Continuous delivery system comprising cannabinoid and medical use thereof

Abstract

Compositions comprising 0.1 to 50% delta-9-tetrahydrocannabinol and / or cannabidiol, the forms of which are suitable for continuous delivery, and their use in the treatment of various diseases and pathological conditions are disclosed. In a preferred embodiment, the composition is in a form suitable for delivery by a portable infusion pump or transdermal patch. The conditions to be treated include pain, cancer, seizure conditions, and Parkinson's disease. The composition may optionally further comprise an additional active agent, such as a dopaminergic agent, depending on the condition to be treated.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Serial No. 63 / 391,004, filed on July 21, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] The present disclosure provides systems, compositions and methods for treating and / or preventing and / or controlling indications such as pain management, cancer, epileptic seizure disorders and Parkinson's disease using continuous drug delivery. The continuous drug delivery method and system disclosed herein can provide active agents in several different ways, such as by infusion therapy, such as by intradermal or subcutaneous application, or transdermal or topical application. Infusion therapy is by using a sterile capillary such as a catheter inserted into the body and fixed to administer the drug. For this purpose, a pump delivery system and any other delivery system for continuous infusion can be used, such as depot injection and a portable pump. Continuous drug delivery systems and methods can also include, for example, transdermal systems. In transdermal drug delivery, a transdermal patch or transdermal composition is topically applied to the skin surface. In the entire continuous process of topical application of a transdermal patch or transdermal composition, the drug is continuously released and delivered (by transcellular, intercellular and through the attachment pathway) through the intact skin to achieve a systemic effect. Thus, once a transdermal composition or transdermal patch is applied, it may deliver the drug to the systemic circulation throughout the day or even for more than a day, depending on the duration of its application (even up to a week).

[0004] In continuous drug delivery, the active agent is continuously released and delivered to the patient to achieve a systemic effect. Thus, once a continuous drug delivery system is applied, it can deliver the active agent to the systemic circulation throughout the day or even more than one day, depending on the duration of its application (which can even be up to a week).

[0005] By continuous drug delivery, for example, purified tetrahydrocannabinol (THC), cannabidiol (CBD) or a combination thereof can be delivered throughout the continuous process of application. Depending on the needs, the continuous process of application can be once a day, once in two days, once in three days, once in four days, once in five days, once in a week. Therefore, continuous drug delivery can overcome the multiple dose regimen of oral delivery by reducing the frequency of administration.

[0006] In continuous drug delivery, a pharmaceutical composition comprising an active agent is delivered slowly and continuously throughout the duration of administration, so there are no peaks and troughs in the drug plasma concentration of the active agent associated with multiple doses a day (such as oral administration). Thus, through continuous drug delivery of, for example, tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof, a patient can have the therapeutic effect of the drug over an extended period of time without dramatic changes in drug plasma concentration.

[0007] In continuous drug delivery using the systems and methods disclosed herein, the active agent is delivered to the systemic circulation and escapes first-pass liver metabolism, so that less drug is needed to achieve the desired therapeutic activity, resulting in fewer adverse reactions or side effects. Tetrahydrocannabinol (THC) and cannabidiol (CBD) have high lipid solubility and undergo first-pass liver metabolism after oral administration, so only 10%-20% of the administered dose reaches the systemic circulation, so compared to oral doses, continuous drug delivery of small doses of tetrahydrocannabinol (THC), cannabidiol (CBD) or a combination thereof can produce the desired therapeutic effect at a lower dose than oral administration.

[0008] Furthermore, the use of the continuous drug delivery systems and methods disclosed herein is easy, non-invasive, and convenient.Administration of drug compounds via continuous drug administration does not require medical supervision, as the patient can control the administration themselves.

[0009] In certain embodiments, the continuous drug delivery system and method disclosed herein can include a pump device, such as a pump device that is generally used to deliver one or more fluids to a target individual. For example, as part of a medical treatment, a medical infusion pump device can be used to deliver drugs to a patient. The activating agent delivered by the infusion pump device can depend on the patient's condition and the desired treatment plan. For example, the infusion pump device has been used to deliver insulin to the subcutaneous tissue and vascular system of a diabetic patient to regulate blood sugar levels. In some cases, the drug dosage delivered by the infusion pump can be calculated by the infusion pump system. In these cases, when performing this calculation, the infusion pump system can take into account many variables, including user input.

[0010] Other forms of continuous drug delivery systems and methods can utilize fluid delivery to target individuals. For example, a manual syringe or a disposable injection "pen" can be used to inject insulin, glucagon, or another drug. In some cases, when the patient loses consciousness or cannot take glucose orally for other reasons, an injectable form of glucagon is used for emergency assistance for severe hypoglycemia. Glucagon fluid can be quickly injected into the patient's body by intramuscular injection, intravenous injection, or subcutaneous injection, and quickly raises the patient's blood sugar level.

[0011] A class device for delivering this fluid is a pump, which has been developed for the patient suffering from type I and type II diabetes to use insulin and other drugs. Some pumps configured as portable infusion devices can provide continuous medicine for the treatment of diabetes. This therapy can include, for example, insulin is regularly and / or continuously injected or infused into the skin of the person suffering from diabetes, and an alternative to multiple daily injections of insulin by an insulin syringe or an insulin pen is provided. This pump can be a portable / portable infusion pump worn by a user and can use a replaceable cartridge. The example of this pump and the various features related to this pump are included in U.S. Patent Application Serial Number 13 / 557,163, U.S. Patent Application Serial Number 12 / 714,299, U.S. Patent Application Serial Number 12 / 538,018, U.S. Patent Application Serial Number 13 / 838,617, U.S. Patent Application Serial Number 13 / 827,707 and U.S. Patent Application Serial Number 8,287,495, disclosed in those, these patents are each incorporated herein by reference in their entirety.

[0012] 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 small pump that is usually portable and placed directly on the skin under the user's clothing. Such a pump is usually located directly at the injection site, so that no tube is required to deliver insulin or other drugs to the patient. Patch pumps are usually at least partially disposable, meaning that they can be worn for a day or two and then discarded to replace a new patch pump.

[0013] Marijuana is a Schedule I drug in the United States. Cannabis is a flowering plant that contains more than 400 phytonutrients (micronutrients). More than 100 different types of terpenes, essential oils, antioxidants, and cannabinoids have been extracted from this plant. Of all the phytochemicals, only tetrahydrocannabinol (THC) shows significant psychoactive effects. Due to THC's psychoactive and therapeutic effects, many research papers have been published on THC. In addition to THC, several other ingredients have been studied, which also show some therapeutic effects but no psychoactive effects, such as cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabinol (delta-9THC), etc. Cannabis and its derivatives have been shown to be useful for the treatment of pain, type 2-related metabolic disorders, lowering intraocular pressure, Dravet syndrome, Lennox-Gastaut syndrome (LGS), epilepsy, nausea, pain and wasting associated with AIDS, arthritis and rheumatism, migraines, muscle spasms associated with multiple sclerosis and paralysis, alcohol and narcotic withdrawal, stress and depression, asthma, fibromyalgia, inflammatory pain, and pain and / or inflammation associated with chemotherapy, as an antimicrobial agent. FDA-approved Marinol and Syndros contain delta-9-THC and are currently used to treat chemotherapy-related nausea, vomiting, and anorexia. In clinical studies, Sativex (an oromucosal spray containing a cannabinoid extract of THC and CBD) showed improvements in neuropathic pain and sleep quality. In addition, in April 2016, the FDA designated cannabidiol as an orphan drug for the treatment of tuberous sclerosis complex (TSC), Dravet syndrome, and Lennox-Gastaut syndrome. Cannabidiol is an effective oral therapeutic agent for pain and inflammation (Costa, B. The non-psychoactive cannabis constituent cannabidiol is anorally 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).

[0014] About tetrahydrocannabinol (THC), cannabidiol (CBD) or its combination, because can control drug plasma concentration by the speed of controlling drug delivery, therefore expect along with continuous drug delivery, the pharmacological response difference between patients will be smaller.Through continuous drug delivery, a small amount of tetrahydrocannabinol (THC), cannabidiol (CBD) or its combination can be delivered longer than oral administration.The continuous pharmaceutical preparation of tetrahydrocannabinol (THC), cannabidiol (CBD) or its combination can also provide more abuse deterrent than quick-release dosage form.

[0015] Furthermore, continuous drug delivery gives the freedom to terminate the therapy at any time by removing the continuous drug delivery system in case of any adverse reaction, side effect or emergency.

[0016] There is a need for an improved CBD and / or THC drug delivery system that overcomes the disadvantages associated with the oral route. For example, CBD and / or THC alone, free bases thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof, co-crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms thereof, active metabolites thereof, solid solutions thereof, polymorphs thereof, stereoisomers thereof, coated forms thereof, ion pairs thereof, solutions thereof in solvents, or combinations thereof can address challenges associated with oral drug delivery and can be used to treat, prevent and / or control indications such as pain management, cancer, seizure disorders, Parkinson's disease, symptoms associated with PD, and other indications.

[0017] All references cited herein are hereby incorporated by reference in their entirety. Summary of the invention

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

[0019] The present disclosure provides a method for treating, preventing and / or slowing down the onset or progress of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system provides continuous, continuous delivery of a pharmaceutical composition to the patient through a portable / portable infusion pump worn by the patient and that can use a replaceable cartridge. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progress of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system provides continuous, continuous delivery of a pharmaceutical composition to the patient through a patch pump or a micropump. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progress of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system includes a pharmaceutical composition selected from a group consisting of a liquid preparation, a solid preparation, a semisolid preparation, an emulsion preparation, a nanoparticle preparation, a matrix preparation, a film preparation, a patch preparation, a preparation in an infusion pump, and / or a combination thereof. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or associated symptoms, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of a transdermal liquid preparation, a transdermal semisolid preparation, a transdermal gel preparation or a transdermal polymer matrix preparation, a transdermal adhesive matrix preparation, a transdermal film-forming gel, a transdermal film-forming spray preparation, a multilayer transdermal matrix system, a transdermal drug-containing adhesive matrix preparation (transdermal drug-in-adhesive matrix formulation) and a combination thereof. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or associated symptoms, wherein the continuous delivery system includes a pharmaceutical composition formulated into a topical liquid preparation, a topical semisolid preparation, a topical gel preparation, a topical polymer matrix preparation, a topical adhesive matrix preparation, a topical film-forming gel preparation or a topical film-forming spray preparation.

[0020] The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch, wherein the transdermal patch is selected from the group consisting of a reservoir patch, a multilayer transdermal matrix system, a micro-reservoir patch, a matrix patch, a drug-containing adhesive patch, an adhesive matrix patch combined with a polymer, a pressure-sensitive adhesive patch, a delayed-release transdermal film, a liquid reservoir system, a micro-reservoir patch, a mucoadhesive patch, and a combination thereof. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch, wherein the topical patch is selected from the group consisting of a multilayer transdermal matrix system, a reservoir patch, a micro-reservoir patch, a matrix patch, a drug-containing adhesive patch, a pressure-sensitive adhesive patch, a delayed-release transdermal film, a liquid reservoir system, a micro-reservoir patch, a mucoadhesive patch, a microdose patch, an adhesive matrix patch combined with a polymer, and a combination thereof. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progress of a patient's disease or the patient's condition and / or associated symptoms, wherein the continuous delivery system includes the pharmaceutical composition configured as a transdermal patch. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progress of a patient's disease or the patient's condition and / or associated symptoms, wherein the continuous delivery system includes the pharmaceutical composition configured 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. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progress of a patient's disease or the patient's condition and / or associated symptoms, wherein the continuous delivery system includes the pharmaceutical composition configured as a topical patch.

[0021] The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system includes a pharmaceutical composition formulated as a quantitative gel, a quantitative spray, a gel, a cream, a solution, an emulsion, a liquid composition, a semisolid composition, an adhesive matrix or a film-forming preparation combined with a polymer. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system includes a pharmaceutical composition, and the pharmaceutical composition further includes an effective amount of a carrier or component, and the carrier or component is 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 reducing agent, a buffer, a pH stabilizer, a tackifier, a diluent, a filler, a solubilizer, a suspending agent, a dispersant, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidant, and a combination thereof.

[0022] The present disclosure provides a method for treating, preventing and / or slowing 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 in the range of 0.1%-99.5% w / w or w / v, the carrier or ingredient being selected from the group consisting of solvents, gelling agents, polymers, pressure-sensitive adhesive polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, viscosity increasing agents, diluents, fillers, surfactants, antioxidants, oxidants, and combinations thereof. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system includes a pharmaceutical composition formulated into a transdermal preparation, which can be applied in a dosage regimen selected from the group consisting of: once a day, twice a day, three times a day, once every 1-8 hours, once every 1-24 hours, once every 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 days to about 30 days. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system includes a pharmaceutical composition formulated into a topical preparation, which can be applied 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 1-8 hours, once every 1-24 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 days to about 30 days. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to the patient via a microneedle. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a patient's disease or condition and / or related symptoms, 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 method for treating, preventing and / or slowing 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 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 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.

[0023] The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a disease or condition and / or related symptoms in a patient, wherein the continuous delivery system comprises 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 preparation. The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a disease or condition and / or related symptoms in a patient, wherein the continuous delivery system comprises a pharmaceutical composition, wherein THC is selected from a group comprising a single free base, a salt thereof, an isomer thereof, an amorphous form thereof, a crystalline form thereof, a co-crystal 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, or a combination thereof. The present disclosure provides a method for treating, preventing and / or slowing 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 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 naturally occurring 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, or a combination thereof.

[0024] The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or related 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), free bases thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof, co-crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms thereof, naturally occurring forms thereof, active metabolites thereof, polymorphs thereof, solid solutions thereof, coated forms thereof, and combinations thereof, which are in a dosage form for transdermal delivery. The present disclosure provides a method for treating, preventing and / or slowing 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 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 a synthetic pathway. The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system comprises a pharmaceutical composition, wherein the active agent is synthetically produced and, prior to being added to the pharmaceutical composition, has a purity equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w). The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a patient's disease or condition and / or related symptoms, wherein the continuous delivery system comprises a pharmaceutical composition co-administered with at least one additional active agent, the additional active agent being selected from the group consisting of a dopamine precursor, a dopamine receptor agonist, and a combination thereof. The present disclosure provides a method for treating, preventing and / or slowing 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 levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinorole, apomorphine, and any combination thereof.

[0025] The present disclosure provides a method of treating, preventing and / or slowing 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 are selected from the group consisting of cancer, pain, a seizure disorder, Parkinson's disease ("PD") and PD symptoms. The present disclosure provides a method of treating, preventing and / or slowing 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 region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, GBM and blood cancers such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma / primary mediastinal B-cell lymphoma and chronic myeloid leukemia. The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a patient's disease or condition and / or related symptoms, wherein the cancer is glioblastoma, GBM. The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a patient's disease or condition and / or related symptoms, wherein the pharmaceutical composition is co-administered with at least one additional therapeutic agent, the therapeutic agent being selected from the group consisting of: temozolomide, peptides, polypeptides, fusion proteins, nucleic acid molecules, small molecules, mimetics, synthetic drugs, inorganic molecules, organic molecules, chemotherapy, radiotherapy, hormone therapy, anti-angiogenic therapy, targeted therapy and / or biological therapy, including immunotherapy and surgery, and combinations thereof. The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or associated symptoms in a patient, 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 spasm, pain due to increased muscle tone, osteoarthritis 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 a method of treating, preventing and / or slowing 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 absences, 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 other specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex (TSC), refractory epilepsy, refractory 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 a method of treating, preventing and / or slowing 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 secondary to generalization, generalized seizures (including absences, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures and febrile seizures, as well as other specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex (TSC), refractory epilepsy, refractory 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 a method for treating, preventing and / or slowing down the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed down is selected from the group consisting of: (a) at least one non-motor aspect of daily life experience as defined by the first part of the Unified Parkinson's Disease Rating Scale, which is selected from the group consisting of cognitive impairment, hallucinations and confusion, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urinary problems, constipation problems, dizziness on standing and fatigue; (b) at least one non-motor aspect of daily life experience as defined by the second part of the Unified Parkinson's Disease Rating Scale, which is selected from the group consisting of cognitive impairment, hallucinations and confusion, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urinary problems, constipation problems, dizziness on standing and fatigue; (c) at least one motor symptom identified on the Unified Parkinson's Disease Rating Scale, Part III, selected from the group consisting of speech, facial expression, rigidity, finger tapping, hand movement, pronation-supination of the hand, toe tapping, leg flexibility, rising from a chair, gait, freezing of gait, postural stability, posture, bradykinesia, postural tremor of the hand, kinetic tremor of the hand, resting tremor amplitude, and constancy of resting tremor; (d) at least one motor complication identified on the Unified Parkinson's Disease Rating Scale, Part IV, selected from the group consisting of time spent with the movement disorder, functional impact of the movement disorder, time spent in an off state, and duration of resting tremor. (e) constipation; (f) depression; (g) cognitive impairment; (h) short-term or long-term memory impairment; (i) concentration impairment; (j) coordination impairment; (k) movement impairment; (l) speech impairment; (m) confusion; (n) sleep problems, sleep disorders, or sleep disturbances; (o) circadian rhythm dysfunction; (p) hallucinations; (q) fatigue; (r) REM disrupted sleep; (s) REM behavior disorder; (t) erectile dysfunction; (u) postural hypotension; (v) correction of blood pressure or orthostatic hypotension; (w) nocturnal hypertension; (x) temperature regulation; (y) improvement in breathing or apnea; (z) correction of cardiac conduction defects; (aa) pain relief; (bb) restoration of urinary incontinence or bladder sensation and urination; (cc) mood swings; (dd) apathy; (ee) control of nocturia; (ff) neurodegeneration; (gg) anxiety; (hh) improved conversational ability, including the ability to speak in public; and / or (ii) Parkinson's disease dementia.

[0026] The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a disease or condition and / or related symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed down is a sleep problem, a sleep disorder, a sleep disturbance, a circadian rhythm dysfunction, REM disturbed sleep or a REM behavior disorder, and wherein: (a) the sleep disorder or sleep disturbance includes delayed sleep onset, sleep fragmentation, REM behavior disorder, sleep-disordered breathing (including snoring and apnea), daytime sleepiness, microsleep attacks, narcolepsy, hallucinations or any thereof; and / or (b) REM behavior disorder including vivid dreams, nightmares, and acting out dreams during sleep by talking or screaming, or fidgeting or shaking arms or legs; and / or (c) treating sleep problems, sleep disorders, sleep disturbances to prevent or delay 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 determined period of time; and / or (e) the method results in a positive change in the subject's sleep pattern over a determined period of time, wherein the positive change is defined as: ( (i) an increase in the total amount of sleep obtained 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%, and about 100%; and / or (ii) a decrease in the number of nighttime awakenings by a percentage 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%. , about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100%; and / or (f) as a result of the method, the subject obtains the total number of hours of sleep recommended by medical authorities for the subject's age group; and / or (g) wherein each determined time 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 about greater than 12 months.

[0027] The present disclosure provides a method for treating, preventing and / or slowing down the onset or progression of a disease or condition and / or related symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed down is hallucination, and wherein: (a) the hallucinations include visual, auditory, tactile, taste or olfactory hallucinations; and / or (b) treating hallucinations to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (c) the method results in a reduction in the number of hallucinations in a subject over a determined period of time; and / or (d) the method results in a reduction in the number of hallucinations in a subject over a determined period of time, and the reduction in the number of hallucinations is selected from about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, about 500%, about 500%, about 500%, about 500%, about 500%, about 500%, about 500%, 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 results in the absence of hallucinations in the subject; and / or (f) the method results in a decrease in the severity of hallucinations in the subject over a determined time period as measured by one or more medically accepted techniques; and / or (g) the method results in a decrease in the severity of hallucinations in the subject over a determined time period as measured by one or more medically accepted techniques, and the reduction in severity 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 (h) the medically accepted technique is selected from the group consisting of the Chicago Hallucination Assessment Tool (CHAT), the Psychotic Symptom Rating Scale (PSYRATS), the Auditory Hallucination Rating Scale (AHRS), the Hamilton Schizophrenia Voice Questionnaire (HPSVQ), the Auditory Hallucination Characteristics Questionnaire (CAHQ), Mental Health Institute Abnormal Perception Scale (MUPS), Positive and Negative Syndrome Scale (PANSS), Positive Symptom Assessment Scale (SAPS), Launay-Slade Hallucination Scale (LSHS), Cardiff Abnormal Perception Scale (CAPS) and Structured Interview for Assessing Perceptual Abnormalities (SIAPA); and / or (i) each determined time 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 about greater than 12 months.

[0028] The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed is depression, and wherein: (a) depression is treated to prevent and / or delay 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 determined 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 determined period of time as measured by one or more clinically recognized depression rating scales, and the improvement is selected from mood, behavior, physical function (such as eating, sleeping, energy and sexual activity) and / or sadness or 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 subject experiences an improvement 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% after treatment; and / or (e) wherein each determined time 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 about greater than 12 months.The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed is cognitive impairment, and wherein: (a) cognitive impairment is treated to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (b) the progression or onset of cognitive impairment is slowed, stopped or reversed within a determined time period after administration of the pharmaceutical composition as measured by medically recognized techniques; and / or (c) cognitive impairment is positively affected by administration of the pharmaceutical composition as measured by medically recognized techniques; and / or (d) cognitive impairment is positively affected by administration of the pharmaceutical composition as measured by medically recognized techniques, and the positive effect on cognitive decline and / or the progression of cognitive decline is measured by one or more selected from the group consisting of the Mini-Mental State Examination (MMSE), the Mini Cognitive Test and the Cantab or (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 techniques; and / or (f) each determined time 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 about greater than 12 months.

