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WO2023043870A1 - Formulation de lsd sous forme de gomme à mâcher et ses procédés d'utilisation - Google Patents

Formulation de lsd sous forme de gomme à mâcher et ses procédés d'utilisation Download PDF

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Publication number
WO2023043870A1
WO2023043870A1 PCT/US2022/043580 US2022043580W WO2023043870A1 WO 2023043870 A1 WO2023043870 A1 WO 2023043870A1 US 2022043580 W US2022043580 W US 2022043580W WO 2023043870 A1 WO2023043870 A1 WO 2023043870A1
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WIPO (PCT)
Prior art keywords
chewing gum
subject
reducing
disease
alzheimer
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Ceased
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PCT/US2022/043580
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WO2023043870A8 (fr
Inventor
Graham Johnson
David E. Nichols
Shlomi RAZ
Hooshang S. ZAVAREH
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Eleusis Therapeutics US Inc
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Eleusis Therapeutics US Inc
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Publication of WO2023043870A1 publication Critical patent/WO2023043870A1/fr
Publication of WO2023043870A8 publication Critical patent/WO2023043870A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/12—Chewing gum characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums

Definitions

  • Alzheimer's disease (hereinafter "Alzheimer's disease” or “AD”) is a neurodegenerative disease and the most common cause of dementia. This disease manifests as a gradual but progressive decline in memory, thinking skills and behavior that is accelerated relative to normal aging (Reitz et al. 2011 Nat Rev Neurol 7: 137-152). Eventually, patients are unable to recognize familiar people or carry out the simplest task. Alzheimer's disease is, at this time, among the leading causes of death in the United States (US). There are two predominant forms of the disease: Familial Alzheimer's disease is typically caused by dominant genetic mutations. This form of the disease is a rare and devastating illness with onset occurring in mid-life. The second and far more common form of the disease is Sporadic or Late onset Alzheimer's disease.
  • Alzheimer's disease typically occurs after the age of 62 years. As the world population and human longevity increase, so do the numbers of people affected by Alzheimer's disease globally. The estimated worldwide costs of dementia, of which Alzheimer's disease accounts for up to 80% of cases, was US$604 billion in 2010, which was greater than 1% of US GDP (VVimo and Prince 2010 World Alzheimer Report 2010: The Global Economic Impact of Dementia 1 -93). The cost of caring for Alzheimer patients in the US is expected to increase from US$172 million in 2010, to US$1 .07 trillion in 2050 (Alzheimer's Association. "Changing the Trajectory of Alzheimer's Disease: A National Imperative (2010)”).
  • the principal risk factor for Alzheimer's disease is age, and prevalence of the disease increases with age (approximately 10% of individuals over 65 and approximately 50% of individuals over 85).
  • age approximately 10% of individuals over 65 and approximately 50% of individuals over 85.
  • the incidence of the disease doubles every 5 years after 65 years of age, with the diagnosis of about 1 ,275 new cases per year per 100,000 persons older than 65 years of age (Querfurth et al., 2010 NEJM 362:4).
  • Both men and women are affected by Alzheimer's disease, but women generally represent a higher percentage of cases overall (roughly 60% to 40%), possibly due to greater longevity. People suffering from Alzheimer's disease tend to live approximately 3 to 9 years after diagnosis, on average.
  • Alzheimer's disease In view of the fact that more than 4.5 million people in the United States alone suffer from Alzheimer's disease (and this number will continue to grow as the population ages), the wasted and unforgiving degenerative and debilitative nature of Alzheimer's disease as it develops, and the high costs associated with the care for people suffering from Alzheimer's disease, there is a real and immediate need for an effective medical therapy that can ameliorate the symptoms, or delay the onset, of Alzheimer's disease.
  • the invention features a chewing gum composition including a chewing gum base and lysergic acid diethylamide (LSD).
  • the chewing gum includes between 5 pg to 25 pg (e.g., 5 ⁇ 1 pg, 6 ⁇ 1 pg, 7 ⁇ 1 pg, 8 ⁇ 1 pg, 9 ⁇ 1 pg, 10 ⁇ 1 pg, 11 ⁇ 1 pg, 12 ⁇ 1 pg, 13 ⁇ 1 pg, 14 ⁇ 1 pg, 15 ⁇ 1 pg, 16 ⁇ 1 pg, 17 ⁇ 1 pg, 18 ⁇ 1 pg, 19 ⁇ 1 pg, 20 ⁇ 1 pg, 21 ⁇ 1 pg, 22 ⁇ 1 pg, 23 ⁇ 1 pg, 24 ⁇ 1 pg, or 25 ⁇ 1 pg) of lysergic acid diethylamide or a pharmaceutically acceptable salt thereof.
  • the chewing gum includes 10 ⁇ 2 pg of lyse
  • the chewing gum includes no less than 15 pg of lysergic acid diethylamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the chewing gum includes no more than 25 pg of lysergic acid diethylamide or a pharmaceutically acceptable salt thereof.
  • the chewing gum may include a sweetener.
  • the chewing gum includes a plasticizer.
  • the chewing gum includes a softener.
  • the chewing gum includes a buffering agent.
  • the chewing gum includes a flavoring agent.
  • the chewing gum includes a coloring agent.
  • the chewing gum includes a filler.
  • the chewing gum includes a coating.
