fast and controlled delivery of compositions with restored entourage effects

专利摘要:
these are fast acting oral formulations with restored entourage effects. the formulations include beneficial combinations of plant-derived molecules to provide restored entourage effects and one or more carriers. carriers may include n-acylated fatty acids, absorption enhancers and / or various other beneficial carriers. rapid-acting oral formulations can create administration benefits.
公开号:BR112019019776A2
申请号:R112019019776
申请日:2018-03-23
公开日:2020-04-22
发明作者:Leone-Bay Andrea；WESNER Gregory
申请人:Receptor Holdings Inc；
IPC主号:

专利说明:

“FAST AND CONTROLLED DELIVERY OF COMPOSITIONS WITH RESTORED ENTOURAGE EFFECTS”
CROSS REFERENCE TO RELATED APPLICATION [001] This application claims priority of document 62/475763 filed on March 23, 2017, which is incorporated in this document for reference in its entirety as if it were fully presented in this document.
FIELD OF DISSEMINATION [002] The current disclosure provides rapid-acting oral formulations of plant-based compositions with restored entourage effects. The plant-based compositions include combinations of beneficial plant-derived molecules to provide restored entourage effects. The formulations include one or more carriers, which allow fast and controlled delivery of the plant-based compositions. Carriers can include N-acylated fatty acids, absorption enhancers and / or various other beneficial carriers.
BACKGROUND TO THE DISSEMINATION [003] Historically, the plant kingdom has been the most important source of medicinal agents for the treatment of human and animal disease, and for use as preventive agents and nutritional supplements to maintain good health. However, for at least the past 150 years, Western medicine has been dominated by synthetic chemical agents.
[004] However, it is now increasingly recognized that in certain situations plants and plant extracts are preferred over synthetic chemical agents. A single plant can have a large number of physiologically active phytochemicals, and extracts that contain several phytochemicals can exert their effects on a variety of physiological processes. This variety and combination of physiological effects is not readily replicated through the use of individually created synthetic molecules. In some cases, physiologically active phytochemicals increased activity when present in combination with other physiologically active phytochemicals. The benefits that can arise from the use of whole plant extracts are one of the main premises in the field of herbal medicine.
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2/75 [005] An example of the benefits of combined phytochemicals is the synergy in the antioxidant potential of skin extracts, juice and grape seed. Grouped extracts have a greater antioxidant potential than individual extracts (Epps et al., J Food Res. 2013. 2 (6): 33 to 47).
[006] Another example of a beneficial combination of phytochemicals refers to the use of two molecules derived from cannabis to treat multiple sclerosis. Sativex® (GW Pharma, Wilshire, UK) has a 1: 1 ratio of two molecules derived from cannabis, delta-9-tetrahydrocannabinol (Δ ⁹ -ΤΗΟ or THC) and cannabidiol (CBD); and it is approved in several countries to treat spasticity and neuropathy associated with multiple sclerosis (Syed etal., Drug 2014. 74 (5): 563 to 78). The combination of THC and CBD in Sativex® is preferred for THC or CBD alone as THC is highly effective against neuropathic pain, and CBD combats possible side effects of THC, such as tachycardia, intoxication and sedation, while also contributing as a pain reliever (Russian , Med Hypotheses. 2006; 66 (2): 234 to 46).
[007] As indicated, THC and CBD are two examples of cannabinoids. Cannabinoids are a diverse class of compounds that interact with and activate cannabinoid receptors. There are three classes of cannabinoids: 1) endocannabinoids are naturally produced in the body by humans and other animals, 2) phytocannabinoids are produced by plants and 3) synthetic cannabinoids are chemically produced cannabinoids. Synthetic cannabinoids can be identical to cannabinoids that are found in nature, or they can be compounds that do not exist in nature.
[008] Endocannabinoids are part of the endocannabinoid system that includes endogenous cannabinoids and cannabinoid receptors. Cannabinoid receptors (such as CB1 and CB2) are expressed in several cell types, which include brain cells and immune cells. An example of an endocannabinoid is anandamide, a fatty acid neurotransmitter that interacts with cannabinoid receptors that regulate feelings of hunger, motivation and pleasure.
[009] Phytocannabinoids are produced by several types of plants, however, the most well-known cannabinoid-producing plant is Cannabis. Cannabis plants produce more than 60 cannabinoids, many of which, such as THC and CBD, have
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3/75 known therapeutic potential. Cannabis that contains only trace amounts of THC is not psychoactive and is called hemp. Cannabis species include Cannabis sativa, Cannabis indica, Cannabis ruderalis and several hybrid indica / sativa crosses. In fact, hybrid crosses between Cannabis sativa and Cannabis indica are common.
[010] Different cannabis plants that produce cannabinoids include Echinacea purpurea, Echinacea angustifolia, Acmella oleracea, Helichrysum umbraculigerum and Radula marginata. Cannabinoids isolated from Echinacea include lipophilic alkamides (alkylamides), such as cis / trans isomers of dodeca2E, 4E, 8Z, 10E / Z-tetraenoic acid, isobutylamide.
[011] Cannabis can have several medical uses that include addiction treatment (De Vries et al., Psychopharmacology (Berl). July 2003; 168 (1 to 2): 164 to 9); ADHD (O'Connell and Che, Harm Reduction Journal. 2007; 4:16); alcoholism (Basavarajappa & Hungund, Alcohol, January and February 2005; 40 (1): 15 to 24); Alzheimer's disease (Eubanks et al., Mol Pharm. November and December 2006; 3 (6): 773 to 7); amyotrophic lateral sclerosis (ALS) (Raman et al., Amyotroph Lateral Soler Other Motor Neuron Disord, March 2004; 5 (1): 33 to 9); anxiety (The British Journal of Psychiatry February 2001, 178 (2) 107 to 115); asthma (Tashkin etal., American Review of Respiratory Disease, 1975; 112, 377); autoimmune diseases (Lyman etal., J Neuroimmunol. June 1989; 23 (1): 73 to 81); bactehan infections (Nissen et al., Phytotherapy. July 2010; 81 (5): 413 to 9); bone loss (Bab etal., Ann Med. 2009; 41 (8): 560 to 7); brain injury / stroke (Shohami etal., Br J Pharmacol, August 2011; 163 (7): 1,402 to 10); cancer (Guindon & Hohmann, BrJ Pharmacol, August 2011; 163 (7): 1447 to 63); heart disease (Walsh etal., Br J Pharmacol, July 2010; 160 (5): 1234 to 42); Huntington's disease (LastresBecker et al., J Neurochem. March 2003; 84 (5): 1097 to 109); inflammation (AAPS J. March 2009; 11 (1): 109 to 119); Parkinson's disease (Sieradzan etal., Neurology, December 2001, 11; 57 (11): 2,108 to 11); and psoriasis (Trends Pharmacol Sci. August 2009; 30 (8): 411 to 420).
[012] Additional documented uses for the cannabis plant include treating acquired hypothyroidism, acute gasthte, agoraphobia, ankylosis, arthritis, Asperger's syndrome, atherosclerosis, autism, bipolar disorder, blood disorders,
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4/75 cachexia, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia , eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, gastrointestinal disorders, glAUCOma, glioma, Graves' disease, hepatitis, herpes, hypertension, impotence, incontinence, infant mortality, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, migraine, motion sickness, MRSA, muscular dystrophy, nail-patella syndrome, neuroinflammation, nicotine addiction, obesity, obsessive compulsive disorder (OCD), pancreatitis, panic syndrome, periodontal disease , phantom limb pain, poison ivy allergy, premenstrual tension (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), Raynaud's disease, d syndrome numb leg, schizophrenia, scleroderma, septic shock, shingles (herpes zoster), sickle cell disease, seizures, sleep apnea, sleep disorders, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, syndrome de Tourette, traumatic memories, wasting syndrome and abstinence.
[013] Although it is believed that several phytochemicals present in cannabis contribute to the plant's physiological and / or medical benefits, THC and CBD were the most extensively studied.
[014] THC is the main psychoactive component of cannabis. THC exhibits complex effects on the central nervous system (CNS), which includes central sympathomimetic activity. The efficiency of THC in pain treatment has been described in Pharm. J. 1997. 259, 104 and in Pharm. Know. 1997. 3, 546. Oral THC is also useful in the treatment of AIDS symptoms, such as weight loss and pain (J. Pain. Symptom Manage. 1995. 10, 89 to 97). In addition, THC has antiemetic properties and is used to control nausea and vomiting associated with cancer chemotherapy. THC also affects mood, cognition, memory and perception. These effects appear to be dose related.
[015] CBD is another cannabinoid with a wide range of medicinal and / or physiological uses. CBD is antiemetic, neuroprotective, anti-inflammatory
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5/75 (Grotenhermen, et al., Int. 2012. 109 (29 to 30), anxiolytic, antipsychotic and antiarrhythmic (Burstein, Bioorgan Med Chem. 2015. 23, 1377 to 1385). Unlike THC, CBD has no effects psychoactive.
[016] The physiological effects of THC and CBD are affected by the presence of other molecules derived from cannabis, such as additional cannabinoids, terpenes and flavonoids. Terpenes are plant-derived molecules that often have potent distinctive aromas and can have desirable effects. For example, the linalool terpene is responsible for the aroma and relaxing properties of lavender. Flavonoids are a class of molecules that are ubiquitous among plants, and many are consumed as nutritional supplements for their antioxidant properties. Certain terpenes and flavonoids can interact with cannabinoid receptors, and this is believed to be a reason why they contribute to the effects of cannabis. Consumption of THC and / or CBD in combination with other molecules derived from cannabis can intensify the desired effects of THC and / or CBD, and the combinatorial action of molecules derived from cannabis can be termed entourage effects. Entourage effects can enhance the therapeutic potential of cannabinoids, such as THC and CBD, with respect to pain, inflammation, depression, anxiety, addiction, epilepsy, cancer and infections (Russo, E. 2011. British Journal of Pharmacology. 163 (7) : 1344 to 1364). Entourage effects can also combat side effects of THC, such as dysphoria, and / or can intensify cannabis-induced euphoria.
[017] Entourage effects also play an important role in the distinct effects of different strains of cannabis. Entourage effects can contribute to the effects of sedation, energizing, intensifying concentration, relaxing and / or other effects induced by particular cannabis strains.
[018] Smoking is the most common route for cannabis consumption. When cannabis is heated to smoke, cannabinoid molecules become decarboxylated, to create the physiologically active form of the molecules (for example, tetrahydrocannabivarinic acid or THCA if you take THC). However, smoking poses health hazards and can irritate the lungs and respiratory tract, so it is not an option for many cannabis users.
[019] Cannabis is also frequently consumed orally, however,
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6/75 this consumption route results in a slow start. While smoking cannabis can result in almost instant effects, oral administration provides an onset of 0.5 to 1 hour and a peak effect in 2 to 4 hours. The duration of action for psychoactive effects can be 4 to 6 hours, but the appetite-stimulating effect can continue for 24 hours or more after administration. In addition to the slow onset, the poor bioavailability of cannabinoids is another potential drawback to oral cannabis consumption. However, due to a combined effect of going through liver metabolism and low water solubility first, only 10 to 20% of the administered dose reaches the systemic circulation. Therefore, oral cannabis consumption is characterized by low cannabinoid bioavailability and slow onset.
[020] Smoked cannabis undergoes thermal decarboxylation in situ during the smoking process. Cannabis for oral consumption, however, must be decarboxylated before ingestion. This is generally done through heating. Unfortunately, this thermal processing of cannabis often results in the loss of heat-labile molecules, such as terpenes and flavonoids. Additionally, orally consumed synthetic cannabinoids do not contain many phytochemicals that are present in whole cannabis. Therefore, cannabis and / or cannabinoid products orally consumed typically lack phytochemicals that contribute to entourage effects.
SUMMARY OF THE DISCLOSURE [021] The current disclosure provides rapid-acting oral formulations of plant-derived compositions with restored entourage effects. The formulations provide fast acting delivery of the compositions including an absorption enhancing carrier, such as an N-acylated fatty acid. Entourage effects are restored in the oral formulations of molecules derived from cannabis including, with one or more primary cannabinoids , additional cannabinoids, terpenes, flavonoids and / or other entourage restoration molecules. Combination of one or more primary cannabinoids (such as THC and / or CBD) with entourage restoration molecules can restore and / or intensify certain cannabis physiological effects, and the presence of an absorption enhancing carrier provides rapid and controlled delivery of
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7/75 compositions.
[022] In particular embodiments, carriers include N-acylated fatty acids, absorption enhancing agents and / or various other beneficial carriers, such as surfactants, detergents, azones, pyrrolidones, glycols and bile salts. In particular embodiments, N-acylated fatty acids can be linear, branched, cyclic, bicyclic or aromatic which include, for example, 1 to 50 carbon atoms.
[023] In particular modalities, the one or more primary cannabinoids are cannabinoids that exert the main physiological effects of cannabis. In particular embodiments, the one or more primary cannabinoids include THC and / or CBD, or derivatives and / or analogs thereof.
[024] In particular embodiments, the entourage restoration molecules include additional cannabinoids. In particular embodiments, additional cannabinoids may include A8-tetrahydrocannabinol (A8-THC), Δ11tetrahydrocannabinol (A11-THC), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicycles (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), var. cannabinol propyl (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA) and / or tetrahydrocannabivarinic acid (THCVA).
[025] In particular embodiments, entourage restoration molecules can include one or more terpenes. The one or more terpenes may include β-mycrene, a-pinene, β-pinene, linalool, d-limonene, β-caryophyllene, caryophyllene oxide, nerolidol, phytol, ocimene, terpinolene, terpinene, humulene, carene, bisabolol, valencene , elemene, farnesene, menthol, geraniol, guaiol, camphene, camphor, eucalyptol, pulegone, sabinene and / or feladrene.
[026] In particular embodiments, the entourage restoration molecules can include one or more flavonoids. The one or more flavonoids can include canaflavin A, canaflavin B, canaflavin C, vitexin, isovitexin, apigenin, kaempferol, quercetin, luteolin, cinnamaldehyde and / or orientin.
[027] In particular modalities, the molecules of restoration of
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8/75 entourage can additionally include volatile compounds that impart cannabis-derived aroma and flavor. Molecules that impart flavor and flavor derived from cannabis include 2-heptanone, methyl heptanoate, methyl salicylate, methyl anthranylate and hexanal.
[028] Rapidly acting oral formulations with restored entourage effects can create various administration benefits in a variety of conditions. Exemplary administration benefits include increased absorption, increased bioavailability, faster onset of action, higher peak concentrations, faster time to peak concentrations, increased subjective efficacy, increased objective efficacy, improved taste and / or improved taste.
BRIEF DESCRIPTION OF THE FIGURES [029] Figures 1A and 1 B show an established correlation between water solubility and the SNAC's ability to improve a molecule absorption. Figure 1A shows the SNAC enhancement multiples plotted for chromoline, vitamin B12, atorvastatin and ibandronate, along with the aqueous solubility of each molecule. The plotted data show a marked fit in a logarithmic trend line (R ² = 0.998), which indicates a logarithmic relationship between the aqueous solubility of each and the degree to which SNAC improves absorption. As the molecule's water solubility increases, SNAC's ability to enhance its absorption also increases. Figure 1 B plots the aqueous solubility of heparin, acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, yy peptide and THC according to the logarithmic trend line derived from Figure 1A.
[030] Figure 2 provides modified amino acids from compounds I to XXXV.
[031] Figure 3 provides fatty acid amino acids of Formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), 0 ), (k), (I), (m), (n), (o), (p), (q) and (r), where R1 is an alkyl group that includes 5 to 19 carbon atoms , R2 is H (ie, hydrogen) or CH3 (ie, methyl group), and R3 is H; or a salt or the free acid form of it.
[032] Figure 4 provides exemplary cannabinoid structures.
[033] Figure 5 provides several molecules derived from cannabis, such as
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9/75 terpenes and flavonoids.
[034] Figures 6A and 6B provide the average results of the study comparing the start and duration of action of cannabis / N- [8- (2hydroxybenzoyl) amino] caprylate (SNAC) formulation and orally administered cannabis formulation (without SNAC) . Figure 6A provides a bar graph of the results, with the SNAC formulation results represented with black bars and the results for the formulation without SNAC represented with white bars. Figure 6B provides a line graph of the results, with the SNAC formulation results represented with circles and the results for the formulation without SNAC represented with triangles.
[035] Figures 7A to 7F provide the results for each individual participant in the study comparing the start and duration of action of cannabis formulation / N- [8- (2-hydroxybenzoyl) amino] caphlate (SNAC) (black bars) and oral cannabis formulation (without SNAC) (white bars). Figure 7A shows results for Study Participant # 1 (S1); Figure 7B shows results for Study Participant # 2 (S2); Figure 7C shows results for Study Participant # 3 (S3); Figure 7D shows results for Study Participant # 4 (S4); Figure 7E shows results for Study Participant No. 5 (S5) and Figure 7F shows results for Study Participant No. 6 (S6).
[036] Figure 8 shows a comparison of intensity, duration and onset of orally formulated cannabis formulations with a high dose of SNAC (200 mg, high dose), a low dose of SNAC (100 mg, low dose) and no SNAC (control).
[037] Figure 9 shows intensity, duration and onset of cannabis formulated with orally administered SNAC (PO) compared to inhaled cannabis (INH).
[038] Figure 10 shows THC and CBD Cmax and AUC after a single oral administration in rats.
[039] Figure 11 shows THC and CBD Cmax (ng / ml) and AUC (h * ng / ml) after a single oral administration in rats.
[040] Figure 12 shows the intensity, duration and onset of action of
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10/75 formulation of cannabis / N- [8- (2-hydroxybenzoyl) amino] caprylic acid (NAC, test) and formulation only with cannabis (without NAC, control) orally administered.
DETAILED DESCRIPTION [041] The current disclosure provides rapid-acting oral formulations of plant-derived compositions with restored entourage effects. The formulations provide fast acting delivery of the compositions including an absorption enhancing carrier, such as an N-acylated fatty acid. Entourage effects are restored in the oral formulation of molecules derived from cannabis including, with one or more primary cannabinoids , additional cannabinoids, terpenes, flavonoids and / or other entourage restoration molecules. Combination of one or more primary cannabinoids (such as THC and / or CBD) with entourage restoration molecules can restore the physiological effects of certain cannabis extracts.
[042] In particular modalities, carriers include N-acylated fatty acids, absorption-enhancing agents and / or various other beneficial carriers, such as surfactants, detergents, azones, pyrrolidones, glycols and bile salts. In particular embodiments, N-acylated fatty acids can be linear, branched, cyclic, bicyclic or aromatic which include, for example, 1 to 50 carbon atoms.