[0029] The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed is constipation, and wherein: (a) constipation is treated to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (b) administration of the pharmaceutical composition causes bowel movements in the subject; and / or (c) the method results in an increase in the frequency of bowel movements in the subject over a determined period of time; and / or (d) the method results in an increase in the frequency of bowel movements in the subject, and the increase in bowel movement frequency is defined as: (i) an increase in the number of bowel movements per week by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 46%, about 47%, about 48%, about 50%, about 51%, about 52%, about 53%, about 54%, 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 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 100%, about 100%, about 0%, 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 (ii) the amount of time between each consecutive bowel movement is reduced by a percentage 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 frequency of bowel movements recommended by medical authorities for the subject's age group.

[0030] The present disclosure provides a method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or associated symptoms in a patient, wherein the PD symptom to be treated, prevented and / or slowed is neurodegeneration associated with PD, and wherein: (a) neurodegeneration is treated to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (b) the method results in treating, preventing and / or delaying the progression and / or onset of neurodegeneration in a subject; and / or (c) the progression or onset of neurodegeneration is slowed, stopped or reversed within a determined time period after administration of the pharmaceutical composition as measured by medically accepted techniques; and / or (d) neurodegeneration is positively affected by administration of the pharmaceutical composition as measured by medically accepted techniques; and / or (e) the neurodegeneration is positively affected by administration of the pharmaceutical composition as measured by one or more selected from electroencephalogram (EEG), neuroimaging, functional MRI, structural MRI, diffusion tensor imaging (DTI), [18F]fluorodeoxyglucose (FDG) PET, labeled amyloid (f) the progression or onset of neurodegeneration is slowed, halted, or reversed by about 5%, about 10%, about 15%, about 20%, about 25%, or about 30%, as measured by medically accepted techniques. , 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 (g) each determined time 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 about greater than 12 months.

[0031] The present disclosure provides a continuous delivery system comprising a pharmaceutical composition, the pharmaceutical composition comprising at least one active agent, the active agent selected from the group consisting of: about 0.1% to about 50% of an active agent 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; about 0.1% to about 50% of an active agent 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 active agent, and combinations thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to mitigate the peak and trough behavior of the pharmacokinetics of the active agent. The present disclosure provides a continuous delivery system, wherein the continuous delivery system is administered 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, providing continuous, sustained delivery of a pharmaceutical composition. The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition by intravenous or subcutaneous infusion. The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition by subcutaneous infusion. The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition by an infusion pump device.

[0032] The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides continuous and sustained delivery of a pharmaceutical composition by a portable / portable infusion pump worn by a patient and that can use a replaceable cartridge. The present disclosure provides a continuous delivery system, wherein the continuous delivery system provides continuous and sustained delivery of a pharmaceutical composition by a patch pump or a micropump. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of a liquid preparation, a solid preparation, a semi-solid preparation, an emulsion preparation, a nanoparticle preparation, a matrix preparation, a film preparation, a patch preparation, a preparation in an infusion pump and / or a combination thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition selected from the group consisting of a transdermal liquid preparation, a transdermal semi-solid preparation, a transdermal gel preparation or a transdermal polymer matrix preparation, a transdermal adhesive matrix preparation, a transdermal film-forming gel, a transdermal film-forming spray preparation, a multilayer transdermal matrix system, a transdermal drug-containing adhesive matrix preparation and a combination thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition formulated into a local liquid preparation, a local semisolid preparation, a local gel preparation, a local polymer matrix preparation, a local adhesive matrix preparation, a local film-forming gel preparation or a local film-forming spray preparation. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition formulated into a transdermal patch, wherein the transdermal patch is selected from the group such as a reservoir patch, a multilayer transdermal matrix system, a micro-reservoir patch, a matrix patch, a drug-containing adhesive patch, an adhesive matrix patch combined with a polymer, a pressure-sensitive adhesive patch, a time-delayed release transdermal film, a liquid storage system, a micro-reservoir patch, a mucoadhesive patch and a combination thereof. The present disclosure provides a kind of continuous delivery system, wherein the continuous delivery system comprises the pharmaceutical composition being formulated into a topical patch, wherein the topical patch is selected from the group of a multilayer transdermal matrix system, a reservoir patch, a micro-reservoir patch, a matrix patch, a drug-containing adhesive patch, a pressure-sensitive adhesive patch, a time-delayed release transdermal film, a liquid storage system, a micro-reservoir patch, a mucoadhesive patch, a microdose patch, an adhesive matrix patch combined with a polymer, and a combination thereof. The present disclosure provides a kind of continuous delivery system, wherein the continuous delivery system comprises the pharmaceutical composition being formulated into a transdermal patch. The present disclosure provides a kind of continuous delivery system, wherein the continuous delivery system comprises the pharmaceutical composition being formulated into 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. The present disclosure provides a kind of continuous delivery system, wherein the continuous delivery system comprises the pharmaceutical composition being formulated into a topical patch.

[0033] The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition formulated into a quantitative gel, a quantitative spray, a gel, a cream, a solution, an emulsion, a liquid composition, a semi-solid composition, an adhesive matrix combined with a polymer, or a film-forming preparation. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition, and the pharmaceutical composition further includes an effective amount of a carrier or component, and the carrier or component is 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 reducing agent, a buffer, a pH stabilizer, a tackifier, a diluent, a filler, a solubilizer, a suspending agent, a dispersant, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidant, and a combination thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition, the pharmaceutical composition further comprising an effective amount of a carrier or ingredient in the range of 0.1%-99.5% w / w or w / v, the carrier or ingredient being selected from the group consisting of solvents, gelling agents, polymers, pressure-sensitive adhesive polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, viscosity increasing agents, diluents, fillers, surfactants, antioxidants, oxidants, and combinations thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition formulated into a transdermal preparation, the transdermal preparation can be applied in a dosage regimen selected from the group consisting of: once a day, twice a day, three times a day, once every 1-8 hours, once every 1-24 hours, once every 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. The present disclosure provides a continuous delivery system, wherein the continuous delivery system comprises a pharmaceutical composition formulated into a topical preparation, which can be applied 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 1-8 hours, once every 1-24 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. The present disclosure provides a continuous delivery system, wherein the continuous delivery system comprises a pharmaceutical composition formulated into microneedles.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, wherein the continuous delivery system includes 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 preparation. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes 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%, and about 1% to about 5% of the preparation.

[0034] The present disclosure provides a continuous delivery system, wherein the continuous delivery system comprises a pharmaceutical composition, wherein THC is selected from the group comprising 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 naturally occurring 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, or a combination thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system comprises a pharmaceutical composition, wherein CBD is selected from the group comprising 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 naturally occurring 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, or a combination thereof. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition, the pharmaceutical composition includes one or more active agents selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), 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 naturally occurring form, its active metabolite, its polymorph, its solid solution, its coated form, and its combination, which is a dosage form for transdermal delivery. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition, wherein the 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 its combination are produced by a synthetic route. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition, wherein the active agent is synthetically produced and has a purity equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w) before being added to the pharmaceutical composition. The present disclosure provides a continuous delivery system, wherein the continuous delivery system includes a pharmaceutical composition co-administered with at least one additional active agent, the additional active agent being selected from the group consisting of a dopamine precursor, a dopamine receptor agonist, and a combination thereof.The present disclosure provides a continuous delivery system, wherein the 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, ropinorole, apomorphine, and any combination thereof.

[0035] The present disclosure provides use of the composition of the present disclosure in the manufacture of a medicament for preventing and / or treating the indications described herein.

[0036] According to another embodiment, the present disclosure provides for use of the above-described pharmaceutical composition in an amount effective for use in medicine, most preferably for use as a medicament for treating a disease or condition, such as described herein, in a subject.

[0037] According to another embodiment, the present disclosure provides for use of the above-described pharmaceutical composition and at least one additional therapeutic agent in an amount effective for use in medicine, most preferably for use as a medicament for treating a disease or a condition associated with the disease, e.g., as described herein, in a subject.

[0038] The present disclosure provides a method for treating and / or preventing a disease or condition described herein in a patient, wherein the method comprises: selecting a patient in need of treatment and / or prevention of a disease or condition described herein; administering a therapeutically effective amount of a composition of the present disclosure to the patient, thereby treating and / or preventing the disease in the patient. DETAILED DESCRIPTION

[0039] As used herein, the term "active pharmaceutical ingredient" ("API") or "pharmaceutically active agent" is a drug or medicament that can be used as disclosed herein and is intended for use in the human or animal body in order to cure, alleviate, prevent or diagnose a disease, discomfort, physical injury or pathological symptoms; to allow a state, condition or function of the body or mental state to be recognized; to replace active substances produced by the human or animal body or body fluids; to defend against, eliminate or render harmless pathogens, parasites or foreign substances, or to affect a state, condition or function of the body or mental state. The drugs in use can be found in reference books, for example, RoteListe or Merck Index. Examples that may be mentioned include, for example, tretinoin.

[0040] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the therapeutic compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of the active agent. Pharmaceutically acceptable salts include conventional non-toxic salts, such as salts 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, aminosulfonic acid, phosphoric acid, nitric acid, and the like; and salts prepared from 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and other salts known to those of ordinary skill in pharmaceutical science. Lists of suitable salts can be found in textbooks such as Remington's Pharmaceutical Sciences, 18th edition (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990); Remington: the Science and Practice of Pharmacy 19th edition (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd edition (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12th edition (Walter Lund, ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee, ed.). E. Limbird, ed.; McGraw Hill, 1992), the disclosure of which is incorporated herein by reference.

[0041] As used herein, an amount is "effective" when it provides an effect in a subject. As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to significantly induce a positive benefit, including the benefits disclosed herein alone or in combination, but low enough to avoid serious side effects, i.e., to provide a reasonable benefit to risk ratio within the reasonable judgment of a skilled person. For those skilled in the art, the effective amount, as well as the dosage and frequency of administration, can be determined according to their knowledge and standard methods based on only routine experiments of the present disclosure.

[0042] 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., cattle, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkeys and humans), most preferably humans. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, pig or cattle) or a pet (e.g., a dog or cat). In a specific embodiment, the subject is an elderly human. In another embodiment, the subject is an adult human. In another embodiment, the subject is a human child. In yet another embodiment, the subject is a human toddler.

[0043] As used herein, the phrase "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0044] As used herein, the terms "prevent" and "preventing" in the context of administering a therapy to a subject refers to preventing or inhibiting the recurrence, onset and / or development of a disease or condition, or a combination of therapies (e.g., a combination of prophylactic or therapeutic agents).

[0045] As used herein, the term "therapy" may refer to any method, composition, and / or agent that can be used to prevent, treat, and / or manage a disease or condition, or one or more symptoms thereof.

[0046] As used herein, the term "treat," ...

[0047] As used herein, the terms "continuous delivery," "continuously administering," or "continuous administration" refer to substantially uninterrupted administration of a drug or medicament to a subject. Administration is non-stop (uninterrupted) except when it is necessary to refill the drug or drug supply or the next dose in the administration regimen. "Continuous delivery" refers to the uninterrupted administration of a drug or medicament, and the administration rate or absorption rate may fluctuate within the dosing interval.

[0048] As used herein, the term "multiparticulate" refers to one or more unit dosage systems, such as, but not limited to, pellets, beads, spheres, tablets, seeds, spheroids or granules with a modified drug release profile. Multiparticulates include a film or matrix, such as a polymer film or matrix, that controls the release of the drug and / or protects the drug, and whose integrity or efficiency is susceptible to certain conditions, such as heat or mechanical forces that may occur during post-processing. The expression "core material" describes the characteristics of the interior of the multiparticulate, which may also include a functional coating. Exemplary "core materials" can be pellets (spherical matrix systems containing drugs and further excipients), granules (smaller spherical particles consisting almost entirely of drugs) or colored sugar beads (nonpareils) (spherical particles that do not contain drugs).

[0049] As used herein, the term "about" when used in conjunction with a stated value or range has the meaning reasonably given to it by one skilled in the art, ie, means slightly more or less than the stated value or range.

[0050] Active Agent

[0051] The term "active agent" or "active ingredient" refers to an agent, active ingredient compound or other substance, or a combination thereof, that provides some pharmacological (usually beneficial) effect. Reference to a specific active ingredient should include the active ingredient and its pharmaceutically acceptable salts, as appropriate. The present disclosure provides, for example, continuous drug delivery systems and methods comprising one or more of the following active agents (e.g., tetrahydrocannabinol (THC), cannabidiol (CBD), and combinations thereof).

[0052] The term "active agent" or "active ingredient" refers to an agent, active ingredient compound or other substance, or a combination and mixture thereof that provides some pharmacological (usually beneficial) effect. When referring to a specific active ingredient, the active ingredient and its pharmaceutically acceptable salts should be included as appropriate. The present disclosure provides, for example, a continuous drug delivery system and method comprising one or more of the following active agents: Cannabinoids are a group of 21-carbon terpene phenolic compounds produced by the cannabis species. Cannabinoids can also be produced synthetically. The term "cannabinoid" refers hereinafter to a class of different compounds that act on cannabinoid receptors on cells to inhibit the release of neurotransmitters 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 of plant origin; and synthetic cannabinoids. This type of cannabinoid is usually divided into the following subcategories: cannabigerol (CBG); cannabichromene (CBC); cannabidiol (CBD; CBDL); tetrahydrocannabinol (THC); cannabinol (CBN); cannabicyclol (CBL); cannabielsoin (CBE); and cannabitriol (CBT).

[0053] 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

[0054] The chemical structure is shown in the following formula I

[0055]

[0056] Tetrahydrocannabinol (THC) IUPAC name (-)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol Chemical formula: C 21 H 30 O2 molecular weight: 314.47 Daltons chemical structure is shown in the following formula II

[0057]

[0058] As used herein, the term cannabis refers to all pharmaceutically acceptable forms of cannabis and its derivatives, alone or in combination, for example in the following forms, but not limited to, such as free base or salt or isomer or amorphous or crystalline or co-crystal or solid solution or prodrug or analog or derivative or metabolite or polymorph or stereoisomer or coated form or ion pair. For example, the free base of cannabidiol or its salt or isomer or amorphous form or crystalline form or co-crystal form or solid solution or prodrug or analog or derivative or synthetic form or polymorph or stereoisomer or ion pair. The compound can be in the form of a pharmaceutically acceptable salt, such as 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 being hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, phosphates, hydrogenphosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, succinates, saccharides, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and pamoates. Suitable base salts are formed from bases which form non-toxic salts, examples being sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts.

[0059] As used herein, the term "cannabidiol" 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, its biosynthetic form, its active metabolite, its solid solution, its polymorph, its stereoisomer, its powder form, its liquid form, its ion pair, a solution of cannabidiol in a solvent (such as but not limited to methanol), etc., alone or in combination.

[0060] As used herein, the term "THC" 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, its biosynthetic form, its active metabolite, its solid solution, its powder form, its liquid form, its ion pair, its polymorph, its stereoisomer, a solution of THC in a solvent (such as but not limited to methanol, heptane), etc., alone or in combination.

[0061] As used herein, synthetic cannabinoids include at least the following substances: AM-087 is an analgesic drug, which is a cannabinoid agonist derivative of Δ8THC substituted on the 3-side chain and a potent CB1 agonist; AM-251 is an inverse agonist of the CB1 cannabinoid receptor, and has close structural similarity to SR141716A (rimonabant), both of which are biarylpyrazole cannabinoid receptor antagonists and μ-opioid receptor antagonists; Methanandamide (AM-356) is a stable chiral analog of anandamide, which acts on cannabinoid receptors, with a Ki of 17.9nM at CB1 and 868nM at CB2; AM-374—palmitoylsulfonyl AM-404, also known as N-arachidonoylaminophenol, is an active metabolite of paracetamol (acetaminophen) and is thought to induce its analgesic effects through its activity on the endocannabinoid, COX, and TRPV systems, all of which are present in pain and temperature regulation pathways; AM-411 is an analgesic, which is a cannabinoid agonist; AM-411 is a potent and fairly selective CB1 full agonist and produces effects similar to other cannabinoid agonists, such as analgesia, sedation, and anxiolysis; AM-630 (6-lodopravadoline) is a cannabinoid AM-661—1-(N-methyl-2-piperidinyl)methyl-2-methyl-3-(2-iodo)benzoyl indole; JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM-678 is an analgesic chemical from the naphthoyl indole 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 the cannabinoid receptor CB1; AM-735—3 -Bornyl-Δ8-THC, a mixed CB1 / CB2 agonist; AM-855 is an analgesic cannabinoid agonist for CB1 and CB2, with moderate selectivity for CB1; AM-881—a chlorine-substituted anandamide stereoisomer with a Ki of 5.3 nM at CB1 and 95 nM at CB2; AM-883 is an allyl-substituted anandamide stereoisomer with a Ki of 9.9 nM at CB1 and 226 nM at CB2; AM-905 is an analgesic cannabinoid that acts as a potent and moderately selective agonist of the CB1 cannabinoid receptor; AM-906 is an analgesic drug that is a cannabinoid agonist and is a potent and selective agonist of the CB1 cannabinoid receptor;AM-919 is an analgesic cannabinoid receptor agonist that is potent for both CB1 and CB2; AM-926 is a potent agonist for both CB1 and CB2 with moderate selectivity for CB1; AM-938 is an analgesic that is a cannabinoid receptor agonist that is moderately selective for CB2, although it is still a potent agonist for both CB1 and CB2; AM-1116 is a dimethylated stereoisomer of anandamide; AM-1172 is an endocannabinoid analog that was specifically designed as a potent and selective inhibitor of AEA uptake, which is resistant to F AAH hydrolysis; AM-1220 is a potent and moderately selective agonist of the cannabinoid receptor CB1; AM-1221 is a potent and selective agonist of the cannabinoid receptor CB2; AM-1235 (1-(5-fluoropentyl)-3-(naphthalene-1-yl)-6-nitroindole) is a potent and moderately selective agonist of the cannabinoid receptor CB1; AM-1241 (1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole) is a potent and selective agonist of the cannabinoid receptor CB2, with analgesic effects in mammals The drug is used for the treatment of atypical pain, 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 is a moderately potent agonist of cannabinoid receptors CB1 and CB2; AM-1710 is a CB2-selective cannabidiolide with 54-fold selectivity over CB1; AM-1714 is a moderately selective agonist of the peripheral cannabinoid receptor CB2 with analgesic and antiallodynic effects; AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole) is a A potent but non-selective full agonist of cannabinoid receptors; AM-2212 - a potent agonist of CB1 and CB2; AM-2213 - a potent agonist of CB1 and CB2; AM-2232 (1-(4-cyanobutyl)-3-(naphthalene-1-yl)indole) acts as a potent but non-selective agonist of cannabinoid receptors CB1 and CB2; AM-2233 acts as a highly potent full agonist of cannabinoid receptors CB1 and CB2 and has been found in certain mammalian studies to fully replace THC with a potency lower than that of JWH-018 but higher than that of WIN 55,212-2; AM-2389 as a potent and moderately selective agonist of the CB1 receptor; AM-3102—oleoylethanolamide analog (endogenous agonist of proliferator-activated receptor α (PPARα)), as a weak cannabinoid agonist of CB1 and CB2; AM-4030 is an analgesic that is a potent agonist of CB1 and CB2 but also moderately selective for CB1; AM-4054 ​​is a potent but slow-acting agonist with CB1 affinity and CB1 selectivity over CB2; AM-4113—a CB1-selective neutral antagonist;AM-6545 is a peripherally selective silent antagonist of CB1, developed for the treatment of obesity; JWH-007 is an analgesic, as a cannabinoid agonist at the CB1 receptor and CB2 receptor, with some selectivity for CB2, JWH-007 is an analgesic, as a cannabinoid agonist at the CB1 receptor and CB2 receptor; JWH-015 is a subtype selective cannabinoid agonist, which binds to CB2 almost 28 times more strongly than CB1 and has been shown to have immunomodulatory effects and can be used to treat and / or prevent and / or control cancers such as glioblastoma, GBM; JWH-018 is an analgesic, as a full agonist at the CB1 and CB2 cannabinoid receptors, producing effects similar to THC; JWH-019 —CB1 and CB2 receptor agonist, an analgesic from the naphthoyl indole family, it acts as a cannabinoid agonist at CB1 and CB2 receptors; JWH-030 — an analgesic, it 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 is a more potent agonist for CB2, JWH-057 — a 1-deoxy analog of Δ8-THC, it has a very high affinity for the CB2 receptor, but also has a high affinity for the CB1 receptor; JWH-073 — an analgesic, acts as a cannabinoid agonist at the CB1 and CB2 receptors. It is slightly selective for the CB1 subtype; JWH-081—analgesic, acts as an agonist at both the cannabinoid CB1 and CB2 receptors; JWH-098—a potent and fairly selective CB2 agonist; JWH-116—a CB1 ligand; JWH-120—a potent and 173-fold selective CB2 agonist; JWH-122—a potent and fairly selective CB1 agonist; JWH-133—a potent and highly selective CB2 receptor agonist; 1JWH-139—3-(1,1-dimethylpropyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene; JWH-147—analgesic from the naphthoylpyrrole family, which acts as a CB1 and C Cannabinoid agonist for B2 receptors; JWH-148—moderately selective ligand for CB2 receptors, with selectivity more than 8 times that of the CB1 subtype; JWH-149—potent and fairly 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—analgesic, as a cannabinoid receptor agonist; JWH-175—(1-pentylindol-3-yl)naphthalen-1-ylmethane, 22 nM at CB1, JWH-176—1-([(1E)-3-pentylindole-1-ylidene)methyl)naphthalene;JWH-181—potent cannabinoid agonist; JWH-164—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-methylnaphth-1-ylmethane; JWH-193—(1-(2-morpholin-4-ylethyl)indol-3-yl)-4-methylnaphth-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-naphthylmethyl)-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 as a cannabinoid receptor agonist; JWH-203—from An analgesic from the phenylacetylindole family, acting as a cannabinoid agonist with approximately equal affinity for CB1 and CB2 receptors; JWH-205—1,4-(2-methyl-1-pentylindol-3-yl)-2-phenylethanone; JWH-210—an analgesic chemical from the naphthoylindole family, acting as a potent cannabinoid agonist for both CB1 and CB2 receptors; JWH-213—a potent and fairly selective CB2 agonist; JWH-229—1-methoxy-3-(1′,1′-dimethylhexyl)-Δ8-THC, a dibenzopyran cannabinoid, which is a potent CB2 agonist; JWH-234—a cannabinoid agonist, selective for CB2; JWH-250—an analgesic from the phenylacetylindole family , as a cannabinoid agonist for CB1 and CB2 receptors; JWH-251—(1-pentyl-3-(2-methylphenylacetyl)indole); JWH-258—a potent and moderately selective CB1 agonist; JWH-302—(1-pentyl-3-(3-methoxyphenylacetyl)indole); JWH-307—an analgesic from the naphthoylpyrrole family, as a cannabinoid agonist for CB1 and CB2 receptors, with slight selectivity for the CB2 subtype; JWH-350—11-nor-1-methoxy-3-(1′,1′-dimethylheptyl)-9α-hydroxyhexahydrocannabinol, with 33-fold selectivity for CB2 receptors, high affinity for CB2 receptors, and almost no affinity for CB1 receptors;JWH-359 — dibenzopyran cannabinoid, which is a potent and selective CB2 receptor agonist; JWH-387 — 1-pentyl-3-(4-bromo-1-naphthoyl)indole, an analgesic from the naphthoyl indole family, acts as a potent cannabinoid agonist at both CB1 and CB2 receptors; JWH-398 — an analgesic chemical from the naphthoyl indole family, acts as a potent cannabinoid agonist at both receptors, with a Ki of 2.3nM at CB1 and 2.8nM at CB2; JWH-424 — a potent and moderately selective CB2 agonist, with a Ki of 5.44nM at CB2 and 20.9nM at CB1; HU-210 is a cannabinoid that is 100 to 800 times more potent than natural THC from cannabis, has a long duration of action, is a potent analgesic, and has many of the same effects as natural THC; Ajulemic Acid (AB-III-56, HU-239, IP-751, CPL7075, CT-3, Resunab) is a cannabinoid derivative of the non-psychoactive THC metabolite 11-nor-9-carboxy-THC, which has useful analgesic and anti-inflammatory effects without causing subjective "highs". It is being developed for the treatment of neuropathic pain and inflammatory conditions such as arthritis, as well as for the treatment of life-threatening orphan inflammatory diseases; HU-243 (AM-4056) is a cannabinoid that is a potent agonist of CB1 and CB2 receptors; HU-308, as a cannabinoid agonist, is highly selective for the CB2 receptor subtype. It has analgesic effects, promotes neural stem cell proliferation, and protects liver and vascular tissue from oxidative stress by inhibiting tumor TNF-α; HU-331 is a quinone anticancer drug synthesized from cannabidiol; HU-336 is a strong antiangiogenic compound that inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro-angiogenic and anti-angiogenic cytokines and their receptors; HU-345 (cannabidiol quinone) is a drug that can inhibit aortic ring angiogenesis more potently than its parent compound cannabidiol; CP 47,497 or (C7)-CP 47,497 is a cannabinoid receptor agonist drug. ;

