TRANSDERMAL PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF CHRONIC PAIN - Patent application

Abstract

The present disclosure relates to the transdermal administration of active agents such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, for the treatment and / or prevention and / or control of chronic pain.

Description

[Background technology]

[0001] Pain results from noxious stimulation of nerve endings. Nociceptive pain is caused by noxious stimulation of nociceptors, which transmit impulses through intact nerve pathways to spinal cord neurons and then to the brain. Peripheral neuropathic pain is pain due to damage to nerve endings, mostly found in the skin, especially the epidermis. These damaged nerve endings may generate impulses in the absence of stimulation, may be hypersensitive to normal stimulation, and / or may be triggered by residual local inflammatory stimulation. Even a very small number of damaged and overactive small nerve fibers in the epidermis are sufficient to cause peripheral neuropathic pain. Neuropathic pain can be debilitating and can considerably reduce the quality of life of the patient. This pain may persist for months or years beyond the apparent healing of any damaged tissue.

[0002] Neuropathic pain has a local inflammatory component that leads to sensitization of nerve fibers.Other intact nerve fibers, such as nociceptors that are present in the granular layer and innervate the same area, may also be sensitized and contribute to the clinical symptoms of neuropathic pain (e.g., hyperalgesia).This leads to a situation of local neurogenic inflammation that leads to many different clinical features, such as burning sensation, freezing, electric shock, itching, tingling, numbness, hyperalgesia, and allodynia (pain resulting from non-painful stimuli such as light touch or stroke).

[0003] Peripheral nerve injury can result in enhanced transmitter release in the spinal cord, leading to central sensitization. Increased peripheral input via primary afferents is crucially involved in the maintenance of central sensitization and neuropathic pain. Peripherally acting drugs such as lidocaine 5% medicated patch and capsaicin 8% patch have demonstrated the ability to reduce pain in neuropathic pain syndromes. However, lidocaine patches are not easy to apply, especially to the toes by the elderly, as the patch must be cut off and many elderly people cannot reach their toes properly. Application of capsaicin creams and patches very often induces intolerable side effects such as increased burning sensation, and the procedure must often be combined with a local anesthetic to neutralize this side effect.

[0004] In general chronic pain, oral analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are part of the guidelines aimed at reducing pain. However, chronic use of such oral analgesics may induce serious and even fatal side effects and / or adverse drug-drug interactions.

[0005] Topical analgesic pharmaceutical compositions are also being investigated to provide relief to patients suffering from chronic pain. The two most commonly used topical compounds in neuropathic pain are capsaicin (a vanilloid receptor agonist and counterirritant) and lidocaine (a membrane stabilizer), both of which have obvious drawbacks.

[0006] Clearly, there remains a pressing and long felt need in the art to develop treatment options for chronic and neuropathic pain in general, and in particular, to develop new and effective pharmaceutical compositions for use in the treatment of chronic pain that have reduced side effects in patients.

[0007] Cannabis (marijuana) is a Schedule I drug in the United States. Cannabis is a flowering plant that contains over 400 phytonutrients (micronutrients). Over 100 different types of terpenoids, essential oils, antioxidants, and cannabinoids have been extracted from the plant. From all the phytochemicals, only tetrahydrocannabinol (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 components such as cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and delta 9-tetrahydrocannabinol (delta 9 THC) have been studied, which also showed some therapeutic effects without psychoactive effects. Cannabis and its derivatives can be used to treat pain, type 2-related metabolic disorders, intraocular pressure reduction, Dravet syndrome, Lennox-Gastaut syndrome (LGS), epilepsy, nausea, AIDS-related pain and wasting, arthritis and rheumatism, migraine, muscle spasticity associated with multiple sclerosis and paralysis, alcohol and narcotic withdrawal symptoms, stress and depression, asthma, fibromyalgia, inflammatory pain, and chemotherapy-related pain and / or inflammation, and have been shown to act as antibacterial agents. The FDA has approved dronabinol (Marinol and Syndros), which contains delta 9-THC, and is currently used to treat nausea, vomiting, and anorexia associated with chemotherapy treatments. Additionally, in April 2016, the FDA designated cannabidiol an orphan drug 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).

[0008] Diclofenac has analgesic properties and is widely used to treat various types of pain, including both chronic and acute pain manifestations.This drug is administered to treat musculoskeletal and joint disorders such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis; periarticular disorders such as bursitis and tendonitis; soft tissue disorders such as sprains and strains, and other pain conditions such as renal colic, acute gout, dysmenorrhea, and after some surgical procedures.

[0009] There is a need for an improved drug delivery system for diclofenac and / or CBD and / or THC that can overcome the shortcomings associated with the oral route.Transdermal delivery of diclofenac and / or CBD and / or THC, their free bases, their salts, their isomers, their amorphous forms, their crystalline forms, their co-crystalline forms, their prodrugs, their analogs, their derivatives, their synthetic forms, their biosynthetic forms, their active metabolites, their ion pairs, their solid solutions, their polymorphs, their stereoisomers, their coated forms, their solutions in solvents, alone or in combination, can address the challenges associated with oral drug delivery and are useful, for example, for the treatment, prevention, and / or control of chronic pain.

[0010] All references cited herein are hereby incorporated by reference in their entirety. [Prior art documents] [Non-patent literature]

[0011] [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. Vol. 556, No. 1-3, February 5, 2007, pp. 75-83 Summary of the Invention

[0012] The present disclosure provides compositions and methods for treating and / or preventing and / or controlling, for example, chronic pain, using transdermal drug delivery. In transdermal drug delivery, a transdermal patch or a transdermal composition is applied topically to the skin surface. Over the duration of topical application of a transdermal patch or a transdermal composition, drug is continuously released and delivered through intact skin (via transcellular, intercellular, and transappendage pathways) to achieve systemic effect. Thus, once applied, a transdermal composition or a transdermal patch can deliver drug to systemic circulation throughout the day, or even beyond the day, depending on the duration of its application, which can be up to one week, up to 15 days.

[0013] Transdermal delivery can reduce the frequency of administration of, for example, diclofenac and / or CBD and / or THC, which is currently administered several times a day. Through transdermal delivery, for example, a transdermal composition or a transdermal formulation or a transdermal patch of diclofenac and / or CBD and / or THC can be applied locally to the skin, thereby delivering the drug for the duration of the topical application. If necessary, the duration of the 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, once every 15 days. Thus, transdermal delivery can overcome the multiple-dose regimen of oral delivery by reducing the frequency of administration.

[0014] Furthermore, in transdermal drug delivery, the drug is delivered slowly and continuously over the duration of topical application, and thus there are no peaks and troughs in drug plasma concentration associated with multiple doses in a day.Thus, for example, by transdermal delivery of diclofenac and / or CBD and / or THC, patients can have the therapeutic effect of the drug for an extended period of time without dramatic changes in drug plasma concentration.

[0015] Moreover, transdermal delivery is easy, non-invasive and convenient.Transdermal patch or transdermal composition administration does not require medical supervision, because patients can locally apply transdermal patch or transdermal composition themselves.Therefore, transdermal delivery can overcome the shortcomings of injection, which is often painful and requires medical supervision.

[0016] For diclofenac and / or CBD and / or THC, the interpatient variability of pharmacological response is expected to be less with transdermal delivery since the drug plasma concentration can be controlled by controlling the rate of drug delivery from the transdermal composition or transdermal patch. With transdermal delivery, small amounts of diclofenac and / or CBD and / or THC can be delivered for a longer period of time than oral administration. For example, transdermal formulations of diclofenac and / or CBD and / or THC also provide more abuse deterrence than immediate release dosage forms. Furthermore, in case of any adverse effects, side effects, or emergency, transdermal delivery gives the freedom to terminate treatment at any time by removing the transdermal patch or transdermal composition from the skin. Furthermore, transdermal delivery can avoid the common side effects of nausea and abdominal pain associated with oral diclofenac administration.

[0017] For the above reasons, transdermal delivery can provide a more patient-friendly, simple and convenient treatment regimen than conventional delivery systems for the treatment and / or prevention and / or control of chronic pain.Transdermal delivery can reduce the administration frequency of diclofenac and / or CBD and / or THC.As needed, administration frequency can be 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 15 days.

[0018] The transdermal administration of drug combination can deliver two or more drugs 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 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 15 days.This will be a great reinforcement for patient compliance.