  • the invention features a method of treating Alzheimer’s disease in a subject including administering to the subject any one of the chewing gums including lysergic acid diethylamide described herein, in an amount sufficient to treat said Alzheimer’s disease.
  • the method includes improving cognitive function, reducing the severity of an AD-associated neuropsychiatric condition, delaying the loss of cognitive function, or delaying the onset of an AD-associated neuropsychiatric condition in said subject.
  • the method includes reducing agitation, reducing irritability, reducing apathy, or reducing aggression in said subject.
  • the method includes delaying the onset of agitation, irritability, apathy, or aggression in said subject.
  • the method includes improving memory in said subject; improving learning capacity in said subject; or delaying the loss of memory in said subject. In certain embodiments, the method includes delaying the loss of learning capacity in said subject. In some embodiments, the method of includes reducing the severity of dementia in said subject or delaying the onset of dementia in said subject. In some embodiments, the method includes reducing the severity of depression in said subject or delaying the onset of depression in said subject. In particular embodiments, the method includes reducing the severity of anxiety in said subject or delaying the onset of anxiety in said subject.
  • the method includes reducing agitation, reducing apathy, reducing irritability, or reducing aggression in a subject having Alzheimer’s disease with comorbid dementia. In certain embodiments, the method includes reducing agitation, reducing apathy, reducing irritability, or reducing aggression in a subject having Alzheimer’s disease with mild cognitive impairment due to Alzheimer’s disease. In some embodiments, the method includes reducing agitation, reducing apathy, reducing irritability, or reducing aggression in a subject having Alzheimer’s disease with asymptomatic Alzheimer’s disease.
  • the method includes reducing agitation, reducing apathy, reducing irritability, or reducing aggression in a subject having Alzheimer’s disease with prodromal Alzheimer’s disease.
  • the method includes improving cognitive function or reducing the severity of dementia in a subject having Alzheimer’s disease with comorbid dementia.
  • the method includes improving cognitive function or reducing the severity of depression in a subject having Alzheimer’s disease with comorbid depression.
  • improving cognitive function or reducing the severity of anxiety in a subject having Alzheimer’s disease with comorbid anxiety is provided.
  • the method includes delaying the loss of cognitive function or reducing the severity of an AD-associated neuropsychiatric condition in a subject having Alzheimer’s disease with comorbid dementia. In certain embodiments, delaying the loss of cognitive function or delaying the onset of an AD-associated neuropsychiatric condition in a subject with mild cognitive impairment due to Alzheimer’s disease. In particular embodiments, the method includes delaying the loss of cognitive function or delaying the onset of an AD-associated neuropsychiatric condition in a subject with asymptomatic Alzheimer’s disease. In some embodiments, the method includes delaying the loss of cognitive function or delaying the onset of an AD-associated neuropsychiatric condition in a subject with prodromal Alzheimer’s disease.
  • said AD-associated neuropsychiatric condition is depression and/or anxiety. In some embodiments, said AD-associated neuropsychiatric condition is apathy. In particular embodiments, said AD-associated neuropsychiatric condition is apathy. In certain embodiments, said AD-associated neuropsychiatric condition is aggression. In certain embodiments, said AD-associated neuropsychiatric condition is irritability. In some embodiments, said cognitive function is memory and/or learning capacity.
  • said chewing gum including lysergic acid diethylamide, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen from once daily to once weekly. In certain embodiments, said dosing regimen is once every three, four, or five days.
  • said dosing regimen includes administering the chewing gum including an average of from 8 pg to 90 pg (e.g., 8 ⁇ 2 pg, 10 ⁇ 2 pg, 12 ⁇ 2 pg, 14 ⁇ 2 pg, 16 ⁇ 2 pg, 18 ⁇ 2 pg, 20 ⁇ 10 pg, 30 ⁇ 10 pg, 40 ⁇ 10 pg, 50 ⁇ 10 pg, 60 ⁇ 10 pg, 70 ⁇ 10 pg, 80 ⁇ 10 pg, and 90 ⁇ 10 pg) lysergic acid diethylamide, or a pharmaceutically acceptable salt thereof, to said subject per week.
  • said pharmaceutical composition is formulated for sustained release.
  • the subject has difficulty swallowing.
  • the lysergic acid diethyl amide is released within 1 hour (e.g., within 1 minute, within 10 minutes, within 30 minutes, and within 60 minutes) from the chewing gum. In some embodiments, the lysergic acid diethyl amide is absorbed through the buccal mucosa.
  • chewing gum means all chewable gum products such as extruded chewing gum, centre-filled chewing gum, toffee-imitating chewing gum, compressed chewing gum, slabs or sticks.
  • improving cognitive function refers to improving memory, learning capacity, communication language, thinking, decision making, judgment, and/or attention in a subject receiving treatment according to a method of the invention in comparison to the performance of the subject prior to receiving the treatment.
  • the cognitive function can be evaluated using any of a variety of known tests for measuring and monitoring changes in cognitive function.
  • “delaying the loss of cognitive function” refers to delaying the loss of memory, learning capacity, communication language, thinking, decision making, judgment, and/or attention in a subject receiving treatment according to a method of the invention in comparison to the average onset of loss of cognitive function observed for untreated subjects at the same stage of disease.
  • the cognitive function can be evaluated using any of a variety of known tests for measuring and monitoring changes in cognitive function.