[0062] The present disclosure also provides methods for biosynthesizing cannabinoids, and methods for using eukaryotic or prokaryotic expression systems to produce biosynthetic enzymes that can be used to make cannabinoids and cannabinoid analogs. Yeast and eukaryotic and prokaryotic cells are suitable for cloning and expression of cannabinoid acid synthases, including but not limited to Escherichia coli, yeast and baculovirus hosts. Therefore, the present disclosure provides a method for using cannabinoid acid synthases, including but not limited to tetrahydrocannabinolic acid (THCA) synthase and cannabidiol acid (CBDA) synthase, to produce biosynthetic cannabinoids such as THC and / or CBD. The present disclosure further provides a continuous drug delivery system and method disclosed herein, which comprises, for example, a biosynthetic CBD alone or in combination with other active agents.

[0063] According to certain embodiments, the continuous drug delivery systems and methods described herein are used to prevent and / or control and / or treat cancer.

[0064] According to certain embodiments described herein, pharmaceutical compositions or continuous drug delivery systems and methods contain cannabidiol and / or THC, free alkalis thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof, co-crystallized forms thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms thereof, active metabolites thereof, polymorphs thereof, stereoisomers thereof, coated forms thereof, solid solutions thereof, ion pairs thereof, solutions thereof in solvents, alone or in combination thereof. More preferably, continuous drug delivery systems and methods may include cannabidiol, free alkalis thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof, co-crystallized forms thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms thereof, active metabolites thereof, polymorphs thereof, ion pairs thereof, stereoisomers thereof, coated forms thereof, cannabidiol solutions in methanol, alone or in combination thereof. More preferably, the continuous drug delivery system and method may include 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 ion pair, its synthetic form, its biosynthetic form, its active metabolite, its polymorph, its stereoisomer, its coated form, cannabidiol solution in methanol, alone or in combination thereof.

[0065] As used herein, the term active agent refers to all pharmaceutically acceptable forms of active agents and their derivatives, alone or in combination, for example in the following forms, but not limited to, such as free base or salt or isomer or amorphous or crystalline or co-crystal or solid solution or prodrug or analog or derivative or metabolite. For example, the free base of the active agent or its salt or isomer or amorphous form or crystalline form or co-crystal form or solid solution or prodrug or analog or derivative or synthetic form. The compound can be in the form of, for example, a pharmaceutically acceptable salt, such as an acid addition salt or a base salt, or a solvate thereof, including a hydrate thereof. Suitable acid addition salts are formed from acids that form non-toxic salts, examples being hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, sucrose salt, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. Suitable base salts are formed from bases that form non-toxic salts, examples being sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts. The active ingredient may be present in the form of a free base or in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts forming part of the present invention are intended to define, but are not limited to, salts of carboxylic acid moieties, such as 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 and aluminum salts. The salt may be an acid addition salt, which defines, but is not limited to, sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmitates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, etc.

[0066] As used herein, the term "active agent" includes its free base, its salt, its isomer, its amorphous form, its crystalline form, its co-crystallized 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 exists as a highly purified active agent extract, which constitutes at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.75% (w / w) of the preparation. In certain embodiments, the dosage of the active agent is greater than, for example, 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 greater than, for example, 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 may include a concentration 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 79%, about 80%, about 81%, about 81%, about 82%, about 83%, about 84%, about 85 %, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75% and about 80% of active agent. In exemplary embodiments, the formulations of the present disclosure may include an active agent at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, the active agent will account for about 1 wt% to 75 wt%, preferably 2 wt% to 30 wt%, and more preferably 5 wt% to 20 wt% of the formulation.

[0067] In exemplary embodiments, the formulations disclosed herein can include a concentration of 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%, In some embodiments, the present invention relates to an active agent having 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 of the active agent.

[0068] In certain embodiments, the active agent is present as a highly purified active agent extract that constitutes at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.75% (w / w) of the preparation.

[0069] In certain embodiments, the active agent is present in provided formulations 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).

[0070] In certain embodiments, the activating agent is 100% synthetic. In certain embodiments, the purity of the activating agent is equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w). In certain embodiments, the activating agent is synthetically produced and its purity is equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w). In certain embodiments, the active agent is a combination of active agents, and each active agent can be synthetically produced and independently have a purity equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w).

[0071] In certain embodiments, the dose of the active agent is equal to or greater than, 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. In certain embodiments, the dose of the active agent is equal to or greater than, 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, 1000ng / day, 0.001μg / day, 0.01μg / day, 0.025μg / day, 0.050μg / day, 0.1μg / day, 0.25μg / day, 0.5μg / day, 1μg / day, 2.5μg / day, 5μg / day, 10μg / day, 25μg / day, 50μg / day, 100μg / day, 250μg / day or 500μg / day. In certain embodiments, the dose of the active agent is equal to or greater than, 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. In certain embodiments, the dose of the active agent is equal to or greater than, 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.In exemplary embodiments, the formulations of the present disclosure may comprise 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 mg, 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg. In exemplary embodiments, the formulations of the present disclosure may comprise 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 comprise 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.

[0072] In exemplary formulations disclosed herein, the active agent will comprise about 1 wt% to 75 wt%, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.% of the total weight.

[0073] In other embodiments, the pharmaceutical composition further comprises one or more other materials, such as a pharmaceutically compatible carrier, a binder, a viscosity modifier, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a surfactant, a preservative, a lubricant, a colorant, a diluent, a solubilizer, a wetting agent, a stabilizer, a humectant, an antiadherent, a parietal cell activator, an antifoaming agent, an antioxidant, a chelating agent, an antifungal agent, an antibacterial agent, or one or more combinations thereof.

[0074] Continuous drug delivery

[0075] According to the embodiment provided herein, the continuous delivery system includes a preparation selected from the group consisting of liquid preparations, solid preparations, semisolid preparations, emulsion preparations, nanoparticle preparations, matrix preparations, film preparations, patch preparations, infusion pumps and / or its combination. These embodiments are intended to be formulated into continuous, sustained delivery is provided, to alleviate the peak and valley behavior of the pharmacokinetics associated with the standard quick-release oral delivery form. These embodiments are intended to be formulated into the route of administration provided to be selected from the group consisting of oral, oral, mucosal, rectal, transdermal, local, parenteral and / or implantable and / or its combination.

[0076] In one aspect, a method for providing a continuous drug delivery system and a method for treating an effective amount of a pharmaceutical composition or formulation is provided, wherein the pharmaceutical composition or formulation comprises an active agent, such as THC and / or CBD. In some embodiments, the continuous drug delivery system and method continuously deliver THC and / or CBD at a predetermined hourly rate. In some embodiments, the predetermined hourly rate may be in the range of 16 to 1400 μg / hour, for example 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, such as 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 an hourly rate between any two of these listed rates (including the end values), for example between 35-140 μg / hour or 75-280 μg / hour or 190-700 μg / hour.

[0077] In some embodiments, the continuous drug delivery systems and methods continuously deliver active agents to achieve steady-state plasma levels of THC and / or CBD compounds in the range of 3-140 μg / L, such as 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.

[0078] In some embodiments, continuous drug delivery system and method deliver active agent continuously in predetermined number of days.In some embodiments, predetermined number of days is one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days or fourteen days.In other embodiments, predetermined number of days is between 1-14 days, 1-12 days, 1-10 days, 1-7 days, 1-5 days, 1-3 days, 2-14 days, 2-12 days, 2-10 days, 2-7 days, 2-5 days, 2-3 days, 3-14 days, 3-12 days, 3-10 days, 3-7 days, 3-5 days, 4-14 days, 4-10 days, 7-14 days or 7-10 days.

[0079] In some embodiments, the hourly rate is selected to obtain a plasma concentration comparable to the plasma concentration of the active agent provided by an oral dose of 0 to 24 hours after intake, such as about 1 to 24 hours, further such as about 5 to 24 hours, and even further such as about 5 hours to 23 hours or about 10 hours to 16 hours. The oral dose can be 2.5 to 50 mg once a day, for example, 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 a day or every two days. The phrase "comparable to the plasma concentration of an oral dose of 0 to 24 hours" can be understood from the description of Examples 6-9. For example, for an interval of 0-24 hours, the area of ​​the time concentration curve (AUC) calculated by the trapezoidal rule from the graph of the plasma concentration of the oral dose versus time divided by hours (24 hours) is the hourly blood concentration associated with AUC. The hourly AUC obtainable by the hourly rate of the continuous delivery method described herein will produce a similar drug exposure over time as shown by the oral dose. This hourly rate of the continuous delivery method described herein is the rate at which a plasma concentration is achieved that is comparable to the blood levels at 0 to 24 hours of an oral dose. In another embodiment, the AUC obtained by the continuous delivery method described herein is comparable to the AUC obtained by an oral dose of the same compound within 0-24 hours after the dosing period.

[0080] In some embodiments, continuous drug delivery systems and methods continuously deliver active agents in a manner where its AUC is between 10-60% of the exposure obtained from standard care treatment. Standard care treatment can be intraperitoneal injection, such as 500mcg once a day, or can be oral 2.5 to 50mg once a day, such as once a day or once every two days, 2.5mg, 4.0mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg or 50mg of CBD and / or THC compounds are orally administered. In another embodiment, the continuous drug delivery system and method herein provide continuous administration of active agents to provide an AUC between about 10% to 60% of the AUC provided by standard care treatment. In some embodiments, standard care treatment is an oral dose of CBD and / or THC of 2.5mg to 50mg once a day, such as once a day or once every two days, 2.5mg, 5mg, 10mg, 15mg, 20mg or 25mg or 50mg.

[0081] In some embodiments, the continuous drug delivery system and method continuously delivers an active agent compound (such as CBD and / or THC) at a dose rate that provides a blood level (μg / L) equivalent to the blood level obtained from a daily oral dose of 2.5-50 mg (e.g., 2.5 mg, 5 mg, 10 mg, or 25 mg active agent once daily) at a time point of 10 hours to 16 hours. 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 daily oral dose of 2.5 to 50 mg (e.g., 5 mg, 10 mg, or 25 mg active agent once daily).

[0082] In some embodiments, the continuous drug delivery systems and methods continuously deliver the active agent compound (such as THC and / or CBD) at a dose rate such that the daily dose of the method is 10-75%, such as 15-70%, 15-25%, 40-50%, 10-45%, 45%-70%, 60-70%, 15%, 16%, 17%, 18%, 19%, 20%, 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 daily dose of the standard of care treatment. In some embodiments, the standard of care treatment is a once daily intraperitoneal injection, for example 500 mcg. In some embodiments, the standard of care treatment is a once daily oral dose of an FDA-approved active agent, such as 5 mg, 10 mg, or 25 mg orally once daily.

[0083] Continuous drug delivery system and method provide the continuous delivery of the activating agent comprising a pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier should be compatible with other components of preparation (if any), and harmless to the health of the subject.When continuous delivery includes infusion, the formulation ingredients can be selected to promote the infusion of the formulation.Exemplary carriers for the preparation of continuous delivery include but are not limited to water, carboxymethyl cellulose (CMC), Tween 80, dimethyl sulfoxide (DMSO), ethanol, 2-hydroxypropyl-β-cyclodextrin, glucose and PEG400.When the preparation is in liquid form, in some embodiments, the activating agent is present in a concentration of about 0.01-20mg / mL, 0.05-5mg / mL, 0.05-3mg / mL, 0.1-4mg / mL, 0.1-2.0mg / mL or about 0.1-1mg / mL.

[0084] In certain embodiments, the continuous drug delivery system and method comprising a transdermal system or topical preparation can be in the form of a liquid or gel and can be incorporated in a transdermal patch. For example, but not limited to, the transdermal preparation can include a polymer matrix, which can be viscous or non-viscous, such as, but not limited to, a polyacrylic acid adhesive. Matrix patches include patches with a single matrix layer or multiple matrix layers.

[0085] Using continuous drug delivery systems and methods, such as transdermal and topical systems as described herein, the dosage will vary according to the mode of administration, the specific condition to be treated, and the desired effect. The dosage can be a transdermal application once a day for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days or longer. Alternatively, the application can be several times a day for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days or longer. Alternatively, the application can be once a day, once every 2 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days.

[0086] In some embodiments, continuous drug delivery systems and methods, such as transdermal or topical preparations, provide a predetermined delivery rate of the active ingredient of a transdermal patch in a predetermined time period. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks or 15 days. In some further embodiments, the predetermined rate is a substantially constant rate, with a coefficient of variation of less than about 90%, 85% or 80% in a predetermined time period.

[0087] In further embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations, provide a series of predetermined serum levels of transdermal patch active components for the patient over a predetermined time. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks or 15 days.

[0088] In further embodiments, continuous drug delivery systems and methods, such as transdermal or topical formulations, provide the patient with a plasma concentration of the transdermal patch active component within the therapeutic range within a predetermined time. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks or 15 days.

[0089] In further embodiments, the continuous drug delivery systems and methods described herein, such as transdermal or topical formulations, allow for reduced variability in the dosage of the active ingredient in a patient 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 to 13 days, two weeks, or 15 days.

[0090] In some embodiments, the continuous drug delivery systems and methods provided herein, such as transdermal or topical formulations, can be administered with a dosage regimen, such as once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every 8 to about 13 days, once every two weeks, once every 15 to about 30 days.

[0091] In a further embodiment, the blood sample of the experimenter treated with transdermal delivery system as herein described is carried out pharmacokinetic assessment.According to pharmacokinetic assessment, transdermal preparation is adjusted.For example, dosage can be adjusted, thereby smaller patch, larger patch or multiple transdermal patches are applied to the experimenter, or the patch with or more or less dosage active ingredient can be applied.In some embodiments, the preparation can be obtained with various dosage strengths and patch sizes, so as to obtain the best therapeutic effect based on the needs of the experimenter.In one embodiment, more than one transdermal system or topical preparation is applied to the experimenter, and in some embodiments, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3 patches are applied, and in other embodiments, 1, 2, 3, 4, 5 or 6 patches are applied.

[0092] cancer

[0093] The present disclosure provides a method for treating neoplasia in a patient in need of such treatment, 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 neoplasia therapeutic agent. As used herein, the term "neoplasia" also refers to tumors, proliferative diseases, malignancies, and metastases thereof.

[0094] Cancer is an abnormal growth of cells that tends to multiply in an uncontrolled way and, in some cases, metastasize (spread). Cancer is not one disease. It is a group of more than 100 different and unique diseases. Cancer can involve any tissue in the body and has many different forms in each body part. Most cancers are named after the type of cell or organ in which they start. Tumors can be cancerous or benign. A benign tumor means that the tumor can grow but will not spread. A cancerous tumor is malignant, which means that it can grow and spread to other parts of the body. If cancer spreads (metastasizes), the new tumor has the same name as the original (primary) tumor. The incidence of a particular cancer may depend on gender. Although skin cancer is the most common type of malignancy in both men and women, the second most common type in men is prostate cancer, and the second most common type in women is breast cancer.

[0095] Examples of cancer diseases are adenocarcinomas 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 (ovary, fallopian tube, endometrium, cervix and vagina, ureter, bladder, testis, epididymis, prostate) and skin appendages; squamous cell carcinomas of the head and neck (including salivary glands and oral cavity), gastrointestinal tract (including pharynx, esophagus, anus), lung, intrahepatic and extrahepatic bile duct tree (including gallbladder), pancreas, genitourinary tract (including endometrium, cervix, vagina, ureter, bladder, testis, epididymis, prostate) and skin appendages; germ cell tumors (including malignant teratoma, embryonal carcinoma, ovarian thyroid tumor, yolk sac tumor, seminoma, choriocarcinoma); sarcomas (including leiomyosarcoma, rhabdomyosarcoma , angiosarcoma, hemangioendothelioma, liposarcoma, chondrosarcoma, fibrosarcoma, Ewing sarcoma, malignant nerve sheath tumor, alveolar soft tissue sarcoma, clear cell sarcoma, synovial sarcoma, osteosarcoma); central nervous system malignancies (including astrocytoma, oligodendroglioma, glioblastoma, GBM, medulloblastoma); salivary gland malignancies (including adenoid cystic carcinoma, adenosquamous carcinoma, clear cell carcinoma, cystadenocarcinoma, mucoepidermoid carcinoma); mixed carcinoma cholangiocarcinoma, carcinosarcoma, mixed adeno-neuroendocrine carcinoma, adenosquamous carcinoma); hepatocellular carcinoma; blastic malignancies (including hepatoblastoma, neuroblastoma, ganglioneuroblastoma, Wilms' tumor); renal cell carcinoma; neuroendocrine carcinoma; thyroid cancer (including papillary carcinoma, follicular carcinoma, medullary carcinoma, anaplastic carcinoma); parathyroid carcinoma, pituitary cancer, adrenal cancer (including adrenocortical carcinoma, 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, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, GBM, and blood cancers such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma / primary mediastinal B-cell lymphoma, or chronic myeloid leukemia.

[0096] The method of the present disclosure can be used to treat any type of cancer known in the art. Non-limiting examples of cancers treated by the method of the present disclosure may include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), pancreatic cancer, 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 malignant tumors. In addition, the present invention includes refractory or recurrent malignant tumors that can inhibit their growth using the method of the present invention. In some embodiments, cancers to be treated by the method of the present disclosure include, for example, carcinoma, squamous cell carcinoma (e.g., cervical canal, eyelid, conjunctiva, vagina, lung, oral cavity, skin, bladder, head and neck, tongue, larynx and esophagus) and adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast and ovary). In some embodiments, cancers to be treated by the methods of the present disclosure further include sarcomas (eg, myogenic sarcomas), leukocytic hyperplasias, neuromas, melanomas, and lymphomas.

