Transdermal Delivery of Cannabidiol

Abstract

Transdermal drug delivery systems are provided that include cannabidiol or cannabidiol salts, alone or in combination, that can provide drug plasma concentrations at a predetermined rate for a predetermined period of time with a simplified treatment regimen by reducing the frequency of administration for the treatment and / or prevention of pain and / or inflammation.

Description

[Background technology]

[0001] Pain and inflammation are physiological responses of the body to tissue injury, infection, and genetic changes. These responses can be divided into two phases: acute and chronic. The acute phase is an initial, nonspecific phase and is characterized by local vasodilation, increased capillary permeability, accumulation of fluid and blood proteins in the interstitial space, migration of neutrophils from the capillaries, and release of inflammatory mediators. Pain is caused by all these inflammatory inducers, which also lead to hyperalgesia through activation of the corresponding receptors expressed by nonreceptive terminals. If the condition causing the injury is not resolved, the inflammatory process progresses towards subacute / chronic inflammation, which is characterized by immunopathological changes such as infiltration of inflammatory cells, overexpression of proinflammatory genes, dysregulation of cell signaling, and loss of barrier function. 1 .

[0002] Chronic pathological pain states, including neuropathic pain, are a major health problem worldwide because they can persist even after the cause of the pain has resolved and severely impact quality of life. 2 Unlike physiological pain, where tissue injury and inflammation induce reversible adaptive changes in the sensory nervous system resulting in protective sensitization, in neuropathic pain the changes in sensitivity become persistent or chronic. Furthermore, neuropathic pain involves damage to the peripheral nervous system of the central nervous system. It is characterized by pain in the absence of noxious stimuli and can be spontaneous in nature with a temporary character or can be triggered by sensory stimuli.

[0003] Arthritis is a classic example of chronic pain inflammation, as well as various other diseases and conditions such as cardiovascular and neurodegenerative diseases, diabetes, cancer, and asthma. Synthetic anti-inflammatory compounds are one of the common ways to control chronic inflammation and pain. These synthetic anti-inflammatory drug products have several common side effects, such as gastric inflammation and ulcer formation, renal and hepatic failure, hemolytic anemia, and asthma exacerbation. Increasing evidence indicates that the endocannabinoid system is actively involved in the pathophysiology of osteoarthritis-associated joint pain. Overall, preclinical and clinical data support the potentially effective anti-inflammatory properties of endocannabinoid agonists targeting CB2 (cannabinoid receptor 2) receptors. 3 .

[0004] Cannabis (marijuana) is a Schedule I drug in the United States. Cannabis is a flowering plant that contains over 400 phytonutrients (micronutrients). Over 100 terpenoids, essential oils, antioxidants, and cannabinoids have been extracted from cannabis. Of all these phytochemicals, only tetrahydrocambinol (THC) has shown significant psychoactive effects. Many research papers have been published on THC due to its psychoactive and therapeutic effects. Apart from THC, several other compounds have also been studied that show some therapeutic effects without psychoactive effects, such as cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), tetrahydrocambivarin (THCV), and delta 9-tetrahydrocambinol (delta 9 THC). Cannabis and its derivatives have been shown to be useful in the treatment of pain, antibacterials, type 2-related metabolic disorders, intraocular pressure reduction, Dravet syndrome, Lennox-Gastaut syndrome (LGS), epilepsy, nausea, pain, AIDS-related wasting diseases, arthritis and rheumatism, migraine headaches, muscle spasms associated with multiple sclerosis and paralysis, alcohol and narcotic withdrawal symptoms, stress and depression, asthma, fibromyalgia, inflammatory pain, and chemotherapy-associated pain and / or inflammation, where they act as antibacterial agents. The FDA-approved Marinol and Syndros contain delta 9-THC, which are currently used to treat nausea, vomiting, and anorexia associated with chemotherapy treatments. Additionally, in April 2016, the FDA granted orphan drug designation to cannabidiol for the treatment of tuberous sclerosis complex (TSC), Dravet syndrome, and Lennox-Gastaut syndrome. Cannabidiol is an orally effective treatment for pain and inflammation. (Non-Patent Document 1).

[0005] Currently, 107 cannabinoids have been identified in Cannabis sativa. These compounds resemble the endocannabinoid group, which consists of long-chain polyunsaturated fatty acids. 4 There are two types of cannabinoid receptors: I) CB1 and II) CB2.

[0006] The endocannabinoid system is an important endogenous lipid signaling pathway and is composed of cannabinoid receptors, endogenous ligands for cannabinoid receptors (endocannabinoids), and enzymes that regulate endocannabinoid biosynthesis and inactivation. The lipid signaling system is involved in many important physiological functions in the central nervous system, peripheral nervous system, endocrine system, and immune system. These receptors belong to the family of guanosine-binding protein-coupled receptors, are widely expressed, and are distinguished by their specific functions, localization, and signaling mechanisms. 5,3 Cannabinoid receptor 1 (CB1) inhibits adenylate cyclase, decreasing cAMP levels and protein kinase A (PKA) activity, resulting in activation of A-type potassium channels and decreased cellular potassium levels. This receptor is found primarily in adipose tissue, gastrointestinal tract, spinal cord, adrenal glands, thyroid, liver, reproductive organs, and immune cells. 6 .

[0007] Cannabidiol (CBD), the major non-psychoactive plant cannabinoid, has little affinity for CB1 and CB2 and acts as a partial antagonist of CB1 and a weak inverse agonist of CB2. 7 .

[0008] Selective CB2 agonists have shown considerable efficacy in various preclinical models of neuropathic pain. Meanwhile, a growing body of evidence from clinical studies confirms the potential of the cannabinoid system to benefit patients with chronic pain and chronic inflammatory diseases (arthritis). Currently, the most frequent users of therapeutic cannabis products are patients with chronic arthritis and musculoskeletal pain. 8 .

[0009] Preclinical studies have shown that cannabinoid receptor agonists block pain and reduce inflammation in a variety of acute and chronic pain models. 9~11Both CB1 and CB2 receptor agonists, whether used alone or in combination, exhibit antinociceptive effects. CB2 activity is thought to affect microglial cells, thereby reducing neuroinflammatory mechanisms. 12,13 CB2 receptors are thought to be particularly important in central pain circuits because agonist activity induces dopamine release in midbrain regions, contributing to the control of descending pain and the placebo effect. 14 Inflammatory effects may be modulated by upregulation of cannabinoid receptor activity or increased production of endocannabinoids may result in reduced joint destruction in preclinical models of inflammatory arthritis that mimic human rheumatoid arthritis. 8,10 Similarly, CB1 and CB2 receptors, proteins, and endocannabinoids are found in human synovial tissue from patients with both rheumatoid arthritis and osteoarthritis. 15 .

[0010] Using a complete Freund's adjuvant-induced monoarthritis knee joint model, transdermal CBD delivery demonstrated therapeutic potential in alleviating arthritis pain-related behaviors, exerting anti-inflammatory effects without obvious psychoactive effects. Results also showed that a dose of 6.2 mg / day reduced knee joint swelling, with an increase to a dose of 62 mg / day not providing further improvement. 16 .

[0011] Many orally administered drugs irritate the gastrointestinal mucosa, and many drugs, including CBD, are subject to extensive "first-pass" inactivation by the liver. The compositions and methods of the present disclosure aim to deliver drugs directly to the systemic circulation via application to the skin, thus overcoming these problems by avoiding hepatic metabolism of the active agent after absorption, and also by avoiding gastrointestinal irritation.

[0012] These side effects associated with oral anti-inflammatory drugs can be avoided by using the transdermal route.Furthermore, transdermal dosage forms provide a constant delivery of drug molecules at a defined dosage rate, avoiding the peaks and valleys in plasma concentrations that accompany oral administration.

[0013] Many patents have been obtained regarding cannabidiol, but the usefulness of these patents has not been evaluated. One example is Patent Document 1. Patent Document 1 describes several examples, but there is no in vitro or in vivo data for these examples. Due to the lack of these data, they lack practicality.

[0014] US Patent No. 5,999,633 provides examples of reservoir and adhesive matrix patches. All of these examples contain a mixture of cannabinoids (such as delta-8-THC, delta-9-THC, cannabidiol, and cannabinol) rather than cannabidiol alone. THC is a psychoactive and addictive substance, limiting its usefulness.

[0015] There is a need for an improved drug delivery system for cannabidiol that can overcome the shortcomings associated with the oral route. Transdermal delivery of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrugs, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, can address the challenges associated with oral drug delivery. The present disclosure addresses all the above shortcomings and provides a patent with real-world utility. Additionally, the present disclosure provides for the use of synthetic versions of cannabidiol that are produced in a more controlled environment than plant sources of cannabidiol. Additionally, synthetic versions of cannabidiol can provide higher permeability compared to impure versions. Additionally, the present disclosure is directed to transdermal matrix patches that can deliver synthetic cannabidiol for, for example, 1 day, and / or 2 days, and / or 3 days, and / or 4 days, and / or 5 days, and / or 6 days, and / or 7 days, and / or up to 15 days.

[0016] All references cited herein are incorporated by reference in their entirety. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] U.S. Pat. No. 9,375,417 [Patent Document 2] U.S. Patent No. 6,328,992 [Non-patent literature]

[0018] [Non-Patent Document 1] Costa, B. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. European Journal of Pharmacology. Volume 556, Issue 1-3, February 5, 2007, Pages 75-83 Summary of the Invention

[0019] In transdermal drug delivery, transdermal patch or transdermal composition is applied topically to the skin surface.During the topical application period of transdermal patch or transdermal composition, drug is continuously released and delivered through intact skin (via transcellular, intercellular and transappendage pathways) to achieve systemic effect.Therefore, once applied, transdermal composition or transdermal patch can deliver drug to systemic circulation all day, or for more than a day depending on the application period, possibly up to a week.

[0020] Transdermal delivery can reduce the frequency of administration of cannabidiol, its free base, its salt, its isomer, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination. Through transdermal delivery, transdermal compositions or transdermal formulations or transdermal patches of cannabidiol, its free base, its salt, its isomer, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination, can be applied topically to the skin, thereby delivering the drug throughout the period of topical application. Depending on the need, the period of topical application can be once a day, once every two days, once every three days, once every four days, once every five days, once a week. Thus, transdermal delivery can overcome the multiple dose schedule of oral delivery by reducing the frequency of administration.

[0021] Furthermore, with transdermal drug delivery, the drug is delivered slowly and continuously throughout the topical application period, eliminating the peaks and valleys in drug plasma concentrations associated with multiple daily doses. Thus, transdermal delivery of cannabidiol, its free base, its salts, its isomers, its amorphous forms, its crystalline forms, its co-crystalline forms, its prodrugs, its analogs, its derivatives, its synthetic forms, its biosynthetic forms, its active metabolites, alone or in combination, allows the patient to obtain the therapeutic effect of the drug for an extended period of time without significant changes in the plasma concentration of the drug.

[0022] When a drug is administered orally, its bioavailability is usually reduced due to incomplete absorption and first-pass metabolism, which may vary from patient to patient. The compositions of the present disclosure overcome these problems because in transdermal delivery, the active drug is delivered directly through the skin into the systemic circulation, avoiding first-pass hepatic metabolism, requiring less drug to achieve the desired therapeutic activity, resulting in fewer adverse effects and side effects. Compared to oral administration, transdermal delivery requires a lower dose of cannabidiol to achieve the desired therapeutic effect, since cannabinol is highly lipid soluble and undergoes first-pass metabolism in the liver after oral administration, with only 10%-20% of the administered dose reaching the systemic circulation. Transdermal delivery is simple, non-invasive, and convenient. The administration of the transdermal patch or transdermal composition does not require medical supervision, as the patient can apply the transdermal patch or transdermal composition topically.

[0023] Furthermore, if any adverse effects, side effects or emergency situations occur, transdermal delivery provides the freedom to terminate treatment at any time by removing the transdermal patch or transdermal composition from the skin.

