JP2024514843A - Pharmaceutical compositions and methods for treating seizure disorders - Google Patents

Abstract

The present disclosure relates to the transdermal administration of cannabidiol (CBD) to reduce seizure frequency in the treatment of "treatment-resistant epilepsy" (TRE).

Description

The present disclosure relates to the transdermal administration of cannabidiol (CBD) to reduce seizure frequency in the treatment of "treatment-resistant epilepsy" (TRE), including, for example, treatment-resistant childhood epilepsy, or tuberous sclerosis complex (TSC), Dravet syndrome, and Lennox-Gastaut syndrome. In one embodiment, the patient suffering from TRE is a child or young adult. CBD is believed to be particularly effective when the TRE is Dravet syndrome; myoclonic absence seizures, or febrile infection-related epilepsy syndrome (FIRES). In these indications, a significant number of patients have been shown to reduce total seizure frequency by more than 50%, and more than 70% to 90%. Indeed, a significant number of patients are seizure-free at the end of three months of treatment.

In certain embodiments disclosed herein, the CBD used is in the form of a highly purified cannabis extract, such that, for example, the CBD is greater than 98% of the total extract (w/w). present and other components of the extract are characterized. In particular, tetrahydrocannabinol (THC) is substantially removed, for example to a level of 0.15% (w/w) or less. In certain embodiments disclosed herein, it is synthetically produced CBD (see US Pat.

CBD may be used concomitantly with one or more other anti-epileptic drugs (AEDs). Alternatively, CBD may be formulated for separate, sequential, or simultaneous administration with one or more AEDs, or the combination may be provided in a single dosage form. If CBD is formulated for separate, sequential, or simultaneous administration, it may be provided as a kit or with instructions for administering one or more components in that manner.

Cannabis (marijuana) is a Schedule I drug in the United States. Cannabis is a flowering plant that contains over 400 phytonutrients (micronutrients). More than 100 terpenoids, essential oils, antioxidants, and cannabinodis have been extracted from cannabis. Of all these phytochemicals, only tetryhydrocannbinol (THC) showed significant psychoactive effects. Many research papers have been published on THC because of its psychoactive and therapeutic effects. Apart from THC, there are other psychoactive compounds such as cannabidiol (CBD), cambinol (CBN), cannabichromene (CBC), cannabigerol (CBG), tetrahydrocambivarin (THCV), delta 9-tetrahydrocambinol (delta 9 THC), etc. Several other ingredients that exhibit some therapeutic effect without action are also being investigated. Cannabis and its derivatives are used in the treatment of pain, antibiotics, type 2-related metabolic disorders, reduced intraocular pressure, Dravet syndrome, Lennox-Gastaut syndrome (LGS), epilepsy, nausea, pain, AIDS-related debilitating diseases, arthritis and rheumatism, Treatment of migraines, muscle spasms associated with multiple sclerosis and paralysis, alcohol and drug withdrawal, stress and depression, asthma, fibromyalgia, inflammatory pain, and pain and/or inflammation associated with chemotherapy. It has been shown that it can be used for FDA-approved Marinol and Syndros contain delta-9-THC, which is currently used for pain and inflammation associated with chemotherapy treatments. Additionally, in April 2016, the FDA granted orphan drug designation to cannabidiol for the treatment of tuberous sclerosis complex (TSC), Dravet syndrome, and Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that usually manifests in infancy or early childhood. Onset of LGS is usually between 2 and 7 years, with peak onset between 3 and 5 years. Affected children experience several different types of seizures, but the most common are atonic seizures, tonic seizures, and atypical absence seizures.

In 2018, GW Pharmaceuticals received FDA approval for Epidiolex (cannabidiol), a fast-track designation drug to treat two orphan diseases in children: LGS and Dravet syndrome (DS).

Epidiolex contains naturally derived cannabidiol from the Sativex plant in the form of an oral solution (100 mg/ml). According to the FDA label, the recommended doses of Epidiolex are listed in Table 1.

Epidiolex has ^five main dose-dependent side effects: 1) hepatocellular injury, 2) somnolence and sedation, 3) suicidal behavior and thoughts, 4) hypersensitivity reactions, and 5) antiepileptic drug withdrawal.

Epidiolex discontinuation rates are high due to side effects of hepatocellular injury, somnolence, and sedation. During clinical trials, 1.3% of patients taking Epidiolex 10 mg/kg/day and 5.9% of patients taking Epidiolex 20 mg/kg/day discontinued due to hepatocellular damage. became. Additionally, 0% of patients taking the 10 mg/kg/day dose and 3% of patients taking the 20 mg/kg/day dropped out due to somnolence and sedation. Table 2 shows ^the dose-dependent side effects caused by Epidiolex1.

These side effects are dose-related, so patients should be monitored and the dose reduced if necessary.
Many orally administered drugs irritate the gastrointestinal mucosa, and many drugs, including CBD, are subject to extensive "first-pass" inactivation by the liver. The disclosed compositions and methods are directed to direct drug delivery to the systemic circulation via application to the skin, thus overcoming the problems of gastrointestinal tract inflammation and hepatic first-pass metabolism by avoiding hepatic metabolism of the active agent after absorption, as well as avoiding gastrointestinal irritation because it is not administered orally.

However, TDDS systems continuously deliver drug molecules at a defined input rate. Instead of peaks and troughs in plasma concentrations as with oral delivery, TDDS maintains average plasma concentrations at a given, constant dosing rate.

There are patent documents available regarding cannabidiol, but the shortcomings of these disclosures are overcome by the compounds and methods disclosed herein. For example, US Pat. No. 6,233,633 provides no in vitro or in vivo data. US Pat. No. 6,233,633 discloses reservoir patches and adhesive matrix patches, but these examples contain a mixture of cannabinoids (such as delta-8-THC, delta-9-THC, cannabidiol, and cannabinol) rather than cannabidiol alone. THC is a psychoactive and addictive substance, making its usefulness questionable.