[0097] In some embodiments, the patient or patient population to be treated with the combination therapy disclosed herein suffers from solid tumors. In some embodiments, solid tumors are 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 to be treated with the combination therapy disclosed herein suffers from blood cancer. In some embodiments, the patient suffers from blood cancer, such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin lymphoma ("HL"), non-Hodgkin lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML") or multiple myeloma ("MM").

[0098] Neoplasia therapy

[0099] According to the methods, compositions and combinations disclosed herein, any therapy (e.g., therapeutic agent or prophylactic agent) that is used, has been used, is currently used or can be used to prevent, treat and / or manage neoplasia can be used to prevent, treat and / or manage neoplasia and / or cancer in patients. In addition, neoplasia and / or cancer monitoring can be used in combination with any cancer therapy according to the present invention. Therapies (e.g., therapeutic agents 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 therapy include chemotherapy, radiotherapy, hormone therapy, anti-angiogenic therapy, targeted therapy and / or biological therapy, including immunotherapy and surgery. In certain embodiments, the effective regimen for prevention and / or treatment includes a combination of administered therapies.

[0100] Examples of neoplastic agents or therapies include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; acetate; aminoglutethimide; amsacrine; anastrozole; anthracyclines; anthramycin; asparaginase; asperlin; azacitidine (Vidaza); azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate dimesylate; bisphosphonates (e.g., pamidronate (Aredria), sodium clondronate (Bonefos), zoledronic acid (Zometa), alendronate sodium (Fosamax), etidronate, ibandornate, cimadronate, risedromate, and tiludromate); bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; actinomycin C; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine;crisnatol mesylate; cyclophosphamide; cytarabine (Ara-C); dacarbazine; actinomycin D; daunorubicin hydrochloride; decitabine (Dacogen); demethylating agents; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride hydrochloride; EphA2 inhibitors; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium 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 α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-Ia; interferon γ-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate;lenalidomide (Revlimid); letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; nitrogen mustard hydrochloride; anti-CD2 antibodies (e.g., siplizumab (MedImmune Inc.; International Publication No. WO 02 / 098370, which is incorporated herein by reference in its entirety)); megestrol acetate; melenestrol acetate; acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mifepristone; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid acid; nocodazole; nogalamycin; ormaplatin; oxaliplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; RU486; safingol; safingol hydrochloride; semustine; simtrazene; spalfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tubulozole hydrochloride hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate;Vorozole; zeniplatin; zinostatin; doxycycline hydrochloride.

[0101] Other examples of cancer therapies include, but are not limited to: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; amidox; amifostine; aminolevulinic acid; acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycine glycinate; apoptosis gene regulator; apoptosis regulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; β-lactam derivatives; β-alethine; β-clarithromycin B B); betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafil; bistratene A; biszelesin; breflate; bropiridamine; budotitane; buthionine sulfoxide; calcipotriol; calphostin C; camptothecin derivatives; canarypoxIL-2; capecitabine;carboxyamide aminotriazole; carboxyamide triazole; CaRest M3; CARN 700; cartilage-derived inhibitor; cardezolexin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogs; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A A); cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermidine; dihydro-5-azacytidine; dihydropaclitaxel; dioxamycin; diphenylspiromustine; docetaxel; docosinol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA SA); ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadroxil;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezlastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; HMG CoA reductase inhibitors (such as atorvastatin, cerivastatin, fluvastatin, lescol, lupitor, lovastatin, rosuvastatin, and simvastatin); hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iodobenzylguanidine; iodoxorubicin; ipomeanol; 4-iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F F); lamellarin-Ntriacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon alpha;Leuprorelin + estrogen + progestin; leuprorelin; levamisole; LFA-3TIP (Biogen, Cambridge, Mass.; International Publication No. WO 93 / 0686 and U.S. Pat. No. 6,162,432); lirazole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A A); marimastat; masoprocol; maspin; matrix lytic factor (matrilysin) inhibitor; matrix metalloproteinase inhibitor; menolide; merbarone; meterelin; methioninease; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitogu azone; mitolactol; mitomycin analog; mitonafide; mitotoxin; fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+ mycobacterial cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent anticancer agent); mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamide; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin;neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetic acid; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitors; platinum complex complex); platinum compounds; platinum-triamine complex; porphyrin sodium; porphyromycin; prednisone; propyl diacridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; microalgae protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridines; pyridoxalyl hemoglobin polyoxyethylene; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylraltiptine; rhenium Re 186 Etidronic acid; rhizoxin; ribozyme; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl;safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction regulator; γ-secretase inhibitor; single-chain antigen binding protein; sizofuran; sobuzoxane; sodium borocarb; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparlfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 1); squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycan; tallimustine; 5-fluorouracil; folinic acid; tamoxifen methyl iodide; tauromustine; tazarotene; tecogalan sodium sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene dichloride bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitor; retinoic acid; 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; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; anti-integrin antibodies (e.g., anti-integrin αvβ3 antibodies); vorozole; zanoterone; zeniplatin; zilascorb; and netstatin benzene polymers.

[0102] A non-limiting list of compounds that can be used to target neoplasia and / or cancer 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 γ-secretase inhibitors; Sonic hedgehog / smoothened pathway inhibitors, including cyclopamine and its analogs; CD96 antibodies; certain NF-κB / proteasome inhibitors, including parthenolide and its analogs; certain triterpenoids, including celastrol; certain mTOR inhibitors; compounds targeting urokinase receptors and antibodies; sinefungin; certain inosine monophosphate dehydrogenase (IMPDH) inhibitors; PPAR-α and PPAR-γ agonists and antagonists (including pioglitazone, tesaslitazar, muraglitazar, peliglitazar, lobeglitazone, balaglitazone, ragaglitazar, rosiglitazone, farglitazar, sodeglitazone, s odelglitazar, reglitazar, naveglitazar, oxeglitazar, metaglidasen, netoglitazone, darglitazone, englitazone, thiazolidinediones, aleglitazar, edaglitazone, rivoglitazone, troglitazone, imiglitazar, and sipoglitazone itazar); telomerase inhibitors; EpCAM antibodies (ESAs); GSK-3β agonists and antagonists (including lithium, 6-bromoisatin-3'-oxime (BIO), TDZD8); Wnt pathway inhibitors, including Frizzled antibodies or small molecules that inhibit Disheveled / Frizzled or β-catenin; anti-CD20 antibodies and their conjugates (e.g., Rituxan, Bexxar, Zevalin), newly used in multiple myeloma or melanoma; anti-CD133 antibodies; anti-CD44 antibodies; IL-4 antibodies; certain differentiation agents, such as versnarinone;Compounds targeting CD33, such as antibodies or betulinic acid; compounds targeting lactadherin, such as antibodies; small molecules or antibodies targeting CXCR4 or SDF-1; small molecules or antibodies targeting multidrug resistance pumps; survivin inhibitors; XIAP inhibitors; small molecules targeting Bcl-2; CLL-1 antibodies; and furin inhibitors (e.g., cucurbitacins).

[0103] An additional non-limiting list of compounds that can also be used to target cancer and / or cancer cells include: i) antibodies, antibody fragments and proteins, either naked or conjugated to therapeutic moieties that target certain cell surface targets on cancer cells, or ii) small molecules known in the art, including small molecules that can be further optimized (e.g., by chemistry) or identified by cancer cell-based screening (e.g., such as by standard methods to determine whether a compound impairs the proliferation or viability of cancer cells, cell surface and intracellular targets include (not meant to be exhaustive): Rex1 (Zfp42), CTGF, Activin A, Wnt, FG F-2, HIF-1, AP-2γ, Bmi-1, nuclear stem cell factor (nucleostemin), hiwi, Moz-TIF2, Nanog, β-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.

[0104] In some embodiments, the therapy is an immunomodulator. Non-limiting examples of immunomodulators include protein agents such as cytokines, peptide mimetics and antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, 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. Specifically, immunomodulators include but are not limited to methotrexate, leflunomide, cyclophosphamide (cyclophosphamide), cyclophosphamide (cytoxan), Immuran, cyclosporin A, minocycline, azathioprine, antibiotics (e.g., FK506 (tacrolimus)), methylprednisolone (MP), corticosteroids, steroids, mycophenolate mofetil (mycophenolate mofetil), rapamycin (sirolimus), mizoribine, deoxyspergualin, buquina, malononitriloamides (malononitriloamides) (e.g., leflunamide (leflunamide)), T cell receptor modulators, cytokine receptor modulators and modulator mast cell modulators. Other examples of immunomodulators can be found in, for example, U.S. Publication No. 2005 / 0002934A1, paragraphs 259-275, which are incorporated herein by reference in their entirety. In one embodiment, an immunomodulator is a chemotherapeutic agent. In another embodiment, an immunomodulator is an immunomodulator different from a chemotherapeutic agent. In some embodiments, the therapy used in accordance with the present invention is not an immunomodulatory agent.

[0105] 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, Fvs, ScFvs, Fab or F(ab)2 fragments or antigen-binding fragments thereof), such as antibodies that specifically bind to TNF-α, nucleic acid molecules (e.g., antisense molecules or triple helices), organic molecules, inorganic molecules, and small molecules that reduce or inhibit angiogenesis.

[0106] In certain embodiments, therapy is an alkylating agent, nitrosourea, antimetabolite and anthracycline, topoisomerase II inhibitor or mitotic inhibitor. Alkylating agents include but are not limited to busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, decarbazine, nitrogen mustard, mephalen and thiozolomide (themozolomide). 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 invention, therapy comprises administration of cantharidin or an analog thereof. The invention encompasses the use of agents that target cancer cells. In certain embodiments, the agent acts alone. In other embodiments, the agent is attached directly or indirectly 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, cytarabine, fluorouracil, methotrexate, aminopterin, mitomycin C, demecolcine, etoposide, mithramycin, calicheamicin, CC-1065, chlorambucil, or melphalan), radionuclides, therapeutic enzymes, cytokines, toxins (including toxins of plant origin, toxins of fungal origin, toxins of bacterial origin (e.g., deglycosylated ricin A chain, ribosome inactivating proteins, α-sarcin, aspergillus, restiric acid, tocin, ribonuclease, diphtheria toxin, Pseudomonas exotoxin, bacterial endotoxin or the lipid A portion of bacterial endotoxin), growth regulators and ribonucleases. In some embodiments, the agent used is an agent that binds to a marker, such as an antigen on a cancer cell. In a specific embodiment, the agent binds to an antigen that is expressed at a higher level on cancer cells than on normal cells. In a specific embodiment, the agent specifically binds to a cancer cell antigen of a non-normal cell. In other embodiments, the therapy is an agent that binds to a marker on a cancer cell. In one embodiment, the agent that binds to a marker on a cancer cell is an antibody or an antibody coupled to a therapeutic portion, or an antibody fragment coupled to a therapeutic portion.

[0107] For example, in a specific embodiment, 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 that is specific to IL-3R. In some embodiments, the antibody or antibody fragment is chemically or by recombinant technology coupled to a therapeutic moiety (e.g., a chemotherapeutic agent, a toxin from a plant, fungus or bacteria source, a radionuclide) using a linker to achieve a cell killing response. In certain embodiments, an antibody, an antibody conjugate, an antibody fragment or an antibody fragment conjugate binds to the α subunit of IL-3R (i.e., the CD 123 antigen). In other embodiments, an antibody, an antibody conjugate, an antibody fragment or an antibody fragment conjugate binds to IL-3R, comprising both α and β subunits. Methods for preparing IL-3R antibodies and IL-3R antibody mimetics are described in U.S. Patent No. 6,733,743B2, which is incorporated herein by reference in its entirety.

[0108] In other embodiments, the agent that binds to a marker on a cancer cell is a ligand. In some embodiments, the ligand is a cytokine that binds to a cytokine receptor on a cancer cell. In a specific embodiment, the ligand is interleukin-3 (IL-3), which can be coupled to a therapeutic moiety that includes a chemotherapeutic agent, a toxin from a plant, fungus or bacterial source, or a radionuclide. In embodiments where the conjugate is a toxin and the toxin is a protein such as diphtheria toxin, the IL-3-conjugate preventive and / or therapeutic therapy or regimen can be in the form of a recombinant fusion protein.

[0109] In certain embodiments, the antibody or fragment thereof that binds to a marker on a cancer cell is substantially non-immunogenic in the subject being treated. Methods for obtaining non-immunogenic antibodies include, but are not limited to, chimerization of antibodies, humanization of antibodies, and isolation of antibodies from the same species as the subject receiving therapy. Antibodies or fragments thereof that bind to a marker in a cancer cell can be produced using techniques known in the art.

[0110] In some embodiments, therapy includes the use of X-rays, gamma rays, and other radiation sources to destroy cancer cells and / or cancerous cells. In certain embodiments, radiation therapy is implemented as external beam radiation or teletherapy, where radiation is directed from a remote source. In other embodiments, radiation therapy is implemented as internal therapy or brachytherapy, where a radiation source is placed in the body close to cancer cells, cancerous cells, and / or tumor masses.

[0111] In some embodiments, the therapy used is a proliferation-based therapy. Non-limiting examples of such therapies include chemotherapy and radiation therapy as described above.

[0112] Currently available therapies and their dosages, routes of administration, and recommended uses are known in the art and described in literature, such as the Physician's Desk Reference (60th edition, 2006).

[0113] When two preventive and / or therapeutically effective regimens are administered to a subject simultaneously, the term "simultaneously" is not limited to administering cancer therapeutic agents at exactly the same time, but refers to their administration to the subject in a certain order and time interval so that they can work together (e.g., synergistically to provide an increased benefit than when they are administered in other ways). For example, cancer therapeutic agents can be administered sequentially in any order simultaneously or at different time points; however, if not administered simultaneously, they should be administered at a sufficiently close time to provide the desired therapeutic effect, preferably in a synergistic manner. The combined cancer therapeutic agent can be administered separately in any suitable form and by any suitable route. When the components of the combined cancer therapeutic agent are not administered in the same pharmaceutical composition, it should be understood that they can be administered to a subject in need thereof in any order. For example, a first prophylactic 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), concurrently 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) administration of a second cancer therapeutic to a subject in need thereof. In various embodiments, the cancer therapeutics are administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, no more than 24 hours, or no more than 48 hours. In one embodiment, the cancer therapeutics are administered at the same visit. In another embodiment, the combination cancer therapeutics are administered at intervals of 1 minute to 24 hours.

[0114] In a specific embodiment, the combination therapy has the same mechanism of action. In another specific embodiment, each of the combination therapy has a different mechanism of action.

[0115] Indications

[0116] The present disclosure provides continuous drug delivery systems and methods for treating and / or preventing and / or controlling indications using continuous drug delivery, such as pain management, cancer, seizure disorders, Parkinson's disease, symptoms associated with PD, and other indications. According to the present disclosure, suitable conditions for treatment include, for example, seizure disorders, pain syndromes, neurodegenerative diseases (including motor neuron diseases, myelopathy, radiculopathy, and sympathetic nervous system disorders), dementia, cerebrovascular conditions, movement disorders, brain trauma, cranial nerve disorders, neuropsychiatric disorders, and other disease neuropathies (including virus-related neuropathy, diabetes-related neuropathy, Guillian-Barre syndrome, dysproteinemia, thyroxine transporter protein-induced neuropathy, and carpal tunnel syndrome). As used herein, seizure disorders include complex partial seizures, simple partial seizures, partial seizures secondary to generalization, generalized seizures (including absences, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as other 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, as well as seizures associated with CNS mass lesions.

[0117] Pain syndromes include, for example, headaches (e.g., migraine, tension and cluster headaches), acute pain, chronic pain, neuropathic pain, nociceptive pain, central pain and inflammatory pain, drug-induced neuropathic pain, causalgia, complex regional pain syndrome type I and II, and reflex sympathetic dystrophy (RSDS).

[0118] Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, ALS, spinal muscular atrophy, muscular dystrophy, prion-related diseases, cerebellar ataxia, Friedrich's ataxia, SCA, Wilson's disease, RP, Gullain Barre syndrome, adrenoleukodystrophy, Menke syndrome (Menke's Sx), cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL), CharcotMarie Tooth disease, neurofibromatosis, von-Hippel Lindau, Fragile X syndrome, spastic paraplegia, tuberous sclerosis, Wardenburg syndrome, spinal motor atrophy, Tay-Sach disease, Sandoff disease, familial spastic paraplegia, myelopathy, radiculopathy, encephalopathy associated with trauma, radiation, drugs and infection, and sympathetic nervous system disorders (e.g., Shy Drager (familial dysautonomia), diabetic neuropathy, drug-induced and alcohol-induced neuropathy).

[0119] Dementias include Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, Huntington's disease, and MCI.

[0120] Cerebrovascular conditions that may be treated in accordance with the present disclosure include cerebrovascular disease and stroke (eg, thrombotic, embolic, thromboembolic, hemorrhagic [including AVM and berry aneurysm], venous compression, and venous).

[0121] Movement disorders include Parkinson's disease, dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, and Tourette's syndrome.

[0122] As used herein, brain trauma includes traumatic brain injury and spinal cord injury, as well as brain damage caused by radiation.

[0123] Cranial nerve disorders include trigeminal neuropathy, trigeminal neuralgia, Menier's syndrome, glossopharangela neuralgia, dysphagia, dysphonia, cranial nerve palsies, and Bell's palsy.

[0124] Neuropsychiatric disorders include panic syndrome, general anxiety disorder, all types of phobia syndromes, mania, manic-depressive disorder, hypomania, unipolar depression, depression, stress disorders, PTSD, somatoform disorders, personality disorders, psychosis, and schizophrenia) as well as drug dependence / addiction (e.g., alcohol, psychoactive drugs (e.g., crack, cocaine, speed, methamphetamine (meth)), opioids, and nicotine) and drug-induced psychotic disorders.

[0125] Other disease neuropathies that can be treated with the compositions and methods described herein include Guillain-Barre, diabetic-associated neuropathy, dysproteinemia, transthyretin-induced neuropathy, HIV-associated neuropathy, herpes virus (including shingles), or other viral infections, 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 polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy, post-meningitis syndrome, post-polio syndrome, prion disease, and radiation-related neuropathy syndrome.

[0126] Other diseases treatable with the present disclosure include fatigue syndromes (eg, chronic fatigue syndrome and fibromyalgia), ataxia syndromes, olivopontoicerebellar degeneration, striatonigral degeneration, and axonal brain damage.

[0127] The present disclosure is particularly useful for treating neuropsychiatric disorders such as depression, agitation, anxiety, seizure disorders such as grand mal seizures, status epilepticus, migraine treatment and prevention, Alzheimer's disease, Parkinson's disease, and traumatic brain and spinal cord injuries.

[0128] Furthermore, the higher doses enabled by the present disclosure are expected to be particularly important for dementias (including Alzheimer's disease, Parkinson's disease, and vascular dementia), pain syndromes (including headaches and migraines), seizure disorders, movement disorders, and brain trauma.

[0129] Furthermore, the provided dosage forms are easy to use and convenient, developed to deliver therapeutically effective amounts once daily or less frequently from the start of treatment, and have value in treating dementias, including Alzheimer's and Parkinson's diseases, seizure disorders, pain syndromes, and cerebrovascular conditions.

[0130] Another aspect of the present disclosure relates to the use of the continuous drug delivery system and method disclosed herein as a therapeutic agent for preventing and / or treating immunoinflammatory disorders. The term "immunoinflammatory disorder" includes a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory skin diseases. Immunoinflammatory disorders lead to the destruction of healthy tissues through inflammatory processes, immune system disorders, and unnecessary cell proliferation.Examples of immunoinflammatory disorders are 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; Behcet's disease; Bell's palsy; bullous pemphigoid; cerebral ischemia; chronic obstructive pulmonary disease; cirrhosis; Cogan's syndrome 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-Schonlein purpura purpura); herpes gestationis; hirsutism; idiopathic keratoscleritis; 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; multiple sclerosis; myasthenia gravis; myositis; nonspecific fibrosing lung disease; osteoarthritis; pancreatitis; pemphigoid gestationis; pemphigus vulgaris; periodontitis; polyarteritis nodosa; polymyalgia rheumatica; pruritus scrotum; pruritus / inflammation, psoriasis; psoriatic arthritis; pulmonary histoplasmosis; rheumatoid arthritis; relapsing polychondritis; rosacea due to sarcoidosis; rosacea due to scleroderma; Sweet's syndrome syndrome; rosacea due to systemic lupus erythematosus; rosacea due to urticaria; rosacea due to pain associated with herpes zoster; sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock syndrome; tendinitis or bursitis of the shoulder; Sjogren's syndrome; Still's disease; brain cell death caused by stroke; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu'sarteritis; temporal arteritis; toxic epidermal necrolysis; transplant rejection and transplant rejection-related syndrome; tuberculosis; type 1 diabetes mellitus; ulcerative colitis; uveitis; vasculitis; and Wegener's granulomatosis.