[0024] For the above reasons of preventing pain and / or inflammation, transdermal delivery can provide a more patient-friendly, simplified and convenient treatment plan compared to conventional delivery systems.Transdermal delivery can reduce the frequency of administration of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination.Depending on the need, the administration frequency can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0025] By transdermally administering drug combination, two or more drugs can be delivered at the same time.If necessary, the frequency of administration of transdermal patch or transdermal composition containing drug combination can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week.This is a great advantage for patient compliance.

[0026] The present disclosure provides pharmaceutical compositions comprising cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, in a dosage form for transdermal delivery. The present disclosure provides pharmaceutical compositions comprising cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, in the range of 0.01%-95% w / w or w / v. The present disclosure provides pharmaceutical compositions formulated as transdermal liquid formulations, transdermal semisolid formulations, or matrix patch formulations. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, a gelling agent, a polymer, a penetration enhancer, an emollient, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, a gelling agent, a polymer, a penetration enhancer, an emollient, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, a bulking agent, a pressure sensitive adhesive, and combinations thereof, in the range of 0.01%-95% w / w or w / v. The present disclosure provides pharmaceutical compositions wherein the carrier is present in the range of 0.01%-99.8% w / w or w / v. The present disclosure provides pharmaceutical compositions formulated as a transdermal patch. The present disclosure provides a pharmaceutical composition formulated as a transdermal patch, the transdermal patch being selected from the group including a reservoir patch, a microreservoir patch, a matrix patch, a pressure sensitive adhesive patch, a sustained release transdermal film, a liquid reservoir system, a microreservoir patch, a matrix patch, a pressure sensitive adhesive patch, a mucoadhesive patch, and combinations thereof.The present disclosure provides pharmaceutical compositions indicated for the treatment of headache, migraine, tension-type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain, burning pain, complex regional pain syndrome type I and II, reflex sympathetic dystrophy (RSDS), pain and debilitation associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis. The present disclosure provides pharmaceutical compositions formulated as transdermal formulations that can be administered in a dosage regimen selected from the group consisting of once a day, twice a day, three times a day, once every 1-8 hours, once every 1-24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, and once every 15 to about 30 days. The present disclosure provides pharmaceutical compositions that can be formulated as microneedles.The present disclosure provides pharmaceutical compositions in which the CBD or derivatives thereof are produced by synthetic or biosynthetic pathways.

[0027] The present disclosure provides a method for the treatment and / or prevention and / or control of pain and / or inflammation, comprising: selecting a patient in need of treatment and / or prevention and / or control of pain and / or inflammation; topically applying a pharmaceutical composition disclosed herein. The present disclosure provides a method for the treatment and / or prevention and / or control of pain and / or inflammation, wherein the topical application of a transdermal patch for the treatment and / or prevention and / or control of pain and / or inflammation is selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every ten days. The present disclosure provides a method for the treatment and / or prevention and / or control of pain and / or inflammation, further comprising providing a constant rate of delivery of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for the treatment and / or prevention and / or control of pain and / or inflammation, further comprising providing a constant rate of absorption of the active ingredient of the transdermal patch over a period of time. The present disclosure provides methods for the treatment and / or prevention and / or control of pain and / or inflammation, further achieving a consistent serum level of an active ingredient of a transdermal patch over a period of time.The present disclosure provides methods for the treatment and / or prevention and / or control of pain and / or inflammation, further achieving a reduced variability in the dosage of an active ingredient of a transdermal patch over a period of time.The present disclosure provides methods for the treatment and / or prevention and / or control of pain and / or inflammation, further providing a plasma concentration of an active ingredient of a transdermal patch within a therapeutic range over a period of time.

[0028] The present disclosure provides pharmaceutical compositions comprising cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, in a dosage form for transdermal delivery. The present disclosure provides pharmaceutical compositions comprising cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, in the range of 0.01%-95% w / w or w / v. The present disclosure provides pharmaceutical compositions formulated as transdermal liquid formulations, transdermal semisolid formulations, or matrix patch formulations. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, a gelling agent, a polymer, a penetration enhancer, an emollient, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, a gelling agent, a polymer, a penetration enhancer, an emollient, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof in the range of 0.01%-95% w / w or w / v. The present disclosure provides pharmaceutical compositions wherein the carrier is present in the range of 0.01%-99.8% w / w or w / v. The present disclosure provides pharmaceutical compositions formulated as a transdermal patch. The present disclosure provides pharmaceutical compositions formulated as a transdermal patch, the transdermal patch being selected from the group including, without limitation, transdermal matrix patches such as reservoir patch, microreservoir patch, liquid reservoir system, microreservoir patch, matrix patch, pressure sensitive adhesive patch, mucoadhesive patch, and combinations thereof, adhesive matrix patch, non-adhesive matrix patch, pressure sensitive adhesive matrix patch, sustained release transdermal film, drug in adhesive matrix patch.The present disclosure provides a pharmaceutical composition indicated for the treatment of a condition selected from the group consisting of headache, migraine, tension-type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain, burning pain, complex regional pain syndrome types I and II, reflex sympathetic dystrophy (RSDS), pain and debilitation associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and pediatric autism spectrum disorder (ASD), pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with kidney disease, pain and / or inflammation in patients with liver cancer, pain and / or inflammation in patients with kidney cancer, pain and / or inflammation in patients with cancer, and combinations thereof. The present disclosure provides pharmaceutical compositions that are formulated as transdermal formulations that are applied to a patient for a period of time selected from the group consisting of about 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 108 hours, 120 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, and 4 months. The present disclosure provides pharmaceutical compositions that may be formulated as microneedles. The present disclosure provides pharmaceutical compositions in which the CBD or derivatives thereof are produced by a synthetic or biosynthetic pathway.

[0029] The present disclosure provides a pharmaceutical composition comprising cannabidiol (CBD) in a dosage form for transdermal delivery, the pharmaceutical composition comprising about 9% to about 12% w / w CBD; optionally, about 30% to about 99% solvent; optionally, about 1% to about 20% penetration enhancer, the pH of the composition being maintained at about 4.0 to 8.0. The present disclosure provides a pharmaceutical composition formulated as a transdermal liquid formulation, a transdermal semisolid formulation, or a transdermal polymer matrix formulation. The present disclosure provides a pharmaceutical composition further comprising an effective amount of a carrier or component selected from the group consisting of a gelling agent, a polymer, an emollient, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or component selected from the group consisting of gelling agents, polymers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, oxidizing agents, and combinations thereof, in the range of 0.01%-95% w / w or w / v. The present disclosure provides pharmaceutical compositions formulated as transdermal patches. The present disclosure provides pharmaceutical compositions formulated as transdermal patches, the transdermal patch being selected from the group including reservoir patches, microreservoir patches, matrix patches, pressure sensitive adhesive patches, sustained release transdermal films, liquid reservoir systems, microreservoir patches, matrix patches, pressure sensitive adhesive patches, mucoadhesive patches, and combinations thereof. The present disclosure provides pharmaceutical compositions that can be administered in a dosage regimen selected from the group consisting of once a day, twice a day, three times a day, once every 1-8 hours, once every 1-24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, and once every 15 to about 30 days. The present disclosure provides pharmaceutical compositions that can be formulated as microneedles. The present disclosure provides pharmaceutical compositions in which the CBD or derivatives thereof are produced by a synthetic route.

[0030] The present disclosure provides a method for treating and / or preventing and / or reducing and / or controlling pain and / or inflammation, comprising: selecting a patient in need of treatment and / or prevention and / or control of pain and / or inflammation; topically applying a pharmaceutical composition disclosed herein. The present disclosure provides a method for treating and / or preventing and / or controlling pain and / or inflammation, wherein the topical application of a transdermal patch for treating and / or preventing and / or controlling pain and / or inflammation is selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every ten days. The present disclosure provides a method for treating and / or preventing and / or controlling pain and / or inflammation, further comprising providing a constant rate of delivery of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for treating and / or preventing and / or controlling pain and / or inflammation, further comprising providing a constant rate of absorption of the active ingredient of the transdermal patch over a period of time. The present disclosure provides methods for the treatment and / or prevention and / or control of pain and / or inflammation, further achieving a consistent serum level of an active ingredient of a transdermal patch over a period of time.The present disclosure provides methods for the treatment and / or prevention and / or control of pain and / or inflammation, further achieving a reduced variability in the dosage of an active ingredient of a transdermal patch over a period of time.The present disclosure provides methods for the treatment and / or prevention and / or control of pain and / or inflammation, further providing a plasma concentration of an active ingredient of a transdermal patch within a therapeutic range over a period of time.The disclosure provides a method for the treatment and / or prevention and / or control of pain and / or inflammation, wherein the topical application of a transdermal patch is for the treatment and / or prevention and / or control of pain and / or inflammation of a condition selected from the group consisting of headache, migraine, tension type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug induced neuropathic pain, causal pain, complex regional pain syndrome types I and II, reflex sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and autism spectrum disorder (ASD) in pediatric patients, pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with kidney disease, pain and / or inflammation in patients with liver cancer, treatment of pain and / or inflammation in patients with kidney cancer, pain and / or inflammation in patients with cancer, and combinations thereof.

[0031] The present disclosure provides a transdermal and / or topical pharmaceutical composition comprising about 0.1% to about 20% of an active agent selected from the group consisting of synthetic cannabidiol, natural cannabidiol, and combinations thereof; about 35% to about 99% of at least one adhesive and / or polymer; optionally, about 0.1% to about 30% of at least one penetration enhancer; and optionally, about 0.1% to about 40% of a gelling agent. The present disclosure provides a transdermal and / or topical pharmaceutical composition, wherein the CBD or derivatives thereof are produced by a synthetic route. The present disclosure provides a transdermal and / or topical pharmaceutical composition, wherein the active agent is a high purity cannabis extract comprising at least about 90% (w / w) cannabidiol (CBD). The present disclosure relates to a method for preparing a viscoelastic adhesive, comprising administering to a patient an effective amount of at least one of the following: the adhesive and / or polymer is selected from the group consisting of hydroxyl propyl methylcellulose, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971pNF, polyethylene and copolymers thereof, clays, silicates, bentonite, silicon dioxide, polyvinyl alcohol, acrylic polymers, Eudragit, acrylic acid esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and copolymers, PVP, Kollidon® 30, poloxamers, isobutylene, ethyl acetate vinyl copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives, biocompatible adhesives, and the like. The present invention provides a transdermal and / or topical pharmaceutical composition comprising a composition selected from the group consisting of PSA® 4302, Bio-PSA® 4501, 4202, acrylic pressure sensitive adhesives, Duro-TAK® 87-2156, Duro-TAK® 387-2287, polyisobutylene, low molecular weight polyisobutylene, medium molecular weight polyisobutylene, 35000 mw polyisobutylene, acrylic copolymers, rubber adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and / or organic solvent swellable polymers, and combinations thereof.The present disclosure provides a method for the preparation of a composition comprising the steps of: providing at least one penetration enhancer present, the penetration enhancer being dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, decimethyl sulfoxide, dimethyl isosorbide, 1,3-butanediol, azone, pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone, esters, fatty acid esters, propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monolaurate, glycerol monolaurate, methyl laurate, lauryl laurate, fatty acids, capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, The present invention provides a transdermal and / or topical pharmaceutical composition comprising a component selected from the group consisting of acids, linoleic acid, stearic acid, palmitic acid, alcohols, fatty alcohols and glycols, oleyl alcohol, nathanol, dodecanol, propylene glycol, glycerol, ether alcohols, diethylene glycol monoethyl ether, urea, triglycerides, triacetin, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, esters of fatty alcohols, essential oils, surfactant type enhancers, brij®, sodium lauryl sulfate, Tween®, polysorbates, terpenes, terpenoids, and combinations thereof.The present disclosure provides a method for preparing a gelling agent comprising the steps of: providing a gelling agent comprising: at least one gelling agent is present, the gelling agent being selected from the group consisting of natural polymers, polysaccharides and derivatives thereof, agar, alginic acid and derivatives, cassia, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan gum, copal, starch, chitosan, resins, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971, polyethylene and copolymers thereof, clays, silicates, polyvinyl chloride ... alcohol, polyacrylamide, polyvinylpyrrolidone homopolymer and copolymer, PVP, poloxamer, acrylic acid or its esters, polyacrylate copolymer, isobutylene, ethylene vinyl acetate copolymer, natural rubber, synthetic rubber such as styrene-diene copolymer, styrene-butadiene block copolymer, isoprene block copolymer, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, silicone-based pressure sensitive adhesives, hot melt adhesives, and combinations thereof. The present disclosure provides transdermal and / or topical pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides transdermal and / or topical pharmaceutical compositions formulated as a transdermal patch. The present disclosure provides transdermal and / or topical pharmaceutical compositions formulated as a transdermal patch, wherein the transdermal patch is selected from the group including a reservoir patch, a microreservoir patch, a matrix patch, a pressure sensitive adhesive patch, a sustained release transdermal film, a liquid reservoir system, a microreservoir patch, a matrix patch, a pressure sensitive adhesive patch, a mucoadhesive patch, and combinations thereof.The present disclosure provides transdermal and / or topical pharmaceutical compositions indicated for the treatment of a condition selected from the group consisting of headache, migraine, tension-type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain, burning pain, complex regional pain syndrome types I and II, reflex sympathetic dystrophy (RSDS), pain and debilitation associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and pediatric autism spectrum disorder (ASD), pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with kidney disease, pain and / or inflammation in patients with liver cancer, pain and / or inflammation in patients with kidney cancer, pain and / or inflammation in patients with cancer, and combinations thereof. The present disclosure provides transdermal and / or topical pharmaceutical compositions that are formulated as transdermal formulations that are applied to a patient for a period of time selected from the group consisting of, for example, about 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 108 hours, 120 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, and 4 months. The present disclosure provides transdermal and / or topical pharmaceutical compositions that may be formulated as microneedles. The present disclosure provides transdermal and / or topical pharmaceutical compositions in which the CBD or derivatives thereof are produced by a synthetic route. The present disclosure provides transdermal and / or topical pharmaceutical compositions that are co-administered with at least one additional active agent selected from the group consisting of analgesics, anti-inflammatory agents, opioid agents, and combinations thereof. The present disclosure provides transdermal and / or topical pharmaceutical compositions further comprising at least one additional active agent selected from the group consisting of analgesics, anti-inflammatory agents, opioid agents, and combinations thereof.