[043] In particular modalities, the one or more primary cannabinoids include cannabinoids that exert the main physiological effects of cannabis. In particular embodiments, primary cannabinoids include THC and / or CBD, and / or derivatives and / or analogues thereof.
[044] In particular modalities, fast acting oral formulations include one or more entourage restoration molecules. The one or more entourage restoration molecules may include additional cannabinoids, terpenes, flavonoids and / or volatile substances that impart flavor and aroma.
[045] In particular embodiments, the entourage restoration molecules include one or more additional cannabinoids. In particular embodiments, the one or more additional cannabinoids may include A8-tetrahydrocannabinol (Δδ-THC), Δ11-tetrahydrocannabinol (A11-THC), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL ), cannabicyclol
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11/75 (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabicromevarina (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, CBD (CBD)) , cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA) and / or tetrahydrocannabivarinic acid (THCVA).
[046] In particular embodiments, entourage restoration molecules can include one or more terpenes. The one or more terpenes may include β-mycrene, a-pinene, β-pinene, linalool, d-limonene, β-caryophyllene, caryophyllene oxide, nerolidol, phytol, ocimene, terpinolene, terpinene, humulene, carene, bisabolol, valencene , elemene, farnesene, menthol, geraniol, guaiol, camphene, camphor, eucalyptol, pulegone, sabinene and / or feladrene.
[047] In particular embodiments, entourage restoration molecules can include one or more flavonoids. The one or more flavonoids can include canaflavin A, canaflavin B, canaflavin C, vitexin, isovitexin, apigenin, kaempferol, quercetin, luteolin, cinnamaldehyde and / or orientin.
[048] In particular embodiments, entourage restoration molecules can include one or more volatile compounds that impart cannabis-derived aroma and flavor. The one or more molecules that impart flavor and aroma derived from cannabis can include 2-heptanone, methyl heptanoate, methyl salicylate, methyl anthranylate and / or hexanal.
[049] Rapidly acting oral formulations with restored entourage effects can create various administration benefits in a variety of conditions. Exemplary administration benefits include increased absorption, increased bioavailability, faster onset of action, higher peak concentrations, faster time to peak concentrations, increased subjective efficacy, increased objective efficacy, improved taste and / or improved taste.
[050] The following sections will describe in detail i) carriers that provide fast acting delivery, ii) primary cannabinoids iii) molecules that restore entourage effects, iv) obtaining molecules derived from cannabis v) restoration of entourage effects by combining derived molecules cannabis, vi) formulation of compositions with a carrier to provide fast delivery
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12/75 performance and vii) methods to provide physiological effects delivering fast acting formulations with restored entourage effects.
[051] Carriers that Provide Fast Acting Delivery. Modalities disclosed in this document include one or more carriers that provide fast performance of components in the compositions. Fast acting delivery can mean a faster start of action of a composition, compared to the start of action of an equivalent composition that lacks a carrier.
[052] In particular modalities, carriers disclosed in this document create administration benefits selected from: increased absorption, increased bioavailability, faster onset of action, higher peak concentrations, faster time to peak concentrations, increased subjective efficacy , increased objective effectiveness, improved taste and improved taste. Administration benefits related to increased absorption, increased bioavailability, faster onset of action, higher peak concentrations and faster time to peak concentrations can alleviate adverse conditions more quickly (eg, pain relief). “Taste refers to aspects unrelated to the taste of pleasantness experienced by a person during ingestion (for example, chewing or swallowing) of an oral dosage form. Aspects of taste include the hardness and fragility of a formulation, if the formulation is rubbery, sandy, oily, creamy, watery, sticky, easily dissolved, astringent, effervescent and the like, and the size, shape and form of the formulation (tablet, powder , gel, etc.). In particular embodiments, the administration benefit is a dose-dependent administration benefit. A dose-dependent administration benefit can refer to an administration benefit that occurs when the carrier is within a dose range, or a range of relative doses (relative to an active ingredient). In particular embodiments, the dose-dependent administration benefits occur when the carrier is at a dose that is one to one hundred times or one to twenty times the dose of an active ingredient.
[053] In particular modalities, carriers include one or more modified amino acids, surfactants, detergents, azones, pyrrolidones, glycols and
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13/75 bile salts.
[054] An amino acid is any carboxylic acid that has at least one free amine group and includes naturally occurring, non-naturally occurring and synthetic amino acids. Polyamino acids are peptides or two or more amino acids linked by a bond formed by other groups that can be linked, for example, an ester, anhydride, or an anhydride bond. Peptides are two or more amino acids linked by a peptide bond. Peptides can vary in length from dipeptides with two amino acids to polypeptides with hundreds of amino acids. See Chambers Biological Dictionary, editor: Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Dipeptides, tripeptides, tetrapeptides and pentapeptides can also be used.
[055] Modified amino acid carriers include acylated fatty acid amino acids (FA-aa) or salts thereof, which are typically prepared by modifying the amino acid or an ester thereof through acylation or sulfonation. Acylated fatty acid amino acids include N-acylated FA-aa or an acylated amino acid in its alpha amino group with a fatty acid.
[056] In particular modalities, N-acylated fatty acids act as absorption enhancing agents, thus creating an administration benefit. Absorption enhancing agents refer to compounds that promote gastrointestinal absorption. Absorption enhancing agents can improve drug absorption by improving the solubility of the drug in the gastrointestinal tract or by enhancing membrane penetration, compared to a formulation that does not include absorption enhancing agents. Additional examples of absorption enhancing agents include surfactants, detergents, azones, pyrrolidones, glycols or bile salts.
[057] In particular modalities, N-acylated fatty acids act as bio-availability enhancing agents. Bioavailability refers to the fraction of the active ingredient that is actually absorbed by an individual and reaches the bloodstream. In particular embodiments, bioavailability enhancing agents increase the fraction of active ingredient in the bloodstream or result in detection of active ingredient in the bloodstream.
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14/75 blood earlier, compared to a formulation that does not include the bioavailability enhancing agent.
[058] In particular embodiments, administration benefits created by absorption enhancing agents and / or bioavailability enhancing agents include faster onset of action, higher peak concentrations, faster time to peak concentrations, increased subjective efficacy and / or increased objective efficacy compared to a control formulation based on them, similar in all aspects, however, for inclusion of absorption enhancing agents and / or bioavailability enhancing agents.
[059] Modalities that use absorption enhancing agents and / or bioavailability enhancing agents (for example, and in particular modalities, N-acylated fatty amino acids) can be beneficial because several oral formulations designed to solve various physiological conditions are characterized by a delayed onset of action and low bioavailability. These modalities may allow for faster absorption and higher bioavailability compared to formulations of molecules derived from cannabis ingested by currently available oral dosage forms.
[060] Delayed onset of action presents challenges in indications that need rapid effect (for example, pain and migraine); and low bioavailability require that patients ingest significantly higher doses than would be required by alternative dosage forms (eg, smoking, vaporization). Particular modalities disclosed in this document provide oral formulations with improved bioavailability and shorter time to onset.
[061] As stated, in particular modalities, fatty amino acids acylated with N act as intensifying agents of subjective efficacy. Intensification of subjective efficacy refers to a notable physiological change, such as relief of a symptom, as perceived by an individual. In particular embodiments, subjective efficacy enhancing agents increase the magnitude of a desired physiological effect, such as relieving a symptom, or induce the desired physiological effect more quickly, compared to a formulation
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15/75 that does not include the intensifying agent of subjective efficacy.
[062] In particular modalities, fatty amino acids acylated with N act as intensifying agents of objective efficacy. Intensification of objective efficacy may refer to a physiological effect as determined by quantitative and / or qualitative measurement of an outcome. For example, enhancement of objective efficacy may refer to the relief of a clinical measurement, such as a nutritional deficiency detected by a blood or saliva test or a well-being test, as administered by a physician. In particular embodiments, objective efficacy enhancing agents increase relief from an objective clinical measurement or result in relief more quickly, compared to a formulation that does not include the objective efficacy enhancing agent.
[063] Exemplary N-acylated fatty acid salts include sodium N [8- (2-hydroxybenzoyl) amino] caprylate (SNAC). Other names for SNAC include sodium N-salicyloyl-8-aminocaprilate, monosodium 8- (N-salicyloylamino) octanoate: N- (salicyloyl) -8-amino-octanoic acid monosodium salt, N- {8- (2hydroxybenzoyl) amino } monosodium octanoate or sodium 8 - [(2-hydroxybenzoyl) amino] octanoate. SNAC has the structure:
[064] SNAC salts can also be used as a carrier.
[065] Other forms of SNAC include:
[066] where X and Z are independently H, a monovalent cation, a divalent metal cation or an organic cation. Examples of monovalent cations include sodium and potassium. Examples of divalent cations include calcium and magnesium. Examples of organic cations include ammonia and
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16/75 tetramethylammonia.
[067] Exemplary modified amino acids, such as N-acylated FA-aas, are provided as compounds I to XXXV (see Figure 2). Salts of these compounds and another N-acylated FA-aa can also be used as carriers.
[068] Many of the compounds can be readily prepared from amino acids using methods contained in the skill of those skilled in the art based on the present disclosure. For example, compounds I to VII are derived from aminobutyric acid. Compounds VIII to X and XXXI to XXIIV are derived from aminocaproic acid. Compounds XI to XXVI and XXXV are derived from aminocaprylic acid. For example, the modified amino acid compounds above can be prepared by reacting the only amino acid with the appropriate modifying agent that reacts with the chemical portion of free amino present in the amino acids to form amides. Protective groups can be used to prevent unwanted side reactions as would be known to those skilled in the art.
[069] The amino acid can be dissolved in an aqueous alkaline solution of a metal hydroxide, for example, sodium or potassium hydroxide, and heated to a temperature in the range between 5 ° C and 70 ° C, preferably between 10 ° C and 40 ° C, for a period in the range between 1 hour and 4 hours, preferably 2.5 hours. The amount of alkali employed by the equivalent of NH2 groups in the amino acid is generally in the range between 1.25 and 3 mmol, preferably between 15 and 2.25 mmol per equivalent of NH2. The pH of the solution is generally between 8 and 13, preferably between 10 and 12.
[070] After this, the appropriate amino acid modifying agent is added to the amino acid solution during stirring. The temperature of the mixture is maintained at a temperature that is generally in the range between 5 ° C and 70 ° C, preferably between 10 ° C and 40 ° C, for a period in the range between 1 and 4 hours. The amount of amino acid modifying agent used in relation to the amount of amino acid is based on the moles of total free NH2 in the amino acid. In general, the amino acid modifying agent is used in an amount in the range between 0.5 and 2.5 molar equivalents, preferably between
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0.75 and 1.25 equivalents, per molar equivalent of the total NH2 group in the amino acid.
[071] The reaction is quenched by adjusting the pH of the mixture with a suitable acid, for example, concentrated hydrochloric acid, until the pH reaches between 2 and 3. The mixture separates at rest at room temperature to form a layer transparent top and a white or off-white precipitate. The top layer is discarded and the modified amino acid is collected from the bottom layer through filtration or decantation. The modified crude amino acid is then dissolved in water at a pH in the range between 9 and 13, preferably between 11 and 13. Insoluble materials are removed by filtration and the filtrate is dried in vacuo. The yield of the modified amino acid is generally in the range between 30 and 60%, and usually 45%.
[072] If desired, amino acid esters, such as, for example, benzyl, methyl or ethyl esters of amino acid compounds, can be used to prepare the modified amino acids. The amino acid ester, dissolved in a suitable organic solvent, such as dimethylformamide, pyridine or tetrahydrofuran, can be reacted with the appropriate amino acid modifying agent at a temperature in the range between 5 ° C and 70 ° C, preferably 25 ° C, for a between 7 and 24 hours. The amount of amino acid modifying agent used with respect to the amino acid ester is the same as described above for amino acids. This reaction can be carried out with or without a base, such as, for example, triethylamine or diisopropylethylamine.
[073] After this, the reaction solvent is removed under negative pressure and the ester function is removed by hydrolyzing the modified amino acid ester with a suitable alkaline solution, for example, 1N sodium hydroxide, at a temperature in the range of 50 ° C and 80 ° C, preferably 70 ° C, for a period of time sufficient to hydrolyze the ester group and form the modified amino acid that has a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, for example, 25% aqueous hydrochloric acid solution, to a pH in the range between 2 and 2.5. The modified amino acid precipitates out of solution and is recovered by conventional means, such as filtration or decantation. Benzyl esters can be removed by hydrogenation in an organic solvent using a transition metal catalyst.
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18/75 [074] The modified amino acid can be purified by recrystallization or by fractionation on solid column supports. Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation can be carried out on a suitable solid column support, such as alumina, using mixtures of methanol and n-propanol as the mobile phase; reverse phase column supports using mixtures of trifluoroacetic acid and acetonitrile as the mobile phase; and ion exchange chromatography using water as the mobile phase. When anion exchange chromatography is performed, a subsequent 0 to 500 mM sodium chloride gradient is preferably employed.
[075] In particular modalities, modified amino acids that have the Formula
O
H Q. Q p> 1 y ^ 3
I
R ² [076] where Y is
II
T or SCh;
[077] R ¹ is Cs -C24 alkylene, C2 -C20 alkenylene, C2 -C20 alkylene, cycloalkylene or an aromatic, such as arylene;
[078] R ² is hydrogen, C1-C4 alkyl or C2-C4 alkenyl; and [079] R ³ is C1-C7 alkyl, C3-C10 cycloalkyl, aryl, thienyl, pyrrole or pyridyl, and [080] R ³ is optionally substituted by one or more of the C1-C5 alkyl group, C2-C4 alkenyl group , F, Cl, OH, OR ¹ , SO2, COOH, COOR ¹ or SO3H;
[081] can be prepared [082] by reacting in water and in the presence of a lactam base that has the
O
Formula in which a compound has the Formula R ³ --Y - X, where Y, R ¹ , R ² and R ³ are as above and X is a leaving group. A lactam, as shown
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19/75 in the above Formula can be prepared, for example, using the method described in Olah et al., Synthesis, 537-538 (1979).
[083] In particular embodiments, modified amino acids also include an amino acid acylated in its alpha amino group with a fatty acid, which can be represented by the general Formula A to X, where A is the alpha amino acid residue and X is a linked fatty acid by acylation to the alpha-amino group A. Amino acids include cationic and non-cationic amino acids. In particular embodiments, the term non-cationic amino acid refers to an amino acid selected from the group consisting of non-polar hydrophobic amino acids, uncharged polar amino acids and polar acid amino acids. In particular embodiments, the term non-cationic amino acid, as used in this document, refers to amino acids selected from the group consisting of Alanine (Ala), Valine (Vai), Leucine (Leu), Isoleucine (llle), Phenylalanine ( Phe), Tryptophan (Trp), Methionine (Met), Proline (Pro), Sarcosine, Glycine (Gly), Serine (Ser), Threonine (Thr), Cysteine (Cys), Tyrosine (Tyr), Asparagine (Asn) and Glutamine (Gin), Aspartic acid (Asp) and Glutamic acid (Glu).
[084] In particular embodiments, the acylated FA-aa includes an alpha amino acid residue from a non-polar hydrophobic amino acid. In particular embodiments, the acylated FA-aa can be represented by the general Formula A to X, where A is the amino acid residue of a non-polar hydrophobic amino acid and X is a fatty acid linked by acylation to the alpha amino group A. In particular, the term non-polar hydrophobic amino acid, as used herein, refers to the categorization of amino acids used by the person skilled in the art. In particular embodiments, the term non-polar hydrophobic amino acid refers to an amino acid selected from the group consisting of Ala, Vai, Leu, lie, Phe, Trp, Met, Pro and Sarcosine.
[085] In particular embodiments, the acylated FA-aa includes the amino acid residue of an uncharged polar amino acid. In particular embodiments, the acylated FA-aa can be represented by the general Formula A to X, where A is the amino acid residue of an uncharged polar amino acid and X is a fatty acid linked by acylation to the alpha amino group A. particulars, the term “uncharged polar amino acid” as used herein, if
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20/75 refers to the categorization of amino acids used by the person skilled in the art. In particular embodiments, the term uncharged polar amino acid refers to an amino acid selected from the group consisting of Gly, Ser, Thr, Cys, Tyr, Asn and Gin.
[086] In particular embodiments, the acylated FA-aa includes the amino acid residue of a polar acid amino acid. In particular embodiments, the acylated FA-aa can be represented by the General Formula A to X, where A is the amino acid residue of a polar acid amino acid and X is a fatty acid linked by acylation to the alpha amino group A. In particular modalities , the term "polar acid amino acid", as used herein, refers to the categorization of amino acids used by the person skilled in the art. In particular embodiments, the term polar acid amino acid refers to an amino acid selected from the group consisting of Asp and Glu.
[087] In particular embodiments, the amino acid residue of the acylated FA-aa includes the amino acid residue of an amino acid that is not encoded by the genetic code. Amino acid modifications by acylation can readily be carried out using acylating agents known in the art that react with the free alpha amino group of the amino acid.
[088] In particular embodiments, the alpha amino acids or alpha amino acid residues in this document are L-shaped even if stated otherwise.
[089] In particular embodiments, the amino acid residue is in the form of free acid and / or a salt thereof, such as a sodium salt (Na +) of the same.
[090] Exemplary modalities of acylated FA-aas can be represented by the general Formula I of Fa-aa:
[091] where R1 is an alkyl or aryl group that includes 5 to 19 carbon atoms; R2 is H (ie, hydrogen), CH3 (ie, methyl group) or is covalently attached to R4 through a group (Chhjs; R3 is H or is absent; and R4 is an amino acid side chain or is covalently connected to R2 by
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21/75 means of a group (Chhjs; or a salt of the same.
[092] FA-aa can be acylated with a fatty acid that includes a substituted or unsubstituted alkyl group consisting of 5 to 19 carbon atoms. In particular embodiments, the alkyl group consists of 5 to 17 carbon atoms. In particular embodiments, the alkyl group consists of 5 to 15 carbon atoms. In particular embodiments, the alkyl group consists of 5 to 13 carbon atoms. In particular embodiments, the alkyl group consists of 6 carbon atoms.
[093] In particular embodiments, the acylated FA-aa is soluble in intestinal pH values, particularly in the pH range of 5.5 to 8.0, as well as in the pH range of 6.5 to 7.0. In particular embodiments, the acylated FA-aa is soluble below pH 9.0.