[0019] The present disclosure provides pharmaceutical compositions comprising the active agents tetrahydrocannabinol (THC), cannabidiol (CBD), and / or diclofenac, alone or in combination, in a dosage form for transdermal delivery. The present disclosure provides pharmaceutical compositions in which THC is selected from the group consisting of 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 metabolite, its polymorphs, its solid solutions, its ion pairs, its coated forms, its stereoisomers, its solid solutions, its solutions, its powder forms, its liquid forms, alone and in combination. The present disclosure provides a pharmaceutical composition in which CBD is selected from the group consisting of 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, its polymorph, its solid solution, its ion pair, its coated form, its stereoisomer, its solid solution, its solution, its powder form, its liquid form, alone and in combination. The present disclosure provides a pharmaceutical composition in which diclofenac is selected from the group consisting of its free acid, 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, its polymorph, its solid solution, its coated form, its stereoisomer, its solid solution, its ion pair, alone and in combination. The present disclosure provides pharmaceutical compositions in which the salt of diclofenac is selected from the group consisting of diclofenac sodium, diclofenac potassium, and diclofenac epolamine, alone and in combination.The present disclosure provides pharmaceutical compositions in a dosage form for transdermal delivery, comprising one or more active agents selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), diclofenac, a free base thereof, a salt thereof, an isomer thereof, an amorphous form thereof, a crystalline form thereof, a co-crystalline form thereof, a prodrug thereof, an analog thereof, a derivative thereof, a synthetic form thereof, a biosynthetic form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, an ion pair thereof, and a combination thereof.The present disclosure provides pharmaceutical compositions comprising at least about 0.5% to about 70% (w / w) of an active agent. The present disclosure provides pharmaceutical compositions comprising at least about 2% to about 30% of an active agent. The present disclosure provides pharmaceutical compositions formulated as transdermal liquid formulations, transdermal semisolid formulations, transdermal gel formulations, or transdermal polymer matrix formulations, transdermal adhesive matrix formulations, film-forming gel formulations, and / or film-forming spray formulations. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or component selected from the group consisting of a solvent, a gelling agent, a polymer, a pressure-sensitive adhesive polymer, a penetration enhancer, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a tackifier, a diluent, a bulking agent, 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 solvents, gelling agents, polymers, pressure-sensitive adhesive polymers, penetration enhancers, emollients, skin irritation reducers, buffers, pH stabilizers, solubilizers, tackifiers, bulking agents, diluents, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, oxidizing agents, and combinations thereof in the range of 0.5%-98% (w / w or w / v). The present disclosure provides pharmaceutical compositions in which the carrier is present in the range of 70%-98% (w / w or w / v). The present disclosure provides pharmaceutical compositions formulated as transdermal patches. The present disclosure provides pharmaceutical compositions formulated as metered-dose transdermal gels, metered-dose transdermal sprays, film-forming gels, film-forming sprays. The present disclosure provides pharmaceutical compositions formulated as transdermal patches selected from the group of 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, film forming gels, film forming sprays, microdosed patches, mucoadhesive patches, and combinations thereof, etc. The present disclosure provides pharmaceutical compositions indicated for the treatment and / or prevention and / or control of chronic pain in a patient.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 1-8 hours, once 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, once every 15 to about 30 days. The present disclosure provides pharmaceutical compositions formulated as microneedles. The present disclosure provides pharmaceutical compositions in which tetrahydrocannabinol (THC), cannabidiol (CBD), diclofenac, their free bases, their salts, their isomers, their amorphous forms, their crystalline forms, their co-crystalline forms, their prodrugs, their analogs, their polymorphs, their ion pairs, their stereoisomers, their coated forms, their derivatives, their synthetic forms, their biosynthetic forms, their active metabolites, and combinations thereof are produced by synthetic routes. The present disclosure provides a pharmaceutical composition co-administered with at least one additional active agent selected from the group consisting of medicaments administered for the treatment and / or management and / or prevention and / or control of symptoms associated with neuropathic pain, peripheral neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, pain due to increased muscle tone, osteoarthritic pain, muscle headache, tension headache, migraine, cluster headache, atypical facial pain, referred pain, vulvodynia, perianal pain, and any combination thereof.The present disclosure provides a pharmaceutical composition further comprising at least one additional active agent selected from the group consisting of tricyclic antidepressants, amitriptyline, imipramine, nortriptyline, desipramine, acetaminophen, aspirin, ibuprofen, carbamazepine, gabapentin, lamotrigine, pregabalin, valproic acid, duloxetine, and combinations thereof.

[0020] The present disclosure provides a method for treating and / or preventing and / or controlling chronic pain in a patient, comprising the steps of selecting a patient in need of chronic pain treatment and / or prevention and / or control, and topically applying a transdermal pharmaceutical composition of the present disclosure.The present disclosure provides a method, wherein the chronic pain is selected from the group consisting of neuropathic pain, peripheral neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, pain due to increased muscle tone, osteoarthritic pain, muscle headache, tension headache, migraine, cluster headache, atypical facial pain, referred pain, vulvodynia, perianal pain, and any combination thereof.The present disclosure provides a method, wherein the topical application of the transdermal pharmaceutical composition is for treating and / or preventing and / or controlling chronic pain in a patient, and the transdermal patch is applied for 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, once every ten days, and once every fifteen days. The present disclosure provides a method further 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 further providing a stable absorption rate of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method further achieving a constant serum level of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method further achieving reduced variability in the dosage of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method further providing a plasma concentration of the active ingredient of the transdermal patch within a therapeutic range over a period of time. The present disclosure provides a method further providing a plasma concentration of the active ingredient of the transdermal patch within a therapeutic range of about 0.5 ng / mL to about 500 ng / mL. The present disclosure provides a method further providing a plasma concentration of the active ingredient of the transdermal patch within a therapeutic range of about 0.5 ng / mL to about 300 ng / mL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] It is to be understood that the invention is not limited to the particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0022] The detailed description of the present invention is divided into various sections for the convenience of the reader only, and the disclosure found in any section may be combined with the disclosure of another section. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0023] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the following meanings:

[0025] The term "chronic pain" or "chronic pain condition" as used herein is defined as any pain that lasts for longer than, for example, about 6 to about 12 weeks. The term "neuropathic pain" as used herein has its conventional meaning, and herein refers to pain that occurs as a direct or indirect result of injury or disease that affects the somatosensory system (central and / or peripheral).Neuropathic pain as used herein includes all types of neuropathic pain (e.g., peripheral neuropathy caused by type 1 or type 2 diabetes, peripheral neuropathy induced by various harmful substances such as alcohol, various deficiencies (e.g., vitamin B1, B6 and / or B12 deficiency), various poisonings (e.g., vitamin B6 excess), hypothyroidism, chemotherapy compounds (e.g., paclitaxel or other taxane derivatives, vincristine or other vinca alkaloids, cisplatin or other platinum derivatives), drug-induced neuropathy, compounds for the treatment of infectious diseases (e.g., streptomycin, didanosine, or zalcitabine), or any other chemical toxic compounds). Other peripheral neuropathies include: trigeminal neuralgia, post-herpetic neuralgia, intercostal neuralgia, entrapment neuropathy (e.g., carpal tunnel syndrome, tarsal tunnel syndrome, abdominal cutaneous nerve entrapment syndrome), small fiber neuropathy, hereditary motor and sensory neuropathy, chronic inflammatory demyelinating polyneuropathy, sciatica, chronic idiopathic sensory neuropathy, infectious disease states (post-polio syndrome, AIDS or HIV related, Lyme related, Sjogren's related, etc.), lymphomatous neuropathy, myeloma neuropathy, cancer neuropathy, acute panautonomic neuropathy, vasculitic / ischemic neuropathy, and other single and polyneuropathies. Additionally, the term "neuropathic pain" also includes: complex regional pain syndrome types I and II (reflex sympathetic dystrophy), central neuropathic pain (e.g., thalamic neuropathy, spinal cord injury neuropathy, post-stroke pain, multiple sclerosis neuropathy, syringomyelia, spinal cord tumors), phantom limb pain, restless genital syndrome (pain), post-surgical scar pain including cardiac surgery and mastectomy.

[0026] The term "inflammatory pain" as used herein has its conventional meaning and refers herein to pain resulting from inflammation that may be caused by, but is not limited to, trauma, burns, extreme cold, fractures, (osteo)arthritis, rheumatoid arthritis, chronic contusions, surgery, infections and autoimmune diseases, excessive stretching, infections, and vasoconstriction. Multiple inflammatory mediators may affect nociceptors directly or may sensitize nociceptors to touch or movement even at some distance from the area of ​​inflammation.

