Continuous delivery systems containing cannabinoids and their pharmaceutical uses

Abstract

Disclosed are compositions comprising 0.1-50% delta-9-tetrahydrocannabinol and / or cannabidiol in a form suitable for continuous delivery, and their use in the treatment of various diseases and pathological disorders. In preferred embodiments, the compositions are in a form suitable for delivery via a portable infusion pump or transdermal patch. Disorders to be treated include pain, cancer, seizure disorders, and Parkinson's disease. Depending on the disorder being treated, the compositions may optionally further comprise an additional active agent, for example, a dopamine agonist.

Description

[Technical Field]

[0001] The present invention relates to a continuous delivery system containing cannabinoids and its pharmaceutical uses. [Background technology]

[0002] The present disclosure provides systems, compositions, and methods for treating and / or preventing and / or controlling indications such as pain management, cancer, seizure disorders, and Parkinson's disease using continuous drug delivery. The continuous drug delivery methods and systems disclosed herein can provide active agents in several different ways, for example, through infusion therapy, for example, via intradermal or subcutaneous application, or transdermal or topical application. Infusion therapy administers medications using a sterile, thin tube such as a catheter that is inserted and secured inside the body. Pump delivery systems and any other delivery systems that deliver continuous infusion, such as depot injections and ambulatory pumps, can be used for this purpose. Continuous drug delivery systems and methods can also include, for example, transdermal systems. In transdermal drug delivery, a transdermal patch or transdermal composition is applied topically to the skin surface. Throughout the period of topical application of the transdermal patch or transdermal composition, the drug is continuously released and delivered through intact skin (via transcellular, paracellular, and transappendicular pathways) to achieve a systemic effect. Thus, once applied, a transdermal composition or transdermal patch may deliver a drug to the systemic circulation throughout the day or for more than one day, depending on the duration of its application, which may even be up to a week.

[0003] In continuous drug delivery, the active agent is continuously released and delivered to the patient to achieve a systemic effect. Thus, once applied, a continuous drug delivery system can deliver the active agent to the systemic circulation throughout the day or for more than one day, depending on the duration of application, which can even be up to one week.

[0004] Continuous drug delivery can deliver, for example, purified tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof throughout the application period. Depending on the need, the application period can be once a day, once every two days, once every three days, once every four days, once every five days, or once a week. Thus, continuous drug delivery can overcome the multiple-dose regimens of oral delivery by reducing the dosing frequency.

[0005] In continuous drug delivery, a pharmaceutical composition containing an active agent is delivered slowly and continuously throughout the administration period, and therefore there are no peaks and troughs in drug plasma concentrations of the active agent associated with multiple doses, such as oral administration, in one day. Thus, for example, continuous drug delivery of tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof, allows a patient to experience the therapeutic effects of the drug over an extended period of time without dramatic changes in drug plasma concentrations.

[0006] In continuous drug delivery using the systems and methods disclosed herein, the active agent is delivered to the systemic circulation, avoiding first-pass hepatic metabolism, thus requiring less drug to achieve the desired therapeutic activity and resulting in fewer adverse or side effects. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are highly lipid-soluble and undergo first-pass hepatic metabolism after oral administration, resulting in only 10% to 20% of the administered dose reaching the systemic circulation. Therefore, compared to oral administration, continuous drug delivery of low doses of tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof may provide the desired therapeutic effect at lower doses than oral administration.

[0007] Furthermore, using the continuous drug delivery systems and methods disclosed herein is easy, non-invasive, and convenient. Continuous drug administration of drug compounds does not require medical supervision because patients can self-regulate the administration.

[0008] In certain embodiments, the continuous drug delivery systems and methods disclosed herein may include pump devices, such as those commonly used to deliver one or more fluids to a target individual. For example, a medical infusion pump device may be used to deliver medication to a patient as part of a medical procedure. The active agent delivered by the infusion pump device may depend on the patient's condition and desired treatment plan. For example, infusion pump devices are used to deliver insulin to the subcutaneous tissue and vasculature of diabetic patients to regulate blood glucose levels. In some situations, the dosage of medication delivered by the infusion pump may be calculated by the infusion pump system. In these situations, the infusion pump system may take into account many variables, including user input, when making such calculations.

[0009] Other forms of continuous drug delivery systems and methods may utilize fluid delivery to a target individual. For example, insulin, glucagon, or another medication may be injected using a manual syringe or a single-use injection "pen." In some situations, injectable forms of glucagon are used in emergency relief of severe hypoglycemia when the affected individual is unconscious or otherwise unable to ingest glucose orally. Glucagon liquid may be rapidly injected into a patient by intramuscular, intravenous, or subcutaneous injection, rapidly raising the patient's blood glucose levels.

[0010] One category of devices for delivering such fluids is that of pumps developed for the administration of insulin and other medications for those suffering from both Type I and Type II diabetes. Some pumps configured as portable infusion devices can provide continuous medication for the treatment of diabetes. Such therapy can include, for example, regular and / or continuous injections or infusions of insulin into the skin of a person suffering from diabetes, providing an alternative to multiple daily injections of insulin with an insulin syringe or insulin pen. Such pumps can be handheld / portable infusion pumps worn by the user and can use replaceable cartridges. Examples of such pumps and various features that can be associated with them include those disclosed in U.S. Patent Nos. 6,229,999; 6,229,999; 6,229,999; 6,229,999; 6,229,999; and 6,229,999, each of which is incorporated herein by reference in its entirety.

[0011] In certain embodiments disclosed herein, the continuous drug delivery system may include, for example, a patch pump or a micropump. A patch pump is a typically portable, miniature pump that is carried directly on the skin under the user's clothing. Such pumps are generally placed directly at the injection site so that no tubing is required to deliver insulin or other medication to the patient. Patch pumps are typically at least partially disposable and are intended to be worn for one or two days and then discarded for a new patch pump.

[0012] Cannabis (marijuana) is a Schedule I drug in the United States. Cannabis is a flowering plant containing over 400 phytonutrients (micronutrients). Over 100 different types of terpenoids, essential oils, antioxidants, and cannabinoids have been extracted from the plant. Of 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 compounds have been studied, such as cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and delta-9-tetrahydrocannabinol (delta-9THC), which also showed some therapeutic benefits 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 spasms associated with multiple sclerosis and paralysis, alcohol and opioid withdrawal, 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-approved Marinol and Syndros contain delta-9-THC, which is currently used to treat chemotherapy-related nausea, vomiting, and anorexia. In clinical trials, Sativex (a cannabinoid extract oromucosal spray containing THC and CBD) demonstrated improvement in neuropathic pain and sleep quality. Furthermore, in April 2016, the FDA granted orphan drug designation to cannabidiol for the treatment of tuberous sclerosis complex (TSC), Dravet syndrome, and Lennox-Gastaut syndrome. Cannabidiol is an orally effective treatment for pain and inflammation (Non-Patent Document 1).

[0013] For tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof, inter-patient variability in pharmacological response is expected to be smaller with continuous drug delivery, since drug plasma concentrations can be controlled by controlling the rate of drug delivery. Continuous drug delivery may deliver small amounts of tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof for a longer period than oral administration. Continuous drug formulations of tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof may also provide more abuse prevention than immediate-release dosage forms.

[0014] Furthermore, in the event of any adverse effects, side effects or emergency continuous drug delivery, the freedom to terminate therapy at any time is provided by disconnecting the continuous drug delivery system. There is a need for improved drug delivery systems for CBD and / or THC that can overcome the drawbacks associated with the oral route. For example, continuous drug delivery of CBD and / or 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 solid solution, its polymorph, its stereoisomer, its coated form, its ion pair, its solution in a solvent, alone or in combination, can address the challenges associated with oral drug delivery and be useful for the treatment, prevention, and / or control of indications such as pain management, symptoms associated with cancer, seizure disorders, Parkinson's disease, PD, and other indications.

[0015] All references cited herein are incorporated by reference in their entirety. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] U.S. Patent Application No. 13 / 557,163 [Patent Document 2] U.S. Patent Application Serial No. 12 / 714,299 [Patent Document 3] U.S. Patent Application No. 12 / 538,018 [Patent Document 4] U.S. Patent Application No. 13 / 838,617 [Patent Document 5] U.S. Patent Application No. 13 / 827,707 [Patent Document 6] Specification of U.S. Patent No. 8,287,495 [Non-Patent Document]

[0017] [Non-Patent Document 1] Costa, B. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. European Journal of Pharmacology. Volume 556, Issues 1-3, 5 February 2007, Pages 75-83 [Summary of the Invention]

[0018] The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, comprising selecting a patient in need of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms, and administering to the patient in a continuous delivery system a pharmaceutical composition, wherein the pharmaceutical composition is selected from the group consisting of cannabidiol (CBD), synthetic forms thereof, biosynthetic forms thereof, free base forms thereof, salts thereof, isomers thereof, amorphous forms thereof, derivatives thereof, and combinations thereof. and administering a pharmaceutical composition comprising at least one active agent selected from the group consisting of: about 0.1% to about 50% of an active agent selected from the group consisting of tetrahydrocannabinol (THC), its synthetic forms, biosynthetic forms, free base forms, salts thereof, isomers thereof, amorphous forms thereof, derivatives thereof, and combinations thereof; optionally, at least one additional active agent; and combinations thereof, wherein a disease or condition and / or associated symptoms are treated, prevented, and / or delayed in a patient. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to mitigate peak and valley pharmacokinetic behavior of the active agent. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition via administration to the patient by a route selected from the group consisting of parenteral, intravenous, subcutaneous, intramuscular, intrathecal, oral, buccal, mucosal, intranasal, rectal, vaginal, transdermal, implantable, topical, and combinations thereof. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to the patient via intravenous or subcutaneous infusion. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to the patient via subcutaneous infusion.The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to the patient via an infusion pump device.

[0019] The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to the patient via a portable / ambulatory infusion pump worn by the patient and which may use replaceable cartridges. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to the patient via a patch pump or micropump. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition selected from the group consisting of a liquid formulation, a solid formulation, a semi-solid formulation, an emulsion formulation, a nanoparticle formulation, a matrix formulation, a film formulation, a patch formulation, a formulation in an infusion pump, and / or combinations thereof. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition selected from the group consisting of a transdermal liquid formulation, a transdermal semisolid formulation, a transdermal gel formulation, or a transdermal polymer matrix formulation, a transdermal adhesive matrix formulation, a transdermal film-forming gel, a transdermal film-forming spray formulation, a multi-layer transdermal matrix system, a transdermal drug-in-adhesive matrix formulation, and combinations thereof. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical liquid formulation, a topical semisolid formulation, a topical gel formulation, a topical polymer matrix formulation, a topical adhesive matrix formulation, a topical film-forming gel formulation, or a topical film-forming spray formulation.

[0020] The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch, the transdermal patch being selected from the group including a reservoir patch, a multi-layer transdermal matrix system, a microreservoir patch, a matrix patch, a drug-containing adhesive patch, an adhesive matrix patch in combination with a polymer, a pressure-sensitive adhesive patch, a sustained-release transdermal film, a liquid reservoir system, a microreservoir patch, a mucoadhesive patch, and combinations thereof. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch, wherein the topical patch is selected from the group including a multi-layer transdermal matrix system, a reservoir patch, a microreservoir patch, a matrix patch, a drug-containing adhesive patch, a pressure-sensitive adhesive patch, a sustained-release transdermal film, a liquid reservoir system, a microreservoir patch, a mucoadhesive patch, a microdosing patch, an adhesive matrix patch in combination with a polymer, and combinations thereof. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a multi-layer transdermal matrix system, a metered-dose transdermal gel, a metered-dose transdermal spray, a film-forming gel, a film-forming spray, or a metered-dose aerosol. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch.The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a metered-dose gel, metered-dose spray, gel, cream, solution, emulsion, liquid composition, semi-solid composition, adhesive matrix in combination with a polymer, or film-forming formulation. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition further comprising an effective amount of a carrier or ingredient 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 tackifier, a diluent, a bulking agent, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof.

[0021] The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition further comprising an effective amount of a carrier or ingredient 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 in the range of 0.1% to 99.5% w / w or w / v. The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal formulation that can be administered at a dosage regimen selected from the group consisting of once daily, twice daily, three times daily, once every 1 to 8 hours, once every 1 to 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once weekly, once every 8 to about 13 days, once every 2 weeks, and once every 15 to about 30 days. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical formulation that can be administered at a dosing regimen selected from the group consisting of once daily, twice daily, three times daily, four times daily, five times daily, six times daily, once every 1 to 8 hours, once every 1 to 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once weekly, once every 8 to about 13 days, once every 2 weeks, and once every 15 to about 30 days. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to the patient via microneedles.The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system provides a serum level of an active agent selected from the group consisting of about 0.01 ng / mL, about 0.02 ng / mL, about 0.05 ng / mL, about 0.1 ng / mL, about 0.2 ng / mL, about 0.5 ng / mL, about 1 ng / mL, about 2 ng / mL, about 5 ng / mL, about 10 ng / mL, about 20 ng / mL, about 50 ng / mL, about 100 ng / mL, about 200 ng / mL, about 500 ng / mL, about 1 μg / mL, about 2 μg / mL, and about 5 μg / mL. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition, wherein the active agent is present in a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 0.1 to about 50%, about 1 to 20%, about 5% to 25%, about 10% to about 20%, or about 15% to about 18%, about 30% to about 70%, and about 35% to about 65% of the formulation.

[0022] The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system comprises a pharmaceutical composition, wherein an active agent is present at a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, and about 1% to about 5% of the formulation. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition, wherein THC is selected from the group including its free base, 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, a naturally occurring form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, a stereoisomer thereof, a solid solution thereof, an ion pair thereof, a solution thereof, a powder form thereof, a liquid form thereof, alone or in combination thereof. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition, wherein CBD is selected from the group comprising: 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, a naturally occurring form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, an ion pair thereof, a stereoisomer thereof, a solid solution thereof, a solution thereof, a powder form thereof, a liquid form thereof, alone or in combination thereof. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition comprising one or more active agents selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), 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, a naturally occurring form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, and combinations thereof, in a dosage form for transdermal delivery.The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition, wherein tetrahydrocannabinol (THC), cannabidiol (CBD), its free base, its salt, its isomer, its amorphous form, its polymorphic form, its stereoisomer, its ion pair, its coated form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its naturally occurring form, its active metabolite, and combinations thereof are produced by synthetic routes. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition, wherein the active agent is synthetically produced and has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or greater prior to addition to the pharmaceutical composition. The present disclosure provides a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition co-administered with at least one additional active agent selected from the group consisting of a dopamine precursor, a dopamine receptor agonist, and combinations thereof. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein a continuous delivery system comprises a pharmaceutical composition co-administered with at least one additional active agent selected from the group consisting of levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, and any combination thereof.

[0023] The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the disease or condition and / or associated symptoms is selected from the group consisting of cancer, pain, seizure disorders, Parkinson's disease ("PD"), and symptoms of PD. The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the cancer is selected from the group consisting of endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, small intestine cancer, squamous cell carcinoma of the anogenital area, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, GBM, and hematological cancers such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma / primary mediastinal large B-cell lymphoma, and chronic myeloid leukemia. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the cancer is glioblastoma, GBM. The present disclosure provides a method for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the pharmaceutical composition is co-administered with at least one additional therapeutic agent selected from the group consisting of temozolomide, peptides, polypeptides, fusion proteins, nucleic acid molecules, small molecules, mimetics, synthetic drugs, inorganic molecules, organic molecules, chemotherapy, radiation therapy, hormonal therapy, anti-angiogenic therapy, targeted therapy, and / or biological therapy, including immunotherapy and surgery, and combinations thereof. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the pain is chronic pain 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-type headache, migraine, cluster headache, atypical facial pain, referred pain, vulvodynia, rectal pain, and any combination thereof. The present disclosure provides methods for treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient.and / or delaying seizures, wherein the seizure disorder is selected from the group consisting of complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, and myoclonus), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as additional specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis syndrome (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, and progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the seizure disorder is selected from the group consisting of complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonus), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as additional specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis syndrome (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, and progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom treated, prevented, and / or delayed is (a) at least one non-motor aspect of experience of daily living as defined by Part I of the Unified Parkinson's Disease Rating Scale selected from the group consisting of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, blunted affect, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urination problems, constipation problems, lightheadedness, and fatigue; (b) speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, turning in bed, tremor, getting in and out of bed or a car or a deep chair, walking and balance;and freezing; (c) at least one motor aspect of experience of daily living as defined by Part II of the Unified Parkinson's Disease Rating Scale selected from the group consisting of speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination, toe tapping, foot agility, chair rise, gait, gait freezing, postural stability, posture, bradykinesia, postural tremor of the hand, kinetic tremor of the hand, resting tremor amplitude, and resting tremor persistence; (d) at least one motor symptom as defined by Part IV of the Unified Parkinson's Disease Rating Scale selected from the group consisting of time spent with dyskinesia, functional impact of dyskinesia, time spent in off-state, functional impact of diurnal variation, complexity of diurnal variation of motor symptoms, and painful off-state dystonia. At least one motor complication, (e) constipation, (f) depression, (g) cognitive impairment, (h) short-term or long-term memory impairment, (i) concentration problems, (j) coordination problems, (k) motor dysfunction, (l) speech disorders, (m) mental confusion, (n) sleep problems, sleep abnormalities or disorders, (o) circadian rhythm dysfunction, (p) hallucinations, (q) fatigue, (r) REM sleep disorder, (s) REM behavior disorder, (t) erectile dysfunction, (u) postural hypotension, (v) blood pressure or orthostatic hypotension (w) correction of blood pressure, (x) regulation of temperature, (y) improvement of breathing or apnea, (z) correction of cardiac conduction disorders, (aa) amelioration of pain, (bb) restoration of urinary incontinence or bladder sensation and voiding, (cc) mood swings, (dd) blunted affect, (ee) control of nocturia, (ff) neurodegeneration, (gg) anxiety, (hh) improving speech ability, including the ability to speak in public, and / or (ii) Parkinson's disease dementia.

[0024] The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom being treated, prevented, and / or delayed is a sleep problem, sleep abnormality, sleep disorder, circadian rhythm dysfunction, REM sleep disorder, or REM behavior disorder, and (a) the sleep abnormality or sleep disorder comprises delayed sleep onset, sleep fragmentation, REM behavior disorder, sleep-disordered breathing including snoring and apnea, daytime sleepiness, microsleep episodes, narcolepsy, hallucinations, or any combination thereof; and / or (b) the REM behavior disorder comprises vivid dreams, nightmares, and dream act-outs by talking or screaming, or fidgeting or thrashing of arms or legs during sleep; and / or (c) treating the sleep problem, sleep abnormality, sleep disorder prevents or delays the onset and / or progression of Parkinson's disease; and / or (d) the method results in a positive change in the subject's sleep pattern over a defined period of time; and / or (e) the method results in a positive change in the subject's sleep pattern over a defined period of time. and / or (ii) an increase in the total amount of sleep obtained of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%. (f) the method results in the subject achieving the total number of hours of sleep recommended by a medical authority for the subject's age group; and / or (g) each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

[0025] The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom being treated, prevented, and / or delayed is a hallucination, and (a) the hallucination includes visual, auditory, tactile, gustatory, or olfactory hallucinations; and / or (b) treating the hallucinations prevents and / or delays the onset and / or progression of Parkinson's disease; and / or (c) the method results in a reduction in the number of hallucinations in the subject over a defined period of time; and / or (d) the method results in a reduction in the number of hallucinations in the subject over a defined period of time, wherein the reduction in number is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95 ... (e) the method does not cause the subject to hallucinate; and / or (f) the method results in a reduction in the severity of the subject's hallucinations over a defined period of time as measured by one or more medically recognized techniques; and / or (g) the method results in a reduction in the severity of the subject's hallucinations over a defined period of time, the reduction in severity being selected from the group consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized techniques; and / or (h) the medically recognized techniques are Hallucination Assessment Tool (CHAT), The Psychotic Symptom Rating Scales (PSYRATS), Auditory Hallucinations Rating Scale (AHRS), Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ), Characteristics of Auditory Hallucinations Questionnaire (CAHQ), Mental Health Research Institute Unusual Perceptionand / or (i) each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

[0026] The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom being treated, prevented, and / or delayed is depression, and (a) treating the depression prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) the method results in an improvement in the subject's depression over a defined period of time as measured by one or more clinically recognized depression rating scales, and / or (c) the method results in an improvement in the subject's depression over a defined period of time as measured by one or more clinically recognized depression rating scales, wherein the improvement is related to mood, behavior, physical function, e.g., eating, sleep, energy, and sexual activity. and / or (d) the method results in an improvement in the subject's depression as measured by one or more clinically recognized depression rating scales, wherein the subject experiences an improvement following treatment of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100%; and / or (e) each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom being treated, prevented, and / or delayed is cognitive impairment, and (a) treating the cognitive impairment prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) the progression or onset of the cognitive impairment is slowed, halted, or reversed for a defined period of time following administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (c) the cognitive impairment is positively affected by administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (d) the cognitive impairment is positively affected by administration of the pharmaceutical composition, as measured by medically recognized techniques, and a positive impact on cognitive decline and / or its progression is observed, as measured by the Mini-Mental State Exam (MMSE), Mini-cog test, and Cantab (e) the progression or onset of cognitive impairment is slowed, stopped, or reversed by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as measured by medically recognized technology; and / or (f) each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

[0027] The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom being treated, prevented, and / or delayed is constipation, and wherein (a) treating the constipation prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) administering a pharmaceutical composition causes the subject to have a bowel movement, and / or (c) the method results in an increase in the frequency of bowel movements in the subject over a defined period of time, and / or (d) the method results in an increase in the frequency of bowel movements in the subject, wherein the increase in bowel movement frequency is (i) about 5%, about 10%, about 15%, about 20%, about 25%, about 30% per week , about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100% increase in the number of bowel movements; and / or (ii) a percentage reduction in the time between successive bowel movements selected from the group consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%; and / or (e) as a result of the method, the subject has a bowel movement frequency recommended by a medical authority for the subject's age group.

