WO2020115750A1 - Compositions à base de cannabis pour le traitement de la migraine et des céphalées - Google Patents

Compositions à base de cannabis pour le traitement de la migraine et des céphalées Download PDF

Info

Publication number
WO2020115750A1
WO2020115750A1 PCT/IL2019/051332 IL2019051332W WO2020115750A1 WO 2020115750 A1 WO2020115750 A1 WO 2020115750A1 IL 2019051332 W IL2019051332 W IL 2019051332W WO 2020115750 A1 WO2020115750 A1 WO 2020115750A1
Authority
WO
WIPO (PCT)
Prior art keywords
headache
thc
cannabis
migraine
composition
Prior art date
Application number
PCT/IL2019/051332
Other languages
English (en)
Inventor
Lihi BAR-LEV SCHLEIDER
Sid TAUBENFELD
Original Assignee
To Pharmaceuticals Llc
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 To Pharmaceuticals Llc filed Critical To Pharmaceuticals Llc
Publication of WO2020115750A1 publication Critical patent/WO2020115750A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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 

Definitions

  • the present invention generally relates to therapeutic products and methods applicable to the treatment of headache and migraine, and specifically those using certain cannabis-based preparations.
  • Cannabinoids the active ingredients of cannabis, are present in significantly higher concentrations in resin- producing pistillate inflorescences of cannabis plants.
  • Various types of cannabis such as C. Sativa, C. Indica and C. Ruder alis, may contain more than 100 different types of cannabinoids in distinct concentrations and proportions.
  • the two predominant types, the tetrahydrocannabinol (THC) and cannabidiol (CBD) have been related to a number of clinically beneficial effects attributed to their analgesic, antiemetic, antioxidative, neuroprotective and anti-inflammatory activities in mammals and humans.
  • the mammalian endocannabinoid system is a signal transduction system acting predominantly in the brain, and also in the peripheral tissues.
  • cannabinoid receptors have been identified so far, the most prominent being the cannabinoid receptors types 1 and 2 (CB 1 and CB 2 ).
  • CB 1 and CB 2 cannabinoid receptors types 1 and 2
  • the endocannabinoid system has been implicated in maintenance of pain, appetite, memory, immunity and inflammation, among others. This underlies the notion of high therapeutic potential of exogenous cannabinoids and cannabis-based medicines, and the likelihood of their broad clinical applications.
  • a rationalized use of cannabinoids still imposes significant challenges due to lack of significant controlled clinical trials.
  • Marinol capsules containing dronabinol, a synthetic D 9 - THC isoform, in oil - were approved in a number of countries as an antiemetic in cancer patients under chemotherapy and in patients with AIDS.
  • Cesamet capsules with a synthetic THC analog were approved as a Marinol substitute.
  • Additional formulations such as Namisol and Arvisol tablets with pure THC and pure CBD, respectively, are now under clinical trial for various indications. More recently, orphan cannabis-derived compositions such as Sativex have been approved for spasticity in multiple sclerosis and Epidolex - for rare forms of epilepsy.
  • the invention is relevant to a group of conditions collectively named headache, Headache is an almost universal human experience, being one of the most common complaints encountered in medicine and neurology. References to headache, migraine, and neuralgia have been traced to most ancient texts and relics.
  • TTH tension-type headache
  • Migraine occurs most commonly between the ages of 25 and 55 years and is 3 times more common in women.
  • migraine remains underdiagnosed and undertreated.
  • Chronic daily headaches of long duration include chronic migraine, chronic TTH, hemicrania continua and new daily persistent headache.
  • Worldwide prevalence of chronic daily headache has been consistent at 3%-5%, most of which likely represents chronic migraine.
  • the etiology of headache is heterogeneous and complex.
  • headache is classified into primary and secondary headaches, the latter being the result of another condition causing traction or inflammation of pain-sensitive structures. Therefore, the approach to treatment of many of the secondary headaches is focused on treatment of the suspected cause (e.g., sinus infection, psychiatric condition).
  • the suspected cause e.g., sinus infection, psychiatric condition.
  • the primary headache however, the underlying cause of the majority of these conditions remains unknown.
  • the most common primary headaches include migraine, TTH and cluster headache.