Furthermore, US Patent No. 5,399,663 discloses the delivery of a cumulative amount of 60,600 ng through human cadaver skin in 48 hours. This amount represents a flux of 1,925 ng/cm2/hr. The patch area can be calculated using the following formula:

In-Vitro flow rate (μg/cm2/hour) = (Css (μg/l) x CL (L/hour)/patch area (cm2)
Patch area (cm2) = (Css (μg/l) x CL (L/h)/In-Vitro flow rate (μg/cm2/h)
=(10×74.4)/1.925
=386 square cm
To deliver 5 mg/kg/day of cannabidiol, the patient would need to apply the formulation to a surface area of 386 square cm. This is an impractical patch size for a transdermal drug delivery system (TDDS). Additionally, the '908 patent discloses the use of the receiving medium PBS:PEG-400 (60:40). It is well known that PEG-400 is a permeation enhancer, and its incorporation into the receptor medium can also damage the skin from the dermal side and increase the amount of permeation through non-viable skin samples.

There is a need for improved drug delivery systems for cannabidiol that can overcome the drawbacks associated with oral and IV routes. Transdermal delivery of high purity cannabidiol can address the challenges associated with oral and IV drug delivery described herein. The present invention addresses all of the above drawbacks and provides real world utility. Additionally, disclosed herein is the use of synthetic versions of cannabidiol that are produced in a more controlled environment than botanical sources of cannabidiol. Synthetic versions of cannabidiol offer higher permeability compared to impure versions. Further, the present disclosure provides, for example, synthetic cannabidiol for 1 day, and/or 2 days, and/or 3 days, and/or 4 days, and/or 5 days, and/or 6 days, and/or 7 days. , and/or transdermal matrix patches that can be delivered for up to 15 days.

All references cited herein are incorporated by reference in their entirety.

U.S. Pat. No. 1,019,5159 U.S. Pat. No. 9,375,417 US Patent No. 6,328,992 U.S. Pat. No. 8,449,908

The present disclosure provides compositions and methods for the treatment and/or prevention and/or control of seizure disorders using transdermal drug delivery. In transdermal drug delivery, a transdermal patch or transdermal composition is applied topically to the skin surface. During the topical application of the transdermal patch or transdermal composition, the drug is continuously released and delivered through intact skin (via transcellular, intercellular and transappendage pathways) to achieve a systemic effect. Thus, once applied, the transdermal composition or transdermal patch can deliver the drug to the systemic circulation throughout the day, or for more than a day depending on the duration of application, potentially up to a week.

Transdermal delivery can reduce the frequency of CBD administration, which is currently administered several times a day. Transdermal delivery allows a transdermal composition or formulation or patch of high-purity CBD to be applied locally to the skin, thereby delivering the drug throughout the duration of the topical application. Depending on the need, the duration of topical application can be once a day, once every two days, once every three days, once every four days, once every five days, or once a week. Thus, transdermal delivery can overcome the multiple-dose schedule of oral delivery by reducing the frequency of administration.

In addition, with transdermal drug delivery, the drug is delivered slowly and continuously throughout the duration of topical application, eliminating the peaks and valleys in drug plasma concentrations associated with multiple daily doses. Thus, by delivering high-purity CBD transdermally, patients can obtain the therapeutic effects of the drug for an extended period of time without significant changes in the drug's plasma concentrations.

When a drug is administered orally, its bioavailability is usually reduced due to incomplete absorption and first-pass metabolism, which may vary from patient to patient. Compositions of the present disclosure, in transdermal delivery, deliver the active agent directly through the skin into the systemic circulation, avoiding first-pass hepatic metabolism, thereby requiring less drug to achieve the desired therapeutic activity. This overcomes these problems because it results in fewer negative effects and side effects. Cannabinol is highly fat-soluble and undergoes first-pass metabolism in the liver after oral administration, so only 10% to 20% of the administered dose reaches the systemic circulation, making it less effective for oral administration than for oral administration. Dermal delivery allows lower doses of cannabidiol to achieve the desired therapeutic effect.

Additionally, transdermal delivery is simple, non-invasive, and convenient. Because the administration of transdermal patches and compositions does not require medical supervision, patients themselves can apply transdermal patches or compositions topically. Thus, transdermal delivery can overcome the disadvantages of injections, which are often painful and require medical supervision.

Regarding cannabidiol, transdermal delivery is expected to result in less variability in pharmacological response between patients because drug plasma concentrations can be controlled by controlling the rate of drug delivery from transdermal compositions or transdermal patches. . Transdermal delivery can deliver small amounts of cannabidiol for longer periods of time than oral administration. Transdermal formulations of cannabidiol also have greater abuse deterrent properties than immediate-release dosage forms.

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

For the reasons discussed above regarding the treatment and/or prevention and/or control of seizure disorders, transdermal delivery can provide a more patient-friendly, simplified, and convenient treatment regimen compared to traditional delivery systems. Transdermal delivery can reduce the frequency of administration of high-purity CBD. Depending on the needs, the administration frequency can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

Transdermal administration of drug combinations allows for the simultaneous delivery of two or more drugs. If desired, the frequency of administration of the transdermal patch or transdermal composition containing the drug combination may be once a day, once every two days, once every three days, once every four days, or once every five days. It can be once, once every 6 days, once a week. That is a huge advantage for patient compliance.