[0131] As used herein, "non-dermatological inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease. "Skin inflammatory disorder" or "inflammatory skin disease" refers to an inflammatory disorder selected from the group consisting of psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, acute febrile neutrophilic dermatosis, eczema, dry eczema, dyshidrotic eczema, vesicular palmoplantar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, dyshidrosis, rosacea, rosacea caused by sarcoidosis, rosacea caused by scleroderma, rosacea caused by Sweet's syndrome, rosacea caused by systemic lupus erythematosus, rosacea caused by urticaria, herpes zoster Related pain caused by rosacea, Sweet's disease, neutrophilic hidradenitis, sterile pustulosis, drug eruption, seborrheic dermatitis, pityriasis rosea, skin kikuchi disease, pruritic urticarial papules and plaques of pregnancy, Stevens-Johnson syndrome and toxic epidermal necrolysis, tattoo reaction, Wells syndrome (eosinophilic cellulitis), reactive arthritis (Reiter syndrome), gut-related dermatosis-arthritis syndrome, rheumatoid neutrophilic dermatosis, neutrophilic hidradenitis, neutrophilic dermatosis of the back of the hands, plasma cell localized balanitis (balanitis circumscripta plasmacellularis), balanoposthitis, Behçet's disease, erythema annulare centrifugal, erythema dyschromatotica perstans, erythema multiforme, granuloma annulare, hand dermatitis, lichen luminescens, lichen planus, lichen sclerosus atrophicus, lichen simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, subcorneal pustular dermatosis, urticaria, and transient acantholytic dermatosis.

[0132] "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 cell carcinoma and squamous cell carcinoma of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, exacerbated anterior keratosis, acne and seborrheic dermatitis. As will be appreciated by those skilled in the art, a particular disease, disorder or condition may be characterized as both a proliferative skin disease and an inflammatory skin disease. An example of such a disease is psoriasis.

[0133] Symptoms and signs of inflammation associated with specific conditions include: Rheumatoid arthritis: -- pain, swelling, fever, and tenderness involving joints; generalized stiffness 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 and hands and feet, peripheral edema, bradycardia; Multiple sclerosis: -- spasticity, blurred vision, vertigo, weakness of the limbs, paresthesia; Uveoretinitis: -- decreased night vision, loss of peripheral vision; Lupus erythematosus: -- joint pain, rash, photosensitivity, fever, muscle pain, swelling of the hands and feet, abnormal urine tests (hematuria, casts, proteinuria), glomerulonephritis, cognitive dysfunction, vascular thrombosis, pericarditis; Scleroderma: -- Raynaud's disease (Raynaud's disease); swelling of the hands, arms, legs, and face; thickening of the skin; pain, swelling, and stiffness of the fingers and knees; gastrointestinal disturbances; restrictive lung disease; pericarditis; renal failure; other arthritic conditions with an inflammatory component, such as rheumatoid spondylitis, osteoarthritis, septic arthritis, and polyarthritis: -- fever, pain, swelling, tenderness; other inflammatory brain conditions, such as meningitis, Alzheimer's disease, AIDS dementia Encephalitis: -- photophobia, cognitive dysfunction, memory loss; Other inflammatory eye inflammation, such as retinitis: - decreased vision; Inflammatory skin conditions, such as eczema, other dermatitis (e.g. atopic dermatitis, contact dermatitis), psoriasis, burns caused by UV radiation (sun rays and similar UV sources): - erythema, pain, scaling, swelling, tenderness; Inflammatory bowel disease, such as Crohn's disease, ulcerative colitis: - pain, diarrhea, constipation, rectal bleeding, fever, arthritis; Asthma: - shortness of breath, wheezing; Other allergic conditions, such as allergic rhinitis: - -Sneezing, itching, runny nose symptoms associated with acute trauma such as brain damage after stroke -loss of sensation, movement, cognition; cardiac tissue damage caused by myocardial ischemia: -pain, shortness of breath; lung injury, such as occurs in adult respiratory distress syndrome: -shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates; inflammation associated with infection, such as sepsis, septic shock, toxic shock syndrome: -fever, respiratory failure, tachycardia, hypotension, leukocytosis; and Other inflammatory conditions associated with specific organs or tissues, for example: (i) Nephritis (e.g., glomerulonephritis): -- oliguria, abnormal urine test results; (ii) Appendicitis: -- fever, pain, tenderness, leukocytosis; (iii) Gout: -- pain, tenderness, swelling and erythema of the involved joints, elevated uric acid in serum and / or urine; (iv) Gallbladder inflammation: -- 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 disease, such as atherosclerosis and restenosis: -- pain, loss of sensation, decreased pulse, loss of function; and (ix) Alloimmunization leading to transplant rejection: -- pain, tenderness, fever.

[0134] Another aspect of the present disclosure relates to the use of the continuous drug delivery system and method disclosed herein as a therapeutic agent for preventing and / or treating neurodegenerative diseases.

[0135] The present disclosure also relates generally to the fields of neurology and psychiatry, and methods of protecting mammalian central nervous system cells from damage or injury. Various injuries or traumas to the central nervous system (CNS) or peripheral nervous system (PNS) can produce profound and lasting neurological and / or psychiatric symptoms and disorders. One form this may take is the progressive death of neurons or other cells of the central nervous system (CNS), i.e., neurodegeneration or neuronal degeneration.

[0136] Neuronal degeneration is due to, for example: Alzheimer's disease, multiple sclerosis, cerebrovascular accident (CVA) / stroke, traumatic brain injury, spinal cord injury, optic nerve degeneration (such as ischemic optic neuropathy or retinal degeneration) and other central nervous system disorders, which have become huge medical and public health problems due to their 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 promote cell death in these conditions. When damage or ischemic damage, damaged neurons release a large amount of neurotransmitter glutamate, which is excitotoxic to surrounding neurons. Glutamate is a negatively charged amino acid and is an excitatory synaptic transmitter in the mammalian nervous system.

[0137] Such nervous system injury may be in the form of sudden injury or acute injury to the nervous system, for example, acute neurodegenerative disorders, including but not limited to: acute injury resulting in neuronal cell death or damage, hypoxia-ischemia or a combination thereof. Acute injury includes but is not limited to traumatic brain injury (TBI), including closed, blunt or penetrating brain trauma, focal brain trauma, diffuse brain injury, spinal cord injury, intracranial or intraspinal injury (including but not limited to contusion, penetration, shearing, compression or avulsion injury of the spinal cord or whiplash shaken baby syndrome).

[0138] In addition, lack of oxygen or insufficient blood supply often leads to acute injuries such as hypoxia and / or ischemia, including but not limited to, cerebrovascular insufficiency, cerebral ischemia or cerebral infarction (including cerebral ischemia or infarction caused by embolic occlusion and thrombosis), retinal ischemia (diabetic or other), glaucoma, retinal degeneration, multiple sclerosis, toxic and ischemic optic neuropathy, acute ischemia followed by reperfusion, perinatal hypoxic-ischemic injury, cardiac arrest or any type of intracranial hemorrhage (including but not limited to epidural, subdural, subarachnoid or intracerebral hemorrhage).

[0139] Trauma or injury to nervous system tissue may also take the form of more chronic and progressive neurodegenerative disorders, such as those associated with progressive neuronal cell death or damage over a period of time, including, but not limited to, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multiple system degeneration (Shy-Drager syndrome), chronic epileptic conditions associated with neurodegeneration, motor neuron disease (amyotrophic lateral sclerosis), multiple sclerosis, degenerative ataxias, corticobasal degeneration, ALS-Parkinson-Dementia Syndrome of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies (including multiple system atrophy), primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease, or Spinocerebellar ataxia type 3 and olivopontocerebellar degeneration, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach disease, Sandhoff disease, familial spastic disorder, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, familial dysautonomia (Riley-Day syndrome), or prion diseases (including but not limited to Creutzfeld-Jakob disease, Gerstmann-Strussler-Scheinker disease, Kuru disease, or fatal familial insomnia).

[0140] Additionally, trauma and progressive damage to the nervous system can occur in a variety of psychiatric disorders, including but not limited to progressive, worsening forms of bipolar or schizoaffective disorder or schizophrenia, impulse control disorders, obsessive compulsive disorder (OCD), behavioral changes in temporal lobe epilepsy, and personality disorders.

[0141] In a preferred embodiment, the continuous drug delivery system and method of the present disclosure can be used to provide neuroprotection in various psychiatric disorders involving trauma and progressive damage to the nervous system. These disorders will be selected from the group consisting of: schizoaffective disorder, schizophrenia, impulse control disorders, obsessive-compulsive disorder (OCD) and personality disorders.

[0142] In addition, trauma and injury manifest in the form of conditions associated with significant and widespread memory loss, including but not limited to neurodegenerative conditions associated with age-related dementia, vascular dementia, diffuse white matter disease (Binswanger disease), dementia of endocrine or metabolic origin, head traumatic dementia and diffuse brain injury, pugilistic dementia or frontal lobe dementia, including but not limited to Pick's disease.

[0143] Other conditions associated with neuronal damage include, but are not limited to, conditions associated with chemical, toxic, infectious, and radiation damage to the nervous system (including the retina), damage during fetal development, prematurity at birth, hypoxia-ischemia, damage of hepatic, glycemic, uremic, electrolyte, and endocrine origin, damage of psychiatric origin (including, but not limited to, psychopathology, depression, or anxiety), damage caused by peripheral disease and plexopathy (including plexus palsy), or damage caused by a neuropathy (including a neuropathy selected from the group consisting of multifocal, sensory, motor, sensory-motor, autonomic, sensory-autonomous, or demyelinating neuropathy (including, but not limited to, Guillain-Barre syndrome or chronic inflammatory demyelinating sheathing polyradiculoneuropathy), or those neuropathies arising from infection, inflammation, immune disorders, substance abuse, medication, toxins, trauma (including but not limited to compression, crushing, laceration or segmentation 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 related), Friedreich's ataxia, metachromatic leukodystrophy, Refsum's disease, adrenomyoneuropathy, ataxia-telangiectasia, Djerine-Sottas (including but not limited to types A or B), Lambert-Eaton syndrome, or cranial nerve disorders.

[0144] A further indication is cognitive disorder. The term "cognitive disorder" shall refer to anxiety disorders, delirium, dementia, amnesic disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia, psychotic disorders, sexual and gender identity disorders, sleep disorders, somatoform disorders, acute stress disorders, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, specific phobias, social phobias, substance withdrawal delirium, Alzheimer's disease, Creutzfeldt-Jakob disease, head trauma, Huntington's disease, HIV disease, Parkinson's disease, Pick's disease, learning disabilities, motor skill disorders, developmental coordination disorders, communication disorders, speech disorders, pervasive developmental disorders, Asperger's disorder, autism, 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, dissociative fugue, dissociative identity disorder, anorexia nervosa, bulimia nervosa, bipolar disorder, schizophrenia-like 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 disorder, breathing-related sleep disorder, circadian rhythm sleep disorder, hypersomnia, insomnia, narcolepsy, sleep abnormalities, parasomnias, nightmare disorder, sleep panic disorder, sleepwalking, parasomnias, body dysmorphic disorder, conversion disorder, hypochondriasis, pain disorder, somatization disorder, alcohol-related disorder, amphetamine-related disorder, caffeine-related disorder, cannabis-related disorder, cocaine-related disorder, hallucinogen-related disorder, inhalant-related disorder, nicotine-related disorder, opioid-related disorder, phencyclidine-related disorder, abuse, persistent amnesia disorder, intoxication, withdrawal.

[0145] The term "bipolar and clinical disorders" shall refer to adjustment disorders, anxiety disorders, delirium, dementia, amnesia and other cognitive disorders, disorders usually first diagnosed in infancy (for example), childhood or adolescence, dissociative disorders (such as dissociative amnesia, depersonalization disorder, dissociative fugue disorder and dissociative identity disorder), eating disorders, pseudodisorders, impulse control disorders, mental 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, sexual and gender identity disorders, sleep disorders, somatoform disorders, substance-related disorders, generalized anxiety disorders (such as acute stress disorder, post-traumatic stress disorder), panic disorder, phobias, agoraphobia, obsessive-compulsive disorder, stress, acute stress disorder, anxiety neurosis, nervousness, phobias, post-traumatic stress disorder, post-traumatic stress disorder (PTSD), abuse, obsessive-compulsive disorder (OCD), manic-depressive disorder, specific phobias, social phobia, adjustment disorder with anxious features.

[0146] Examples of disorders that are often first diagnosed in infancy, childhood, or adolescence include: intellectual disability, learning disability, mathematics disability, dyslexia, written expression disorder, motor skill disorder, developmental coordination disorder, communication disorder, expressive language disorder, speech disorder, mixed receptive-expressive language disorder, stuttering, pervasive developmental disorder, Asperger's syndrome, autism, childhood disintegrative disorder, Rett syndrome, pervasive developmental disorder, attention-deficit / hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, feeding disorder in infancy or early childhood, pica, rumination disorder, tic disorder, chronic motor or vocal tic disorder, Tourette syndrome, elimination disorder, encopresis, enuresis, selective mutism, separation anxiety disorder, reactive attachment disorder in infancy or early childhood, and stereotypic movement disorder.

[0147] Examples of substance-related disorders are: alcohol-related disorder, amphetamine-related disorder, caffeine-related disorder, cannabis-related disorder, cocaine-related disorder, hallucinogen-related disorder, inhalant-related disorder, nicotine-related disorder, opioid-related disorder, psychotic disorder, psychotic disorder, phencyclidine-related disorder, abuse, persistent amnestic disorder, anxiety disorder, persistent dementia, dependence, intoxication, toxic delirium, mood disorder, psychotic disorder, withdrawal, withdrawal delirium, sexual dysfunction, sleep disorder.

[0148] As used herein, the term "neuroprotection" shall mean: inhibiting, preventing, improving or reducing the severity of dysfunction, degeneration or death of nerve cells, axons or their supporting cells in the central or peripheral nervous system of mammals (including humans). This includes treating or preventing neurodegenerative diseases; protecting patients in need from excitotoxicity or improving the cytotoxic effects of compounds (e.g., excitatory amino acids such as glutamate; toxins; or preventive or therapeutic compounds that produce immediate or delayed cytotoxic side effects (including but not limited to immediate or delayed induction of apoptosis)).

[0149] As used herein, the term "patient in need of treatment with a neuroprotective drug" refers to any patient currently suffering from or at risk of suffering from any of the above syndromes or disorders, or any patient currently suffering from or at risk of suffering from any disorder in which the patient's current clinical condition or prognosis may benefit from providing neuroprotection to prevent the development, extension, worsening, or increased resistance to treatment of any neurological or psychiatric disorder.

[0150] As used herein, the term "combination administration" of a compound, therapeutic agent, or known drug with a combination of the present disclosure refers to the administration of the drug and one or more compounds at a time when the known drug and / or combination will have a therapeutic effect. In some cases, this therapeutic effect will be synergistic. With respect to the administration of the composition and / or combination of the present disclosure, such concomitant administration may include administration of the drug simultaneously (i.e., at the same time), before, or after. One of ordinary skill in the art will have no difficulty determining the appropriate timing, sequence, and dosage of administration of a particular drug of the present disclosure.

[0151] Another aspect of the present disclosure relates to the use of the continuous drug delivery systems and methods disclosed herein as therapeutic agents for preventing and / or treating heart disease. Heart disease is a general term used to describe many different heart conditions. For example, coronary artery disease is the most common heart disease, characterized by constriction or narrowing of the arteries that supply oxygen-rich blood to the heart, and can lead to myocardial infarction, which is the death of a portion of the heart muscle. Heart failure is a condition caused by the inability of the heart to pump sufficient amounts of blood to the entire body. Heart failure is not a sudden, unexpected cessation of heart activity, but typically develops slowly over many years as the heart gradually loses its ability to pump blood effectively. Risk factors for heart failure include coronary artery disease, high blood pressure, valvular heart disease, cardiomyopathy, myocardial disease, obesity, diabetes, and / or a family history of heart failure.

[0152] Examples of cardiovascular diseases and disorders are: aneurysm, stable angina, unstable angina, angina pectoris, angioedema, aortic stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular dysplasia, atherosclerosis, 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, Epstein's Anomaly, Eisenmenger syndrome, complex), cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart disease, congestive heart failure, heart valve disease, heart attack, epidural hematoma, hematoma, subdural hematoma, Hippel-Lindau disease, congestion, hypertension, pulmonary hypertension, cardiomegaly, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, 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.

[0153] Vascular disease is often the result of decreased perfusion of the vascular system or physical or biochemical damage to the vessels.

[0154] Peripheral vascular disease (PVD) is defined as a frequently encountered vascular disorder that manifests as narrowing of the blood vessels in the extremities. These conditions are of two main types: functional diseases, which do not involve vascular defects but are caused by stimuli such as cold, stress or smoking, and organic diseases, which are caused by structural defects in the vasculature, such as atherosclerotic lesions, local inflammation or traumatic injury. This can lead to vascular occlusion, abnormal blood flow, and ultimately tissue ischemia.

[0155] A more clinically significant form of PVD is peripheral arterial disease (PAD). PAD is typically treated with angioplasty and stenting or arterial bypass surgery. The clinical presentation depends on the location of the occluded blood vessel. For example, narrowing of the arteries supplying blood to the intestines can cause severe postprandial pain in the lower abdomen due to the inability of the occluded vessels to meet the increased oxygen demand during digestion and absorption. In severe forms, the ischemia can lead to intestinal necrosis. Similarly, PAD in the legs can cause intermittent pain, usually in the calves, that comes and goes with activity. This condition, called intermittent claudication (IC), can progress to constant pain at rest, ischemic ulcers, and even amputation.

[0156] Peripheral vascular disease also manifests as atherosclerotic stenosis of the renal arteries, which can lead to renal ischemia and renal dysfunction.

[0157] One disease in which vascular disease and its complications are very common is diabetes. Diabetes causes a variety of physiological and anatomical abnormalities, the most prominent of which is the body's inability to properly utilize glucose, which leads to hyperglycemia. Chronic diabetes can lead to complications of the vascular system, including atherosclerosis, abnormalities involving large and medium-sized blood vessels (macroangiopathy), and abnormalities involving small blood vessels such as arterioles and capillaries (microangiopathy).

[0158] People with diabetes are at increased risk of developing one or more foot ulcers due to established long-term complications of the disease, including impaired nerve function (neuropathy) and / or ischemia. Localized tissue ischemia is a key factor in the development of diabetic foot ulcers.

[0159] In addition to macrovascular disease, diabetics suffer from further threats to their skin perfusion in at least two additional aspects. First, non-conduit arteries are involved, which are adversely affected by the atherosclerotic process, and secondly, and perhaps more importantly, the impairment of the microcirculatory control mechanism (small vessel disease). Typically, when a part of the body is subjected to some form of trauma, as part of the body's healing mechanism, the body part will experience increased blood flow. When both small vessel disease and ischemia are present, as in the case of many diabetics, this naturally increased blood flow response is significantly reduced. This fact, together with the tendency of diabetics to form blood clots (thrombosis) in the microcirculatory system during low-level blood flow, is considered to be an important factor in the pathogenesis of ulcers.

[0160] 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, such as chronic arterial occlusions including atherosclerosis, atherosclerotic occlusive disease and thromboangiitis obliterans (Buerger's disease), macroangiopathy, microangiopathy, diabetes, thrombophlebitis, venous occlusion, Raynaud's disease, Raynaud's syndrome, CREST syndrome, vibration-induced health hazards, Sudeck syndrome, intermittent claudication, cold extremities, paresthesia of the extremities, sensitivity to cold, Meniere's disease, Meniere's syndrome, numbness, loss of sensation, anesthesia, rest pain, causalgia (burning pain), peripheral circulatory dysfunction, nerve dysfunction, motor function Derangements, motor paralysis, diabetic peripheral circulatory disorders, lumbar spinal stenosis, diabetic neuropathy, shock, autoimmune diseases (such as lupus erythematosus, rheumatoid disease, and rheumatoid arthritis), autonomic neuropathy, diabetic autonomic neuropathy, autonomic dysregulation, orthostatic hypotension, erectile dysfunction, female sexual dysfunction, retrograde ejaculation, cystopathy, neurogenic bladder, insufficient vaginal lubrication, exercise intolerance, cardiac denervation, heat intolerance, gustatory sweating, complications of diabetes, hyperglycemia, asymptomatic hypoglycemia, hypoglycemia without response; 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 eye inflammation, choroiditis, retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, Thygeson's keratitis , progressive Mooren ulcer, skin damage, skin ulcer (including foot ulcer, diabetic ulcer, burn ulcer, leg ulcer, postoperative ulcer, traumatic ulcer, postherpetic ulcer, radiation ulcer, drug-induced ulcer), frostbite (cold injury), frostbite, gangrene and sudden gangrene, angina pectoris / variant vasculitis, coronary atherosclerosis (chronic ischemic heart disease, asymptomatic ischemic heart disease, atherosclerotic cardiovascular disease), myocardial infarction, heart failure, congestive heart failure and painless ischemic heart disease, pulmonary edema, hypertension, pulmonary hypertension; portal hypertension, diabetic nephropathy, bedsores, renal failure.

[0161] Other active agents

[0162] As used herein, the term "combined administration" of a compound, therapeutic agent, or known drug with a continuous drug delivery system and method disclosed herein refers to the administration of the drug and one or more compounds at a time when the known drug and / or combination will have a therapeutic effect. In some cases, this therapeutic effect will be synergistic. With respect to the administration of the composition and / or combination of the present invention, this concomitant administration can include administration of the drug at the same time (i.e., at the same time), before, or after. One of ordinary skill in the art will have no difficulty determining the appropriate timing, sequence, and dosage of administration of a particular drug of the present invention.

[0163] Furthermore, where applicable, the active ingredient may be present in the form of one substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof.