[0028] The present disclosure provides methods of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptoms being treated, prevented, and / or delayed are neurodegeneration correlated with PD, and (a) treating the neurodegeneration prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) the method results in the treatment, prevention, and / or delay of the progression and / or onset of neurodegeneration in the subject, and / or (c) the progression or onset of neurodegeneration is slowed, halted, or reversed for a defined period of time following administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (d) the neurodegeneration is positively affected by administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (e) the positive effect and / or progression of neurodegeneration is determined by electroencephalogram (EEG), neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI), [F]fluorodeoxyglucose (FDG) PET, an amyloid-labeling agent, [F]F-dopa and / or (f) progression or onset of neurodegeneration is greater than or equal to about 5%, about 10%, about 15%, about 20%, about 25%, or more than about 5% of the patients with neurodegeneration, as measured quantitatively or qualitatively by one or more techniques selected from the group consisting of PET, radiotracer imaging, volumetric analysis of local tissue loss, specific imaging markers of abnormal protein deposition, multimodal imaging, and biomarker analysis; and / or %, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% delayed, stopped, or reversed; and / or (g) each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

[0029] The present disclosure provides a continuous delivery system comprising a pharmaceutical composition comprising at least one active agent selected from the group consisting of cannabidiol (CBD), its synthetic forms, biosynthetic forms, free base forms, salts, isomers, amorphous forms, derivatives, and combinations thereof, at about 0.1% to about 50% of an active agent selected from the group consisting of tetrahydrocannabinol (THC), its synthetic forms, biosynthetic forms, free base forms, salts, isomers, amorphous forms, derivatives, and combinations thereof, optionally at least one additional active agent, and combinations thereof. The present disclosure provides a continuous delivery system that provides continuous, sustained delivery of the pharmaceutical composition to mitigate peak and valley pharmacokinetic behavior of the active agent. The present disclosure provides a continuous delivery system, which provides continuous, sustained delivery of a pharmaceutical composition via administration to a patient by a route selected from the group consisting of parenteral, intravenous, subcutaneous, intramuscular, intrathecal, oral, buccal, mucosal, intranasal, rectal, vaginal, transdermal, implantable, topical, and combinations thereof. The present disclosure provides a continuous delivery system, which provides continuous, sustained delivery of a pharmaceutical composition via intravenous or subcutaneous infusion. The present disclosure provides a continuous delivery system, which provides continuous, sustained delivery of a pharmaceutical composition via subcutaneous infusion. The present disclosure provides a continuous delivery system, which provides continuous, sustained delivery of a pharmaceutical composition via an infusion pump device.

[0030] The present disclosure provides a continuous delivery system, which provides continuous, sustained delivery of a pharmaceutical composition via a portable / handheld infusion pump worn by a patient and which may use replaceable cartridges. The present disclosure provides a continuous delivery system, which provides continuous, sustained delivery of a pharmaceutical composition via a patch pump or micropump. The present disclosure provides a continuous delivery system, which includes a pharmaceutical composition selected from the group consisting of a liquid formulation, a solid formulation, a semisolid formulation, an emulsion formulation, a nanoparticle formulation, a matrix formulation, a film formulation, a patch formulation, a formulation in an infusion pump, and / or a combination thereof. The present disclosure provides a continuous delivery system, which includes a pharmaceutical composition selected from the group consisting of a transdermal liquid formulation, a transdermal semisolid formulation, a transdermal gel formulation, a transdermal polymer matrix formulation, a transdermal adhesive matrix formulation, a transdermal film-forming gel, a transdermal film-forming spray formulation, a multi-layer transdermal matrix system, a transdermal drug-containing adhesive matrix formulation, and a combination thereof. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition formulated as a topical liquid formulation, a topical semisolid formulation, a topical gel formulation, a topical polymer matrix formulation, a topical adhesive matrix formulation, a topical film-forming gel formulation, or a topical film-forming spray formulation. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition formulated as a transdermal patch, the transdermal patch being selected from the group including a reservoir patch, a multi-layer transdermal matrix system, a microreservoir patch, a matrix patch, a drug-containing adhesive patch, an adhesive matrix patch combined with a polymer, a pressure-sensitive adhesive patch, a sustained-release transdermal film, a liquid reservoir system, a microreservoir patch, a mucoadhesive patch, and combinations thereof.The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a topical patch, wherein the topical patch is selected from the group consisting of a multi-layer transdermal matrix system, a reservoir patch, a microreservoir patch, a matrix patch, a drug-containing adhesive patch, a pressure-sensitive adhesive patch, a sustained-release transdermal film, a liquid reservoir system, a microreservoir patch, a mucoadhesive patch, a microdosing patch, an adhesive matrix patch combined with a polymer, and combinations thereof. The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a transdermal patch. The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a multi-layer transdermal matrix system, a metered-dose transdermal gel, a metered-dose transdermal spray, a film-forming gel, a film-forming spray, or a metered-dose aerosol. The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a topical patch.

[0031] The present disclosure provides continuous delivery systems, including pharmaceutical compositions formulated as a metered gel, a metered spray, a gel, a cream, a solution, an emulsion, a liquid composition, a semi-solid composition, an adhesive matrix in combination with a polymer, or a film-forming formulation. The present disclosure provides continuous delivery systems, including pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, a gelling agent, a polymer, a pressure-sensitive adhesive polymer, a penetration enhancer, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a tackifier, a diluent, a bulking agent, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides continuous delivery systems, including pharmaceutical compositions 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, suspending agents, dispersing agents, stabilizers, plasticizers, tackifiers, diluents, bulking agents, surfactants, antioxidants, oxidizing agents, and combinations thereof in the range of 0.1% to 99.5% w / w or w / v. The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a transdermal formulation that can be administered at a dosage regimen selected from the group consisting of once daily, twice daily, three times daily, once every 1 to 8 hours, once every 1 to 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 two weeks, and once every 15 to about 30 days. The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a topical preparation that can be administered at a dosage regimen selected from the group consisting of once daily, twice daily, three times daily, four times daily, five times daily, six times daily, once every 1 to 8 hours, once every 1 to 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 two weeks, and once every 15 to about 30 days. The present disclosure provides a continuous delivery system, comprising a pharmaceutical composition formulated as a microneedle.The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides a serum level of an active agent selected from the group consisting of about 0.01 ng / mL, about 0.02 ng / mL, about 0.05 ng / mL, about 0.1 ng / mL, about 0.2 ng / mL, about 0.5 ng / mL, about 1 ng / mL, about 2 ng / mL, about 5 ng / mL, about 10 ng / mL, about 20 ng / mL, about 50 ng / mL, about 100 ng / mL, about 200 ng / mL, about 500 ng / mL, about 1 μg / mL, about 2 μg / mL, and about 5 μg / mL. The present disclosure provides a continuous delivery system comprising a pharmaceutical composition, wherein the active agent is present at a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 0.1% to about 50%, about 1% to about 20%, about 5% to about 25%, about 10% to about 20%, or about 15% to about 18%, about 30% to about 70%, and about 35% to about 65% of the formulation. The present disclosure provides a continuous delivery system comprising a pharmaceutical composition, wherein the active agent is present at a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, and about 1% to about 5% of the formulation.

[0032] The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition, wherein THC is selected from the group including its free base, 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, a naturally occurring form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, a stereoisomer thereof, a solid solution thereof, an ion pair thereof, a solution thereof, a powder form thereof, a liquid form thereof, alone or in combination thereof. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition, wherein CBD is selected from the group comprising its free base, 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, a naturally occurring form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, an ion pair thereof, a stereoisomer thereof, a solid solution thereof, a solution thereof, a powder form thereof, a liquid form thereof, alone or in combination thereof. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition comprising one or more active agents selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), 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, a naturally occurring form thereof, an active metabolite thereof, a polymorph thereof, a solid solution thereof, a coated form thereof, and combinations thereof, in a dosage form for transdermal delivery. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition, wherein tetrahydrocannabinol (THC), cannabidiol (CBD), its free base, its salt, its isomer, its amorphous form, its polymorphic form, its stereoisomer, its ion pair, its coated form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its naturally occurring form, its active metabolite, and combinations thereof are produced by synthetic routes.The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition, wherein the active agent is synthetically produced and has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or greater before being added to the pharmaceutical composition. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition co-administered with at least one additional active agent selected from the group consisting of a dopamine precursor, a dopamine receptor agonist, and combinations thereof. The present disclosure provides a continuous delivery system, the continuous delivery system comprising a pharmaceutical composition co-administered with at least one additional active agent selected from the group consisting of levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, and any combination thereof.

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

[0034] According to yet another embodiment, the present disclosure provides the use of the above-described pharmaceutical composition and at least one additional therapeutic agent, in an effective amount, for use in medicine, most preferably for use as a medicine to treat, e.g., a disease or disease-related disorder described herein in a subject.

[0035] The present disclosure provides a method for treating and / or preventing a disease or condition described herein in a patient, said method comprising selecting a patient in need of treatment and / or prevention of said disease or condition described herein, and administering to the patient a therapeutically effective amount of a composition of the present disclosure, thereby treating and / or preventing said disease in the patient. DETAILED DESCRIPTION OF THE INVENTION

[0036] As used herein, the term "active pharmaceutical ingredient" ("API") or "pharmaceutically active agent" refers to a drug or agent that may be used as disclosed herein and is intended for use in the human or animal body to cure, alleviate, prevent, or diagnose a disease, illness, physical injury, or pathological condition; to enable identification of a physical or mental state, condition, or function; to replace an active substance or fluid produced by the human or animal body; to defend against, eliminate, or render harmless pathogens, parasites, or exogenous agents, or to affect a physical or mental state, condition, or function. Drugs that have been used may be found in reference works such as, for example, the Rote Liste or the Merck Index. Examples that may be mentioned include, for example, tretinoin.

[0037] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the therapeutic compound is modified by making its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of the active agent. Pharmaceutically acceptable salts include conventional non-toxic salts, such as salts derived from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and organic acids such as amino acids, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and others known to those skilled in the art of pharmacy. Lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990); Remington: The Science and Practice of Pharmacy 19 th Ed.(Lippincott, Williams & Wilkins,1995);Handbook of Pharmaceutical Excipients,3 rd Ed.(Arthur H.Kibbe,ed.;Amer.Pharmaceutical Assoc.,1999);the Pharmaceutical Codex:Principles and Practice of Pharmaceutics 12 thEd. (Walter Lund ed.; Pharmaceutical Press, London, 1994); United States Pharmacopeia: National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: The Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are incorporated herein by reference.

[0038] As used herein, an amount is "effective" if it produces an effect in a subject. As used herein, the term "effective amount" refers to an amount of a compound or composition that is sufficient to significantly induce positive benefits, including those disclosed herein, either individually or in combination, but low enough to avoid serious side effects, i.e., that provides a reasonable benefit-to-risk ratio within the sound judgment of a person skilled in the art. For those skilled in the art, the effective amount, as well as the dosage and frequency of administration, can be determined according to standard methodologies based on their knowledge and the present disclosure, and by no more than routine experimentation.

[0039] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to an animal, preferably a mammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkeys and humans), most preferably a human. In some embodiments, the subject is a non-human animal such as a livestock animal (e.g., a horse, pig, or cow) or a pet (e.g., a dog or cat). In certain embodiments, the subject is an elderly human. In other embodiments, the subject is a human adult. In other embodiments, the subject is a human child. In yet other embodiments, the subject is a human infant.

[0040] As used herein, the phrase "pharmaceutically 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.

[0041] As used herein, the terms "prevent," "preventing," and "prevention" in the context of administration of a therapy to a subject refer to prevention or inhibition of the recurrence, onset, and / or progression of a disease or condition, or combination of therapies (e.g., a combination of prophylactic or therapeutic agents).

[0042] 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.

[0043] As used herein, the terms "treat," "treatment," and "treating" in the context of administering a therapy to a subject refer to reducing or inhibiting the progression and / or duration of a disease or condition, reducing or ameliorating the severity of a disease or condition, and / or ameliorating one or more symptoms thereof that results from the administration of one or more therapies.

[0044] As used herein, the terms "continuous delivery," "continuously administering," or "continuous administration" refer to the essentially uninterrupted administration of a pharmaceutical or drug to a subject. Administration is non-stop (uninterrupted) except as needed to replenish the supply of pharmaceutical or drug or to administer the next dose in a regimen. "Continuous delivery" means that there is uninterrupted administration of pharmaceutical or drug, and that the rate of administration or absorption may vary over the dosing interval.

[0045] As used herein, the term "multiparticulates" refers to one or more unit dose systems, such as, but not limited to, pellets, beads, spheres, minitablets, seeds, spheroids, or granules, having a modified drug release profile. Multiparticulates include a drug-release-controlling and / or drug-protecting film or matrix, such as a polymer film or matrix, the integrity or efficiency of which is susceptible to certain conditions, such as heat or mechanical forces, that may occur during post-processing. The term "core material" refers to the nature of the interior portion of the multiparticulate, which may also include a functional coat. Exemplary "core materials" can be pellets (spherical matrix systems containing drug and additional excipients), granules (less spherical particles composed almost entirely of drug), or nonpareils (spherical particles without drug).

[0046] As used herein, the term "about," when used in conjunction with a stated numerical value or range, has the meaning reasonably ascribed to it by one of ordinary skill in the art, i.e., to some degree more or some degree less than the stated value or range.

[0047] activator The term "active agent" or "active ingredient" refers to a drug, active ingredient compound or other substance, or composition and mixtures thereof, that provides some pharmacological, often beneficial, effect. 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, continuous drug delivery systems and methods that include one or more of the following active agents, such as tetrahydrocannabinol (THC), cannabidiol (CBD), and combinations thereof.

[0048] The term "active agent" or "active ingredient" refers to a drug, active ingredient compound, or other substance, or composition and mixtures thereof, that provides some pharmacological, often beneficial, effect. Reference to a specific active ingredient includes, where appropriate, the active ingredient and its pharmaceutically acceptable salts. The present disclosure provides continuous drug delivery systems and methods, for example, including one or more of the following active agents: cannabinoids are a group of 21-carbon-containing terpenoid-based compounds produced by cannabis species. Cannabinoids may 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 neurotransmitter release in the brain. These receptor proteins include endocannabinoids (naturally produced 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 derived 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).

[0049] 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.

[0050] [ka]

[0051] Tetrahydrocanthol (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.

[0052] The chemical structure is shown below as Formula II.

[0053] [ka]

[0054] As used herein, the term "cannabis" refers to all pharmaceutically acceptable forms of cannabis and its derivatives, either alone or in combination, including, but not limited to, the following forms: free base or salts or isomers or amorphous or crystalline or co-crystalline or solid solutions or prodrugs or analogs or derivatives or metabolites or polymorphs or stereoisomers or coated forms or ion pairs. For example, cannabidiol free base or a salt thereof or an isomer thereof or an amorphous form thereof or a crystalline form thereof or a co-crystalline form thereof or a solid solution thereof or a prodrug thereof or an analog thereof or a derivative thereof or a synthetic form thereof or a polymorph thereof or a stereoisomer thereof or an ion pair thereof. 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, examples of which are hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. Suitable base salts are formed from bases which form non-toxic salts, examples of which are sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts.

[0055] As used herein, the term "cannabidiol" includes its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolite, its solid solution, its polymorphs, its stereoisomers, its powder form, its liquid form, its ion pair, a solution of cannabidiol in a solvent such as, but not limited to, methanol, alone or in combination thereof.

[0056] As used herein, the term "THC" includes its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogs, its derivatives, its synthetic form, its biosynthetic form, its active metabolite, its solid solution, its powder form, its liquid form, its ion pair, its polymorphs, its stereoisomers, solutions of THC in solvents such as, but not limited to, methanol, heptane, alone or in combination.

[0057] As used herein, synthetic cannabinoids include at least the following: AM-087, a cannabinoid agonist derivative of Δ8THC substituted at the 3-side chain, is a potent CB1 agonist and analgesic; AM-251, an inverse agonist of the CB1 cannabinoid receptor, shares close structural similarity with SR141716A (rimonabant), both of which are biarylpyrazole cannabinoid receptor antagonists and μ-opioid receptor antagonists; methanandamide (AM-356), an anandamide derivative. and act on cannabinoid receptors with a Ki of 17.9 nM at CB1 and 868 nM at CB2; AM-374 (palmitylsulfonyl fluoride); AM-381 (stearylsulfonyl fluoride); AM404, also known as N-arachidonoylaminophenol, is an active metabolite of paracetamol (acetaminophen) that is thought to induce its analgesic effects via its activity on the endocannabinoid, COX, and TRPV systems, all of which are present in pain and thermoregulatory pathways; AM-411, a cannabinoid AM-411 is a potent and highly selective CB1 full agonist, producing effects similar to those of other cannabinoid agonists, such as analgesia, sedation, and anxiolysis; AM-630 (6-rhodopravadrine) acts as a potent and selective inverse agonist at the cannabinoid receptor CB2, more selective than CB1 and acting as a weak partial agonist; AM-661 (1-(N-methyl-2-piperidine)methyl-2-methyl-3-(2-iodo)benzoylindole); JWH-0 18 (1-pentyl-3-(1-naphthoyl)indole) or AM-678 is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both CB1 and CB2 cannabinoid receptors, with some selectivity for CB2; AM-679 acts as a moderately potent agonist at cannabinoid receptors; AM-694 (1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole) acts as a potent and selective agonist at cannabinoid receptor CB1;AM-735 (3-bornyl-Δ8-THC, a mixed CB1 / CB2 agonist); AM-855 is an analgesic cannabinoid agonist at both CB1 and CB2, with moderate selectivity for CB1; AM-881 (a chlorine-substituted stereoisomer of anandamide with a K = 5.3 nM at CB1 and 95 nM at CB2); AM-883 (an allyl-substituted stereoisomer of anandamide with a K = 9.9 nM at CB1 and 226 nM at CB2); and AM-905 are potent and moderately selective agonists for the CB1 cannabinoid receptor. AM-906 is a cannabinoid agonist and an analgesic that is a potent and selective agonist at the CB1 cannabinoid receptor; AM-919 is an analgesic cannabinoid receptor agonist that is potent at both CB1 and CB2; AM-926 (a potent agonist at both CB1 and CB2 with moderate selectivity for CB1); AM-938 is a cannabinoid receptor agonist and an analgesic that remains potent at both CB1 and CB2. AM-1116 (a dimethylated stereoisomer of anandamide); AM-1172 (an endocannabinoid analog specifically designed to be a potent and selective inhibitor of AEA uptake that is resistant to FAAH hydrolysis); AM-1220 is a potent and moderately selective agonist for cannabinoid receptor CB1; AM-1221 acts as a potent and selective agonist for cannabinoid receptor CB2; and AM-1235 (1-(5-fluoropentyl)-3-methyl-2-propanol). -(naphthalen-1-oyl)-6-nitroindole) acts as a potent and moderately selective agonist at the cannabinoid receptor CB1; AM-1241 (1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole) is a potent and selective agonist at the cannabinoid receptor CB2 and 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 at both cannabinoid receptors CB1 and CB2; AM-1710 (a CB2-selective cannabilactone with 54-fold selectivity over CB1); AM-1714 acts as a moderately selective agonist at the peripheral cannabinoid receptor CB2 and has both analgesic and antiallodynic effects; and AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole) acts as a potent but nonselective full agonist at cannabinoid receptors. AM-2212 (a potent agonist at both CB1 and CB2); AM-2213 (a potent agonist at both CB1 and CB2); AM-2232 (1-(4-cyanobutyl)-3-(naphthalene-1-oyl)indole) acts as a potent but nonselective agonist at cannabinoid receptors CB1 and CB2; AM-2233 acts as a highly potent full agonist at cannabinoid receptors CB1 and CB2, with lower potency than JWH-018 but higher potency than WIN55,212-2. and has been found to completely replace THC in certain mammalian studies; AM-2389, which acts as a potent and moderately selective agonist at the CB1 receptor; AM-3102, an analog of oleoylethanolamide (an endogenous agonist of proliferator-activated receptor alpha (PPARα)) that acts as a weak cannabinoid agonist at CB1 and CB2; AM-4030, an analgesic that is a potent agonist at both CB1 and CB2 but is also moderately selective for CB1; AM-4054, a potent but 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 CB1 and CB2 receptors and has some selectivity for CB2; JWH-007 is an analgesic that acts as a cannabinoid agonist at both CB1 and CB2 receptors;JWH-015 acts as a subtype-selective cannabinoid agonist that binds to CB2 approximately 28 times more strongly than CB1 and has been shown to have immunomodulatory effects and may be useful in the treatment and / or prevention and / or control of cancers such as glioblastoma, GBM, etc.; JWH-018 (a painkiller that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, producing effects similar to those of THC); JWH-019 (an agonist at both the CB1 and CB2 receptors, producing cannabinoid agonists at both the CB1 and CB2 receptors); JWH-030 (an analgesic that is a partial agonist at the CB1 receptor); JWH-047 (a potent and selective agonist at the CB2 receptor), JWH-048 (a potent and selective agonist at the CB2 receptor), JWH-051 (an analgesic with high affinity for the CB1 receptor but a much stronger agonist at the CB2 receptor), JWH-057 (a Δ8-THC with very high affinity for the CB2 receptor but also with high affinity for the CB1 receptor) 1-deoxy analog of); JWH-073 (an analgesic that acts as a cannabinoid agonist at both CB1 and CB2 receptors, with some selectivity for the CB1 subtype); JWH-081 (an analgesic that acts as an agonist at both cannabinoid CB1 and CB2 receptors); JWH-098 (a potent and highly selective CB2 agonist); JWH-116 (a CB1 ligand); JWH-120 (a potent and 173-fold selective CB2 agonist); JWH-122 (a potent and highly selective CB1 agonist); JWH-133 (a potent and highly selective CB1 agonist) JWH-139 (3-(1,1-dimethylpropyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene); JWH-147 (an analgesic from 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 for the CB1 subtype); JWH-149 (a potent and highly selective CB2 agonist);JWH-161 (CB1 ligand); JWH-164 (potent cannabinoid agonist); JWH-166 (potent and highly selective CB2 agonist); JWH-167 (weak cannabinoid agonist from the phenylacetylindole family); JWH-171 (an analgesic that acts as a cannabinoid receptor agonist); JWH-175 ((1-pentylindol-3-yl)naphthalen-1-ylmethane, 22 nM at CB1), JWH-176-1 (([(1E)-3-pentylindene-1 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-methylnaphthalene) 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 (analgesic from the aminoalkyl indole family that acts as a cannabinoid receptor agonist);JWH-203 (an analgesic from the phenylacetylindole family that acts as a cannabinoid agonist with roughly equal affinity at both CB1 and CB2 receptors); JWH-205 (142-methyl-1-pentylindol-3-yl)-2-phenylethanone); JWH-210 (an analgesic chemical from the naphthoylindole family that acts as a potent cannabinoid agonist at both CB1 and CB2 receptors); JWH-213 (a potent and highly selective CB2 agonist); JWH-229 (1-methoxy-3-(1',1'-dimethylhexyl)-Δ8-THC, a dibenzopyran cannabinoid that is a potent CB2 agonist); JWH-234 (a cannabinoid agonist with selectivity for CB2); JWH-250 (an analgesic from the phenylacetylindole family that acts as a cannabinoid agonist at both CB1 and CB2 receptors); JWH-251 ((1-pentyl-3-(2-methylphenylacetyl)indole)); JWH-258 (a potent and mildly selective CB1 agonist); JWH-302 (1-pentyl-3-(3-methoxyphenylacetyl)indole); JWH-307 (a cannabinoid agonist with selectivity for both CB1 and CB2 receptors) These include: a naphthoylpyrrole family analgesic that acts as a cannabinoid agonist in both the brain and the body, with some selectivity 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); and 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 from the naphthoylindole family that acts as a potent cannabinoid agonist at both CB1 and CB2 receptors); JWH-398 (an analgesic chemical from the naphthoylindole family that acts as a potent cannabinoid agonist at both receptors with a K i of 2.3 nM at CB1 and 2.8 nM at CB2); JWH-424 (a potent analgesic chemical from the naphthoylindole family that acts as a potent cannabinoid agonist at both receptors with a K i of 5.44 nM at CB2 and 20.9 nM at CB1). and a moderately selective CB2 agonist; HU-210, a cannabinoid 100–800 times more potent than natural THC derived from cannabis, has a long duration of action, and is a potent analgesic with many of the same effects as natural THC; ajuremic acid (AB-III-56, HU-239, IP-751, CPL7075, CT-3, Resunab) is a cannabinoid derivative of the non-psychoactive THC metabolite 11-nor-9-carboxy-THC that exhibits useful analgesic and anti-inflammatory effects without causing a subjective "high."It is being developed for the treatment of inflammatory conditions such as neuropathic pain and arthritis, as well as for the treatment of orphan life-threatening inflammatory diseases; HU-243 (AM-4056) is a cannabinoid that is a potent agonist at both CB1 and CB2 receptors; HU-308 acts as a cannabinoid agonist and is highly selective for the CB2 receptor subtype. It has analgesic effects, promotes neural stem cell proliferation, and protects both the liver and vascular tissue from oxidative stress through the inhibition of TNF-α; HU-331 is a quinone anticarcinogen synthesized from cannabidiol; HU-336 is a potent antiangiogenic compound that inhibits angiogenesis by directly inducing endothelial cell apoptosis without altering the expression of pro- and antiangiogenic cytokines and their receptors; HU-345 (cannabinol quinone) is a drug that can inhibit aortic ring angiogenesis more potently than its parent compound cannabinol; CP47,497 or (C7)-CP47,497 is a cannabinoid receptor agonist drug.