[0032] The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, comprising: selecting a patient in need of treatment and / or prevention and / or reduction and / or control of pain and / or inflammation; treating and / or preventing and / or reducing and / or controlling pain and / or inflammation by topically applying a pharmaceutical composition disclosed herein. The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, wherein the topical application of a transdermal patch for the treatment and / or prevention and / or control of pain and / or inflammation is selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to once every 30 days. The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, which further provides a constant rate of delivery of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days.The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, which further provides a steady rate of absorption of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, further achieving a constant therapeutic serum level of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days.The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, further achieving a reduced variability in the dosage of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days.The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, further providing a therapeutic plasma concentration of the active ingredient of the transdermal patch within the therapeutic range for a period of time selected from the group consisting of once daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. The present disclosure provides a method for the treatment and / or prevention and / or reduction and / or control of pain and / or inflammation, wherein the topical application of a transdermal patch is for the treatment and / or prevention and / or control of pain and / or inflammation of a condition selected from the group consisting of headache, migraine, tension type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug induced neuropathic pain, causal pain, complex regional pain syndrome type I and type II, reflex sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and autism spectrum disorder (ASD) in pediatric patients, pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with kidney disease, pain and / or inflammation in patients with liver cancer, treatment of pain and / or inflammation in patients with kidney cancer, pain and / or inflammation in patients with cancer, and combinations thereof.

[0033] The disclosure provides for the use of a composition of the invention for the manufacture of a medicament for treating an indication described herein. According to further embodiments, the present disclosure provides the use of the above pharmaceutical compositions in an amount effective for use in medicine, and most preferably, for use as a medicine to treat a disease or disorder in a subject.

[0034] According to yet another embodiment, the present disclosure provides for the use of the above pharmaceutical composition and at least one additional therapeutic agent in an amount effective for use in medicine, and most preferably, in an amount effective for use as a medicine to treat a disease or disorder associated with the disease in a subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description Cannabinoids are a group of 21-carbon terpenophenolic compounds produced by cannabis species. Cannabinoids may also be produced synthetically. Hereinafter, the term "cannabinoid" refers to a diverse class of compounds that act on cannabinoid receptors on cells that inhibit neurotransmitter release in the brain. These receptor proteins include endocannabinoids (produced naturally in the body by humans and animals), phytocannabinoids (found in cannabis and other plants), and synthetic cannabinoids. Lipophilic cannabinoids are typically classified as endocannabinoids (most typically mammalian endocannabinoids); plant-derived phytocannabinoids; and synthetic cannabinoids. Such cannabinoids are also frequently classified into the following subclasses: cannabigerol (CBG); cannabichromene (CBC); cannabidiol (CBD; CBDL); tetrahydrocannabinol (THC); cannabinol (CBN); cannabicyclol (CBL); cannabielsoin (CBE); and cannabiditriol (CBT).

[0036] Cannabidiol IUPAC name 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol Chemical formula: C 21 H 30 O2 molecular weight: 314.46 Daltons The chemical structure is shown below as Formula I.

[0037] [ka]

[0038] Tetrahydrocanbinol (THC) IUPAC name (-)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol Chemical formula: C 21 H 30 O2 molecular weight: 314.47 Daltons. The chemical structure is shown below as Formula II.

[0039] [ka]

[0040] As used herein, the term cannabis refers to all pharma- ceutically acceptable forms of cannabis and its derivatives, alone or in combination, including, but not limited to, in the following forms: free base or salt or isomer or amorphous or crystalline or co-crystalline or solid solution or prodrug or analog or derivative or metabolite. For example, the free base of cannabidiol or its salt or its isomer or its amorphous form or its crystalline form or its co-crystalline form or its solid solution or its prodrug or its analog or its derivative or synthetic form. The compound may be in the form of a pharma- ceutically acceptable salt, such as, for example, an acid addition salt or a base salt, or a solvate, including a hydrate. Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which are the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, sugar, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. Suitable base salts are formed from bases which form non-toxic salts, examples of which are the sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts.

[0041] As used herein, the term "cannabidiol" includes its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination. As used herein, the term "cannabidiol" includes its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, and its synthetic form, alone or in combination. In certain embodiments, the CBD is highly purified. In certain embodiments, the CBD is present as a high-purity cannabis extract containing at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75% (w / w) CBD. In exemplary embodiments, the formulations of the disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 9.25%, about 9.5%, about The composition may be present in a concentration of about 9.75%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may contain CBD in a concentration of about 1-25%, about 3% to about 6%, about 5% to about 20%, about 8% to about 15%, or about 9% to about 14%, about 9% to about 13%, or about 9% to about 12% (w / w) of the formulation.

[0042] In certain embodiments, the dose of CBD is, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 mg / kg / day. In certain embodiments, the dose of CBD is, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, or 275 mg / day.

[0043] In one embodiment, the CBD is present as a high purity cannabis extract containing at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75% (w / w) CBD.

[0044] As used herein, the term "pharmaceutically acceptable salts" includes acid addition salts or free base addition salts. The term "pharmaceutically acceptable salts" of cannabidiol includes within its scope all possible isomers and mixtures thereof, as well as any pharmaceutically acceptable metabolites, bioprecursors and / or prodrugs, such as compounds that have a structural formula different from one of the compounds of the present disclosure, but that are nevertheless converted in vivo, directly or indirectly, to a compound of the present disclosure when administered to a subject, such as a mammal, particularly a human.

[0045] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to an animal, preferably a mammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkeys and humans), and most preferably a human. In some embodiments, the subject is a non-human animal, such as a livestock animal (e.g., horse, pig, or cow) or a pet (e.g., dog or cat). In certain embodiments, the subject is a human. As used herein, the term "agent" refers to any molecule, compound, methodology, and / or substance for use in the prevention, treatment, management, and / or diagnosis of a disease or condition. As used herein, the term "effective amount" refers to the amount of a therapy sufficient to prevent the development, recurrence, or onset of a disease or condition and one or more symptoms thereof, thereby enhancing or improving the prophylactic efficacy of another therapy, reducing the severity, duration of a disease or condition, ameliorating one or more symptoms of a disease or condition, preventing the progression of a disease or condition, causing regression of a disease or condition, and / or enhancing or improving the therapeutic efficacy of another therapy.

[0046] As used herein, the phrase "pharmaceutical acceptable" means approved by a regulatory agency of the Federal or state government or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0047] As used herein, the term "therapeutic agent" refers to any molecule, compound, and / or substance used to treat and / or manage a disease or disorder. As used herein, the term "therapy" may refer to any method, composition, and / or agent that can be used in the prevention, treatment, and / or management of a disease or condition, or one or more symptoms thereof. In certain embodiments, the term "therapy" refers to a small molecule therapy.

[0048] The term "derivative" or "derivatized" as used herein includes, for example, chemical modifications of the disclosed compounds, or compounds extracted from plant sources, or pharma- ceutically acceptable salts thereof, or mixtures thereof. That is, a "derivative" may be a functional equivalent of a disclosed compound that is capable of inducing improved pharmacological functional activity in a given subject.

[0049] As used herein, the terms "composition" and "formulation" are used interchangeably. As used herein, the terms "transdermal matrix patch" and "matrix patch" are used interchangeably.