The present disclosure provides pharmaceutical compositions comprising at least about 90% (w/w) cannabidiol (CBD) in a dosage form for transdermal delivery. The present disclosure provides pharmaceutical compositions containing at least about 95% CBD. The present disclosure provides pharmaceutical compositions containing at least about 98% CBD. The present disclosure provides pharmaceutical compositions containing at least about 99% CBD. The present disclosure provides pharmaceutical compositions formulated as transdermal liquid formulations, transdermal semisolid formulations, or transdermal polymeric matrix formulations. The present disclosure includes solvents, gelling agents, polymers, penetration enhancers, emollients, skin irritation reducers, buffers, pH stabilizers, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, A pharmaceutical composition is provided further comprising an effective amount of a carrier or ingredient selected from the group consisting of surfactants, antioxidants, oxidizing agents, and combinations thereof. The present disclosure includes solvents, gelling agents, polymers, penetration enhancers, emollients, skin irritation reducers, buffers, pH stabilizers, solubilizers, suspending agents, dispersants, stabilizers, plasticizers, A pharmaceutical composition further comprising an effective amount of a carrier or ingredient selected from the group consisting of surfactants, antioxidants, oxidizing agents, and combinations thereof in the range of 0.01% to 95% w/w or w/v. provide something. The present disclosure provides pharmaceutical compositions in which the carrier is present in a range of 0.01% to 99.8% w/w or w/v. The present disclosure provides pharmaceutical compositions that are formulated as transdermal patches. The present disclosure provides pharmaceutical compositions formulated as transdermal patches, which include reservoir patches, microreservoir patches, matrix patches, pressure sensitive adhesive patches, sustained release transdermal films, liquid reservoir systems. , microreservoir patches, matrix patches, pressure sensitive adhesive patches, mucoadhesive patches, and combinations thereof. The present disclosure provides pharmaceutical compositions adapted for the treatment and/or prevention and/or control of seizure disorders in patients, where seizure disorders include, for example, complex partial seizures, simple partial seizures, secondary Partial seizures with sexual generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), convulsions in newborns and infants, drug-induced seizures, Traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, medial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic Includes epilepsy and seizures associated with CNS mass lesions. The present disclosure may include once a day, twice a day, three times a day, once every 1 to 8 hours, once every 1 to 24 hours, once every 2 days, once every 3 days, once every 4 days. Select from the group consisting of once, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, and once every 15 to about 30 days. The present invention provides pharmaceutical compositions that are formulated as transdermal formulations that can be administered according to a specific dosage regimen. The present disclosure provides pharmaceutical compositions that can be formulated as microneedles. The present disclosure provides pharmaceutical compositions in which said CBD or derivative thereof is produced by a synthetic route. The present disclosure provides pharmaceutical compositions co-administered with at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. provide something. The present disclosure provides a pharmaceutical composition further comprising at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. provide.

The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, comprising: selecting a patient in need of treatment and/or prevention and/or control of a seizure disorder; and topically applying a pharmaceutical composition disclosed herein. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, including complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides methods for the treatment and/or prevention and/or control of a patient's seizure disorders, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, e.g., juvenile myoclonic seizures. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, the method further comprising providing a constant rate of delivery of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, the method further comprising providing a constant rate of absorption of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, the method further comprising providing a constant rate of absorption of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, the method further comprising achieving a constant serum level of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, further achieving reduced variability in the dosage of an active ingredient of a transdermal patch over a period of time. The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, further providing a plasma concentration of an active ingredient of a transdermal patch within a therapeutic range over a period of time.

The present disclosure provides a pharmaceutical composition comprising a high-purity cannabis extract comprising at least about 90% (w/w) cannabidiol (CBD) in a dosage form for transdermal delivery. The present disclosure provides a pharmaceutical composition wherein the high-purity cannabis extract comprises at least about 95% CBD. The present disclosure provides a pharmaceutical composition wherein the high-purity cannabis extract comprises at least about 98% CBD. The present disclosure provides a pharmaceutical composition wherein the high-purity cannabis extract comprises at least about 99% CBD. The present disclosure provides a pharmaceutical composition formulated as a transdermal liquid formulation, a transdermal semi-solid formulation, or a transdermal polymer matrix formulation. The present disclosure provides a pharmaceutical composition further comprising an effective amount of a carrier or component selected from the group consisting of a solvent, a gelling agent, a polymer, a penetration enhancer, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of solvents, gelling agents, polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, oxidants, and combinations thereof, in the range of 0.01% to 95% w/w or w/v. The present disclosure provides pharmaceutical compositions wherein the carrier is present in the range of 0.01% to 99.8% w/w or w/v. The present disclosure provides pharmaceutical compositions formulated as a transdermal patch. The present disclosure provides pharmaceutical compositions formulated as a transdermal patch, wherein the transdermal patch is selected from the group including reservoir patch, microreservoir patch, matrix patch, pressure sensitive adhesive patch, sustained release transdermal film, liquid reservoir system, microreservoir patch, matrix patch, pressure sensitive adhesive patch, mucoadhesive patch, and combinations thereof. The present disclosure provides pharmaceutical compositions adapted for the treatment and/or prevention and/or control of seizure disorders in a patient, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides a pharmaceutical composition formulated as a transdermal formulation that can be administered in a dosage regimen selected from the group consisting of once daily, twice daily, three times daily, once 1-8 hours, once 1-24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, once every 15 to about 30 days. The present disclosure provides a pharmaceutical composition that can be formulated as a microneedle. The present disclosure provides a pharmaceutical composition in which the CBD or derivatives thereof are produced by a synthetic route. The present disclosure provides a pharmaceutical composition that is co-administered with at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. The present disclosure provides pharmaceutical compositions further comprising at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin.

The present disclosure provides a pharmaceutical composition comprising a high-purity cannabis extract containing at least about 90% (w/w) cannabidiol (CBD) in a dosage form for transdermal delivery, the pharmaceutical composition comprising about 9% to about 12% w/w high-purity CBD; optionally, about 30% to about 99% solvent; optionally, about 1% to about 20% penetration enhancer, the pH of the composition being maintained at about 4.0 to 8.0. The present disclosure provides a pharmaceutical composition formulated as a transdermal liquid formulation, a transdermal semi-solid formulation, or a transdermal polymer matrix formulation. The present disclosure provides a pharmaceutical composition further comprising an effective amount of a carrier or component selected from the group consisting of a gelling agent, a polymer, an emollient, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of gelling agents, polymers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, oxidizing agents, and combinations thereof, in the range of 0.01% to 95% w/w or w/v. The present disclosure provides pharmaceutical compositions formulated as transdermal patches. The present disclosure provides pharmaceutical compositions formulated as transdermal patches, the transdermal patch being selected from the group including reservoir patches, microreservoir patches, matrix patches, pressure sensitive adhesive patches, sustained release transdermal films, liquid reservoir systems, microreservoir patches, matrix patches, pressure sensitive adhesive patches, mucoadhesive patches, and combinations thereof. The present disclosure provides pharmaceutical compositions adapted for the treatment and/or prevention and/or control of a patient's seizure disorders, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides a pharmaceutical composition formulated as a transdermal formulation that can be administered in a dosage regimen selected from the group consisting of once daily, twice daily, three times daily, once 1-8 hours, once 1-24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, once every 15 to about 30 days. The present disclosure provides a pharmaceutical composition that can be formulated as a microneedle. The present disclosure provides a pharmaceutical composition in which the CBD or derivatives thereof are produced by a synthetic route. The present disclosure provides a pharmaceutical composition that is co-administered with at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. The present disclosure provides pharmaceutical compositions further comprising at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin.