[0027] The term "musculoskeletal pain" as used herein has its conventional meaning, and herein refers to pain that affects muscles, ligaments, tendons, bones, joints, and / or soft tissues that are part of the musculoskeletal system.Musculoskeletal pain as used herein includes all types of pain caused by muscle tissue damage as a result of the wear and tear of daily activities.Trauma to an area (convulsion, car accident, fall, sports injury, fracture, sprain, strain, dislocation, and direct impact to muscle) can also cause musculoskeletal pain.Other causes of musculoskeletal pain include postural distortion, repetitive motion, overuse, and prolonged immobilization, muscle misuse, fibromyalgia, back pain, pain due to increased muscle tone, and tendonitis due to overuse.

[0028] The term "treatment" as used herein has its conventional meaning and should be considered in its broadest context herein. The term "treatment" is intended to include topical administration of an active compound, i.e., an active pharmaceutical ingredient in, for example, a pharmaceutical composition according to the present disclosure, for the purpose of alleviating an undesirable condition, and therapeutic administration to eliminate or reduce the extent or symptoms of the condition. Treatment does not necessarily mean that the subject is treated until complete recovery.

[0029] The term "analgesic" as used herein has its conventional meaning and refers herein in its broadest context to a compound, agent, drug, or substance that relieves pain. The term "coanalgesic agent" as used herein has its conventional meaning and refers herein to a compound, agent, drug or substance whose primary indication is for a purpose other than pain relief and which exhibits analgesic activity.

[0030] The term "restoring analgesic effect" as used herein has its ordinary scientific meaning and refers herein to the ability (of a compound or composition) to restore the analgesic effect of at least one analgesic compound or at least one co-analgesic compound when a decrease in analgesic effect occurs following repeated use of a topical formulation containing at least one analgesic compound or at least one co-analgesic compound.

[0031] The term "effect booster" or "co-analgesic effect booster" or "therapeutic effect booster" or "booster effect" or "synergistic effect" as used herein has its conventional meaning and refers herein to 1) an enhanced therapeutic effect of an active pharmaceutical ingredient for the purpose of relieving neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, and / or other chronic pain conditions, 2) a faster onset of pain relief effect, 3) a longer duration of analgesia, and / or 4) an enhancement of the therapeutic effect induced by a co-analgesic compound ("co-analgesic agent") that results in a decrease in analgesic effect following repeated use of at least one analgesic compound ("analgesic agent") or a topical pharmaceutical composition containing a co-analgesic compound.

[0032] The term "topical formulation" as used herein has its conventional meaning and refers herein to a formulation that can be applied to the skin or mucosa for the purpose of penetrating a therapeutically active compound into and / or through the skin, e.g., a topical pharmaceutical composition of the present disclosure, e.g., a pharmaceutical composition provided as a topical cream.

[0033] As used herein, the term "transdermal delivery" means delivery of a drug through the skin into the systemic circulation. As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to an animal, preferably a mammal (e.g., non-primates (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and primates (e.g., monkeys and humans)), 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, method, 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 treatment that is sufficient to result in prevention of the onset, recurrence, or development of a disease or condition and one or more symptoms thereof, to enhance or improve the prophylactic efficacy of another treatment, to reduce the severity, duration of a disease or condition, to ameliorate one or more symptoms of a disease or condition, to prevent the progression of a disease or condition, to effect regression of a disease or condition, and / or to enhance or improve the therapeutic efficacy of another treatment.

[0034] 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 particularly in humans.

[0035] 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" can 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.

[0036] The term "derivative" or "derivated" as used herein includes, for example, chemical modifications of the disclosed compounds, or those 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.

[0037] As used herein, the terms "composition" and "formulation" are used interchangeably. Active Agent The term "active ingredient" refers to drugs, active ingredient compounds, or other substances or compositions that provide some pharmacological, often beneficial, effect, and mixtures thereof. Reference to a particular active ingredient is intended to include the active ingredient and its pharmaceutically acceptable salts, where appropriate. The present disclosure provides, for example, transdermal formulations that include one or more of the following active agents:

[0038] Cannabinoids are a group of 21-carbon-containing terpeno-phenolic compounds produced by cannabis species. Cannabinoids can also be synthetically produced. The term "cannabinoid" hereafter refers to a diverse class of chemical compounds that act on cannabinoid receptors on cells that inhibit the release of neurotransmitters in the brain. These receptor proteins include endocannabinoids (produced naturally in the body by humans and animals), phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids. Lipophilic cannabinoids are generally classified as endocannabinoids (most typically mammalian endocannabinoids), phytocannabinoids from plant sources, and synthetic cannabinoids. Such cannabinoids are also often divided into the following subclasses: cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD; CBDL), tetrahydrocannabinol (THC), cannabinol (CBN), cannabicyclol (CBL), cannabielsoin (CBE), and cannabiditriol (CBT).

[0039] 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.

[0040] [ka]

[0041] Tetrahydrocannabinol (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.

[0042] [ka]

[0043] Diclofenac IUPAC name: 2-[2-(2,6-dichloroanilino)phenyl]acetic acid Molecular weight: 296.15g / mol Molecular formula:C 14 H 11 C l2 NO2 The chemical structure is shown below as Formula III.

[0044] [ka]

[0045] As used herein, the term cannabis refers to all pharmaceutically acceptable forms of cannabis and its derivatives, such as, but not limited to, free base, or salt, or isomer, or amorphous, or crystal, or co-crystal, or solid solution, or prodrug, or analog, or polymorph, or stereoisomer, or ion pair, or coated form, or derivative, or metabolite, alone or in combination. 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 polymorph, or stereoisomer, or ion pair, or its coated analog, or its derivative, or synthetic form. The compound may be in the form of a pharmaceutically acceptable salt, such as, for example, an acid addition salt or a base salt, or a solvate thereof, including a hydrate thereof. Suitable acid addition salts are formed from acids which form non-toxic salts, such as, for example, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts. Suitable base salts are formed from bases which form non-toxic salts, such as, for example, the sodium, potassium, aluminum, calcium, magnesium, zinc, and diethanolamine salts.

[0046] 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 prodrugs, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolites, its ion pairs, its solid solutions, its polymorphs, its stereoisomers, its powder form, its liquid form, solutions of cannabidiol in solvents such as, but not limited to, methanol, alone or in combination.

[0047] As used herein, the term "THC" includes 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, its solid solutions, its powder forms, its liquid forms, its polymorphs, its stereoisomers, solutions of THC in solvents such as, but not limited to, methanol, heptane, alone or in combination.

[0048] As used herein, the term "diclofenac" includes its free base, its free acid, its salts, its isomers, its amorphous forms, its crystalline forms, its co-crystalline forms, its prodrugs, its analogs, its derivatives, its synthetic forms, its active metabolites, its solid solutions, its polymorphs, its stereoisomers, its ion pairs, alone or in combination. Salts of diclofenac include, but are not limited to, diclofenac sodium, diclofenac potassium, diclofenac epolamine, and the like.