[0050] As used herein, the term "transdermal delivery" means delivery of a drug through the skin into the systemic circulation. As used herein, synthetic cannabinoids include at least the following: AM-087 is a cannabinoid agonist derivative of Δ8THC substituted at the 3-position of the side chain, and is a potent CB1 agonist analgesic. AM-251 is an inverse agonist of the CB1 cannabinoid receptor and is structurally similar to SR141716A (rimonabant), both of which are biarylpyrazole cannabinoid receptor antagonists and μ-opioid receptor antagonists. Methanandamide (AM-356) is a stable chiral analog of anandamide that acts on cannabinoid receptors with a Ki of 17.9 nM at CB1 and 868 nM at CB2. AM-374 (palmitylsulfonyl fluoride). AM-381 (stearylsulfonyl fluoride). AM404, also known as N-arachidonoylaminophenol, is an active metabolite of paracetamol (acetaminophen) and is believed to induce its analgesic effects through activity on the endocannabinoid, COX, and TRPV systems, all of which are present in pain and thermoregulatory pathways. AM-411 is a cannabinoid agonist analgesic. AM-411 is a potent and fairly selective CB1 full agonist, producing effects similar to other cannabinoid agonists, such as analgesia, sedation, and anxiolysis. AM-630 (6-lodopravadoline) acts as a potent and selective inverse agonist at the cannabinoid receptor CB2, with selectivity exceeding that of CB1, where they act as weak partial agonists. AM-661 (1-(N-methyl-2-piperidine)methyl-2-methyl-3-(2-iodo)benzoylindole). JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM-678 is an analgesic drug of the naphthoylindole family that acts as a full agonist at both CB1 and CB2 cannabinoid receptors with some selectivity for CB2. AM-679 acts as a moderately potent agonist at cannabinoid receptors. AM-694 (1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole) acts as a potent and selective agonist at cannabinoid receptor CB1. AM-735 (3-bornyl-Δ8-THC), a mixed CB1 / CB2 agonist.AM-855 is an analgesic cannabinoid agonist at both CB1 and CB2 with moderate selectivity for CB1. AM-881 (a chlorine-substituted stereoisomer of anandamide with Ki=5.3 nM at CB1 and 95 nM at CB2. AM-883 (an allyl-substituted stereoisomer of anandamide with Ki=9.9 nM at CB1 and 226 nM at CB2. AM-905 is an analgesic cannabinoid that acts as a potent and moderately selective agonist at the CB1 cannabinoid receptor. AM-906 is an analgesic cannabinoid agonist that is a potent and selective agonist at the CB1 cannabinoid receptor. AM-919 is a potent analgesic cannabinoid receptor agonist at both CB1 and CB2. AM-926 is a potent agonist for both CB1 and CB2, with moderate selectivity for CB1. AM-938 is an analgesic that is a cannabinoid receptor agonist, still a potent agonist for both CB1 and CB2, but moderately selective for CB2. AM-1116 (a dimethylated stereoisomer of anandamide). AM-1172 (specifically designed to be a potent and selective inhibitor of AEA uptake that is resistant to FAAH hydrolysis) AM-1220 is a potent and moderately selective agonist for the cannabinoid receptor CB1. AM-1221 acts as a potent and selective agonist for the cannabinoid receptor CB2. AM-1235 (1-(5-fluoropentyl)-3-(naphthalene-1-oyl)-6-nitroindole) acts as a potent and moderately selective agonist for the cannabinoid receptor CB1. AM-1241 (1-( AM-1248 is a potent and selective agonist for the cannabinoid receptor CB2, and has analgesic effects in mammals, especially for "atypical" pain such as hyperalgesia and allodynia. It has also been shown to be effective in treating amyotrophic lateral sclerosis in mammalian models. AM-1248 acts as a moderately potent agonist for both cannabinoid receptors CB1 and CB2.AM-1710 (a CB2-selective cannabilactone with 54-fold selectivity over CB1). AM-1714 acts as a moderately selective agonist of the peripheral cannabinoid receptor CB2 and has both analgesic and antiallodynic effects. AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole) acts as a potent but nonselective full agonist at cannabinoid receptors. AM-2212 (a potent agonist at both CB1 and CB2). AM-2213 (a potent agonist at both CB1 and CB2). AM-2232 (1-(4-cyanobutyl)-3-(naphthalene-1-oyl)indole) acts as a potent but nonselective agonist at cannabinoid receptors CB1 and CB2. AM-2233 acts as a very potent full agonist at cannabinoid receptors CB1 and CB2, and has been found to fully replace THC in certain mammalian studies, with a potency lower than JWH-018, but higher than WIN55,212-2. AM-2389 acts as a potent and moderately selective agonist at the CB1 receptor. AM-3102 is an analog of oleoylethanolamide (an endogenous agonist of proliferator-activated receptor alpha (PPARα)) that acts as a weak cannabinoid agonist at CB1 and CB2. AM-4030 is a potent agonist at both CB1 and CB2, as well as a moderately selective analgesic for CB1. AM-4054 ​​is a potent but slow-acting agonist with affinity and selectivity for CB1 over CB2. AM-4113 (CB1-selective neutral antagonist). AM-6545 acts as a peripherally selective silent antagonist of CB1 and was developed for the treatment of obesity. JWH-007 is an analgesic that acts as a cannabinoid agonist at both CB1 and CB2 receptors, with some selectivity for CB2. JWH-007 is an analgesic that acts as a cannabinoid agonist at both CB1 and CB2 receptors. JWH-015 acts as a subtype-selective cannabinoid agonist, binding to CB2 nearly 28 times more tightly than CB1. It has also been shown to have immunomodulatory effects and may be useful in the treatment of pain and inflammation.JWH-018 is an analgesic that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, producing effects similar to THC. JWH-019 is an analgesic of the naphthoylindole family that is an agonist at both the CB1 and CB2 receptors and acts as a cannabinoid agonist at both the CB1 and CB2 receptors. JWH-030 (an analgesic that is a partial agonist at the CB1 receptor). JWH-047 (a potent and selective agonist at the CB2 receptor). JWH-048 (a potent and selective agonist at the CB2 receptor). JWH-051 is an analgesic with high affinity for the CB1 receptor, but is a more potent agonist for CB2. JWH-057 is a 1-deoxy analog of Δ8-THC that has very high affinity for the CB2 receptor, but also has high affinity for the CB1 receptor. JWH-073 (analgesic that acts as a cannabinoid agonist at both the CB1 and CB2 receptors), which is somewhat selective for the CB1 subtype. JWH-081 (analgesic that acts as an agonist at both the cannabinoid CB1 and CB2 receptors). JWH-098 (a potent and fairly selective CB2 agonist). JWH-116 (a CB1 ligand); JWH-120 (a potent and 173-fold selective CB2 agonist). JWH-122 (a potent and fairly selective CB1 agonist). JWH-133 (a potent and highly selective CB2 receptor agonist). 1JWH-139 (3-(1,1-dimethylpropyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene); JWH-147 are analgesics of the naphthoylpyrrole family that act as cannabinoid agonists at both the CB1 and CB2 receptors. JWH-148 is a moderately selective ligand for the CB2 receptor, more than 8-fold more selective than the CB1 subtype. JWH-149 (a potent and fairly selective CB2 agonist). JWH-161 (a CB1 ligand); JWH-164 (a potent cannabinoid agonist). JWH-166 (a potent and highly selective CB2 agonist). JWH-167 (a weak cannabinoid agonist of the phenylacetylindole family.JWH-171 (analgesic drug acting as a cannabinoid receptor agonist); JWH-175 ((1-pentylindol-3-yl)naphthalen-1-ylmethane, 22 nM at CB1); JWH-176 (1-([(1E)-3-pentylinden-1-ylidine]methyl)naphthalene); JWH-181 (potent cannabinoid agonist); JWH-182 (potent cannabinoid agonist with some selectivity for CB1); JWH-184 (1-pentyl-1H-indol-3-yl-(4-methyl-1-naphthyl)methane). JWH-185 (1-pentyl-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane. JWH-192 ((1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methylnaphthalen-1-ylmethane). JWH-193 ((1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methylnaphthalen-1-ylmethanone). JWH-194 (2-methyl-1-pentyl-1H-indol-3-yl)methane). JWH-195 ((1-(2-morpholin-4-ylethyl)indol-3-yl)-naphthalen-1-ylmethane; JWH-196 (2-methyl-3-(1-naphthalenylmethyl)-1-pentyl-1H-indole); JWH-197 (2-methyl-1-pentyl-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane). JWH-198 ((1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methoxynaphthalen-1-ylmethanone). JWH-199 ((1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methoxynaphthalen-1-ylmethane). JWH-200 is an analgesic in the aminoalkyl indole family that acts as a cannabinoid receptor agonist. JWH-203 is an analgesic in the phenylacetyl indole family that acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors. JWH-205 (142-methyl-1-pentylindol-3-yl)-2-phenylethanone). JWH-210 is an analgesic in the naphthoylindole family that acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors.JWH-213 (a potent and fairly selective CB2 agonist). JWH-229 (1-methoxy-3-(1',1'-dimethylhexyl)-Δ8-THC, a dibenzopyran cannabinoid that is a potent CB2 agonist). JWH-234 (a cannabinoid agonist with selectivity for CB2). JWH-250 is an analgesic of the phenylacetylindole family that inhibits CB. It acts as a cannabinoid agonist at both CB1 and CB2 receptors. JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole). JWH-258 (a potent and moderately selective CB1 agonist). JWH-302 (1-pentyl-3-(3-methoxyphenylacetyl)indole); JWH-307 are analgesics of the naphthoylpyrrole family that act as cannabinoid agonists at both CB1 and CB2 receptors, with some selectivity for the CB2 subtype. JWH-350, 11-nor-1-methoxy-3-(1',1'-dimethylheptyl)-9α-hydroxyhexahydrocannabinol, has 33-fold selectivity for the CB2 receptor and high affinity for the CB2 receptor, with little affinity for the CB1 receptor. JWH-359 (a dibenzopyran cannabinoid that is a potent and selective CB2 receptor agonist). JWH-387 is a 1-pentyl-3-(4-bromo-1-naphthoyl)indole, an analgesic agent of the naphthoylindole family that acts as a potent cannabinoid agonist at both receptors CB1 and CB2. JWH-398 is an analgesic chemical of the naphthoylindole family that acts as a potent cannabinoid agonist at both receptors, with a Ki of 2.3 nM at CB1 and 2.8 nM at CB2. JWH-424 (a potent and moderately selective CB2 agonist with a Ki of 5.44 nM at CB2 and 20.9 nM at CB1). HU-210 is a cannabinoid that is 100-800 times more potent than natural THC from cannabis, with a longer duration of action and is a potent analgesic agent with many of the same effects as natural THC. Ajulemic acid (AB-III-56, HU-239, IP-751, CPL7075, CT-3, Resunab) is a cannabinoid derivative of the non-psychoactive THC metabolite 11-nor-9-carboxy-THC that exhibits useful analgesic and anti-inflammatory effects without producing a subjective "high." It is being developed for the treatment of inflammatory conditions such as neuropathic pain and arthritis, as well as for the treatment of rare life-threatening inflammatory diseases. HU-243 (AM-4056) is a cannabinoid that is a potent agonist at both the CB1 and CB2 receptors.HU-308 acts as a cannabinoid agonist and is highly selective for the CB2 receptor subtype. It has analgesic effects, promotes neural stem cell proliferation, and protects both liver and vascular tissue from oxidative stress by inhibiting TNF-α. HU-331 is a quinone anticarcinogen synthesized from cannabidiol. HU-336 is a potent antiangiogenic compound that inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without altering the expression of pro- and antiangiogenic cytokines and their receptors. HU-345 (cannabinol quinone) is a drug that can inhibit angiogenesis in aortic rings more potently than the parent compound cannabinol. CP47,497 or (C7)-CP47,497 is a cannabinoid receptor agonist drug.

[0051] The present disclosure also provides methods for the biosynthesis of cannabinoids, and for the use of eukaryotic or prokaryotic expression systems for the production of biosynthetic enzymes that can be used to manufacture cannabinoids and cannabinoid analogs. Yeast and eukaryotic and prokaryotic cells are suitable for cloning and expressing cannabinoid acid synthase enzymes, including but not limited to E. coli, yeast and baculovirus hosts. Thus, the present disclosure provides methods for producing biosynthetic cannabinoids, such as, for example, THC and / or CBD, using cannabinoid acid synthase enzymes, including but not limited to, tetrahydrocannabinolic acid (THCA) synthase and cannabidiolic acid (CBDA) synthase. The present disclosure further provides transdermal compositions as disclosed herein, including, for example, biosynthetic CBD, alone or in combination with other active agents.

[0052] According to certain embodiments, the transdermal compositions described herein are for the prevention and / or treatment of pain and / or inflammation. According to certain embodiments, the transdermal compositions described herein are for reducing the severity of pain and / or inflammation.

[0053] According to certain embodiments described herein, the pharmaceutical composition or transdermal formulation comprises cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination. More preferably, the transdermal formulation may comprise cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination.

[0054] One embodiment of the present disclosure can be a transdermal drug delivery system, including but not limited to transdermal formulations, transdermal patches, topical formulations, microneedles, iontophoresis, and metered dose transdermal sprays.

[0055] Transdermal formulations include liquids, such as, but not limited to, solutions, suspensions, dispersions, emulsions, etc. Transdermal formulations include semi-solids, such as, but not limited to, gels, ointments, emulsions, creams, suspensions, pastes, lotions, balms, etc. Liquid and / or gel formulations incorporated into a transdermal patch are preferred. Transdermal formulations include, but are not limited to, matrix patches, such as adhesive matrix patches, non-adhesive matrix patches, pressure sensitive adhesive matrix patches, sustained release transdermal films, drug in adhesive matrix patches, etc.

[0056] Without any limitation, the transdermal patch may preferably include, but is not limited to, a reservoir patch, a matrix patch, a bilayer matrix patch, a multilayer matrix patch, a microreservoir patch, an adhesive system, a transdermally applicable tape, and any other transdermal drug delivery system described in the art.