[0058] The present disclosure also provides methods for the biosynthesis of cannabinoids, as well as methods for using eukaryotic or prokaryotic expression systems to produce 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, Escherichia coli, yeast, and baculovirus hosts. Thus, the present disclosure provides methods for producing biosynthetic cannabinoids, such as THC and / or CBD, using cannabinoid acid synthase enzymes, including, but not limited to, tetrahydrocannabinolic acid (THCA) synthase and cannabidiolic acid (CBDA) synthase. The present disclosure further provides continuous drug delivery systems and methods disclosed herein, including, for example, biosynthetic CBD, alone or in combination with other active agents.

[0059] According to certain embodiments, the continuous drug delivery systems and methods described herein are for the prevention and / or control and / or treatment of cancer. According to certain embodiments described herein, the pharmaceutical compositions or continuous drug delivery systems and methods contain cannabidiol and / or THC - its free base, its salt, its isomer, its amorphous form, its amorphous 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 coated form, its solid solution, its ion pair, its solution in a solvent, alone or in combination thereof. More preferably, the continuous drug delivery systems and methods may include cannabidiol, its free base, its salt, its isomer, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analog, its derivative, its synthetic form, its biosynthetic form, its active metabolite, its polymorph, its ion pair, its stereoisomer, its coated form, a solution of cannabidiol in methanol, alone or in combination thereof. More preferably, the continuous drug delivery systems and methods may include THC, its free base, its salts, its isomers, its amorphous form, its crystalline form, its co-crystalline form, its prodrug, its analogue, its derivative, its ion pair, its synthetic form, its biosynthetic form, its active metabolite, its polymorph, its stereoisomer, its coated form, a solution of cannabidiol in methanol, alone or in combination thereof.

[0060] As used herein, the term "active agent" refers to all pharmaceutically acceptable forms of the active agent and its derivatives, either alone or in combination, including, but not limited to, the following forms: free base or salt or isomer or amorphous or crystalline or co-crystalline or solid solution or prodrug or analog or derivative or metabolite. For example, the free base of the active agent or a salt thereof or an isomer thereof or an amorphous form thereof or a crystalline form thereof or a co-crystalline form thereof or a solid solution thereof or a prodrug thereof or an analog or a derivative thereof or a 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 hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. Suitable base salts are formed from bases which 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 a pharmaceutically acceptable salt. Pharmaceutically acceptable salts that form part of the present invention are intended to define, but are not limited to, salts of carboxylic acid moieties, for example, 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, etc.; ammonium or substituted ammonium salts, and aluminum salts. The salts may be acid addition salts, including, but not limited to, sulfate, nitrate, phosphate, perchlorate, borate, hydrohalide, acetate, tartrate, maleate, citrate, succinate, palmoate, methanesulfonate, benzoate, salicylate, hydroxynaphthoate, benzenesulfonate, ascorbate, glycerophosphate, ketoglutarate, etc.

[0061] As used herein, the term "active agent" includes 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, 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 comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75% (w / w) of the formulation. In certain embodiments, the dose of the active agent is, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 mg / kg / day. In certain embodiments, the dose of the active agent is, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, or 275 mg / day. 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 active agent may be present in a concentration of about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, formulations of the present disclosure may 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 approximately 1-75% by weight of the formulation, preferably 2-30%, and more preferably 5-20%.

[0062] In exemplary embodiments, the formulations disclosed herein provide a soluble soluble cellulose solution containing 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%, The active agent may be present in a concentration of 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 disclosed herein may contain the active agent in a concentration of about 1 to about 20%, about 5 to about 25%, about 10 to about 20%, or about 15 to about 18%, about 30 to about 70%, about 35 to about 65%, about 63.13%, and about 40 to about 64% w / w.

[0063] In certain embodiments, the active agent is present as a highly purified extract of the active agent comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75% (w / w) of the formulation.

[0064] In certain embodiments, the active agent is present in the provided formulation at a concentration of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75%, or 100% (w / w).

[0065] In certain embodiments, the active agent is 100% synthetic. In certain embodiments, the active agent has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or greater. In certain embodiments, the active agent is synthetically produced and has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or greater. In certain embodiments, the active agent is a combination of active agents, each of which may be synthetically produced and independently have a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or greater.

[0066] In certain embodiments, the dose of the active agent is, for example, about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 mg / kg / day or more. In certain embodiments, the dose of the active agent is, for example, about 0.001 ng / day, 0.01 ng / day, 0.025 ng / day, 0.05 ng / day, 0.1 ng / day, 0.25 ng / day, 0.5 ng / day, 1 ng / day, 10 ng / day, 25 ng / day, 50 ng / day, 100 ng / day, 250 ng / day, 500 ng / day, 1000 ng / day, 0.001 microgram / day, 0.01 microgram / day, 0.025 microgram / day, micrograms / day, 0.050 micrograms / day, 0.1 micrograms / day, 0.25 micrograms / day, 0.5 micrograms / day, 1 microgram / day, 2.5 micrograms / day, 5 micrograms / day, 10 micrograms / day, 25 micrograms / day, 50 micrograms / day, 100 micrograms / day, 250 micrograms / day, or 500 micrograms / day or more. In certain embodiments, the dose of active agent is, for example, about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 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 ng / day or more. In certain embodiments, the dose of the active agent is, for example, about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 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 or more.In exemplary embodiments, the formulations of the present disclosure may include an active agent at a concentration of about 0.001 ng, 0.01 ng, 0.025 ng, 0.05 ng, 0.1 ng, 0.25 ng, 0.5 ng, 1 ng, 10 ng, 25 ng, 50 ng, 100 ng, 250 ng, 500 ng, 1000 ng, 0.001 micrograms, 0.01 micrograms, 0.025 micrograms, 0.05 micrograms, 0.1 micrograms, 0.25 micrograms, 0.5 micrograms, 1 microgram, 2.5 micrograms, 5 micrograms, 10 micrograms, 25 micrograms, 50 micrograms, 100 micrograms, 250 micrograms, or 500 micrograms. In exemplary embodiments, the formulations of the present disclosure may include an active agent at a concentration of about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 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 ng. In exemplary embodiments, the formulations of the present disclosure may include an active agent at a concentration of about 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 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.

[0067] In exemplary formulations disclosed herein, the active agent represents approximately 1% to 75% by weight of the total weight, preferably 2% to 30% by weight, and more preferably 5% to 20% by weight.

[0068] In other embodiments, the pharmaceutical composition further comprises one or more additional ingredients such as a pharmaceutically compatible carrier, binder, viscosity modifier, filler, suspending agent, flavoring agent, sweetener, disintegrant, surfactant, preservative, lubricant, colorant, diluent, solubilizing agent, moisturizing agent, stabilizer, humectant, anti-adhesive agent, paracellular activator, anti-foaming agent, antioxidant, chelating agent, anti-fungal agent, anti-bacterial agent, or one or more combinations thereof.

[0069] Continuous Drug Delivery According to embodiments provided herein, continuous delivery systems include formulations selected from the group consisting of liquid formulations, solid formulations, semisolid formulations, emulsion formulations, nanoparticle formulations, matrix formulations, film formulations, patch formulations, infusion pumps, and / or combinations thereof. It is contemplated that embodiments may be formulated to provide continuous, sustained delivery to mitigate the peak and valley pharmacokinetic behavior associated with standard immediate-release oral delivery forms. It is contemplated that embodiments may be formulated to provide a route of administration selected from the group consisting of oral, buccal, mucosal, rectal, transdermal, topical, parenteral, and / or implantable, and / or combinations thereof.

[0070] In one aspect, methods are provided for providing continuous drug delivery systems and methods for a therapeutically effective amount of a pharmaceutical composition or formulation comprising an active agent, such as THC and / or CBD. In some embodiments, the continuous drug delivery systems and methods continuously deliver THC and / or CBD at a predetermined time rate. In some embodiments, the predetermined time rate can be in the range of 16 to 1400 μg / hour, e.g., 30 μg to 750 μg / hour, 30 μg to 145 μg / hour, 70 μg to 285 μg / hour, or 185 μg to 725 μg / hour, e.g., 35 μg / hour, 75 μg / hour, 90 μg / hour, 140 μg / hour, 180 μg / hour, 190 μg / hour, 275 μg / hour, 450 μg / hour, or 700 μg / hour, or a time rate between any two of these recited rates (inclusive), e.g., 35 to 140 μg / hour, or 75 to 280 μg / hour, or 190 to 700 μg / hour.

[0071] In some embodiments, the continuous drug delivery systems and methods continuously deliver the active agent to achieve steady-state plasma levels of THC and / or CBD compounds in the range of 3-140 μg / L, e.g., 3.5-140 μg / L, 3-75 μg / L, 3.5-75 μg / L, 3.5-14 μg / L, 7.5-28 μg / L, 19-70 μg / L, 9 μg / L, 18 μg / L, or 45 μg / L.

[0072] In some embodiments, continuous drug delivery systems and methods continuously deliver an active agent for a predetermined number of days. In some embodiments, the predetermined number of days is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In other embodiments, the predetermined number of days is 1 to 14 days, 1 to 12 days, 1 to 10 days, 1 to 7 days, 1 to 5 days, 1 to 3 days, 2 to 14 days, 2 to 12 days, 2 to 10 days, 2 to 7 days, 2 to 5 days, 2 to 3 days, 3 to 14 days, 3 to 12 days, 3 to 10 days, 3 to 7 days, 3 to 5 days, 4 to 14 days, 4 to 10 days, 7 to 14 days, or 7 to 10 days.

[0073] In some embodiments, the time rate is selected to achieve a plasma concentration comparable to the active agent plasma concentration provided by an oral dose 0-24 hours, e.g., about 1-24 hours, further e.g., about 5-24 hours, further e.g., about 5-23 hours, or about 10-16 hours after ingestion. The oral dose can be 2.5-50 mg once daily, e.g., 2.5 mg, 4.0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 50 mg of THC and / or CBD compounds once daily or once every two days. The phrase "comparable to the plasma concentration of an oral dose 0-24 hours" can be understood from Examples 6-9. For example, the area under the time-concentration curve (AUC) calculated by the trapezoidal rule for the 0-24 hour interval from a graph of the plasma concentration versus time of an oral dose divided by time (24 hours) is the hourly blood concentration associated with the AUC. The AUC per hour achievable by the time rate of the continuous delivery methods described herein will result in a drug exposure over time similar to that exhibited by an oral dose. Such time rates of the continuous delivery methods described herein achieve plasma concentrations comparable to the blood levels from 0 to 24 hours following oral administration. In another embodiment, the continuous delivery methods described herein achieve an AUC comparable to the AUC from oral administration of the same compound over the period 0 to 24 hours following administration.

[0074] In some embodiments, the continuous drug delivery systems and methods continuously deliver the active agent in a manner that provides an AUC that is 10-60% of the exposure obtained from standard of care treatment. The standard of care treatment can be, for example, a 500 mcg intraperitoneal injection once daily, or 2.5-50 mg orally once daily, e.g., 2.5 mg, 4.0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 50 mg of CBD and / or THC compounds via oral administration once daily or once every two days. In another embodiment, the continuous drug delivery systems and methods herein provide continuous administration of the active agent to provide an AUC that is about 10-60% of the AUC provided by standard of care treatment. In some embodiments, the standard of care treatment is an oral dose of CBD and / or THC of 2.5 mg to 50 mg once daily, e.g., 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg or 50 mg once daily or once every two days.

[0075] In some embodiments, continuous drug delivery systems and methods continuously deliver an active agent compound (e.g., CBD and / or THC) at a dose rate that provides a blood level (μg / L) equivalent to the 10-16 hour blood level obtained from a once-daily oral dose of 2.5-50 mg (e.g., 2.5 mg, 5 mg, 10 mg, or 25 mg of active agent once daily). In a most preferred embodiment, the method continuously delivers an active agent compound at a dose rate that provides a blood level equivalent to the 12 hour blood level obtained from a once-daily oral dose of 2.5-50 mg (e.g., 5 mg, 10 mg, or 25 mg of active agent once daily).

[0076] In some embodiments, the continuous drug delivery systems and methods provide an active agent compound (e.g., THC and / or CBD) such that the daily dose of the method is 10-75%, e.g., 15-70%, 15-25%, 40-50%, 10-45%, 45%-70%, 60-70%, 15%, 16%, 17%, 18%, 19%, 20%, or 30% of the daily dose of the standard of care treatment. , 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% of the dose rate. In some embodiments, the standard of care treatment is, for example, a 500 mcg intraperitoneal injection once daily. In some embodiments, the standard of care treatment is an FDA-approved once-daily oral dose of active agent, for example, a 5 mg, 10 mg, or 25 mg oral dose once daily.

[0077] The continuous drug delivery system and method provide continuous delivery of an active agent containing a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier should be compatible with other components of the formulation, if any, and not harmful to the subject's health. When the continuous delivery involves injection, the formulation components can be selected to facilitate injection of the formulation. Exemplary carriers for formulations for continuous delivery include, but are not limited to, water, carboxymethylcellulose (CMC), Tween 80, dimethyl sulfoxide (DMSO), ethanol, 2-hydroxypropyl-β-cyclodextrin, dextrose, and PEG 400.

[0078] When the formulation is in liquid form, the active agent is, in some embodiments, present in a concentration of about 0.01 to 20 mg / mL, 0.05 to 5 mg / mL, 0.05 to 3 mg / mL, 0.1 to 4 mg / mL, 0.1 to 2.0 mg / mL, or about 0.1 to 1 mg / mL.

[0079] In certain embodiments, continuous drug delivery systems and methods include transdermal systems or topical formulations, which may be in liquid or gel form and incorporated into transdermal patches. For example, but not limited to, transdermal formulations may include a polymer matrix, which may be adhesive or non-adhesive, such as, but not limited to, a polyacrylic adhesive. Matrix patches include those with a single matrix layer or multiple matrix layers.

[0080] The use of continuous drug delivery systems and methods, such as the transdermal and topical systems described herein, has dosages that vary depending on the mode of administration, the particular condition being treated, and the desired effect. Dosage can be a once-daily transdermal application for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more. Alternatively, application can be several times a day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more. Alternatively, application can be once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0081] In some embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations, provide a predetermined delivery rate of the active ingredient of the transdermal patch over 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. In some further embodiments, the predetermined rate is an essentially constant rate with a coefficient of variation of less than about 90%, 85%, or 80% over the predetermined period of time.

[0082] In still further embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations, provide a predetermined serum level range of the active ingredient of the transdermal patch in a patient over a predetermined period of time, which in some embodiments is 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0083] In still further embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations, provide plasma concentrations of the active ingredient of the transdermal patch in the therapeutic range in a patient over a predetermined period of time, which in some embodiments is 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0084] In still further embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations described herein, allow for reduced variability in the dosage of an active ingredient in a patient over a period of time, which in some embodiments is 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0085] In some embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations provided herein, can be administered in a dosing regimen of once daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, once every 15 to about 30 days, etc.

[0086] In still further embodiments, pharmacokinetic evaluations are performed on blood samples from subjects treated using the transdermal delivery systems described herein. The transdermal formulation is adjusted in response to the pharmacokinetic evaluations. For example, dosing may be adjusted so that a smaller patch, a larger patch, or multiple transdermal patches are applied to the subject, or patches with higher or lower doses of active ingredient are applied. In some embodiments, formulations are available in various dosage strengths and patch sizes to achieve optimal therapeutic results based on the subject's requirements. In one embodiment, two or more transdermal systems or topical formulations are applied to the subject; in some embodiments, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, or 2 to 3 patches are applied; and in other embodiments, 1, 2, 3, 4, 5, or 6 patches are applied.

[0087] cancer The present disclosure provides a method for treating a neoplasm in a patient in need thereof, comprising administering to the patient a continuous drug delivery system and method as disclosed herein comprising a therapeutically effective amount of, for example, tetrahydrocannabinol (THC), cannabidiol (CBD), and combinations thereof, as exemplified herein, optionally further combined with, for example, a neoplasm therapeutic agent. As used herein, the term "neoplasm" also refers to tumors, proliferative diseases, malignancies, and their metastases.

[0088] Cancer is an abnormal growth of cells that tends to grow in an uncontrolled manner and, in some cases, metastasize (spread). Cancer is not one disease; it is a group of over 100 different, specific diseases. Cancer can involve any tissue in the body and can have many different forms in each body area. Most cancers are named for the type of cell or organ in which they begin. Tumors can be cancerous or benign. A benign tumor means that the tumor can grow but not spread. A cancerous tumor is malignant, meaning that it can grow and spread to other parts of the body. When cancer spreads (metastasizes), the new tumor has the same name as the original (primary) tumor. The frequency of certain cancers may depend on gender. Skin cancer is the most common type of malignant tumor for both men and women, while the second most common type in men is prostate cancer and in women is breast cancer.

[0089] Examples of cancerous diseases include adenocarcinoma of the head and neck (including salivary glands and oral cavity), gastrointestinal tract (including pharynx, esophagus, stomach, small intestine, large intestine, anus), lung, liver (including hepatocellular carcinoma, cholangiocarcinoma, and mixed tumors), extrahepatic bile duct and gallbladder, pancreas (including ductal and acinar types), genitourinary tract (ovaries, fallopian tubes, endometrium, cervix, and vagina, ureter, bladder, testis, epididymis, prostate), and skin adnexa; squamous cell carcinomas of the lungs, rectum, and oral cavity, gastrointestinal tract (including the pharynx, esophagus, and anus), lung, intrahepatic and extrahepatic bile ducts (including the gallbladder), pancreas, genitourinary tract (including the endometrium, cervix, vagina, ureters, bladder, testes, epididymis, and prostate), and skin adnexa; germ cell tumors (including malignant teratomas, embryonal carcinomas, ovarian goiters, yolk sac tumors, seminoma, and choriocarcinoma); sarcomas (leiomyosarcoma, malignant tumors of the central nervous system (including astrocytoma, oligodendroglioma, glioblastoma, GBM, medulloblastoma); malignant tumors of the salivary gland (including adenoid cystic carcinoma, adenosquamous carcinoma, clear cell carcinoma, cystic adenocarcinoma, and mucoepidermoid carcinoma); mixed carcinomas (including hepatocellular-cholangiocarcinoma, carcinosarcoma, mixed adenocarcinoma, and adenosquamous carcinoma); hepatocellular carcinoma; blastic malignancies (including hepatoblastoma, neuroblastoma, ganglioneuroblastoma, and nephroblastoma); renal cell carcinoma; neuroendocrine carcinoma; thyroid carcinoma (including papillary, follicular, medullary, and anaplastic carcinoma); parathyroid carcinoma, pituitary carcinoma, and adrenal carcinoma (including adrenocortical carcinoma and pheochromocytoma), and combinations thereof. In some embodiments of the present disclosure, the cancer is endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, small intestine cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, GBM, and hematological cancers such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma / primary mediastinal large B-cell lymphoma, or chronic myeloid leukemia.

[0090] The method of the present disclosure can be used to treat any type of cancer known in the art. Non-limiting examples of cancers that can be treated by the method of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), esophageal cancer, squamous cell carcinoma, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, GBM, glioma, leukemia, lymphoma, mesothelioma, sarcoma, and other tumor malignant tumors. Furthermore, the present invention includes refractory or recurrent malignant tumors whose growth can be inhibited using the method of the present invention. In some embodiments, cancers treated by the methods of the present disclosure include, for example, carcinoma, squamous cell carcinoma (e.g., of the cervix, eyelid, conjunctiva, vagina, lung, oral cavity, skin, bladder, head and neck, tongue, larynx, and esophagus), and adenocarcinoma (e.g., of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, and ovary). In some embodiments, cancers treated by the methods of the present disclosure further include sarcoma (e.g., myogenic sarcoma), leukemia, neuroma, melanoma, and lymphoma.

[0091] In some embodiments, the patient or patient population treated with the combination therapy of the present disclosure has a solid tumor. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, or Merkel cell carcinoma. In some embodiments, the patient or patient population treated with the combination therapy of the present disclosure has a hematological cancer. In some embodiments, the patient has a hematological cancer such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin's lymphoma ("HL"), non-Hodgkin's lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML"), or multiple myeloma ("MM").