  • reducing the severity of an AD-associated neuropsychiatric condition refers to reducing one or more symptoms of an AD-associated neuropsychiatric condition, such as depression, anxiety, apathy, agitation, irritability, or aggression in comparison to the performance of the subject prior to receiving the treatment.
  • the symptoms of the AD-associated neuropsychiatric condition can be evaluated using any of a variety of tests known in the art.
  • “delaying the onset of an AD-associated neuropsychiatric condition” refers to delaying one or more symptoms of an AD-associated neuropsychiatric condition in a subject receiving treatment according to a method of the invention in comparison to the average onset of the AD- associated neuropsychiatric condition observed for untreated subjects at the same stage of disease.
  • the methods of the invention can be used to delay the onset of AD-associated depression and/or anxiety in a subject.
  • the symptoms of the AD-associated neuropsychiatric condition can be evaluated using any of a variety of tests known in the art.
  • reducing the severity of dementia refers to reducing one or more symptoms of dementia in a subject receiving treatment according to a method of the invention in comparison to the performance of the subject prior to receiving the treatment.
  • the symptoms of dementia can be evaluated using any of a variety of tests known in the art.
  • “delaying the onset of dementia” refers to delaying one or more symptoms of dementia in a subject receiving treatment according to a method of the invention in comparison to the average onset of dementia observed for untreated subjects at the same stage of disease.
  • the symptoms of dementia can be evaluated using any of a variety of tests known in the art.
  • the term “gum base” refers to the mainly water insoluble and hydrophobic gum base ingredients that are mixed together before the bulk portion of the chewing gum formulation is added.
  • the terms “pharmacologically effective amount,” “therapeutically effective amount,” and the like, when used in reference to a therapeutic composition refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results. For example, in the context of treating depression, described herein, these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition.
  • the quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like.
  • An “effective amount,” "pharmacologically effective amount,” or the like, of a composition of the present disclosure also includes an amount that results in a beneficial or desired result in a subject as compared to a control.
  • treating refers to administering treatment to a patient diagnosed with Alzheimer’s disease (i) to ameliorate the disease and improve the patient’s condition; or (ii) to delay the progression of Alzheimer’s disease.
  • compositions of chewing gum including LSD that are useful in therapy, such as in the treatment of a patient having or at risk for Alzheimer’s disease. Furthermore, this disclosure provides methods of using the chewing gum compositions described herein to treat Alzheimer’s disease. Chewing gum compositions will be more acceptable than a tablet that must be swallowed by an AD patient. In addition, being in a chewing gum formulation will prevent diversion of the LSD, as it will be extremely difficult to extract the LSD from the gum.
  • LSD has the structure:
  • LSD has a high affinity for various 5-hydroxytryptamine (5-HT) receptors, including 5-HTIA, 5- HT2A, 5-HT2B, 5-HT2C, 5-HTSA, and 5-HTe, which play a key role in regulating mood, sexual behavior, aggression, impulsivity, cognitive function, appetite, pain, sleep, and memory along with other behaviors.
  • 5-HT 5-hydroxytryptamine
  • the lysergic acid diethylamide, or a pharmaceutically acceptable salt thereof is contained in an appropriate amount in a chewing gum.
  • the LSD formulated in the chewing gum may be appropriate for delivery of the chewing gum through the buccal mucosa of the subject who is administered the chewing gum comprising LSD.
  • the chewing gum comprising LSD of the present invention may also include additional ingredients to improve or modify the properties of the chewing gum.
  • additional ingredients include plasticizers, buffering agents, sweeteners, flavoring agents, fillers, coloring agents, coatings, and mixtures of the foregoing.
  • the chewing gum comprising LSD of the present invention includes gum base.
  • the chewing gum base used in the present invention can be any type of conventional gum base.
  • the gum base can be a natural or synthetic product.
  • natural gum bases include Chicle-, Jelutong-, Lechi di Caspi-, Soh-, Siak-, Katiau-, Sorwa-, Balata-, Pendare-, Perillo-, Malaya-, and Percha-gums, natural caoutchouc such as Crepe, Latex, and Sheets and natural resins such as Dammar and Mastix.
  • Examples of synthetic gum bases include polyvinylacetate (“Vinnapas”), "Dreyco” commercial gum base, polyvinyl esters, polyisobutylene and non-toxic butadiene-styrene lattices.
  • Examples of the chewing gum bases are provided in U.S. Pat. Nos. 3,877,468; 6,344,222 and 6,627,234, which are incorporated herein by reference.
  • Plasticizers which are sometimes referred to as and may include softeners and emulsifiers, can be added to the chewing gum comprising LSD of the present invention to reduce the viscosity of the gum base to a favorable or desirable consistency.
  • the plasticizer may include lecithin, lanolin, glycerides (mono- and di-), stearic acid, sodium stearate, potassium stearate, glycerol triacetate, glycerol monostearate and mixtures of thereof.
  • the chewing gum comprising LSD may include an elastomer plasticizer.
  • the elastomer plasticizer may be natural rosin esters often referred to as ester gums. Natural rosin esters known in the art include methyl, glycerol, and pentaerythritol esters of rosins and modified rosins, such as hydrogenated, dimerized and polymerized rosins.