[094] In particular embodiments, the acylated FA-aa has a solubility of at least 5 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 10 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 20 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 30 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 40 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 50 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 60 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 70 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 80 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 90 mg / ml. In particular embodiments, the acylated FA-aa has a solubility of at least 100 mg / ml. In particular embodiments, the solubility of the acylated FA-aa is determined in an aqueous solution at a pH value of 1 unit above or below the FA-aa pKa at 37 ° C. In particular embodiments, the solubility of the acylated FA-aa is determined in an aqueous solution at pH 8 at 37 ° C. In particular embodiments, the solubility of the acylated FA-aa is determined in an aqueous solution at a pH value of 1 unit above or below pi of the FA-aa at 37 ° C. In particular modalities, the solubility of the FA-aa
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22/75 aqueous solution at a pH value 1 unit above or below pi of the FA-aa at 37 ° C, wherein said FA-aa is two or more ionizable groups with opposite charges. In particular embodiments, the solubility of FA-aa is determined in a 50 mM aqueous sodium phosphate buffer, pH 8.0 at 37 ° C.
[095] In particular modalities the FA-aa is selected from the group consisting of Formula (a), (b), (c), (d), (e), (f), (g), ( h), (i), (j), (k), (I), (m), (n), (o), (p), (q), and (r), where R1 is a group alkyl including 5 to 19 carbon atoms, R2 is H (ie, hydrogen) or CH3 (ie, methyl group) and R3 is H; or a salt or the free acid form of it. Formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), Ü)>(k)> (D, ( ^m ) , ( ⁿ )>(°)>(P)> (d), θ ( ^Γ ) θθ ⁰ provided in Figure 3.
[096] In particular modalities, the acylated FA-aa can be selected from one or more of sodium N-dodecanoyl alaninate, N-dodecanoyl L-alanine, sodium N-dodecanoyl isoleucinate, N-dodecanoyl-L- isoleucine, sodium N-dodecanoyl leucinate, N-dodecanoyl-L-leucine, sodium Ndodecanoyl methioninate, N-dodecanoyl-L-methionine, sodium N-dodecanoyl phenylalaninate, N-dodecanoyl-L-phenylalanine, prolin Sodium N-dodecanoyl, Ndodecanoyl-L-proline, Sodium N-dodecanoyl tryptophanate, N-dodecanoyl-Ltryptophan, Sodium N-dodecanoyl valinate, N-dodecanoyl-L-valine, Sodium N-dodecanyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium N-oleoyl sarcosinate, sodium N-decyl leucine, sodium N-decanoyl alaninate, N-decanoylL-alanine, sodium N-decanoyl leucinate, N-decanoyl- L-leucine, sodium N-decanoyl phenylalaninate, N-decanoyl-L-phenylalanine, sodium N-decanoyl valinate, N-decanoyl-L-valine, N-decanoyl isoleucinate sodium la, N-decanoyl-Lysoleucine, sodium N-decanoyl methioninate, N-decanoyl-L-methionine, sodium N-decanoyl prolinate, N-decanoyl-L-proline, sodium N-decanoyl threoninate, N-decanoyl-L-threonine, sodium N-decanoyl tryptophanate, N-decanoyl-Ltryptophan, sodium N-decanoyl sarcosinate, N-decanoyl-L-sarcosine, N-dodecanoyl asparaginate, N-dodecanoyl-L- asparagine, sodium Ndodecanoyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium N-dodecanoyl cysteine, N-dodecanoyl-L-cysteine, sodium N-dodecanoyl glutaminate, Ndodecanoyl-L-glutamine, glycate Sodium N-dodecanoyl, N-dodecanoyl-glycine, sodium N-dodecanoyl serinate, N-dodecanoyl-L-serine, sodium threoninate
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Sodium N-dodecanoyl, N-dodecanoyl-L-threonine, Sodium N-dodecanoyl tyrosinate, N-dodecanoyl-L-tyrosine, Sodium N-decanoyl asparaginate, N-decanoylL-asparagine, N-decanoyl aspartic acid sodium, N-decanoyl-Laspartic acid, sodium N-decanoyl cysteine, N-decanoyl-L-cysteine, sodium N-decanoyl glutaminate, N-decanoyl-L-glutamine, sodium N-decanoyl glycinate, N-decanoyl-L-glycine, sodium N-decanoyl serinate, N-decanoyl-L-serine, sodium N-decanoyl glycinate, N-decanoyl-L-tyrosine, sodium Ndodecanoyl asparaginate, N-glutamic acid -dodecanoyl sodium, Ndodecanoyl-L-glutamic acid, sodium N-decanoyl glutamic acid, Ndecanoyl-L-glutamic acid, Amisoft HS-11 P (sodium stearoyl glutamate, Amisoft MS-11 (sodium myristyl glutamate) ), Amisoft LS-11 (sodium dodecanoyl glutamate), Amisoft CS-11 (sodium cocoyl glutamate), sodium N-cocoyl glutamate, Amisoft HS-11 P, Amisoft HS-11 P (N- glutamate es sodium thearoyl), (sodium N-myristoyl glutamate)), (sodium N-dodecanoyl glutamate) and Amisoft HS-11 P.
[097] The following extended FA-aas are commercially available:
Commercial name Chemical name Supplier (as of April 14, 2011) Hamposyl L-95 Sodium N-dodecanoyl sarcosinate Chattem Chemicals Hamposyl O Sodium N-oleoyl sarcosinate Chattem Chemicals Hamposyl C Sodium N-cocoyl sarcosinate Chattem Chemicals Hamposyl L-30 Sodium N-dodecanoyl sarcosinate Chattem Chemicals Amisoft HS-11 P Sodium N-stearoyl glutamate Ajinomoto Amisoft LS-11 Sodium N-dodecanoyl glutamate Ajinomoto Amisoft CS-11 Sodium N-cocoyl glutamate Ajinomoto Amisoft MS-11 Sodium N-myristoyl glutamate Ajinomoto Amilite GCS-11 Sodium N-cocoyl glycinate Ajinomoto
[098] In particular embodiments, the terms “N fatty acid acylated amino acid”, fatty acid acylated amino acid, or acylated amino acid are used interchangeably in this document and refer to a
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24/75 amino acid that is acylated with a fatty acid in its alpha amino group.
[099] Primary cannabinoids. Rapid-acting oral formulations also include one or more primary cannabinoids. In particular modalities, primary cannabinoids are cannabinoids that exert the desired primary physiological effects of cannabis. Examples of cannabinoids that exert the desired primary physiological effects of cannabis include A9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Primary cannabinoids can also include cannabinoid derivatives and / or analogues that exert a desired primary physiological effect from cannabis.
[0100] The term derivative refers to a compound that is obtained from a similar compound or a precursor compound through a chemical reaction. The term analog (also structural analog or chemical analog ”) refers to a compound that is structurally similar to another compound, however, it differs with respect to certain components, such as an atom, a functional group and / or a substructure. Examples of THC analogs include nabilone, ajulemic acid and (-) H11-210. An example of a CBD analog is abn-CBD.
[0101] In particular embodiments, primary cannabinoids include THC. THC is the predominant cannabinoid present in several strains of cannabis, often in 10 to 20% of the dry weight of cannabis flowers. The THC content in cannabis can vary from trace amounts (<1%) to more than 30%. Several strains of dominant THC cannabis contain only trace amounts of CBD (<1%). An example of a dominant low-CBD THC cannabis strain is Acid Diesel (22% THC and 0.1% CBD). Cannabis and / or cannabis extracts that contain THC (> 1%) can be useful to provide a physiological and / or medical benefit of THC. An exemplary THC structure is shown in Figure 4.
[0102] In particular modalities, primary cannabinoids include CBD. In certain strains of cannabis, such as Charlotte's Web ™ (Stanley Brothers Social Enterprises, LLC, Colorado Springs, CO), CBD is the predominant cannabinoid. Charlotte's Web ™ contains an average of 20% CBD and trace amounts of THC (0.3%), as measured in dry weight in cannabis flowers. Cannabis strains of dominant CBD (> 1%) and low THC content (<
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1%) can be used for medicinal and nutritional benefits, and may be desired in certain situations as they lack the psychoactive effects of THC. The CBD content in cannabis can be in the range of trace amounts (<1%) to more than 20%. An exemplary CBD structure is shown in Figure
4.
[0103] In particular modalities, fast acting oral formulations include a combination of THC and CBD. Examples of cannabis strains containing THC and CBD (more than 1% each) include harlequin, (5% THC and 12% CBD) and CBD Mango Haze (14% THC and 16% CBD). The health benefits of THC and CBD can be enhanced when the two molecules are supplied together. For example, a combination of THC and CBD is believed to optimize certain analgesic and anxiolytic properties of the two cannabinoids. Additionally, CBD can reduce or eliminate negative side effects from THC. The THC: CBD ratio in cannabis strains can range from> 100: 1 THC: CBD to <0.01: 1 THC: CBD.
[0104] In particular modalities, primary cannabinoids include nabilone. Nabilone is a synthetic THC analogue that is used with anxiolytic and antiemetic properties, and is also useful to treat pain of various etiologies, such as multiple sclerosis (MS), peripheral neuropathy and spinal injuries (Lancet, 1995, 345, 579, Pharm. J. 259, 104, 1997; Baker & Pryce, Expert Opin Investig Drugs, April 2003; 12 (4): 561-7). Nabilone is usually administered in doses of 1 to 2 mg, up to 6 mg per day. An exemplary structure of nabilone is shown in Figure 4.
[0105] Molecules that Restore Entourage Effects. In particular embodiments, oral formulations of rapid action include one or more molecules of entourage restoration. Entourage restoration molecules can refer to molecules that, when supplied in a THC and / or CBD composition, restore or enhance particular desired effects, compared to the effects of THC and / or CBD alone. In particular embodiments, one or more entourage restoration molecules may include additional cannabinoids, terpenes, flavonoids and / or volatile substances that impart flavor and aroma.
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26/75 [0106] Additional cannabinoids. In particular embodiments, the entourage restoration molecules include additional cannabinoids (in addition to primary cannabinoids THC and / or CBD). Cannabis produces more than 60 different cannabinoids (Brenneisen, Marijuana and the Cannabinoids, Ch. 2, 2007, Humana Press). Cannabinoids are produced through the cannabis trichome secretion glands, which are highly concentrated in the flowers of female plants. Cannabinoids can also be found in other parts of the cannabis plant, which include the stems and leaves.
[0107] Cannabinoids other than THC and CBD contribute to the various physiological effects of cannabis. For example, cannabigerol (CBG) fights THC-induced paranoia and is anti-inflammatory, antibacterial and anxiolytic. Cannabichrome (CBC) is anti-inflammatory and analgesic. Cannabinol (CBN), which is produced by the breakdown of THC, is analgesic, anxiolytic and has slightly psychoactive effects. Tetrahydrocannabivarin (THCV), in contrast to THC, is an appetite suppressant.
[0108] Cannabinoid content can vary widely depending on the plant strain, age, growing conditions and storage conditions. Cannabis strains vary in their cannabinoid content without THC and CBD. For example, while the Purple Kush strain contains 0.02% CBN; 0.4% CBG; 0.1% THCV; 0.05% CBC; and 0.1% CBL, the Durban Poison strain contains 0.1% CBN; 1% CBG; 1% THCV; 0.05% CBC; and 1.2% CBL (averages reported by Steep Hill Labs, Inc.). The variation in cannabinoid content across cannabis strains contributes to the distinct entourage effects of each strain.
[0109] In particular embodiments, entourage restoration molecules include one or more of A8-tetrahydrocannabinol (A8-THC), Δ11-tetrahydrocannabinol (A11-THC), cannabigerol (CBG), cannabichromene (CBC), cannabinol ( CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarina (CBCV), cannabigerovarin (CBGV), cannabigerol acid methyl, CBGM) cannabidiolic (CBDA), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabivarinic acid (THCVA).
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27/75 [0110] Terpenes. In particular embodiments, the entourage restoration molecules include terpenes. Terpenes can refer to terpenes or terpenoids, or derivatives and / or analogues thereof. Terpenes are a large class of organic molecules that include one or more isoprene units (Cshs). Terpene molecules that include additional functional groups are also known as terpenoids. The isoprene units of terpenes can be linked to form linear molecules or rings. Terpenes can be classified by the number of isoprene subunits present. For example, hemiterpenes contain an isoprene subunit, monoterpenes contain two isoprene subunits, sesquiterpenes contain three isoprene subunits and diterpenes contain four isoprene subunits.
[0111] In particular embodiments, entourage restoration molecules include one or more cannabis-derived terpenes. More than 100 terpenes have been identified in cannabis plants (Rothschild et al., Bot J Linn Soc. 2005. 147 (4): 387-397 and Brenneisen Forensic Science and Medicine: Marijuana and the Cannabinoids chapter 2, ed. M ElSohly, Humana Press, New York, NY, 2007). Like cannabinoids, terpenes are produced through cannabis trichome glands, which are concentrated in cannabis flowers. However, terpenes can also be found in other parts of the cannabis plant, such as in stems and leaves. Examples of cannabis-derived terpenes include βmircene, a-pinene, β-pinene, linalool, d-limonene, β-caryophyllene, caryophyllene oxide, nerolidol, phytol, ocimene, terpinolene, terpinene, humulene, carene, bisabolol, valencene, elenene , farnesene, menthol, geraniol, guaiol, camphene, camphor, eucalyptol, pulegone and feladrene. In particular embodiments, the one or more terpenes include aloaromadendrene, (Z) -a-cis-bergamotene, (Z) -a-transbergamotene, β-bisabolol, epi-a-bisabolol, β-bisabolene, borneol (canfol), cis -ybisabolene, borneol acetate (bornyl acetate), α-cadinene, cis-carveol, ahumulene (a-caryophyllene), y-cadinene, Δ-3-carene, caryophyllene oxide, 1,8-cineol, citral A, citral B, α-copaene (aglaiene), γ-curcumene, p-cymene, β-elemene, γelemene, eucalyptol, a-eudesmol, β-eudesmol, γ-eudesmol, eugenol, cis-βfarnesene (Ο-β-farnesene) , trans-a-farnesene, trans-3-farnesene, trans-γbisabolene, fenchone, fenchol (norbornanol, β-fenchol), α-guaiene, ipsdienol,
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28/75 lemenol, d-limonene, linalyl alcohol (β-linolol), α-longipinene, menthol, γ-murolene, trans-nerolidol, nerol, β-ocimene (cis-ocimene), α-feladrene, 2-pinene, sabinene, cis-sabinene hydrate (cis-thujanol), β-selinene, a-selinene, γ-terpinene, isoterpin, terpineol (a-terpineol), terpineol-4-ol, α-terpinene (terpinene), a-tujeni (origanene), viridiflorene (ledene) and / or a-ilange.
[0112] In particular modalities, terpenes include linalool. Linalool is a naturally occurring monoterpene in several plants that include cannabis, lavender, laurel, citrus and mint, among others. Linalool exists naturally as two isomers, known as lycareol and coriandrol. Several studies have demonstrated anti-inflammatory (Peana et al., Phytomedicine 2002. 9 (8): 721-6), analgesic (Peana et al., Eur J Pharmacol 2003 460 (1): 37-41) and anti-anxiety (Linck et al., Phytomedicine 2002. 17 (8-9): 679-83; Souto-Major et al., Pharmacol Biochem Behav 2011. 100 (2): 259-63) of linalool. Linalool is normally used as a food additive and is generally recognized as safe by the U.S. Food and Drug Administration (FDA).
[0113] In particular embodiments, terpenes include nerolidol. Nerolidol is a cannabis-derived terpene that has sedative properties (Binet etal., Ann Pharm Fr 1972. 30: 611-616). Therefore, nerolidol contributes to the sedative effects of particular cannabis strains.
[0114] In particular modalities, terpenes include pinene. Pinene is a monoterpene that exists as two isomers, α-pinene and β-pinene. Pineno has a pine-like smell and occurs naturally in pines and cannabis. Pineno has anti-inflammatory effects (Gil et al., Pharmazie 1989. 44 (4): 284-7), antimicrobial properties (Nissen et al., Phytotherapy 2010. 81 (5): 413-19) and is a bronchodilator in low concentration (Falk et al., Scand J Work Environ Health 1990. 16: 372-378). Pineno can also improve memory (Perry, et al, Journal of Pharmacy and Pharmacology 2000. 52 (7): 895-902) and, therefore, is believed to combat the short-term memory loss that can be induced by THC.
[0115] In particular modalities, terpenes include karyophylene (or βcaryophylene). β-karyophylene is a naturally occurring sesquiterpene in rosemary, hops, cannabis, cloves, black pepper, lavender, cumin, basil and cinnamon, βcariophylene has anti-inflammatory effects (Gertsch et al., PNAS. 2008. 105 (26):
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9099104), antianalgesic (Katsuyama etal., European Journal of Pain. 2013. 17 (5): 664-675), neuroprotective (Guimaraes-Santos, J Evid Based Complementary Altern Med. 2012. 1 -9), antianxiety and antidepressant ( Bahi et al., Physiology & Behavior. 2014. 135: 119-124). Karyophyllene is a direct agonist of the CB2 cannabinoid receptor, which is present in immune cells, and can enhance the anti-inflammatory properties of cannabis.
[0116] In particular modalities, terpenes include limonene. Limonene is a monoterpene that occurs naturally in citrus, citronella, verbena and cannabis plants. Limonene is the main component of citrus fruit that imparts the citrus-like aroma. Limonene has anti-inflammatory (Piccinelli et al. Life Sci. 2016 S0024-3205 (16): 30669-5) and antidepressant (Komori et al., 1995). Limonene is normally used as a food additive and is generally recognized as safe by the F.D.A. from the USA.
[0117] In particular modalities, terpenes include β-mircene, βmircene is a monoterpene that is normally found in hops, parsley, thyme, bay leaves, mangoes, citronella and cannabis, β-mircene has analgesic effects (Paula-Freire et al., Planta Med. 2016; 82 (3): 211-6), anti-inflammatory (Lorenzetti et al., J of Ethnopharmacology. 1991,34 (1): 43-48), antimicrobial (Yoshihiro et al., Natural Medicines. 2004. 58 (1), 10-14) and sedative (Rao et al., J Pharm Pharmacol. 1990. 42 (12): 877-878). Cannabis indica strains have a high content of β-mycrene (> 0.5%), and β-mycrene contributes to sedation, inducing couch-lock inducing effects or dominant indica strains.