  • migraine and other primary headaches are not uniform but is proportioned to the severity of symptoms and disability. Mild and infrequent symptoms may be initially treated with lifestyle modifications, stress management techniques, and over-the- counter (OTC) abortive medications. Prescription medications are added as warranted to impede disability and maintain function. A distinction is made between prescription of abortive and preventive medications in the management of headaches. Abortive medications are prescribed to treat an individual attack, and preventative medications - to reduce the frequency and severity of chronic attacks.
  • migraine for example, during attacks acute treatment is managed with abortive medications, including: triptans (serotonin receptor agonists), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, ergotamine tartrate, dihydroergotamine or OTC medications (e.g., aspirin, paracetamol).
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • acetaminophen e.g., aspirin, paracetamol
  • OTC medications e.g., aspirin, paracetamol
  • the presently disclosed invention seeks to provide a comprehensive therapeutic solution for headache, including acute and chronic headache attacks, and thereby also to functional disability and secondary symptoms of this condition.
  • the invention provides a complete framework of compositions and methods serving at the same time as abortive and/or preventive medications for alleviation of acute and chronic headaches.
  • the invention is equally relevant to the primary as well as secondary headaches, when in the latter it serves for immediate alleviation of pain.
  • One example of particular population that can benefit from the invention includes patients suffering from migraine or TTH (primary headache) who do not respond to tripans or have a contraindication for using tripans, constituting a substantial proportion of patients.
  • TTH primary headache
  • At the core of the invention is certain type of cannabis-based compositions generally characterized as being enriched in THC.
  • the compositions of the invention have been found effective for treating acute migraine attacks, in terms of alleviation of pain (headache) and secondary migraine specific symptoms (e.g., photophobia, phonophobia, nausea, vomiting), and also in terms of recurrence and/or frequency of attacks, their overall severity and duration.
  • Cannabinoids act on the CB 1 and CB 2 receptors in the endocannabinoid system.
  • the CB 1 receptor is thought to be one of the most widely expressed G protein-coupled receptors in the brain, most notably in the brainstem and the trigeminal ganglia responsible for sensation and motor function in the head and face (biting and chewing).
  • the CB 1 receptors are also expressed in the peripheral nervous system.
  • the CB 2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues and organs, such as lymph nodes, the spleen, tonsils and other specialized tissues in the mucous membranes of the bowel, for example. That said, the involvement of the endocannabinoid system in the pathophysiology of migraine, and headache in general, remains unknown.
  • compositions of the invention for alleviation of headache and for acute migraine in particular is now exemplified with oil extracts of certain type of THC enriched cannabis strains.
  • An exemplary member of this group is the strain referred to herein as 'Erez' generally described in US Plant Patent Application No. 2014/0245494.
  • Erez herein encompasses a group of strains or cultivars produced from the original Avidekel strain selected due to its particularly THC content, starting from THC as high as 18% and more.
  • a typical Erez strain can comprise THC in the range of 18-25% (w/w), and CBD and CBN in the range of 1% (w/w), and other cannabinoids in a lesser concertations.
  • Erez can be further defined as a cannabis strain comprising THC up to at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% or more (w/w).
  • Erez strain is about 70% Indica breed.
  • crude plant material of Erez can be extracted in oil, e.g., olive oil or other vegetable or natural oil, using known in the art methods.
  • oil e.g., olive oil or other vegetable or natural oil
  • the advantage of this procedure is that it preserves other plant components, such as terpenes, contributing to beneficial medicinal effects and other properties of this product (flavor and smell).
  • the THC concentration is carefully titrated with olive oil to achieve with final concentrations of 3% THC (w/w) (see Example 1).
  • oil preparations of Erez can be defined as comprising THC up to at least 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).
  • THC amount typically a single drop of Erez oil comprises about 1.2 mg THC, 2 drops - about 2.4 mg THC, 3 drops - about 3.6 mg THC, and 4 drops, being the maximal dose used in this study - about 4.8 mg THC (see Example 3 and Table 3).
  • Erez oil can include additional types of cannabinoids, at much lesser concentrations and proportions, and also teipenes, all of which can potentially contribute to the presently demonstrated therapeutic effects.