The present disclosure provides a method for treating and/or preventing and/or controlling a seizure disorder in a patient, comprising: selecting a patient in need of treatment and/or prevention and/or control of a seizure disorder; and locally applying a pharmaceutical composition disclosed herein. ... wherein the seizure disorder includes complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides methods of topical application of a transdermal patch for the treatment and/or prevention and/or control of a patient's seizure disorders, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epileptic syndromes, e.g., juvenile onset seizures, Myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions, selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every ten days. The present disclosure provides a method that further provides a constant rate of delivery of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method that further provides a stable absorption rate of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method that further achieves a constant serum level of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method that further achieves a reduced variation in the dosage of the active ingredient of the transdermal patch over a period of time. The present disclosure provides a method for further providing plasma concentrations of the active ingredient of a transdermal patch within the therapeutic range over a period of time.

The present disclosure provides a transdermal and/or topical pharmaceutical composition comprising about 0.1% to about 20% of an active agent selected from the group consisting of synthetic cannabidiol, natural cannabidiol, and combinations thereof; about 35% to about 99% of at least one adhesive and/or polymer; optionally, about 0.1% to about 30% of at least one penetration enhancer; and optionally, about 0.1% to about 40% of a gelling agent. The present disclosure provides a transdermal and/or topical pharmaceutical composition in which the CBD or derivatives thereof are produced by a synthetic route. The present disclosure provides a transdermal and/or topical pharmaceutical composition in which the active agent is a high purity synthetic comprising at least about 90% (w/w) cannabidiol (CBD). The present disclosure relates to adhesives and/or polymers including, but not limited to, hydroxylpropylmethylcellulose, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971pNF, polyethylene and copolymers thereof, clays, silicates, bentonite, silicon dioxide, polyvinyl alcohol, acrylic polymers, Eudragit, acrylic acid esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and copolymers, PVP, Kollidon® 30, poloxamers, isobutylene, ethylvinyl acetate copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives, biocompatible adhesives, biodegradable ... The present invention provides a transdermal and/or topical pharmaceutical composition comprising a composition selected from the group consisting of psa® 4302, bio-psa® 4501, 4202, acrylic pressure sensitive adhesives, duro-tak® 87-2156, duro-tak® 387-2287, polyisobutylene, low molecular weight polyisobutylene, medium molecular weight polyisobutylene, 35000 mw polyisobutylene, acrylic copolymers, rubber adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and/or organic solvent swellable polymers, and combinations thereof. The present disclosure provides a composition comprising at least one permeation enhancer present, the composition being dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, decimethyl sulfoxide, dimethyl isosorbide, 1,3-butanediol, azone, pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone, esters, fatty acid esters, propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monolaurate, glycerol monolaurate, methyl laurate, lauryl laurate, fatty acids, capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, The present invention provides a transdermal and/or topical pharmaceutical composition selected from the group consisting of acids, linoleic acid, stearic acid, palmitic acid, alcohols, fatty alcohols and glycols, oleyl alcohol, nathanol, dodecanol, propylene glycol, glycerol, ether alcohols, diethylene glycol monoethyl ether, urea, triglycerides, triacetin, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, esters of fatty alcohols, essential oils, surfactant type enhancers, brij®, sodium lauryl sulfate, Tween®, polysorbates, terpenes, terpenoids, and combinations thereof. The present disclosure provides a method for preparing a gelling agent comprising the steps of: providing a gelling agent comprising at least one gelling agent, selected from the group consisting of natural polymers, polysaccharides and derivatives thereof, agar, alginic acid and derivatives, cassia, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan gum, copal, starch, chitosan, resins, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971, polyethylene and copolymers thereof, clays, silicates, polyvinyl chloride ... alcohol, polyacrylamide, polyvinylpyrrolidone homopolymer and copolymer, PVP, poloxamer, acrylic acid or its esters, polyacrylate copolymers, isobutylene, ethylene vinyl acetate copolymer, natural rubber, synthetic rubber such as styrene-diene copolymer, styrene-butadiene block copolymer, isoprene block copolymer, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, silicone based pressure sensitive adhesives, hot melt adhesives, and combinations thereof. The present disclosure provides transdermal and/or topical pharmaceutical compositions further comprising an effective amount of a carrier or ingredient selected from the group consisting of a solvent, an emollient, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. The present disclosure provides transdermal and/or topical pharmaceutical compositions formulated as a transdermal patch. The present disclosure provides transdermal and/or topical pharmaceutical compositions formulated as a transdermal patch, the transdermal patch being selected from the group including reservoir patch, microreservoir patch, matrix patch, pressure sensitive adhesive patch, sustained release transdermal film, liquid reservoir system, microreservoir patch, matrix patch, pressure sensitive adhesive patch, mucoadhesive patch, polymeric adhesive matrix patch, and combinations thereof. The present disclosure provides transdermal and/or topical pharmaceutical compositions adapted for the treatment and/or prevention and/or control of seizure disorders in a patient, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides transdermal and/or topical pharmaceutical compositions formulated as transdermal formulations that can be administered at a dosage schedule selected from the group consisting of once daily, twice daily, three times daily, once 1-8 hours, once 1-24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, once every 15 to about 30 days. The present disclosure provides transdermal and/or topical pharmaceutical compositions that can be formulated as microneedles. The present disclosure provides transdermal and/or topical pharmaceutical compositions that are co-administered with at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. The present disclosure provides transdermal and/or topical pharmaceutical compositions further comprising at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin.

The present disclosure provides a method for selecting patients in need of treatment and/or prevention and/or control of seizure disorders; Methods are provided for the treatment and/or prevention and/or control of a seizure disorder in a patient, including treating and/or preventing and/or controlling the disease.