[0092] neoplastic therapy Any therapy (e.g., therapeutic or prophylactic agent) that is useful, has been used, is currently being used, or can be used for the prevention, treatment, and / or management of neoplasms can be used to prevent, treat, and / or manage patients with neoplasms and / or cancers in accordance with the methods, compositions, and combinations of the present disclosure. Neoplasm and / or cancer monitoring can also be used in combination with any therapy for cancer according to the present invention. Therapies (e.g., therapeutic or prophylactic agents) include, but are not limited to, peptides, polypeptides, fusion proteins, nucleic acid molecules, small molecules, mimetics, synthetic drugs, inorganic molecules, and organic molecules. Non-limiting examples of cancer therapies include chemotherapy, radiation therapy, hormonal therapy, antiangiogenic therapy, targeted therapy, and / or biological therapy, including immunotherapy and surgery. In certain embodiments, a prophylactically and / or therapeutically effective regimen comprises the administration of a combination of therapies.

[0093] Examples of neoplastic agents or therapies include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthracyclines; anthramycin; asparaginase; asparin; azacitidine (Vidaza); azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bisphosphonates (e.g., paclitaxel); thiazolinone (Aredria), clondronate sodium (Bonefos), zoledronic acid (Zometa), alendronate (Fosamax), etidronate, ibandronate, cimadronate, risedronate, and tiludronate); bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calsterone; caracemide; carbetamycin; carboplatin; carmustine; carrubicin hydrochloride; carzelesin; cedefingol; chlorambucil; ciloremycin; cisplatin ;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine (Ara-C);Dacarbazine;Dactinomycin;Daunorubicin hydrochloride;Decitabine (Dacogen);Demethylating agents, dexormaplatin;Dezaguanine;Dezaguanine mesylate;Diaziquone;Docetaxel;Doxorubicin;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;EphA2 inhibitors;Elsamitrucin;Enloplatin; Enpromate; Epipropizine; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine sodium phosphate; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine phosphate; Fluorouracil; Fluorocitabine; Foskidone; Fostriecin sodium; Gemcitabine; Gemcitabine hydrochloride; Histone deacetylase inhibitors (HDAC-Is) Hydroxyurea; Idarubicin hydrochloride; Ifosfamide;Ilmofosine; imatinib mesylate (Gleevec, Glivec); interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; lenalidomide (Revlimid); letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; anti-CD2 antibodies (e.g., siplizumab (MedImmune) Inc.; WO 02 / 098370, incorporated herein by reference in its entirety); megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; metholedepa; mifepristone; mitindomide; mitocalcin; mitochromin; mitogillin; mitomarcine; mitomycin; mitospar; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxaliplatin; oxisulan; paclitaxel; pegaspargase; periomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; protease inhibitors Mestan; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; Ribopurine; Rogletimide; RU486; Safingol; Safingol hydrochloride; Semustine; Cintrazene; Sparsophosphate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Surofenur; Tallysomycin; Tecogalan sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teroxiron; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene citrate; Trestron acetate; Triciribine phosphate;Trimetrexate; trimetrexate glucuronate; triptorelin; tubrozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisine sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride;

[0094] Other examples of cancer therapies include, but are not limited to, 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogens, prostate cancer; antiestrogens; antineoplastic agents; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; aldesleukin Ginine deaminase; Aslaculin; Atamestane; Atlimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxins; Azatyrosine; Baccatin III derivatives; Balanol; Batimastat; BCR / ABL antagonists; Benzochlorins; Benzoylstaurosporines; Beta-lactam derivatives; Beta-arretin; Betaclamycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Visnafide; Bistraten A; Bizelesin; Brefrate; Bropirimine; Budotitanium; Buthionine sulfoximine; Calcipotriol; Calphostin C; Camptothecin derivatives; Canaripox IL-2; Capecitabine; Carboxamido-amino-triazoles; Carboxamidotriazoles; CaRest M3; CARN700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorine; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; clambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanethraquinone; cycloplatam; sipemycin; cytarabine ocfosfate; cytolytic factors;Cytostatin; Daclizumab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexfosfamide; Dexrazoxane; Dexverapamil; Diaziquone; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, dioxamycin; Diphenylspiromustine; Docetaxel; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflomitine; Elemene; Emitefur; E Pirubicin; epristeride; estramustine analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunornithine hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; HMG CoA reductase inhibitors (e.g., atorvastatin, cerivastatin, fluvastatin, lescol, lupitor, lovastatin, rosuvastatin, and simvastatin); hepsulfame; heregulin; hexamethylene bisacetamide; hypericin; ibandronate; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulating peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferon Lon; Interleukin; Iobenguane; Iododoxorubicin; Ipomenol, 4-Ilopraact; Irsogladine; Isobengazole; Isohomohalochondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole;LFA-3TIP (Biogen, Cambridge, Mass.; WO 93 / 0686 and U.S. Pat. No. 6,162,432); liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lysocrine amide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matri Metalloproteinase inhibitors; menogaril; mervalone; meterulin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofalotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A + Myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressor 1 Based therapy; Mustard anticancer agents; Mycaperoxide B; Mycobacterial cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamides; Nafarelin; Nagressip; Naloxone + pentazocine; Napavine; Naphthoterpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrulline; O6-benzylguanine; Octreotide; Oxenon; Oligonucleotides; Onaplistone; Oracin; Oral cytokine inducers Inducers; Ormaplatin; Osateron; Oxaliplatin; Oxanomycin; Paclitaxel; Paclitaxel analogs; Paclitaxel derivatives; Palauamine; Palmitoylrhizoxin; Pamidronic acid; Panaxytriol; Panomyphen; Parabactin; Pazoliptin; Pegaspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin;Piritrexim; Prasetin A; Prasetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porfimer sodium; Porfiromycin; Prednisone; Propylbis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridines; Pyridoxylated hemoglobin polyoxyethylene Ethylene; raf antagonists; raltitrexed; ramosetron; ras farnesyl-protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated leteriptin; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukin; romurtide; roquinimex; rubidinone B1; ruboxil; safingol; saintpin; SarCNU; sarcophytol A; sargramostim; Sdi1 mimics; semustine; senescence-derived inhibitor 1; sense oligonucleotides; signal Signal transduction inhibitors; Signal transduction modulators; Gamma secretase inhibitors, single-chain antigen-binding proteins; Schizofuran; Sobuzoxane; Sodium borocaprylate; Sodium phenylacetate; Sorbrol; Somatomedin-binding proteins; Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongistatin 1; Squalamine; Stem cell inhibitors; Stem cell division inhibitors; Stipiamide; Stromelysin inhibitors; Sulfinosine; Superactive vasoactive intestinal peptide antagonists; Sladista; Suramin; Swainsonine; Synthetic Synthetic glycosaminoglycans; toluimustine; 5-fluorouracil; leucovorin; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; telapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonists; thymotrin; thyroid-stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride;Topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; thalidomide; veraresol; veramine; verudin; verteporfin; vinorelbine; vinzartine; anti-integrin antibodies (e.g., anti-integrin a.sub.vb.sub.3 antibodies); vorozole; zanoteron; zeniplatin; dilascorub; and zinostatin stimalamer.

[0095] A non-limiting list of compounds that may be used to target neoplasms and / or cancers includes inhibitors of interleukin-3 receptor (IL-3R) and CD123 (including peptides, peptide conjugates, antibodies, antibody-conjugates, antibody fragments, and antibody fragment-conjugates that target IL-3R or CD123); cantharidin; norcantharidin and its analogs and derivatives; Notch pathway inhibitors, including gamma secretase inhibitors; sonic hedgehog / smoothened pathway inhibitors, including cyclopamine and its analogs; antibodies against CD96; Certain NF-kB / proteasome inhibitors, including ruthenolide and its analogs; certain triterpenes, including celastrol; certain mTOR inhibitors; compounds and antibodies targeting the urokinase receptor; sinefungin; certain inosine monophosphate dehydrogenase (IMPDH) inhibitors; PPAR-alpha and PPAR-gamma agonists and antagonists (pioglitazone, tesaslitazar, muraglitazar, peliglitazar, lobeglitazone, balaglitazone, ragaglitazar, rosiglitazone, farglitazar, soderglitazar, leglitazone, etc.) including glitazar, naveglitazar, oxeglitazar, metaglidasen, netoglitazone, darglitazone, englitazone, thiazolidinediones, aleglitazar, edaglitazone, rivoglitazone, troglitazone, imiglitazar, and sitoglitazar; telomerase inhibitors; antibodies to EpCAM (ESA); GSK-3 beta agonists and antagonists (including lithium, 6-bromoinirubin-3'-oxime (BIO), TDZD8); frizzled or disheveled / frizzled or betacam Wnt pathway inhibitors, including antibodies against small molecules that inhibit tenin; anti-CD20 antibodies and conjugates (e.g., Rituxan, Bexxar, Zevalin) for novel use in multiple myeloma or melanoma; anti-CD133 antibodies; anti-CD44 antibodies; antibodies against IL-4; specific differentiation agents such as velsnarinone; compounds that target CD33, such as antibodies or betulinic acid; compounds that target lactadherin, such as antibodies; small molecules or antibodies that target CXCR4 or SDF-1; small molecules or antibodies that target multidrug resistance pumps; inhibitors of survivin;These include inhibitors of XIAP; small molecules that target Bcl-2; antibodies against CLL-1; and furin inhibitors (e.g., cucurbitacins).

[0096] An additional non-limiting list of compounds that can be used to target cancer and / or cancer cells includes (but is not limited to) i) antibodies, antibody fragments, and proteins, either naked or conjugated to therapeutic moieties that target specific cell surface targets on cancer cells, or ii) small molecules known in the art, including those that can be further optimized (e.g., by chemistry) or identified by cancer cell-based screening (e.g., determining whether a compound impairs cancer cell growth or viability by standard methods), including (but not limited to) cell surface and intracellular targets. These include Rex1 (Zfp42), CTGF, activin A, Wnt, FGF-2, HIF-1, AP-2 gamma, Bmi-1, nucleostemin, hiwi, Moz-TIF2, Nanog, beta-arrestin-2, Oct-4, Sox2, stella, GDF3, RUNX3, EBAF, TDGF-1, nodal, ZFPY, PTNE, Evi-1, Pax3, Mcl-1, c-kit, Lex-1, Zfx, lactadherin, aldehyde dehydrogenase, BCRP, telomerase, CD133, Bcl-2, CD26, Gremlin, and FoxC2.

[0097] In some embodiments, the therapy is an immunomodulatory agent. Non-limiting examples of immunomodulatory agents include proteinaceous agents such as cytokines, peptidomimetics, and antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fv, ScFv, Fab or F(ab)2 fragments or epitope-binding fragments), nucleic acid molecules (e.g., antisense nucleic acid molecules and triple helices), small molecules, organic compounds, and inorganic compounds. In particular, immunomodulatory agents include, but are not limited to, methotrexate, leflunomide, cyclophosphamide, cytoxan, imuran, cyclosporin A, minocycline, azathioprine, antibacterial agents (e.g., FK506 (crolimus)), methylprednisolone (MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin, brequinar, malononitriloamide (e.g., leflunamide), T cell receptor modulators, cytokine receptor modulators, and mast cell modulators. Other examples of immunomodulatory agents can be found, for example, in paragraphs 259-275 of U.S. Patent Application Publication No. 2005 / 0002934, which is incorporated herein by reference in its entirety. In one embodiment, the immunomodulatory agent is a chemotherapeutic agent. In another embodiment, the immunomodulatory agent is an immunomodulatory agent other than a chemotherapeutic agent. In some embodiments, the therapy used in accordance with the present invention is not an immunomodulatory agent.

[0098] In some embodiments, the therapy is an anti-angiogenic agent. Non-limiting examples of anti-angiogenic agents include proteins, polypeptides, peptides, fusion proteins, antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fv, ScFv, Fab fragments, F(ab2 fragments, and antigen-binding fragments thereof), such as antibodies that specifically bind to TNF-alpha, nucleic acid molecules (e.g., antisense molecules or triple helices), organic molecules, inorganic molecules, and small molecules that reduce or inhibit angiogenesis.

[0099] In certain embodiments, the therapy is an alkylating agent, a nitrosourea, an antimetabolite, and an anthracycline, a topoisomerase II inhibitor, or a mitotic inhibitor. Alkylating agents include, but are not limited to, busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine, mechlorethamine, mephalen, and temozolomide. Nitrosoureas include, but are not limited to, carmustine (BCNU) and lomustine (CCNU). Antimetabolites include, but are not limited to, 5-fluorouracil, capecitabine, methotrexate, gemcitabine, cytarabine, and fludarabine. Anthracyclines include, but are not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone. Topoisomerase II inhibitors include, but are not limited to, topotecan, irinotecan, etoposide (VP-16), and teniposide. Mitotic inhibitors include, but are not limited to, taxanes (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine, and vinorelbine). In some embodiments of the present invention, therapy involves administration of cantharidin or an analog thereof. The present invention involves the use of agents that target cancer cells. In certain embodiments, the agent acts alone. In other embodiments, the agent is directly or indirectly conjugated to another therapeutic moiety.Non-limiting examples of therapeutic moieties include, but are not limited to, alkylating agents, antimetabolites, plant alkaloids, cytotoxic agents, chemotherapeutic agents (e.g., steroids, cytosine arabinoside, fluorouracil, methotrexate, aminopterin, mitomycin C, demecolcine, etoposide, mithramycin, calicheamicin, CC-1065, chlorambucil, or melphalan), radionuclides, therapeutic enzymes, cytokines, toxins including plant-derived toxins, fungal-derived toxins, and bacterial-derived toxins (e.g., deglycosylated ricin A chain, ribosome-inactivating protein, alpha-sarcin, aspergillin, restiltocin, ribonuclease, diphtheria toxin, Pseudomonas exotoxin, bacterial endotoxin, or the lipid A moiety of a bacterial endotoxin), growth regulators, and RNases. In some embodiments, the agent used is an agent that binds to a marker, e.g., an antigen on cancer cells. In certain embodiments, the agent binds to an antigen that is expressed at a higher level on cancer cells than on normal cells. In certain embodiments, the agent specifically binds to a cancer cell antigen but not to a normal cell antigen. In other embodiments, the therapy is an agent that binds to a marker on cancer cells. In one embodiment, the agent that binds to a marker on cancer cells is an antibody or an antibody conjugated to a therapeutic moiety, or an antibody fragment conjugated to a therapeutic moiety.

[0100] For example, in certain embodiments, the agent specifically binds to the IL-3 receptor (IL-3R). In some embodiments, the agent that binds to IL-3R is an antibody or antibody fragment specific for IL-3R. In some embodiments, the antibody or antibody fragment is conjugated to a therapeutic moiety (e.g., a chemotherapeutic agent, a plant-, fungal-, or bacterial-derived toxin, a radionuclide) using a linking agent, either chemically or via recombinant technology, to produce a cell-killing response. In certain embodiments, the antibody, antibody conjugate, antibody fragment, or antibody fragment conjugate binds to the alpha subunit of IL-3R (i.e., the CD123 antigen). In other embodiments, the antibody, antibody conjugate, antibody fragment, or antibody fragment conjugate binds to an IL-3R containing both the alpha and beta subunits. Methods for preparing antibodies to IL-3R and mimetics of antibodies to IL-3R are described in U.S. Pat. No. 6,733,743 B2, which is incorporated herein by reference in its entirety.

[0101] In other embodiments, the agent that binds to a marker on cancer cells is a ligand. In some embodiments, the ligand is a cytokine that binds to a cytokine receptor on cancer cells. In certain embodiments, the ligand is interleukin-3 (IL-3), which may be conjugated to a therapeutic moiety, including a chemotherapeutic agent, a plant-derived toxin, a fungal-derived toxin, or a bacterial-derived toxin, or a radionuclide. The IL-3 conjugate prophylactic and / or therapeutic therapy or regimen may be in the form of a recombinant fusion protein in embodiments where the conjugate is a toxin, and the toxin is a protein such as diphtheria toxin.

[0102] In certain embodiments, antibodies or fragments thereof that bind to markers on cancer cells are substantially non-immunogenic in the subject being treated. Methods for obtaining non-immunogenic antibodies include, but are not limited to, chimerizing the antibody, humanizing the antibody, and isolating the antibody from the same species as the subject being treated. Antibodies or fragments thereof that bind to markers in cancer cells can be produced using techniques known in the art.

[0103] In some embodiments, therapy involves the use of X-rays, gamma rays, and other radiation sources to destroy cancer cells and / or tumor masses. In certain embodiments, radiation therapy is administered as external beam radiation or teletherapy, where radiation is directed from a remote source. In other embodiments, radiation therapy is administered as internal therapy or brachytherapy, where a radiation source is placed inside the body in close proximity to cancer cells, tumor masses, and / or tumor masses.

[0104] In some embodiments, the therapy used is a proliferation-based therapy, non-limiting examples of which include chemotherapy and radiation therapy, as described above. Currently available therapies and their dosages, routes of administration and recommended usage are known in the art and described in such publications as the Physician's Desk Reference (60th ed., 2006).

[0105] When two prophylactically and / or therapeutically effective regimens are administered to a subject simultaneously, the term "simultaneously" does not mean limited to the administration of the cancer therapeutics at exactly the same time, but rather means that they are administered to a subject in an order and within a time interval such that they can act together (e.g., synergistically to provide increased benefit than if they were administered otherwise). For example, the cancer therapeutics may be administered simultaneously or sequentially in any order at different times; however, if not administered simultaneously, they should be administered sufficiently close in time to provide the desired therapeutic effect, preferably in a synergistic manner. The combined cancer therapeutics may be administered separately in any suitable form and by any suitable route. It is understood that if the components of the combined cancer therapeutic are not administered in the same pharmaceutical composition, they may be administered to a subject in need thereof in any order. For example, the first prophylactically and / or therapeutically effective regimen can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second cancer therapeutic to a subject in need thereof. In various embodiments, the cancer therapeutic agents are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than an hour apart, 1 hour apart, 1-2 hours apart, 2-3 hours apart, 3-4 hours apart, 4-5 hours apart, 5-6 hours apart, 6-7 hours apart, 7-8 hours apart, 8-9 hours apart, 9-10 hours apart, 10-11 hours apart, 11-12 hours apart, 24 hours or less apart, or 48 hours or less apart. In one embodiment, the cancer therapeutic agents are administered within the same office visit. In another embodiment, the combination cancer therapeutic agents are administered 1 minute to 24 hours apart.

[0106] In certain embodiments, the combination therapies have the same mechanism of action. In other certain embodiments, the combination therapies each have a different mechanism of action. Indications The present disclosure provides continuous drug delivery systems and methods for treating and / or preventing and / or controlling conditions, such as pain management, cancer, seizure disorders, Parkinson's disease, symptoms associated with PD, and other indications, using continuous drug delivery. Conditions suitable for treatment by the present disclosure include, for example, seizure disorders, pain syndromes, neurodegenerative diseases (including motor neuron diseases, myelopathies, radiculopathies, and disorders of the sympathetic nervous system), dementia, cerebrovascular conditions, movement disorders, brain trauma, cranial nerve disorders, neuropsychiatric disorders, and other disease-related neuropathies (including viral-associated neuropathies, diabetes-associated neuropathies, Guillain-Barré syndrome, dysproteinemia, transthyretin-induced neuropathies, and carpal tunnel syndrome). As used herein, seizure disorders include complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, and myoclonus), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as additional specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, and progressive myoclonic epilepsy, and seizures associated with CNS mass lesions.

[0107] Pain syndromes include, for example, headache (e.g., migraine, tension, and cluster), acute pain, chronic pain, neuropathic pain, nociceptive pain, central and inflammatory pain, drug-induced neuropathic pain, caustic pain, complex regional pain syndrome types I and II, and reflex sympathetic dystrophy (RSDS).

[0108] Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, ALS, spinal muscular atrophy, prion-related muscular dystrophy, cerebellar ataxia, Friedrich's ataxia, SCA, Wilson's disease, RP, Garlin-Barré syndrome, adrenoleukodystrophy, Menkes-Sx, cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL), Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau, fragile X, spastic paraplegia, tuberous sclerosis syndrome, Ward-Enble syndrome, spinal motor atrophy, Tay-Sachs disease, Sandoff disease, familial spastic paraplegia, myelopathy, radiculopathy, encephalopathies associated with trauma, radiation, drugs, and infections, and disorders of the sympathetic nervous system (e.g., Shy-Drager (familial dysautonomia), diabetic neuropathy, drug-induced and alcoholic neuropathy).

[0109] Dementia includes Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, Huntington's disease, and MCI. Cerebrovascular conditions suitable for treatment according to the present disclosure include cerebrovascular disease and stroke (e.g., thrombotic, embolic, thromboembolic, hemorrhagic (including AVM and mulberry aneurysm), venous stenotic, and venous).

[0110] Movement disorders include Parkinson's disease, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, and Tourette's syndrome. As used herein, brain trauma includes traumatic brain and spinal cord injury, and radiation-induced brain injury.

[0111] Cranial nerve disorders include trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, cranial nerve palsy, and Bell's palsy. Neuropsychiatric disorders include panic disorders, generalized anxiety disorders, all types of phobic syndromes, mania, manic-depressive disorders, hypomania, unipolar depression, depression, stress disorders, PTSD, somatoform disorders, personality disorders, psychoses, and schizophrenia), and substance dependence / addictions (e.g., to alcohol, psychostimulants (e.g., crack, cocaine, speed, meth), opioids, and nicotine), and drug-induced psychiatric disorders.

[0112] Other disease neuropathy that may be treated with the compositions and methods described herein include Guillain-Barré syndrome, diabetes-related neuropathy, dysproteinemia, transthyretin-induced neuropathy, neuropathy associated with HIV, herpes virus (including herpes zoster) or other viral infection, neuropathy associated with Lyme disease, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, cranial polyneuropathy, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, post-meningitis syndrome, post-polio syndrome, prion disease, and radiation-associated neuropathy syndrome.

[0113] Other diseases suitable for treatment with the present disclosure include fatigue syndromes (e.g., chronic fatigue syndrome and fibromyalgia), ataxia syndromes, olivopontocerebellar degeneration, striatonigral degeneration, and axonal brain injury.

[0114] The present disclosure is particularly useful in the treatment of neuropsychiatric disorders such as depression, agitation, anxiety, seizure disorders such as grand mal seizures, status epilepticus, migraine pain treatment and prevention, Alzheimer's disease, Parkinson's disease, and traumatic brain and spinal cord injury.

[0115] The higher doses enabled by the present disclosure are also expected to be particularly important in dementia, including Alzheimer's disease, Parkinson's disease, and vascular dementia, pain syndromes, including headaches and migraines, seizure disorders, movement disorders, and brain trauma.