[0049] As used herein, synthetic cannabinoids include at least the following: AM-087, a cannabinoid agonist derivative of Δ8THC substituted at the 3-side chain, which is a potent CB1 agonist analgesic; AM-251, an inverse agonist of the CB1 cannabinoid receptor with close structural similarity to SR141716A (rimonabant), both of which are biarylpyrazole cannabinoid receptor antagonists and μ-opioid receptor antagonists. methanandamide (AM-356), a stable chiral analogue 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, which is believed to induce its analgesic effects through its activity on the endocannabinoid, COX, and TRPV systems, all of which are involved in pain and response modulation pathways. AM-411 (a potent and fairly selective CB1 full agonist that produces effects similar to other cannabinoid agonists, such as analgesia, sedation, and anxiolysis); AM-630 (6-lodopravadoline) (a potent and selective inverse agonist at the cannabinoid receptor CB2 and a weak partial agonist); more selective than CB1); 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 (analgesic chemicals of the naphthoylindole family that act as full agonists 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), which acts as a potent and selective agonist at the cannabinoid receptor CB1; AM-735 (3-bornyl-Δ8-THC, a mixed CB1 / CB2 agonist); AM-855 (an analgesic cannabinoid agonist at both CB1 and CB2, with moderate selectivity for CB1); AM-881 (an anandaminium with Ki=5.3 nM at CB1 and Ki=95 nM at CB2) AM-883 (an allyl-substituted stereoisomer of anandamide with Ki=9.9 nM at CB1 and Ki=226 nM at CB2); AM-905 (an analgesic cannabinoid that acts as a potent and moderately selective agonist at the CB1 cannabinoid receptor); AM-906 (an analgesic cannabinoid agonist that is a potent and selective agonist at the CB1 cannabinoid receptor); AM-919 (an analgesic cannabinoid receptor agonist that is AM-926 (a potent agonist at both CB1 and CB2 with moderate selectivity for CB1); AM-938 (an analgesic that is a cannabinoid receptor agonist, remaining a potent agonist at both CB1 and CB2 but moderately selective for CB2); AM-1116 (a dimethylated stereoisomer of anandamide); AM-1172 (a potent inhibitor of AEA uptake that is resistant to FAAH hydrolysis) endocannabinoid analogs specifically designed to be selective inhibitors; AM-1220 (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-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole) (a potent and selective agonist for the cannabinoid receptor CB2, which has analgesic effects in mammals, particularly for "atypical" pain such as hyperalgesia and allodynia, and has also shown efficacy in the treatment of amyotrophic lateral sclerosis in mammalian models); AM-1248 (acts as a moderately potent agonist for both cannabinoid receptors CB1 and CB2); AM-1710 (a potent agonist for 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 non-selective agonist for cannabinoid receptors CB1 and CB2);AM-2233 (acts as a very potent full agonist for cannabinoid receptors CB1 and CB2 and has been found to fully substitute for THC in certain mammalian studies, with lower potency than JWH-018 but higher potency than WIN55,212-2);AM-2389 (a potent and moderately selective agonist for the CB1 receptor agonist); AM-3102 (an analogue of oleoylethanolamide (an endogenous agonist of proliferator-activated receptor alpha (PPARα)) that acts as a weak cannabinoid agonist at CB1 and CB2); AM-4030 (an analgesic that is a potent agonist at both CB1 and CB2 but is also moderately selective for CB1); AM-4054 ​​(a potent but slow-acting agonist with CB1 affinity and selectivity over CB2); AM-4113 (a CB1-selective neutral antagonist);AM-6545 (acts as a peripherally selective silent antagonist for CB1 and was developed for the treatment of obesity); JWH-007 (an analgesic that acts as a cannabinoid agonist at both the CB1 and CB2 receptors and has some selectivity for CB2; JWH-007 is an analgesic that acts as a cannabinoid agonist at both the CB1 and CB2 receptors; JWH-015 (acts as a subtype-selective cannabinoid agonist that binds nearly 28-fold more strongly to CB2 than to CB1 and has immunomodulatory effects) and may be useful in the treatment of pain and inflammation); JWH-018 (an analgesic that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors and produces effects similar to THC); JWH-019 (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 analgesic at the CB2 receptor and may be useful in the treatment of pain and inflammation); selective agonist), JWH-048 (a potent and selective agonist for the CB2 receptor), JWH-051 (an analgesic with high affinity for the CB1 receptor, but which is a much stronger agonist for CB2), JWH-057 (a 1-deoxy analogue of Δ8-THC with very high affinity for the CB2 receptor, but also with high affinity for the CB1 receptor); JWH-073 (an analgesic that acts as a cannabinoid agonist at both the CB1 and CB2 receptors; it is somewhat selective for the CB1 subtype); JWH-0 81 (analgesic drug acting 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 (analgesic agent of the naphthoylpyrrole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors); JWH-148 (a moderately selective ligand for the CB2 receptor with over 8-fold selectivity over 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 phenylacetyl indole ligand); a weak cannabinoid agonist of the benzoyl 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 (a potent cannabinoid agonist); JWH-182 (a 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- (4-Methyl-1-naphthyl)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 (analgesics of the aminoalkyl indole family that act as cannabinoid receptor agonists); JWH-203 (analgesics of the phenylacetyl indole family that act as cannabinoid agonists with roughly equal affinity at both the CB1 and CB2 receptors); JWH-205 (142-methyl-1-pentylindol-3-yl)-2-phenylethanone); JWH-210 (analgesics of the naphthoylindole family that act as potent cannabinoid agonists 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 dibenzo-, a potent CB2 agonist; pyran cannabinoids; JWH-234 (a cannabinoid agonist with selectivity for CB2); JWH-250 (an analgesic of the phenylacetylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors); JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole); JWH-258 (a potent, mildly selective CB1 agonist); JWH-302 (1-pentyl-3-(3-methoxyphenylacetyl)indole); JWH-307 (a potent, mildly selective CB1 agonist that inhibits both CB1 and CB2 receptors); analgesics of the naphthoylpyrrole family that act as cannabinoid agonists at both B2 receptors and are somewhat selective for the CB2 subtype; JWH-350 (11-nor-1-methoxy-3-(1',1'-dimethylheptyl)-9α-hydroxyhexahydrocannabinol, which has 33-fold selectivity and high CB2 receptor affinity for the CB2 receptor and little affinity for the CB1 receptor); JWH-359 (a dibenzopyran cannabinoid that is a potent and selective CB2 receptor agonist); JWH-387 (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 (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 analgesic agent with a Ki of 5.44 nM at CB2 and 20.9 nM at CB1) CB2 agonists); HU-210 (a cannabinoid that is 100-800 times more potent than natural THC derived from cannabis, has an extended duration of action, and is a ponntent analgesic with many of the same effects as natural THC); ajuremic acid (AB-III-56, HU-239, IP-751, CPL7075, CT-3, Resunab) (a cannabinoid derivative of the non-psychoactive THC metabolite 11-nor-9-carboxy-THC that exhibits useful analgesic and anti-inflammatory effects without causing a subjective "high."It is being developed for the treatment of neuropathic pain and inflammatory conditions such as arthritis, as well as for the treatment of life-threatening inflammatory rare diseases; HU-243 (AM-4056), a cannabinoid that is a potent agonist at both the CB1 and CB2 receptors; HU-308, which 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 via inhibition of TNF-α; HU-331, HU-336, 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), a drug that can inhibit aortic ring angiogenesis more potently than its parent compound cannabinol; CP47,497 or (C7)-CP47,497, a cannabinoid receptor agonist drug.

[0050] 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, diclofenac and / or CBD and / or THC, 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.

[0051] Diclofenac Diclofenac is a non-steroidal anti-inflammatory drug ("NSAID") with a molecular weight of 296.1 daltons, known chemically as [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid.

[0052] [ka]

[0053] The drug was developed in the 1960s by scientists at Ciba-Geigy and is marketed worldwide by Novartis under various trade names, including Cataflam™ in the United States and Voltaren®. A wet granulation formulation of diclofenac potassium was developed to increase its absorption rate and its pharmacokinetic properties were tested against commercial diclofenac potassium tablets. (Reiner et al.,Increased absorption rate of diclofenac from fast acting formulations containing its potassium salt. Arzniem-Forsch. / Drug Res.2001;51:885-890). According to the authors, the granule formulation showed a higher Cmax than diclofenac potassium tablets, a shorter Tmax (i.e., time to Cmax), and a similar AUC when compared to the tablet form.

[0054] Diclofenac is widely used to treat various types of pain, including both chronic and acute pain episodes, because the compound has analgesic properties.The drug is administered to treat musculoskeletal and joint disorders, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis; periarticular disorders, such as bursitis and tendonitis; soft tissue disorders, such as sprains and strains, and other painful conditions, such as renal colic, acute gout, dysmenorrhea, and after some surgical procedures (Martindale (2000) Diclofenac. In: Reynolds, The Extra Pharmacopoeia. London: The Pharmaceutical Press; p. 31-33). Diclofenac has also been studied for the treatment of headaches resulting from migraine attacks using a variety of doses and formulations, including a 75 mg intramuscular injection (Del Bene et al., Intramuscular treatment of migraine attacks using diclofenac sodium: a cross-over trial. J. Int. Med. Res. 1987;1544-8), a 100 mg suppository (Del Bene et al., Migraine attack treatment with diclofenac sodium. Cephalosporin 1985;5:144-5), and a 50 mg enteric-coated tablet (Massiou et al., Effectiveness of oral diclofenac in the acute treatment of common migraine attacks: a double blind study versus placebo. Cephalosporin 1991;1:59-63).

[0055] According to certain embodiments, the transdermal compositions described herein are for the prevention and / or treatment of chronic pain. According to certain embodiments, the transdermal compositions described herein are for the reduction of the severity of chronic pain.