[0057] In certain embodiments of the present disclosure, the transdermal patch comprises a transdermal formulation containing cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination, contained in a reservoir or matrix, and an adhesive that allows the transdermal patch to adhere to the skin and allows the cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination, to pass from the transdermal patch through the patient's skin. The transdermal delivery system may be occlusive, semi-occlusive, or non-occlusive, and may be adhesive or non-adhesive.

[0058] In certain embodiments of the present disclosure, the pharmaceutical composition disclosed herein can be co-administered with at least one additional active agent.In certain embodiments of the present disclosure, the pharmaceutical composition disclosed herein can further comprise at least one additional active agent.Examples of the additional active agent include, for example, analgesics and anti-inflammatory agents, such as aloxiprine, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac;Opioid analgesics, such as codeine, dextropropionyloxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine, midazolam, fentanyl, codeine, buprenorphine, tramadol, fentany, hydromonorphone, morphine, oxycodone / naloxone, opiates, opium, acetyldihydrocodeine, alfentany, allylprozine, alphamethylfentanyl, alphaprozine, benzylmorphine, betaprozine, benzyltriamide, buprenorphine , butorphanol, bremazocine, carfentan (carfentanil), contin, dextromoramide, dextropropoxyphene, dezocine, diacetylmorphine, diamorphine, dihydrocodeine, dihydromorphine, dihydromorphone, diphenoxylate, dipipanone, enadrine, ethylketazocine, ethylmorphine, etonitazene, etorphine, fentanyl, heroin, hydrocodone, hydromorphine (hydromorphine), hydromorphone, ketazocine, ketobemidone, lefetamine, levomethadone, Levomethadyl, Levomethorphan, Levorphanol, Loperamide, Meperidine, Meptazinol, Methadone, Methadyl, Methylmorphine, Morphine (morphine), Nalbuphine, Narcotic, Nicocodeine, Nicomorphine, Normorphine, Noscapine, Ormefentanyl, Oripavine, Oxycodone, Oxycontin, Oxymorphone, Papaveretam, Papaverine, Pentazocine, Percocet, Peronine, Pethidine, Phenazocine, Phencyclidine, Pholcodine, Piritramid (priitramidine), Prozine, Promedol, Prostaglandin poxyphene, remifentanil, sufentanil, tapentadol, thebaine, tilidine, tramadol, ultracet, morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nabulfina, propoxyphene, pentazocine, and pharmaceutically acceptable salt derivatives thereof;

[0059] Transdermal formulations containing cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination, can be incorporated into a patch, and the patch can be applied topically to the skin surface. The patch can be left on the subject for any suitable period of time. In certain embodiments, the transdermal patch is applied to the patient for, for example, about 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 108 hours, 120 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months.

[0060] In some embodiments, the transdermal patch provides a constant rate of delivery of the active ingredient of the transdermal patch over a predetermined period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0061] In yet another embodiment, the transdermal patches described herein provide a steady rate of absorption of the active ingredient of the transdermal patch by the patient over a period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0062] In yet another embodiment, the transdermal patches described herein provide a constant serum level of the active ingredient of the transdermal patch in a patient over a period of time, hi some embodiments, the period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0063] In yet another embodiment, the transdermal patches described herein provide a plasma concentration of the active ingredient of the transdermal patch within the therapeutic range of the patient for a predetermined period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0064] In some embodiments, a matrix patch comprising cannabidiol, its free base, its salts, its isomers, its amorphous forms, its crystalline forms, its co-crystalline forms, its prodrugs, its analogs, its derivatives, its synthetic forms, its biosynthetic forms, its active metabolites, alone or in combination, can be prepared as a transdermal matrix patch, and the matrix patch can be topically applied to the skin surface. The matrix patch can be left on the subject for any suitable period of time.

[0065] In some embodiments, the matrix patch provides a constant rate of delivery of the active ingredient of the matrix patch over a predetermined period of time, hi some embodiments, the predetermined period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0066] In yet another embodiment, the matrix patches described herein provide a steady rate of absorption of the active ingredient of the matrix patch by the patient over a period of time, hi some embodiments, the period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0067] In yet another embodiment, the matrix patches described herein provide a constant serum level of the active ingredient of the matrix patch in a patient over a predetermined period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0068] In yet another embodiment, the matrix patches described herein provide a plasma concentration of the active ingredient of the matrix patch within the patient's therapeutic range for a predetermined period of time, hi some embodiments, the predetermined period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0069] In yet another embodiment, the matrix patches described herein allow for reduced fluctuations in the dosage of an active ingredient in a patient over a period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0070] In further embodiments, the transdermal patches described herein allow for reduced fluctuations in dosage of the active ingredient in a patient over a period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0071] Topical formulations described in the art include, but are not limited to, semi-solids such as ointments, creams, emulsions, microemulsions, nanoemulsions, pastes, balms, gels, lotions, mousses, etc.; liquids such as solutions, suspensions, microsuspensions, nanosuspensions, dispersions, nanodispersions, etc.; sprays, aerosols, magmas, etc. Topical formulations comprising cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, can be applied topically to the skin surface for transdermal delivery of cannabidiol.

[0072] The transdermal and / or topical formulations of some embodiments of the present disclosure may include an effective amount of a carrier or ingredient, such as, but not limited to, the following carriers or ingredients, alone or in combination: solvents, gelling agents, polymers, biodegradable polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, tackifiers, surfactants, volatile chemicals, antioxidants, oxidizing agents, fillers, pressure sensitive adhesives, chelating agents, complexing agents, excipients, materials for making patches, materials for making transdermal matrix patches, materials for making reservoir patches, and the like.

[0073] Cannabidiol can be dissolved, suspended, dispersed, or homogeneously mixed in the above single carrier, mixture of carriers, and combination of carriers. Any combination of two or more drugs, such as cannabidiol, can be dissolved, suspended, dispersed, or homogeneously mixed in the above single carrier, mixture of carriers, and combination of carriers.

[0074] Desired optimal transdermal and / or topical formulations of cannabidiol alone or in combination may include, but are not limited to, the carriers set forth below in Examples 1-13, alone or in combination.

[0075] The present invention will be described in more detail below with reference to examples, but it should be understood that the present invention is not limited to these examples. Working Example Example 1 The transdermal and / or topical formulations of the present disclosure may include solvents known to those of skill in the art, either alone or in combination, including, but not limited to, alcohols C1-C 20Solvents that may be used include, but are not limited to, polyhydric alcohols (methanol, ethanol, isopropyl alcohol, butanol, propanol, etc.), glycols (propylene glycol, polyethylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, glycerol, etc.), derivatives of glycols, pyrrolidones (N-methyl 2-pyrrolidone, 2-pyrrolidone, etc.), sulfoxides (dimethyl sulfoxide, decimethyl sulfoxide, etc.), dimethyl isosorbide, mineral oils, vegetable oils, water, polar solvents, semi-polar solvents, non-polar solvents, volatile chemicals that may be used to make the matrix patch (ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA), acids (acetic acid, lactic acid, levulinic acid, bases, and others), more preferably in the range of 0.01% to 95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 The solvent may be included in concentrations of about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include a solvent in concentrations of about 30-99%, about 35%-95%, about 40%-90% w / w. In exemplary formulations of the present disclosure, the solvent is present at about 1%-75% by weight of the formulation, preferably 2%-30% by weight, and more preferably 5%-20% by weight.

[0076] Example 2 The transdermal and / or topical formulations of the present disclosure may include gelling agents and / or thickening agents and / or suspending agents and / or polymers and / or pressure sensitive adhesives known to those skilled in the art, alone or in combination, including, but not limited to, natural polymers, polysaccharides and derivatives thereof, such as, but not limited to (agar, alginic acid and derivatives, cassia tora, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan, gum copal, chitosan, resins, etc.), semi-synthetic polymers and derivatives thereof, such as, but not limited to, cellulose and derivatives thereof (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), synthetic polymers and derivatives thereof, such as, but not limited to, carboxyvinyl polymers or carbomers (carbopol® 940, carbopol® 934, carbopol® 950, carbopol® 960, carbopol® 970, carbopol® 980, carbopol® 990, carbopol® 910, carbopol® 920, carbopol® 930, carbopol® 940, carbopol® 950, carbopol® 930, carbopol® 940, carbopol® 93 ... (registered trademark) 971pNF), polyethylene and its copolymers, clays, such as, but not limited to, (silicates, bentonite), silicon dioxide, polyvinyl alcohol, acrylic polymers (Eudragit), acrylic acid esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers, such as, but not limited to, (PVP, Kollidon® 30, poloxamer), isobutylene, ethyl acetate vinyl copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives, such as, but not limited to, silicone polymers, such as, but not limited to, (bioPSA® 4302, Bio-PSA® 4202, etc.), acrylic pressure sensitive adhesives, including but not limited to (Duro-TAK® 87-2156, Duro-TAK® 387-2287, etc.), polyisobutylenes, including but not limited to (low molecular weight polyisobutylene, medium molecular weight polyisobutylene, 35000mw polyisobutylene, etc.), acrylic copolymers, rubber adhesives, hot melt adhesives, styrene-butadiene copolymers, all water and / or organic solvent swellable polymers, etc. More preferably, the range is 0.1% to 95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 , about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include gelling agents and / or thickening agents and / or suspending agents at concentrations of about 1-20%, about 5%-25%, about 10%-20%, or about 15-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the gelling agents and / or thickening agents and / or suspending agents may comprise about 1%-75% by weight, preferably 2%-30% by weight, and more preferably 5%-20% by weight of the formulation.

[0077] Example 3 The transdermal and / or topical formulations of the present disclosure may include penetration enhancers or permeation enhancers known to one of skill in the art, either alone or in combination, including, but not limited to, sulfoxides and similar chemicals, such as, but not limited to, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, decimethyl sulfoxide, dimethyl isosorbide, 1,3-butanediol, azones, pyrrolidones, such as, but not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, esters, fatty acid esters, such as, but not limited to, propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monolaurate, glycerol monolaurate, methyl laurate, lauryl laurate, lauryl lactate, oleyl ole ... ethyl phosphate, methyl laurate, etc.), fatty acids, such as, but not limited to, capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, etc., alcohols, fatty alcohols and glycols, such as, but not limited to, oleyl alcohol, naphthol, dodecanol, propylene glycol, glycerol, etc., ether alcohols, such as, but not limited to, diethylene glycol monoethyl ether, urea, triglycerides, such as, but not limited to, triacetin, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, esters of fatty alcohols, essential oils, surfactant-type enhancers, such as, but not limited to, brij®, sodium lauryl sulfate, Tween®, polysorbates, terpenes, terpenoids, and those described in the book "Percutaneous Acetylcholine Activation and Sterilization." Any of the penetration enhancers or permeation enhancers referenced in “Penetration Enhancers” (Eric W. Smith, Howard I. Maibach, 2005, Nov, CRC press). More preferably, in the range of 0.01% to 95% w / w or w / v.In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 The permeation enhancer may be included in a concentration of about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, formulations of the present disclosure may include a penetration enhancer or permeation enhancer at a concentration of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the permeation enhancer may comprise about 1%-75% by weight of the formulation, preferably 2%-30% by weight, and more preferably 5%-20% by weight.

[0078] Example 4 The transdermal and / or topical formulations of the present disclosure may contain plasticizers known to those skilled in the art, alone or in combination, including but not limited to: glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacates, citrates, tartrates, adipates, phthalates, triacetin, oleates, and all plasticizers that can be used in transdermal drug delivery systems referenced in the book "Handbook of Plasticizers" (George Wypych, 2004, Chem Tec Publishing), more preferably in the range of 0.01% to 95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 The plasticizer may be included in concentrations of about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include a plasticizer at a concentration of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the plasticizer may comprise about 1%-75% by weight of the formulation, preferably 2%-30% by weight, and more preferably 5%-20% by weight.