[0118] Flavonoids. In particular embodiments, the entourage restoration molecules include flavonoids. Flavonoids are a class of secondary metabolites found in plants and fungi that contain a 15-carbon skeleton each, including two phenyl rings and a heterocyclic ring. Flavonoids can be classified into three groups: i) bioflavonoids or flavonoids, ii) isoflavonoids and iii) neoflavonoids. Flavonoids that occur naturally in cannabis plants include canaflavin A, canaflavin B, canaflavin C, vitexin, isovitexin, apigenin, kaempferol, quercetin, luteolin, cinnamaldehyde and orientin. See Figure 5 for exemplary structures of particular flavonoids.
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30/75 [0119] In particular embodiments, the entourage restoration molecules include canaflavin A, canaflavin B and / or canaflavin C. Canaflavins are flavonoids that are unique in cannabis plants. Canaflavin A and canaflavin B both have anti-inflammatory activity (Barrett et al., Experientia 1986. 15; 42 (4): 452-3).
[0120] In particular embodiments, the entourage restoration molecules include apigenin. Apigenin is a naturally occurring flavonoid in several plants, such as cannabis, parsley, celery and chamomile. Apigenin is an opioid receptor agonist and has several beneficial health effects that include specifically inducing cancer cell death, anxiolytic activity (Salgueiro et al., Pharmacol Biochem Behav 1997. 58, 887-891) and neurogenesis stimulation.
[0121] In particular embodiments, the entourage restoration molecules include kaempferol. Kaempferol is a flavonoid commonly found in many plant-based foods, which include apples, grapes, tomatoes, potatoes, onions, broccoli, pumpkin, cucumber and berries. There is a wide range of positive health effects on kaempferol intake. For example, kaempferol has antioxidant, anti-inflammatory, antimicrobial, anti-cancer, cardioprotective, neuroprotective, anti-diabetic, anti-osteoporotic, anxiolytic, analgesic and anti-allergic properties (Calderon-Montano et al., Mini Rev Med Chem. 2011. 11 (4): 298 -344).
[0122] In particular embodiments, the entourage restoration molecules include quercetin. Quercetin is a flavonoid found in several plants, which include cannabis, common beans, capers, coriander, onion, cabbage, plum, cranberry and sweet potato. Quercetin can have antioxidant and anticancer effects (Alam etal., Environ Sei Pollut Res Int 2016).
[0123] In particular embodiments, the entourage restoration molecules include orientin. Orientina is a flavonoid that can be found in cannabis, passionflower, açaí, barley and millet. The medicinal properties of orientin include antioxidant, anti-aging, antimicrobial, anti-inflammatory, vasodilator, radiation protector, neuroprotective, antidepressant, antiadipogenesis and antinociceptive effects (Lam et al., Mv Pharmacol Sei. 2016.
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2016: 4104595).
[0124] Other molecules derived from cannabis. In particular embodiments, the entourage restoration molecules include other molecules derived from cannabis. In addition to terpenes and flavonoids, certain volatile compounds impart distinctive aroma and flavor profiles to cannabis. Examples of volatile substances that impart flavor and aroma that are present in cannabis are listed in Rice & Koziel. PLoS One. 2015. 10 (12): e0144160. Molecules derived from particular cannabis that contribute to the aroma and flavor of cannabis include 2-heptanone, methyl heptanoate, methyl salicylate, methyl anthranylate and hexanal. These molecules are volatile compounds, which means that they have a high tendency to vaporize. Therefore, volatile compounds that impart cannabis flavor and flavor are often lost during the production of cannabis extracts for human consumption. The 2-heptanone, methyl heptanoate, methyl salicylate, methyl anthranylate and hexanal molecules, as well as other volatile cannabis-derived compounds, are food additives approved by the F.D.A. of the U.S. In particular embodiments, low concentrations (1% or less) of these volatile substances can be used to impart particular flavors and flavors to oral formulations described in this document.
[0125] Obtain Cannabis Derived Molecules. In particular embodiments, fast-acting oral formulations with restored entourage effects include one or more primary cannabinoids (THC and / or CBD) and one or more entourage restoration molecules. Extraction and decarboxylation of THC and / or CBD for oral consumption can result in loss of entourage effect on molecules. Therefore, compositions with THC and / or CBD can be supplemented with molecules derived from cannabis to restore entourage effects.
[0126] Primary cannabinoids. In particular embodiments, decarboxylated cannabis extracts are included in the formulations to provide primary cannabinoids. Decarboxylated cannabis extracts containing THC and / or CBD may be commercially available from sources including BioCBD +, active CBD oil, RSHO ™ (Medical Marijuana, Inc., Poway, CA), and Ethos Innovates ™ (One LED Corp , Bainbridge Island, WA). Commercially available THC cannabis extracts include Zoots ™ (Natural Extractions, LLC, University
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Place, WA); Dixie Elixirs, Marijuana Drops (Marijuana Market) and Ethos Innovates.
[0127] In particular embodiments, primary cannabinoids can be purchased as non-decarboxylated cannabis extracts (which contain THCA and / or CBDA instead of THC and / or CBD), and can be decarboxylated during formulation. The relative cannabinoid content of a cannabis strain is typically preserved during extraction (for example, CO2 or BHO extraction). Extracts from a single strain can be useful to mimic the entourage effects of a particular strain by providing the natural repertoire of the primary and additional cannabinoid strain. Non-decarboxylated cannabis extracts are usually available for a wide variety of cannabis strains, such as Acid Diesel, Super Lemon Haze, Pure Kush, Charlotte's Web ™ and Durban Poison.
[0128] In particular modalities, cannabinoids that are supplied in non-decarboxylated cannabis extracts are decarboxylated before formulating compositions for oral delivery. Decarboxylation of cannabinoids in a cannabis extract can be accomplished by heating the cannabis extract in a boiling water bath for 90 minutes. In particular modalities, decarboxylation of cannabinoids is performed before mixing with entourage restoration molecules, as certain entourage restoration molecules can be destroyed by heat.
[0129] Entourage restoration molecules. In particular embodiments, entourage restoration molecules can be obtained from commercially available sources. Various terpenes and flavonoids, such as linalool, β-mircene, a-pinene, β-pinene, karyophylene, quercetin and apigenin are commercially available from various sources. Examples of companies that provide food grade terpenes and flavonoids include Sigma Aldrich, True Terpenes and NHR Organic Oils. Examples of companies providing volatile substances that impart flavor and aroma include Sigma Aldrich, Eastman Chemical Company, Foodchem International Corporation and Aurochemicals.
[0130] In particular modalities, entourage restoration molecules are produced synthetically.
[0131] In particular modalities, cannabinoids can be produced
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33/75 synthetically. Examples of techniques for the synthetic production of cannabinoids can be found in documents n ° LIS2016 / 0355853; JP2016 / 509842; Petrzilka et al., Helv Chim Acta. 1967. 50 (2) 719-723; Kobayashi et al., Org Lett. 2006. 8 (13): 2699-2702; and Mechoulam & Gaoni, J Am Chem Soc. 1965. 87 (14): 3273-3275.
[0132] In particular modalities, terpenes can be produced synthetically. Examples of techniques for the synthetic production of terpenes can be found in documents n ° US2004 / 0161819; and W02006134523. In particular modalities, organisms can be genetically altered to overexpress particular terpenes and terpenes can be isolated from the organism. Examples of techniques for obtaining terpenes from a genetically modified organism can be found in documents No. W020061111924 and US2010 / 0297722.
[0133] In particular modalities, flavonoids can be produced synthetically. Exemplary techniques for synthesizing flavonoids can be found in Mamoalosi & Van Heerden, Molecules. 2013. 18: 4739-4765 and Wagner & Farkas, The Flavonoids. Chapter: Synthesis of Flavonoids. 1975. 127213. Springer.
[0134] In particular embodiments, the entourage restoration molecules are derived from plant matter. Vegetable material is material produced through a plant and includes any whole plant or part of a plant (for example, bark, wood, leaves, stems, roots, flowers, fruits, seeds or parts thereof) and / or exudates or extracts thereof . In particular embodiments, the compositions may include botanical products. Botanical products may include plant materials, algae, macroscopic fungi and / or combinations thereof. In particular embodiments, the compositions include a mixture of various types of plant material.
[0135] In particular modalities, entourage restoration molecules can be prepared through spraying, decoction, expression and extraction of a vegetable starting product. The term extract can include all different types of preparations that contain some or all of the active ingredients found in the relevant plants. Extracts can be produced through
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34/75 cold extraction techniques that use a variety of different extraction solvents that include water, fatty solvents (such as olive oil) and alcoholic solvents (for example, 70% ethanol). Cold extraction techniques are typically applied to softer parts of the plant, such as leaves and flowers, or in cases where the desired plant components are heat-labile (for example, terpene) or have a low boiling point (eg volatile). Alternatively, the solvents mentioned above can be used to produce extracts of the desired plants using a hot extraction technique, wherein said solvents are heated to a high temperature, where the precise value of said temperature is dependent on the properties of the solvent chosen and maintained at that temperature throughout the extraction process. Hot extraction techniques are usually applied to the hardest, most rigid parts of the plant, such as bark, branches and thicker roots. In some cases, sequential extractions can be performed in more than one solvent and at different temperatures. The plant extract can be used in a concentrated form. Alternatively, the extract can be diluted as appropriate for your desired use.
[0136] Additional procedures for producing plant extracts (which include hot extraction, cold extraction and other techniques) are described in publications that include Medicinal plants: a field guide to the medicinal plants of the Land of Israel (in Hebrew), author: N. Krispil, Har Gilo, Israel, 1986 and Making plant medicine, author: R. Cech, pub. by Horizon Herbs, 2000.
[0137] In particular modalities, additional cannabinoids (cannabinoids without THC and without CBD), can be supplied in a cannabis extract that contains THC and / or CBD. Cannabis extracts (for example, CO2 or BHO extracts) can be rich in cannabinoids and preserve the cannabinoid content of the cannabis strain used for extraction. Cannabinoid-rich cannabis extracts are commercially available from a variety of sources.
[0138] In particular modalities, terpenes, flavonoids and / or volatile substances that impart flavor and aroma can be extracted from plants. Exemplary techniques for extracting terpenes from plants can be found in Breitmaier, Terpenes: Flavors, Fragrance, Pharmaca, Pheromones. Chapter 10.
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2006. John Wiley & Sons, documents No. WO2013174854 and CN 101439074. An exemplary technique for obtaining a flavonoid-rich plant extract can be found in Victorio et al., Eel. Quinn. 2009. 34 (1): 29-24. Techniques for extracting volatile compounds that impart aroma and flavor include cold pressing and ethanol extraction.
[0139] In particular modalities, entourage restoration molecules are obtained from extracts from plants other than cannabis. In particular embodiments, entourage restoration molecules are obtained from any plant that produces the desired molecule. For example, vitexin is a flavonoid derived from cannabis that is also found in hawthorn and passionflower plants, so vitexin can be obtained from hawthorn or passiflora extract.
[0140] Restoration of Entourage Effects by Combining Cannabis-Derived Molecules. As indicated, in particular embodiments, compositions with restored entourage effects are created by combining one or more primary cannabinoids (such as THC and / or CBD) with one or more entourage restoration molecules.
[0141] In particular embodiments, the relative amount of each cannabis-derived molecule in the composition can be chosen to mimic the entourage effects of a particular cannabis strain. Cannabis strains can be tested to quantify primary cannabinoids and entourage molecules in a strain. The amounts of various cannabis-derived molecules present in a cannabis sample can be determined by analytical laboratory techniques, such as mass spectrometry, gas chromatography or high performance liquid chromatography. Chemical profiling of cannabis strains is routinely performed by commercial testing laboratories, such as Steep Hill Labs, Inc., The Were Shop, SC Labs and Analytical 360. Examples of terpenes quantified by commercial cannabis profiling laboratories include limonene, β- mircene, karyophylene, a-pinene, β-pinene, bisabolol, humulene, linalool and terpinolene. Cannabinoids analyzed by commercial cannabis testing laboratories include THC, CBD, CBV, THCA, THCV, CBN, CBDA, CBL and CBG.
[0142] In particular modalities, primary cannabinoids and
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36/75 entourage molecules are combined in a ratio that mimics their ratio in a particular cannabis strain, as measured through analytical testing. For example, compositions can be created to mimic the entourage effects of the Acid Diesel strain, for which a cannabinoid and terpene analysis is publicly available (as in Strain Fingerprint®, Steep Hill Labs, Inc., Oakland CA). Acid Diesel can contain an average of 20% THC, 0.2% CBD, 0.5% CBG, 0.3% CBL, 0.3% β-mycrene, 0.3% limonene and 0, 25% karyophylene. Therefore, a composition with restored acidic Diesel entourage effects can be created by combining 100 mg THC, 1 mg CBD, 2.5 mg CBG, 1.5 mg CBL, 1.5 mg β-mycrene, 1.5 mg of limonene and 1.25 mg of karyophylene, which mimics the relative strain concentration of each of these components, which provides a restored entourage effect compared to an otherwise equivalent composition that lacks one or more of the entourage restoration molecules. Other strains of cannabis with publicly available cannabinoid and terpene analyzes include Super Lemon Haze, Agent Orange, Berry While, Blue Dream, Cherry Pie, Durban Poison, Grape Ape and Purple Kush.
[0143] In particular embodiments, the total primary cannabinoid (or cannabinoid) concentration (for example, THC and / or CBD) in the composition can be 1 µg / ml or ug / mg, 10 µg / ml or ug / mg, 50 ug / ml or ug / mg, 100 ug / ml or ug / mg, 200 ug / ml or ug / mg, 300 ug / ml or ug / mg, 400 ug / ml or ug / mg, 500 ug / ml or ug / mg, 600 ug / ml or ug / mg, 700 ug / ml or ug / mg, 800 ug / ml or ug / mg, 900 ug / ml or ug / mg or 950 mg / ml or mg / mg.
[0144] In particular modalities, the ratio of primary cannabinoids for each entourage restoration molecule in the composition can be 1000: 1, 500: 1, 200: 1, 100: 1,50: 1,20: 0, 10: 1, 1: 1.0,2: 1 or 0.1: 1. For example, a formulation with 5 mg of CBD and 5 mg of THC (10 mg of totally primary cannabinoids) with 1 mg of β-mycrene would have a 10: 1 ratio of primary cannabinoid ^ -myrcene. In particular embodiments, the ratio of primary cannabinoids to any entourage restoration molecule can be chosen based on their ratio in any cannabis strain.
[0145] Formulation of Compositions with a Carrier to Provide Fast Acting Delivery. Particular modalities include compositions of
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37/75 restored entourage effect prepared as fast acting oral formulations. Exemplary oral formulations include capsules, coated tablets, edible products, elixirs, emulsions, gels, gelatin capsules, granules, gums, juices, liquids, oils, pastes, pellets, pills, powders, fast-dissolving tablets, sachets, semi-solids, sprays, solutions, suspensions, syrups, tablets, tinctures, etc.
[0146] Liquid preparations for oral administration may take the form of, for example, tinctures, solutions, syrups or suspensions, or they may present themselves as a dry product for reconstitution with water or other suitable vehicles before use.
[0147] Exemplary formulation methods. Suspension formulation. In particular embodiments, a composition with restored entourage effects and one or more N-acylated fatty acids are combined in water, an aqueous / organic solvent mixture or an organic solvent mixture. The resulting blend can be agitated to suspend.
[0148] Formulation of solution. In particular embodiments, a composition with restored entourage effects and one or more N-acylated fatty acids are combined in an aqueous / organic solvent mixture. The resulting mixture is stirred vigorously for an hour. If the solution is incomplete, a surfactant can be added and stirring can continue to prepare the final formulation.
[0149] Gelatin capsule formulation. In particular embodiments, a suspension formulation or solution formulation can be loaded into a gelatin capsule to contain up to 1 g of a composition. The gelatin capsule can be treated with an enteric coating or used without a coating.
[0150] Tablet / capsule formulation. The solution formulation and / or the suspension formulation can be dried by evaporation, lyophilization or spray drying. The resulting dry product can be combined with tablet excipients and compressed into tablets or capsules to contain up to 1 g of the composition. Alternatively, the dry product can be loaded into capsules.
[0151] In particular modalities, oral formulations of rapid action
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38/75 include dyes. Tinctures are extracts or drugs dissolved in a solution of alcohol or alcohol and water. In particular embodiments, dyes can be produced by mixing a carrier and a composition with entourage effects restored with 20% to 99% aqueous ethanol or 100% ethanol.
[0152] In particular modalities, oral formulations of fast acting include edible products. Edible products refer to any product that can be consumed as a food or drink. In some cases, edible products can be produced by infusing food formulations. Examples of edible foods suitable for use include candy, a chocolate bar, bread, a brownie, cake, cheese, chocolate, cocoa, a cookie, candy, a lollipop, a mint candy, a pastry, peanut butter, popcorn, a protein bar, rice cake, yogurt, etc. Although they are technically not edible, chewing gum can also be used. Examples of edible drinks include alcohol, beer, juice, flavored milk, flavored water, liquor, milk, punch, a shake, soda, tea and water. In particular embodiments, edible products are produced by combining formulations with ingredients used to produce an edible product.
[0153] In particular modalities, the primary cannabinoid (or cannabinoids), entourage and carrier restoration molecule (or molecules) can be added separately to edible products. In particular embodiments, a butter or oil can be heated (boiled for 3 to 4 hours) with an extract of cannabis or components of a cannabis plant (for example, flowers, stems and / or leaves) to decarboxylate cannabinoids, and the oil infused cannabinoid or fat can be used as an ingredient in the food product. Examples of food-grade fats and oils include butters and plant-based oils, such as coconut oil, grape seed oil, olive oil, palm oil, papaya seed oil, peanut oil, sesame oil , germinated wheat oil, wheat germ oil or any combination thereof. In particular embodiments, heat sensitive components of the compositions (for example, terpenes) can be added after decarboxylation or after cooking (for example, by infusion).
[0154] Particular modalities include swallowable formulations.
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Swallowable formulations are those that do not readily dissolve when placed in the mouth and can be swallowed whole without chewing or discomfort. U.S. Patent Documents 5215754 and 4374082 describe methods for preparing swallowable formulations. In particular embodiments, the swallowable formulations may have a shape that does not contain sharp edges and contains a smooth, uniform and substantially bubble-free outer coating.
[0155] To prepare swallowable formulations, each of the ingredients can be combined in mixture by intimate addition with a suitable carrier according to conventional composition techniques. In particular embodiments of the swallowable formulations, the surface of the compositions can be coated with a polymeric film. Such a film coating has several beneficial effects. First, it reduces the adhesion of the compositions to the internal surface of the mouth, thus increasing the individual's ability to swallow the compositions. Second, the film can help to hide the unpleasant taste of certain ingredients. Third, the film coating can protect the compositions against atmospheric degradation. Polymeric films that can be used in the preparation of swallowable formulations include vinyl polymers, such as polyvinylpyrrolidone, polyvinyl alcohol and acetate, cellulosics, such as methylcellulose and ethylcellulose, hydroxyethylcellulose and hydroxylpropylmethylcellulose, acrylates and methacrylates, such as vinyl copolymer types. and styrenomaleic acid, and natural gums and resins, such as zein, gelatin, shellac and acacia.