  • natural rosin esters include glycerol ester of wood and gum rosin, glycerol ester of partially hydrogenated wood and gum rosin, glycerol ester of polymerized wood and gum rosin, glycerol ester of partially dimerized wood and gum rosin, glycerol ester of tall oil rosin, pentaerythritol ester of wood and gum rosin, pentaerythritol esters of partially and fully hydrogenated wood and gum rosin, methyl esters of wood and gum rosins and partially and fully hydrogenated methyl esters of wood and gum rosin.
  • the elastomer plasticizer may be a synthetic elastomer plasticizer.
  • the synthetic elastomer plasticizer may be a terpene resin derived from alpha-pinene, beta-pinene and/or d-limonene.
  • Waxes such as beeswax, microcrystalline wax, rice bran wax, polyethylene wax, petroleum wax, paraffin, carnauba wax, candelilla wax, cocoa butter and degreased cocoa powder may also be used as plasticizers.
  • Additional plasticizers that may be used include oils such as completely or partially hydrogenated vegetable oils, hydrogenated cottonseed oil, hydrogenated coconut oil, mineral oil and olive oil. Animal fats may also be used as plasticizers in the present invention.
  • glycerine, lecithin, and combinations thereof may be included as a plasticizer. In some embodiments, combinations of any of the above plasticizers may also be used.
  • the plasticizer should comprise about 0.005% to about 15% by weight of the chewing gum final composition; for example, the plasticizer may be in an amount of between 0.5% and 15.0% (w/w) (e.g., between 0.5% and 5.0% (w/w), or between 5% and 15.0% (w/w)) of the chewing gum final composition, [.
  • the chewing gum comprising LSD of the present invention may include a softener.
  • a softener may have an influence on the softness of the gum base.
  • Softeners may modify the texture, cause the hydrophobic and hydrophilic components of the gum base to be miscible, and may further plasticize components of the gum base.
  • Emulsifiers which belong to the group of softeners, provide the gum base with water-binding properties, which confer to the gum base a pleasant smooth surface and reduce its adhesive properties.
  • the chewing gum comprises at least one softener.
  • the softener may include, for example, tallow, hydrogenated tallow, hydrogenated and partially hydrogenated vegetable oils, cocoa butter, glycerol monostearate, glycerol triacetate, lecithin, mono-, di- and triglycerides, acetylated monoglycerides, fatty acids, such as stearic, palmitic, oleic and linoleic acids, and mixtures thereof.
  • the chewing gum includes a triglyceride softener.
  • the triglyceride softener may include cottonseed, palm, palm kernel, coconut, safflower, rapeseed, sunflower, tallow, soybean, cocoa butter, medium-chained triglycerides and the like.
  • the caproic, caprylic, capric, myristic, lauric and palmitic fatty acids of the triglycerides tend to be preferred for their ability to also function as plasticizers.
  • the chewing gum includes a softener that is an emulsifier.
  • the emulsifier may be a monoglyceride, diglyceride, acetylated mono and diglyceride, distilled mono- and diglyceride, glycerol monostearate, propylene glycol monostearate, Na-, K-, Mg- and Ca-stearate, glycerol triacetate, fatty acid monoglyceride (e.g.
  • stearic, palmitic, oleic and linoleic acids lactic acid ester, and acetic acid ester of a mono- and diglyceride, a sugar ester of an edible fatty acid also referred to as a sucrose polyester, including those disclosed in WO 00/25598, lecithin and hydroxylated lecithin.
  • the chewing gum comprising LSD of the present invention includes a softener that may be used alone or with at least two or more in combination.
  • the chewing gum comprising LSD may further include a buffering agent.
  • the buffering agent may be a carbonate such as bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium or sodium, or ammonium; sodium hydroxide, potassium hydroxide, calcium oxide, and mixtures thereof.
  • the buffering agent may be trisodium or tripotassium citrate, and mixtures thereof.
  • the buffering agents may be calcium hydroxide, magnesium hydroxide, aluminum hydroxide or carbonates and phosphate salts, such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate trisodium phosphate, calcium hydroxide, trisodium phosphate, disodium hydrogen phosphate; and tripotassium phosphate, dipotassium hydrogen phosphate, and mixtures thereof. Mixtures of the foregoing may also be employed.
  • the buffering agent may be present in an amount of about 0.1 to about 10% of the final composition of the chewing gum composition.
  • the amount of the buffering agent or agents in the gum formulation is preferably sufficient in the specific embodiments to maintain the pH of the saliva in the range of 6-8.
  • the chewing gum comprising LSD may include one or more flavoring agents.
  • the flavoring agents may include natural or synthetic flavorings in the form of natural vegetable components, essential oils, essences, extracts, powders, including acids and other substances capable of affecting the taste profile.
  • liquid and powdered flavorings include coconut, coffee, chocolate, vanilla, grape fruit, orange, lime, menthol, licorice, caramel aroma, honey aroma, peanut, walnut, cashew, hazelnut, almonds, pineapple, strawberry, raspberry, tropical fruits, cherries, cinnamon, peppermint, Wintergreen, spearmint, eucalyptus, and mint, fruit essence such as from apple, pear, peach, strawberry, apricot, raspberry, cherry, pineapple, and plum essence.
  • the essential oils include peppermint, spearmint, menthol, eucalyptus, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg, and oils of the fruits (e.g. lemon, bergamot, and orange).