[0079] Example 5 The transdermal and / or topical formulations of the present disclosure may contain emollients, moisturizers, skin irritation reducing agents, and similar compounds or chemicals known to those of skill in the art, alone or in combination, including but not limited to: petrolatum, lanolin, mineral oil, dimethicone, zinc oxide, glycerol, propylene glycol, etc., more preferably in the range of 0.01% to 95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure contain emollients, moisturizers, skin irritation reducers, and similar compounds or chemicals at about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about The composition may be present in concentrations of about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include emollients, moisturizers, skin irritation reducers, and similar compounds or chemicals in concentrations of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the emollients, moisturizers, skin irritation reducers, and similar compounds or chemicals may comprise about 1%-75% by weight of the formulation, preferably 2%-30% by weight, and more preferably 5%-20% by weight.

[0080] Example 6 The transdermal and / or topical formulations of the present disclosure may include solubilizers, surfactants, emulsifiers, dispersing agents, and similar compounds or chemicals known to those of skill in the art, alone or in combination, including, but not limited to, the following: polysorbates (e.g., TWEEN®), including, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.; spans, including, but not limited to, span 80, span 20, etc.; surfactants, including, but not limited to, anionic, cationic, nonionic, and amphoteric, propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate, etc. glycol, medium chain triglyceride, propylene glycol monolaurate type II, linoleoyl polyoxyl-6 glyceride, oleoyl-polyoxyl-6-glyceride, lauroyl polyoxyl-6-glyceride, ethyl oleate, polyglyceryl-3-dioleate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglyceryl-3-dioleate, caprylocaproyl polyoxyl-8 glyceride, cyclodextrin, LABRASOL® (caprylocaproyl macrogol glyceride, caprylocaproyl macrogol-8 glyceride EP, caprylocaproyl polyoxyl-8 glyceride NF), etc. More preferably, the range is 0.01% to 95% w / w or w / v.In exemplary embodiments, the formulations of the present disclosure contain solubilizers, surfactants, emulsifiers, dispersants, and similar compounds or chemicals at about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about The composition may be present in concentrations of about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include solubilizers, surfactants, emulsifiers, dispersants, and similar compounds or chemicals at concentrations of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the solubilizers, surfactants, emulsifiers, dispersants, and similar compounds or chemicals may comprise about 1%-75% by weight of the formulation, preferably 2%-30% by weight, and more preferably 5%-20% by weight.

[0081] Example 7 Various techniques and ingredients, including but not limited to coating, encapsulation, microencapsulation, nanoencapsulation, lyophilization, chelating agents, complexing agents, and the like, can be used to enhance the stability and / or solubility of cannabidiol, its free base, its salts, its isomers, its amorphous forms, its crystalline forms, its co-crystalline forms, its prodrugs, its analogs, its derivatives, its synthetic forms, its biosynthetic forms, its active metabolites, alone or in combination, in the formulation.

[0082] Example 8 The transdermal and / or topical formulations of the present disclosure may contain auxiliary pH buffers and pH stabilizers and similar compounds known to those skilled in the art that aid in maintaining the appropriate pH of the formulation, preferably in the range of 4.0-8.0, either alone or in combination, including but not limited to: phosphate buffer, acetate buffer, citrate buffer, etc.; acids, including but not limited to (carboxylic acids, inorganic acids, sulfonic acids, vinyl-based carboxylic acids, etc.); bases, including but not limited to (sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate), etc., more preferably in the range of 0.01%-30% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 Supplementary pH buffering agents and pH stabilizers and similar compounds may be included at concentrations of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include supplemental pH buffering agents and pH stabilizers and similar compounds at concentrations of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, supplemental pH buffering agents and pH stabilizers and similar compounds may comprise about 1%-75% by weight, preferably 2%-30% by weight, and more preferably 5%-20% by weight of the formulation. In certain embodiments, the pH of the formulation is maintained at about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0.In certain embodiments, the pH of the formulation is maintained in the range of about 4.0 to about 8.0, about 4.5 to about 7.5, or about 5.0 to about 7.0.

[0083] Example 9 The transdermal and / or topical formulations of the present disclosure may contain antioxidants known to those skilled in the art to aid in obtaining a stable formulation, such as, but not limited to, (sodium metabisulfite, citric acid, ascorbic acid, BHA, BHT), oxidizing agents, stabilizers, discolorants, preservatives, and similar compounds or chemicals, alone or in combination, more preferably in the range of 0.01% to 50% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 The antioxidant may be included at a concentration of about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include an antioxidant at a concentration of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the antioxidant may comprise about 1%-75% by weight of the formulation, preferably 2%-30% by weight, and more preferably 5%-20% by weight.

[0084] Example 10 The transdermal and / or topical formulations of the present disclosure may be formulated in ointment and / or cream bases known to those of skill in the art.

[0085] Example 11 Materials for making the transdermal delivery system of the present disclosure in the form of a patch known to those skilled in the art include, for example, but are not limited to, reservoir patches, transdermal matrix patches, etc., which may include, for example, but are not limited to, polymers, copolymers, derivatives, backing films, release membranes, release liners, etc., alone or in combination. Pressure sensitive adhesives (for example, but are not limited to, silicone polymers, rubber adhesives, acrylic polymers, acrylic copolymers, polyisobutylene, acrylic acid-isooctyl acrylate copolymers, hot melt adhesives, polybutylene, acrylic pressure sensitive adhesives such as Duro-Tak® 9301, Duro-Tak® 2516, Duro-Tak® 2207, Duro-Tak® 87-2516, Duro-Tak® 87-4287, Duro-Tak® 87-900A, Duro-Tak® 87-9301, etc.), backings, etc. Films (for example, but not limited to, ethylene vinyl acetate copolymer, vinyl acetate resin, polyurethane, polyvinyl chloride, metal foil, polyester, aluminum plated film, polyethylene, light-resistant backing film, etc.), release films (for example, but not limited to, polyethylene microporous film, polypropylene microporous film, rate-controlling ethylene vinyl acetate copolymer film, etc.), release liners (for example, but not limited to, siliconized polyester film, fluororesin coated polyester film, polyester film, siliconized polyethylene terephthalate film, etc.), tapes, etc.

[0086] Example 12 The transdermal and / or topical formulations of the present invention may contain fillers such as but not limited to colloidal silicon dioxide, lactose, mannitol, talc, titanium dioxide, clays such as but not limited to kaolin, bentonite, etc., alone or in combination, more preferably in the range of 0.01% to 70% w / w or w / v.

[0087] Example 13 The transdermal and / or topical formulations of the present invention may include crystallization inhibitors, tackifiers, crosslinkers, resins, and the like, either alone or in combination.

[0088] The transdermal formulations and / or topical formulations and / or transdermal delivery systems of the present disclosure may deliver at least a therapeutically effective amount of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination thereof, in human plasma, the amount of therapeutically effective cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination thereof, required to treat and / or prevent pain and / or inflammation. A therapeutically effective amount of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination, refers to the therapeutic concentration of these forms of cannabidiol in human plasma required to treat and / or prevent pain and / or inflammation. Furthermore, the exact therapeutically effective amount of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, alone or in combination, in a transdermal or topical formulation or transdermal delivery system or transdermal patch can be determined by one skilled in the art based on factors such as, but not limited to, the condition of the patient. The transdermal or topical formulation or transdermal delivery system or transdermal patch will be available in various dosage strengths and patch sizes to achieve optimal therapeutic results based on the patient's requirements.

[0089] In yet another embodiment, the transdermal formulation and / or topical formulation and / or transdermal delivery system or transdermal patch of the present disclosure may deliver at least a therapeutically effective amount of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination. Therapeutically effective cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, refers to the therapeutic concentration of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, in human plasma required to treat and / or prevent and / or control a condition and / or disease and / or disorder related to pain. Pain syndromes include, for example, headache, migraine, tension-type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain, causalgia, complex regional pain syndrome types I and II, reflex sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and pediatric autism spectrum disorder (ASD), pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with renal disease.

[0090] Another aspect of the disclosure relates to the use of the transdermal compositions disclosed herein as prophylactic and / or therapeutic agents for treating pain and / or inflammation, for example, in patients with liver cancer, and as therapeutic agents for treating pain as a side effect of liver cancer medications and treatments. Another aspect of the disclosure relates to the use of the transdermal compositions disclosed herein as prophylactic and / or therapeutic agents for treating pain and / or inflammation, for example, in patients with kidney cancer, and as therapeutic agents for treating pain as a side effect of kidney cancer medications and treatments. Another aspect of the disclosure relates to the use of the transdermal compositions disclosed herein as prophylactic and / or therapeutic agents for treating pain and / or inflammation, for example, in patients with cancer, and as therapeutic agents for treating pain as a side effect of cancer medications and treatments.

[0091] Another aspect of the present disclosure relates to the use of the transdermal compositions disclosed herein as therapeutic agents, for example for the prevention and / or treatment of immunoinflammatory disorders. The term "immunoinflammatory disorders" encompasses a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory skin diseases. Immunoinflammatory diseases cause the destruction of healthy tissues by inflammatory processes, dysregulation of the immune system, and unwanted proliferation of cells.Examples of immune inflammatory diseases include acne vulgaris; acute respiratory syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammatory disease, antineutrophil cytoplasmic antibody (ANCA)-associated small vasculitis; ankylosing spondylitis; arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune hepatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous pemphigoid; cerebral ischemia; chronic obstructive pulmonary disease; cirrhosis; Cogan's syndrome;contact dermatitis;COPD;Crohn's disease;Cushing's syndrome;Dermatomyositis;Diabetes mellitus;Discoid lupus erythematosus;Eosinophilic fasciitis;Erythema nodosum;Exfoliative dermatitis;Fibromyalgia;Focal glomerulosclerosis;Focal segmental glomerulosclerosis;Giant cell arteritis;Gout;Gouty arthritis;Graft-versus-host disease;Hand eczema;Henoch-Schönlein purpura;Herpes of gestation;Hypertrichosis;Idiopathic keratoscleritis cerato-scleritis);idiopathic pulmonary fibrosis;idiopathic thrombocytopenic purpura;immune thrombocytopenic purpura,inflammatory bowel or gastrointestinal disease,inflammatory skin disease;lichen planus;lupus nephritis;lymphomatous tracheobronchitis;macular edema;multiple sclerosis;myasthenia gravis;myositis;nonspecific fibrosing lung disease;osteoarthritis;pancreatitis;pemphigoid of pregnancy;pemphigus vulgaris;periodontitis;polyarteritis nodosa;polymyalgia rheumatica;scrotal pruritus;itch / inflammation,psoriasis;psoriatic arthritis;pulmonary histoplasmosis;rheumatoid arthritis;relapsing polychondritis;rosacea caused by sarcoidosis;rosacea caused by scleroderma ;rosacea caused by Sweet's syndrome;rosacea caused by systemic lupus erythematosus;rosacea caused by hives;rosacea caused by the pain associated with shingles;sarcoidosis;scleroderma;segmental glomerulosclerosis;septic shock syndrome;shoulder tendonitis or bursitis;Sjogren's syndrome;Still's disease;brain cell death due to stroke;Sweet's disease;systemic lupus erythematosus;systemic sclerosis;Takayasu's arteritis;temporal arteritis;toxic epidermal necrolysis;transplant rejection and transplant rejection-related syndrome;tuberculosis;type 1 diabetes mellitus;ulcerative colitis;uveitis;vasculitis;andWegener's granulomatosis.