[0164] The active ingredients may include one or more of the following therapeutic classes, but are not limited to, adrenergic drugs; adrenocortical hormones; adrenocortical inhibitors; aldosterone antagonists; amino acids; anabolic drugs; stimulants; analgesics; anesthetics; appetite suppressants; anti-acne drugs; anti-adrenergic drugs; anti-allergic drugs; anti-amoebic drugs; antianemic drugs; anti-anginal drugs; anti-arthritic drugs; anti-asthmatic drugs; anti-atherosclerotic drugs; antibacterial drugs; anticholinergic drugs; anticoagulants; anticonvulsants; antidepressants; antidiabetic drugs; antidiarrheal drugs; antidiuretics; antiemetic drugs; antiepileptic drugs; antifibrinolytic drugs; Antifungal drugs; hemostatic drugs; antihistamines; antihyperlipidemic drugs; antihypertensive drugs; antihypotensive drugs; anti-infective drugs; anti-inflammatory drugs; antimicrobial drugs; antimigraine drugs; antimitotic drugs; antifungal drugs; antinausea drugs; antineoplastic drugs; antineutropenic drugs; antiparasitic drugs; antiproliferative drugs; antipsychotic drugs; antirheumatic drugs; antiseborrheic drugs; antisecretory drugs; antispasmodics; antithrombotic drugs; antiulcer drugs; antiviral drugs; appetite suppressants; blood sugar regulators; bone resorption inhibitors; bronchodilators; cardiovascular drugs; cholinergic drugs; inhibitors; diagnostic aids; Urine agents; dopaminergic drugs; estrogen receptor agonists; fibrinolytic drugs; fluorescent agents; oxygen free radical scavengers; gastric acid inhibitors; gastrointestinal motility effectors; glucocorticoids; hair growth stimulants; hemostatic drugs; histamine H2 receptor antagonists; hormones; cholesterol-lowering drugs; blood sugar-lowering drugs; lipid-lowering drugs; antihypertensive drugs; imaging agents; immune agents; immunomodulators; immunoregulators; immunostimulants; immunosuppressants; keratolytics; LHRH agonists; mood regulators; mucolytics; mydriatics; nasal decongestants; neuromuscular Meat blockers; neuroprotectants; NMDA antagonists; non-hormonal steroid derivatives; plasminogen activators; platelet activating factor antagonists; platelet aggregation inhibitors; psychotropic drugs; radiopharmaceuticals; scabicides; sclerosants; sedatives; sedative-hypnotic drugs; selective adenosine A1 antagonists; serotonin antagonists; serotonin inhibitors; serotonin receptor antagonists; steroids; thyroid hormones; thyroid suppressants; thyroid mimetic drugs; tranquilizers; amyotrophic lateral sclerosis drugs; cerebral ischemia drugs; Paget's disease drugs; unstable angina drugs; vasoconstrictors; vasodilators; wound healing drugs; xanthine oxidase inhibitors.

[0165] As described above, the continuous drug delivery systems and methods disclosed herein may include auxiliary excipients, such as diluents, binders, lubricants, surfactants, disintegrants, plasticizers, anti-adherents, opacifiers, pigments, etc. As will be appreciated by those skilled in the art, the exact choice of excipients and their relative amounts will depend to some extent on the final oral dosage form.

[0166] Parkinson's disease

[0167] The present disclosure provides a continuous drug delivery system and method for treating and / or preventing and / or controlling, for example, Parkinson's disease (PD). PD is a degenerative disorder of the central nervous system that primarily affects the motor system, belongs to a group of conditions called motor system disorders, and is the result of the loss of dopamine-producing cells in the substantia nigra. The cause of this cell death is largely unknown. In the early stages of the disease, the most obvious symptoms are movement-related; these symptoms include tremors, stiffness, slow movements, and difficulty walking and gait. Subsequently, thinking and behavioral problems may occur, and dementia usually occurs in the late 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 the elderly, with most cases occurring after the age of 50; when it occurs in young adults, it is called young-onset PD (YOPD).

[0168] The four main symptoms of PD are tremors or shaking of the hands, arms, legs, jaw, and face; stiffness or rigidity of the limbs and trunk; bradykinesia, or slow movements; 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 mood changes; difficulty swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and disrupted sleep. There are currently no blood or laboratory tests that have been shown to help diagnose sporadic PD, and the diagnosis is based on medical history and a neurological examination.

[0169] The main motor symptoms are collectively called parkinsonism, or "parkinsonian syndrome". The disease can be primary or secondary. Primary parkinsonism is called idiopathic (of unknown cause), although some atypical cases have a genetic cause, while secondary parkinsonism is caused by a known cause such as toxins. Many risk and protective factors have been investigated: the clearest evidence is that people exposed to certain pesticides have an increased risk of PD, while smokers have a reduced risk. The pathological hallmarks of the disease are the accumulation of proteins in neurons called Lewy bodies, and insufficient formation and activity of dopamine in certain parts of the midbrain. Where the Lewy bodies are located often correlates with the presentation and extent of an individual's symptoms. Diagnosis in typical cases is based primarily on symptoms, with confirmation using tests such as neuroimaging.

[0170] Currently, PD has no cure, but various medications can relieve symptoms. Treatment, typically with the drugs L-DOPA and dopamine agonists, improves early symptoms of the disease. As the disease progresses and loss of dopaminergic neurons continues, these drugs eventually become ineffective in treating symptoms, while developing complications characterized by involuntary writhing movements. Diet and some forms of rehabilitation have shown some success in improving symptoms. In severe cases where medications are ineffective, surgery and deep brain stimulation have been used as a last resort to reduce motor symptoms. Research directions include studying new animal models of the disease and the potential usefulness of gene therapy, stem cell transplants, and neuroprotectants. Drugs also exist to treat non-motor related symptoms of PD such as sleep disturbances and emotional problems.

[0171] Since 1967, levodopa (L-DOPA) has been the most widely used treatment. L-DOPA is converted to dopamine in dopaminergic neurons by the enzyme dopa decarboxylase. Since motor symptoms are caused by a lack of dopamine in the substantia nigra, administering L-DOPA temporarily reduces motor symptoms. Typically, affected individuals are given levodopa with carbidopa, which delays the conversion of levodopa to dopamine until it reaches the brain. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. Although levodopa helps in at least three-quarters of Parkinson's cases, not all symptoms respond equally to this medication. Bradykinesia and rigidity respond best, while tremors may only be slightly reduced. Problems with balance and other symptoms may not be relieved at all. Anticholinergic drugs may help control tremors and rigidity. Other drugs, such as bromocriptine, pramipexole, and ropinirole, mimic the effects of dopamine in the brain, causing neurons to respond as if they were to dopamine. The antiviral drug amantadine also appears to reduce symptoms.

[0172] An estimated 53 million people have PD, resulting in approximately 103,000 deaths worldwide. Parkinson's disease typically develops in people over the age of 60, with men being affected more often than women. The average life expectancy after diagnosis is between 7 and 14 years. Parkinson's disease is often idiopathic (with no specific known cause); however, a subset of cases can be attributed to known genetic factors. For example, mutations in specific 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). LRRK2 mutations are the most common known cause of both 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 the pathogenesis of PD. Although treatment of PD is available, more effective therapies are needed.

[0173] Modern treatment attempts to control the early motor symptoms of the disease, primarily through the use of levodopa and dopamine agonists. As the disease progresses and dopamine neurons continue to be lost, these drugs eventually become ineffective in treating symptoms, while producing complications characterized by involuntary writhing movements called dyskinesias. Therefore, there is a need in the art to be able to deliver large oral equivalent doses of, for example, CBD to achieve therapeutic effects and eliminate or reduce withdrawals, adverse events, and side effects, such as diarrhea, drowsiness, abdominal pain, weight gain, headaches, etc., as adverse events, such as elevated liver enzymes, associated with large oral doses to treat motor symptoms in Parkinson's disease subjects, including Parkinson's disease symptoms as well as symptoms indirectly related to Parkinson's disease, such as symptoms that occur as side effects of treatment.

[0174] The present disclosure provides continuous drug delivery systems and methods for treating and / or preventing and / or managing Parkinson's disease in a patient, comprising administering CBD and / or THC, e.g., as described herein.

[0175] Epileptic seizure symptoms

[0176] The present disclosure provides a continuous drug delivery system and method for treating and / or preventing and / or controlling epileptic seizures in a patient, including administering CBD and / or THC, for example, as described herein. An epileptic seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "epileptic seizure" is often used interchangeably with "convulsion." A convulsion is a rapid and uncontrolled shaking of a person's body. During a convulsion, a person's muscles repeatedly contract and relax.

[0177] Based on the type of behavior and brain activity, seizures are divided into two main categories: generalized and partial (also called localized or focal). Classifying the type of seizure helps doctors diagnose whether a person has epilepsy.

[0178] Generalized seizures are produced by electrical impulses from the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain where the seizure occurs is sometimes called the focus.

[0179] There are six types of generalized seizures. The most common, most violent, and best known is a generalized convulsion, also called a grand mal seizure. During this type of seizure, the person loses consciousness and usually passes out. Loss of consciousness is followed by a period of generalized stiffness (called the "tonic" phase of the seizure) lasting 30 to 60 seconds, followed by violent shaking (the "clonic" phase) lasting 30 to 60 seconds, after which the person falls into a deep sleep (the "postictal" or post-seizure phase). During a grand mal seizure, injuries and accidents can occur, such as biting the tongue and urinary incontinence.

[0180] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. The patient (most often a child) typically stops activity and stares blankly. These seizures start and end suddenly and may occur several times a day. Patients are usually unaware that they are having a seizure, except that they may be aware of "time passing." Myoclonic seizures consist of sporadic shaking, usually on both sides of the body. Patients sometimes describe the shaking as brief electric shocks. When violent, these seizures may cause falling or involuntary throwing of objects. Clonic seizures are repetitive, rhythmic shaking that involves both sides of the body at the same time. Tonic seizures are characterized by muscle rigidity. Flaccid seizures consist of a sudden and complete loss of muscle tone, especially in the arms and legs, often resulting in a fall.

[0181] The seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; uninterrupted seizures; prolonged seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; flaccid seizures; benign Rolandic seizures; febrile seizures; affective seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; micro-seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

[0182] Epilepsy

[0183] The present disclosure provides a continuous drug delivery system and method for treating and / or preventing and / or controlling epilepsy in a patient, including administering CBD and / or THC, for example, as described herein. Epilepsy is a brain disorder characterized by repeated epileptic seizures over time. The types of epilepsy may include, but are not limited to, generalized epilepsy, for example, childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures during awakening, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex (TSC), refractory epilepsy, refractory childhood epilepsy, partial epilepsy, for example, temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

[0184] Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, definitive status epilepticus, refractory status epilepticus, and super-refractory status epilepticus; non-convulsive status epilepticus, such as 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 attacks, and may include early status epilepticus, definitive status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Definitive status epilepticus is characterized by status epilepticus attacks that continue despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by status epilepticus attacks that continue despite treatment with first-line and second-line therapy, and general anesthetics are usually administered. Super-refractory status epilepticus is characterized by status epilepticus attacks that continue despite treatment with first-line therapy, second-line therapy, and general anesthetics for 24 hours or more.

[0185] Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, and minimal non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0186] The compositions described herein can also be administered as a prophylactic agent to a subject suffering from a CNS disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, definitive status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic hemi-epileptiform discharges; prior to an epileptic seizure.

[0187] Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that usually becomes apparent in infancy or early childhood. LGS usually develops between the ages of 2 and 7, with a peak incidence between the ages of 3 and 5. Affected children experience several different types of seizures, the most common being flaccid, tonic, and atypical absence seizures.

[0188] In 2018, GW Pharmaceutical received FDA approval for its Fast Track-designated drug Epidiolex (cannabidiol) to treat two orphan conditions in children—LGS and Dravet syndrome (DS).

[0189] Epidiolex contains naturally derived cannabidiol (100 mg / ml) from the Sativex plant in the form of an oral solution. According to the FDA label, the recommended dosage of Epidiolex is described in Table 1.

[0190] Table 1: Recommended Dosages of Epidiolex for LGS and DS 1

[0191]

[0192] Epidiolex has five major dose-dependent side effects: 1) hepatocellular damage, 2) drowsiness and sedation, 3) suicidal behavior and thoughts, 4) hypersensitivity reactions, and 5) anti-epileptic drug withdrawal. 1 .

[0193] Epidiolex has a high discontinuation rate due to hepatocellular injury and drowsiness and sedation side effects. During clinical trials, 1.3% of patients taking 10 mg / kg / day of Epidiolex and 5.9% of patients taking 20 mg / kg / day discontinued due to hepatocellular injury. In addition, 0% of patients taking the 10 mg / kg / day dose and 3% of patients taking the 20 mg / kg / day dose withdrew due to drowsiness and sedation. Table 2 provides the dose-dependent side effects produced by Epidiolex. 1 .

[0194] Table 2: Dose-dependent adverse reactions: (FDA) 1

[0195]

[0196]

[0197]

[0198] These side effects are dose-related, so patients need to be monitored and the dose reduced if necessary.

[0199] Many orally delivered drugs irritate the gastrointestinal mucosa, and a large number of drugs, including CBD, undergo extensive "first-pass" inactivation by the liver. The compositions and methods of the present disclosure involve delivering drugs directly to the systemic circulation, and thus the compositions and methods of the present disclosure overcome the problems of gastrointestinal irritation and first-pass metabolism in the liver, because the active agent avoids being metabolized by the liver after absorption, and also avoids gastrointestinal irritation because it is not administered orally.

[0200] However, the continuous drug delivery systems and methods disclosed herein constantly deliver drug molecules at a determined input rate. Unlike the peaks and valleys of plasma concentrations in oral delivery, the continuous drug delivery systems and methods disclosed herein maintain average plasma concentrations at a predetermined constant input rate.

[0201] Although patents about cannabidiol are available, these disclosed shortcomings are overcome by compounds and methods disclosed herein. For example, US 9375417 does not provide any in vitro or in vivo data. US 6328992 discloses reservoir and adhesive matrix patch, but these embodiments comprise cannabinoid mixtures (such as δ-8-THC, δ-9-THC, cannabidiol and cannabinol), rather than only comprising cannabidiol. THC is a psychoactive substance, also a kind of addictive substance, so its effectiveness is unresolved.

[0202] In addition, US 8449908 discloses a cumulative amount of 60600 ng delivered through human cadaver skin within 48 hours. This amount represents a flux of 1925 ng / sqcm / hr. The patch area can be calculated using the following formula.

[0203] In vitro flux (ug / sqcm / hr) = (Css (ug / l) * CL (L / hr) / patch area (Sqcm)

[0204] Patch area (Sqcm) = (Css (ug / l) * CL (L / hr) / in vitro flux (ug / sqcm / hr)

[0205] =(10*74.4) / 1.925

[0206] =386sqcm

[0207] In order to deliver 5 mg / kg / day of cannabidiol, the patient must apply the formulation on a surface area of ​​386 sq cm. This is an impractical patch size for any transdermal drug delivery system (TDDS). In addition, the '908 patent discloses the use of a receiving medium PBS:PEG-400 (60:40). As is well known, PEG-400 is a penetration enhancer, and by incorporating it into the receiving medium, the skin is damaged from the dermis side, which also increases the amount of penetration because the skin sample cannot survive.

[0208] pain

[0209] The present disclosure provides continuous drug delivery systems and methods for treating and / or preventing and / or managing pain in a patient, comprising administering CBD and / or THC, for example, as described herein. As used herein, the following terms have the following meanings.

[0210] As used herein, the term "chronic pain" or "chronic pain state" is defined as any pain that persists for more than, for example, about 6 to about 12 weeks.

[0211] As used herein, the term "neuropathic pain" has its conventional meaning and refers herein to pain that is produced as a direct or indirect consequence of a lesion or disease that affects the somatosensory system (central and / or peripheral). As used herein, neuropathic pain includes all types of neuropathic pain, such as peripheral neuropathy caused by type 1 or type 2 diabetes, induced by various noxious substances such as alcohol, due to various deficiencies such as vitamin B1, B6 and / or B12 deficiency, various poisonings such as vitamin B6 hypervitaminosis, hypothyroidism, chemotherapeutic compounds (e.g., paclitaxel or other taxane derivatives, vincristine or other vinca alkaloids, cisplatin or other platinum derivatives), drug-induced neuropathy, compounds used to treat infectious diseases (e.g., streptomycin, didanosine or zalcitabine) or any other chemical toxic compound. Other peripheral neuropathies include the following: trigeminal neuralgia, postherpetic neuralgia, intercostal neuralgia, entrapment neuropathies (e.g., carpal tunnel syndrome, tarsal tunnel syndrome, abdominal cutaneous nerve entrapment syndrome), small fiber neuropathies, hereditary motor sensory neuropathy, chronic inflammatory demyelinating polyneuropathy, sciatica, chronic idiopathic sensory neuropathy, infectious disease conditions such as post-polio syndrome, AIDS or HIV-related, Lyme disease-related, Sjögren's syndrome-related, lymphomatous neuropathy, myelomatous neuropathy, carcinomatous neuropathy, acute panautonomic neuropathy, vasculitic / ischemic neuropathy, and other mono- and polyneuropathies. In addition, the term "neuropathic pain" also includes the following: 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), postoperative scar pain including cardiac surgery and mastectomy.

[0212] As used herein, the term "inflammatory pain" has its conventional meaning and refers herein to pain caused by inflammation, which may be caused by, but is not limited to, trauma, burns, extreme cold, fractures, (osteo)arthritis, rheumatoid arthritis, chronic strain, surgery, infection and autoimmune diseases, overstretching, infection and vasoconstriction. Various inflammatory mediators can directly affect nociceptors or can make them sensitive to touch or movement, even if the nociceptors are some distance from the area of ​​inflammation.

[0213] As used herein, the term "musculoskeletal pain" has its conventional meaning and refers to pain affecting muscles, ligaments, tendons, bones, joints and / or soft tissues that are part of the musculoskeletal system in this article. As used herein, musculoskeletal pain includes all types of pain caused by muscle tissue damage due to wear and tear caused by daily activities. Trauma in one area (shaking sports, car accidents, falls, sports injuries, fractures, sprains, strains, dislocations, and direct blows to muscles) can also cause musculoskeletal pain. Other causes of musculoskeletal pain include postural tension, repetitive movements, overuse and prolonged immobilization, muscle misuse, fibromyalgia, low back pain, pain caused by increased muscle tension, and tendinitis caused by overuse.

[0214] As used herein, the term "analgesic" or "analgesic" has its conventional meaning and is used herein in its broadest sense to refer to a compound, agent, drug or substance that relieves pain.

[0215] As used herein, the term "co-analgesic" or "co-analgesic" has its conventional meaning and refers herein to compounds, agents, drugs or substances whose primary indication is for purposes other than pain relief, which compounds exhibit analgesic activity.

[0216] As used herein, the term "restoration of analgesic effect" has its conventional scientific meaning and refers herein to the ability of (a compound or composition) to restore the analgesic effect of at least one analgesic compound or at least one co-analgesic compound when a decrease in analgesic effect occurs after repeated use of a topical formulation containing at least one analgesic or co-analgesic compound.

[0217] As used herein, the terms "effect enhancer" or "co-analgesic effect enhancer" or "therapeutic effect enhancer" or "enhanced effect" or "synergistic effect" have their conventional meanings and refer herein to the enhancement of the therapeutic effect caused by a co-analgesic compound ("co-analgesic"), resulting in 1) an increase in the therapeutic effect of the active pharmaceutical ingredient for the purpose of reducing neuropathic pain, inflammatory pain, musculoskeletal pain, pain caused by muscle spasm and / or other chronic pain states, 2) a faster onset of pain relief, 3) a longer duration of analgesia, and / or 4) restoration of analgesia when a decrease in analgesia occurs after repeated use of a topical pharmaceutical composition containing at least one analgesic compound ("analgesic") or co-analgesic compound.

[0218] Pain is caused by noxious stimulation of nerve endings. Nociceptive pain is caused by noxious stimulation of nociceptors, which transmit impulses to spinal neurons through intact nerve pathways and then to the brain. Peripheral neuropathic pain is pain caused by damage to nerve endings and occurs primarily in the skin, especially the epidermis. These damaged nerve endings can generate impulses in the absence of stimulation, can be hypersensitive to normal stimulation, and / or can be triggered by residual local inflammatory stimulation. Even a very small number of damaged and overactive small nerve fibers in the epidermis are sufficient to trigger peripheral neuropathic pain. Neuropathic pain can be debilitating and can significantly reduce a patient's quality of life. This pain may persist for months or years, outlasting any apparent healing of damaged tissue.

[0219] Neuropathic pain has a local inflammatory component that leads to sensitization of nerve fibers. Other intact nerve fibers that innervate the same area, such as nociceptors present in the stratum granulosum, can also be sensitized and participate in the clinical symptoms of neuropathic pain (e.g., hyperalgesia). This leads to a situation of local neurogenic inflammation, resulting in many different clinical features, such as burning, freezing, electric shock (electric shock), itching, tingling, numbness, hyperalgesia, and allodynia (pain caused by non-painful stimuli such as light touch or stroke).

[0220] Peripheral nerve injury results in increased transmitter release within the spinal cord and can lead to central sensitization. Increased peripheral input via primary afferents plays a key role in central sensitization and the maintenance of neuropathic pain. Peripherally acting medications, such as lidocaine 5% medicated patch and capsaicin 8% patch, have demonstrated the ability to reduce pain in neuropathic pain syndromes. However, lidocaine patches are not easy to apply, especially on the toes and by the elderly, as the patch must be cut and many elderly people cannot fully reach their toes. Application of capsaicin creams and patches often causes intolerable side effects, such as increased burning sensation, and often treatment must be combined with local anesthesia to neutralize this side effect.