[0056] According to certain embodiments described herein, the pharmaceutical composition or transdermal formulation contains cannabidiol and / or THC and / or diclofenac, their free bases, their salts, their isomers, their amorphous forms, their polymorphs, their ion pairs, their stereoisomers, their coated forms, their solid solutions, their solutions in solvents, their crystalline forms, their co-crystalline forms, their prodrugs, their analogs, their derivatives, their synthetic forms, their biosynthetic forms, their active metabolites, alone or in combination. More preferably, the transdermal formulation may contain cannabidiol, its free bases, its salts, its isomers, its amorphous forms, its crystalline forms, its co-crystalline forms, its polymorphs, its ion pairs, its stereoisomers, its coated forms, cannabidiol in methanol, its prodrugs, its analogs, its derivatives, its synthetic forms, its biosynthetic forms, its active metabolites, alone or in combination. More preferably, the transdermal formulation may comprise THC, 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, its polymorph, its stereoisomer, its ion pair, its coated form, or a methanol solution of THC, alone or in combination.More preferably, the transdermal formulation may comprise diclofenac, its free base, its free acid, its salt, its isomer, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its active metabolite, its solid solution, its polymorph, its stereoisomer, or its ion pair, alone or in combination.

[0057] As used herein, the term active agent refers to all pharma- ceutically acceptable forms of the active agent and its derivatives, such as, but not limited to, free base, or salt, or isomer, or amorphous, or polymorph, or ion pair, or stereoisomer, or coated form, or crystal, or cocrystal, or solid solution, or prodrug, or analog, or derivative, or metabolite, alone or in combination. For example, the free base of the active agent, or its salt, or its polymorph, or its ion pair, or its isomer, or its coated form, or its isomer, or its amorphous form, or its crystalline form, or its cocrystal 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 its solvate, including its hydrate. Suitable acid addition salts are formed from acids that form non-toxic salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. Suitable base salts are formed from bases that form non-toxic salts, such as sodium, potassium, aluminum, calcium, magnesium, zinc, and diethanolamine salts. The active ingredient may be present in the form of a free base or in the form of a pharma- ceutically acceptable salt. The pharma- ceutically acceptable salts that form part of this invention are intended to define, but are not limited to, salts of carboxylic acid moieties (e.g., alkali metal salts such as Li, Na, and K salts; alkaline earth metal salts such as Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, and the like; ammonium or substituted ammonium salts, and aluminum salts).The salts may be acid addition salts, including, but not limited to, sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarate salts, and the like.

[0058] As used herein, the term active agent includes its free base, its salts, its isomers, its amorphous forms, its crystalline forms, its polymorphic forms, its ion pair forms, its stereoisomers, its coated forms, its co-crystalline forms, its prodrugs, its analogs, its derivatives, its synthetic forms, alone or in combination. In certain embodiments, the active agent is highly purified. In certain embodiments, the active agent is present as a highly purified extract of the active agent that constitutes at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75% (w / w) of the formulation, and in certain embodiments, the dosage of the active agent is, for example, greater than about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.5, 0.75, 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 dosage of the active agent is, for example, greater than about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.5, 0.75, 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. 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 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 8 %, 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% of the active agent.In exemplary embodiments, the formulations of the present disclosure may contain the active agent at a concentration of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the active agent represents about 1 wt%-75 wt%, preferably 2 wt%-30 wt%, and more preferably 5 wt%-20 wt% of the formulation.

[0059] As used herein, the term "pharmaceutically acceptable salts" includes acid addition salts or free base addition salts. The term "pharmaceutically acceptable salts" of active agents within its scope includes 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 that of the compounds of the present disclosure, but that are converted directly or indirectly in vivo to the compounds of the present disclosure when administered to a subject, such as a mammal, particularly a human.

[0060] As used herein, the term "transdermal delivery" means delivery of a drug through the skin into the systemic circulation. Additional active agents As used herein, the term "combined administration" of a compound, therapeutic agent, or combination of a known drug and the present invention means administration of the drug and one or more compounds at a time such that both the known drug and / or combination have a therapeutic effect. In some cases, this therapeutic effect will be synergistic. Such co-administration may include administration of the drug concomitantly (i.e., simultaneously), before, or after administration of the composition and / or combination of the present invention. One of skill in the art will have no difficulty in determining the appropriate timing, sequence, and dosage of administration for a particular drug of the present invention.

[0061] Additionally, the active ingredient may, where applicable, be present in the form of either one substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof.

[0062] The active ingredient may include one or more of the following therapeutic classes, but is not limited to: adrenergic agents; corticosteroids; adrenal suppressants; aldosterone antagonists; amino acids; anabolic agents; analgesics; anesthesia; appetite suppressants; anti-acne agents; anti-adrenergic agents; anti-allergy agents; anti-amebic agents; anti-anemic agents; anti-anginal agents; anti-arthritic agents; anti-asthmatic agents; anti-atherosclerotic agents; antibacterial agents; anticholinergic agents; anticoagulants; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheal agents; antidiuretics; anti-emetic agents; anti-epileptic agents; anti Fibrinolytics;Antifungals;Antihemorrhagic;Antihistamines;Antilipidemics;Antihypertensives;Antihypotensives;Antiinfectives;Antiinflammatory;Antimicrobials;Antimigraine;Antimitotics;Antifungals;Antiemetics;Antineoplastics;Antineutropenic;Anthelmintics;Antiproliferatives;Antipsychotics;Antirheumatics;Antiseborrheic;Antisecretory;Anticonvulsants;Antithrombotic;Antiulcer;Antiviral;Appetite suppressants;Blood glucose regulators;Bone resorption inhibitors;Bronchiodilators;Cardiovascular agonists;Cholinergic agonists;Depressants;Diagnostic aids;Diuretics;Dopamine agonists;Estrogen receptor antagonists ,fibrinolytics;fluorescent agents;oxygen free radical scavengers;gastric acid suppressants;gastrointestinal motility effectors;glucocorticoids;hair growth stimulants;hemostatics;histamine H2 receptor antagonists;hormones;cholesterol lowering agents;hypoglycemic agents;lipid lowering agents;hypertensive agents;imaging agents;immunological agents;immunostimulants;immunosuppressants;keratolytics;LHRH agonists;mood regulators;mucolytics;mydriatics;nasal decongestants;neuromuscular blocking agents;neuroprotectants;NMDA antagonists;non-hormonal sterol derivatives;prostaglandins; Lasminogen activators;platelet activating factor antagonists;platelet aggregation inhibitors;psychotropic drugs;radioactive agents;anticeptics;sclerosing agents;sedatives;sedative-hypnotics;selective adenosine Al antagonists;serotonin antagonists;serotonin inhibitors;serotonin receptor antagonists;steroids;thyroid hormone agents;thyroid inhibitors;thyroid hormone mimetics;tranquilizers;amyotrophic lateral sclerosis agents;cerebral ischemia agents;Paget's disease agents;unstable angina agents;vasoconstrictors;vasodilators;wound healing agents;xanthine oxidase inhibitors.

[0063] Examples of active ingredients include, but are not limited to, any of the following, for example, alone or in combination: tricyclic antidepressants (amitriptyline, imipramine, nortriptyline, desipramine, etc.), acetaminophen, aspirin, ibuprofen, carbamazepine, gabapentin, lamotrigine, pregabalin, valproic acid, duloxetine, etc., and combinations thereof.

[0064] As indicated, the pharmaceutical formulations disclosed herein may include auxiliary excipients, such as, for example, diluents, binders, lubricants, surfactants, disintegrants, plasticizers, tackifiers, opacifiers, pigments, etc. As will be appreciated by one of skill in the art, the exact selection of excipients and their relative amounts will depend, in part, on the final transdermal dosage form.

[0065] Pharmaceutical Compositions According to certain embodiments described herein, the pharmaceutical composition or transdermal formulation contains an active agent such as cannabinoids and derivatives of these compounds.More preferably, the transdermal formulation may contain an active agent such as diclofenac and / or CBD and / or THC, and derivatives of these compounds.

[0066] An embodiment of the present disclosure may be a transdermal drug delivery system which may include, but is not limited to, transdermal formulations, transdermal patches, topical formulations, microneedles, iontophoresis, metered dose transdermal sprays, transdermal film-forming formulations, transdermal drug-containing adhesive patches, transdermal matrix patches, transdermal aerosols, and metered dose transdermal gels.

[0067] Transdermal formulations include, for example, liquids such as, but not limited to, solutions, suspensions, dispersions, and emulsions. Transdermal formulations include, for example, semi-solids such as, but not limited to, gels, ointments, emulsions, creams, suspensions, pastes, lotions, and balms. Liquid and / or gel formulations are incorporated into, but not limited to, transdermal patches, metered-dose transdermal systems, sachets, and the like. Preferred transdermal formulations include, but are not limited to, polymer matrix patches, such as adhesive matrix patches, non-adhesive matrices, drug-containing adhesive matrix patches, transdermal matrix formulations as drug-containing adhesive matrix patches. Other transdermal formulations include, but are not limited to, transdermal gels, metered-dose transdermal sprays, metered-dose transdermal aerosols, transdermal film-forming formulations, transdermal microneedles, and the like.