[0092] Another aspect of the present disclosure relates to the use of the transdermal compositions disclosed herein as therapeutic agents, for example, for the prevention and / or treatment of inflammation. Symptoms and signs of inflammation associated with certain conditions include: Rheumatoid arthritis: pain, swelling, warmth, tenderness of the involved joints; generalized and morning stiffness; Insulin-dependent diabetes mellitus - insulitis; this condition can lead to various complications due to inflammatory components such as retinopathy, neuropathy, nephropathy; Coronary artery disease, peripheral vascular disease, and cerebrovascular disease; Autoimmune thyroiditis: weakness, constipation, shortness of breath, swelling of face, hands and feet, peripheral edema, bradycardia; Multiple sclerosis: spasticity, blurred vision, dizziness, weakness of hands and feet, paresthesia; Uveoretinitis: poor night vision. loss of peripheral vision; lupus erythematosus: joint pain, rash, photosensitivity, fever, muscle pain, swelling of hands and feet, abnormal urinalysis (hematuria, cylinduria, proteinuria), glomerulonephritis, cognitive impairment, vascular thrombosis, pericarditis; scleroderma: Raynaud's disease; swelling of hands, arms, legs, face; thickened skin; pain, swelling and stiffness in fingers and knees, gastrointestinal dysfunction, restrictive lung disease; pericarditis; renal failure; other arthritic conditions with an inflammatory component, e.g., rheumatoid spondylitis, osteoarthritis, septic arthritis and polyarthritis: fever, pain, swelling, tenderness; other inflammatory brain disorders , e.g., meningitis, Alzheimer's disease, AIDS dementia, encephalitis: photophobia, cognitive impairment, memory loss; other inflammatory eye inflammations such as retinitis: decreased vision; inflammatory skin disorders, e.g., eczema, other dermatitis (e.g., atopic, contact), psoriasis, burns caused by UV radiation (sunlight and similar UV sources): erythema, pain, scaling, swelling, tenderness; inflammatory bowel diseases such as Crohn's disease, ulcerative colitis: pain, diarrhea, constipation, rectal bleeding, fever, arthritis; asthma: shortness of breath, wheezing; other allergic diseases such as allergic rhinitis: loss of sensation due to stroke, movement Sneezing, itching, runny nose associated with acute trauma such as brain injury following loss of movement and cognitive loss; heart tissue damage due to myocardial ischemia: pain, shortness of breath; lung injury as occurs in adult respiratory distress syndrome: shortness of breath, hyperventilation, reduced oxygen supply, pulmonary infiltrates; inflammation associated with infection such as sepsis, septic shock, and toxic shock syndrome: fever, respiratory failure, tachycardia, hypotension, leukocytosis; other inflammatory conditions associated with specific organs or tissues, for example: (i) nephritis (e.g., glomerulonephritis): oliguria, abnormal urinalysis; (ii) inflammation of the appendix: fever, pain, tenderness, leukocytosis;(iii) gout: pain, tenderness, swelling and erythema of the involved joint, elevated serum and / or urinary uric acid; (iv) inflammation of the gallbladder: abdominal pain and tenderness, fever, nausea, leukocytosis; (v) congestive heart failure: shortness of breath, rales, peripheral edema; (vi) type II diabetes: end-organ complications including cardiovascular disease, eye disease, kidney disease, and peripheral vascular disease; (vii) pulmonary fibrosis: hyperventilation, shortness of breath, reduced oxygen supply; (viii) vascular disease such as atherosclerosis and restenosis: pain, loss of sensation, reduced pulse, loss of function; and (ix) alloimmunity causing transplant rejection: pain, tenderness, fever. Another aspect of the present disclosure relates to the use of the transdermal compositions disclosed herein as therapeutic agents for the prevention and / or treatment of autism spectrum disorder (ASD), and in pediatric patients.;

[0093] Transdermal formulations or transdermal patches of cannabidiol, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, alone or in combination, may be applied to the skin surface, preferably with a dosing regimen, such as, but not limited to, any of the following: once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, or once every 15 days.

[0094] Example 14 Synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation Nos. 001, 002, 003, 004, and 005) were prepared by mixing the ingredients shown in Table 1.

[0095] [Table 1]

[0096] All ingredients in Table 1 except CBD were mixed under stirring for 18 hours. The final transdermal formulation was then prepared by adding CBD to the excipient mixture. The following flux measurement tests were then performed on the prepared transdermal formulations. Human cadaver skin stored at -80°C was thawed at room temperature in phosphate buffered saline (PBS) and visually inspected for defects before use in the study. The transdermal flux was then measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment with a volume of 13 mL. The human cadaver skin was clamped between the two compartments with the dermal side facing the receptor compartment. The donor compartment was filled with the transdermal CBD formulation prepared as described above. The receptor compartment was filled with receptor medium, kept at a constant temperature, and constantly stirred to collect the CBD that diffuses through the skin into the receptor compartment. It is important to ensure that the receptor fluid is in constant contact with the skin. The receptor compartment was emptied at 24-h intervals for assay of CBD and replaced with fresh receptor solution. To maintain sink conditions in the receptor compartment, it is important to keep the CBD concentration in the receptor compartment below 10% of its solubility. The experimental conditions are shown in Table 5.

[0097] [Table 2]

[0098] The flux of CBD through human cadaver skin was measured for the shortest period of time, 144 hours (6 days), and the results of the flux measurements are shown in Table 6.

[0099] [Table 3]

[0100] Example 15 Additional synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation Nos. 006-014) were prepared by mixing the ingredients shown in Table 4.

[0101] [Table 4]

[0102] Synthetic cannabidiol formulations (006-014) for transdermal delivery were prepared by the same procedure as described in Example 1. Flux measurements were also performed as described in Example 1. The experimental conditions were the same as those shown in Table 2 of Example 1.

[0103] The flux of CBD through human cadaver skin was measured for a minimum period of 48 hours. The results of the flux measurement experiments are shown in Table 5.

[0104] [Table 5]

[0105] Example 16 Additional synthetic cannabidiol (CBD) formulations for transdermal delivery patches (Formulation Nos. 015-018) were prepared by mixing the ingredients shown in Table 6.

[0106] [Table 6]

[0107] To prepare the transdermal patch containing synthetic cannabidiol, all ingredients in Table 6 except CBD were mixed with stirring for 18 hours. CBD was then added 30 minutes before spreading the formulation. The formulation was spread using a commercially available bench top spreader. Specifically, the formulation matrix was spread evenly to a thickness of 0.5 mm on a 20×36 cm (8×14 in) sheet of release liner (such as 3M 9744). The sheet was then placed in a 38° C. (100° F.) oven for 1 hour to evaporate the ethyl acetate and ethanol adhesive solvents. An opaque backing film with low oxygen permeability (such as 3M 9730NR film) is then carefully attached to the sheet by hand to avoid the formation of bubbles or voids in order to inhibit photodegradation and oxidative degradation. A circular mold (4 cm (1.5 in.) diameter) was used to cut patches (7 cm 2 inch (1.5 in.) diameter) for subsequent studies. 2 ) was cut out.

[0108] The general procedure for measuring the flux of the transdermal formulations in the above examples is as follows: Human cadaver skin stored at -80°C was thawed at room temperature in PBS and visually inspected for defects before use. Transdermal flux was measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment of 13 mL volume. Human cadaver skin was clamped between the two compartments with the dermis side facing the receptor compartment. The general procedure for measuring the flux of the transdermal adhesive patch is as follows: The release liner is removed from the patch and the adhesive side is applied to a piece of human cadaver skin. The transdermal patch is adhered to the skin with the skin side of the patch in contact with the donor compartment. The receptor compartment is filled with receptor medium and kept at a constant temperature and constantly stirred to collect the CBD that diffuses from the adhered patch through the skin into the receptor compartment. It was ensured that the receptor fluid was in contact with the skin at all times. The receptor compartment was emptied at 24-hour intervals and replaced with fresh receptor solution for CBD assay. To maintain sink conditions in the receptor compartment, the CBD concentration in the receptor compartment was kept below 10% of its solubility. The experimental conditions were the same as those shown in Table 2 of Example 15.

[0109] Example 17 Synthetic cannabidiol (CBD) formulations for transdermal delivery (formulation numbers 047-055) were prepared by mixing the ingredients shown in Table 7.

[0110] [Table 7]

[0111] The above ingredients (Table 7) are blended by stirring for 18 hours, after which the matrix is ​​spread evenly onto a 20 x 36 cm (8 x 14 in) sheet of release liner (such as 3M 9744) to a thickness of 0.5 mm using a commercial bench-top spreader. The sheet is then placed in a 30 °C (86 F) oven for 120 minutes to allow the ethyl acetate adhesive solvent to evaporate. An opaque backing film with low oxygen permeability (such as 3M 9730NR film) is then carefully applied by hand to avoid the formation of bubbles or voids to inhibit photodegradation and oxidative degradation. A circular mold (4 cm (1.5 in) diameter) is used to cut out patches (1.76 square cm) for subsequent studies. The drug adhesive matrix after drying has a surface density of 2-30 mg / square cm and contains 5% w / w CBD.

[0112] The prepared formulations were then subjected to release testing as follows: After weighing the patches (n=3), the release liner was removed and the patches were placed in a 20 ml scintillation vial with 15 ml of receiving medium. The receiving medium was a PBS solution at pH 7.4 containing 0.5% Brij®(O)20. The vials were placed on a roller overnight at 20 RPM. Samples were taken every 24 hours up to 72 hours, with a complete change of medium each time. The samples were then analyzed by HPLC to determine the % release of CBD from the different formulations.

[0113] The prepared formulations are also analyzed for uniformity of drug content. Patches (n=3) were weighed for each formulation, the release liner was removed, and the patch (including release liner) was placed in a 20 ml scintillation vial with 15 ml of IPA:Ethanol (190 proof) (50:50) solution. The vial was then placed on a roller at 20 RPM and left overnight. To determine the drug content of each formulation, samples were taken from each vial and analyzed by HPLC.

[0114] [Table 8]

[0115] The % release of CBD through the matrix system was measured for a minimum period of 48 hours (2 days) and the % release results are shown in Table 12.

[0116] [Table 9]

[0117] The drug content study showed that the recovery of CBD in the extract was between 96 and 107% for all the formulations produced. Furthermore, the release test showed that the silicone adhesive 4501 showed more than 90% release within the first 24 hours. Based on the release profile, the most suitable adhesives for CBD formulations are: BIOPSA®-4501>2054=2194>2074>2516>2852=2287>9301.

[0118] Release studies have shown that functional groups and crosslinkers affect CBD release from acrylic adhesives. Current research has shown that acrylic adhesives containing -COOH functional groups along with crosslinkers release the greatest amount of CBD from all acrylic adhesive patches.

[0119] Example 18 Additional synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation Nos. 057-064) were prepared by mixing the ingredients shown in Table 10.

[0120] [Table 10]

[0121] Synthetic cannabidiol formulations (057-064) for transdermal delivery were prepared by the same procedure as described in Example 17. The following flux measurement tests were then performed on the prepared transdermal formulations. Human cadaver skin stored at -80°C was thawed at room temperature in phosphate buffered saline (PBS) and visually inspected for defects before use in the study. The transdermal flux was then measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment with a volume of 13 mL. The human cadaver skin was clamped between the two compartments with the dermal side facing the receptor compartment. The donor compartment was filled with the transdermal CBD formulation prepared as described above. The receptor compartment was filled with receptor medium and kept at a constant temperature and with constant stirring to collect the CBD diffusing through the skin into the receptor compartment. It is important to ensure that the receptor fluid is in constant contact with the skin. The receptor compartment was emptied at 24-h intervals for assay of CBD and replaced with fresh receptor solution. To maintain sink conditions in the receptor compartment, it is important to keep the CBD concentration in the receptor compartment below 10% of its solubility. The experimental conditions are shown in Table 11:

[0122] [Table 11]

[0123] The flux of CBD through human cadaver skin was measured for a minimum period of 96 hours (4 days). The results of the flux measurements are shown in Table 12. Once the flux test was completed, the used patch was carefully removed and the CBD was extracted from the used patch using IPA:ethanol (50:50). Human cadaver skin was also soaked in IPA:ethanol (50:50) to extract CBD therefrom. Samples were analyzed using HPLC. The data in Table 12 shows the amount of CBD present in the skin and remaining patch.