  • the flavoring agent should comprise about 0.01% to about 5% of the final chewing gum composition.
  • Many of the conventional and commercially available flavoring agents employ a liquid carrier.
  • the chewing gum flavor may be a natural flavoring agent, which is freeze-dried, preferably in the form of a powder, slices, pieces or combinations thereof.
  • the particle size may be less than 3 mm, preferably less than 2 mm, more preferably less than 1 mm, calculated as the longest dimension of the particle.
  • Various synthetic flavors, such as mixed fruit flavors may also be used in the chewing gum including LSD.
  • the aroma agent may be used in quantities smaller than those conventionally used.
  • the aroma agents and/or flavors may be used in an amount of from 0.01 to about 30% by weight (preferably from 0.01 to about 15% by weight) of the final product depending on the desired intensity of the aroma and/or flavor used.
  • the content of aroma/flavor is in the range of from 0.2 to 3% by weight of the total composition.
  • the chewing gum including LSD described herein may include one or more sweeteners.
  • the sweeteners often fill the role of bulking agents in the chewing gum.
  • the sweetener improves the juiciness of the gum and supports the flavor profile of the gum.
  • the sweetener includes bulk sweeteners.
  • Bulk sweeteners include both sugar and sugarless components. Examples of sweeteners that may be used include saccharide materials such as mono-, di-, tri- and polysaccharides as well as oligosaccharides.
  • Sugars such as sucrose, dextrose, maltose, saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, glucose syrup, hydrogenated glucose syrup, and the like, alone or in combination may be used.
  • the sweetener can be used in combination with sugarless sweeteners.
  • Sugar free or non-sucrose formulations can include saccharin and its various salts such as sodium saccharin and calcium saccharin, and/or cyclamic acid and its various salts.
  • Dipeptide sweeteners chlorinated sugar derivatives, sucralose, dihydrochalcone, glycyrrhin, Stevia rebaudiana (Stevioside) and sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolyzates, maltitol, isomalt, erythritol, lactitol, hexa-resorcinal may also be used.
  • Additional sweeteners that may be used include aspartame, acesulfame potassium, thaumatin, maltodextrin and polydextrose. If a low calorie gum is desired, a low caloric bulking agent can be used.
  • low caloric bulking agents examples include polydextrose; RaftiloseTM, RaftilinTM; Fructooligosaccharides (NutraFloraTM); Palatinose oligosaccharide; Guar Gum Hydrolysate (SunFiberTM); or indigestible dextrin (FibersolTM).
  • other low calorie-bulking agents can be used.
  • a more complete list of sweeteners can be found in U.S. Pat. Nos. 6,344,222 and 5,487,902, which are incorporated herein by reference.
  • bulk sweeteners can also be used in combination high-intensity sweeteners.
  • Preferred high intensity sweeteners include, but are not limited to sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, cyclamate, glycyrrhizin, dihydrochalcones, thaumatin, monellin, sterioside and the like, alone or in combination.
  • Such techniques as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, coascervation, encapsulation in yeast cells and fibre extrusion may be used to achieve the desired release characteristics.
  • the encapsulation can also be performed in another material such as resin.
  • the chewing gum including LSD described herein may include at least one coloring agent.
  • the chewing gum may comprise color agents and Whiteners such as FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide, and combinations thereof.
  • Further useful chewing gum base components include antioxidants, e.g. butylated hydroxytoluene (BHT), butyl hydroxyanisol (BHA), propylgallate and tocopherols, and preservatives.
  • the chewing gum may include a coloring agent to improve the color and appearance of the final composition. Examples of coloring agents include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide and mixtures of the foregoing.
  • the coloring agent can be a solid material.
  • Fillers may be used in the chewing gum including LSD.
  • the fillers used in gum base may be used to modify the texture of the gum base and aid in processing.
  • Particle size has an effect on cohesiveness, density, and processing characteristics of the gum base and its compounding. The smaller the particle size, the more dense and cohesive the final gum base.
  • initial mass compounding may be varied, thus allowing alteration of the compounding characteristics of the initial mass during gum base processing and ultimately the final chew characteristics of gums made from these gum bases.
  • a chewing gum base formulation may, if desired, include one or more fillers/texturizers including as examples, magnesium and calcium carbonate, sodium sulphate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide, silicon dioxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof.
  • fillers/texturizers including as examples, magnesium and calcium carbonate, sodium sulphate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide, silicon dioxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof.
  • Talc filler may be used in the chewing gum of the present invention that may come in contact with or employ acid flavors or provide an acidic environment needed to prevent degradation of an artificial sweetener by reacting with calcium carbonate type fillers.
  • Mean particle size for calcium carbonate and talc fillers typically range from about 0.1 micron to about 15 microns.
  • the fillers may also include natural organic fibers such as fruit vegetable fibers, grain, rice, cellulose and combinations thereof.
  • the chewing gum of the present invention may include a coating.
  • the coating may take the form of a coating suspension.
  • the coating suspension includes an aqueous solution of a sugar, a sugar alcohol, an artificial sweetener or mixtures thereof, preferably an aqueous solution of saccharose, dextrose, sorbitol, xylitol, tagatose, mannitol, maltitol, isomalt, aspartame, acesulfame K, saccharin, cyclamate, thalline, and neohespiridine.