  • compositions of the invention have been evaluated in a double-blind, placebo controlled randomized clinical trial (Example 3).
  • the compositions of the invention have been tested as a monotherapy for acute migraine.
  • the effective dose of the cannabis oil has been titrated in each patient starting from 2 drops and increasing the dose to 3 and 4 drops in 40 min intervals, if the treatment has been ineffective and in absence of adverse events.
  • Rescue medicines (conventional drugs) could be applied in cases wherein cannabis oil has been found ineffective 2 hours after administration.
  • compositions of the invention have been demonstrated using the ICHD-III criteria (International Classification Headache Society disorders 3 rd edition), and further questionnaires for the assessment of a series of clinically relevant parameters:
  • Patient overall assessment of disease activity also referred to as Patient-Reported Outcomes (PRO) or Patient Global Assessment (PGA) determined at a number of time points;
  • PRO Patient-Reported Outcomes
  • PGA Patient Global Assessment
  • ii Pain relief manifested in a reduction of headache severity assessed on a 4 Point Assessment Severity Scale (4-PASS) as a result of administration of the cannabis oil
  • iii Pain free manifested in a reduction of headache severity up to complete abolition of headache according to 4-PASS as a result of the administration;
  • This clinical trial has further provided tools for establishing therapeutically effective doses and regimens for maximization of beneficial clinical outcomes and avoidance of side effects and cross-drug interaction.
  • this study provided an exemplary framework for applying the compositions of the invention in a rationalized manner to achieve more effective and safe treatment of acute headache.
  • compositions of the invention have been presently administered via an oral route, specifically by sublingual administration.
  • Another advantageous route of administration could be topical administration on a head surface, as temples or forehead.
  • a particularly advantageous form could be as atransdermal patch.
  • compositions and methods of the invention being proven as efficacious safe, can replace other abortive and preventive medications for headache, and provide a constructive solution for patients with intolerability to the existing drags.
  • Tetrahydrocannabinol refers herein to a class of psychoactive cannabinoids characterized by high affinity to CB 1 and CB2 receptors, having a molecular formula C 21 H 30 O 2 , an average mass of approximately 314.46 Da, and a general structure of Formula I.
  • THC is responsible for the psychoactive ('high') effect of cannabis.
  • THC herein further refers to isomers, derivatives, or precursors of this molecule, such as (-)-trans-D9-tetrahydrocannabinol (D9-THC), D8-THC, and further to THC derived from the 2-carboxylic acid (2-COOH), THC- A.
  • THC refers to a synthetic or semi-synthetic or a natural cannabinoid (i.e. purified or extracted from a cannabis plant).
  • Cannabis-based and cannabis-derived these terms herein are interchangeable and denote a composition or a constituent thereof purified or extracted from a cannabis plant using known in the art technologies. These terms can further relate to a crude dry plant material.
  • extracts there are number of methods for producing a concentrated cannabis-derived material, e.g., filtration, maceration, infusion, percolation, decoction in various solvents, Soxhlet extraction, microwave- and ultrasound- assisted extractions and other methods. Certain oil extracts from the cannabis strain Erez are presently exemplified.
  • therapeutic dose or therapeutically effective dose relate to doses of the compositions of the invention, in any dosage form, capable of producing an improvement/ reduction of at least one symptom of headache, chronic or acute, according to clinically accepted criteria (e.g., Example 3). Such improvement can be further evaluated according to severity scales.
  • an improvement in this context relates to a type and/or a number of symptoms, a severity, a frequency of symptom(s), specific groups of symptoms (partial symptoms), and/or overall manifestation of symptoms in a subject or a group evaluated by a physician or self-reporting and estimated as at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 100% reduction or total abolition thereof.
  • Therapeutically effective amount herein denotes an amount of active agent needed to provide a desired level physiological response or improvement as above.
  • the precise amount depends on numerous factors, e.g. type of an agent, activity of a composition, intended patient use (e.g. number of doses per day), patient's considerations, and others.
  • An effective amount of an agent can be administered in one administration, or multiple administrations. The exact amount can be the result of empirical and/or individualized (case-by-case) determination.