[0124] [Table 12]

[0125] Example 19 Effect of gelling agent and its concentration on the permeation of CBD through human cadaver skin. CBD gel formulations may be prepared using gels containing natural polymers such as, but not limited to, natural polymers, polysaccharides and their derivatives, including, but not limited to, (agar, alginic acid and derivatives, cassia, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan gum, copal, starch, chitosan, resins, etc.), synthetic polymers and their derivatives, including, but not limited to, carboxyvinyl polymers or carbomers (carbopol® 940, carbopol® 934, carbopol® 971), polyethersulfones, terpenes, sorbitols ... The CBD may be gelled by gelling agents such as clays such as silicates, polyvinyl alcohol, polyacrylamides, polyvinylpyrrolidone homopolymers and copolymers thereof (PVP, poloxamers), acrylic acid and its esters, polyacrylate copolymers, isobutylene, ethylene vinyl acetate copolymers, natural rubber, synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, isoprene block copolymers, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, and silicone-based pressure sensitive adhesives or "hot melt adhesives". In addition to human cadaver skin, CBD may also be evaluated in other artificial membranes, including but not limited to cellulose membranes, silicone membranes (polydimethylsiloxane), liposome-coated membranes, solid-supported liquid membranes, lecithin organogel membranes, etc. In addition to gel formulations of CBD, other formulations may be used, including but not limited to ointments, creams, emulsions, liposomes, etc.

[0126] Example 20 The effect of enhancers or solubilizers on the flux of CBD through human cadaver skin was evaluated. The desired optimal composition of the CBD gel formulation included dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), lactic acid, Tween®-20, high-purity diethylene glycol monoethyl ether (Transcutol P), dipropylene glycol, polyethylene glycol-400, propylene glycol (PG), hexylene glycol (HG), and lauroglycol-90. Apart from the above mentioned enhancers and / or solubilizers, transdermal delivery of CBD can be achieved using solvents such as water, sulfoxides and similar chemicals, including but not limited to (dimethyl sulfoxide, dimethylacetamide, dimethylformamide, decyl methyl sulfoxide, dimethyl isosorbide, etc.), azones, pyrrolidones, including but not limited to (N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), esters, including but not limited to (propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monooleate, glycerol monolaurate, lauryl laurate, etc.), fatty acids, including but not limited to (capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, etc.). etc.), alcohols, fatty alcohols and glycols, such as but not limited to (oleyl alcohol, naphthol, dodecanol, propylene glycol, glycerol, etc.), ethers, such as but not limited to (diethylene glycol monoethyl ether), urea, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, esters of fatty alcohols, esters of long chain fatty acids with methyl, ethyl or isopropyl alcohol, esters of fatty alcohols with acetic acid, lactic acid, and diethanolamine oleate, essential oils, terpenes and terpenoids, such as but not limited to (terpineol, limonene, thymol, cineol, etc.), surfactant type enhancers (polysorbate 80, polysorbate 20, etc.), liposomes, niosomes, transferomes, ethanolosomes, polysorbates,For example, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc., spans, for example, but not limited to, span 80, span 20, etc., surfactants, for example, anionic, cationic, nonionic and amphoteric, propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate, medium chain triglycerides, propylene glycol monolaurate type II, linoleoyl polyoxyl-6 glycerides, The composition may be affected by enhancers and / or solubilizers, including but not limited to glycerides, caprylic acid glycerides, oleoyl-polyoxyl-6-glycerides, lauroyl polyoxyl-6-glycerides, polyglyceryl-3-diolate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, etc., cyclodextrins, polyhydric alcohols, especially 1,2-propanediol, butanediol, glycerol, polyethylene glycol (molecular weight 100 or more), dimethyl sulfoxide, dimethyl isosorbide, tetrahydrofurfuryl alcohol, diethyl tolumide, monoisopropylidene glycerin, etc. Solubilizers, surfactants, emulsifiers, dispersants and similar compounds or chemicals known to those skilled in the art may be used alone or in combination.

[0127] Example 21 The oral bioavailability of CBD is only 13-19%. For calculation purposes, we took the average bioavailability to be 15%. 17 Therefore, the actual dose delivered to patients upon oral delivery is shown in Table 13.

[0128] [Table 13]

[0129] Thus, a 50 cm2 patch with a flux of 0.78 μg / cm2 / hr delivers 0.93 mg of drug per day through the transdermal route, which corresponds to an oral dose of 6.2 mg / day. As we know, a dose of 6.2 mg / day is very effective in reducing knee joint swelling. This formulation can deliver the required amount of CBD to reduce arthritis pain.

[0130] Some research studies have shown that the oral bioavailability of CBD is in the range of 5-6%. 17、18 This indicates that patch size may be reduced based on first-in-human bioavailability data.

[0131] References:

[0132] [Table 14-1]

[0133] [Table 14-2]

[0134] Although the present invention has been described in detail with reference to specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A transdermal and / or topical pharmaceutical composition comprising: from about 0.1% to about 20% of an active agent selected from the group consisting of synthetic cannabidiol, natural cannabidiol, and combinations thereof; From about 35% to about 99% of at least one adhesive and / or polymer; Optionally, from about 0.1% to about 30% of at least one penetration enhancer; Optionally, from about 0.1% to about 40% of a gelling agent 23. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the CBD or a derivative thereof is produced by a synthetic route.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the active agent is a high-purity cannabis extract containing at least about 90% (w / w) cannabidiol (CBD).

4. The adhesive and / or polymer may be selected from the group consisting of hydroxylpropylmethylcellulose, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971pNF, polyethylene and copolymers thereof, clays, silicates, bentonite, silicon dioxide, polyvinyl alcohol, acrylic polymers, Eudragit, acrylic acid esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and copolymers, PVP, Kollidon® 30, poloxamers, isobutylene, ethylvinyl acetate copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives, bio 3. The pharmaceutical composition of claim 1 or 2, wherein the adhesive is selected from the group consisting of PSA® 4302, Bio-PSA® 4501, 4202, acrylic pressure sensitive adhesives, Duro-Tak® 87-2156, Duro-Tak® 387-2287, polyisobutylene, low molecular weight polyisobutylene, medium molecular weight polyisobutylene, 35000 mw polyisobutylene, acrylic copolymers, rubber adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and / or organic solvent swellable polymers, and combinations thereof.

5. The at least one penetration enhancer is present and is dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, decimethyl sulfoxide, dimethyl isosorbide, 1,3-butanediol, azone, pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone, esters, fatty acid esters, propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monolaurate, glycerol monolaurate, methyl laurate, lauryl laurate, fatty acids, capric acid, caprylic acid, lauric acid, oleic acid, myristic acid.

3. The pharmaceutical composition of claim 1 or 2, wherein the active ingredient is selected from the group consisting of acids, linoleic acid, stearic acid, palmitic acid, alcohols, fatty alcohols and glycols, oleyl alcohol, nathanol, dodecanol, propylene glycol, glycerol, ether alcohols, diethylene glycol monoethyl ether, urea, triglycerides, triacetin, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, esters of fatty alcohols, essential oils, surfactant type enhancers, brij®, sodium lauryl sulfate, Tween®, polysorbates, terpenes, terpenoids, and combinations thereof.

6. The at least one gelling agent is present and may be selected from the group consisting of natural polymers, polysaccharides and derivatives thereof, agar, alginic acid and derivatives, cassia, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan gum, copal, starch, chitosan, resins, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971, polyethylene and its copolymers, clays, silicates, polyvinyl 3. The pharmaceutical composition of claim 1, wherein the adhesive is selected from the group consisting of polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone homopolymer and copolymer, PVP, poloxamer, acrylic acid and its esters, polyacrylate copolymers, isobutylene, ethylene vinyl acetate copolymers, natural rubber, synthetic rubber such as styrene-diene copolymers, styrene-butadiene block copolymers, isoprene block copolymers, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, silicone based pressure sensitive adhesives, hot melt adhesives, and combinations thereof.

7. 3. The pharmaceutical composition of claim 1 or 2, further comprising an effective amount of a carrier or ingredient selected from the group consisting of solvents, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, oxidizing agents, and combinations thereof.

8. 3. The pharmaceutical composition of claim 1 or 2, formulated as a transdermal patch.

9. 3. The pharmaceutical composition of claim 1 or 2, formulated as a transdermal patch, said transdermal patch being selected from the group including reservoir patch, microreservoir patch, matrix patch, pressure sensitive adhesive patch, sustained release transdermal film, liquid reservoir system, microreservoir patch, matrix patch, pressure sensitive adhesive patch, mucoadhesive patch, and combinations thereof.

10. 3. The pharmaceutical composition of claim 1 or 2, which is indicated for the treatment of a condition selected from the group consisting of headache, migraine, tension-type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain, burning pain, complex regional pain syndrome types I and II, reflex sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and pediatric ASD, pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with kidney disease, pain and / or inflammation in patients with liver cancer, pain and / or inflammation in patients with kidney cancer, pain and / or inflammation in patients with cancer, and combinations thereof.

11. 3. The pharmaceutical composition of claim 1 or 2, which is formulated as a transdermal formulation applied to a patient for a period of time selected from the group consisting of, for example, about 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 108 hours, 120 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, and 4 months.

12. The pharmaceutical composition of claim 1 or 2, which can be formulated as a microneedle.

13. 3. The pharmaceutical composition of claim 1 or 2, wherein the CBD or a derivative thereof is produced synthetically or by a synthetic route.

14. 3. The pharmaceutical composition of claim 1 or 2, co-administered with at least one additional active agent selected from the group consisting of analgesics, anti-inflammatory agents, opioid agents, and combinations thereof.

15. 3. The pharmaceutical composition of claim 1 or 2, further comprising at least one additional active agent selected from the group consisting of analgesics, anti-inflammatory agents, opioid agents, and combinations thereof.

16. 3. A pharmaceutical composition according to claim 1 or 2 for use in a method for the treatment and / or prevention and / or alleviation and / or control of pain and / or inflammation, said method comprising: Selecting a patient in need of treatment and / or prevention and / or reduction and / or control of pain and / or inflammation; topically applying said pharmaceutical composition 13. A pharmaceutical composition comprising:

17. 17. The pharmaceutical composition of claim 16, wherein the topical application of the transdermal patch for the treatment and / or prevention and / or control of pain and / or inflammation is selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days.

18. The pharmaceutical composition of claim 16, wherein the method further comprises providing a constant rate of delivery of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every 10 days up to once every 30 days.

19. The pharmaceutical composition of claim 16, wherein the method further comprises providing a steady absorption rate of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every 10 days up to once every 30 days.

20. The pharmaceutical composition of claim 16, wherein the method further comprises achieving a constant therapeutic serum level of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every 10 days up to once every 30 days.

21. The pharmaceutical composition of claim 16, wherein the method further comprises achieving reduced variability in dosage of the active ingredient of the transdermal patch over a period selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every 10 days up to once every 30 days.

22. The pharmaceutical composition of claim 16, wherein the method further comprises providing a therapeutic plasma concentration of the active ingredient of the transdermal patch within the therapeutic range for a period of time selected from the group consisting of once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every 10 days up to once every 30 days.

23. 17. The pharmaceutical composition of claim 16, wherein the topical application of the transdermal patch is for the treatment and / or prevention and / or control of pain and / or inflammation of conditions selected from the group consisting of headache, migraine, tension type headache, cluster headache, acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain, inflammatory pain, fibromyalgia, drug induced neuropathic pain, burning pain, complex regional pain syndrome type I and type II, reflex sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis and rheumatism, migraine, muscle spasms associated with multiple sclerosis and paralysis, autism spectrum disorder (ASD) and pediatric autism spectrum disorder (ASD), pain and / or inflammation in patients with liver disease, pain and / or inflammation in patients with kidney disease, pain and / or inflammation in patients with liver cancer, treatment of pain and / or inflammation in patients with kidney cancer, pain and / or inflammation in patients with cancer, and combinations thereof.