The present disclosure provides methods for treating seizure disorders including complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The present disclosure provides methods of topical application of a transdermal patch for the treatment and/or prevention and/or control of a patient's seizure disorders, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epileptic syndromes, such as juvenile myoclonic convulsions, ... -epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions, selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. The present disclosure further provides a method that provides a constant rate of delivery of the active ingredient of the transdermal patch over a period of time selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. The present disclosure provides a method further providing a stable absorption rate of the active ingredient of the transdermal patch over a period selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once from 10 days up to 30 days. The present disclosure provides a method further achieving a constant therapeutic serum level of the active ingredient of the transdermal patch over a period selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once from 10 days up to 30 days. The present disclosure provides a method further achieving a reduced dosage variability of the active ingredient of the transdermal patch over a period selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once from 10 days up to 30 days. The present disclosure provides a method that further provides a therapeutic plasma concentration of the active ingredient of the transdermal patch within the therapeutic range for a period selected from the group consisting of once daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once per week, and once every 10 days up to 30 days.

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

According to yet another embodiment, the present disclosure provides for the use of the above pharmaceutical composition and at least one additional therapeutic agent in an amount effective for use in medicine, and most preferably, for use as a medicine to treat a disease or disorder associated with, for example, a disease of the subject disclosed herein.

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

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 O ₂ Molecular weight: 314.46 Daltons The chemical structure is shown below as Formula I.

Tetrahydrocambinol (THC) IUPAC name (-)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-1- All Chemical formula: C ₂₁ H ₃₀ O ₂ Molecular weight: 314.47 Daltons. The chemical structure is shown below as Formula II.

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

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

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

As used herein, the term "pharmaceutically acceptable salt" includes acid addition salts or free base addition salts. The term "pharmaceutically acceptable salts" of cannabidiol includes within its scope all possible isomers and mixtures thereof, as well as any pharmaceutically acceptable metabolites, bioprecursors and/or Prodrugs, e.g., having a different structural formula than one of the compounds of the present disclosure, but which are nevertheless converted directly or indirectly into a compound of the present disclosure in vivo upon administration to a subject, such as a mammal, particularly a human. Contains compounds.

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

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

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

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

As used herein, the terms "composition" and "formulation" are used interchangeably.
As used herein, the term "transdermal delivery" means delivery of a drug through the skin into the systemic circulation.

In certain embodiments, the transdermal compositions described herein are for the treatment and/or prevention and/or control of a patient's seizure disorder, including, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions.

Epilepsy Epilepsy is a brain disease characterized by repeated seizures over long periods of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures upon awakening, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis. treatment-resistant epilepsy, treatment-resistant childhood epilepsy, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

Status epilepticus (SE) includes, for example, convulsive status epilepticus, such as early status epilepticus, confirmed status epilepticus, refractory status epilepticus, very refractory status epilepticus, and Convulsive status epilepticus may include, for example, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic lateral epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and includes early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. obtain. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus seizures despite treatment with first-line therapy, and second-line therapy is implemented. Refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line and second-line therapies, and general anesthetics are generally administered. Super-refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line therapy, second-line therapy, and general anesthesia for more than 24 hours.

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

The compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established 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 lateral epileptiform discharges, before seizures begin.

Seizures A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." Convulsions are rapid and uncontrollable shaking of a person's body. During a spasm, a person's muscles repeatedly contract and relax.

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

Generalized seizures are caused by electrical impulses from the entire brain, whereas focal seizures (at least initially) are caused by electrical impulses from a relatively small part of the brain. The part of the brain that causes seizures is sometimes called the focus.

There are six types of generalized seizures. The most common and dramatic, and therefore best known, is the generalized convulsion, also called grand mal. In this type of seizure, the patient loses consciousness and usually collapses. Loss of consciousness is followed by 30-60 seconds of the whole body stiffening (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent convulsions (the "clonic" phase), after which the patient falls into a deep sleep state (the "postictal" or postictal phase). During a grand mal seizure, injuries and accidents such as tongue biting or urinary incontinence may occur.

Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Patients, most often children, typically stop their activities and stare blankly. These attacks begin and end suddenly and may occur several times a day. Patients are usually unaware that they are having a seizure, other than that they are "losing time."

Myoclonic seizures consist of sporadic jerks that usually occur on both sides of the body. Patients sometimes describe the jerks as brief electric shocks. These seizures can become so severe that they can cause the person to drop or throw things involuntarily.

Clonic seizures are repeated rhythmic seizures that occur simultaneously on both sides of the body.
Tonic seizures are characterized by muscle stiffness.

Cataplexy consists of a sudden general loss of muscle tone, especially in the arms and legs, often leading to falls.
Seizures as described herein include epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; incessant seizures; prolonged seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive epilepsy. Status seizures, non-convulsive status epilepticus; intractable seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence Seizures; cataplexy; benign rolandic seizures; febrile convulsions; affective seizures; focal seizures; laughter seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; severe bilateral myoclonic seizures; multifocal seizures; neonatal-onset seizures; nocturnal seizures; They may include occipital lobe seizures; post-traumatic seizures; micro-seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

Refined CBD
The present disclosure provides that CBD is present in an amount that reduces the total seizure frequency by more than 70% relative to the seizure frequency achieved with the concomitant antiepileptic drug (AED). More preferably, CBD is present in an amount that reduces the total seizure frequency by more than 90% relative to the seizure frequency achieved with the concomitant antiepileptic drug (AED). Even more preferably, CBD is present in an amount that reduces the total seizure frequency by 100% relative to the seizure frequency achieved with the concomitant antiepileptic drug (AED).

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

The one or more AEDs are preferably selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. In certain embodiments, CBD is used in combination with clobazam. Preferably, the number of different anti-epileptic drugs or the dose of AED used in combination with CBD is reduced. More preferably, the AED whose dose is reduced is clobazam.

In certain embodiments, the dose of CBD is, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 mg/kg/day. For example, for a 15 kg patient, a dose of CBD greater than 75 mg per day may be provided. It is contemplated that doses greater than 5 mg/kg/day, such as greater than 10 mg/kg/day, greater than 15 mg/kg/day, greater than 20 mg/kg/day, and greater than 25 mg/kg/day, may also be effective. In certain embodiments, the dose of CBD is, for example, greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, or 275 mg/day.