[0116] Additionally, the ease and convenience of use of dosage forms developed and provided to deliver therapeutically effective amounts once daily or less frequently from the start of therapy would be valuable in the treatment of dementias, including Alzheimer's disease and Parkinson's disease, seizure disorders, pain syndromes, and cerebrovascular conditions.

[0117] Another aspect of the present disclosure relates to the use of the continuous drug delivery systems and methods disclosed herein as therapeutic agents for the prevention and / or treatment of immunoinflammatory disorders. The term "immunoinflammatory disorder" encompasses a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory skin diseases. Immunoinflammatory disorders result in the destruction of healthy tissue due to inflammatory processes, dysregulation of the immune system, and unwanted proliferation of cells.Examples of immune inflammatory disorders include acne vulgaris, acute respiratory distress syndrome, Addison's disease, allergic rhinitis, allergic intraocular inflammatory disease, antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis, ankylosing spondylitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet's disease, Bell's palsy, bullous pemphigoid, cerebral ischemia, chronic obstructive pulmonary disease, cirrhosis, Cogan's syndrome, contact dermatitis, COPD, Crohn's disease, Cushing's syndrome, Dermatomyositis;Diabetes mellitus;Discoid lupus erythematosus;Eosinophilic fasciitis;Erythema nodosum;Exfoliative dermatitis;Fibromyalgia;Focal glomerulosclerosis;Focal segmental glomerulosclerosis;Giant cell arteritis;Gout;Gouty arthritis;Graft-versus-host disease;Hand eczema;Henoch-Schönlein purpura;Heresy gestationis;Hypertrichosis;Idiopathic dermatoscleritis;Idiopathic pulmonary fibrosis;Idiopathic thrombocytopenic purpura;Immune thrombocytopenic purpura,Inflammatory bowel or gastrointestinal disorders,Inflammatory skin diseases;Lichen planus;Lupus nephritis;Lymphomatous tracheobronchitis;Macular edema tumors; multiple sclerosis; myasthenia gravis; myositis; nonspecific fibrotic pulmonary disease; osteoarthritis; pancreatitis; pemphigoid of pregnancy; pemphigus vulgaris; periodontitis; polyarteritis nodosa; polymyalgia rheumatica; scrotal pruritus; pruritus / inflammation, psoriasis; psoriatic arthritis; pulmonary histoplasmosis; rheumatoid arthritis; relapsing polychondritis; rosacea caused by sarcoidosis; rosacea caused by scleroderma; rosacea caused by Sweet's syndrome; rosacea caused by systemic lupus erythematosus; rosacea Rosacea caused by measles; rosacea caused by shingles-associated pain; sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock syndrome; shoulder tendonitis or bursitis; Sjogren's syndrome; Still's disease; stroke-induced brain cell death; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu's arteritis; temporal arteritis; toxic epidermal necrolysis; graft rejection and graft rejection-related syndrome; tuberculosis; type 1 diabetes; ulcerative colitis; uveitis; vasculitis; and Wegener's granulomatosis.

[0118] As used herein, "non-cutaneous inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease. "Inflammatory skin disorder" or "inflammatory skin disease" refers to psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, acute febrile neutrophilic dermatosis, eczema, asteatotic eczema, dyshidrotic eczema, bullous palmoplantar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, dyshidrotic eczema, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet's syndrome, rosacea due to systemic lupus erythematosus, rosacea due to urticaria, rosacea due to shingles-associated pain, Sweet's disease, neutrophilic hidradenitis, sterile pustulosis, drug eruption, seborrheic dermatitis, pityriasis rosea, cutaneous eczema, and pruritic urticarial papules. and plaques of pregnancy, Stevens-Johnson syndrome and toxic epidermal necrolysis, tattoo reaction, Wells' syndrome (eosinophilic cellulitis), reactive arthritis (Reiter's syndrome), gut-related dermatopathic-arthritis syndrome, rheumatoid neutrophilic dermatitis, neutrophilic eccrine hidradenitis, neutrophilic dermatitis of the dorsum of the hands, dermatitis annulare, balanoposthitis, Behcet's disease, erythema annulare centrifugally, erythema dyschromicus perstans, erythema multiforme, granuloma annulare, hand dermatitis, lichen nitidus, lichen planus, lichen sclerosus and atrophicus, lichen simplex chronicus, lichen spinous, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, subcorneal pustular dermatosis, urticaria, and transient acantholytic dermatosis.

[0119] "Proliferative skin disease" refers to a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of proliferative skin diseases are psoriasis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinoma of the skin, lamellar ichthyosis, epidermolytic keratosis, premalignant keratosis, acne, and seborrheic dermatitis. As will be understood by those skilled in the art, certain diseases, disorders, or conditions can be characterized as both proliferative and inflammatory skin diseases. An example of such a disease is psoriasis.

[0120] Symptoms and signs of inflammation associated with specific conditions include: rheumatoid arthritis: pain, swelling, warmth, and tenderness in the involved joints; generalized and morning stiffness; insulin-dependent diabetes mellitus - insulitis; this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease, and cerebrovascular disease; autoimmune thyroiditis: weakness, constipation, shortness of breath, swelling of the face, hands, and feet, peripheral edema, bradycardia; multiple sclerosis: spasticity, blurred vision, dizziness, weakness in the limbs, paresthesia; uveoretinitis: decreased night vision, peripheral vision loss of function; lupus erythematosus: joint pain, rash, photosensitivity, fever, muscle pain, swelling of hands and feet, abnormal urinalysis (hematuria, cylinduria, proteinuria), glomerulonephritis, cognitive impairment, vascular thrombosis, pericarditis; scleroderma: Raynaud's disease; swelling of hands, arms, feet, and face; thickened skin; pain, swelling and stiffness of fingers and knees, gastrointestinal dysfunction, restrictive lung disease; pericarditis; renal failure; other arthritic conditions with an inflammatory component, e.g., rheumatoid spondylitis, osteoarthritis, septic arthritis, and polyarthritis: fever, pain, swelling, tenderness; other inflammatory brain disorders, e.g., meningitis, Alzheimer's disease, AIDS Dementia encephalitis: photophobia, cognitive impairment, memory loss; other inflammatory eye inflammations, e.g., retinitis: decreased vision; inflammatory skin disorders, e.g., eczema, other dermatitis (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sunlight and similar UV sources): erythema, pain, scaling, swelling, tenderness; inflammatory bowel diseases, e.g., Crohn's disease, ulcerative colitis: pain, diarrhea, constipation, rectal bleeding, fever, arthritis; asthma: shortness of breath, wheezing; other allergic disorders, such as allergic rhinitis: sneezing, itching, runny nose; acute trauma, e.g., brain damage after stroke - sensory, motor, and cognitive loss Associated conditions include cardiac tissue damage due to myocardial ischemia: pain, shortness of breath; lung damage such as occurs in adult respiratory distress syndrome: shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates; inflammation associated with infections such as sepsis, septic shock, and toxic shock syndrome: fever, respiratory failure, tachycardia, hypotension, leukocytosis; and other inflammatory conditions associated with specific organs or tissues, such as (i) nephritis (e.g., glomerulonephritis): oliguria, abnormal urinalysis; (ii) inflamed appendix: fever, pain, tenderness, leukocytosis; and (iii) gout: pain, tenderness, swelling, and erythema of the involved joint, elevated serum and / or urinary uric acid.(iv) inflamed gallbladder: abdominal pain and tenderness, fever, nausea, leukocytosis; (v) congestive heart failure: shortness of breath, rales, peripheral edema; (vi) type II diabetes: end-organ complications including cardiovascular, ocular, renal, and peripheral vascular disease; (vii) pulmonary (lung) fibrosis: hyperventilation, shortness of breath, decreased oxygenation; (viii) vascular diseases such as atherosclerosis and restenosis: pain, loss of sensation, decreased pulse, loss of function; and (ix) alloimmunization resulting in graft rejection: pain, tenderness, fever.

[0121] Another aspect of the present disclosure relates to the use of the continuous drug delivery systems and methods disclosed herein as therapeutic agents for the prevention and / or treatment of neurodegenerative diseases. The present disclosure also relates generally to the fields of neurology and psychiatry, and to methods of protecting cells of the mammalian central nervous system from damage or injury. Various types of injury or trauma to the central nervous system (CNS) or peripheral nervous system (PNS) can result in serious, long-term neurological and / or psychiatric symptoms and disorders. One form this can take is the progressive death of neurons or other cells of the central nervous system (CNS), i.e., neurodegeneration or neuronal degeneration.

[0122] Neuronal degeneration, for example as a result of Alzheimer's disease, multiple sclerosis, cerebrovascular accident (CVA) / stroke, traumatic brain injury, spinal cord injury, optic nerve degeneration (e.g., ischemic optic neuropathy or retinal degeneration), and other central nervous system disorders, is an enormous medical and public health problem due to both its high incidence and the frequency of long-term sequelae. Animal studies and clinical trials have shown that amino acid transmitters (especially glutamate), oxidative stress, and inflammatory responses strongly contribute to cell death in these conditions. Upon injury or ischemic insult, damaged neurons release large amounts of the neurotransmitter glutamate, which is excitotoxic to surrounding neurons. Glutamate is a negatively charged amino acid that is an excitatory synaptic transmitter in the mammalian nervous system.

[0123] This nervous system damage can take the form of a sudden insult or acute injury to the nervous system, such as in acute neurodegenerative disorders, including, but not limited to, acute injury resulting in neuronal cell death or damage, hypoxia-ischemia, or a combination thereof. Acute injuries include traumatic brain injury (TBI), including, but not limited to, closed, blunt, or penetrating brain injury, focal brain injury, diffuse brain injury, spinal cord injury, intracranial or intraspinal lesions (including, but not limited to, contusion, penetrating, shearing, compression, or laceration lesions of the spinal cord, or whiplash shaken baby syndrome).

[0124] Furthermore, lack of oxygen or blood supply can generally cause acute injury, such as in hypoxia and / or ischemia, including, but not limited to, cerebrovascular insufficiency, cerebral ischemia or cerebral infarction (cerebral ischemia or infarction resulting from embolic occlusion and thrombus, retinal ischemia (diabetic or otherwise), glaucoma, retinal degeneration, multiple sclerosis, toxic and ischemic optic neuropathy, reperfusion after acute ischemia, perinatal hypoxic-ischemic injury, cardiac arrest, or any type of intracranial hemorrhage (including, but not limited to, epidural, subdural, subarachnoid, or intracerebral hemorrhage).

[0125] Trauma or damage to tissues of the nervous system can also lead to more chronic and progressive neurodegenerative disorders, such as, but not limited to, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steele-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), chronic epileptic conditions associated with neurodegeneration, motor neuron disease (amyotrophic lateral sclerosis), multiple sclerosis, degenerative ataxia, corticobasal degeneration, ALS-Parkinson's disease-Guam dementia complex, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies (including multiple system atrophy), primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease or spinocerebellar degeneration type 3 and oncogenes. This may take the form of disorders associated with progressive neuronal death or damage over a period of time, including Leavenig-Pontocerebellar Degeneration, Ophthalmo- and Pseudobulbar Plegia, Spinal and Spinal-Bulbar Muscular Atrophy (Kennedy's Disease), Primary Lateral Sclerosis, Familial Spastic Paraplegia, Werdnig-Hoffmann Disease, Kugelberg-Welander Disease, Tay-Sachs Disease, Sandhoff Disease, Familial Spasticity, Wohlfart-Kugelberg-Welander Disease, Spastic Paraplegia, Progressive Multifocal Leukoencephalopathy, Familial Dysautonomia (Riley-Day Syndrome) or Prion Diseases (including, but not limited to, Creutzfeldt-Jakob Disease, Gerstmann-Strassler-Scheinker Disease, Kuru or Fatal Familial Insomnia).

[0126] Additionally, trauma and progressive damage to the nervous system can occur in a variety of psychiatric disorders, including, but not limited to, bipolar disorder or schizoaffective disorder or progressively worsening forms of schizophrenia, impulse control disorders, obsessive-compulsive disorder (OCD), behavioral changes in temporal lobe epilepsy, and personality disorders.

[0127] In one preferred embodiment, the continuous drug delivery systems and methods of the present disclosure are used to provide neuroprotection in disorders involving trauma and progressive damage to the nervous system in various psychiatric disorders, these disorders being selected from the group consisting of schizoaffective disorder, schizophrenia, impulse control disorders, obsessive-compulsive disorder (OCD), and personality disorders.

[0128] Additionally, trauma and injury can take the form of disorders associated with overt and widespread memory loss, including, but not limited to, age-related dementia, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain injury, dementia pugilistica, or frontal lobe dementia (including, but not limited to, Pick's disease), and other neurodegenerative disorders.

[0129] Other disorders associated with neuronal damage include, but are not limited to, disorders associated with chemical, toxic, infectious and radiation damage to the nervous system, including the retina; damage during fetal development, prematurity at birth, anoxic-ischemic, hepatic, glycemic, uremic, electrolyte and endocrine origin; damage of psychiatric origin (including, but not limited to, psychopathology, depression or anxiety); damage from peripheral disease and plexopathies (including plexus palsies); or neuropathy selected from multifocal, sensory, motor, sensory-motor, autonomic, sensory-autonomic or demyelinating neuropathies (including, but not limited to, Guillain-Barre syndrome or chronic inflammatory demyelinating polyneuropathy); Neuropathies resulting from infection, inflammation, immune disorders, drug abuse, pharmacological treatment, toxins, trauma (including but not limited to compression, crush, laceration or segmental trauma), metabolic disorders (including but not limited to endocrine or paraneoplastic), Charcot-Marie-Tooth disease (including but not limited to types 1a, 1b, 2, 4a or 1-X linkage), Friedreich's ataxia, metachromatic leukodystrophy, Refsum's disease, adrenomyeloneuropathy, ataxia telangiectasia, Gelin-Sottas disease (including but not limited to types A or B), Lambert-Eaton syndrome or disorders of the cranial nerves.

[0130] A further indication is cognitive disorders. The term "cognitive disorders" includes anxiety disorders, delirium, dementia, amnesic disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia, psychotic disorders, gender identity disorders, sleep disorders, somatoform disorders, acute stress disorders, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, monophobia, social phobia, drug withdrawal, Alzheimer's disease, Creutzfeldt-Jakob disease, head trauma, Huntington's disease, HIV disease, Parkinson's disease, Pick's disease, illness, learning disability, motor skill disorder, developmental coordination disorder, communication disorder, phonological disorder, pervasive developmental disorder, Asperger's disorder, autistic disorder, childhood disintegrative disorder, Rett's disorder, pervasive developmental disorder, attention-deficit / hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, pica, rumination disorder, tic disorder, chronic motor or vocal tic disorder, Tourette's disorder, elimination disorder, encopresis, enuresis, selective mutism, separation anxiety disorder, dissociative amnesia, depersonalization disorder Sexual disorders, dissociative fugue, dissociative identity disorder, anorexia nervosa, bulimia nervosa, bipolar disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, psychotic disorder, shared psychotic disorder, delusions, hallucinations, substance-induced psychotic disorder, orgasmic disorder, sexual pain disorder, dyspareunia, vaginismus, sexual dysfunction, paraphilia, sleep disorders, sleep disorders related to breathing disorders, circadian rhythm sleep disorder, hypersomnia, insomnia, narcolepsy, sleep disorders, Refers to parasomnia, nightmares, sleep terror disorder, sleepwalking, parasomnia, body dysmorphic disorder, conversion disorder, hypochondriasis, pain disorder, somatoform disorder, alcohol-related disorder, amphetamine-related disorder, caffeine-related disorder, cannabis-related disorder, cocaine-related disorder, hallucinogenic substance-related disorder, inhalant-related disorder, nicotine-related disorder, opioid-related disorder, phencyclidine-related disorder, abuse, persistent amnesic disorder, addiction, and withdrawal symptoms.

[0131] The term "bipolar and clinical disorders" includes adjustment disorders, anxiety disorders, delirium, dementia, amnesic and other cognitive disorders, disorders usually first diagnosed in infancy (for example), childhood, or adolescence, dissociative disorders (e.g., dissociative amnesia, depersonalization disorder, dissociative fugue, and dissociative identity disorder), eating disorders, factitious disorder, impulse control disorders, psychotic disorders due to general medical conditions, mood disorders, other conditions that may be the focus of clinical attention, personality disorders, schizophrenia, and other psychotic disorders. This refers to disorders, gender identity disorders, sleep disorders, somatoform disorders, substance-related disorders, generalized anxiety disorders (e.g., acute stress disorder, post-traumatic stress disorder), panic disorders, phobias, agoraphobia, obsessive-compulsive disorders, stress, acute stress disorder, anxiety neurosis, neuroticism, phobias, post-traumatic stress disorder, post-traumatic stress disorder (PTSD), abuse, obsessive-compulsive disorder (OCD), manic-depressive psychosis, monophobia, social phobia, and adjustment disorder with anxiety features.

[0132] Examples of disorders that are usually first diagnosed in infancy, childhood, or adolescence are mental retardation, learning disabilities, mathematics disabilities, reading disabilities, disorders of written expression, motor skill disorders, developmental coordination disorders, communication disorders, expressive language disorders, phonological disorders, mixed receptive-expressive language disorder, stuttering, pervasive developmental disorders, Asperger's disorder, autistic disorders, childhood disintegrative disorder, Rett's disorder, pervasive developmental disorders, attention-deficit / hyperactivity disorder (ADHD), conduct disorders, oppositional defiant disorder, feeding disorders of infancy or early childhood, pica, rumination disorders, tic disorders, chronic motor or vocal tic disorders, Tourette's syndrome, elimination disorders, encopresis, enuresis, selective mutism, separation anxiety disorder, reactive attachment disorder of infancy or early childhood, and stereotypic movement disorders.

[0133] Examples of substance-related disorders are alcohol-related disorders, amphetamine-related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic substance-related disorders, inhalant-related disorders, nicotine-related disorders, opioid-related disorders, psychotic disorders, psychotic disorders, phencyclidine-related disorders, abuse, persisting amnesic disorders, anxiety disorders, persisting dementia, dependence, intoxication, toxic delirium, mood disorders, psychotic disorders, withdrawal, withdrawal delirium, sexual dysfunction, and sleep disorders.

[0134] As used herein, the term "neuroprotection" means inhibiting, preventing, ameliorating, or reducing the severity of dysfunction, degeneration, or death of neurons, axons, or their supporting cells in the central or peripheral nervous system of a mammal, including a human. This includes treating or preventing a neurodegenerative disease; protecting against excitotoxicity or ameliorating the cytotoxic effects of compounds (e.g., prophylactic or therapeutic compounds that exert immediate or delayed cytotoxic side effects, including, but not limited to, excitatory amino acids such as glutamate; toxins; or immediate or delayed induction of apoptosis) in a patient in need thereof.

[0135] As used herein, the term "patient in need of treatment with a neuroprotective agent" refers to any patient who currently has or who may develop any of the syndromes or disorders listed above, or any disorder in which the patient's current clinical condition or prognosis could benefit from providing neuroprotection to prevent the onset, spread, worsening, or increased resistance to treatment of a neurological or psychiatric disorder.

[0136] As used herein, the term "combined administration" of a compound, therapeutic agent, or known drug with a combination of the present disclosure refers to 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 can include simultaneous (i.e., at the same time), prior to, or subsequent administration of the drug with respect to the administration of the composition and / or combination of the present disclosure. One of ordinary skill in the art will have no difficulty determining the appropriate timing, sequence, and dosage of administration for a particular drug of the present disclosure.

[0137] Another aspect of the present disclosure relates to the use of the continuous drug delivery systems and methods disclosed herein as therapeutic agents for the prevention and / or treatment of heart disease. Heart disease is a general term used to describe many different cardiac conditions. For example, coronary artery disease, the most common heart disease, is characterized by constriction or narrowing of the arteries that supply oxygen-rich blood to the heart and can lead to myocardial infarction, the death of a portion of the heart muscle. Heart failure is a condition resulting from the heart's inability to pump an adequate amount of blood through the body. Heart failure is not a sudden, abrupt cessation of cardiac activity, but rather typically develops slowly over many years as the heart gradually loses its ability to pump blood efficiently. Risk factors for heart failure include coronary artery disease, high blood pressure, valvular disease, cardiomyopathy, heart muscle disease, obesity, diabetes, and / or a family history of heart failure.

[0138] Examples of cardiovascular diseases and disorders include aneurysms, stable angina, unstable angina, angina pectoris, angioedema, aortic stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular cardiomyopathy, arteriosclerosis, arteriovenous malformation, atrial fibrillation, Behcet's syndrome, bradycardia, cardiac tamponade, cardiac hypertrophy, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein's anomaly, Eisenmenger's syndrome, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart disease, congestive heart failure, valvular heart disease, heart attack, acute epidural hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, cardiac hypertrophy, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome ... Blood pressure, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long QT syndrome, mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular disease, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud's disease, Sneddon syndrome, superior vena cava syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary hemorrhagic telangiectasia, telangiectasia, temporal arteritis, tetralogy of Fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular disease, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.

[0139] Vascular disease is often the result of reduced perfusion in the vascular system or physical or biochemical damage to the blood vessels. Peripheral vascular disease (PVD) is defined as a vascular disorder that is often encountered as a narrowing of the blood vessels in the extremities. There are two main types of these disorders: functional disorders, which do not involve vascular defects but rather result from stimuli such as cold, stress, or smoking, and organic disorders, which result from structural defects in the vasculature, such as atherosclerotic lesions, local inflammation, or traumatic injury. This can lead to vascular blockage, abnormal blood flow, and ultimately tissue ischemia.

[0140] One of the more clinically significant forms of PVD is peripheral arterial disease (PAD). PAD is often treated by angioplasty and stent implantation or by arterial bypass surgery. Clinical symptoms depend on the location of the blocked vessel. For example, narrowing of an artery supplying blood to the intestine can result in severe postprandial pain in the lower abdomen, resulting from the blocked vessel's inability to meet the increased oxygen demand resulting from the digestive and absorptive processes. In severe forms, ischemia can lead to intestinal necrosis. Similarly, PAD of the legs can result in intermittent pain, usually in the calf, that occurs with activity. This disorder, known as intermittent claudication (IC), can progress to persistent pain at rest, ischemic ulcer formation, and even amputation.