  • the invention provides certain type of cannabis-based compositions for treating, alleviating or reducing headache, characterized in that they comprise THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w).
  • headache encompasses herein a range of disorders with the manifestation of a headache as a primary or a secondary symptom, or the only symptom, and also those including other symptoms related or unrelated to the headache.
  • This term further encompasses acute and chronic headache attacks, and also functional disabilities and secondary symptoms of this condition, such as photophobia and nausea, for example in the case of migraine, or more long-term manifestations as depression and anxiety.
  • compositions of the invention can be regarded, at the same time, as abortive and preventive medicines for the treatment of a wide range of conditions including headache as the only or additional clinical feature.
  • compositions of the invention are meant to provide an immediate relief to an acute headache attack and at the same time to prevent a recurrence of such attacks or reduce duration or frequency thereof.
  • immediate relief is meant to convey the efficacy of the presently disclosed compositions, and mote specifically can be defined by a timeframe up to 0.5h, lh, 1.5h or 2h or more after administration of the compositions of the invention.
  • compositions of the invention are applicable to a chronic headache or an acute headache attack.
  • compositions of the invention can be applied at the time of an attack for an immediate relief, and also between attacks for preventing thereof.
  • a diagnosis of headache is associated with one of the following disorders:
  • Part I The Primary Headaches
  • Part P The Secondary Headaches (including Facial Pain)
  • compositions of the invention are applicable to an individual affected by each one of the above conditions.
  • compositions of the invention are applicable to a type of headache manifested as migraine.
  • migraine a type of headache manifested as migraine.
  • migraneurs, female or male is one of the particular populations that could benefit from the invention.
  • migraine herein encompasses the main subtypes of migraine, as migraine with and without aura.
  • Aura denotes a reversible set of nervous system symptoms, most often visual or sensory symptoms, that typically develops gradually, recedes, and is then followed by headache accompanied by nausea, vomiting, photophobia, and phonophobia. Less common symptoms of aura include speech/language symptoms, motor or brainstem symptoms, or retinal symptoms.
  • aura is another term for a migraine related symptom or a 'secondary migraine related symptom', these terms herein are interchangeable.
  • ICHD HI migraine is diagnosed with:
  • compositions of the invention are applicable to an individual affected by migraine in its various forms and manifestations.
  • the compositions of the invention are applicable for treating, alleviating or reducing least one secondary migraine related symptom, or a symptom of aura.
  • the symptom of aura treatable by the compositions of the invention is selected from the group of nausea, vomiting, photophobia, phonophobia.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • OTC medications e.g., aspirin, paracetamol
  • TAAs TTH - tricyclic antidepressant
  • SSRIs Selective Serotonin Receptor Inhibitors
  • compositions comprise THC at a concentration of at least about 2%.
  • compositions comprising about 3% THC (w/w) have been presently found particularly applicable to the treatment of headache attacks.
  • compositions of the invention can comprise THC up to at least 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).
  • compositions of the invention can comprise a THC dose in the range of at least about 2 mg THC to at least about 6 mg THC or more, or more specifically between 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg THC or more.
  • compositions of the invention are provided in a form of an oil extract of a cannabis strain.
  • Oil extracts are particularly advantageous as they retain a range of lipophilic components, i.e., cannabinoids, terpenes, carotenes and others, in specific proportions and combinations, being responsible as a whole for the presently demonstrated effects.
  • the oil extracts are easily applicable via oral, sublingual and topical routes. Certain type of olive oil extracts of cannabis has been presently exemplified.
  • the term 'oil extract of a cannabis strain' denotes herein various types of oils and various types of plant material from the relevant cannabis strains. With respect to the latter, the most applicable plant material with the highest concentration of actives is the inflorescences female cannabis plants, more precisely the resin-producing part of these flowers. It is possible however that other parts of cannabis (seeds, stem, etc.) can be applicable for the purpose of specific embodiments.