The present disclosure provides a method of treating treatment-resistant epilepsy comprising administering cannabidiol (CBD) to a subject, where the epilepsy is febrile infection-related epilepsy syndrome (FIRES).

The present disclosure provides for administration of cannabidiol (CBD) to a subject in an amount sufficient to reduce total seizure frequency by more than 50% relative to the seizure frequency achieved with one or more concomitant antiepileptic drugs (AEDs). Provided are methods of treating treatment-resistant epilepsy, including treating treatment-resistant epilepsy.

Pharmaceutical Compositions According to certain embodiments described herein, the pharmaceutical compositions or transdermal formulations contain high purity CBD. More preferably, the transdermal formulations may contain high purity CBD.

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

Transdermal formulations include, but are not limited to, liquids such as solutions, suspensions, dispersions, and emulsions. Transdermal formulations include, but are not limited to, semisolids such as gels, ointments, emulsions, creams, suspensions, pastes, lotions, balms, and the like. Liquid and/or gel formulations incorporated into transdermal patches are preferred. Transdermal formulations containing without limitation polymeric matrices, including adhesive matrices and non-adhesive matrices.

Without any limitation, transdermal patches may include, but are not limited to, preferably reservoir patches, matrix patches, bilayer matrix patches, multilayer matrix patches, microreservoir patches, adhesive systems, transdermally applicable tapes, and any other transdermal drug delivery system described in the art.

In certain embodiments of the present disclosure, a transdermal patch includes a transdermal formulation containing highly purified CBD contained in a reservoir or matrix, and a transdermal patch that allows the transdermal patch to adhere to the skin, such that the highly purified CBD is transdermal. and an adhesive that allows passage from the skin patch through the patient's skin. Transdermal delivery systems may be occlusive, semi-occlusive, or non-occlusive, and may be adhesive or non-adhesive.

Transdermal formulations containing highly purified CBD can be incorporated into patches, and the patches can be applied topically to the skin surface. The patch can remain on the subject for any suitable period of time.

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

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

In yet another embodiment, the transdermal patch described herein provides a constant serum level of the active ingredient of the transdermal patch 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, 8-13 days, 2 weeks, or 15 days.

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

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

Topical formulations described in the art include, but are not limited to, semisolids such as ointments, creams, emulsions, microemulsions, nanoemulsions, pastes, balms, gels, lotions, mousses, etc.; liquids such as solutions, suspensions, microsuspensions, nanosuspensions, dispersions, nanodispersions, etc.; sprays, aerosols, magmas, etc. Topical formulations containing high purity CBD can be applied topically to the skin surface for transdermal delivery of cannabidiol.

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

Cannabidiol can be dissolved, suspended, dispersed, or homogeneously mixed in the above single carriers, mixtures of carriers, and combinations of carriers. Any combination of two or more drugs, such as cannabidiol, can be dissolved, suspended, dispersed, or homogeneously mixed in the above single carriers, mixtures of carriers, and combinations of carriers.

The desired optimal transdermal and/or topical formulation of cannabidiol alone or in combination may include, but is not limited to, the carriers described below in Examples 1-11, alone or in combination.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but it should be understood that the present invention is not limited thereto.
Example Example 1
Transdermal and/or topical formulations of the present disclosure may include solvents known to those skilled in the art, including, but not limited to, the following alone or in combination: alcohols C ₁ -C ₂₀ ; For example, without limitation, (methanol, ethanol, isopropyl alcohol, butanol, propanol, etc.), polyhydric alcohols, glycols, such as, but not limited to (propylene glycol, polyethylene glycol, dipropylene glycol, xylene glycol, butylene glycol, glycerol, etc.), derivatives of glycols, pyrrolidones, such as, but not limited to, (N-methyl 2-pyrrolidone, 2-pyrrolidone, etc.), sulfoxides, such as, but not limited to, ( dimethyl sulfoxide, decimethyl sulfoxide, etc.), dimethyl isosorbide, mineral oil, vegetable oil, water, polar solvents, semi-polar solvents, non-polar solvents, volatile chemicals that can be used to create the matrix patch, such as, but not limited to: (ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA), acids such as, but not limited to, acetic acid, lactic acid, levulinic acid, bases, and others. More preferably, it is in the range of 0.01% to 95% w/w or w/v. In exemplary embodiments, a formulation of the present disclosure comprises about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3% of the formulation. , 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 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65% , about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, formulations of the present disclosure may include solvent at a concentration of about 30-99%, about 35%-95%, about 40% to about 90% w/w. In exemplary formulations of the present disclosure, the solvent is present at about 1% to 75%, preferably 2% to 30%, more preferably 5% to 20% by weight of the formulation.

Example 2
The transdermal and/or topical formulations of the present disclosure may contain gelling agents and/or thickening agents and/or suspending agents known to those skilled in the art, including but not limited to: or in combinations thereof: natural polymers, polysaccharides and derivatives thereof, such as, but not limited to, (agar, alginic acid and derivatives, cassia tora, collagen, gelatin, gellum gum, guar gum) , pectin, carrageenan potassium or sodium, tragacanth, xanthan, gum copal, chitosan, resins, etc.), semi-synthetic polymers and their derivatives, such as, but not limited to, cellulose and its derivatives (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropyl) cellulose, hydroxypropyl methylcellulose, etc.), synthetic polymers and their derivatives, such as, but not limited to, carboxyvinyl polymers or carbomers (carbopol® 940, carbopol® 934, carbopol® 971pNF) , polyethylene, and its copolymers, clays such as, but not limited to (silicates, bentonites), silicon dioxide, polyvinyl alcohol, acrylic polymers (Eudragit), acrylic esters, polyacrylate copolymers, polyacrylamides , polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers, such as, but not limited to, (PVP, Kollidon® 30, poloxamers), isobutylene, ethyl vinyl acetate copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives, For example, silicone polymers, such as, but not limited to (BIO-PSA® 4302, BIO-PSA® 4501, 4202, etc.), acrylic pressure sensitive adhesives, such as, but not limited to , (duro-tak® 87-2156, duro-tak® 387-2287, etc.), polyisobutylene, such as, but not limited to (low molecular weight polyisobutylene, medium molecular weight polyisobutylene, 35000 mw (such as polyisobutylene), acrylic copolymers, rubber adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and/or organic solvent swellable polymers, etc. More preferably, it is in the range of 0.1% to 70% w/w or w/v. In exemplary embodiments, a formulation of the present disclosure comprises about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3% of the formulation. , 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 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65% , about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the gelling agent and/or thickening agent and/or suspending agent. may contain a curing agent. In exemplary embodiments, the formulations of the present disclosure contain about 1 to 20%, about 5% to 25%, about 10% to about 20%, or about 15 to about 18%, about 30% to about 70%, Gelling and/or thickening and/or suspending agents may be included at concentrations of about 35% to about 65%, 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 is about 1% to 75%, preferably 2% to 30%, more preferably 2% to 30%, by weight of the formulation. may account for 5% to 20% by weight.