[0221] For example, in general chronic pain, oral analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are part of medication instructions aimed at relieving pain. However, long-term use of such oral analgesics can cause serious and fatal side effects and / or harmful drug-drug interactions.

[0222] Topical analgesic pharmaceutical compositions have also been 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 counterirritant) and lidocaine (a membrane stabilizer), both of which have significant disadvantages.

[0223] Clearly, there remains an urgent and long-felt need in the field of developing treatment options for chronic pain in general and neuropathic pain in particular, and in developing novel and effective pharmaceutical compositions for the treatment of chronic pain that have reduced side effects for the patient.

[0224] Dosage form

[0225] The continuous drug delivery systems and methods disclosed herein can include active agents, such as in liquid formulations. Liquid formulations can also be prepared by dissolving or suspending an active substance or combination of active substances in a conventional liquid vehicle acceptable for administration, thereby providing the desired dose, such as in 1-4 teaspoons.

[0226] The dosage form can be administered to the patient on a regimen of, for example, once, twice, three times, four times, five times, six times or other multiple doses per day.

[0227] In order to more finely adjust the dosage regimen, the active substances can be administered separately in individual dosage units at the same time or at carefully coordinated times. The various substances can be separately formulated into individual unit dosage forms in a manner similar to that described above.

[0228] In formulating the composition, the above-mentioned amounts of active substances may be mixed with physiologically acceptable vehicles, carriers, excipients, binders, viscosity regulators, preservatives, stabilizers, flavoring agents, etc. in a specific type of unit dosage form according to recognized practices.

[0229] Packaging / Treatment Kits

[0230] The present disclosure provides a kit for conveniently and effectively implementing the method according to the present disclosure. Such a kit may be suitable for delivery of solid oral forms such as tablets or capsules. Such a kit may include a number of unit doses. Such a kit may include a device for containing doses oriented in the order in which they are intended to be used. An example of a device for containing doses in the order in which they are intended to be used 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. If necessary, the blisters may be in the form of child-safe blister packs, i.e., blisters that are difficult for children to open but can be easily opened by adults. If necessary, a memory aid may be provided, such as in the form of numbers, letters or other markings, or with calendar features and / or calendar inserts, indicating the date and part of the day in the treatment regimen in which the dose may be administered, for example, an AM dose is packaged with a "noon" and PM dose; or an AM dose is packaged with a PM dose. Alternatively, a placebo dose or a vitamin or dietary supplement in a form similar or different from the active dose may be included.

[0231] The present disclosure provides compositions, including preparations, formulations and / or kits, comprising a combination of ingredients as described above (including a multi-ingredient combination of a drug), which can be used as a therapy for treating, preventing or improving the conditions, states and diseases provided by the present invention. 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 alternative aspects, the packaging, kit or container includes a blister package, a clamshell package, a tray, a shrink wrap, etc.

[0232] In one aspect, the package, kit or container comprises a "blister pack" (also known as a blister pack or bubble pack). In one aspect, a blister pack consists of two or more separate compartments. Such a blister pack consists of two separate material elements: a clear plastic cavity, which is shaped to conform to the product, and a blister sheet backing. The two elements are then joined together by a heat sealing process so that the product can be hung or displayed. Exemplary types of "blister packs" include: face seal blister packs, group run blister packs, simulated blister packs, interactive blister packs, and slide blister packs.

[0233] Blister packs, flip-top packs or trays are packaging forms for commercial products; therefore, the present invention provides blister packs, flip-top packs or trays containing the composition of the present invention (e.g., a combination of active ingredients (a multi-ingredient combination of the drug of the present invention)). The blister pack, flip-top pack or tray can be designed to be non-reclosed, so consumers can tell whether the package has been opened. They are used to package goods for sale where product intervention is a concern, such as the medicaments of the present invention. In one aspect, the blister package of the present invention comprises a molded PVC substrate with a raised area ("blister") to accommodate tablets, pills, etc. containing the combination of the present invention, and is covered by a foil. The tablets, pills, etc. are removed from the package by peeling back the foil or by pushing the blister to force the tablet to break the foil. In one aspect, a special form of the blister package is a strippack.

[0234] In one aspect, blister packaging also includes a packaging method in which a composition comprising the combination of ingredients of the present invention is contained between a card and a clear PVC. The PVC can be clear so that the items (pills, tablets, geltabs, etc.) can be easily seen and inspected; and in one aspect, can be vacuum formed around a mold so that it can tightly contain the items and have an open space when purchased. In one aspect, the card is brightly colored and designed according to the items inside (pills, tablets, geltabs, etc.), and the PVC is fixed to the card using a pre-formed label where the adhesive is placed. The adhesive can be strong enough so that the package can be hung on a hook, but also weak enough so that people can tear the seam and access the items. Sometimes for large items or multiple packaged pills, tablets, geltabs, etc., the card has a perforated window for access. In one aspect, more secure blister packaging is used, such as for items such as pills, tablets, geltabs, etc. of the present invention, and they can include two vacuum-formed PVC sheets that are dovetailed together at the edges, with an information card inside.

[0235] In one aspect, a blister package includes at least two components (e.g., a multi-ingredient combination of a drug of the invention): a thermoformed "blister" containing the product (e.g., a combination of the invention), followed by a "blister card," which is a printed card with an adhesive coating on the front surface. During assembly, the blister assembly, typically made of PVC, is attached to the blister card using a blister machine. Conventional blister packages can also be sealed.

[0236] As discussed herein, articles of manufacture of the invention can include packaging of the therapeutic combinations of the invention, either singly or in combination, as a "blister pack" or as multiple packs, including as a blister pack with lid, a blister or blister card or pack with lid, or shrink wrap.

[0237] In one aspect, any article of manufacture of the invention (including a kit or blister pack) includes a memory-aid to help remind the patient when and how to take the agent of the invention.

[0238] Therapeutic kits can be constructed in various forms familiar to those of ordinary skill in the art. The kit comprises at least one active substance for a unit dose administered according to a daily regimen and a device for accommodating the unit dose. For example, the therapeutic kit can be constructed for once a day, twice a day, three times a day, four times a day, multiple times a day, or other dosage regimens. The kit includes a device for daily administration of the medicament of the present invention. In one embodiment, the kit includes about 1 to about 4 unit doses.

[0239] In one embodiment, the device for accommodating the unit dose is a card, including, for example, a card that can be folded. The card will be referred to herein as a main card, or a principal card or a first card, to distinguish it from additional optional cards, rounds, or other such materials that may be associated with the kit. This main card can be folded with a simple fold, or folded with a double fold to display a spine, similar to the spine of a closed book. The main card may include a printable surface, i.e., a surface on which the product name, appropriate instructions for use, product information, illustrations, logos, memory aids, calendar features, etc. may be printed. The main card may include a device for accommodating the unit dose or different doses specified for different times of the day, and a memory aid for administering the one or more unit doses. The main card, especially if it is prepared from two or more laminated paperboard surfaces, may include a slit or pocket, such as in an inner paperboard surface of a folded card. The slit or pocket may be used to accommodate a removable secondary card, i.e., a second card or an insert card, which is not permanently attached or attached to the main card.

[0240] 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 the preferred day of the week for administering therapy. The memory aid may include a list of times of the day, with appropriate space for the patient to select and indicate on the card the preferred time of the day for administering therapy (e.g., AM, PM, noon). The memory aid may also include a removable sticker with an appropriate pressure-sensitive adhesive for easy removal and refastening to a desired surface, such as a calendar or dayminder. The removable sticker may be located on the primary card, or may be located on a secondary card that is configured so that it can be easily inserted into and removed from the optional slit of the primary card. In addition, the optional slit may include additional patient information and other notifications.

[0241] Other devices for containing the unit doses may include bottles and vials, wherein the bottle or vial includes a memory aid, such as a printed label for administering the one or more unit doses. The label may also include a removable reminder sticker for placement on a calendar or schedule to further help the patient remember when to take a dose or when a dose has been taken.

[0242] The present invention will be described in more detail with reference to the following examples, but it should be understood that the present invention is not limited thereto.

[0243] Example

[0244] Example 1

[0245] The continuous drug delivery system and method disclosed herein may include solvents known to those skilled in the art, alone or in combination, and are not limited to the following substances, such as alcohols C1-C 20, such as but not limited to (methanol, ethanol, isopropanol, butanol, propanol, etc.), polyols, glycols, such as but not limited to (propylene glycol, polyethylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, glycerol, etc.), ethylene glycol derivatives, pyrrolidones, such as but not limited to (N-methyl 2-pyrrolidone, 2-pyrrolidone, etc.), sulfoxides, such as but not limited to (dimethyl sulfoxide, decyl methyl sulfoxide, etc.), dimethyl isosorbide, mineral oil, vegetable oil, sesame oil water, polar solvents, semi-polar solvents, non-polar solvents, volatile chemicals that can be used to prepare matrix patches, such as but not limited to (ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA, hexane), acids, such as but not limited to acetic acid, lactic acid, levulinic acid, bases, etc., pentane, dimethylformamide, butane, lipids. More preferably, it is in the range of 0.01%-95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure may include a concentration 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 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86 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% solvent. In exemplary embodiments, the formulations of the present disclosure may include a solvent at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, the solvent will comprise about 1 wt% to 75 wt%, preferably 2 wt% to 30 wt%, and more preferably 5 wt% to 20 wt% of the formulation.

[0246] Example 2

[0247] The continuous drug delivery system and method disclosed herein may include gelling agents and / or thickening agents and / or suspending agents and / or polymers and / or viscous polymers and / or pressure-sensitive viscous polymers known to those skilled in the art, alone or in combination, and are not limited to the following substances, such as natural polymers, polysaccharides and their derivatives, such as but not limited to (agar, alginic acid and derivatives, cassia, collagen, gelatin, gellan gum, guar gum, pectin, carrageenan potassium or sodium, tragacanth gum, xanthan gum, Kohlrabi gum, chitosan, resins, etc.), semi-synthetic polymers and their derivatives, such as but not limited to cellulose and its derivatives (methyl cellulose, ethyl cellulose, etc.), cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), synthetic polymers and their derivatives, such as but not limited to carboxyvinyl polymers or carbomers (carbomer 940, carbomer 934, carbomer 971pNF), polyethylene and its copolymers, etc., clays, such as but not limited to (silicates, bentonites), silica, polyvinyl alcohol, acrylic acid polymers (eudragit), acrylates, polyacrylate copolymers, polyacrylamides, polyvinyl pyrrolidone homopolymers and polyvinyl pyrrolidone copolymers, such as but not limited to (PVP, Kollidon 30, poloxamer), isobutylene, ethyl vinyl acetate copolymer, natural rubber, synthetic rubber, pressure sensitive adhesives such as silicone polymers, such as but not limited to (Bio PSA 4302, Bio-PSA 4202, etc.), acrylic pressure sensitive adhesives, such as but not limited to (Duro-Tak 87-2156, Duro-Tak 387-2287, Duro-Tak87-9301, Duro-Tak 387-2051, etc.), polyisobutylene, such as but not limited to (polyisobutylene low molecular weight, polyisobutylene medium molecular weight, polyisobutylene 35000mw, etc.), acrylic copolymers, rubber-based adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and / or organic solvent swellable polymers, etc.In exemplary embodiments, the formulations of the present disclosure may include a concentration 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% 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% of gelling agent and / or thickening agent and / or suspending agent and / or polymer and / or viscous polymer and / or pressure-sensitive adhesive polymer. In exemplary embodiments, the formulations of the present disclosure may include a gelling agent and / or thickening agent and / or suspending agent and / or polymer and / or viscous polymer and / or pressure-sensitive viscous polymer at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, the gelling agent and / or thickening agent and / or suspending agent and / or polymer and / or viscous polymer and / or pressure-sensitive viscous polymer will account for about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt% to 20 wt%, and more preferably in the range of 0.1%-80% w / w or w / v.

[0248] Example 3

[0249] The continuous drug delivery system and method disclosed herein may include permeation enhancers known to those skilled in the art, alone or in combination, such as, but not limited to, sulfoxides and similar chemicals, such as, but not limited to (dimethyl sulfoxide, dimethylacetamide, dimethylformamide, decyl methyl sulfoxide, dimethyl isosorbide, etc.), azones, pyrrolidones, such as, but not limited to (N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), esters, fatty acid esters, such as, but not limited to (propylene glycol monolaurate, butyl acetate, ethyl acetate, isopropyl myristate, isopropyl palmitate, methyl acetate, lauryl lactate, ethyl oleate, decyl oleate, glyceryl monooleate, glyceryl monolaurate Esters, lauryl laurate, etc.), fatty acids, such as but not limited to (capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, etc.), alcohols, fatty alcohols and diols, such as but not limited to (oleyl alcohol, naphthyl alcohol, 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, polysorbate), terpenes, terpenoids and all penetration enhancers or permeability enhancers mentioned in the book "Percutaneous Penetration Enhancers" (Eric W. Smith, Howard I. Maibach, 2005. Nov, CRC press). In an exemplary embodiment, the formulations of the present disclosure may include a concentration 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 79%, about 80%, about 81%, about 81%, about 82%, about 83%, about 84%, about 8 0%, 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% penetration enhancer.In exemplary embodiments, the formulations of the present disclosure may include a penetration enhancer at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, the penetration enhancer will comprise about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.%, more preferably in the range of 0.01%-95% w / w or w / v.

[0250] Example 4

[0251] The continuous drug delivery system and method disclosed herein may include plasticizers known to those skilled in the art, alone or in combination, and are not limited to the following substances, such as glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacates, citrates, tartaric acid esters, adipates, phthalates, triacetin, oleate and all plasticizers mentioned in the book "Handbook of Plasticizers" (George Wypych, 2004, Chem Tec Publishing) that can be used in continuous drug delivery systems. In exemplary embodiments, the formulations of the present disclosure may include a concentration 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 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86 %, 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% plasticizer. In exemplary embodiments, the formulations of the present disclosure may include a plasticizer at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, the plasticizer will comprise about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.%, more preferably in the range of 0.01%-95% w / w or w / v.

[0252] Example 5

[0253] The continuous drug delivery system and method disclosed herein may include emollients, humectants, skin irritation reducing agents and similar compounds or chemicals known to those skilled in the art, alone or in combination, and are not limited to the following substances, such as petrolatum, lanolin, mineral oil, polydimethylsiloxane, zinc oxide, glycerin, propylene glycol, etc. More preferably, it is in the range of 0.01%-95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure may include a concentration 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 79%, about 80%, about 80%, about 81%, about 81%, about 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% of emollients, humectants, skin irritation reducing agents and similar compounds. In exemplary embodiments, the formulations of the present disclosure may include emollients, humectants, skin irritation reducing agents and similar compounds at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, emollients, humectants, skin irritation reducing agents and similar compounds will account for about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.%, more preferably in the range of 0.01%-95% w / w or w / v.

[0254] Example 6

[0255] The continuous drug delivery system and method disclosed herein may include solubilizers, surfactants, emulsifiers, dispersants and similar compounds or chemicals known to those skilled in the art, alone or in combination, and are not limited to the following substances, such as polysorbates, for example but not limited to (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.), Span, for example 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 monolaurate type II, linoleoyl polyoxyethylene-6 glyceride, oleoyl-polyoxyethylene-6-glyceride, lauroyl polyoxyethylene-6-glyceride, polyglycerol-3-dioleate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglycerol-3-dioleate, caprylocaproyl polyoxyethylene-8 glyceride, etc., cyclodextrin, etc. More preferably, it is in the range of 0.01%-95% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure can include a concentration 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 79%, about 80%, 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% of solubilizers, surfactants, emulsifiers, dispersants and similar compounds. In exemplary embodiments, the formulations of the present disclosure may include solubilizers, surfactants, emulsifiers, dispersants, and similar compounds at concentrations of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, solubilizers, surfactants, emulsifiers, dispersants, and similar compounds will account for about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.%, and more preferably in the range of 0.01%-95% w / w or w / v.

[0256] Example 7

[0257] Different techniques and ingredients can be used to increase 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 can be used to increase the stability of the active agent in the formulation, etc.

[0258] Example 8

[0259] The continuous drug delivery system and method disclosed herein may include auxiliary pH buffers and pH stabilizers and similar compounds known to those skilled in the art to help maintain the appropriate pH of the formulation within the range of preferably 4.0-8.0, alone or in combination, such as phosphate buffer, acetate buffer, citrate buffer, etc., acids, such as but not limited to (carboxylic acids, inorganic acids, sulfonic acids, ethylene-interval carboxylic acids, etc.), bases, such as but not limited to (sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate), etc. More preferably, it is within the range of 0.01%-30% w / w or w / v. In an exemplary embodiment, the formulations of the present disclosure may include a concentration 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 79%, about 80%, about 81%, about %, 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% of pH buffers and pH stabilizers and the like. In exemplary embodiments, the formulations of the present disclosure may include pH buffers and pH stabilizers and similar chemicals at a concentration of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, pH buffers and pH stabilizers and similar chemicals will account for about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.%, and more preferably in the range of 0.01%-30% w / w or w / v.

[0260] Example 9

[0261] The continuous drug delivery system and method disclosed herein may include antioxidants (such as but not limited to (sodium metabisulfite, citric acid, ascorbic acid, BHA, BHT)), oxidants, stabilizers, decolorants, preservatives and similar compounds or chemicals known to those skilled in the art to help obtain stable formulations, which may be used alone or in combination without any limitation. More preferably, within the range of 0.01%-50% w / w or w / v. In exemplary embodiments, the formulations of the present disclosure may include a concentration 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 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86 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% antioxidants. In exemplary embodiments, the formulations of the present disclosure may include antioxidants at concentrations of about 1% to 20%, about 5% to 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. In exemplary formulations of the present disclosure, the antioxidant will comprise about 1 wt% to 75 wt% of the formulation, preferably 2 wt% to 30 wt%, more preferably 5 wt.% to 20 wt.%, more preferably in the range of 0.01%-50% w / w or w / v.

[0262] Example 10

[0263] The continuous drug delivery systems and methods disclosed herein may include drugs formulated into ointments and / or cream bases and / or gels 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.

[0264] Embodiment 11

[0265] The materials for making the continuous drug delivery system and method of the present disclosure are known to those skilled in the art, such as but not limited to pumps, reservoir patches, matrix patches, drugs in adhesives, film-forming preparations, microdose transdermal patches, transdermal films, and may include, for example but not limited to polymers, copolymers, derivatives, backing films, release films, release liners, etc., alone or in combination thereof. Pressure-sensitive adhesives (such as 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 (such as but not limited to ethylene vinyl acetate copolymers, vinyl acetate resins, polyurethanes, polyvinyl chloride, metal foils, polyesters, aluminized films, polyethylene, etc.), release films (such as but not limited to microporous polyethylene films, microporous polypropylene films, rate-controlled ethylene vinyl acetate copolymer films, etc.), release liners (such as but not limited to siliconized polyester films, fluoropolymer-coated polyester films, polyester films, siliconized polyethylene terephthalate films, etc.), tapes, etc.

[0266] The continuous drug delivery system and method disclosed herein can deliver at least a therapeutically effective dose of an active agent, such as CBD and / or THC and derivatives of these compounds, in the human plasma in need of treatment and / or prevention and / or control of chronic pain, alone or in combination. The dosage of therapeutically effective active agents such as CBD and / or THC and derivatives of these compounds refers to the therapeutic concentration in the human plasma in need of treatment and / or prevention and / or control of chronic pain. In addition, in a continuous drug delivery system, such as a pump, a transdermal preparation or a topical preparation or a transdermal delivery system, the precise therapeutically effective dose of derivatives such as CBD and / or THC and these compounds can be determined by those skilled in the art according to a variety of factors, such as but not limited to the patient's condition, etc. Transdermal preparations or topical preparations or transdermal delivery systems will have different dosage strengths and patch sizes to achieve the best therapeutic effect according to the needs of the patient.

[0267] Continuous drug delivery systems and methods, such as pumps, or transdermal formulations or transdermal patches of active agents (such as CBD and / or THC and derivatives of these compounds) can be applied to the skin surface at any of the following dosage schedules: once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once in the range of about 8 to about 13 days, once every two weeks, or once every 15 days.

[0268] Example 12

[0269] Example Formulations

[0270] Components %W / W Active ingredients (THC and / or CBD) 1％-30％ Solvents 2％-30％ Penetration enhancers 2％-30％ Pressure sensitive adhesive polymer 20％-80％ polymer 1％-10％

[0271] Example Formulations

[0272] Components %W / W Active ingredients (THC and / or CBD) 1％-30％ Solvents 2％-30％ Penetration enhancers 2％-30％ Pressure sensitive adhesive polymer 20％-80％

[0273] While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made to the invention without departing from the spirit and scope of the invention.

Claims

1. A method for treating, preventing and / or slowing the onset or progression of a disease or condition and / or associated symptoms in a patient, comprising: - Selecting patients in need of treatment, prevention and / or slowing of the onset or progression of a disease or condition and / or associated symptoms; - administering to a patient a pharmaceutical composition in a continuous delivery system, said pharmaceutical composition comprising at least one active agent selected from the group consisting of: - from about 0.1% to about 50% of an active agent 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; - from about 0.1% to about 50% of an active agent selected from the group consisting of tetrahydrocannabinol (THC), synthetic forms thereof, biosynthetic forms thereof, free base forms thereof, salts thereof, isomers thereof, amorphous forms thereof, derivatives thereof, and combinations thereof; - optionally, at least one additional active agent, and - combinations thereof, wherein the patient's disease or condition and / or associated symptoms are treated, prevented and / or alleviated.