  • oils can be applicable for producing the cannabis extracts of the invention, vegetable oils in general (e.g., soybean, canola, com, cotton seed, sunflower, peanut, sesame, rice bran oils), and also essential oils (e.g., lemon, cinnamon, lemongrass, clary sage, lavender, tea tree, eucalyptus).
  • vegetable oils in general e.g., soybean, canola, com, cotton seed, sunflower, peanut, sesame, rice bran oils
  • essential oils e.g., lemon, cinnamon, lemongrass, clary sage, lavender, tea tree, eucalyptus.
  • the transdermal patches can comprises higher concentrations of actives.
  • compositions can be adapted for oral, sublingual, topical or transdermal administration.
  • compositions of the invention can be provided in the form of a transdermal patch, or incorporated into various transdermal delivery systems by means of known in the art technologies, including first-, second- and more recent third- generation delivery systems.
  • first-generation transdermal delivery systems are systems where the drag is stored in a reservoir enclosed on one side with an impermeable backing and on the other side - with an adhesive contacting to the skin. This term encompasses systems wherein the drag is dissolved in a liquid or gel-based reservoir, and also systems where the drag is incorporated into a solid polymer matrix.
  • the transdermal delivery system of the invention can be composed of four layers, including an impermeable backing membrane, a drag reservoir, a semi-permeable membrane that may serve as a rate-limiting barrier, and an adhesive layer.
  • an impermeable backing membrane for example, a polymethyl methacrylate copolymer
  • a drag reservoir for example, a polymethyl methacrylate copolymer
  • a semi-permeable membrane that may serve as a rate-limiting barrier
  • an adhesive layer can permit the use of liquid chemical enhancers, such as ethanol.
  • transdermal delivery systems can have three layers, by eliminating the semi- permeable membrane, or just two layers, by incorporating the drag directly into the adhesive.
  • transdermal delivery systems employs second-generation delivery systems, i.e., those using chemical enhancers, non-cavitational ultrasound and iontophoresis.
  • transdermal delivery systems are third-generation delivery systems, i.e., target their effects to skin’s barrier layer of stratum comeum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound.
  • compositions of the invention can incorporated into delivery systems permitting controlled or suspended release of actives.
  • These types of systems have been subject to intensive R&D, yielding first-, second- and third-generation delivery systems, including so-called ' smart' polymers and hydrogels to make systems that are triggered by changes in environmental factors, such as pH, temperature, or glucose.
  • Controlled drug delivery systems are applicable to oral and transdermal forms of the presently disclosed compositions.
  • compositions of the invention can be made of extracts of the cannabis strain designated herein as Erez.
  • Such compositions using olive oil extracts of female flowers Erez strain have been presently exemplified.
  • the method comprises administering to the subject a therapeutically effective amount of a cannabis-based composition comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w).
  • the methods of the invention apply cannabis-based compositions comprising about 3% THC (w/w).
  • compositions and methods of the invention are at the same time abortive and/or preventive regarding treatment, alleviation or a reduction of headache.
  • the methods of the invention are applicable to a chronic headache or an acute headache attack.
  • compositions and methods of the invention can be assessed using ICHD IP, the gold standard diagnostic criteria for headache, and further specific severity scales for the assessment of intensity of headache and other accompanying symptoms.
  • the impact of the present compositions and methods on the severity of headache can be measured using a 4 Point Assessment Severity Scale (4- PASS).
  • 4- PASS 4 Point Assessment Severity Scale
  • the type and severity of the secondary- symptoms in migraine can be measured using an analogous 4-point scale. Applicability of such methods have been presently exemplified (see Example 3).
  • compositions and methods of the invention are applicable to the treatment and alleviation of migraine or specific secondary migraine related symptoms (i.e., at least one symptom of aura such as nausea, photophobia, phonophobia).
  • compositions and methods of the invention can alleviate or reduce each one of these symptoms, or any combination thereof, in terms of intensity, frequency and/or duration.