[0156] In particular embodiments, oral formulations may include chewable formulations. Chewable formulations are those that have a palatable taste and taste, are relatively soft and break quickly into smaller pieces and start to dissolve after chewing, so that they are swallowed substantially as a solution.
[0157] U.S. Patent No. 6495177 describes methods for preparing chewable formulations with improved taste. U.S. Patent No. 5,965,162 describes kits and methods for preparing edible units that disintegrate rapidly in the mouth, especially when chewed.
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40/75 [0158] In order to create chewable formulations, certain ingredients must be included to obtain the attributes already described. For example, chewable formulations should include ingredients that create a pleasant taste and taste, and promote relative softness and dissolving ability in the mouth. The following discussion describes ingredients that can help achieve these characteristics.
[0159] Sugars, such as white sugar, corn syrup, sorbitol (solution), maltitol (syrup), oligosaccharide, isomalto-oligosaccharide, sucrose, fructose, lactose, glucose, licasine, xylitol, lactitol, erythritol, mannitol, isomaltose dextrose, polydextrose, dextrin, compressible cellulose, compressible honey, compressible molasses and mixtures of them can be added to improve taste and palatability. Topping or gums, such as gelatin, agar, gum arabic, guar gum and carrageenan can be added to improve the chewability of the formulations. Fatty materials that can be used include vegetable oils (which include palm oil, hydrogenated palm oil, hydrogenated corn germ oil, hydrogenated castor oil, cottonseed oil, olive oil, peanut oil, olein oil palm oil and palm stearin oil), animal oils (which include refined oil and refined lard whose melting point is in the range of 30 ° C to 42 ° C), cocoa fat, margarine, butter and vegetable fat.
[0160] Alkyl polysiloxanes (commercially available polymers sold in a variety of molecular weight ranges and with a variety of different substitution patterns) can also be used to enhance texture, taste or both chewable formulations. By intensifying the texture, it is understood that the alkyl polysiloxane improves one or more of the rigidity, fragility and chewability of the chewable formulation, in relation to the same preparation that lacks the alkyl polysiloxane. By intensifying the taste, it is understood that the alkyl polysiloxane reduces the sandy texture of the chewable formulation, since it has liquefied in the mouth, in relation to the same preparation that lacks the alkyl polysiloxane.
[0161] Alkyl polysiloxanes generally include a polymeric backbone containing silicon and oxygen with one or more alkyl groups hanging from the silicon atoms of the backbone. Depending on your grade,
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41/75 they may additionally include silica gel. Alkyl polysiloxanes are generally viscous oils. Exemplary alkyl polysiloxanes that can be used in swallowable, chewable or dissolvable formulations include monoalkyl or dialkyl polysiloxanes, wherein the alkyl group is independently selected at each occurrence from a C-i-Ce alkyl group optionally substituted by a phenyl group. A specific alkyl polysiloxane that can be used is dimethyl polysiloxane (usually called simethicone). More specifically, a granular simethicone preparation called GS simethicone can be used. Simethicone GS is a preparation that contains 30% simethicone USP. Simethicone USP contains less than 90.5% by weight of (CH3) 3 - Si {OSi (CH3) 2} CH3 in admixture with 4.0% to 7.0% by weight of S1O2.
[0162] To avoid the stickiness that may appear in some chewable formulations and to facilitate the conversion of the active ingredients into emulsion or suspension after ingestion, the formulations may additionally include emulsifiers, such as glycerin fatty acid ester, sorbitan monostearate , sucrose fatty acid ester, lecithin and mixtures thereof. In particular embodiments, one or more of such emulsifiers can be present in an amount of 0.01% to 5.0% by weight of the formulations administered. If the level of emulsifier is lower or higher, in particular modalities, an emulsification cannot be performed, or the wax value will increase.
[0163] In particular embodiments, oral formulations include one or more carriers (as described above) and one or more excipients. For the sake of clarity, carriers contribute to providing an administration benefit. Excipients may, however, not need to contribute to an administration benefit.
[0164] Excipients are commercially available from companies such as Aldrich Chemical Co., FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt, Rhodia, ISP and others.
[0165] Exemplary excipient classes include binders, buffers, chelators, coating agents, dyes, complexing agents, diluents
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42/75 (i.e. fillers), disintegrants, emulsifiers, flavoring agents, non-stick agents, lubricants, preservatives, release agents, surfactants, stabilizing agents, solubilizing agents, sweeteners, thickening agents, wetting agents and vehicles.
[0166] Binders are substances used to cause powder particles to adhere to granulations. Exemplary binders include acacia, compressible sugar, gelatin, sucrose and its derivatives, maltodextrin, cellulosic polymers, such as ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and methylcellulose, acrylic polymers such as acrylate and acrylate copolymer, acrylate and ammonium acrylate and ammonium acrylate. povidones, copovidones, polyvinyl alcohols, alginic acids, sodium alginate, starch, pregelatinized starch, guar gum and polyethylene glycol.
[0167] Dyes can be included in formulations to impart color to the formulation. Exemplary dyes include grape peel extract, red beet powder, beta-carotene, anato, carmine, turmeric and paprika. Additional dyes include FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, FD&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide.
[0168] Diluents can intensify the granulation of formulations. Exemplary diluents include microchstalline cellulose, sucrose, dicalcium phosphate, starches, lactose and polyols with less than 13 carbon atoms, such as mannitol, xylitol, sorbitol, maltitol and pharmaceutically acceptable amino acids, such as glycine.
[0169] Disintegrants can also be included in formulations to facilitate dissolution. Disintegrants, which include permeabilization and capillarity agents, have the ability to drain water or saliva into oral formulations, which promotes dissolution from within as well as from outside oral formulations. Such disintegrants, permeabilizing and / or capillarity agents that can be used include starches, such as corn starch, potato starch, pregelatinized and modified starches thereof, cellulosic agents, such as Ac-di-sol, montmorillonite clays, Crosslinked PVP, sweeteners, bentonite, microcrystalline cellulose, croscarmellose sodium, alginates,
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43/75 sodium starch glycolate, gums such as agar, guar, carob, karaya, pectin, arabic, xanthan and tragacanth, silica with a high affinity for aqueous solvents, such as colloidal silica, precipitated silica, maltodextrins, βcyclodextrins, polymers, such as carbopol, and cellulosic agents, such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Dissolution of oral formulations can be facilitated by including relatively small particles of the ingredients used.
[0170] Exemplary dispersing or suspending agents include acacia, alginate, dextran, tragacanth, gelatin, hydrogenated edible fats, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, sorbitol syrup and synthetic natural gums.
[0171] Exemplary emulsifiers include acacia and lecithin.
[0172] Flavors are natural or artificial compounds used to impart a pleasant taste and, often, odor to oral formulations. Exemplary flavorings include, natural and synthetic flavor oils, aromatic flavorings, plant extracts, leaves, flowers and fruits, and combinations thereof. Such flavorings include anise oil, cinnamon oil, vanilla, vanillin, cocoa, chocolate, natural chocolate flavor, menthol, grape, mint oil, gualteria oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, cassia oil; citrus oils, such as lemon, orange, lime and grape oils; and fruit essences, which include apple, pear, peach, berry, berries, date, blueberry, kiwi, strawberry, raspberry, cherry, plum, pineapple and apricot. In particular embodiments, flavorings that can be used include natural berry extracts and mixed natural berry flavor, as well as citric and malic acid.
[0173] Non-stick agents improve the flow of powder mixtures during manufacture and minimize the variation in formulation weight. Exemplary nonstick agents include silicon dioxide, colloidal or fumed silica, magnesium stearate, calcium stearate, stearic acid, corn starch and talc.
[0174] Lubricants are substances used in formulations that reduce friction during compression of the formulation. Exemplary lubricants include
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44/75 stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, mineral and vegetable oils, benzoic acid, poly (ethylene glycol), glyceryl behenate, stearyl fumarate and sodium lauryl sulfate.
[0175] Exemplary preservatives include methyl p-hydroxybenzoates, propyl p-hydroxybenzoates and sorbic acid.
[0176] Exemplary sweeteners include aspartame, dextrose, fructose, high fructose corn syrup, maltodextrin, monoammonium glycyrrhizinate, neo-hesperidin dihydrocalcone, potassium acesulfame, saccharin sodium, stevia, sucralose and sucralose.
[0177] In addition to those described above, any appropriate fillers and excipients can be used in the preparation of the swallowable, chewable and / or dissolvable formulations or any other oral formulation described in this document as long as they are consistent with the objectives described.
[0178] Additional information can be found in Wade & Waller, Handbook of Pharmaceutical Excipients (2nd ^2nd ed. 1994) and Remington's Pharmaceutical Sciences, 18th ed ^2. Mack Printing Company, 1990.
[0179] In particular modalities, the composition with restored entourage effects can be present in the formulation in a concentration of at least 0.1% in w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; or at least 95% w / v or w / w of the oral formulation.
[0180] In particular modalities, 10 g of the composition can be used in 150 ml of water. This can generate an effective composition concentration between 1 and 99% in (w / w), between 2 and 80% in (w / w), and between 5 and 50% in (w / w) in the formulation.
[0181] Formulations can be prepared to meet sterility, pyrogenicity, general safety and purity standards, as required by the F.D.A. U.S. and / or other relevant foreign regulatory agencies.
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45/75 [0182] Oral formulations can be individually wrapped or packaged as multiple units in one or more packages, cans, flasks, blister packs or bottles of any size. Doses are sized to provide therapeutically effective amounts.
[0183] Particular modalities use one or more molecules derived from plants (for example, a cannabinoid) with low solubility, or very low solubility. In particular embodiments, low solubility can refer to less than 0.2 mg / ml solubility in water or an aqueous solution, or less than 0.1 mg / ml solubility in water or an aqueous solution. Particular modalities use plant-derived molecules that are essentially insoluble in water. In particular modalities, water solubility is defined as low to insoluble by the United States Pharmacopoeia (USP 32) according to the amount of water required for the dissolution of a part of the solute: Low solubility: 100 to 1000 parts of water needed to dissolve a part of solute; very low solubility: 1000 to 10,000 parts of water required; essentially insoluble in water, more than 10,000 parts of water needed. At a basic pH, however, SNAC and other modified amino acids and FA-aas described in this document are water soluble. Accordingly, the management benefits, as described in this document, could not be reasonably anticipated and are unexpected.
[0184] Methods to Provide Physiological Effects Delivering Fast-acting Formulations with Restored Entourage Effects. Formulations disclosed in this document can be used to treat individuals (humans, animals (dogs, cats, reptiles, birds, etc.), livestock (horses, cattle, goats, pigs, chickens, etc.), and animals for research ( monkeys, rats, mice, fish, etc.)). Treatment of individuals includes providing effective amounts. Effective amounts include prophylactic treatments, therapeutic treatments and / or effective amounts.
[0185] An effective amount ”is the amount of a formulation needed to result in a desired physiological change in an individual. Effective amounts are often administered for recreational or research purposes. Effective amounts of research disclosed in this document
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46/75 can reduce pain perception in an animal model (neuropathic pain, acute pain, visceral pain), stimulate appetite in an animal model, reduce seizures (eg, epileptic seizures) in an animal model, reverse bone loss in an animal model, relieve migraine (cranial blood vessel vasoconstriction) in an animal model, treating addiction in an animal model, reducing anxiety in an animal model and / or reducing asthma symptoms in an animal model. Effective recreational amounts can be used to elicit a desired physiological change that is not intended to provide medicinal or nutritional value.
[0186] A prophylactic treatment includes treatment given to an individual who does not show signs or symptoms of a disease or nutritional deficiency, or shows only early signs or symptoms of a disease or nutritional deficiency, so that treatment is administered for the purposes to decrease, prevent or decrease the risk of further developing the disease or nutritional deficiency. Thus, a prophylactic treatment works as a preventive treatment against the development of diseases or nutritional deficiencies.
[0187] As an example of prophylactic treatment, a formulation disclosed in this document can be administered to an individual who is at risk of developing a migraine. An effective prophylactic treatment against a migraine occurs when the number of migraines experienced per month by an individual is reduced by at least 10% or in particular modalities, by 25%.
[0188] As another example of prophylactic treatment, a formulation disclosed in this document can be administered to an individual who is at risk of having an epileptic seizure. An effective prophylactic treatment against epileptic seizures occurs when the number of seizures per month is reduced by at least 10% or in particular modalities, by 25%.
[0189] As another example of prophylactic treatment, a formulation disclosed in this document can be administered to an individual who is at risk of suffering from neuropathic pain. An effective prophylactic treatment against neuropathic pain occurs when the occurrence of neuropathic pain is reduced by at least 10%, or in particular modalities, by 25%, as measured by a subjective or objective pain assessment.
[0190] As another example of prophylactic treatment, a formulation
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47/75 disclosed in this document can be administered to an individual who is at risk of developing incidental pain. An effective prophylactic treatment against incidental pain occurs when the incidence of incidental pain is reduced by 10%, and in particular modalities, by 25% by a subjective or objective pain assessment.
[0191] As another example of prophylactic treatment, a formulation disclosed in this document can be administered to an individual who is at risk of developing chemotherapy-induced nausea and vomiting (CINV). An effective prophylactic treatment against CINV occurs when CINV is reduced by 10%, and in particular modalities, by 25%, as measured by a subjective or objective CINV assessment.
[0192] As an example of prophylactic treatment of a nutritional deficiency, a formulation disclosed in this document can be administered to an individual who is at risk of developing rickets from insufficient vitamin C, anemia from insufficient dietary iron, and / or bone loss from insufficient calcium. An effective prophylactic treatment of these conditions occurs when the conditions are avoided or delayed due to nutritional supplementation with an oral formulation disclosed in this document.
[0193] A therapeutic treatment includes treatment administered to an individual who has a nutritional disease or deficiency and is administered to the individual for the purpose of curing or reducing the severity of the disease or nutritional deficiency.
[0194] As an example of a therapeutic treatment, a formulation disclosed in this document can be administered to an individual who has a migraine. An effective therapeutic treatment of migraine occurs when the severity of the migraine is reduced or completely relieved and / or the migraine resolves more quickly, as measured by a subjective or objective migraine assessment.
[0195] Another example of a therapeutic treatment includes administration of a formulation disclosed in this document to an individual who feels CINV. A therapeutic treatment against CINV occurs when vomiting is reduced or
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48/75 ceases (or ceases more quickly) and nausea is relieved as measured by a subjective or objective CINV assessment.
[0196] Another example of a therapeutic treatment, includes administration of a formulation disclosed to an individual who has osteoporosis. An effective therapeutic treatment against osteoporosis occurs when bone density has increased by 10% and in particular modalities, by 25%.
[0197] Another example of a therapeutic treatment includes administering a formulation disclosed in this document to an individual who has anxiety. An effective therapeutic treatment against anxiety occurs when the severity of anxiety is reduced or alleviated completely and / or more quickly as measured by a subjective or objective anxiety assessment.
[0198] Another example of a therapeutic treatment includes administering a formulation disclosed herein to an individual who has multiple sclerosis. An effective therapeutic treatment against multiple sclerosis occurs when the score on a standard walking test improves by 10% and in particular modalities, by 25%.
[0199] As an example of a therapeutic treatment against nutritional deficiency, a formulation disclosed in this document can be administered to an individual who has rickets from insufficient vitamin C, anemia from insufficient dietary iron and / or bone loss to from insufficient calcium. An effective therapeutic treatment against these conditions occurs when the conditions are reduced or resolved due to nutritional supplementation with a formulation disclosed in this document.
[0200] Therapeutic treatments can be distinguished from effective amounts based on the presence or absence of a research component for administration. As will be understood by a person of ordinary skill in the art, however, in human clinical trials, effective amounts, prophylactic treatments and therapeutic treatments may overlap.
[0201] For administration, therapeutically effective amounts (also referred to in this document as doses) can be initially estimated based on the results of in vitro tests and / or animal model studies. Such
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49/75 information can be used to more accurately determine useful doses in individuals of interest.
[0202] The amount of actual dose administered to a particular individual can be determined by the individual, a doctor, veterinarian or researcher who takes into account parameters, such as physical, physiological and psychological factors that include target, body weight, condition, therapeutic interventions previous or simultaneous and / or idiopathy of the individual.
[0203] Useful doses can be in the range of 0.1 to 5 pg / kg or 0.5 to 1 pg / kg. In other examples without limitation, a dose may include 1 pg / kg, 5 pg / kg, 10 pg / kg, 15 pg / kg, 20 pg / kg, 25 pg / kg, 30 pg / kg, 35 pg / kg, 40 pg / kg, 45 pg / kg, 50 pg / kg, 55 pg / kg, 60 pg / kg, 65 pg / kg, 70 pg / kg, 75 pg / kg, 80 pg / kg, 85 pg / kg, 90 pg / kg, 95 pg / kg, 100 pg / kg, 150 pg / kg, 200 pg / kg, 250 pg / kg, 350 pg / kg, 400 pg / kg, 450 pg / kg, 500 pg / kg, 550 pg / kg, 600 pg / kg, 650 pg / kg, 700 pg / kg, 750 pg / kg, 800 pg / kg, 850 pg / kg, 900 pg / kg, 950 pg / kg, 1000 pg / kg, 0.1 to 5 mg / kg or 0.5 to 1 mg / kg. In other examples without limitation, a dose may include 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 150 mg / kg, 200 mg / kg, 250 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, 500 mg / kg, 550 mg / kg, 600 mg / kg, 650 mg / kg, 700 mg / kg, 750 mg / kg, 800 mg / kg, 850 mg / kg, 900 mg / kg, 950 mg / kg, 1000 mg / kg or more.
[0204] In particular embodiments, useful doses include weight of an active ingredient (for example, a primary cannabinoid or an entourage restoration molecule) per body weight of an individual. In particular embodiments, useful doses can be in the range of 0.1 mg / kg to 100 mg / kg or 0.5 mg / kg to 50 mg / kg. In particular embodiments, useful doses include 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or more than one active ingredient by an individual's body weight.