Example 3
Transdermal and/or topical formulations of the present disclosure may include penetration enhancers or permeation enhancers known to those skilled in the art, including, but not limited to, alone or in combinations thereof, such as: , sulfoxides, and similar chemicals, such as, but not limited to (dimethyl sulfoxide, dimethylacetamide, dimethylformamide, decimethyl sulfoxide, dimethyl isosorbide, etc.), 1,3-butanediol, azone, pyrrolidone, e.g. (N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), esters, fatty acid esters, such as, but not limited to (propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, 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, aliphatic alcohols and glycols, such as, but not limited to (oleyl alcohol, natanol, 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 ether, polyoxyethylene Fatty acid esters, esters of fatty alcohols, essential oils, surfactant-type promoters, such as, but not limited to (brij®, sodium lauryl sulfate, Tween®, polysorbates), terpenes, terpenoids. , and all penetration enhancers or permeation enhancers referenced in the book "Percutaneous Penetration Enhancers" (Eric W. Smith, Howard I. Maibach, 2005, Nov. CRC press). More preferably, it is in the range of 0.01% to 95% w/w or w/v. In exemplary embodiments, a formulation of the present disclosure comprises about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3% of the formulation. , 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 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65% , about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, formulations of the present disclosure contain about 1-20%, about 5%-25%, about 10% to about 20%, or about 15% to about 18%, about 30% to about 70% , about 35% to about 65%, and about 40% to about 64% w/w. In exemplary formulations of the present disclosure, the permeation enhancer may represent about 1% to 75%, preferably 2% to 30%, more preferably 5% to 20% by weight of the formulation.

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

Example 5
The transdermal and/or topical formulations of the present disclosure may contain emollients, moisturizers, skin irritation relieving agents, and similar compounds or chemicals known to those skilled in the art, alone or in combination, including but not limited to the following: petrolatum, lanolin, mineral oil, dimethicone, zinc oxide, glycerol, propylene glycol, and the like, more preferably in the range of 0.01% to 95% w/w or w/v. In exemplary embodiments, the formulations of the present disclosure contain emollients, moisturizers, skin irritation reducers, and similar compounds or chemicals at about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about The composition may be present in concentrations of about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include emollients, moisturizers, skin irritation reducing agents, and similar compounds or chemicals at concentrations of about 1-20%, about 5%-25%, about 10%-about 20%, or about 15%-about 18%, about 30%-about 70%, about 35%-about 65%, and about 40%-about 64% w/w. In exemplary formulations of the present disclosure, the emollients, moisturizers, skin irritation reducing agents, and similar compounds or chemicals may comprise about 1%-75%, preferably 2%-30%, and more preferably 5%-20% by weight of the formulation.

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

Example 7
Various techniques and ingredients can be used to enhance the stability and/or solubility of high-purity CBD in formulations, including, but not limited to, coating, encapsulation, microencapsulation, nanoencapsulation, lyophilization, Chelating agents, complexing agents, etc. can be used.

Example 8
The transdermal and/or topical formulations of the present disclosure may contain auxiliary pH buffers and pH stabilizers and similar compounds known to those skilled in the art that aid in maintaining the appropriate pH of the formulation, preferably in the range of 4.0 to 8.0, alone or in combination, including but not limited to: phosphate buffer, acetate buffer, citrate buffer, and the like; acids, including but not limited to (carboxylic acids, inorganic acids, sulfonic acids, vinyl-based carboxylic acids, and the like); bases, including but not limited to (sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate), and the like, more preferably in the range of 0.01% to 30% w/w or w/v. In exemplary embodiments, the formulations of the present disclosure comprise about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about Supplementary pH buffering agents and pH stabilizers and similar compounds may be included at concentrations of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80%. In exemplary embodiments, the formulations of the present disclosure may include supplemental pH buffering and pH stabilizing agents and similar compounds in concentrations of about 1-20%, about 5%-25%, about 10%-20%, or about 15%-18%, about 30%-70%, about 35%-65%, and about 40%-64% w/w. In exemplary formulations of the present disclosure, supplemental pH buffering and pH stabilizing agents and similar compounds may comprise about 1%-75%, preferably 2%-30%, more preferably 5%-20% by weight of the formulation. In certain embodiments, the pH of the formulation is maintained at about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0. In certain embodiments, the pH of the formulation is maintained in the range of about 4.0 to about 8.0, about 4.5 to about 7.5, or about 5.0 to about 7.0.

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

Example 10
Transdermal and/or topical formulations of the present disclosure may be formulated as ointment and/or cream bases known to those skilled in the art.

Example 11
Materials for making the transdermal delivery system of the present disclosure in the form of a patch known to those skilled in the art include, for example, but are not limited to, reservoir patches, matrix patches, drug in adhesive, transdermal films, etc., which may include, for example, but are not limited to, polymers, copolymers, derivatives, backing films, release membranes, release liners, etc., alone or in combination, such as pressure-sensitive adhesives (for example, but are 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 (for example, but are not limited to, ethylene vinyl acetate copolymers, vinyl acetate resins, polyurethanes, polyvinyl chloride, metal foils, polyesters, aluminum-plated films, polyethylene, etc.), release membranes (for example, but are not limited to, polyethylene microporous membranes, polypropylene microporous membranes, rate-controlling ethylene vinyl acetate copolymer membranes, etc.), release liners (for example, but are not limited to, siliconized polyester films, fluororesin-coated polyester films, polyester films, siliconized polyethylene terephthalate films, etc.), tapes, etc.