  • compositions of the invention should be provided in therapeutically effective doses and under therapeutically effective regimens, and by permissible administration routes.
  • the methods of the invention apply the cannabis-based composition via oral, sublingual, topical or transdermal administration route.
  • compositions can comprise THC up to at least 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).
  • the methods of the invention apply a THC daily dose in the range of at least about 2 mg THC to at least about 6 mg THC or more, or more specifically between 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg THC or more. Applicability of such methods to the treatment of headache has been presently exemplified (Example 3).
  • the methods of the invention apply such daily doses by means of a single daily dose.
  • This type of methods are particularly relevant to the treatment and alleviation of an acute headache attack.
  • the methods of the invention can be also applied for the prevention of recurrence of chronic headache attacks.
  • the methods of the invention can apply said amounts as a single dose or as two or three doses per day, or more.
  • the therapeutically effective amount of the cannabis-based compositions can be personalized.
  • the exact therapeutically effective amount is established for each patient by titration of the dose and monitoring of therapeutic effects.
  • the methods of the invention can be applied as a monotherapy therapy, potentially replacing other conventional headache medicines. Medicines belonging to this group have been referred to above.
  • compositions are particularly applicable for personalization and careful titration to achieve a therapeutically effective dose.
  • the methods of the invention apply the cannabis-based compositions comprising an oil extract of the strain Erez in the manner and therapeutic amounts as described above. Applicability of such methods has been presently exemplified.
  • such oral dosage forms can comprise THC up to at least 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or more (w/w).
  • the oral dosage forms can comprise a THC amount in the range between 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg THC or more.
  • the oral dosage forms of the invention can be applied for treating, alleviating or reducing headache, the headache being a chronic headache or an acute headache attack.
  • a cannabis-derived material for manufacture/ preparation of a medicament for treating, alleviating or reducing headache
  • the medicament comprising THC at a concentration of at least about 2% or more (w/w) and other cannabinoids at respective concentrations of about 0.1% or less (w/w).
  • such medicaments can be used an abortive or a preventive headache medicine for chronic headache or acute headache attacks.
  • Cannabis oil can be taken orally by ingesting a small number of drops under the tongue several times a day.
  • An extract ofErez flowers is dissolved in olive oil.
  • Erez oil usually comprises THC (D9-THC) at a concentrations of about 3%. Fine tuning of THC concentration is achieved by a titration with pure THC and/or olive oil .
  • one drop of Erez oil (about 0.04 ml) contains about 1.2 mg THC, two drops - 2.4 mg THC; three drops - 3.6 mg THC and four drops -4.8 mg THC.
  • Erez oil usually comprises about 93% olive oil, 3% THC, 0.1% CBG, ⁇ 0.1% CBD, ⁇ 0.1% CBN, ⁇ 0.1% CBC, ⁇ 0.1% CBDV and other unidentified cannabinoids reaching up to 3.5%, and further certain percentages of terpenes, flavonoids, waxes and chlorophyll.
  • IP is stored at room temperature.
  • IP is indicated upon the occurrence of an acute migraine attack which is not spontaneously resolved. IP is administered in the form of drops under the tongue, starting with the dose of two drops (2.4 mg total THC), with optional third drop (3.6 mg total THC) if there is no improvement after 40 min, and optional fourth drop (4.8 mg total THC), in absence of adverse events. The maximal dose has been limited to four drops ofErez oil .
  • IP is given as a monotherapy under proper titration of effective dose, and monitoring of adverse events If found unsuccessful or upon adverse events, a patient can shift to a conventional headache medication.
  • the inventors analyzed data collected on patients treated with cannabis.
  • the population group included 82 patients with chronic headache (average age 47.2 ⁇ 15.0 years, 39% males, 45.1% employed, about 1/2 reported previous use of cannabis).
  • the median pain intensity was 9/10 (IQR 8-10).
  • Additional symptoms included: sleep problems (81.7%), vomiting (57.3%), weakness (37.8%) and anxiety (39%).
  • the median number of different medications per day was four.
  • the proportion of subjects achieving a headache relief at 2h after administration measured as an improvement of at least 2 levels in migraine severity from baseline.