[0068] Transdermal patches include, but are not limited to, all transdermal drug delivery systems described in the art, preferably, but not limited to, reservoir patches, matrix patches, bilayer matrix patches, multilayer matrix patches, microreservoir patches, adhesive systems, transdermal film-forming formulations, transdermal gels, transdermal applicable tapes, and the like.

[0069] In certain embodiments of the present disclosure, the transdermal patch contains a transdermal formulation containing an active agent, such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, contained in a reservoir or matrix, and an adhesive that adheres the transdermal patch to the skin, allowing the active agent, such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, 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.

[0070] A transdermal formulation containing an active agent such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, may be incorporated into the patch, which may be applied topically to the skin surface. The patch may be left in contact with the subject for any suitable period of time.

[0071] 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.

[0072] In further embodiments, 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, in 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.

[0073] In still further embodiments, 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, in 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.

[0074] In still further embodiments, the transdermal patches described herein provide a therapeutic range of plasma concentrations of the active ingredient of the transdermal patch in a patient for a predetermined period of time, in 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.

[0075] In yet further embodiments, the transdermal patches described herein allow for reduced variability in the dosage of an active ingredient in a patient over a period of time, in 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.

[0076] In yet further embodiments, the transdermal patch described herein provides a therapeutic range of plasma concentration of the active ingredient of the transdermal patch in a patient over a period of time. In exemplary embodiments disclosed herein, the transdermal patch provides a serum level of the active agent selected from, but not limited to, about 0.01ng / mL, about 0.02ng / mL, about 0.05ng / mL, about 0.1ng / mL, about 0.2ng / mL, about 0.5ng / mL, about 1ng / mL, about 2ng / mL, about 5ng / mL, about 10ng / mL, about 20ng / mL, about 50ng / mL, about 100ng / mL, about 200ng / mL, about 500ng / mL, about 1μg / mL, about 2μg / mL, about 5μg / mL and ranges thereof. In one embodiment, the transdermal patch provides a serum level of the active agent selected from the ranges, but not limited to, 45-3000 ng / ml, 90-2000 ng / mL, 180-1000 ng / mL, 270-900 ng / mL, 360-450 ng / mL, 900-4000 ng / mL, and 9-18 μg / mL.

[0077] Topical formulations described in the art include, for example, but are not limited to, semisolids 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, suspensions, etc. Topical formulations containing diclofenac and / or CBD and / or THC, and derivatives of these compounds, etc., can be applied topically to the skin surface for transdermal delivery of such diclofenac and / or CBD and / or THC, and derivatives of these compounds.

[0078] The transdermal and / or topical formulations of some embodiments of the present disclosure may comprise an effective amount of a carrier or ingredient, alone or in combination, including, but not limited to, a carrier or ingredient such as a solvent, a gelling agent, a polymer, a pressure sensitive adhesive polymer, an adhesive polymer, a biodegradable polymer, a penetration enhancer, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a tackifier, a bulking agent, a diluent, a surfactant, a volatile chemical, an antioxidant, an oxidizing agent, a chelating agent, a complexing agent, a diluent, an excipient, a material for preparing a patch, a material for preparing a matrix patch, a material for preparing a reservoir patch, or the like.

[0079] The active agent may be dissolved, suspended, dispersed, or homogeneously mixed in the above single carrier, carrier mixture, and carrier combination. Any combination of two or more drugs, such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, may be dissolved, suspended, dispersed, or homogeneously mixed in the above single carrier, carrier mixture, and carrier combination.

[0080] The desired optimal transdermal and / or topical formulations of diclofenac and / or CBD and / or THC, and derivatives of these compounds, may include, without limitation, the following carriers, alone or in combination, as set forth in Examples 1-12:

[0081] According to certain embodiments, the transdermal compositions described herein are for the treatment and / or prevention and / or control of, for example, chronic pain. Indications One embodiment of the present disclosure is a pharmaceutical composition for use in the treatment of chronic pain according to the present disclosure, the composition contains an active agent disclosed herein, and the composition is administered every other day, every day, twice a day, three times a day, or four times a day for at least one day, at least one week, at least two weeks, any time between two weeks and one year, at least one year, or more.One embodiment of the present disclosure is a pharmaceutical composition for use in the treatment of chronic pain according to the present disclosure, the composition is administered every other day, every day, twice a day, three times a day, or four times a day for at least one day, at least one week, at least two weeks, any time between two weeks and one year, at least one year, or more.In this way, when the pharmaceutical composition of the present disclosure is administered to a patient suffering from chronic pain, a sustained reduction in (peripheral) neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, and / or other chronic pain conditions is achieved.

[0082] In one embodiment, the pharmaceutical composition for use in the treatment of chronic pain according to the present disclosure is a pharmaceutical transdermal composition, and the use is a transdermal use in the treatment of chronic pain according to the present disclosure.

[0083] In one embodiment, the pharmaceutical composition for use in the treatment of chronic pain according to the present disclosure is a pharmaceutical transdermal composition, the use of which is transdermal use on the intact skin of the person receiving treatment in the treatment of chronic pain according to the present disclosure.

[0084] In one embodiment, the pharmaceutical composition for use in treating chronic pain according to the present disclosure is a pharmaceutical transdermal composition, the use being a transdermal use in treating chronic pain according to the present disclosure, where the transdermal composition is applied topically to an area of ​​intact skin experiencing pain in treating chronic pain.

[0085] In one embodiment, the pharmaceutical composition for use in treating chronic pain according to the present disclosure is a pharmaceutical transdermal composition, the use of which is transdermal use on healthy, intact skin of a person receiving treatment in treating chronic pain according to the present disclosure, where intact skin and healthy, intact skin have their common scientific meaning, and herein refer to undamaged skin, e.g., free of ulcers, wounds, lesions, cuts, and refer to skin comprising a closed outer layer of the epidermis.

[0086] An embodiment of the present disclosure is a pharmaceutical composition according to the present disclosure or a pharmaceutical composition provided by a method of the present disclosure for use in treating chronic pain according to the present disclosure, wherein the chronic pain is neuropathic pain, peripheral neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, pain due to increased muscle tone, osteoarthritic pain, muscular headache, tension headache, migraine, cluster headache, atypical facial pain, referred pain, vulvodynia, perianal pain, or a combination thereof.

[0087] In one embodiment, the pharmaceutical composition for use in treating chronic pain according to the present disclosure is a pharmaceutical composition wherein the chronic pain is peripheral neuropathic pain. One embodiment of the present disclosure is a pharmaceutical composition according to the present disclosure or a pharmaceutical composition provided by a method of the present disclosure for use in treating chronic pain according to the present disclosure, wherein the chronic pain is caused by peripheral neuropathy caused by type 1 or type 2 diabetes or induced by harmful substances such as alcohol, vitamin B1, B6 and / or B12 deficiency, vitamin B6 excess, hypothyroidism, chemotherapeutic compounds (such as paclitaxel or taxane derivatives, vincristine or vinca alkaloids, cisplatin or platinum derivatives), drug-induced neuropathy, compounds for the treatment of infectious diseases (such as streptomycin, didanosine, or zalcitabine), chemotoxic compounds, trigeminal neuralgia, post-herpetic neuralgia, intercostal neuralgia, entrapment neuropathy (carpal tunnel syndrome, tarsal tunnel syndrome, syndrome, abdominal cutaneous nerve entrapment syndrome, etc.), sciatica, chronic idiopathic sensory neuropathy, small fiber neuropathy, hereditary motor and sensory neuropathy, chronic inflammatory demyelinating polyneuropathy, infectious disease states (post-polio syndrome, AIDS or HIV related, Lyme related, Sjogren's related, etc.), lymphomatous neuropathy, myeloma neuropathy, cancer neuropathy, acute panautonomic neuropathy, vasculitis / ischemic neuropathy, and mono- and polyneuropathy, complex regional pain syndrome types I and II (reflex sympathetic dystrophy), central neuropathic pain (thalamic neuropathy, spinal cord injury neuropathy, post-stroke pain, multiple sclerosis neuropathy, syringomyelia, spinal tumor, etc.), phantom limb pain, restless genital syndrome with pain, post-surgical scar pain including scar pain after cardiac surgery and mastectomy.

[0088] An embodiment of the present disclosure is a pharmaceutical composition according to the present disclosure or provided by the method of the present disclosure for use in treating chronic pain according to the present disclosure, wherein the frequency of administration of the pharmaceutical composition is between once every other day to eight times a day, preferably six, five, four, three, two, or once a day.