[0205] In particular modalities, useful doses include carrier weight (for example, SNAC) per body weight of an individual. In particular embodiments, useful doses can be in the range of 0.1 mg / kg to 100 mg / kg or 0.5 mg / kg to 50 mg / kg. In particular embodiments, useful doses include 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40
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50/75 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, or more of carrier by an individual's body weight.
[0206] In particular modalities, the total dose volume can be in the range of 0.25 ml to 30 ml or from 0.5 ml to 20 ml. In particular embodiments, a total dose volume can include 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml , 0.9 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, ml, 25 ml, 26 ml, 27 ml, 28 ml, 29 ml, 30 ml or more.
[0207] Dose concentration can be expressed as weight of an active ingredient per dose volume (for example, mg of active pharmaceutical ingredient (API) / ml). In particular embodiments, the dose concentration can be in the range of 1 mg / ml to 100 mg / ml or from 5 mg / ml to 50 mg / ml. In particular embodiments, a dose concentration can include 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, mg / ml, 90 mg / ml, 95 mg / ml , 100 mg / ml or more.
[0208] Dose concentration can be expressed as carrier weight (eg SNAC) per dose volume (eg SNAC mg / ml). In particular embodiments, the dose concentration can be in the range of 1 mg / ml to 500 mg / ml or from 50 mg / ml to 300 mg / ml. In particular embodiments, a dose concentration can include 1 mg / ml, 5 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 85 mg / ml, 90 mg / ml, 95 mg / ml, 100 mg / ml, 125 mg / ml, 150 mg / ml, 175 mg / ml, 200 mg / ml, 225 mg / ml, 250 mg / ml, 275 mg / ml, 300 mg / ml, 325 mg / ml, 350 mg / ml, 375 mg / ml, 400 mg / ml, 425 mg / ml, 450 mg / ml, 475 mg / ml, 500 mg / ml or more.
[0209] In particular modalities, the carrier to active ingredient ratio (w / w) can be in the range from 1: 1 to 100: 1 or from 1: 1 to 20: 1. In particular modalities, the ratio may include 1: 1.2: 1.3: 1.4: 1, 5: 1.6: 1.7: 1.8: 1.9: 1, 10: 1, 11: 1,
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51/75
12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1,20: 1,25: 1,30: 1,35: 1,40: 1.45: 1.50: 1, 55: 1.60: 1, 65: 1.70: 1.75: 1, 80: 1.85: 1.90: 1, 95: 1, 100: 1 or more. In particular modalities, the ratio can be 10: 1.
[0210] In particular modalities, the carrier to primary cannabinoid ratio (w / w) can be in the range 1: 1 to 100: 1 or 1: 1 to 20: 1. In particular modalities, the ratio can include 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1 , 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1,20: 1,25: 1,30: 1,35: 1,40: 1,45: 1, 50 : 1, 55: 1, 60: 1, 65: 1, 70: 1, 75: 1, 80: 1, 85: 1, 90: 1, 95: 1, 100: 1 or more. In particular modalities, the ratio can be 10: 1. In particular embodiments, a carrier-to-primary cannabinoid (w / w) ratio between 1: 1 and 100: 1 can provide an administration benefit. In particular embodiments, a carrier-to-primary cannabinoid (w / w) ratio between 1: 1 and 20: 1 can provide an administration benefit.
[0211] In particular modalities, the ratio of primary cannabinoid to entourage restoration molecule can be in the range of 1000: 1 to 0.1: 1. In particular embodiments, the ratio of primary cannabinoid to entourage restoration molecule can be 1000: 1,500: 1,200: 1, 100: 1,50: 1,20: 0, 10: 1, 1: 1, 0,2: 1 or 0.1: 1.
[0212] Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (for example, hourly, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 9 hours, every 12 hours, every 18 hours, daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks or monthly).
[0213] One or more formulations can be administered simultaneously or within a selected period of time, such as within periods of 10 minutes, 1 hour, 3 hours, 10 hours, 15 hours, 24 hours or 48 hours or when the complementary formulation is given within a clinically relevant therapeutic period.
[0214] The Exemplary Modalities and Examples below are included to demonstrate particular modalities of disclosure. Those of skill
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52/75 common in the art must recognize, in the light of this disclosure, that several changes can be made in the specific modalities disclosed in this document and a similar or similar result is obtained without departing from the spirit and scope of the disclosure.
[0215] Exemplary modalities:
[0216] 1. A fast acting oral formulation that includes [0217] (i) one or more of THC, CBD and / or analogs thereof, [0218] (ii) one or more entourage restoration molecules and [0219 ] (iii) a carrier, [0220] in which THC, CBD and / or analogues thereof and one or more entourage restoration molecules are supplied in ratios that mimic their natural ratios within a cannabis strain.
[0221] 2. The oral formulation of rapid action, according to the modality
1, which includes THC and CBD.
[0222] 3. The oral formulation of rapid action, according to the modality
2, where the THC: CBD ratio can be from 0.01 to 100: 1.
[0223] 4. The fast acting oral formulation, according to any of modalities 1 to 3, in which the entourage restoration molecules are selected from one or more of the additional cannabinoids, terpenes, flavonoids and volatile substances that add flavor and aroma.
[0224] 5. The rapid acting oral formulation, according to modality 4, in which additional cannabinoids are selected from one or more of A8-tetrahydrocannabinol (Δδ-THC), Δ11-tetrahydrocannabinol ( A11-THC), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabicevarina (CBCV) ), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabinic acid (THCVA).
[0225] 6. The fast acting oral formulation, according to any of the modalities 4 or 5, in which the terpenes are selected from one or more among β-mycrene, a-pinene, β-pinene, linalool, d-limonene, β-karyophylene, oxide
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53/75 of karyophyllene, nerolidol, phytol, ocimene, terpinolene, terpinene, humulene, carene, bisabolol, valencene, elemene, farnesene, menthol, geraniol, guaiol, camphene, camphor, eucalyptol, pulegone, sabinene efeladrene.
[0226] 7. The fast acting oral formulation, according to any of the modalities 4 to 6, in which the flavonoids are selected from one or more among canaflavin A, canaflavin B, canaflavin C, vitexin, isovitexine, apigenin , kaempferol, quercetin, luteolin, cinnamaldehyde and orientin.
[0227] 8. The fast acting oral formulation, according to any of the modalities 4 to 7, in which the molecules that give flavor and aroma are selected from one or more among 2-heptanone, methyl heptanoate, salicylate methyl, methyl anthranylate and hexanal.
[0228] 9. The fast acting oral formulation, according to any of modalities 1 to 8, in which one or more entourage restoration molecules are each present in the formulation in a ratio of 0.1 to 100 : 1 of entourage restoration molecule: THC and / or CBD.
[0229] 10. The fast acting oral formulation, according to any of modalities 1 to 9, in which the carrier includes a fatty amino acid acylated with N or a salt thereof.
[0230] 11. The fast acting oral formulation, according to modality 10, in which the N-acylated fatty acid includes one or more of Compounds I to XXXV (Figure 2) or Compounds a to r (Figure 3).
[0231] 12. The fast acting oral formulation, according to modality 10, in which the N-acylated fatty acid is selected from monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicylyl-8- aminocaprilat and N- (salicyloyl) -8-aminocaprylic acid.
[0232] 13. The fast acting formulation, according to modality 10, in which the fatty amino acid acylated with N or a salt thereof includes
[0233] where X and Z are independently H, a monovalent cation, a
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54/75 divalent metal cation or an organic cation.
[0234] 14. The fast acting formulation, according to modality 13, where X is H.
[0235] 15. The fast acting formulation, according to modality 13, where X is a monovalent cation, such as sodium or potassium.
[0236] 16. The fast acting formulation, according to modality 13, where X is a metal cation, such as calcium or magnesium.
[0237] 17. The fast acting formulation, according to modality 13, where X is an organic cation, such as ammonia or tetramethylammonia.
[0238] 18. The fast acting formulation, according to any of the modalities 13 to 17, where Z is H.
[0239] 19. The fast acting formulation, according to any of the modalities 13 to 17, in which Z is a monovalent cation, such as sodium.
[0240] 20. The fast acting formulation, according to any of the modalities 13 to 17, in which Z is a divalent cation, such as calcium or magnesium.
[0241] 21. The fast acting formulation, according to modality 13, where X is H and Z is H.
[0242] 22. The fast acting formulation, according to modality 13, where X is H and Z is sodium.
[0243] 23. The fast acting formulation, according to modality 13, where X is sodium and Z is sodium.
[0244] 24. The fast acting formulation, according to any of the modalities 1 to 23, which additionally includes a surfactant, detergent, azone, pyrrolidone, glycol or bile salt.
[0245] 25. The fast acting formulation, according to any of modalities 1 to 24, in which the composition with restored entourage effects includes one or more plant extracts.
[0246] 26. The oral formulation, according to any of modalities 1 to 25, in which the oral formulation is swallowed or chewable.
[0247] 27. The oral formulation of rapid action, according to any of modalities 1 to 26, in which the oral formulation is liquid or solid.
[0248] 28. The oral formulation of rapid action, according to any one
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55/75 of modalities 1 to 27, in which the oral formulation is a solution, suspension, gel, juice, oil, paste, emulsion, tincture or spray.
[0249] 29. The oral formulation of rapid action, according to any of the modalities 1 to 28, in which the oral formulation is a tablet, capsule, edible product, pill, gelatin capsule, granule, gum or sachet.
[0250] 30. The oral formulation of rapid action, according to modalities 1 to 29, in which the formulation is savored.
[0251] 31. The oral formulation of rapid action, according to any of modalities 1 to 30, which includes an effective amount of the formulation.
[0252] 32. The oral formulation of rapid action, according to modality 31, in which the effective amount is a therapeutic amount, a prophylactic amount, an effective amount of research or a recreational effective amount.
[0253] 33. The oral formulation of rapid action, according to modality 31 or 32, in which the effective amount includes 0.1 mg to 100 mg of THC.
[0254] 34. The oral formulation of rapid action, according to any of the modalities 30 to 33, in which the effective amount includes 0.1 mg to 100 mg of CBD.
[0255] 35. The oral formulation of fast acting, according to any of the modalities 10 to 34, in which the fatty amino acid acylated with N is in a dose of 100 to 200 mg.
[0256] 36. The oral formulation of rapid action, according to any of the modalities 10 to 35, in which the fatty amino acid acylated with N or its salt is in a dose concentration of 100 mg / ml to 300 mg / ml .
[0257] 37. The oral formulation of rapid action, according to any of the modalities 10 to 36, in which the fatty amino acid acylated with N or its salt is in a dose concentration of 250 mg / ml.
[0258] 38. The oral formulation of rapid action, according to any of the modalities 10 to 37, in which the fatty amino acid acylated with N or its salt is in a dose of one to one hundred times the dose of one or more cannabinoids .
[0259] 39. A nutritional supplement that includes a formulation, according to any of modalities 1 to 38, and i) a vitamin or a mineral, or ii)
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56/75 a vitamin and a mineral.
[0260] 40. The nutritional supplement, according to modality 39, in which the vitamin includes Vitamin A, Vitamin B1, Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E or Vitamin K.
[0261] 41. The nutritional supplement, according to modality 39 or 40, in which the mineral includes calcium, chromium, iodine, iron, magnesium, selenium or zinc.
[0262] 42. A method for preparing a composition that includes (i) THC and / or CBD and / or an analog thereof, and (ii) one or more entourage restoration molecules, wherein the method includes adding a absorption to the composition and where the composition has a faster onset of action than an equivalent composition without an absorption enhancer.
[0263] 43. The method, according to modality 42, in which the absorption intensifier is a fatty amino acid acylated with N or a salt thereof.
[0264] 44. The method, according to modality 43, in which the fatty amino acid acylated with N includes one or more of Compounds I to XXXV (Figure 2) or Compounds a to r (Figure 3).
[0265] 45. The method, according to modality 43, in which the N-acylated fatty acid is selected from monosodium-N-salicyloyl-8aminocaprilat, disodium-N-salicyloyl-8-aminocaprilate and N- ( salicyloyl) -8aminocapril.
[0266] 46. The method, according to modality 43, in which the N-acylated fatty acid or a salt thereof includes [0267] in which X and Z are independently H, a monovalent cation, a divalent metal cation or an organic cation.
[0268] 47. The method, according to modality 46, where X is H.
[0269] 48. The method, according to modality 46, in which X is a monovalent cation, such as sodium or potassium.
[0270] 49. The method, according to modality 46, where X is a cation
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57/75 of divalent metal, such as calcium or magnesium.
[0271] 50. The method, according to modality 46, in which X is an organic cation, such as ammonia or tetramethylammonia.
[0272] 51. The method, according to any of the modalities 46 to 50, where Z is H.
[0273] 52. The method, according to any of the modalities 46 to 50, in which Z is a monovalent cation, such as sodium or potassium.
[0274] 53. The method, according to any of the modalities 46 to 50, in which Z is a divalent cation, such as calcium or magnesium.
[0275] 54. The method, according to modality 46, where X is H and Z is H.
[0276] 55. The method, according to modality 46, where X is H and Z is sodium.
[0277] 56. The method, according to modality 46, where X is sodium and Z is sodium.
[0278] 57. A method for treating an individual who needs it includes administering a therapeutically effective amount of a formulation, according to any of modalities 1 to 38, to the individual, thus treating the individual who needs the same.
[0279] 58. The method, according to modality 57, wherein the therapeutically effective amount provides an effective amount, a prophylactic treatment and / or a therapeutic treatment.
[0280] 59. The method, according to modality 57 or 58, in which the N-acylated fatty acid provides an administration benefit.
[0281] 60. The method, according to any of the modalities 59, wherein the administration benefit is a dose dependent administration benefit.
[0282] 61. The method, according to modality 60, in which the benefit of dose-dependent administration is in a dose of 100 to 200 mg.
[0283] 62. The method, according to modality 60, in which the benefit of dose-dependent administration is in a dose concentration of 100 mg / ml to 300 mg / ml of fatty amino acid acylated with N or salt thereof.
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58/75 [0284] 63. The method, according to modality 60, in which the benefit of dose-dependent administration is in a dose concentration of 1 to 500 mg / ml of fatty amino acid acylated with N or salt thereof.
[0285] 64. The method, according to modality 63, in which the benefit of dose-dependent administration is in a dose concentration of 250 mg / ml of N-acylated fatty acid or salt thereof.
[0286] 65. The method, according to any of the modalities 60 to 64, in which the benefit of dose-dependent administration of the N-acylated fatty acid or its salt is in a dose of one to one hundred times the dose of one or more synthetic cannabinoids.
[0287] 66. A method for reducing or eliminating one or more symptoms of a disease or disorder in a human subject, [0288] wherein said method includes delivering a therapeutically effective amount of a formulation, according to any of the modalities 1 to 38, to the individual, in this way, one or more symptoms of the disease or disorder is reduced or eliminated, and [0289] in which said disease or disorder is acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, related anorexia AIDS, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ankylosis, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cys fibrosis depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, gastrointestinal disorders, glAUCOma, glioma, Graves' disease, heart disease, hepatitis, herpes, Huntington's disease, hypertension, impotence, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, injuries of the mucosa, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy,
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59/75 neuroinflammation, nicotine addiction, obesity, obsessive compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic syndrome, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual tension (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, dormant leg syndrome, schizophrenia, scleroderma, septic shock, shingles (herpes zoster), sickle cell disease, seizures , sleep apnea, sleep disorders, spinal injuries, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome or withdrawal syndrome.
[0290] Example 1. Dosage form of oral cannabinoid that provides improved bioavailability and shortened onset time.
[0291] Considering the capabilities of medical conditions that potentially benefit from cannabis therapy, a significant unmet need exists for a faster-acting product that provides improved bioavailability in an oral format. Current oral cannabis products include edible products and traditional pharmaceutical dosage forms that are challenged by low bioavailability and long-term onset. The present disclosure addresses the disadvantages of all oral cannabis products currently available to provide an improved onset time and improved bioavailability.
[0292] Orally administered cannabis / SNAC composition onset and duration of action. This study was designed to assess the usefulness of SNAC in allowing an oral form of rapid cannabis activity.
[0293] Selection of Participants. Six study participants were recruited to ingest cannabis compositions and record the beginning, duration and intensity of cannabis-induced euphoria and / or dysphoria. Study participants participated in two separate tests: 1) use of a control substance, which included liquid cannabis extract dissolved in aqueous ethanol and 2) use of a test substance, which included liquid cannabis extract dissolved in aqueous ethanol, as well like SNAC.
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60/75 [0294] Formulations. The selected cannabis concentrate is commercially available and was provided to participants in an ethanol solution. The concentrate contains 8 mg THC per dose. It was selected because it contains a high percentage of THC, which provides a notable effect on the euphoria ”reported by the user. Water-based ethanol was used as a solvent as it effectively dissolves cannabis extract, as well as SNAC.
[0295] Methods. For the control experiment, each participant mixed the cannabis concentrate with 15 ml (one tablespoon) of aqueous ethanol and immediately swallowed the mixture.
[0296] For the test experiment, each participant mixed the cannabis concentrate with a premixed solution of aqueous ethanol and 200 mg of SNAC, and immediately swallowed the dissolved mixture.
[0297] For both the control experiment and the test experiment, each participant recorded the time of dose administration, the time of onset of euphoria and / or dysphoria, and the level of euphoria and / or dysphagia observed at intervals of fifteen minutes for five hours after administering the cannabis dose. Euphoria and dysphoria were reported using a scale value, ranging from 1 to 10. Table 1 shows descriptions of levels of euphoria and dysphoria for each scale value.
Table 1: Scale Values for Reporting Euphoria and Dysphoria Scale Value description 0 No observed effect 1 a2 Light effect observed; possibly psychological 3a4 Definitive effect, however, mild 5a6 Substantial definitive effect 7a8 Strong effect 9a 10 Intense effect
[0298] Results. The results shown below are the average scale values obtained for all six participants (also shown in Figures 6A and 6B).
