 2023-05-30 梁志全 一种水溶性cbd的制备方法及水溶性cbd
CN110204426A (zh) * 2019-07-02 2019-09-06 黑龙江康源生物科技有限公司 一种水溶性cbd的制备方法及水溶性cbd
CN115038430A (zh) * 2019-10-18 2022-09-09 快饮科学公司 自微乳化的多种可递送物的系统
WO2021077061A1 (fr) * 2019-10-18 2021-04-22 Quicksilver Scientific, Inc. Systèmes multi-livrables auto-microémulsifiants
WO2021081010A1 (fr) * 2019-10-20 2021-04-29 Respira Technologies, Inc. Liquides pour aérosolisation et inhalation à l'aide de dispositifs électroniques
JP7421027B2 (ja) 2019-12-06 2024-01-24 漢義生物科技（北京）有限公司 カンナビノイドナノミセル製剤及びその製造方法
US11633351B2 (en) 2019-12-13 2023-04-25 Nordiccan A/S Fast disintegrating cannabinoid tablets
US11975098B2 (en) 2020-05-22 2024-05-07 Colorado School Of Mines Nanosuspensions of cannabidiol for developing water-dispersible formulations
US11478447B2 (en) 2020-07-17 2022-10-25 Canna Chemistries Llc Solid Δ9-tetrahydrocannabinol (Δ9-THC) compositions
WO2022016060A1 (fr) * 2020-07-17 2022-01-20 Canna Chemistries Llc Compositions solides de δ9-tétrahydrocannabinol (δ9-thc)
CN114748429A (zh) * 2020-12-29 2022-07-15 汉义生物科技（北京）有限公司 一种水溶性大麻素制剂及其制备方法
WO2023144165A1 (fr) 2022-01-25 2023-08-03 Kemijski inštitut Complexes cannabinoïdes ayant des propriétés améliorées
LU501323B1 (en) 2022-01-25 2023-07-25 Kemijski Inst Cannabinoid complexes with improved properties
WO2024097327A1 (fr) * 2022-11-02 2024-05-10 Progressive Therapeutics, Inc. Formulations de cannabinoïdes et utilisation pour le traitement de troubles émotionnels et d'un dysfonctionnement sexuel

Similar Documents

Publication Publication Date Title
WO2017183011A1 (fr) Complexes d&#39;inclusion hydrosolubles à base de cannabinoïdes
US20210228534A1 (en) Self-emulsifying compositions of cannabinoids
CN110035774B (zh) 大麻素的可稀释制剂及其制备方法
AU2018286647B2 (en) Sleep disorder compositions and treatments thereof
US20180221333A1 (en) Optimized cannabis-based aphrodisiac and mood enhancer
US20180000727A1 (en) Composition and methods to improve stability, dosing, pharmacodynamics and product shelf life of endocannabinoids, phytocannabinoids and synthetic cannabinoids delivered by nasal inhaer
US11801278B2 (en) Method for obtaining an extract of a plant biomass
US20230087359A1 (en) Cannabinoid compositions and methods of use thereof
AU2021293891A1 (en) Compositions for supplementing products with therapeutic agents and methods of use thereof
AU2020349528A1 (en) Compositions of cannabinoids for delivery by inhalation
BR112020027060A2 (pt) Composição de canabinoide e método para tratar tept e/ou ansiedade
Grotenhermen Cannabinoids for therapeutic use: designing systems to increase efficacy and reliability
WO2019175290A1 (fr) Cannabis ou compositions dérivées du cannabis pour favoriser l&#39;arrêt de la dépendance chimique
CN114642635A (zh) 萜烯类药物组合物的口服乳剂及其制备方法和用途
US20230038771A1 (en) Sleep quality using full spectrum hemp oil
IL262049A (en) Compounds for the treatment of ADHD
WO2024059819A2 (fr) Compositions de cannabinoïdes pour administration par inhalation
EP4188363A1 (fr) Préparations de micelles d&#39;huile de chanvre à spectre complet pour le traitement du diabète de type ii, la réduction de l&#39;inflammation pendant le covid-19 et l&#39;amélioration de la qualité du sommeil
Musika Developing of lipid-based nanocarriers for increasing gastro-intestinal absorption of plant flavonoids
IL309778A (en) Methods for treating opioid use syndrome using cannabinoids
Singha et al. Cannabis sativa a Promising Therapeutic Agent in Treatment of Various Health Associated Problem
WO2019241804A1 (fr) Compositions et méthodes de traitement de la narcolepsie et de troubles associés

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17785559

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17785559

Country of ref document: EP

Kind code of ref document: A1