  • the coating suspension may be applied in approximately 2 to 90 increment(s), preferably in approximately 30-60 increments to achieve a uniform coating with a suitable thickness.
  • the coating may take place in tilted, round or horizontally placed cylindrical coating kettles that rotate during the whole process.
  • the coating kettles may be made from copper, stainless steel or fiberglass-reinforced polyester, and are often equipped with a piping system that supplies and exhausts air and doses the coating suspension.
  • polishing may also take place in rotating coating kettles in which a polishing suspension or a polishing powder is added to the coated cores in one or more portion(s).
  • the polishing suspension often consists of wax, emulsifier, shellac, gum arabic, water, etc.
  • the polishing powder often consists of wax only, or of wax mixed with emulsifier, gum arabic or talc, etc.
  • the chewing gum can be provided in individual unit doses, each including LSD in an amount between 5 pg to 25 pg (e.g., 5 ⁇ 1 pg, 6 ⁇ 1 pg, 7 ⁇ 1 pg, 8 ⁇ 1 pg, 9 ⁇ 1 pg, 10 ⁇ 1 pg, 11 ⁇ 1 pg, 12 ⁇ 1 pg, 13 ⁇ 1 pg, 14 ⁇ 1 pg, 15 ⁇ 1 pg, 16 ⁇ 1 pg, 17 ⁇ 1 pg, 18 ⁇ 1 pg, 19 ⁇ 1 pg, 20 ⁇ 1 pg, 21 ⁇ 1 pg, 22 ⁇ 1 pg, 23 ⁇ 1 pg, 24 ⁇ 1 pg, and 25 ⁇ 1 pg) LSD or a pharmaceutically acceptable salt thereof.
  • LSD e.g., 5 ⁇ 1 pg, 6 ⁇ 1 pg, 7 ⁇ 1 pg, 8 ⁇ 1 pg, 9 ⁇ 1 pg, 10 ⁇ 1 pg, 11 ⁇ 1
  • the chewing gum includes 10 ⁇ 2 pg of LSD or a pharmaceutically acceptable salt thereof.
  • the chewing gum may include no less than 15 pg of LSD or a pharmaceutically acceptable salt thereof.
  • the chewing gum may include 15 ⁇ 1 pg, 16 ⁇ 1 pg, 17 ⁇ 1 pg, 18 ⁇ 1 pg, 19 ⁇ 1 pg, 20 ⁇ 1 pg, 21 ⁇ 1 pg, 22 ⁇ 1 pg, 23 ⁇ 1 pg, 24 ⁇ 1 pg, or 25 ⁇ 1 pg of LSD or a pharmaceutically acceptable salt thereof.
  • the chewing gum may include no more than 25 pg of lysergic acid diethylamide or a pharmaceutically acceptable salt thereof.
  • the chewing gum may include 25 ⁇ 1 pg, 24 ⁇ 1 pg, 23 ⁇ 1 pg, 22 ⁇ 1 pg, 21 ⁇ 1 pg, 20 ⁇ 1
  • the chewing gum including LSD, or a pharmaceutically acceptable salt thereof may be selfadministered in a dosing regimen from once daily to once weekly (e.g. once every other day, once every two days, once every three days, once every four days, once every five days, or once every six days).
  • the dosing regimen is once every three, four, or five days.
  • the LSD in the chewing gum may be released in an amount between 5% and 100% (w/w) of the total LSD included in the chewing gum. For example, the between 50% and 100% (w/w) of the LSD included in the chewing gum may be released.
  • the LSD may be released from the chewing gum in a time period between 1 minute and 1 hour. In some embodiments, the LSD is released from the chewing gum in a time period between 1 minute and 30 minutes. In some embodiments, the LSD is released from the chewing gum in a time period of between 1 minute and 10 minutes.
  • Alzheimer’s disease is a devastating condition leading to progressive cognitive decline, functional impairment and loss of independence. It affects 5% of individuals over 65, 20% over 80 and more than a third of those over 90.
  • Alzheimer's disease The symptoms of Alzheimer's disease are primarily marked by cognitive deficits including memory impairment, language dysfunction, and visuospatial skills; functional impairment that may span occupational and social issues (e.g., activities of daily living); and behavioral symptoms including depression, anxiety, aggression and psychosis may also appear as the disease progresses in severity.
  • AD dementia is used to describe dementia that is due to the pathophysiologies of Alzheimer's disease.
  • methods for diagnosing probable Alzheimer's disease can be used in combination. These methods include determining an individual's ability to carry out daily activities and identifying changes in behavior and personality. Dementia of the AD type is also typically characterized by an amnestic presentation (memory deficit) or language, visuospatial or executive function deficits.
  • Cognitive ability/impairment may be determined by art-accepted methods, including, but not limited to, validated instruments that assess global cognition (e.g., the Modified Mini Mental State Examination (3MS-E)), and specific domains such as visual and verbal memory (e.g., the Brief Visuospatial Memory Test (Revised) (BVMT-R) and the Hopkins Verbal Learning Test (Revised) (HVLT-R), respectively), language (e.g., the Generative Verbal Fluency Test (GVFT)), executive function and attention (e.g., the Digit Span Test (DST)), a Rey Auditory and Verbal Learning Test (RAVLT), Cambridge Neuropsychological Test Automated Battery (CANTAB), a Contextual Memory Test; a Continuous Recognition Memory Test (CMRT), a Denman Neuropsychology Memory Scale, a Fuld Object Memory Evaluation (FOME), a Graham-Kendall Memory for Designs Test; a Guild Memory Test; a Learning and Memory Battery (LAMB); a
  • the course of Alzheimer’s disease can be divided into stages, with progressive patterns of cognitive and functional impairments.