2. The method of claim 1, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to mitigate peaks and troughs in the pharmacokinetics of the active agent.

3. The method of any one of claims 1 to 2, wherein the continuous delivery system is administered to a patient via 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, providing continuous, sustained delivery of the pharmaceutical composition.

4. The method of any one of claims 1 to 3, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to the patient by intravenous or subcutaneous infusion.

5. The method of any one of claims 1 to 4, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition by subcutaneous infusion.

6. The method of any one of claims 1 to 5, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition via an infusion pump device.

7. The method of any one of claims 1 to 6, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to the patient via a portable / portable infusion pump worn by the patient and that can use replaceable cartridges.

8. The method according to any one of claims 1 to 7, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to the patient via a patch pump or a mini-pump.

9. The method according to any one of claims 1 to 8, wherein the continuous delivery system comprises 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.

10. The method according to any one of claims 1 to 9, 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 multilayer transdermal matrix system, a transdermal drug-containing adhesive matrix formulation, and a combination thereof.

11. The method of any one of claims 1 to 10, 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.

12. The method according to any one of claims 1 to 11, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch, wherein the transdermal patch is selected from the group consisting of a reservoir patch, a multilayer 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 time-release transdermal film, a liquid storage system, a microreservoir patch, a mucoadhesive patch, and a combination thereof.

13. The method according to any one of claims 1 to 12, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch, wherein 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 medicated adhesive patch, a pressure-sensitive adhesive patch, a time-release transdermal film, a liquid storage system, a microreservoir patch, a mucoadhesive patch, a microdose patch, an adhesive matrix patch in conjunction with a polymer, and combinations thereof.

14. The method of any one of claims 1 to 13, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch.

15. The method according to any one of claims 1 to 14, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a multilayer transdermal matrix system, a metered transdermal gel, a metered transdermal spray, a film-forming gel, a film-forming spray, or a metered aerosol.

16. The method of any one of claims 1 to 15, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch.

17. The method of any one of claims 1 to 16, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a metered-dose gel, metered-dose spray, gel, cream, solution, emulsion, liquid composition, semisolid composition, adhesive matrix combined with a polymer, or film-forming formulation.

18. The method of any one of claims 1 to 17, 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 solvents, gelling agents, polymers, pressure-sensitive adhesive polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, viscosity increasing agents, diluents, fillers, solubilizing agents, suspending agents, dispersants, stabilizers, plasticizers, surfactants, antioxidants, oxidants, and combinations thereof.

19. The method of any one of claims 1 to 18, wherein the continuous delivery system comprises a pharmaceutical composition further comprising an effective amount of a carrier or ingredient in the range of 0.1%-99.5% w / w or w / v, the carrier or ingredient being selected from the group consisting of solvents, gelling agents, polymers, pressure-sensitive adhesive polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, viscosity increasing agents, diluents, fillers, surfactants, antioxidants, oxidants, and combinations thereof.

20. The method of any one of claims 1 to 19, 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 a day, twice a day, three times a day, once every 1-8 hours, once every 1-24 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 method of any one of claims 1 to 20, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical formulation that can be administered at 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 1-8 hours, once every 1-24 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 method of any one of claims 1 to 21, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition to the patient via microneedles.

23. according to the method described in any one of claims 1 to 22, wherein the continuous delivery system provides a serum level of 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.

24. The method of any one of claims 1 to 23, 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.

25. The method of any one of claims 1 to 24, 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%, and about 1% to about 5% of the formulation.

26. The method of any one of claims 1 to 25, wherein the continuous delivery system comprises a pharmaceutical composition wherein THC is selected from the group comprising 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 naturally occurring 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, or a combination thereof alone.

27. The method according to any one of claims 1 to 26, wherein the continuous delivery system comprises a pharmaceutical composition, wherein CBD is selected from the group comprising 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 naturally occurring 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, or a combination thereof alone.

28. according to the method described in any one of claims 1 to 27, wherein the continuous delivery system comprises a pharmaceutical composition, the pharmaceutical composition comprises one or more active agents selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), 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 naturally occurring form, its active metabolite, its polymorph, its solid solution, its coated form and its combination, which is a dosage form for transdermal delivery.

29. The method of any one of claims 1 to 28, wherein the continuous delivery system comprises a pharmaceutical composition, wherein the tetrahydrocannabinol (THC), cannabidiol (CBD), free bases thereof, salts thereof, isomers thereof, amorphous forms thereof, polymorphic forms thereof, stereoisomers thereof, ion pairs thereof, coated forms thereof, crystalline forms thereof, co-crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms thereof, naturally occurring forms thereof, active metabolites thereof, and combinations thereof are produced by synthetic pathways.

30. The method of any one of claims 1 to 29, wherein the continuous delivery system comprises a pharmaceutical composition wherein the active agent is synthetically produced and has a purity equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w) prior to addition to the pharmaceutical composition.

31. The method of any one of claims 1 to 30, 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.

32. The method of any one of claims 1 to 31, wherein the 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, ropinorole, apomorphine, and any combination thereof.

33. The method of any one of claims 1 to 32, wherein the disease or condition and / or associated symptoms are selected from the group consisting of cancer, pain, a seizure disorder, Parkinson's disease ("PD") and PD symptoms.

34. The method of any one of claims 1 to 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, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, GBM, and blood cancers such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma / primary mediastinal B-cell lymphoma, and chronic myeloid leukemia.

35. The method of any one of claims 1 to 34, wherein the cancer is glioblastoma, GBM.

36. The method of any one of claims 1 to 35, 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, radiotherapy, hormone therapy, anti-angiogenic therapy, targeted therapy and / or biological therapy, including immunotherapy and surgery, and combinations thereof.

37. The method of any one of claims 1 to 36, 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 spasm, pain due to increased muscle tone, osteoarthritis pain, muscular headache, tension-type headache, migraine, cluster headache, atypical facial pain, referred pain, vulvodynia, rectal pain, and any combination thereof.

38. The method of any one of claims 1 to 37, wherein the seizure disorder is selected from the group consisting of complex partial seizures, simple partial seizures, partial seizures secondary to generalization, generalized seizures (including absences, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures, and other specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex (TSC), refractory epilepsy, refractory 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.

39. The method of any one of claims 1 to 38, wherein the seizure disorder is selected from the group consisting of complex partial seizures, simple partial seizures, partial seizures secondary to generalization, generalized seizures (including absences, grand mal seizures (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures, as well as other specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex (TSC), refractory epilepsy, refractory 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.

40. The method according to any one of claims 1 to 39, wherein the PD symptom to be treated, prevented and / or alleviated is selected from the group consisting of: (a) at least one non-motor aspect of daily living experience as defined by part 1 of the Unified Parkinson's Disease Rating Scale, selected from the group consisting of cognitive impairment, hallucinations and confusion, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain, urinary problems, constipation problems, dizziness on standing, and fatigue; (b) at least one motor aspect 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, feeding tasks, dressing, hygiene, writing, turning over in bed, tremor, getting out of bed, car or deep chair, walking and balance, and freezing; (c) at least one motor symptom identified on part III of the Unified Parkinson's Disease Rating Scale selected from the group consisting of speech, facial expressions, rigidity, finger tapping, hand movements, pronation-supination movements of the hands, toe tapping, leg flexibility, rising from a chair, gait, freezing of gait, postural stability, posture, bradykinesia, postural tremor of the hands, kinetic tremor of the hands, resting tremor amplitude, and constancy of resting tremor; (d) at least one motor complication identified on 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 in the off state, functional impact of fluctuations, complexity of motor fluctuations, and painful off-state dystonia; (e) Constipation; (f) depression; (g) cognitive impairment; (h) short-term or long-term memory impairment; (i) attention deficit disorder; (j) coordination impairment; (k) Mobility impairment; (l) speech disorders; (m) mental disorder; (n) Sleep problems, sleep disorders or sleep disturbances; (o) circadian rhythm dysfunction; (p) Hallucinations; (q) Fatigue; (r) REM disrupts sleep; (s)REM behavior disorder; (t) erectile dysfunction; (u) postural hypotension; (v) correction of blood pressure or orthostatic hypotension; (w) nocturnal hypertension; (x) Temperature regulation; (y) Improvement of breathing or apnea; (z) Correction of cardiac conduction defects; (aa) Pain relief; (bb) restoration of urinary continence or bladder sensation and urination; (cc) mood swings; (dd) indifference; (ee) Control of nocturia; (ff) neurodegeneration; (gg) anxiety; (hh) improving conversational skills, including public conversation skills; and / or (ii) Parkinson's disease dementia.

41. The method according to any one of claims 1 to 40, wherein the PD symptom to be treated, prevented and / or alleviated is a sleep problem, a sleep disorder, a sleep disturbance, a circadian rhythm dysfunction, REM disturbed sleep or a REM behavior disorder, and wherein: (a) the sleep disorder or sleep disturbance includes delayed sleep onset, sleep fragmentation, REM behavior disorder, sleep-disordered breathing including snoring and apnea, daytime sleepiness, microsleep attacks, narcolepsy, hallucinations, or any combination thereof; and / or (b) REM behavior disorder including vivid dreams, nightmares, and acting out dreams during sleep by talking or screaming, or fidgeting or shaking arms or legs; and / or (c) treating sleep problems, sleep disorders, or sleep disturbances to prevent or delay 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 determined period of time; and / or (e) the method results in a positive change in the subject's sleep pattern over a determined period of time, wherein the positive change is defined as: (i) an increase in the total amount of sleep obtained 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%, and about 100%; and / or (ii) a percentage reduction in the number of nighttime awakenings 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 (f) as a result of the method, the subject obtains the total number of hours of sleep recommended by medical authorities for the subject's age group; and / or (g) wherein each determined time 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 about greater than 12 months.

42. The method according to any one of claims 1 to 41, wherein the PD symptom to be treated, prevented and / or alleviated is hallucinations, and wherein: (a) hallucinations including visual, auditory, tactile, gustatory or olfactory hallucinations; and / or (b) treating hallucinations to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (c) the method results in a reduction in the number of hallucinations experienced by the subject over a determined period of time; and / or (d) the method results in a reduction in the number of hallucinations in the subject over a determined period of time, and the reduction in 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 results in the subject experiencing no hallucinations; and / or (f) the method results in a reduction in the severity of hallucinations in the subject over a determined period of time as measured by one or more medically accepted techniques; and / or (g) the method results in a reduction in the severity of hallucinations in the subject over a determined period of time as measured by one or more medically accepted techniques, and the reduction in severity 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 (h) the medically accepted technique is selected from the group consisting of the Chicago Hallucination Assessment Tool (CHAT), the Psychotic Symptom Rating Scale (PSYRATS), the Auditory Hallucination Rating Scale (AHRS), the Hamilton Schizophrenia Voice Questionnaire (HPSVQ), the Auditory Hallucination Characteristics Questionnaire (CAHQ), the Mental Health Institute Anomalous Perception Scale (MUPS), the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Launay-Slade Hallucination Scale (LSHS), the Cardiff Anomalous Perception Scale (CAPS), and the Structured Interview for the Assessment of Perceptual Anomalism (SIAPA); and / or (i) each determined time 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 about greater than 12 months.

43. The method according to any one of claims 1 to 42, wherein the PD symptom to be treated, prevented and / or alleviated is depression, and wherein: (a) treating depression to prevent and / or delay 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 determined 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, and the improvement is in one or more depressive features selected from the group consisting of mood, behavior, physical function such as eating, sleeping, energy and sexual activity, and / or episodes of sadness or apathy; and / or (d) the method results in an improvement in depression in the subject as measured by one or more clinically recognized depression rating scales, and the subject experiences an improvement 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% after treatment; and / or (e) wherein each determined time 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 about greater than 12 months.

44. The method according to any one of claims 1 to 43, wherein the PD symptom to be treated, prevented and / or alleviated is cognitive impairment, and wherein: (a) treating cognitive impairment to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (b) the progression or onset of cognitive impairment is slowed, stopped or reversed within a determined period of time after administration of the pharmaceutical composition as measured by medically accepted techniques; and / or (c) cognitive impairment as measured by medically accepted techniques is positively affected by administration of the pharmaceutical composition; and / or (d) cognitive impairment is positively affected by administration of the pharmaceutical composition as measured by medically accepted techniques, and the positive effect on cognitive decline and / or progression of cognitive decline is quantitatively or qualitatively measured by one or more techniques selected from the group consisting of the Mini-Mental State Examination (MMSE), Mini Cognitive Test, and a computerized test selected from Cantab Mobile, Cognigram, Cognivue, Cognision, or an automated neuropsychological assessment measure; and / or (e) the progression or onset of cognitive impairment is slowed, halted, 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 accepted techniques; and / or (f) each determined time 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 about greater than 12 months.

45. The method according to any one of claims 1 to 44, wherein the PD symptom to be treated, prevented and / or alleviated is constipation, and wherein: (a) treating constipation to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (b) administration of the pharmaceutical composition induces intestinal movement in the subject; and / or (c) the method results in an increase in the frequency of bowel movements in a subject over a determined period of time; and / or (d) the method results in an increase in the frequency of bowel movements in the subject, and the increase in the frequency of bowel movements is defined as: (i) an increase in the number of bowel movements per week 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%, and about 100%; and / or (ii) the amount of time between each consecutive bowel movement is reduced by a percentage 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 frequency of bowel movements recommended by medical authorities for the subject's age group.

46. ​​The method according to any one of claims 1 to 45, wherein the PD symptom to be treated, prevented and / or alleviated is neurodegeneration associated with PD, and wherein: (a) treating neurodegeneration to prevent and / or delay the onset and / or progression of Parkinson's disease; and / or (b) the method results in treating, preventing and / or delaying the progression and / or onset of neurodegeneration in a subject; and / or (c) the progression or onset of neurodegeneration is slowed, halted or reversed within a determined period of time following administration of the pharmaceutical composition as measured by medically accepted techniques; and / or (d) neurodegeneration is positively affected by administration of the pharmaceutical composition as measured by medically accepted techniques; and / or (e) quantitatively or qualitatively measuring the positive effects and / or progression of neurodegeneration 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, agents that label amyloid, [18F]F-DOPA PET, radiotracer imaging, volumetric analysis of regional tissue loss, specific imaging markers of abnormal protein deposition, multimodal imaging, and biomarker analysis; and / or (f) the progression or onset of neurodegeneration is slowed, halted 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 accepted techniques; and / or (g) each determined time 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 about greater than 12 months.

47. A continuous delivery system comprising a pharmaceutical composition comprising at least one active agent selected from the group consisting of: - from about 0.1% to about 50% of an active agent 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; - from about 0.1% to about 50% of an active agent selected from the group consisting of tetrahydrocannabinol (THC), synthetic forms thereof, biosynthetic forms thereof, free base forms thereof, salts thereof, isomers thereof, amorphous forms thereof, derivatives thereof, and combinations thereof; - optionally, at least one additional active agent, and - combinations thereof.

48. The continuous delivery system of claim 47, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition to mitigate peaks and troughs in the pharmacokinetics of an active agent.

49. according to the continuous delivery system described in any one of claims 47 to 48, wherein said continuous delivery system is administered 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, providing continuous, sustained delivery of the pharmaceutical composition.

50. The continuous delivery system of any one of claims 47 to 49, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition by intravenous or subcutaneous infusion.

51. The continuous delivery system of any one of claims 47 to 50, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition by subcutaneous infusion.

52. A continuous delivery system according to any one of claims 47 to 51, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition via an infusion pump device.

53. A continuous delivery system according to any one of claims 47 to 52, wherein the continuous delivery system provides continuous, sustained delivery of a pharmaceutical composition via a portable / portable infusion pump worn by a patient and which can use replaceable cartridges.

54. A continuous delivery system according to any one of claims 47 to 53, wherein the continuous delivery system provides continuous, sustained delivery of the pharmaceutical composition via a patch pump or a miniature pump.

55. according to the continuous delivery system described in any one of claims 47 to 54, wherein the continuous delivery system comprises a pharmaceutical composition selected from the group consisting of a liquid preparation, a solid preparation, a semisolid preparation, an emulsion preparation, a nanoparticle preparation, a matrix preparation, a film preparation, a patch preparation, a preparation in an infusion pump and / or a combination thereof.

56. according to the continuous delivery system described in any one of claims 47 to 554, wherein said continuous delivery system comprises the pharmaceutical composition selected from the group consisting of transdermal liquid preparations, transdermal semisolid preparations, transdermal gel preparations or transdermal polymer matrix preparations, transdermal adhesive matrix preparations, transdermal film-forming gels, transdermal film-forming spray preparations, multilayer transdermal matrix systems, transdermal drug-containing adhesive matrix preparations and combinations thereof.

57. A continuous delivery system according to any one of claims 47 to 56, 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.

58. according to the continuous delivery system described in any one in claim 47 to 57, wherein said continuous delivery system comprises the pharmaceutical composition being formulated into transdermal patch, wherein said transdermal patch is selected from the group such as reservoir patch, multilayer transdermal matrix system, micro-reservoir patch, matrix patch, medicated adhesive patch, adhesive matrix patch combined with polymer, pressure-sensitive adhesive patch, time-delayed release transdermal film, storage system, micro-reservoir patch, mucoadhesive patch and combination thereof.

59. according to the continuous delivery system described in any one in claim 47 to 58, wherein said continuous delivery system comprises the pharmaceutical composition being formulated into topical patch, wherein said topical patch is selected from the group such as multilayer transdermal matrix system, reservoir patch, micro-reservoir patch, matrix patch, medicated adhesive patch, pressure-sensitive adhesive patch, time-delayed release transdermal film, liquid storage system, micro-reservoir patch, mucoadhesive patch, microdose patch, adhesive matrix patch combined with polymer and its combination.

60. The continuous delivery system of any one of claims 47 to 59, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a transdermal patch.

61. according to the continuous delivery system described in any one in claim 47 to 60, wherein said continuous delivery system comprises the pharmaceutical composition being configured to multilayer transdermal matrix system, quantitative transdermal gel, quantitative transdermal spray, film-forming gel, film-forming spray or quantitative aerosol.

62. A continuous delivery system according to any one of claims 47 to 61, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical patch.

63. according to any one of claims 47 to 62, the continuous delivery system, wherein the continuous delivery system comprises a pharmaceutical composition configured as a quantitative gel, a quantitative spray, a gel, an ointment, a solution, an emulsion, a liquid composition, a semisolid composition, an adhesive matrix combined with a polymer, or a film-forming preparation.

64. A continuous delivery system according to any one of claims 47 to 63, wherein the continuous delivery system comprises a pharmaceutical composition, which further comprises 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, viscosity increasers, diluents, fillers, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, surfactants, antioxidants, oxidants and combinations thereof.

65. A continuous delivery system according to any one of claims 47 to 64, wherein the continuous delivery system comprises a pharmaceutical composition, which further comprises an effective amount of a carrier or ingredient in the range of 0.1%-99.5% w / w or w / v, and the carrier or ingredient is 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, dispersants, stabilizers, plasticizers, viscosity increasing agents, diluents, fillers, surfactants, antioxidants, oxidants and combinations thereof.

66. according to any one of claims 47 to 65, wherein the continuous delivery system comprises a pharmaceutical composition formulated into a transdermal preparation, and the transdermal preparation can be administered with a dosage regimen selected from the group consisting of once a day, twice a day, three times a day, once every 1-8 hours, once every 1-24 hours, once every 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 of any one of claims 47 to 66, wherein the continuous delivery system comprises a pharmaceutical composition formulated as a topical formulation that can be administered at 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 1-8 hours, once every 1-24 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 of any one of claims 47 to 67, wherein the continuous delivery system comprises a pharmaceutical composition formulated into microneedles.

69. according to any one of claims 47 to 68, 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.

70. A continuous delivery system according to any one of claims 47 to 69, 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.

71. A continuous delivery system according to any one of claims 47 to 70, 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% and about 1% to about 5% of the formulation.

72. A continuous delivery system according to any one of claims 47 to 71, wherein the continuous delivery system comprises a pharmaceutical composition, wherein THC is selected from the group comprising 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 naturally occurring 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, or a combination thereof.

73. A continuous delivery system according to any one of claims 47 to 72, wherein the continuous delivery system comprises a pharmaceutical composition, wherein CBD is selected from the group comprising 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 naturally occurring 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, or a combination thereof.

74. A continuous delivery system according to any one of claims 47 to 73, 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), free bases thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof, co-crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms thereof, naturally occurring forms thereof, active metabolites thereof, polymorphs thereof, solid solutions thereof, coated forms thereof, and combinations thereof, which is a dosage form for transdermal delivery.

75. A continuous delivery system according to any one of claims 47 to 74, wherein the continuous delivery system comprises a pharmaceutical composition, wherein the 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 analogue, its derivative, its synthetic form, its biosynthetic form, its naturally occurring form, its active metabolite and combinations thereof are produced by a synthetic pathway.

76. A continuous delivery system according to any one of claims 47 to 75, wherein the continuous delivery system comprises a pharmaceutical composition wherein the active agent is synthetically produced and has a purity equal to or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75% or 100% (w / w) prior to addition to the pharmaceutical composition.

77. A continuous delivery system according to any one of claims 47 to 76, 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 a combination thereof.

78. A continuous delivery system according to any one of claims 47 to 77, wherein the 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, ropinorole, apomorphine, and any combination thereof.

Images