[0141] Peripheral vascular disease also manifests in atherosclerotic narrowing of the renal arteries, which can lead to renal ischemia and renal dysfunction. One disease in which vascular diseases and their complications are very common is diabetes.Diabetes causes various physiological and anatomical abnormalities, the most prominent of which is the body's inability to utilize glucose normally, which leads to hyperglycemia.Chronic diabetes can lead to vascular complications, including atherosclerosis, abnormalities involving large and medium-sized blood vessels (macroangiopathy), and abnormalities involving small blood vessels, such as small arteries and capillaries (microangiopathy).

[0142] Patients with diabetes are at high risk of developing one or more foot ulcers as a result of established long-term complications of the disease, including nerve dysfunction (neuropathy) and / or ischemia. Local tissue ischemia is an important contributing factor to diabetic foot ulcer formation.

[0143] In addition to macrovascular disease, diabetic patients face additional threats to skin perfusion in at least two additional ways. First, through the involvement of non-conduit arteries, which are adversely affected by the atherosclerotic process. Second, and perhaps more importantly, through impaired microcirculatory control mechanisms (small vessel disease). Normally, when a body part suffers some form of trauma, the body part experiences increased blood flow as part of the body's healing mechanism. When both small vessel disease and ischemia are present, as in many diabetic patients, this naturally increased blood flow response is significantly diminished. This fact, along with the tendency of diabetic patients to form blood clots in the microcirculatory system (thrombosis) during low levels of blood flow, is thought to be an important factor in ulcer pathogenesis.

[0144] As used herein, the term "peripheral vascular disease" includes any peripheral vascular disease, including peripheral and autonomic neuropathies. Examples of "peripheral vascular disease" include peripheral arterial disease, e.g., arteriosclerosis, chronic arterial occlusive disease, including arteriosclerosis obliterans and thromboangiitis obliterans (Buerger's disease), macroangiopathy, microangiopathy, diabetes, thrombophlebitis, venous embolism, Raynaud's disease, Raynaud's syndrome, CREST syndrome, vibration-related health problems, Sudeck's syndrome, intermittent claudication, cold extremities, paresthesia in the extremities, sensitivity to cold, Meniere's disease, Meniere's syndrome, numbness, loss of sensation, anesthesia, rest pain, caustic pain (burning pain), peripheral circulatory disorders, and nerve function disorders. Disability, motor dysfunction, motor paralysis, diabetic peripheral circulatory disorder, lumbar spinal stenosis, diabetic neuropathy, shock, autoimmune diseases such as lupus erythematosus, rheumatic diseases and rheumatoid arthritis, autonomic neuropathy, diabetic autonomic neuropathy, autonomic imbalance, orthostatic hypotension, erectile dysfunction, female sexual dysfunction, retrograde ejaculation, bladder dysfunction, neurogenic bladder, vaginal lubrication failure, exercise intolerance, cardiac denervation, heat intolerance, gustatory sweating, diabetic complications, hyperglycemia, hypoglycemic unawareness, hypoglycemic unresponsiveness; glaucoma, neovascular glaucoma, Cataract, retinopathy, diabetic retinopathy, diabetic maculopathy, retinal artery occlusion, central retinal artery occlusion, retinal vein occlusion, macular edema, age-related macular degeneration, age-related disciform macular degeneration, cystoid macular edema, eyelid edema, retinal edema, chorioretinopathy, neovascular maculopathy, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinal pigment epitheliitis, conjunctivitis, limbal inflammation, scleritis, sclerotic conjunctivitis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic beaded keratitis, Tiedeson's angle These include: meningitis, progressive Mooren's ulcer, skin injuries, skin ulcers (including foot ulcers), diabetic ulcers, burn ulcers, leg ulcers, postoperative ulcers, traumatic ulcers, post-herpetic ulcers, radiation ulcers, drug-induced ulcers, frostbite (cold injury), chilblains, gangrene and sudden gangrene, angina pectoris / atypical vasculitis, coronary artery sclerosis (chronic ischemic heart disease, asymptomatic ischemic heart disease, arteriosclerotic cardiovascular disease), myocardial infarction, heart failure, congestive heart failure and silent ischemic heart disease, pulmonary edema, hypertension, pulmonary hypertension; portal hypertension, diabetic nephropathy, pressure ulcers, and renal failure.

[0145] Additional activators As used herein, the term "combined administration" of a compound, therapeutic agent, or known drug in combination with the sequential drug delivery systems and methods disclosed herein refers to 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 simultaneous administration can include simultaneous (i.e., at the same time), prior to, or subsequent administration of the drug with respect to the administration of the compositions and / or combinations of the present invention. One of ordinary skill in the art will have no difficulty determining the appropriate timing, sequence, and dosage of administration for a particular drug of the present invention.

[0146] Furthermore, the active ingredient may, where applicable, be present in the form of either a single substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof.

[0147] The active ingredient may include, but is not limited to, one or more of the following therapeutic classes: adrenergic agents; corticosteroids; adrenocortical suppressants; aldosterone antagonists; amino acids; anabolic agents; analgesics; anesthesia agents; appetite suppressants; anti-acne agents; anti-adrenergic agents; anti-allergic 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; antidiarrheals; antidiuretics; antiemetics; anti-epileptic agents. ;Antifibrinolytics;Antifungals;Antihemorrhagic agents;Antihistamines;Antilipidemics;Antihypertensives;Antihypotensives;Antiinfectives;Antiinflammatory agents;Antibacterials;Antimigraine drugs;Mitotic inhibitors;Antifungals, antinausea agents, antineoplastic agents, antineutropenic agents, antiparasitic agents;Antiproliferative agents;Antipsychotics;Antirheumatics;Antiseborrheic agents;Antisecretory agents;Antispasmodics;Antithrombotic agents;Antiulcer agents;Antivirals;Appetite suppressants;Blood glucose regulators;Bone resorption inhibitors;Bronchodilators;Cardiovascular agents;Cholinergics;Depressants;Diagnostic aids;Diuretics;Dopamine agonists;Estrogen receptor agonists ;Fibrinolytic agents;Fluorescent agents;Free oxygen radical scavengers;Gastric acid suppressants;Gastrointestinal motility effectors;Glucocorticoids;Hair growth promoters;Hemostatic agents;Histamine H2 receptor antagonists;Hormones;Hypocholesterolemic agents;Hypoglycemic agents;Hypolipidemic agents;Hypotensive agents;Contrast media;Immunologic agents;Immunomodulators;Immunomodulating agents;Immunosuppressants;Keratolytic agents;LHRH agonists;Mood regulators;Mucolytic agents;Mydriatics;Nasal decongestants;Neuromuscular blocking agents;Neuroprotective agents;NMDA antagonists;Non-hormonal sterol derivatives; Plasminogen activators; platelet-activating factor antagonists; platelet aggregation inhibitors; psychotropic drugs; radioactive drugs; scabicides; sclerosing agents; sedatives; sedative-hypnotics; selective adenosine Al antagonists; serotonin antagonists; serotonin inhibitors; serotonin receptor antagonists; steroids; thyroid hormones; thyroid inhibitors; thyroid hormone-like drugs; tranquilizers; agents for amyotrophic lateral sclerosis; agents for cerebral ischemia; agents for Paget's disease; agents for unstable angina; vasoconstrictors; vasodilators; wound healing agents; xanthine oxidase inhibitors.

[0148] As indicated, the continuous drug delivery systems and methods disclosed herein may include auxiliary excipients, such as, for example, diluents, binders, lubricants, surfactants, disintegrants, plasticizers, anti-adherents, opacifiers, pigments, etc. As will be appreciated by those skilled in the art, the exact selection of excipients and their relative amounts will depend, in part, on the final oral dosage form.

[0149] Parkinson's disease The present disclosure provides continuous drug delivery systems and methods for the treatment and / or prevention and / or control of, for example, Parkinson's disease (PD). PD is a degenerative disorder of the central nervous system that primarily affects the motor system and belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing cells in the substantia nigra. The cause of this cell death is largely unknown. Early in the disease course, the most obvious symptoms are movement-related; these include tremor, rigidity, slowed movements, and difficulty walking and gait. Later, problems with thinking and behavior may occur, and dementia commonly occurs in the advanced stages of the disease. Depression is the most common psychiatric symptom. Other symptoms include sensory, sleep, and emotional problems. Parkinson's disease is more common in older adults, with most cases occurring after age 50; when it occurs in young adults, it is called young-onset PD (YOPD).

[0150] The four cardinal symptoms of PD are tremor, or trembling of the hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. Other symptoms may include depression and other emotional changes; difficulty swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disorders. Currently, there are no blood or laboratory tests proven to help diagnose sporadic PD, and diagnosis is based on medical history and neurological examination.

[0151] The major motor symptoms are collectively referred to as parkinsonism or "parkinsonism." The disease can be either primary or secondary. While some atypical cases have a genetic origin, primary Parkinson's disease is called idiopathic (of unknown cause), while secondary parkinsonism is due to known causes such as toxins. Many risk and protective factors have been investigated; the clearest evidence is an increased risk of PD in people exposed to certain pesticides and a decreased risk in tobacco smokers. The pathology of this disease is characterized by the accumulation of proteins in neurons as Lewy bodies and insufficient formation and activity of dopamine in specific parts of the midbrain. The location of Lewy bodies often correlates with the onset and severity of an individual's symptoms. Diagnosis of typical cases is primarily based on symptoms, with tests such as neuroimaging used for confirmation.

[0152] Currently, there is no cure for PD, but various medications provide symptomatic relief. Treatment, typically the drug L-DOPA and dopamine agonists, improves early symptoms of the disease. As the disease progresses and dopaminergic neurons continue to be lost, these medications eventually become ineffective in treating symptoms, while complications characterized by involuntary writhing movements occur. Diet and some forms of rehabilitation have shown some effectiveness in improving symptoms. Surgery and deep brain stimulation have been used to alleviate motor symptoms as a last resort in severe cases where medications are ineffective. Research directions include investigating new animal models of the disease and the potential usefulness of gene therapy, stem cell transplantation, and neuroprotective agents. Medications also exist to treat non-motor-related symptoms of PD, such as sleep disorders and emotional problems.

[0153] Levodopa (L-DOPA) has been the most widely used treatment since 1967. L-DOPA is converted to dopamine by the enzyme dopa decarboxylase in dopaminergic neurons. Because motor symptoms result from a lack of dopamine in the substantia nigra, administration of L-DOPA temporarily reduces them. Affected individuals are usually administered levodopa in combination with carbidopa, which delays the conversion of levodopa to dopamine until it reaches the brain. Neurons can use levodopa to produce dopamine and replenish the brain's dwindling supply. Levodopa helps at least three-quarters of Parkinson's disease cases, but not all symptoms respond equally to this drug. Bradykinesia and rigidity respond best, but tremor may only be slightly reduced. Problems with balance and other symptoms may not be alleviated at all. Anticholinergic medications can help control tremor and rigidity. Other drugs, such as bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing neurons to respond similarly to dopamine. The antiviral drug amantadine also appears to reduce symptoms.

[0154] An estimated 53 million people have PD, resulting in approximately 103,000 deaths worldwide. Parkinson's disease typically occurs in people over 60 years of age, with men more frequently affected than women. The average life expectancy after diagnosis is 7 to 14 years. Parkinson's disease is typically idiopathic (no specific known cause); however, a portion of cases can be attributed to known genetic factors. For example, mutations in certain genes have been shown to cause PD (e.g., alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), DJ-1, and ATP13A2). Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. The LRRK2 G2019S gain-of-function gene mutation is one of the most common mutations contributing to PD pathogenesis. Although treatments for PD are available, more effective therapies are needed.

[0155] Current treatments primarily use levodopa and dopamine agonists to manage the early motor symptoms of the disease. As the disease progresses and dopamine neurons continue to be lost, these drugs eventually become ineffective in treating the symptoms and simultaneously cause a complication called dyskinesia, characterized by involuntary writhing movements. Therefore, there is a need in the art to deliver a large oral equivalent dose of CBD to achieve therapeutic efficacy and eliminate or reduce interruptions, adverse events, and side effects, such as diarrhea, somnolence, abdominal pain, weight gain, headache, and other adverse events, such as elevated liver enzymes, associated with large oral doses to treat motor symptoms in subjects with Parkinson's disease, including symptoms of Parkinson's disease and symptoms indirectly related to Parkinson's disease, such as those occurring as side effects of treatment.

[0156] The present disclosure provides continuous drug delivery systems and methods for the treatment and / or prevention and / or control of Parkinson's disease in a patient, including, for example, the administration of CBD and / or THC as described herein.

[0157] Seizure disorders The present disclosure provides continuous drug delivery systems and methods for treating and / or preventing and / or controlling seizure disorders in patients, including, for example, administering CBD and / or THC as described herein. A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is when a person's body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0158] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0159] Generalized seizures are caused by electrical impulses throughout the brain, while partial seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that causes the seizure is sometimes called the focus.

[0160] There are six types of generalized seizures. The most common, dramatic, and therefore best known is a generalized convulsion, also called a grand mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. Following the loss of consciousness, there is 30-60 seconds of generalized rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent convulsions (the "clonic" phase), after which the patient enters a deep sleep (the "postictal" or postictal phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0161] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Patients, most often children, typically stop activity and stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware they are having a seizure, except that they may notice they are "losing time." Myoclonic seizures usually consist of sporadic jerks on both sides of the body. Patients may describe the jerks as brief electric shocks. If severe, these seizures can result in dropping or involuntarily throwing objects. Clonic seizures are recurrent, rhythmic jerks involving both sides of the body simultaneously. Tonic seizures are characterized by muscle rigidity. Atonic seizures consist of a sudden and general loss of muscle tone, especially in the arms and legs, which often results in falls.

[0162] Seizures as described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; consecutive seizures; unremitted seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galactoide seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; widespread bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

[0163] epilepsy The present disclosure provides continuous drug delivery systems and methods for treating and / or preventing and / or controlling epilepsy in a patient, including, for example, administering CBD and / or THC as described herein. Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, awakening grand mal epilepsy, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis syndrome (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0164] Status epilepticus (SE) can include, for example, convulsive status epilepticus, e.g., incipient status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and can include incipient status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Incipient status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent bouts of status epilepticus despite treatment with first-line therapy and is treated with second-line therapy. Refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line and second-line therapies, and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line, second-line, and general anesthetics for more than 24 hours.

[0165] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, minimal non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0166] The compositions described herein may also be administered as a prophylactic to a subject prior to the onset of a CNS disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; before the onset of a seizure.

[0167] Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Onset of LGS is usually between the ages of 2 and 7, with a peak onset between the ages of 3 and 5. Affected children experience several different types of seizures, most commonly atonic, tonic, and atypical absence seizures.

[0168] In 2018, GW Pharmaceutical received FDA approval for its fast-tracked drug "Epidiolex" (cannabidiol) to treat two orphan conditions in children: LGS and Dravet syndrome (DS).

[0169] Epidiolex contains naturally derived cannabidiol from the Sativex plant in an oral solution form (100 mg / mL). According to the FDA label, the recommended dosage for Epidiolex is listed in Table 1.

[0170] [Table 1]

[0171] Epidiolex has five main dose-dependent side effects: 1) hepatocellular injury, 2) somnolence and sedation, 3) suicidal behavior and loss of consciousness, 4) hypersensitivity reactions, and 5) antiepileptic drug withdrawal. 1 .

[0172] The discontinuation rate for Epidiolex is high due to side effects of hepatocellular injury and somnolence and sedation. During clinical trials, 1.3% of patients taking 10 mg / kg / day of Epidiolex and 5.9% of patients taking 20 mg / kg / day of Epidiolex discontinued due to hepatocellular injury. Additionally, 0% of patients taking the 10 mg / kg / day dose and 3% of patients taking the 20 mg / kg / day dose dropped out due to somnolence and sedation. Table 2 provides the dose-dependent side effects of Epidiolex. 1 .

[0173] [Table 2]

[0174] These side effects are dose-related, therefore it is necessary to monitor patients and reduce the dose if necessary. Many orally delivered drugs irritate the gastrointestinal mucosa, and many, including CBD, are subject to extensive "first-pass" inactivation by the liver. The compositions and methods of the present disclosure are directed to drug delivery directly to the systemic circulation, thus overcoming the problems of gastrointestinal irritation and hepatic first-pass metabolism because the active agent is not administered orally, avoiding post-absorption metabolism by the liver and also avoiding gastrointestinal irritation.

[0175] However, the continuous drug delivery systems and methods disclosed herein deliver drug molecules at a constant, defined dose rate. Instead of peaks and valleys in plasma concentration as in oral delivery, the continuous drug delivery systems and methods disclosed herein maintain an average plasma concentration at a predetermined, constant dose rate.

[0176] While there are patents available on cannabidiol, the shortcomings of these disclosures are overcome by the compounds and methods disclosed herein. For example, U.S. Patent No. 9,375,417 does not provide in vitro or in vivo data. U.S. Patent No. 6,328,992 discloses a reservoir and adhesive matrix patch, but these examples contain a mixture of cannabinoids (e.g., delta-8-THC, delta-9-THC, cannabidiol, and cannabinol) instead of cannabidiol alone. Because THC is a psychoactive and addictive substance, its usefulness is questionable.

[0177] Furthermore, U.S. Patent No. 8,449,908 discloses the delivery of a cumulative dose of 60,600 ng through human cadaver skin in 48 hours, which corresponds to a flux of 1,925 ng / sq cm / hr. The patch area can be calculated using the following formula:

[0178] In vitro flux (ug / sqcm / hr) = (Css(ug / l) * CL (L / hour) / patch area (Sqcm) Patch area (Sqcm) = (Css (ug / l) * CL (L / hr) / in vitro flux (ug / sqcm / hr) =(10 * 74.4) / 1.925 =386sqcm To deliver 5 mg / kg / day of cannabidiol, the patient must apply the formulation to a surface area of 386 sq cm. This is an impractical patch size for any transdermal drug delivery system (TDDS). Furthermore, the '908 patent discloses the use of a receptor vehicle PBS:PEG-400 (60:40). It is well known that PEG-400 is a permeation enhancer, and its incorporation into the receptor vehicle damages the skin from the dermal side, which can also increase the amount of permeation due to non-viable skin samples.

[0179] pain The present disclosure provides continuous drug delivery systems and methods for the treatment and / or prevention and / or control of pain in a patient, including, for example, the administration of CBD and / or THC as described herein. As used herein, the following terms have the following meanings:

[0180] As used herein, the term "chronic pain" or "chronic pain condition" is defined as any pain that lasts for longer than, for example, about 6 to about 12 weeks. As used herein, the term "neuropathic pain" has its conventional meaning and refers herein to pain resulting directly or indirectly from a lesion or disease affecting the somatosensory system (central and / or peripheral). As used herein, neuropathic pain includes all types of neuropathic pain, such as those caused by type 1 or type 2 diabetes, induced by various harmful substances such as alcohol, various deficiencies such as vitamin B1, B6, and / or B12 deficiency, various intoxications such as 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 peripheral neuropathy caused by any other chemical toxic compound. Other peripheral neuropathies include: trigeminal neuralgia, post-herpetic neuralgia, intercostal neuralgia, entrapment neuropathies (e.g., carpal tunnel syndrome, tarsal tunnel syndrome, abdominal cutaneous nerve entrapment syndrome), small fiber neuropathies, hereditary motor and sensory neuropathies, chronic inflammatory demyelinating polyneuropathy, sciatica, chronic idiopathic sensory neuropathy, infectious disease states such as post-polio syndrome, AIDS or HIV-related, Lyme-related, Sjogren's-related, 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.

[0181] As used herein, the term "inflammatory pain" has its conventional meaning and herein refers to pain resulting from inflammation which may be caused by, but is not limited to, trauma, burns, extreme cold, fractures, (osteo)arthritis, rheumatoid arthritis, chronic strains, surgery, infections and autoimmune diseases, overstretching, 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.

[0182] As used herein, the term "musculoskeletal pain" has its conventional meaning, and herein refers to pain affecting the muscles, ligaments, tendons, bones, joints, and / or soft tissues that are part of the musculoskeletal system. As used herein, musculoskeletal pain includes all types of pain caused by damage to muscle tissue as a result of the wear and tear of daily activities. Trauma to an area (such as spasms, car accidents, falls, sports injuries, fractures, sprains, strains, dislocations, and direct blows to the muscle) can also cause musculoskeletal pain. Other causes of musculoskeletal pain include postural distortions, repetitive movements, overuse and prolonged immobilization, muscle misuse, fibromyalgia, lower back pain, pain due to increased muscle tension, and overuse tendonitis.

[0183] As used herein, the term "analgesic" has its conventional meaning and refers herein in its broadest context to a compound, agent, drug or substance that relieves pain. As used herein, the term "co-analgesic agent" 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.

[0184] As used herein, the term "restoring analgesic effect" has its ordinary scientific meaning and herein refers 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 decline in analgesic effect occurs after repeated use of a topical formulation containing at least one analgesic compound or co-analgesic compound.

[0185] As used herein, the term "efficacy booster" or "co-analgesic effect booster" or "therapeutic effect booster" or "booster effect" or "synergistic effect" has its conventional meaning, and herein refers to an enhancement of the therapeutic effect induced by a co-analgesic compound ("co-analgesic agent") that results in 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; 3) a longer duration of analgesia; and / or 4) restoration of analgesic effect when a decrease in analgesic effect occurs following repeated use of at least one analgesic compound ("analgesic agent") or topical pharmaceutical composition containing a co-analgesic compound.

[0186] Pain results from noxious stimulation of nerve endings. Nociceptive pain is caused by noxious stimulation of nociceptors, which transmit impulses to spinal cord neurons and then to the brain via intact nerve pathways. Peripheral neuropathic pain is pain caused by 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 hyperactive small nerve fibers in the epidermis are sufficient to cause peripheral neuropathic pain. Neuropathic pain can be debilitating and can significantly reduce the patient's quality of life. This pain can persist for months or years, beyond the apparent healing of any damaged tissue.

[0187] Neuropathic pain has a local inflammatory component that leads to sensitization of nerve fibers. Other intact nerve fibers, such as nociceptors in the granular layer that innervate the same area, may also be sensitized and contribute to the clinical symptoms of neuropathic pain (e.g., hyperalgesia). This results in a situation of local neurogenic inflammation, which results in many different clinical characteristics, such as burning, freezing, electric shock, itching, tingling, numbness, hyperalgesia, and allodynia (pain resulting from nonpainful stimuli such as light touch or stroke).

[0188] Peripheral nerve injury can result in enhanced transmitter release in the spinal cord, leading to central sensitization. Increased peripheral input via primary afferent nerves is crucially involved in the maintenance of central sensitization and neuropathic pain. Peripherally acting drugs such as lidocaine 5% medicated patches and capsaicin 8% patches have demonstrated the ability to reduce pain in neuropathic pain syndromes. However, lidocaine patches are difficult to apply, especially to the toes and by the elderly, because the patches must be cut off and many elderly people cannot properly reach their toes. Application of capsaicin creams and patches often induces intolerable side effects, such as increased burning sensations, and treatment must often be combined with local anesthetics to counteract these side effects.