  • the stages include Mild/Early AD (typically lasting 2-4 years and characterized by frequent recent memory loss, particularly of recent conversations and events, mild coordination problems, depression and apathy accompanied by mood swings); Moderate/Middle AD (typically lasting 2-10 years and characterized by pervasive and persistent memory loss, including forgetfulness about personal history and inability to recognize friends and family, rambling speech, unusual reasoning, delusions, aggression, uninhibited behavior, slowness, rigidity, and tremors); and Severe/Late AD (typically lasting 1 -3+ years and characterized by a loss of ability to remember, communicate, or process information, severe to total loss of verbal skills, problems with swallowing, incontinence, and illness, mood, behavior, hallucinations, and delirium).
  • Mild/Early AD typically lasting 2-4 years and characterized by frequent recent memory loss, particularly of recent conversations and events, mild coordination problems, depression and
  • the seven stage Global Deterioration Scale also known as the Reisberg Scale, includes the following dimensions.
  • Stage 2 Minimal Impairment/Normal Forgetfulness. Memory lapses and changes in thinking are rarely detected by friends, family, or medical personnel, especially as about half of all people over 65 begin noticing problems in concentration and word recall.
  • Stage 3 Early Confusional/Mild Cognitive Impairment. While subtle difficulties begin to impact function, the person may consciously or subconsciously try to cover up his or her problems. Subjects experience difficulty with retrieving words, planning, organization, misplacing objects, and forgetting recent learning, which can affect life at home and work. Depression and other changes in mood can also occur. Duration: 2 to 7 years.
  • Stage 4 Late Confusional/Mild Alzheimer’s.
  • Subjects experience problems handling finances result from mathematical challenges. Recent events and conversations are increasingly forgotten, although most people in this stage still know themselves and their family.
  • Subjects experience problems carrying out sequential tasks, including cooking, driving, ordering food at restaurants, and shopping. Subjects often withdraw from social situations, become defensive, and deny problems.
  • Stage 5 Early Dementia/Moderate Alzheimer’s disease. Decline is more severe and subject requires assistance. Subject is no longer able to manage independently or recall personal history details and contact information and is frequently disoriented regarding place and or time. People in this stage experience a severe decline in numerical abilities and judgment skills, which can leave them vulnerable to scams and at risk from safety issues. Basic daily living tasks like eating and dressing require increased supervision.
  • Stage 6 Middle Dementia/Moderately Severe Alzheimer’s disease. Subjects experience a total lack of awareness of present events and inability to accurately remember the past. People in this stage progressively lose the ability to take care of daily living activities like dressing, toileting, and eating, but are still able to respond to nonverbal stimuli, and communicate pleasure and pain via behavior. Agitation and hallucinations often show up in the late afternoon or evening. Dramatic personality changes, such as wandering, or suspicion of family members are common. Many subjects cannot remember close family members, but know they are familiar.
  • Stage 7 Late or Severe Dementia and Failure to Thrive.
  • the subject In this final stage, the subject’s speech and ability to walk becomes severely limited. Total support around the clock is needed for all functions of daily living and care.
  • the methods and compositions of the invention can be used to reduce neuropsychiatric conditions associated with any of the stages of Alzheimer’s disease described above.
  • the methods of the invention can reduce the severity of agitation, apathy, irritability, and aggression in a subject with Alzheimer’s disease (i.e. a subject having AD at any of stages 2 to 7).
  • the methods of the invention can delay the onset of agitation, apathy, irritability, and aggression in a subject with mild cognitive impairment due to Alzheimer’s disease (i.e. a subject having AD at any of stages 2 to 4).
  • the methods and compositions of the invention can be used in subjects with a reduced ability to swallow.
  • the methods and compositions of the invention can be used to treat any of the stages of Alzheimer’s disease described above.
  • the methods of the invention can improve cognitive function or reduce the severity of dementia in a subject with Alzheimer’s disease with comorbid dementia (i.e. a subject having AD at any of stages 5 to 7).
  • the methods of the invention can delay the loss of cognitive function or delay the onset of dementia in a subject with mild cognitive impairment due to Alzheimer’s disease (i.e. a subject having AD at any of stages 2 to 4).
  • the methods of the invention can be to delay the onset of cognitive impairment or delay the onset of dementia in a subject with asymptomatic Alzheimer’s disease (i.e. a subject having AD at stage 1 ) or prodromal Alzheimer’s disease (i.e. a subject having AD at stage 1 or 2 or 3).
  • the therapy of the invention can be used in combination with other therapeutic interventions for the treatment of Alzheimer’s disease, such as ACE inhibitors or NMDA receptor antagonists, such as memantine.
  • the chewing gum containing LSD is formulated using the gum bases, sugar, liquid glucose, glycerin, a sweetener, such as aspartame, stevia, licorice, or sodium saccharin, and a taste-masking material, such as zinc acetate, sodium acetate, or sodium chloride, and a flavoring agent.
  • the mixture of gum bases is softened at 60°C.