[0089] One embodiment of the present disclosure is a pharmaceutical composition for use in treating chronic pain according to the present disclosure, wherein the pharmaceutical composition is administered for a period of at least one day, preferably at least one week, more preferably at least one month, most preferably at least one year, preferably the pharmaceutical composition is administered for one to ten years, more preferably the pharmaceutical composition is administered chronically. It is understood that it is part of the present disclosure that the pharmaceutical composition for use in treating chronic pain according to the present disclosure is administered to a patient suffering from chronic pain for the remainder of his / her life. In this way, the chronic pain is at least less intense, and preferably the patient is largely or even completely relieved from chronic pain.

[0090] The present invention will be described in more detail with reference to the following examples, but it should be understood that the present invention is not limited to these examples. EXAMPLES

[0091] Example 1 The transdermal and / or topical formulations of the present disclosure include, but are not limited to, alcohols C1-C 20(e.g., but not limited to, methanol, ethanol, isopropyl alcohol, butanol, propanol, etc.), polyhydric alcohols, glycols (e.g., but not limited to, propylene glycol, polyethylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, glycerin, etc.), glycol derivatives, pyrrolidones (e.g., but not limited to, N-methyl 2-pyrrolidone, 2-pyrrolidone, etc.), sulfoxides (e.g., but not limited to, dimethyl sulfoxide, decymethyl sulfoxide, The solvent may include, either alone or in combination, solvents known to those skilled in the art, such as ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA, hexane, etc., dimethyl isosorbide, mineral oil, vegetable oil, sesame oil, water, polar solvents, semi-polar solvents, non-polar solvents, volatile chemicals that may be used to make the matrix patch (e.g., but not limited to, ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA, hexane, etc.), acids (e.g., but not limited to, acetic acid, lactic acid, levulinic acid, etc.), bases, and others, such as pentane, dimethylformamide, butane, lipids, etc. More preferably, the solvent ranges from 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 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%, and about 95%.In exemplary embodiments, the formulations of the present disclosure may include a solvent at a concentration of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the solvent represents about 1 wt%-75 wt%, preferably 2 wt%-30 wt%, and more preferably 5 wt%-20 wt% of the formulation.

[0092] Example 2 The transdermal and / or topical formulations of the present disclosure may be prepared using a variety of polymers, 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, gellan 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, hydroxylpropylcellulose, hydroxylpropylmethylcellulose, etc.)), synthetic polymers and derivatives thereof (such as, but not limited to, carboxyvinyl polymers or carbomers (Carbopol 940, Carbopol 934, Carbopol 971p, etc.), NF), polyethylene and its copolymers, clays (e.g., but not limited to, silicates, bentonite, etc.), silicon dioxide, polyvinyl alcohol, acrylic polymers (eudragit®), acrylic esters, polyacrylic acid copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers (e.g., but not limited to, PVP, Kollidon® 30, poloxamers), isobutylene, ethyl vinyl acetate copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives (e.g., but not limited to, silicone polymers (e.g., but not limited to, bio psa® 4302, bio psa4202, etc.), acrylic pressure sensitive adhesives (e.g., but not limited to, duro-tak® 87-2156, duro-tak 387-2287, duro-tak 87-9301, duro-tak 387-2051, etc.), polyisobutylenes (e.g., but not limited to, polyisobutylene low molecular weight, polyisobutylene medium molecular weight, polyisobutylene 35000mw, etc.), acrylic copolymers, rubber adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and / or organic solvent swellable polymers, etc.It may contain gelling agents and / or thickening agents and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure sensitive adhesive polymers known to those skilled in the art, either alone or in combination. 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 composition may contain a gelling agent and / or a thickening agent and / or a suspending agent and / or a polymer and / or an adhesive polymer and / or a pressure sensitive adhesive polymer at a concentration of 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%, and about 85%, and about 90%. In exemplary embodiments, the formulations of the present disclosure may include gelling agents and / or thickening agents and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure-sensitive adhesive polymers at concentrations of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the gelling agents and / or thickening agents and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure-sensitive adhesive polymers represent about 1 wt%-75 wt%, preferably 2 wt%-30 wt%, more preferably 5 wt%-20 wt%, more preferably 0.1%-80% w / w or w / v of the formulation.

[0093] Example 3 Transdermal and / or topical formulations of the present disclosure may include, but are not limited to, sulfoxides and similar chemicals (e.g., but not limited to, dimethylsulfoxide, dimethylacetamide, dimethylformamide, decymethylsulfoxide, dimethylisosorbide, etc.), azones, pyrrolidones (e.g., but not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), esters, fatty acid esters (e.g., but not limited to, propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, lauryl lactate, ethyl oleate, decyl oleate, glycerol monooleate, glyceryl monolaurate ... The permeation enhancers may include permeation enhancers known to those skilled in the art, 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, diethylene glycol monoethyl ether, etc.), 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, etc.), terpenes, terpenoids, and all the permeation enhancers or permeation enhancers mentioned in the book "Percutaneous Penetration Enhancers" (Eric W. Smith, Howard I. Maibach, 2005. Nov, CRC press), either alone or in combination.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 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 8 %, 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 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%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the permeation enhancer represents about 1 wt%-75 wt%, preferably 2 wt%-30 wt%, more preferably 5 wt%-20 wt%, and more preferably in the range of 0.01%-95% w / w or w / v of the formulation.

[0094] Example 4 The transdermal and / or topical formulations of the present disclosure may contain plasticizers known to those skilled in the art, such as, 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 may be used in transdermal drug delivery systems mentioned in the book "Handbook of Plasticizers" (George Wypych, 2004, Chem Tec Publishing), either alone or in combination. 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 at a concentration of about 8%, 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 in a concentration of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the plasticizer represents about 1%-75% by weight of the formulation, preferably 2%-30% by weight, more preferably 5%-20% by weight, and more preferably 0.01%-95% w / w or w / v.

[0095] Example 5 The transdermal and / or topical formulations of the present disclosure may contain emollients, moisturizers, skin irritation reducers, such as, but not limited to, petrolatum, lanolin, mineral oil, dimethicone, zinc oxide, glycerin, propylene glycol, and similar compounds or chemicals known to those skilled in the art, either alone or in combination, 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 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 8 , 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 emollients, moisturizers, skin irritation reducers, 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%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the emollients, moisturizers, skin irritation reducers, and similar compounds represent in the range of about 1 wt%-75 wt%, preferably 2 wt%-30 wt%, more preferably 5 wt%-20 wt%, and more preferably 0.01%-95% (w / w or w / v) of the formulation.

[0096] Example 6 Transdermal and / or topical formulations of the present disclosure may include, but are not limited to, polysorbates (e.g., but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.), span® (e.g., but not limited to, span 80, span 20, etc.), surfactants (e.g., anionic, cationic, nonionic, and amphoteric), propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate, medium chain triglycerides ... The composition may contain solubilizers, surfactants, emulsifiers, dispersants and similar compounds or chemicals known to those skilled in the art, such as oleyl monolaurate type II, linoleoyl polyoxyl-6 glyceride, oleoyl-polyoxyl-6-glyceride, lauroyl polyoxyl-6-glyceride, polyglyceryl-3-dioleate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglyceryl-3-dioleate, caprylocaproyl polyoxyl-8 glyceride, cyclodextrin, alone or in combination. More preferably, the composition is 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 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 8 It may contain solubilizers, surfactants, emulsifiers, dispersants, and similar compounds at concentrations of 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 solubilizers, surfactants, emulsifiers, dispersants, 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%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the solubilizers, surfactants, emulsifiers, dispersants, and similar compounds represent about 1%-75% by weight of the formulation, preferably 2%-30% by weight, more preferably 5%-20% by weight, and more preferably 0.01%-95% w / w or w / v.

[0097] Example 7 Various techniques and ingredients may be used to increase the stability and / or solubility of the active agent in the formulation, including, but not limited to, coating, encapsulation, microencapsulation, nanoencapsulation, lyophilization, chelating agents, complexing agents, packaging for transdermal delivery systems, moisture scavengers, etc. Various stabilizers may be used to increase the stability of the active agent in the formulation, etc.

[0098] Example 8 The transdermal and / or topical formulations of the present disclosure may contain auxiliary pH buffers and pH stabilizers, such as, but not limited to, phosphate buffer, acetate buffer, citrate buffer, etc., acids (e.g., but not limited to, carboxylic acids, inorganic acids, sulfonic acids, vinylic carboxylic acids, etc.), bases (e.g., but not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, etc.), alone or in combination, that help maintain the appropriate pH of the formulation, preferably in the range of 4.0 to 8.0, and similar compounds known to those skilled in the art, more preferably in the range of 0.01% to 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 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 8 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 pH buffers 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%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the pH buffers and pH stabilizers and similar compounds represent a range of about 1 wt%-75 wt%, preferably 2 wt%-30 wt%, more preferably 5 wt%-20 wt%, more preferably 0.01%-30% (w / w or w / v) of the formulation.