  • the study duration is 2 months, including: a) four weeks period for of applying for the cannabis license and coordinating the first trial visit; and b) four weeks of trial period.
  • the trial includes approximately 90 subjects randomly assigned to receive Erez oil or placebo (1:1 ratio).
  • the trial population includes patients diagnosed with migraine, i.e., suffering from at least two migraine attacks per month (followed up by a neurologist).
  • Inclusion criteria include:
  • ICHD-in International classification headache society disorders 3rd edition
  • Exclusion criteria include:
  • Cisapride Patients receiving under Astemizole, Cisapride, Pimozide or Terfenadine;
  • IP/placebo is administered as drops applied under the tongue. IP is titrated in each patient to achieve reach target dose, with overall three dosing options as 2, 3, or maximum 4 drops. All patients start with 2 drops at the first administrations, followed by adding additional 1 or 2 drops, after 40 or 80 minutes, respectively, if the pain intensity is still moderate or severe, and in absence of adverse reaction.
  • a patient still suffering from a moderate or severe headache at 2 h after taking the initial dose of IP is allowed to take optional rescue medications, i.e.: standard analgesics (opiates, acetaminophen (paracetamol), NSAIDs) and antiemetic drags.
  • optional rescue medications i.e.: standard analgesics (opiates, acetaminophen (paracetamol), NSAIDs) and antiemetic drags.
  • patients are prohibited from taking ergotamine or other 5-HT1B/1D agonists from 24 h before and after dosing.
  • IP/placebo is taken as 2 drops, with an optional 3 rd drop after 40 minutes if there is no improvement and no AE, and an optional 4 th drop after another 40 minutes under the same conditions.
  • the following data is recorded by phone: how many attacks were experienced during the past week; how many times the investigational treatment was initiated; how many drops in each attack and whether a rescue treatment was used or not; and the kind and dosage of the rescue treatment.
  • PGA Patient Global Assessment
  • Vital signs are obtained at screening, baseline and EOS, including blood pressure, heart rate measurements, saturation and temperature.
  • Blood samples include routine biochemistry, haematology analyses.
  • Urine samples are detecting previous D 9 -THC use. Women of child bearing potential also perform pregnancy test (bHCG).
  • Table 2 summarized the relevant studies with references to the PubMed/MEDLINE database.
  • Parametric procedures are applied for continuous variables, including paired and unpaired t-test and ANOVA.
  • Non-parametric procedures include Mann-Whitney, Wilcoxon and Spearman Correlation tests.
  • Parametric model assumptions are assessed using Normal-plot or Shapiro-Wilks statistic for verification of normality and Levene’s test for verification of homogeneity of variances.
  • Categorical variables are tested using Pearson’s c 2 test for contingency tables or Fisher Exact test, as appropriate. Correlations between variables are tested using Pearson or Spearman tests, depending on the variables distribution.
  • Multivariable analysis is applied when the two trial groups are different by a baseline or procedural parameters to account for these discrepancies, with treatment success as a dependent variable in a logistic regression model.
  • Safety endpoint - a composite endpoint of all serious adverse events (SAE) at 24 hours after each consumption;
  • N the number of observations (N), mean, 95% confidence interval of the mean, standard deviation, median, inter-quartile range, minimum, and maximum values are determined:
  • the tolerance to cannabis is considered to be relatively good, with only mild side effects.
  • subjects on cannabis reported: dizziness, dry mouth, nausea, sleepiness, psychoactive effects, headaches, confusion and disorientation, increased appetite, weakness, red / irritated eyes, decreased memory, decreased concentration, heart palpitations, restlessness, vomiting and fear. Records include any undesirable experience occurring to a patient (sign, symptom, illness, abnormal laboratory value, or other medical event.
  • a treatment related adverse event relates to any adverse event, for which a causal relationship between the treatment and the event is at least a reasonable possibility, i.e., the relationship cannot be excluded, which is identified or worsens during a clinical trial
  • a serious adverse event relates to one of the following: death, life-threatening condition, hospitalization (initial or prolonged), disability - significant, persistent, or permanent change, impairment, damage or disruption in patient's body function/ structure, physical activities or quality of life.
  • Severe Events that interrupt usual daily activity and generally require a systemic device therapy or other treatment.
  • IP is defined according to the following scale:

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des produits thérapeutiques et des procédés applicables au traitement de la céphalée et de la migraine en particulier. À cet effet, les produits et les procédés de l'invention appliquent un certain type de compositions à base de cannabis à forte teneur en THC et à faible teneur en tous les autres cannabinoïdes, fournies dans des schémas posologiques et des modes d'administration déterminés.
PCT/IL2019/051332 2018-12-06 2019-12-05 Compositions à base de cannabis pour le traitement de la migraine et des céphalées WO2020115750A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862776084P 2018-12-06 2018-12-06
US62/776,084 2018-12-06

Publications (1)

Publication Number Publication Date
WO2020115750A1 true WO2020115750A1 (fr) 2020-06-11

Family

ID=70975279

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2019/051332 WO2020115750A1 (fr) 2018-12-06 2019-12-05 Compositions à base de cannabis pour le traitement de la migraine et des céphalées

Country Status (1)

Country Link
WO (1) WO2020115750A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11607400B2 (en) * 2021-03-29 2023-03-21 Schedule 1 Therapeutics, Inc. Compositions comprising cannabinoids and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6946150B2 (en) * 2002-08-14 2005-09-20 Gw Pharma Limited Pharmaceutical formulation
US20070099989A1 (en) * 2005-06-20 2007-05-03 Lou Barbato Dronabinol treatment for migraines
WO2016092539A1 (fr) * 2014-12-07 2016-06-16 One World Cannabis Ltd Utilisation de cannabis pour traiter la migraine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6946150B2 (en) * 2002-08-14 2005-09-20 Gw Pharma Limited Pharmaceutical formulation
US20070099989A1 (en) * 2005-06-20 2007-05-03 Lou Barbato Dronabinol treatment for migraines
WO2016092539A1 (fr) * 2014-12-07 2016-06-16 One World Cannabis Ltd Utilisation de cannabis pour traiter la migraine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Erez strain", 23 December 2016 (2016-12-23), Retrieved from the Internet <URL:https://tikunolamusa.com/strain/erez> *
BARON EP ET AL.: "Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort", JOURNAL OF HEADACHE AND PAIN, vol. 19, no. 1, 24 May 2018 (2018-05-24), pages 1 - 28, XP021256738, DOI: 10.1186/s10194-018-0862-2 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11607400B2 (en) * 2021-03-29 2023-03-21 Schedule 1 Therapeutics, Inc. Compositions comprising cannabinoids and methods of use
US11712431B2 (en) 2021-03-29 2023-08-01 Schedule 1 Therapeutics, Inc. Compositions comprising cannabinoids and methods of use
US12029721B2 (en) 2021-03-29 2024-07-09 Schedule 1 Therapeutics, Inc. Compositions comprising cannabinoids and methods of use

Similar Documents

Publication Publication Date Title
Sreebny et al. A reference guide to drugs and dry mouth–2nd edition
KR102615486B1 (ko) 펜플루라민을 사용하여 레녹스-가스토 증후군을 치료하는 방법
Cupp Herbal remedies: adverse effects and drug interactions
Cole Therapeutic efficacy of antidepressant drugs: a review
WO2016092539A1 (fr) Utilisation de cannabis pour traiter la migraine
GB2432312A (en) Pharmaceutical compositions for the treatment of pain
JP2021525709A (ja) 自閉症スペクトラム障害の治療のためのカンナビスベースの組成物
US20110155130A1 (en) Dronabinol Treatment for Migraines
CN115605195A (zh) 用于治疗大麻使用病症和缓解大麻素戒断的方法和组合物
Barra et al. Pharmacologic therapies to promote recovery of consciousness
Wu et al. Four types of traditional Chinese medicine inducing epileptic seizures
CN112386589B (zh) 一种抗焦虑/抗抑郁药用组合物及其用途
WO2020115750A1 (fr) Compositions à base de cannabis pour le traitement de la migraine et des céphalées
WO2020115751A1 (fr) Compositions à base de cannabis pour le traitement de la maladie d&#39;alzheimer et de la démence
Gupta et al. Valbenazine for the treatment of adults with tardive dyskinesia
WO2019130215A1 (fr) Compositions de cannabis pour le traitement de troubles cutanés inflammatoires
US20240173339A1 (en) Cannabinoid formulation for management of depression, anxiety and ptsd, and cannabinoid formulation as a sleep aid
CN108451951A (zh) 一种治疗神经性疾病的新药
TW202131910A (zh) 使用mtorc1調節劑的治療方法
Kiran et al. AN OPEN-LABELED, MULTICENTRIC, POST-MARKETING SURVEILLANCE (PMS) TO SUBSTANTIATE THE SAFETY AND EFFICACY OF SINAREST SYRUP IN PATIENTS OF COMMON COLD.
US8222278B2 (en) Treatment of attention-deficit/hyperactivity disorder
GREENHUT et al. SipNose-Topiramate: A Novel Breakthrough Approach to Binge Eating Management
CN116887819A (zh) 大麻二酚和氯巴占在儿童期发病癫痫综合征治疗中的用途
JP2023134464A (ja) 治療不応性うつ病の治療
Augmentin t DENTALABSCESS

Legal Events

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

Ref document number: 19894118

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19894118

Country of ref document: EP

Kind code of ref document: A1