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Table 2: Control experiment (n = 6) Real time Start time “Euphoria” Observed “Dysphoria” Observed 12:00 PM 00:00 (0 to 10) (0 to 10) 12:15 PM 00:15 0.17 0.00 12:30 PM 00:30 0.50 0.00 12:45 PM 00:45 0.83 0.17 13:00 PM 01:00 1.33 0.17 13:15 PM 01:15 1.67 0.50 13:30 PM 1:30 1.83 0.67 13:45 PM 01:45 1.83 0.83 14:00 PM 02:00 2.00 0.50 14:15 PM 02:15 2.17 0.50 14:30 PM 2:30 1.83 0.33 14:45 PM 02:45 1.67 0.33 15:00 PM 03:00 2.17 0.33 15:15 PM 03:15 1.33 0.17 15:30 PM 3:30 1.17 0.00 15:45 PM 03:45 1.00 0.00 4:00 PM 4:00 am 1.00 0.00 16:15 PM 04:15 0.83 0.00 16:30 PM 4:30 0.67 0.00 16:45 PM 04:45 0.50 0.00 17:00 PM 05:00 0.17 0.00
Table 3: Test experiment (n = 6) Real time Start time "Euphoria"Observed "Dysphoria"Observed 12:00 PM 00:00 PM (0 to 10) (0 to 10) 12:03 PM 00:03 PM 3.83 0.67 12:15 PM 00:15 PM 3.83 0.67 12:30 PM 00:30 PM 4.67 0.83 12:45 PM 00:45 PM 4.33 0.50 13:00 PM 01:00 PM 4.33 0.50
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Table 3: Test experiment (n = 6) 13:15 PM 01:15 PM 3.67 0.67 13:30 PM 01:30 PM 2.00 0.17 13:45 PM 01:45 PM 1.83 0.17 14:00 PM 02:00 PM 1.83 0.00 14:15 PM 02:15 PM 1.67 0.00 14:30 PM 02:30 PM 1.83 0.00 14:45 PM 02:45 PM 1.50 0.00 15:00 PM 03:00 PM 1.33 0.17 15:15 PM 03:15 PM 1.33 0.17 15:30 PM 03:30 PM 1.50 1.00 15:45 PM 03:45 PM 1.33 0.00 4:00 PM 04:00 PM 0.50 0.00 16:15 PM 04:15 PM 0.17 0.00 16:30 PM 04:30 PM 0.17 0.00 16:45 PM 04:45 PM 0.00 0.00 17:00 PM 05:00 PM 0.00 0.00
[0299] Start: All six participants reported euphoria five minutes after ingesting the cannabis / SNAC formulation (Test), in which the start time is in the range of two to five minutes. On the other hand, the first point in the euphoria time reported by the participants after ingesting only the cannabis formulation (Control) was fifteen minutes after ingestion, in which the start time is in the range between fifteen minutes and one hour and fifteen minutes (see Figures 7A to 7F for individual participant results). Fifteen minutes after ingestion, the average reported euphoria scale value was 3.8 for the cannabis / SNAC formulation (Test). On the other hand, fifteen minutes after ingesting the cannabis-only formulation (Control), the average reported euphoria scale value was 0.17 (see Figures 6A to 6B for averages at each point in time).
[0300] Intensity: The mean peak euphoria scale value after ingesting the cannabis / SNAC formulation (Test) was 4.7, which occurred thirty minutes after ingestion. On the other hand, the mean euphoria scale value more
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63/75 elevated after ingesting the cannabis-only formulation (Control) was 2.2, which was at the time point of two hours and fifteen minutes (see Figures 6A and 6B). Therefore, ingestion of the cannabis / SNAC formulation resulted in a higher peak euphoria intensity, which occurred an average of one hour and forty-five minutes faster than the cannabis-only formulation was ingested. The observed dysphoria intensity was minimal for both the Test and the Control, with an average peak scale value of 0.83 for both experiments.
[0301] Duration: The results indicate that the addition of an absorption enhancer does not shorten the duration of cannabis action.
[0302] In short, adding an absorption enhancer, such as SNAC, to an oral cannabis dosage formulation provides faster onset of action and higher intensity of action at peak cannabis activity level. In addition, the absorption enhancer has no effect on the duration of action of cannabis, [0303] Example 2. Onset and duration of action of the cannabis / SNAC composition orally administered in a low dose of SNAC. This study was designed to assess the usefulness of SNAC in allowing an oral form of rapid cannabis action at a low dose of SNAC.
[0304] Selection of Participants. Three study participants were recruited to ingest cannabis compositions and record the onset, duration and intensity of cannabis-induced euphoria and / or dysphoria. Study participants participated in two separate tests: 1) use of a control substance, which included liquid cannabis extract dissolved in aqueous ethanol and 2) use of a test substance, which included liquid cannabis extract dissolved in aqueous ethanol, as well like SNAC.
[0305] Formulations. The selected cannabis concentrate is commercially available and was provided to participants in an ethanol solution. The concentrate contains 8 mg THC per dose. It was selected because it contains a high percentage of THC, which provides a notable effect on the euphoria ”reported by the user. Aqueous ethanol was used as a solvent as it effectively dissolves cannabis extract, as well as SNAC.
[0306] Methods. For the control experiment, each participant mixed
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64/75 the cannabis concentrate with 15 ml (one tablespoon) of aqueous ethanol and immediately swallowed the mixture.
[0307] For the test experiment, each participant mixed ο cannabis concentrate with a premixed solution of aqueous ethanol and 100 mg of SNAC, and immediately swallowed the dissolved mixture.
[0308] For both the control experiment and the test experiment, each participant recorded the time of dose administration, the time of onset of euphoria and / or dysphoria, and the level of euphoria and / or dysphagia observed at intervals of fifteen minutes for five hours after administering the cannabis dose. Euphoria and dysphoria were reported using a scale value, ranging from 1 to 10. Table 1 shows descriptions of levels of euphoria and dysphoria for each scale value.
[0309] Results. The results are combined with the data from Example 1 and are reported to all participants in Figure 8.
[0310] Start: All three participants reported euphoria five minutes after ingesting the cannabis / SNAC formulation (Test), in which the start time is in the range of two to five minutes. On the other hand, the first point in the euphoria time reported by the participants after ingesting the cannabis-only formulation (Control) was fifteen minutes after ingestion, in which the onset time is in the range between fifteen minutes and an hour and fifteen minutes. Fifteen minutes after ingestion, the average reported euphoria scale value was 3.0 for the cannabis / SNAC formulation (Test). On the other hand, fifteen minutes after ingesting the cannabis-only formulation (Control), the average reported euphoria scale value was 0.25.
[0311] Intensity: The mean peak euphoria scale value after ingesting the cannabis / SNAC formulation (Test) was 3.4, which occurred thirty minutes after ingestion. On the other hand, the highest mean euphoria scale value after ingesting the cannabis-only formulation (Control) was 2.2, which was at the two-hour and fifteen-minute time point. Compared to Example 1 where the dose of SNAC was 200 mg, participants in Example 2 took only 100 mg of SNAC in combination with the same amount of cannabis used in Example 1. This reduced amount of SNAC
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65/75 resulted in a reduced cannabis effect that demonstrates a clear dose response relationship between the observed cannabis effect (euphoria) and the SNAC dose. Consistent with Example 1, ingesting the cannabis / SNAC formulation resulted in a higher peak euphoria intensity, which occurred an average of one hour and forty-five minutes faster than the cannabis-only formulation was ingested.
[0312] Duration: The results indicate that the addition of an absorption enhancer does not shorten the duration of cannabis action.
[0313] In short, adding an absorption enhancer, such as SNAC, to an oral cannabis dosage formulation provides faster onset and higher intensity of action at peak cannabis activity level. In addition, the absorption enhancer has no effect on the duration of action of cannabis. The varying amount of SNAC produces a clear dose-response relationship between the observed cannabis effect (euphoria) and the SNAC dose.
[0314] Example 3. Inhalation group versus oral response (Figure 9). Comparison of the pharmacodynamic response to inhaled and oral cannabis measured as euphoria reported by individual. Both the oral and inhaled groups reported a similar effect from time to peak (15 to 30 minutes). This is very surprising since oral cannabis is traditionally characterized by a very slow time-to-peak effect (up to 4 hours).
[0315] Example 4. Summary of pharmacokinetic study (PK) in cannabis rat / oral SNAC. The study was designed to characterize the pharmacokinetic profile of cannabis extract that contains 56% THC / CBD in a 1: 1 ratio (by weight) with and without the excipient, SNAC, after a single oral gavage administration to rats. In this study, two doses of cannabis and SNAC and two cannabis ratios for SNAC were tested. The experimental design is shown in Table 4 below.
[0316] Table 4: Experimental project.
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Group No. Group designation Extract Dose Level ¹ (mg / kg) SNAC Dose Level (mg / k g) Dose Volume(ml / kg) Dose Concentration ² (mg API / ml) Dose Concentration ³ (mg SNAC / ml) Number of Males 1 Excipient Control 0 500 2 0 250 6 2 Cannabis Control 25 0 2 12.5 0 6 3 LowDose 25 250 2 12.5 125 6 4 Average dose 25 500 2 12.5 250 6 5 High dose 50 500 2 25 250 6
¹ Extract contains 54% by weight (27% THC + 27% CBD) with API (Active Pharmaceutical Ingredient).
² Dose of cannabis extract contains a mixture of THC: CBD in a ratio of 1: 1 by weight.
³ SNAC dose is 10 times (THC + CBD) the dose for groups 3 and 5 and 20 times for group 4.
[0317] Methods. Animals were dosed on Day 1 and a series of blood samples were collected over a period of 4 hours after the dose for pharmacokinetic evaluation. Animals were euthanized after the collection of their last blood sample.
[0318] Results. After a single oral administration of cannabis extract containing THC / CBD in a 1: 1 ratio in combination with the absorption enhancing excipient (SNAC) in 25 mg extract / kg and 250 mg SNAC / kg (Group 3 ), 25 mg extract / kg and 500 mg SNAC / kg (Group 4), or 50 mg extract / kg and 500 mg SNAC / kg (Group 5), mean maximum concentration Cmax was in the range of 31.7 at 159.3 ng / ml for CBD and from 111.5 to 546.17 ng / ml for THC. The time to reach the mean maximum plasma concentration (Tmax)
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67/75 was in the range of 0.25 to 1 hour after the dose for CBD and was reached in 1 hour after the dose for the low and medium dose groups and in 2 hours after the dose for the high dose group for THC . AUCo-Tiast was in the range of 13.17 to 382.14 h * ng / ml for CBD and from 170.64 to 1256.49 h * ng / ml for THC.
[0319] Regarding the tested dose range, Cmax and AUCo-Tiast, for THC were higher than for CBD. When administering the same dose of cannabis extract (THC / CBD) (total cannabinoid dose of 25 mg / kg; 12.5 mg / kg of THC / 12.5 mg / kg of CBD) with and without SNAC, for THC , a 1.4-fold increase in Cmax over cannabis alone was observed at SNAC doses of 250 or 500 mg / kg. AUC was 1.1 times higher in the 250 mg / kg SNAC group, however, lower in the 500 mg / kg SNAC group, compared to the cannabis group alone. For CBD, increases in Cmax of 2.9 times and 2.8 times over cannabis alone were observed at SNAC doses of 250 or 500 mg / kg. AUC was lower in both groups, compared to the cannabis group alone. Increasing both doses of cannabis and SNAC by 2 times to 500 mg / kg of SNAC and 50 mg / kg of cannabis extract (25 mg / kg of THC / 25 mg / kg of CBD) resulted in an increase of 14.2 CBD Cmax and a 6.9-fold increase in THC Cmax. AUCo-Tiast for CBD and THC, were increased 22.1 times and 6.3 times, respectively (Figure 10 and Figure 11). Regarding the tested dose range, Cmax and AUCo-Tiast for THC were higher than for CBD. When administering the same dose of cannabis extract (THC / CBD) in the presence of SNAC (250 mg / kg or 500 mg / kg), both THC and CBD Cmax were increased 1.4 times and 2.8 times, respectively, about the cannabis group alone. AUCo-Tiast were comparable. This observation suggests that a 10: 1 cannabis to SNAC ratio facilitates an increase in Cmax, however, increasing the ratio to 20: 1 does not provide additional benefit. Increasing both doses of cannabis and SNAC by 2 times resulted in increases in Cmax of THC and CBD of 6.9 times and 14.2 times, respectively, over the cannabis group alone. AUCo-Tiast for THC and CBD increased by 6.3 times and 22.1 times, respectively, over the cannabis group alone. This is a larger than expected increase based on the near-linear dose response observed for oral cannabis (Information for Health Care Providers - Cannabis and the Cannabinoids; Health Canada, February 2013). Above all, these data suggest that SNAC intensifies
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68/75 cannabis absorption when administered to rats through oral gavage.
[0320] Example 5. Start and duration of orally administered cannabis / NAC composition. This study was designed to evaluate the usefulness of the SNAC acid form, N- [8- (2-hydroxybenzoyl) amino] caprylic acid (NAC), in allowing an oral form of rapid cannabis action.
[0321] Study Participant. A study participant was recruited to ingest cannabis compositions and record the onset, duration and intensity of cannabis-induced euphoria and / or dysphoria. The study participant participated in two separate tests: 1) use of a control substance, which included cannabis concentrate oil in a mixture of herbal extract dissolved in aqueous ethanol, and 2) use of a test substance, which included the cannabis concentrate oil in a mixture of herbal extract dissolved in aqueous ethanol, as well as NAC.
[0322] Formulations. The selected cannabis concentrate oil is commercially available in a capsule and the contents of the capsule were supplied to the participant in an ethanol solution. One capsule contains 9 mg of CBD, 7.7 mg of THC, mix of herbal extract (Magnolia bark, Ashwagandha, Astragalus) and stearic acid (from vegetable oil), and the potency stated per capsule is: 9.0 mg CBD, 0.0 mg THCA and 7.6 mg THC. The formulation was selected because it provides a remarkable effect on euphoria ”reported by the user and the CBD content should mitigate the dysphoric effects if Test 2 delivers a very high dose of cannabinoids.
[0323] Methods. For the control experiment, the participant mixed the cannabis concentrate with 15 ml (one tablespoon) of aqueous ethanol and immediately swallowed the mixture.
[0324] For the test experiment, the participant mixed the cannabis concentrate with 15 ml of premixed aqueous ethanol solution and 100 mg of NAC, and immediately swallowed the dissolved mixture.
[0325] For both the control experiment and the test experiment, the participant recorded the time of dose administration, the time of onset of euphoria and / or dysphoria, and the level of euphoria and / or dysphoria observed at intervals of fifteen minutes for five hours after administering the dose of
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69/75 cannabis. Euphoria and dysphoria were reported using a scale value, ranging from 1 to 5. Table 5 shows descriptions of levels of euphoria and dysphoria for each scale value.
Table 5: Scale Values for Reporting Euphoria and Dysphoria Scale Value description 0 No observed effect 1 Light effect observed; possibly psychological 2 Definitive effect, however, mild 3 Substantial definitive effect 4 Strong effect 5 Intense effect
[0326] Results. The results shown below are scale values obtained for the participant in the control experiment (Table 6) and in the test experiment (Table 7). The values are plotted in Figure 12.
Table 6: Control experiment (n = 1) Real Time 11:13 AM Start Time 00:00 PM Observed “euphoria” (0a5) Observed “dysphoria” (0 to 5) 11:28 AM : 15 0 0 11:43 AM : 30 1 0 11:58 AM : 45 2 0 12:13 PM 01:00 PM 2 0 12:28 PM 01:15 PM 3 1 12:43 PM 01:30 PM 3 1 12:58 PM 01:45 PM 3 1 13:13 PM 02:00 PM 4 1 13:28 PM 02:15 PM 4 1 13:43 PM 02:30 PM 4 1 13:58 PM 02:45 PM 3 0 14:13 PM 03:00 PM 3 0 14:28 PM 03:15 PM 3 0 14:43 PM 03:30 PM 2 0
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Table 6: Control experiment (n = 1) 14:58 PM 03:45 PM 2 0 15:13 PM 04:00 PM 2 0 15:28 PM 04:15 PM 1 0 15:43 PM 04:30 PM 1 0 15:58 PM 04:45 PM 0 0 16:13 PM 05:00 PM 0 0
Table 7: Test experiment (n = 1) Real time11:20 AM Start time 00:00 PM “Euphoria” Observed(0 to 5) “Dysphoria” Observed(0 to 5) 11:24 AM : 04 1 0 11:26 AM : 06 2 0 11:35 AM : 15 3 1 11:50 AM : 30 4 0 12:05 PM : 45 4 0 12:20 PM 01:00 PM 4 0 12:35 PM 01:15 PM 4 0 12:50 PM 01:30 PM 3 0 13:05 PM 01:45 PM 3 0 13:20 PM 02:00 PM 3 0 13:35 PM 02:15 PM 2 0 13:50 PM 02:30 PM 2 0 14:05 PM 02:45 PM 2 0 14:20 PM 03:00 PM 1 0 14:35 PM 03:15 PM 1 0 14:50 PM 3: 30 * 0 0
'Experiment ended [0327] Start: The participant reported euphoria six minutes after ingesting the cannabis / NAC formulation (Test, Table 7 and Figure 12). On the other hand, the first point in euphoria reported by the participant after ingestion of the formulation
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71/75 of cannabis alone (Control, Table 6 and Figure 12) was forty five minutes after ingestion. Thirty minutes after ingestion, the participant reported strong euphoria (scale value 4) for the cannabis / NAC formulation. On the other hand, thirty minutes after ingesting the cannabis-only formulation, the participant observed only a mild effect that was possibly psychological (scale value 1).
[0328] Intensity: The peak euphoria scale value after ingesting both cannabis only (Control) and cannabis / NAC (Test) formulations was 4. However, the peak euphoria intensity was reached thirty minutes after ingestion with the cannabis / NAC formulation (Test), while the peak euphoric intensity was reached two hours after ingestion with the cannabis only formulation (Control). Therefore, ingesting the cannabis / NAC formulation resulted in a peak intensity of euphoria that occurred an hour and thirty minutes faster than when the cannabis-only formulation was ingested. The intensity of dysphoria observed was minimal for both the Test and the Control, although the participant observed more effects of mild dysphoria with the formulation only of cannabis (Control).
[0329] In short, NAC, the acid form of SNAC, behaves similarly to SNAC when included in an oral cannabinoid formulation, a cannabinoid / NAC formulation provides faster onset of action compared to a formulation only cannabinoid.
[0330] As will be understood by a person of ordinary skill in the art, each modality disclosed in this document may comprise, consist essentially of or consists of its particular element, stage, ingredient or component stated. Thus, the terms include or include must be interpreted to quote: understand, consist of or consist essentially of. As used herein, the transitional term comprises or includes means, however, without limitation, and allows the inclusion of elements, steps, ingredients or components not specified, even in larger quantities. The transition phrase that consists of excludes any unspecified element, step, ingredient or component. The transition phrase that essentially consists of limiting the scope of the modality to the specified elements, steps, ingredients or components and to those that do not
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72/75 materially affect the modality. As used herein, a material effect would cause a statistically significant reduction in an administration benefit when assessed on an animal model disclosed herein.