[0099] Example 9 The transdermal and / or topical formulations of the present disclosure may contain antioxidants (e.g., but not limited to, sodium metabisulfite, citric acid, ascorbic acid, BHA, BHT, etc.), oxidizing agents, stabilizers, discolorants, preservatives, and similar compounds or chemicals known to those skilled in the art to aid in obtaining a stable formulation, which may be used alone or in combination, but are not limited thereto, 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 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 8 %, 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% antioxidant. 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%, about 63.13%, and about 40%-64% w / w. In exemplary formulations of the present disclosure, the antioxidant represents a range of about 1 wt%-75 wt% of the formulation, preferably 2 wt%-30 wt%, more preferably 5 wt%-20 wt%, more preferably 0.01%-50% (w / w or w / v).

[0100] Example 10 The transdermal and / or topical formulations of the present disclosure may be formulated into ointment and / or cream bases and / or gel and / or film-forming transdermal formulations and / or transdermal matrix formulations and / or drug-containing adhesive matrix patches and / or matrix patches known to those skilled in the art.

[0101] Example 11 Materials for making the transdermal delivery system of the present disclosure in the form of a patch are known to those of skill in the art and include, for example, but are not limited to, reservoir patches, matrix patches, drug in adhesive, film-forming formulations, microdosed transdermal patches, transdermal films, and the like, and may include, for example, but are not limited to, polymers, copolymers, derivatives, backing films, release membranes, release liners, and the like, alone or in combination. Pressure sensitive adhesives (e.g., but not limited to, silicone polymers, rubber adhesives, acrylic polymers, acrylic copolymers, polyisobutylene, acrylic acid-isooctyl acrylate copolymers, hot melt adhesives, polybutylene, etc.), backing films (e.g., but not limited to, ethylene vinyl acetate copolymers, vinyl acetate resins, polyurethanes, polyvinyl chloride, metal foils, polyesters, aluminized films, polyethylene, etc.), release films (e.g., but not limited to, microporous polyethylene films, microporous polypropylene films, rate-limiting ethylene vinyl acetate copolymer films, etc.), release liners (e.g., but not limited to, silicone treated polyester films, fluoropolymer coated polyester films, polyester films, silicone treated polyethylene terephthalate films, etc.), tapes, etc.

[0102] The transdermal formulation and / or topical formulation and / or transdermal delivery system of the present disclosure can deliver at least a therapeutically effective dose of active agents, such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, alone or in combination, in human plasma required to treat and / or prevent and / or control chronic pain. The dosage of a therapeutically effective active agent, such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, refers to the therapeutic concentration in human plasma required to treat and / or prevent and / or control chronic pain. Furthermore, the exact therapeutically effective dose of diclofenac and / or CBD and / or THC, and derivatives of these compounds, in a transdermal formulation or topical formulation or transdermal delivery system can be determined by a person skilled in the art based on factors such as, but not limited to, the patient's condition. The transdermal formulation or topical formulation or transdermal delivery system is available in different dosage strengths and patch sizes to achieve optimal therapeutic results based on the patient's requirements.

[0103] Transdermal formulations or transdermal patches of active agents such as diclofenac and / or CBD and / or THC, and derivatives of these compounds, may be applied to the skin surface in any of the following dosing regimens: 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 about 8 to about 13 days, once every 2 weeks, or once every 15 days.

[0104] Example 12

[0105] [Table 1]

[0106] [Table 2]

[0107] While the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention.

Claims

1. A pharmaceutical composition comprising about 0.5% to about 30% of an active agent selected from the group consisting of diclofenac, its free base, its salts, and combinations thereof; From about 0.1% to about 30% of an active agent selected from the group consisting of synthetic cannabidiol, its free base, its salts, and combinations thereof; and / or from about 0.1% to about 30% of an active agent selected from the group consisting of synthetic tetrahydrocannabinol, its free base, its salts, and combinations thereof; and A transdermal pharmaceutical composition in the form of a matrix patch further comprising the combination thereof, Furthermore, the pharmaceutical composition comprises from about 2% to about 30% of at least one solvent comprising propylene glycol; about 2% to about 30% of at least one permeation enhancer comprising oleic acid; Optionally, from about 20% to about 80% of an adhesive and / or polymer, including a silicone pressure sensitive adhesive; and At least one polymer / crystallization inhibitor comprising silicon dioxide; The pharmaceutical composition is administered at a dosing regimen selected from the group consisting of once every 6 days, once a week, once about 8 to about 13 days, once every two weeks, and once every 15 to about 30 days.

2. 2. The pharmaceutical composition of claim 1, wherein the salt of diclofenac is selected from the group consisting of diclofenac sodium, diclofenac potassium, diclofenac epolamine, and combinations thereof.

3. 10. The pharmaceutical composition of claim 1, formulated as a transdermal liquid formulation, a transdermal semisolid formulation, a transdermal gel formulation, or a transdermal polymer matrix formulation, a transdermal adhesive matrix formulation, a film-forming gel formulation, and / or a film-forming spray formulation.

4. 10. The pharmaceutical composition of claim 1, further comprising an effective amount of a carrier or component selected from the group consisting of a solvent, a gelling agent, a polymer, a pressure sensitive adhesive polymer, a penetration enhancer, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a tackifier, a diluent, a bulking agent, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof.

5. 10. The pharmaceutical composition of claim 1, further comprising an effective amount of a carrier or ingredient selected from the group consisting of solvents, gelling agents, polymers, pressure sensitive adhesive polymers, penetration enhancers, emollients, skin irritation reducers, buffers, pH stabilizers, solubilizers, tackifiers, bulking agents, diluents, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, oxidizing agents, and combinations thereof in the range of 0.5% to 98% (w / w or w / v).

6. 10. The pharmaceutical composition of claim 1, formulated as a transdermal patch.

7. 10. The pharmaceutical composition of claim 1, formulated as a metered dose transdermal gel, a metered dose transdermal spray, a film-forming gel, or a film-forming spray.

8. 10. The pharmaceutical composition of claim 1, adapted for the treatment and / or control of chronic pain in a patient.

9. The pharmaceutical composition of claim 1 , formulated as a microneedle.

10. 10. The pharmaceutical composition of claim 1, further comprising at least one additional active agent selected from the group consisting of medicaments administered for the treatment and / or management and / or prevention and / or control of symptoms associated with neuropathic pain, peripheral neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, pain due to increased muscle tone, osteoarthritic pain, muscular headaches, tension headaches, migraines, cluster headaches, atypical facial pain, referred pain, vulvodynia, perianal pain, and any combination thereof.

11. 10. The pharmaceutical composition of claim 1, further comprising at least one additional active agent selected from the group consisting of tricyclic antidepressants, amitriptyline, imipramine, nortriptyline, desipramine, acetaminophen, aspirin, ibuprofen, carbamazepine, gabapentin, lamotrigine, pregabalin, valproic acid, duloxetine, and combinations thereof.

12. A pharmaceutical composition according to any one of claims 1 to 11 for use in the treatment and / or prevention and / or control of chronic pain in a patient.

13. 13. The pharmaceutical composition of claim 12, wherein the chronic pain is selected from the group consisting of neuropathic pain, peripheral neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasm, pain due to increased muscle tone, osteoarthritic pain, muscular headache, tension headache, migraine, cluster headache, atypical facial pain, referred pain, vulvodynia, perianal pain, and any combination thereof.

14. 13. The pharmaceutical composition of claim 12, wherein the topical application of the transdermal pharmaceutical composition is for the treatment and / or prevention and / or control of chronic pain in a patient, and wherein the pharmaceutical composition is applied for a period selected from the group consisting of once every 6 days, once a week, once every 10 days, and once every 15 days.

15. 13. The pharmaceutical composition of claim 12 configured to provide a constant rate of delivery of the active agent over a period of time.

16. 13. The pharmaceutical composition of claim 12, configured to provide a steady rate of absorption of the active agent over a period of time.

17. 13. The pharmaceutical composition of claim 12, configured to achieve a constant serum level of the active agent over a period of time.

18. 13. The pharmaceutical composition of claim 12, configured to provide a plasma concentration of the active agent within a therapeutic range over a period of time.

19. 13. The pharmaceutical composition of claim 12, configured to provide a plasma concentration of the active agent within a therapeutic range of about 0.5 ng / mL to about 500 ng / mL.