  • LSD or a pharmaceutically acceptable salt thereof, sugar, liquid glucose, glycerin, and other ingredients (Table 1 ) are added to the base to which was finally added the flavor at 40°C.
  • the uniform mixture is cut into the pieces of suitable shape and size and kept at room temperature for 48 h.
  • the chewing gum is coated by acacia aqueous solution (2% w/v). Sugar dusting followed by acacia, sugar, and calcium carbonate coating is carried out until a smooth surface is produced.
  • the formulations are investigated for considering the effect of different flavoring agents on masking the slight bitter taste of LSD and making the gum more palatable.
  • Selected formulations according to organoleptic characteristics are prepared by using flavoring of cherry, eucalyptus, peppermint, banana, cola, tutti-frutti, and raspberry.
  • LSD gums are selected randomly. Each gum is first dissolved in 50 mL chloroform. Phosphate buffer pH 6.8 is then used to extract drug into the aqueous phase. The amount of LSD is determined by measuring the drug absorbance at 260.8 nm using a UV-visible spectrophotometer.
  • a drug release study is performed using a mastication device that simulates the mastication of chewing gum in a human.
  • the device consists of a piston that strokes the gum (60 strokes/min) at different points on a random base and a chamber that holds the gum and the release medium (pH 6.8 phosphate buffer). Water is circulated at 37°C through a jacket around the receiver chamber to simulate body temperature. Aliquots of 1 mL are removed at 0, 5, 10, 15, 20, 25, 30, and 45 min, and their absorbance is measured at 260.8 nm, as described above.
  • Example 2 Evaluation of LSD chewing gum formulations
  • the organoleptic characteristics of the LSD chewing gum are assessed in a clinical study of the pharmacokinetic performance of the gum in normal subjects. 10 subjects are asked to chew each LSD gum formulation described in Example 1 for 20 minutes and express their opinions about chewing hardness, gum adhering to teeth, the plumpness, and the taste, according to the Likert scale of 1 -5 where 1 is very poor, 2 is poor, 3 is average, 4 is good, and 5 is excellent.
  • Subjects suffering from Alzheimer’s disease are treated using LSD formulated in a chewing gum.
  • the subjects are first diagnosed by a clinician with Alzheimer’s disease using a physical and neurological exam, lab tests, and/or brain imaging.
  • the subjects are provided the LSD containing chewing gum having between 15 pg and 25 pg of LSD per piece.
  • the subjects chew the chewing gum for a period of at least 5 minutes.
  • the subjects chew one piece of chewing gum daily in order to treat the symptoms associated with Alzheimer’s disease.
  • Two weeks after beginning treatment with the chewing gum containing LSD the subject is evaluated by a clinician to identify any changes in the subject’s symptoms associated with Alzheimer’s disease.
  • the subject may experience fewer of the symptoms associated with Alzheimer’s disease and may experience improved cognitive function, reduced the severity of an AD- associated neuropsychiatric condition, delayed the loss of cognitive function, reduced agitation, reduced irritability, reduced apathy, reduced aggression, improved memory, improved learning capacity, reduced severity of dementia, reduced severity of depression, or reduced severity of anxiety.

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Abstract

La présente invention concerne des compositions de gomme à mâcher comprenant du LSD qui sont utiles en thérapie, par exemple dans le traitement d'un patient atteint de la maladie d'Alzheimer ou risquant de développer une telle maladie. En outre, la présente invention concerne des procédés d'utilisation des compositions de gomme à mâcher décrites dans la description pour traiter la maladie d'Alzheimer.
PCT/US2022/043580 2021-09-15 2022-09-15 Formulation de lsd sous forme de gomme à mâcher et ses procédés d'utilisation Ceased WO2023043870A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180036303A1 (en) * 2015-03-10 2018-02-08 Eleusis Benefit Corporation, Pbc Lsd for the treatment of alzheimer's disease
US20210268036A1 (en) * 2019-03-08 2021-09-02 The Regents Of The University Of California Compositions and methods for modulating lipid and steroid metabolism
WO2022008627A2 (fr) * 2020-07-07 2022-01-13 Compass Pathfinder Limited Procédé amélioré pour la production de diéthylamide d'acide lysergique (lsd) et nouveaux dérivés associés

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Publication number Priority date Publication date Assignee Title
US20180036303A1 (en) * 2015-03-10 2018-02-08 Eleusis Benefit Corporation, Pbc Lsd for the treatment of alzheimer's disease
US20210268036A1 (en) * 2019-03-08 2021-09-02 The Regents Of The University Of California Compositions and methods for modulating lipid and steroid metabolism
WO2022008627A2 (fr) * 2020-07-07 2022-01-13 Compass Pathfinder Limited Procédé amélioré pour la production de diéthylamide d'acide lysergique (lsd) et nouveaux dérivés associés

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DI RADO ALICIA, DEBRA CANO: "Unsuspecting Students Given LSD-Laced Gum : Drugs: Seven teens from Marina High School in O.C. are recovering from hallucinations, other effects", LOS ANGELES TIMES, US, 2 December 1994 (1994-12-02), US, pages 1 - 5, XP093049608, Retrieved from the Internet <URL:https://www.latimes.com/archives/la-xpm-1994-12-02-mn-4120-story.html> [retrieved on 20230525] *

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