[0331] Unless otherwise stated, all numbers expressing quantities of ingredients, properties, such as molecular weight, reaction conditions, etc., used in the specification and in the claims should be understood as being modified in all situations by the term about. Consequently, unless otherwise indicated, the numerical parameters presented in the specification and in the appended claims are approximations that may vary, depending on the desired properties sought by the present invention. At least, and without trying to limit the application of the doctrine of equivalents to the scope of the claim, each numerical parameter should at least be interpreted in light of the number of significant digits presented and applying common rounding techniques. When more clarity is needed, the term about has the meaning reasonably assigned to it by a person skilled in the art when used in combination with a stated value or numerical range, that is, it denotes a little more or a little less than the value or stated range, within a range of ± 20% of the stated value; ± 19% of the stated value; ± 18% of the stated value; ± 17% of the stated value; ± 16% of the stated value; ± 15% of the stated value; ± 14% of the stated value; ± 13% of the stated value; ± 12% of the stated value; ± 11% of the stated value; ± 10% of the stated value; ± 9% of the stated value; ± 8% of the stated value; ± 7% of the stated value; ± 6% of the stated value; ± 5% of the stated value; ± 4% of the stated value; ± 3% of the stated value; ± 2% of the stated value; or ± 1% of the stated value.
[0332] Nevertheless, these numerical ranges and parameters that present the broad scope of the invention are approximations, the numerical values presented in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors that necessarily result from the standard deviation found in their respective test measurements.
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73/75 [0333] The terms one and one and “w / o and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be interpreted as covering both the singular and the plural, unless otherwise indicated otherwise in this document or clearly contradicted by the context. Quotation of ranges of values in this document is merely intended to serve as an abbreviated method for referring individually to each separate value that is within the range. Unless otherwise indicated in this document, each individual value is incorporated into the specification as if it were individually quoted in this document. All methods described in this document may be performed in any appropriate order unless otherwise indicated in this document or otherwise clearly contradicted by the context. The use of any and all examples, or example language (for example, such as) provided herein, is intended merely to better illuminate the invention and is not a limitation on the scope of the invention, unless otherwise stated. No language in the specification should be interpreted as an indication of any unclaimed element essential to the practice of the invention.
[0334] Groupings of alternative elements or modalities of the invention disclosed in this document should not be interpreted as limitations. Each group member can be named and claimed individually or in any combination with other group members or other elements found in this document. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any inclusion or deletion occurs, the specification should contain the group as modified, thus making a written description of all Markush groups used in the attached claims.
[0335] Certain embodiments of this invention are described herein, including the preferred embodiment, known to the inventors, for carrying out the invention. Obviously, variations in these described modalities will become apparent to those of ordinary skill in the technique after reading the previous description. The inventor expects specialists to employ such variations
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74/75 as appropriate, and the inventors want the invention to be practiced in a manner other than that specifically described in this document. Consequently, this invention includes all modifications and equivalents of the matter cited in the claims attached thereto, as permitted by applicable law. In addition, any combination of the elements described above in all possible variations thereof is encompassed by the invention unless otherwise indicated in this document or clearly contradicted by the context.
[0336] Additionally, several references were made to patent documents, printed publications, journalistic articles and other text written throughout this specification (materials cited in this document). Each of the materials cited is individually incorporated into this document as a reference in its entirety for its cited teaching.
[0337] Finally, it should be understood that the modalities of the invention disclosed in this document are illustrative of the principles of the present invention. Other modifications that can be employed are within the scope of the invention. Thus, by way of example, however, without limitation, alternative configurations of the present invention can be used in accordance with the teachings in this document. Consequently, the present invention is not limited to those precisely as shown and described.
[0338] The details shown in this document are by way of example and for illustrative purposes of the preferred modalities of the present invention only and are presented to provide what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the various modalities of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description obtained together with the drawings and / or examples becomes apparent to those skilled in the art such as the various forms of the invention can be incorporated into practice.
[0339] Definitions and explanations used in the present disclosure are intended and should be controls in any future elaboration, unless
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75/75 is clearly and unambiguously modified in the following examples or when the application of meaning generates any meaningless or essentially meaningless elaboration. In cases where the elaboration of the term would render the same meaningless or essentially meaningless, the definition must be obtained from the Webster dictionary, 3rd edition or a dictionary known to those of ordinary skill in the technique, such as the Oxford dictionary of biochemistry and molecular biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004).

权利要求:
Claims (73)
[1]
1. Oral formulation with rapid action characterized by the fact that it comprises:
(i) a cannabinoid comprising THC and / or CBD, (ii) an entourage restoration molecule and (iii) N- [8- (2-hydroxybenzoyl) amino] caprylate (SNAC), where the cannabinoid and entourage restoration molecule are in a ratio of 1000: 1, 500: 1,200: 1, 100: 1,50: 1,20: 0, 10: 1, 1: 1, 0.2: 1 or 0.1: 1 and where cannabinoid and SNAC are in a ratio between 1: 1 and 100: 1.
[2]
2. Rapid acting oral formulation, according to claim 1, characterized by the fact that it comprises THC and CBD.
[3]
3. Rapid acting oral formulation, according to claim 2, characterized by the fact that the THC: CBD ratio is between 0.01: 1 and 100: 1.
[4]
4. Rapid acting oral formulation, according to claim 1, characterized by the fact that the entourage restoration molecule is selected from: an additional cannabinoid, a terpene, a flavonoid and a volatile substance that imparts flavor and aroma .
[5]
5. Rapid acting oral formulation, according to claim 4, characterized by the fact that the additional cannabinoid is selected from: A8-tetrahydrocannabinol (A8-THC), Δ11-tetrahydrocannabinol (A11-THC) , cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicycline (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabycholine (CBCV), cannabycholine (CBCV) CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabinic acid (THCVA).
[6]
6. Rapid acting oral formulation, according to claim 4, characterized by the fact that the terpene is selected from: β-mycrene, apinene, β-pinene, linalool, d-limonene, β-karyophylene, oxide karyophyllene, nerolidol, phytol, ocimene, terpinolene, terpinene, humulene, carene, bisabolol, valencene, elemene, farnesene, menthol, geraniol, guaiol, camphene, camphor, eucalyptol, pulegone, sabinene and feladrene.
Petition 870190094775, of 09/23/2019, p. 85/117
2/9
[7]
7. Rapid acting oral formulation, according to claim 4, characterized by the fact that the flavonoid is selected from: canaflavin A, canaflavin B, canaflavin C, vitexin, isovitexine, apigenin, kaempferol, quercetin, luteolin, cinnamaldehyde and guides.
[8]
8. Rapid acting oral formulation, according to claim 4, characterized by the fact that the molecule that gives flavor and aroma is selected from: 2-heptanone, methyl heptanoate, methyl salicylate, methyl anthranylate and hexanal .
[9]
9. Oral formulation with rapid action characterized by the fact that it comprises:
(i) one or more of THC, CBD and / or analogues thereof, (ii) one or more entourage restoration molecules and (iii) a carrier, where THC, CBD and / or analogues thereof and one or more entourage restoration molecules are provided in ratios that mimic their natural ratios within a cannabis strain.
[10]
10. Rapid acting oral formulation, according to claim 9, characterized by the fact that it comprises THC and CBD.
[11]
11. Rapid acting oral formulation, according to claim 10, characterized by the fact that the THC: CBD ratio is between 0.01 to 100: 1
[12]
12. Rapid acting oral formulation, according to claim 9, characterized by the fact that entourage restoration molecules are selected from one or more of the additional cannabinoids, terpenes, flavonoids and volatile substances that impart flavor and aroma.
[13]
13. Rapid acting oral formulation according to claim 12, characterized by the fact that additional cannabinoids are selected from one or more of A8-tetrahydrocannabinol (A8-THC), A11-tetrahydrocannabinol (A11-THC ), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicycline (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabycholine (CBCV), cannabycholine (CBCV) ), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant
Petition 870190094775, of 09/23/2019, p. 86/117
3/9 (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabivarinic acid (THCVA).
[14]
14. Rapid acting oral formulation, according to claim 12, characterized by the fact that terpenes are selected from one or more of β-mycrene, a-pinene, β-pinene, linalool, d-limonene, β -cariophylene, caryophyllene oxide, nerolidol, phytol, ocimene, terpinolene, terpinene, humulene, carene, bisabolol, valencene, elemene, farnesene, menthol, geraniol, guaiol, camphene, camphor, eucalyptol, pulegone, efeladrene sabinene.
[15]
15. Rapid acting oral formulation, according to claim 12, characterized by the fact that the flavonoids are selected from one or more of canaflavin A, canaflavin B, canaflavin C, vitexin, isovitexine, apigenin, kaempferol, quercetin, luteolin, cinnamaldehyde and orientin.
[16]
16. Rapid acting oral formulation, according to claim 12, characterized by the fact that the molecules that impart flavor and aroma are selected from one or more of 2-heptanone, methyl heptanoate, methyl salicylate, anthranylate methyl and hexanal.
[17]
17. Rapidly acting oral formulation according to claim 9, characterized by the fact that one or more entourage restoration molecules are each present in the formulation in a ratio of 0.1 to 100: 1 of molecule of entourage restoration: THC and / or CBD.
[18]
18. Rapid acting oral formulation, according to claim 9, characterized by the fact that the carrier comprises a fatty amino acid acylated with N or a salt thereof.
[19]
19. Rapid acting oral formulation, according to claim 18, characterized by the fact that the N-acylated fatty acid comprises one or more of Compounds I to XXXV (Figure 2) or Compounds a to r (Figure 3).
[20]
20. Rapid acting oral formulation, according to claim 18, characterized by the fact that the N-acylated fatty acid is selected from monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8aminocaprylate and acid N- (salicyloyl) -8-aminocapryl.
[21]
21. Rapidly acting oral formulation, according to claim 18,
Petition 870190094775, of 09/23/2019, p. 87/117
4/9 characterized by the fact that the fatty amino acid acylated with N or a salt thereof comprises Ó;
where X and Z are independently H, a monovalent cation, a divalent metal cation or an organic cation.
[22]
22. Oral formulation with rapid action, according to claim 21, characterized by the fact that X is H.
[23]
23. Oral formulation with rapid action, according to claim 21, characterized by the fact that X is a monovalent cation comprising sodium or potassium.
[24]
24. Rapidly acting oral formulation according to claim 21, characterized by the fact that X is a divalent metal cation comprising calcium or magnesium.
[25]
25. Oral formulation with rapid action, according to claim 21, characterized by the fact that X is an organic cation that comprises ammonia or tetramethylammonia.
[26]
26. Rapid acting oral formulation, according to claim 21, characterized by the fact that Z is H.
[27]
27. Oral formulation with rapid action, according to claim 21, characterized by the fact that Z is a monovalent cation comprising sodium or potassium.
[28]
28. Oral formulation with rapid action, according to claim 21, characterized by the fact that Z is a divalent cation that comprises calcium or magnesium.
[29]
29. Oral formulation with rapid action, according to claim 21, characterized by the fact that X is H and Z is H.
[30]
30. Oral formulation with rapid action, according to claim 21, characterized by the fact that X is H and Z is sodium.
[31]
31. Oral formulation of rapid action, according to claim 21,
Petition 870190094775, of 09/23/2019, p. 88/117
5/9 characterized by the fact that X is sodium and Z is sodium.
[32]
32. Rapid acting oral formulation, according to claim 18, characterized by the fact that the N-acylated fatty acid is in a dose of 100 to 200 mg.
[33]
33. Rapid acting oral formulation according to claim 18, characterized by the fact that the fatty amino acid acylated with N or its salt is in a dose concentration of 100 mg / ml to 300 mg / ml.
[34]
34. Rapid acting oral formulation according to claim 18, characterized by the fact that the fatty amino acid acylated with N or its salt is in a dose concentration of 250 mg / ml.
[35]
35. Rapid acting oral formulation, according to claim 18, characterized by the fact that the fatty amino acid acylated with N or its salt is in a dose of one to one hundred times the dose of one or more cannabinoids.
[36]
36. Oral formulation with rapid action, according to claim 9, characterized by the fact that it additionally comprises a surfactant, detergent, azone, pyrrolidone, glycol or bile salt.
[37]
37. Rapidly acting oral formulation according to claim 9, characterized by the fact that the formulation comprises one or more plant extracts.
[38]
38. Oral formulation with rapid action, according to claim 9, characterized by the fact that the formulation is swallowed or chewable.
[39]
39. Rapid acting oral formulation, according to claim 9, characterized by the fact that the formulation is liquid or solid.
[40]
40. Rapid acting oral formulation, according to claim 9, characterized by the fact that the formulation is a solution, suspension, gel, juice, oil, paste, emulsion, tincture or spray.
[41]
41. Rapid acting oral formulation, according to claim 9, characterized by the fact that the formulation is a tablet, capsule, edible product, pill, gelatin capsule, granule, gum or sachet.
[42]
42. Rapid acting oral formulation, according to claim 9, characterized by the fact that the formulation is flavored.
[43]
43. Rapidly acting oral formulation, according to claim 9,
Petition 870190094775, of 09/23/2019, p. 89/117
6/9 characterized by the fact that it comprises an effective amount of the formulation.
[44]
44. Rapidly acting oral formulation according to claim 43, characterized by the fact that the effective amount is a therapeutic amount, a prophylactic amount, an effective amount of research or a recreational effective amount.
[45]
45. Rapid acting oral formulation according to claim 43, characterized by the fact that the effective amount comprises 0.1 mg to 100 mg THC.
[46]
46. Rapid acting oral formulation, according to claim 43, characterized by the fact that the effective amount comprises 0.1 mg to 100 mg of CBD.
[47]
47. Nutritional supplement characterized by the fact that it comprises a formulation according to claim 9, and i) a vitamin or a mineral, or ii) a vitamin and a mineral.
[48]
48. Nutritional supplement according to claim 47, characterized by the fact that the vitamin comprises Vitamin A, Vitamin B1, Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E or Vitamin K.
[49]
49. Nutritional supplement, according to claim 47, characterized by the fact that the mineral comprises calcium, chromium, iodine, iron, magnesium, selenium or zinc.
[50]
50. Method for preparing a composition comprising (i) THC and / or CBD and (ii) one or more entourage restoration molecules, characterized in that the method comprises adding an absorption enhancer to the composition and in which the composition it has a faster onset of action than an equivalent composition without an absorption enhancer.
[51]
51. Method according to claim 50, characterized by the fact that the absorption enhancer is a fatty amino acid acylated with N or a salt thereof.
[52]
52. Method according to claim 51, characterized by the fact that the N-acylated fatty acid is selected from monosodium-Nsalicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate and N (salicyloyl) acid -8-aminocaprylic.
Petition 870190094775, of 09/23/2019, p. 90/117
7/9
[53]
53. Method according to claim 51, characterized in that the fatty amino acid acylated with N or a salt thereof comprises in which X and Z are independently H, a monovalent cation, a divalent metal cation or an organic cation .
[54]
54. Method according to claim 53, characterized by the fact that X is H.
[55]
55. Method according to claim 53, characterized in that X is a monovalent cation comprising sodium or potassium.
[56]
56. Method according to claim 53, characterized in that X is a divalent metal cation comprising calcium or magnesium.
[57]
57. Method according to claim 53, characterized by the fact that X is an organic cation comprising ammonia or tetramethylammonia.
[58]
58. Method according to claim 53, characterized by the fact that Z is H.
[59]
59. Method according to claim 53, characterized in that Z is a monovalent cation comprising sodium or potassium.
[60]
60. Method according to claim 53, characterized in that Z is a divalent cation comprising calcium or magnesium.
[61]
61. Method according to claim 53, characterized by the fact that X is H and Z is H.
[62]
62. Method according to claim 53, characterized by the fact that X is H and Z is sodium.
[63]
63. Method according to claim 53, characterized by the fact that X is sodium and Z is sodium.
[64]
64. Method according to claim 53, characterized by the fact that the N-acylated fatty acid provides an administration benefit.
[65]
65. Method according to claim 53, characterized by the fact that the administration benefit is an administration-dependent benefit
Petition 870190094775, of 09/23/2019, p. 91/117
8/9 dose.
[66]
66. Method according to claim 65, characterized in that the benefit of dose-dependent administration is in a dose of 100 to 200 mg.
[67]
67. Method according to claim 65, characterized in that the benefit of dose-dependent administration is in a dose concentration of 100 mg / ml to 300 mg / ml of N-acylated fatty acid or salt thereof.
[68]
68. Method according to claim 65, characterized in that the benefit of dose-dependent administration is in a dose concentration of 1 to 500 mg / ml of N-acylated fatty acid or salt thereof.
[69]
69. Method according to claim 68, characterized in that the benefit of dose-dependent administration is in a dose concentration of 250 mg / ml of N-acylated fatty acid or salt thereof.
[70]
70. Method according to claim 65, characterized in that the benefit of dose-dependent administration of the N-acylated fatty acid or salt thereof is in a dose of one to one hundred times the dose of one or more synthetic cannabinoids.
[71]
71. Method for treating an individual who needs it characterized by the fact that it comprises administering a therapeutically effective amount of a formulation, according to claim 9, to the individual, thus treating the individual who needs it.
[72]
72. Method according to claim 71, characterized in that the therapeutically effective amount provides an effective amount, a prophylactic treatment and / or a therapeutic treatment.
[73]
73. Method for reducing or eliminating one or more symptoms of a disease or disorder in a human subject, characterized in that said method comprises delivering a therapeutically effective amount of a formulation, according to claim 9, to the subject in this way , reduces or eliminates one or more symptoms of the disease or disorder, and in which said disease or disorder is acquired hypothyroidism, gastritis
Petition 870190094775, of 09/23/2019, p. 92/117
Acute 9/9, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ankylosis, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, gastrointestinal disorders, glAUCOma, glioma, Graves' disease, heart disease, hepatitis, herpes , Huntington's disease, hypertension, impotence, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, dys metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic syndrome, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual tension (PMS), proximal myotonic myopathy, posttraumatic stress disorder (PTSD), psoriasis, Raynaud's disease, dormant leg syndrome, schizophrenia, scleroderma, septic shock, shingles (herpes zoster), sickle cell disease, seizures, sleep apnea, sleep disorders, spinal injuries, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome or withdrawal syndrome.

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法律状态:
2021-07-06| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|

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2021-09-21| B11Y| Definitive dismissal - extension of time limit for request of examination expired [chapter 11.1.1 patent gazette]|

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2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762475763P| true| 2017-03-23|2017-03-23|

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PCT/US2018/024188|WO2018175992A1|2017-03-23|2018-03-23|Rapid and controlled delivery of compositions with restored entourage effects|

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