[0189] In common chronic pain, oral analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are part of the guidelines aimed at alleviating pain. However, chronic use of such oral analgesics can induce serious and even fatal side effects and / or adverse drug-drug interactions.

[0190] Topical analgesic pharmaceutical compositions are also being explored to help patients suffering from chronic pain. The two most commonly used topical compounds in neuropathic pain are capsaicin (a vanilloid receptor agonist and anti-irritant) and lidocaine (a membrane stabilizer), both of which have obvious drawbacks.

[0191] Clearly, there remains a pressing and long-felt need in the art to develop treatment options for chronic pain and neuropathic pain in general, and in particular for the development of new and effective pharmaceutical compositions for use in the treatment of chronic pain that have reduced side effects in patients.

[0192] Dosage form The continuous drug delivery systems and methods disclosed herein can include active agents in, for example, a liquid formulation. Liquid formulations can also be prepared by dissolving or suspending one or a combination of active agents in a conventional liquid vehicle acceptable for administration to provide the desired dosage, e.g., 1 to 4 teaspoons.

[0193] Dosage forms may be administered to a patient, for example, once, twice, three times, four times, five times, six times per day, or other multiple dose regimens. To allow for more precise control over the administration schedule, the active agents may be administered separately in individual dosage units, either simultaneously or at carefully coordinated times. Each agent may be individually formulated in separate unit dosage forms in a manner similar to that described above.

[0194] In formulating the composition, the above-mentioned amount of active substance may be compounded in accordance with accepted practice with physiologically acceptable vehicles, carriers, excipients, binders, viscosity modifiers, preservatives, stabilizers, flavoring agents, and the like in a particular type of unit dosage form.

[0195] Packaging / Treatment Kit The present disclosure provides a kit for easily and effectively implementing the method according to the present disclosure. Such a kit may be suitable for delivering a solid oral form, such as a tablet or capsule. Such a kit may include several unit doses. Such a kit may include a means for containing the doses oriented in the order of their intended use. An example of a means for containing the doses in the order of their intended use is a card. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used to package unit dosage forms. Optionally, the blisters may be childproof blisters, i.e., blisters that are difficult for children to open but easy for adults to open. Optionally, a memory aid may be provided, for example, in the form of numbers, letters, or other markings, or with a calendar function and / or calendar insert, which designates the days and daily divisions in the treatment schedule in which the doses may be administered, for example, AM doses packaged with "daytime" and PM doses; or AM doses packaged with PM doses. Alternatively, a placebo dose, or a vitamin or nutritional supplement may be included, either in a similar form to the active dose or in a different form.

[0196] The present disclosure provides compositions, including preparations, formulations, and / or kits, comprising the above-described combinations of ingredients (including multi-ingredient drug combinations), which are useful as therapies for treating, preventing, or ameliorating the conditions, conditions, and diseases provided herein. In one aspect, each member of the combination of ingredients is manufactured in a separate package, kit, or container; or all or a subset of the combination of ingredients is manufactured in a separate package or container. In another aspect, the package, kit, or container comprises a blister package, clamshell, tray, shrink wrap, or the like.

[0197] In one aspect, the package, kit, or container comprises a "blister package" (also called a blister pack or bubble pack). In one aspect, the blister pack consists of two or more separate compartments. The blister package is composed of two separate material elements: a clear plastic cavity molded to fit the product and its blister board backing. These two elements are then joined together by a heat sealing process that allows the product to be suspended or displayed. Exemplary types of "blister packages" include: face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, and slide blister packages.

[0198] Blister packs, clamshells, or trays are forms of packaging used for commercial products; thus, the present invention provides blister packs, clamshells, or trays containing the compositions of the present invention (e.g., combinations of active ingredients (multi-component drug combinations of the present invention)). Blister packs, clamshells, or trays can be designed to be non-reclosable, so that the consumer can know if the package has been opened. They are used to package commercial products where product tampering is a consideration, such as medicaments of the present invention. In one embodiment, the blister pack of the present invention comprises a molded PVC base covered with a foil laminate and having raised areas ("blisters") for receiving tablets, pills, etc., containing the combination of the present invention. The tablets, pills, etc. are removed from the pack either by peeling back the foil or by pressing the blister, causing the tablets to break the foil. In one embodiment, a special form of blister pack is a strip pack.

[0199] In one embodiment, the blister pack also includes a packaging method in which a composition containing a combination of ingredients of the present invention is contained between a card and transparent PVC. The PVC can be transparent to allow easy viewing and inspection of the items (pills, tablets, gel tabs, etc.), and in one embodiment, can be vacuum-formed around a mold to snugly accommodate the items and allow room to open upon purchase. In one embodiment, the card is brightly colored and designed according to the items inside (pills, tablets, gel tabs, etc.), and the PVC is attached to the card using a pre-formed tab onto which adhesive is placed. The adhesive can be strong enough to allow the pack to hang on a peg, but weak enough to allow the joint to be torn open and the items to be accessed in this way. Sometimes, for large items or multiple enclosed pills, tablets, gel tabs, etc., the card has a perforated window for access. In one embodiment, a more secure blister pack is used for items such as pills, tablets, gel tabs, etc. of the present invention, which can include two vacuum-formed PVC sheets interlocked at the edges with an information card inside.

[0200] In one embodiment, the blister pack comprises at least two components (e.g., a multi-component combination of drugs of the present invention): a thermoformed "blister" that contains the product (e.g., a combination of the present invention), and then a "blister card," which is a printed card with an adhesive coating on the front. During the assembly process, the blister components, most commonly made from PVC, are attached to the blister card using a blister machine. Conventional blister packs can also be sealed.

[0201] As discussed herein, the articles of manufacture of the invention may comprise packaging of the therapeutic combinations of the invention, either alone or in combination, as a "blister package" or as multiple packets comprising a blister package with lid, a blister with lid or a blister card or packet, or as shrink wrap.

[0202] In one aspect, any of the articles of manufacture of the invention, including kits or blister packs, includes a memory aid to help remind the patient when and how to take the medication of the invention. Therapeutic kits can be constructed in a variety of forms familiar to those skilled in the art. The kit includes at least one unit dose of an active agent for administration according to a daily regimen and a means for containing the unit dose. Therapeutic kits can be constructed, for example, for once-daily, twice-daily, three-times-daily, four-times-daily, multiple-daily administration, or other dosing regimens. The kit includes a means for daily administration of the agent of the present invention. In one embodiment, the kit includes about 1 to about 4 unit doses.

[0203] In one embodiment, the means for containing the unit doses is a card, including, for example, a foldable card. This card is referred to herein as the main card, or primary card, or first card, to distinguish it from any additional cards, guides, or other such materials that may be associated with the kit. The main card may be folded with a simple crease or a double crease to present a spine similar to the spine of a closed book. The main card may have a printable surface, i.e., a surface on which the product name, appropriate dosing instructions, product information, drawings, logos, memory aids, calendar functions, etc., may be printed. The main card may also include means for containing the aforementioned unit doses or different doses designated for different times of day, and a memory aid for administering the aforementioned unit doses. The main card, particularly if made from two or more laminated paperboard surfaces, may include a slit or pocket, for example, on one of the inner paperboard surfaces of the folded card. The slit or pocket may be used to contain a removable secondary card, i.e., a second or insert card that is not permanently attached or secured to the main card.

[0204] The memory aid may include a list of days of the week, i.e., Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, and Saturday, with appropriate space for the patient to select and indicate on the card a preferred day for administering therapy. The memory aid may include a list of times, with appropriate space for the patient to select and indicate on the card a preferred time for administering therapy (e.g., AM, PM, noon). The memory aid may also include a removable sticker with a suitable pressure-sensitive adhesive to facilitate easy removal and reapplication to a desired surface, such as a calendar or dayminder. The removable sticker may be placed on the main card or on a secondary card configured to be easily inserted into and removed from any slit in the main card. Additionally, any slit may contain additional patient information and other instructions.

[0205] Other means for containing the unit doses may include bottles and vials, with the bottle or vial comprising a memory aid such as a printed label for administering the unit dose. The label may also comprise a removable reminder sticker for placement on a calendar or daydream to further help the patient remember when to take or when the dose has been taken.

[0206] The present invention will be described in more detail below with reference to examples, but it should be understood that the present invention is not limited to these examples. [Example]

[0207] Example 1 The continuous drug delivery systems and methods disclosed herein include, but are not limited to, alcohols C1-C 20Examples of suitable solvents include, but are not limited to, polyhydric alcohols (methanol, ethanol, isopropyl alcohol, butanol, propanol, etc.), glycols (propylene glycol, polyethylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, glycerin, etc.), glycol derivatives, pyrrolidones (N-methyl 2-pyrrolidone, 2-pyrrolidone, etc.), sulfoxides (dimethyl sulfoxide, decimethyl sulfoxide, etc.), etc. The solvent may include, either alone or in combination, solvents known to those skilled in the art, such as 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, including, but not limited to, ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA, hexane, etc., acids, including, but not limited to, acetic acid, butyric 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 1%, 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%.In exemplary embodiments, formulations of the present disclosure may contain 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 approximately 1-75% by weight of the formulation, preferably 2-30%, and more preferably 5-20%.

[0208] Example 2 The continuous drug delivery systems and methods disclosed herein may be used with, but are not limited to, natural polymers, polysaccharides and derivatives thereof, such as, but not limited to, agar, alginic acid and derivatives, cassia tora, collagen, gelatin, gellam gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xantham, gum copal, chitosan, resins, etc.; semi-synthetic polymers and derivatives thereof, such as, but not limited to, cellulose and derivatives thereof (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.); synthetic polymers and derivatives thereof, such as, but not limited to, carboxyvinyl polymers or carbomers (carbopol 940, carbopol 934, car ... bopol971pNF), polyethylene and its copolymers, clays, such as, but not limited to, silicates, bentonite, silicon dioxide, polyvinyl alcohol, acrylic polymers (Eudragit), acrylic esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers, such as, but not limited to, PVP, Kollidon 30, poloxamer, isobutylene, ethyl vinyl acetate rubber copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives, such as, but not limited to, silicone polymers, such as, but not limited to, bio The adhesive may comprise gelling agents and / or thickeners and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure-sensitive adhesive polymers known to those skilled in the art, such as, but not limited to, polyisobutylene low molecular weight, polyisobutylene medium molecular weight, polyisobutylene 35000mw, etc., either alone or in combination thereof; acrylic pressure-sensitive adhesives, such as, but not limited to, polyisobutylene low molecular weight, polyisobutylene medium molecular weight, polyisobutylene 35000mw, etc.; rubber-based adhesives; hot melt adhesives; styrene-butadiene copolymers; bentonite; and all water- and / or organic solvent-swellable polymers.In exemplary embodiments, the formulations of the present disclosure comprise a gelling agent, and / or thickening agent, and / or suspending agent, and / or polymer, and / or adhesive polymer, and / or pressure sensitive adhesive polymer in an amount of 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 %, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% and about 99%. In exemplary embodiments, 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 approximately 1-75% by weight of the formulation, preferably 2-30%, more preferably 5-20%, and more preferably 0.1-80% w / w or w / v.

[0209] Example 3 The continuous drug delivery systems and methods disclosed herein may be used with a wide variety of compounds, including, but not limited to, sulfoxides and similar chemicals, including, but not limited to, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, decyl methyl sulfoxide, dimethyl isosorbide, and the like; azones; pyrrolidones, including, but not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, and the like; esters; fatty acid esters, including, 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, glycerol monolaurate, lauryl laurate, and the like; fatty acids, including, 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, glycerol monolaurate, lauryl laurate, and the like; These may include, either alone or in combination, penetration 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, oleyl alcohol, naphthalene, dodecanol, propylene glycol, glycerol, etc., ether alcohols, such as, but not limited to, diethylene glycol monoethyl ether, urea, triglycerides, such as, but not limited to, triacetin, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, esters of fatty alcohols, essential oils, surfactant-type enhancers, such as, but not limited to, brij, sodium lauryl sulfate, tween, polysorbates, terpenes, terpenoids, and all penetration and permeation enhancers referenced in the book "Percutaneous Penetration Enhancers" (Eric W. Smith, Howard I. Maibach, 2005. Nov., CRC Press).In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 %, about 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%. In exemplary embodiments, 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 approximately 1-75% by weight of the formulation, preferably 2-30%, more preferably 5-20%, and more preferably 0.01-95% w / w or w / v.

[0210] Example 4 The continuous drug delivery systems and methods disclosed herein may include plasticizers known to those skilled in the art, such as, but not limited to, glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacate esters, citrate esters, tartrate esters, adipate esters, phthalate esters, triacetin, oleate esters, and all plasticizers that may be used in continuous drug delivery systems referenced 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 contain 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%, or about 10% of the formulation. ,approx. 0.8%,approx. 0.9%,approx. 1%,approx. 2%,approx. 3%,approx. 4%,approx. 5%,approx. 6%,approx. 7%,approx. 8%,approx. 9%,approx. 10%,approx. 11%,approx. 12%,approx. 13%,approx. 14%,approx. 15%,approx. 16%,approx. 17%,approx. 18%,approx. 19%,approx. 20%,approx. 21%,approx. 22%,approx. 23%,approx. 24%,approx. 25%,approx. 26%,approx. 27%,approx. 28%,approx. 29%,approx. 30%,approx. 35%,approx. 40%,approx. 45%,approx. The formulations of the present disclosure may contain plasticizers at concentrations of 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%. In exemplary embodiments, the formulations of the present disclosure may contain plasticizers at concentrations of about 1-20%, about 5-25%, about 10-20%, about 15-20%, about 20-25%, about 25-30 ... or about 15% to about 18%, about 30% to about 70%, about 35% to about 65%, about 63.13%, and about 40% to about 64% w / w. In exemplary formulations of the present disclosure, the plasticizer represents approximately 1% to 75% by weight of the formulation, preferably 2% to 30% by weight, more preferably 5% to 20% by weight, and more preferably 0.01% to 95% w / w or w / v.

[0211] Example 5 The continuous drug delivery systems and methods disclosed herein may include emollients, moisturizers, skin irritation reducers, and similar compounds or chemicals known to those skilled in the art, such as, but not limited to, petrolatum, lanolin, mineral oil, dimethicone, zinc oxide, glycerin, propylene glycol, 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 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 %, 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%. In exemplary embodiments, 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, emollients, moisturizers, skin irritation reducers, and similar compounds represent approximately 1-75%, preferably 2-30%, more preferably 5-20%, and more preferably 0.01-95% w / w or w / v of the formulation.

[0212] Example 6 The continuous drug delivery systems and methods disclosed herein include, but are not limited to, polysorbates, such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.; spans, such as, but not limited to, span 80, span 20, etc.; surfactants, such as (anionic, cationic, nonionic and amphoteric), propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate, medium chain triglycerides, propylene glycol monocaprylate type II, propylene glycol dicaprylate, propylene glycol monocaprylate type II, propylene glycol mono ..., propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monocapry The composition may contain, alone or in combination, solubilizers, surfactants, emulsifiers, dispersants, and similar compounds or chemicals known to those skilled in the art, such as cyclodextrins, such as oleyl monolaurate type II, linoleoyl polyoxyl-6 glyceride, oleoyl polyoxyl-1-6-glyceride, lauroyl polyoxyl-6-glyceride, polyglyceryl 1-3-dioleate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglyceryl-3-dioleate, caprylocaproyl polyoxyl-8 glyceride, etc. More preferably, the composition may contain 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% of the formulation. , 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%.In exemplary embodiments, 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, solubilizers, surfactants, emulsifiers, dispersants, and similar compounds represent approximately 1-75%, preferably 2-30%, more preferably 5-20%, and more preferably 0.01-95% w / w or w / v of the formulation.

[0213] Example 7 For example, different techniques and ingredients may be used to enhance the stability and / or solubility of the active agent in the formulation, such as, but not limited to, coating, encapsulation, microencapsulation, nanoencapsulation, lyophilization, chelating agents, complexing agents, continuous drug delivery system packaging, moisture scavengers, etc. Different stabilizers may be used to increase the stability of the active agent in the formulation, etc.

[0214] Example 8 The continuous drug delivery systems and methods disclosed herein may contain supplemental pH buffers and pH stabilizers known to those skilled in the art, such as, but not limited to, phosphate buffers, acetate buffers, citrate buffers, etc., acids, such as, but not limited to, carboxylic acids, inorganic acids, sulfonic acids, vinylic carboxylic acids, etc., bases, such as, but not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, and similar compounds, which, either alone or in combination, help to maintain the appropriate pH of the formulation, preferably in the range of 4.0 to 8.0, 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 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 It may contain pH buffers, pH stabilizers and similar compounds at concentrations of 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% and about 99%. In exemplary embodiments, formulations of the present disclosure may contain pH buffers, 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, pH buffers, pH stabilizers, and similar compounds represent approximately 1-75% by weight of the formulation, preferably 2-30%, more preferably 5-20%, and more preferably 0.01-30% w / w or w / v.

[0215] Example 9 The continuous drug delivery systems and methods disclosed herein may contain antioxidants, oxidizing agents, stabilizers, discolorants, preservatives, and similar compounds or chemicals known to those skilled in the art to aid in obtaining stable formulations, including but not limited to (sodium metabisulfite, citric acid, ascorbic acid, BHA, BHT), which may be used either alone or in combination, more preferably in the range of 0.01% to 50% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 %, 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%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%. In exemplary embodiments, formulations of the present disclosure may include antioxidants 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 antioxidant represents approximately 1-75% by weight of the formulation, preferably 2-30%, more preferably 5-20%, and more preferably 0.01-50% w / w or w / v.

[0216] Example 10 The continuous drug delivery systems and methods disclosed herein may include drugs formulated in 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.

[0217] Example 11 Materials for making the continuous drug delivery systems and methods of the present disclosure are known to those skilled in the art and include, but are not limited to, pumps, reservoir patches, matrix patches, drug-in-adhesives, film-forming formulations, microdosing transdermal patches, transdermal films, and the like, which may include, but are not limited to, polymers, copolymers, derivatives, backing films, release membranes, release liners, and the like, either alone or in combination. Pressure-sensitive adhesives (e.g., but not limited to, silicone polymers, rubber-based 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-controlling 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.

[0218] The continuous drug delivery systems and methods disclosed herein can deliver at least a therapeutically effective amount of an active agent, such as CBD and / or THC, and derivatives of these compounds, alone or in combination, to human plasma as needed to treat and / or prevent and / or control chronic pain. A therapeutically effective dose of an active agent, such as CBD and / or THC, and derivatives of these compounds, refers to the therapeutic concentration in human plasma needed to treat and / or prevent and / or control chronic pain. Furthermore, the exact therapeutically effective dose of CBD and / or THC, and derivatives of these compounds, in a continuous drug delivery system, such as a pump, transdermal or topical formulation, or transdermal delivery system, can be determined by one skilled in the art based on factors such as, but not limited to, the patient's condition. Transdermal or topical formulations or transdermal delivery systems are available in different dosage strengths and patch sizes to achieve optimal therapeutic results based on the patient's requirements.

[0219] Continuous drug delivery systems and methods, such as pumps or transdermal formulations or patches of active agents, such as CBD and / or THC and derivatives of these compounds, can be applied to the skin surface in any of the following dosing regimens: once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every about 8 to about 13 days, once every two weeks, or once every 15 days.

[0220] Example 12

[0221] [Table 3]

[0222] [Table 4]

[0223] 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 without departing from the spirit and scope of the invention.

Claims

1. A continuous delivery system for use in a method of treating, preventing, and / or delaying the onset or progression of a disease or condition and / or related symptoms in a patient, wherein the method is Selecting patients who require treatment, prevention, and / or delay of the onset or progression of a disease or condition and / or related symptoms, The pharmaceutical composition is administered to the patient by the continuous delivery system, wherein the pharmaceutical composition is Approximately 0.1% to approximately 50% of an activator selected from the group consisting of cannabidiol (CBD), its synthetic form, its biosynthetic form, its free base form, its salt, its isomer, its amorphous form, its derivatives, and combinations thereof. Approximately 0.1% to approximately 50% of the activator selected from the group consisting of tetrahydrocannabinol (THC), its synthetic form, its biosynthetic form, its free base form, its salt, its isomer, its amorphous form, its derivatives, and combinations thereof. Optionally, at least one additional activator, and those combinations The administration of an active agent selected from the group consisting of the following, A continuous delivery system in which the aforementioned disease or condition and / or related symptoms are treated, prevented, and / or delayed in the patient.

2. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition, thereby mitigating the peak and valley pharmacokinetic behavior of the activator.

3. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via administration by a route selected from the group consisting of parenteral, intravenous, subcutaneous, intramuscular, intrathecal, oral, buccal, mucosal, nasal, rectal, vaginal, percutaneous, implantable, topical, and combinations thereof.

4. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via intravenous or subcutaneous injection.

5. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via subcutaneous injection.

6. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via an infusion pump device.

7. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via a portable / portable infusion pump that can be worn by the patient and use replaceable cartridges.

8. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via a patch pump or micropump.

9. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of liquid formulations, solid formulations, semi-solid formulations, emulsion formulations, nanoparticle formulations, matrix formulations, film formulations, patch formulations, formulations in an infusion pump, and / or combinations thereof.

10. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of a transdermal liquid formulation, a transdermal semi-solid formulation, a transdermal gel formulation, or a transdermal polymer matrix formulation, a transdermal adhesive matrix formulation, a transdermal film-forming gel, a transdermal film-forming spray formulation, a multilayer transdermal matrix system, a transdermal drug-containing adhesive matrix formulation, and combinations thereof.

11. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a topical liquid formulation, a topical semi-solid formulation, a topical gel formulation, a topical polymer matrix formulation, a topical adhesive matrix formulation, a topical film-forming gel formulation, or a topical film-forming spray formulation.

12. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch, and the transdermal patch is selected from the group consisting of reservoir patches, multilayer transdermal matrix systems, microreservoir patches, matrix patches, drug-containing adhesive patches, adhesive matrix patches combined with polymers, pressure-sensitive adhesive patches, sustained-release transdermal films, liquid reservoir systems, microreservoir patches, mucosal adhesive patches, and combinations thereof.

13. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch, and the topical patch is selected from the group consisting of a multilayer transdermal matrix system, a reservoir patch, a microreservoir patch, a matrix patch, a drug-containing adhesive patch, a pressure-sensitive adhesive patch, a sustained-release transdermal film, a liquid reservoir system, a microreservoir patch, a mucosal adhesive patch, a microdosing patch, an adhesive matrix patch combined with a polymer, and a combination thereof.

14. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a transdermal patch.

15. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a multilayer transdermal matrix system, a quantitative transdermal gel, a quantitative transdermal spray, a film-forming gel, a film-forming spray, or a quantitative aerosol.

16. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a topical patch.

17. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a quantitative gel, quantitative spray, gel, cream, solution, emulsion, liquid composition, semi-solid composition, adhesive matrix in combination with a polymer, or film-forming formulation.

18. The continuous delivery system according to claim 1, further comprising a pharmaceutical composition comprising an effective amount of carrier or component selected from the group consisting of solvents, gelling agents, polymers, pressure-sensitive adhesive polymers, penetration enhancers, skin emollients, skin irritation reducers, buffers, pH stabilizers, tackifiers, diluents, bulking agents, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, surfactants, antioxidants, oxidizing agents, and combinations thereof.

19. The continuous delivery system according to claim 1, further comprising a pharmaceutical composition comprising an effective amount of a carrier or component selected from the group consisting of a solvent in the range of 0.1% to 99.5% w / w or w / v, a gelling agent, a polymer, a pressure-sensitive adhesive polymer, a penetration enhancer, a skin emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersant, a stabilizer, a plasticizer, a tackifier, a diluent, a bulking agent, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof.

20. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a transdermal preparation that can be administered in a drug regimen selected from the group consisting of once a day, twice a day, three times a day, once every 1 to 8 hours, once every 1 to 24 hours, 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 8 to about 13 days, once every two weeks, and once every 15 to about 30 days.

21. The continuous delivery system according to claim 1, wherein the continuous delivery system includes a pharmaceutical composition formulated as a topical preparation that can be administered in a dosage regimen selected from the group consisting of once a day, twice a day, three times a day, four times a day, five times a day, six times a day, once every 1 to 8 hours, once every 1 to 24 hours, 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 8 to about 13 days, once every two weeks, and once every 15 to about 30 days.

22. The continuous delivery system according to claim 1, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via microneedles.

23. The continuous delivery system according to claim 1, wherein the continuous delivery system provides serum levels of an active agent selected from the group consisting of approximately 0.01 ng / mL, approximately 0.02 ng / mL, approximately 0.05 ng / mL, approximately 0.1 ng / mL, approximately 0.2 ng / mL, approximately 0.5 ng / mL, approximately 1 ng / mL, approximately 2 ng / mL, approximately 5 ng / mL, approximately 10 ng / mL, approximately 20 ng / mL, approximately 50 ng / mL, approximately 100 ng / mL, approximately 200 ng / mL, approximately 500 ng / mL, approximately 1 μg / mL, approximately 2 μg / mL, and approximately 5 μg / mL.

24. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition, and the active agent is present in a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 0.1% to about 50%, about 1% to about 20%, about 5% to about 25%, about 10% to about 20%, or about 15% to about 18%, about 30% to about 70%, and about 35% to about 65% of the formulation.

25. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition, and the active agent is present in a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, and about 1% to about 5% of the formulation.

26. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition, and THC is selected from the group including its free base, its salt, its isomer, its amorphous form, its crystalline form, its cocrystalline form, its prodrug, its analogue, its derivative, its synthetic form, its biosynthetic form, its natural form, its active metabolite, its polymorph, its solid solution, its coated form, its stereoisomer, its solid solution, its ion pair, its solution, its powder form, its liquid form, alone or in combination thereof.

27. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition, and CBD is selected from the group including its free base, its salt, its isomer, its amorphous form, its crystalline form, its cocrystalline form, its prodrug, its analogue, its derivative, its synthetic form, its biosynthetic form, its natural form, its active metabolite, its polymorph, its solid solution, its coated form, its ion pair, its stereoisomer, its solid solution, its solution, its powder form, its liquid form, alone or in combination thereof.

28. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition in a dosage form for transdermal delivery, comprising one or more activators selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), its free base, its salt, its isomer, its amorphous form, its crystalline form, its cocrystalline form, its prodrug, its analogue, its derivative, its synthetic form, its biosynthetic form, its natural form, its active metabolite, its polymorph, its solid solution, its coated form, and combinations thereof.

29. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition, and the tetrahydrocannabinol (THC), cannabidiol (CBD), its free base, its salt, its isomers, its amorphous form, its polymorphic form, its stereoisomers, its ion pairs, its coated form, its crystalline form, its cocrystal form, its prodrug, its analogues, its derivatives, its synthetic form, its biosynthetic form, its natural form, its active metabolites, and combinations thereof are produced by a synthetic pathway.

30. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition, and the activator is synthetically produced and has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or higher before being added to the pharmaceutical composition.

31. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition administered simultaneously with at least one additional activator selected from the group consisting of dopamine precursors, dopamine receptor agonists, and combinations thereof.

32. The continuous delivery system according to claim 1, wherein the continuous delivery system comprises a pharmaceutical composition administered simultaneously with at least one additional activator selected from the group consisting of levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, and any combination thereof.

33. The continuous delivery system according to claim 1, wherein the disease or condition and / or related symptoms are selected from the group consisting of cancer, pain, seizure disorder, Parkinson's disease ("PD"), and symptoms of PD.

34. The continuous delivery system according to claim 33, wherein the cancer is selected from the group consisting of endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, small intestine cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, GBM, and hematological cancers, such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma / primary mediastinal large B-cell lymphoma, and chronic myeloid leukemia.

35. The continuous delivery system according to claim 33, wherein the cancer is glioblastoma, GBM.

36. The continuous delivery system according to claim 33, wherein the pharmaceutical composition is administered concurrently with at least one additional therapeutic agent selected from the group consisting of temozolomide, peptides, polypeptides, fusion proteins, nucleic acid molecules, small molecules, mimetic agents, synthetic drugs, inorganic molecules, organic molecules, chemotherapy, radiotherapy, hormone therapy, anti-angiogenic therapy, targeted therapy, and / or biological therapies including immunotherapy and surgery, and combinations thereof.

37. The continuous delivery system according to claim 33, wherein the pain is a chronic pain selected from the group consisting of neuropathic pain, peripheral neuropathic pain, inflammatory pain, musculoskeletal pain, pain due to muscle spasms, pain due to increased muscle tone, osteoarthritis pain, myocardial headache, tension headache, migraine, cluster headache, atypical facial pain, referred pain, vulvovaginal pain, rectal pain, and any combination thereof.

38. The continuous delivery system according to claim 33, wherein the seizure disorder is selected from the group consisting of compound partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonus), neonatal and infantile seizures, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as additional specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis syndrome (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesitemporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with intellectual disability, and progressive myoclonic epilepsy, and seizures associated with CNS mass lesions.

39. The continuous delivery system according to claim 33, wherein the seizure disorder is selected from the group consisting of compound partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonus), neonatal and infantile seizures, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as additional specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis syndrome (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesitemporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with intellectual disability, and progressive myoclonic epilepsy, and seizures associated with CNS mass lesions.

40. The symptoms of Parkinson's disease that are treated, prevented, and / or delayed are (a) At least one non-motor aspect of the experience of daily living as defined by Part I of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, affective blunting, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urinary problems, constipation problems, dizziness, and fatigue. (b) At least one motor activity of the experience of daily living as defined by Part II of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of speech, saliva and drooling, chewing and swallowing, eating, dressing, hygiene, writing, turning over in bed, tremors, getting out of bed, car or deep chair, walking and balance, and freezing. (c) At least one motor symptom as defined in Part III of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of speech, facial expression, rigidity, finger tapping, hand movement, hand pronation-supination, toe tapping, foot agility, standing up from a chair, gait, gait freezing, postural stability, posture, bradykinesia, postural tremor of the hand, motor tremor of the hand, resting tremor amplitude, and resting tremor duration. (d) At least one motor complication as defined in Part IV of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of time spent in dyskinesia, functional effects of dyskinesia, time spent in off-state, functional effects of diurnal variation, complexity of diurnal variation of motor symptoms, and painful off-state dystonia. (e) constipation; (f) depression, (g) Cognitive impairment, (h) Short-term or long-term memory impairment, (i) Difficulty concentrating, (j) Coordination disorder; (k) Motor function impairment, (l) speech disorder, (m) mental confusion; (n) Sleep problems, sleep disorders or sleep disorders, (o) Circadian rhythm dysfunction, (p) hallucinations, (q) fatigue, (r) REM sleep disorder, (s) REM behavioral disorder, (t) erectile dysfunction; (u) Postural hypotension, (v) Correction of blood pressure or orthostatic hypotension, (w) Nocturnal hypertension, (x) Temperature control, (y) Improvement of respiration or apnea, (z) Correction of cardiac conduction disorders, (aa) Improvement of pain, (bb) Urinary incontinence, or recovery of bladder sensation and urination, (cc) Mood fluctuations, (dd) emotional insensitivity; (ee) Control of nocturia, (ff) Neurodegeneration, (gg) anxiety, (hh) To improve speech ability, including the ability to speak in public, and / or (ii) The continuous delivery system according to claim 33, selected from the group consisting of Parkinson's disease and dementia.

41. The PD symptoms to be treated, prevented, and / or delayed are sleep problems, sleep disturbances, sleep disorders, circadian rhythm disorders, REM sleep disorders, or REM behavioral disorders. (a) The sleep disorder or sleep disturbance includes, and / or (b) The REM behavioral disorder includes vivid dreams, nightmares, and the acting out of dreams by talking or shouting, or by fidgeting or slashing of the arms or legs during sleep, and / or (c) By treating sleep problems, sleep disorders, or sleep disturbances, the onset and / or progression of Parkinson's disease will be prevented or delayed, and / or (d) The method results in a positive change in the sleep pattern of the subject over a defined period of time, and / or (e) The method brings about a positive change in the sleep pattern of the subject over a defined period of time, and the positive change is (i) an increase in the total amount of sleep obtained by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%, and / or (ii) Defined as the rate of reduction in the number of nocturnal awakenings selected from the group consisting of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, and / or (f) As a result of the method, the subject obtains the total number of sleep hours recommended by the medical authorities for the subject's age group, and / or (g) The continuous delivery system according to claim 33, wherein each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

42. The PD symptoms that are treated, prevented, and / or delayed are hallucinations. (a) The hallucination includes visual, auditory, tactile, gustatory or olfactory hallucinations, and / or (b) If treating hallucinations prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (c) The method results in a reduction in the number of hallucinations of the subject over a defined period of time, and / or (d) The method results in a reduction in the number of hallucinations of the subject over a defined period, wherein the reduction in the number is selected from the group consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, and / or (e) The method does not cause hallucinations in the subject, and / or (f) The method results in a reduction in the severity of the hallucinations of the subject over a defined period of time, as measured by one or more medically recognized techniques, and / or (g) The method results in a reduction in the severity of the hallucinations of the subject over a defined period, and the reduction in severity is measured by one or more medically recognized techniques, selected from the groups consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, and / or (h) The medically recognized technologies include the Chicago Hallucination Assessment Tool (CHAT), The Psychotic Symptom Rating Scales (PSYRATS), Auditorium Hallucinations Rating Scale (AHRS), Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ), Characteristics of Auditorium Hallucinations Questionnaire (CAHQ), and Mental Health Research Institute Unusual Selected from the group consisting of Perception Schedule (MUPS), positive and negative syndrome scale (PANSS), scale for the assessment of positive symptoms (SAPS), Launay-Slade hallucinations scale (LSHS), the Cardiff anomalous perceptions scale (CAPS), and structured interview for assessing perceptual anomalies (SIAPA), and / or (i) The continuous delivery system according to claim 33, wherein each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

43. The PD symptoms to be treated, prevented, and / or delayed are depression, (a) Treating depression prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) The method results in an improvement in the subject's depression over a defined period of time, as measured by one or more clinically recognized depression rating scales, and / or (c) The method results in an improvement in the subject's depression over a defined period of time, as measured by one or more clinically recognized depression rating scales, wherein the improvement is in one or more depressive characteristics selected from the group consisting of mood, behavior, physical function, e.g., eating, sleep, vitality, and sexual activity, and / or episodes of sadness or emotional blunting, and / or (d) The method results in an improvement in the subject's depression as measured by one or more clinically recognized depression rating scales, and the improvement experienced by the subject after treatment is approximately 5, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, approximately 60, approximately 65, approximately 70, approximately 75, approximately 80, approximately 85, approximately 90, approximately 95, or approximately 100%, and / or (e) The continuous delivery system according to claim 33, wherein each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

44. The PD symptoms to be treated, prevented, and / or delayed are cognitive impairments. (a) Treating cognitive impairment prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) The progression or onset of the cognitive impairment is delayed, halted, or reversed over a defined period following administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (c) The cognitive impairment is positively affected by the administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (d) The cognitive impairment is positively affected by the administration of the pharmaceutical composition, as measured by medically recognized techniques, and the positive effect on cognitive decline and / or its progression is quantitatively or qualitatively measured by one or more techniques selected from the group consisting of the Mini-Mental State Exam (MMSE), Mini-cog test, and computer tests selected from Cantab Mobile, Cognigram, Cognivue, Cognition, or automated neuropsychological assessment matrices, and / or (e) The progression or onset of the cognitive impairment is delayed, stopped, or reversed by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, as measured by medically recognized techniques, and / or (f) The continuous delivery system according to claim 33, wherein each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

45. The PD symptom that is treated, prevented, and / or delayed is constipation. (a) Treating constipation prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) The administration of the pharmaceutical composition causes defecation in the subject, and / or (c) The method results in an increase in the frequency of defecation in the subject over a defined period of time, and / or (d) The method results in an increase in the frequency of defecation in the subject, and the increase in the frequency of defecation is (i) an increase in the number of bowel movements per week of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%, and / or (ii) Defined as the percentage reduction in time between each consecutive bowel movement, selected from the group consisting of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, and / or (e) The continuous delivery system according to claim 33, wherein as a result of the method, the subject has a bowel movement frequency recommended by a medical authority for the age group of the subject.

46. The PD symptoms that are treated, prevented, and / or delayed are neurodegenerative conditions that correlate with PD, (a) Treatment of the neurodegeneration prevents and / or delays the onset and / or progression of Parkinson's disease, and / or (b) The method results in the treatment, prevention, and / or delay of the progression and / or onset of neurodegeneration in the subject, and / or (c) The progression or onset of the neurodegeneration is delayed, halted, or reversed over a defined period following administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (d) The neurodegeneration is positively affected by the administration of the pharmaceutical composition, as measured by medically recognized techniques, and / or (e) The positive effects and / or progression of neurodegeneration are quantitatively or qualitatively measured by one or more techniques selected from the group consisting of electroencephalography (EEG), neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI), [18F]fluorodeoxyglucose (FDG) PET, amyloid-labeling agents, [18F]F-dopa PET, radiotracer imaging, volume analysis of local tissue loss, specific imaging markers for abnormal protein deposition, multimodal imaging, and biomarker analysis, and / or (f) The progression or onset of neurodegeneration is delayed, stopped, or reversed by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, as measured by medically recognized techniques, and / or (g) The continuous delivery system according to claim 33, wherein each defined period is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and more than about 12 months.

47. Approximately 0.1% to approximately 50% of an activator selected from the group consisting of cannabidiol (CBD), its synthetic form, its biosynthetic form, its free base form, its salt, its isomer, its amorphous form, its derivatives, and combinations thereof. Approximately 0.1% to approximately 50% of the activator selected from the group consisting of tetrahydrocannabinol (THC), its synthetic form, its biosynthetic form, its free base form, its salt, its isomer, its amorphous form, its derivatives, and combinations thereof. Optionally, at least one additional activator, and those combinations A continuous delivery system comprising a pharmaceutical composition containing at least one activator selected from the group consisting of the following.

48. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to mitigate the peak and valley pharmacokinetic behavior of the activator.

49. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition to the patient via administration by a route selected from the group consisting of parenteral, intravenous, subcutaneous, intramuscular, intrathecal, oral, buccal, mucosal, nasal, rectal, vaginal, percutaneous, implantable, topical, and combinations thereof.

50. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition via intravenous or subcutaneous injection.

51. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition via subcutaneous injection.

52. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition via an injection pump device.

53. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition via a portable / portable infusion pump that can be fitted by the patient and use replaceable cartridges.

54. The continuous delivery system according to claim 47, wherein the continuous delivery system provides continuous and sustained delivery of the pharmaceutical composition via a patch pump or micropump.

55. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of liquid formulations, solid formulations, semi-solid formulations, emulsion formulations, nanoparticle formulations, matrix formulations, film formulations, patch formulations, formulations in an infusion pump, and / or combinations thereof.

56. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of a transdermal liquid formulation, a transdermal semi-solid formulation, a transdermal gel formulation, or a transdermal polymer matrix formulation, a transdermal adhesive matrix formulation, a transdermal film-forming gel, a transdermal film-forming spray formulation, a multilayer transdermal matrix system, a transdermal drug-containing adhesive matrix formulation, and combinations thereof.

57. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a topical liquid formulation, a topical semi-solid formulation, a topical gel formulation, a topical polymer matrix formulation, a topical adhesive matrix formulation, a topical film-forming gel formulation, or a topical film-forming spray formulation.

58. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch, and the transdermal patch is selected from the group consisting of reservoir patches, multilayer transdermal matrix systems, microreservoir patches, matrix patches, drug-containing adhesive patches, adhesive matrix patches combined with polymers, pressure-sensitive adhesive patches, sustained-release transdermal films, liquid reservoir systems, microreservoir patches, mucosal adhesive patches, and combinations thereof.

59. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch, and the topical patch is selected from the group consisting of a multilayer transdermal matrix system, a reservoir patch, a microreservoir patch, a matrix patch, a drug-containing adhesive patch, a pressure-sensitive adhesive patch, a sustained-release transdermal film, a liquid reservoir system, a microreservoir patch, a mucosal adhesive patch, a microdosing patch, an adhesive matrix patch combined with a polymer, and a combination thereof.

60. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a transdermal patch.

61. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a multilayer transdermal matrix system, a quantitative transdermal gel, a quantitative transdermal spray, a film-forming gel, a film-forming spray, or a quantitative aerosol.

62. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a topical patch.

63. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a quantitative gel, quantitative spray, gel, cream, solution, emulsion, liquid composition, semi-solid composition, adhesive matrix in combination with a polymer, or film-forming formulation.

64. The continuous delivery system according to claim 47, further comprising a pharmaceutical composition 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, a skin emollient, a skin irritation reducer, a buffer, a pH stabilizer, a tackifier, a diluent, a bulking agent, a solubilizer, a suspending agent, a dispersant, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof.

65. The continuous delivery system according to claim 47, further comprising a pharmaceutical composition comprising an effective amount of a carrier or component selected from the group consisting of a solvent in the range of 0.1% to 99.5% w / w or w / v, a gelling agent, a polymer, a pressure-sensitive adhesive polymer, a penetration enhancer, a skin emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersant, a stabilizer, a plasticizer, a tackifier, a diluent, a bulking agent, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof.

66. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a transdermal preparation that can be administered in a drug regimen selected from the group consisting of once a day, twice a day, three times a day, once every 1 to 8 hours, once every 1 to 24 hours, 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 8 to about 13 days, once every two weeks, and once every 15 to about 30 days.

67. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a topical preparation that can be administered in a dosage regimen selected from the group consisting of once a day, twice a day, three times a day, four times a day, five times a day, six times a day, once every 1 to 8 hours, once every 1 to 24 hours, 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 8 to about 13 days, once every two weeks, and once every 15 to about 30 days.

68. The continuous delivery system according to claim 47, wherein the continuous delivery system includes a pharmaceutical composition formulated as a microneedle.

69. The continuous delivery system according to claim 47, wherein the continuous delivery system provides serum levels of an active agent selected from the group consisting of approximately 0.01 ng / mL, approximately 0.02 ng / mL, approximately 0.05 ng / mL, approximately 0.1 ng / mL, approximately 0.2 ng / mL, approximately 0.5 ng / mL, approximately 1 ng / mL, approximately 2 ng / mL, approximately 5 ng / mL, approximately 10 ng / mL, approximately 20 ng / mL, approximately 50 ng / mL, approximately 100 ng / mL, approximately 200 ng / mL, approximately 500 ng / mL, approximately 1 μg / mL, approximately 2 μg / mL, and approximately 5 μg / mL.

70. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition, and the active agent is present in a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 0.1% to about 50%, about 1% to about 20%, about 5% to about 25%, about 10% to about 20%, or about 15% to about 18%, about 30% to about 70%, and about 35% to about 65% of the formulation.

71. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition, and the active agent is present in a concentration selected from the group consisting of about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, and about 1% to about 5% of the formulation.

72. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition, and THC is selected from the group comprising its free base, its salt, its isomer, its amorphous form, its crystalline form, its cocrystalline form, its prodrug, its analogue, its derivative, its synthetic form, its biosynthetic form, its natural form, its active metabolite, its polymorph, its solid solution, its coated form, its stereoisomer, its solid solution, its ion pair, its solution, its powder form, its liquid form, alone or in combination thereof.

73. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition, and CBD is selected from the group including its free base, its salt, its isomer, its amorphous form, its crystalline form, its cocrystalline form, its prodrug, its analogue, its derivative, its synthetic form, its biosynthetic form, its natural form, its active metabolite, its polymorph, its solid solution, its coated form, its ion pair, its stereoisomer, its solid solution, its solution, its powder form, its liquid form, alone or in combination thereof.

74. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition in a dosage form for transdermal delivery that includes one or more activators selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), its free base, its salt, its isomer, its amorphous form, its crystalline form, its cocrystalline form, its prodrug, its analogue, its derivative, its synthetic form, its biosynthetic form, its natural form, its active metabolite, its polymorph, its solid solution, its coated form, and combinations thereof.

75. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition, and the tetrahydrocannabinol (THC), cannabidiol (CBD), its free base, its salt, its isomers, its amorphous form, its polymorphic form, its stereoisomers, its ion pairs, its coated form, its crystalline form, its cocrystal form, its prodrug, its analogues, its derivatives, its synthetic form, its biosynthetic form, its natural form, its active metabolites, and combinations thereof are produced by a synthetic pathway.

76. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition, and the activator is synthetically produced and has a purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, or 100% (w / w) or higher before being added to the pharmaceutical composition.

77. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition administered simultaneously with at least one additional activator selected from the group consisting of dopamine precursors, dopamine receptor agonists, and combinations thereof.

78. The continuous delivery system according to claim 47, wherein the continuous delivery system comprises a pharmaceutical composition administered simultaneously with at least one additional activator selected from the group consisting of levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, and any combination thereof.