The transdermal and/or topical formulations and/or transdermal delivery systems of the present disclosure can deliver at least a therapeutically effective amount of highly purified CBD. Therapeutically effective high purity CBD in human plasma, alone or in combination, for the treatment and/or prevention of pain and/or inflammation. A therapeutically effective high purity CBD dose refers to the therapeutic concentration in human plasma necessary to treat and/or prevent pain and/or inflammation. Additionally, the precise therapeutically effective amount of highly purified CBD in a transdermal or topical formulation or transdermal delivery system can be determined by one of ordinary skill in the art based on factors such as, but not limited to, the condition of the patient. Transdermal or topical formulations or transdermal delivery systems will be available in a variety of dose strengths and patch sizes to achieve optimal therapeutic results based on patient requirements.

In yet another embodiment, the transdermal and/or topical formulations and/or transdermal delivery systems of the present disclosure may deliver at least a therapeutically effective amount of highly purified CBD. Therapeutically effective high-purity CBD refers to therapeutic concentrations of high-purity CBD in human plasma that are necessary for the treatment and/or prevention and/or control of seizure disorders in a patient; Focal seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonates and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, medial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, and mental retardation. These include progressive epilepsy associated with epilepsy, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions.

Transdermal formulations or transdermal patches of high purity CBD can be applied to the skin surface with a dosage regimen that is preferably, but not limited to, any of the following: e.g. Once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, every 2 weeks Once, once every 15 days.

Example 12
Cannabidiol theoretical flux calculations:
The oral bioavailability of CBD is only 13-19%. Our calculations put the average bioavailability of TRPL at 15% ^.2 Therefore, the actual dose delivered to patients upon oral administration is listed in Table 3.

Thus, a 50 square cm patch with a flow rate of 7.5 μg/cm2/hr delivers 9 mg of drug per day. Also, a 100 square cm patch delivers 18 mg of drug with the same flow profile. Several research papers have shown that the oral bioavailability of CBD is in the range of 5-6% ^2,8 .

Example 13
Synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation Nos. 001, 002, 003, 004, and 005) were prepared by mixing the ingredients shown in Table 4.

All ingredients in Table 2 except CBD were mixed with stirring for 18 hours. The final transdermal formulation was then prepared by adding CBD to the excipient mixture.
Next, the following flow measurement test was conducted on the prepared transdermal preparation. Human cadaver skin stored at -80°C was thawed in phosphate buffered saline (PBS) at room temperature and visually inspected for defects before use for research. Transdermal flux was then measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment with a capacity of 13 mL. Human cadaver skin was clamped between two compartments with the dermal side facing the receptor compartment. The donor compartment was filled with the transdermal CBD formulation prepared as described above. The receptor compartment was filled with receptor medium, kept at constant temperature, and constantly stirred to collect the CBD that diffused through the skin into the receptor compartment. It is important to ensure that the receptor fluid is in constant contact with the skin. For CBD assays, the receptor compartment was emptied at 24 hour intervals and replaced with fresh receptor solution. To maintain sink conditions in the receptor compartment, it is important to keep the CBD concentration within the receptor compartment below 10% of its solubility. The experimental conditions are shown in Table 3.

The flow rate of CBD through the skin of a human cadaver was measured for a minimum period of 96 hours (4 days), and the flow rate measurement results are shown in Table 4.

Example 14
Additional synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation Nos. 006-014) were prepared by mixing the ingredients shown in Table 7.

Synthetic cannabidiol formulations (006-014) for transdermal delivery were prepared by the same procedure described in Example 2. Flow measurements were also performed as described in Example 2. The experimental conditions were the same as those shown in Table 5 of Example 2.

The flux of CBD through human cadaver skin was measured for the shortest period of time, 48 hours. The results of the flux measurement experiments are shown in Table 8.

Example 15
Additional synthetic cannabidiol (CBD) formulations for transdermal delivery patches (Formulation Nos. 015-018) were prepared by mixing the ingredients shown in Table 9.

To prepare the transdermal patch containing synthetic cannabidiol, all ingredients in Table 9 except CBD were mixed with stirring for 18 hours. CBD was then added 30 minutes before spreading the formulation. The formulation was spread using a commercially available bench top spreader. Specifically, the formulation matrix was spread evenly to a thickness of 0.5 mm on a sheet of 20 x 36 cm (8 x 14 inches) release liner (such as 3M 9744). The sheet was then placed in an oven at 38°C (100°F) for 1 hour to evaporate the ethyl acetate and ethanol adhesive solvents. An opaque backing film with low oxygen permeability (such as 3M 9730NR film) to inhibit photo- and oxidative degradation was then carefully attached to the sheet by hand to avoid the formation of bubbles or voids. A circular mold (diameter 4 cm (1.5 inches)) was used to cut out patches ( ⁷ cm2) for subsequent studies.

The general procedure for measuring the flux of the transdermal formulations in the above examples is as follows: Human cadaver skin stored at -80°C was thawed at room temperature in PBS and visually inspected for defects before use. Transdermal flux was measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment of 13 mL volume. Human cadaver skin was clamped between the two compartments with the dermis side facing the receptor compartment. The general procedure for measuring the flux of the transdermal adhesive patch is as follows: The release liner is removed from the patch and the adhesive side is applied to a piece of human cadaver skin (Example 15, Table 9 only). The transdermal patch is adhered to the skin with the skin side of the patch in contact with the donor compartment. The receptor compartment was filled with receptor medium, kept at a constant temperature, and constantly stirred to collect the CBD that diffuses from the adhered patch through the skin and into the receptor compartment. It was ensured that the receptor fluid was in constant contact with the skin. The receptor compartment was emptied at 24-hour intervals and replaced with fresh receptor solution for the CBD assay. To maintain sink conditions in the receptor compartment, the CBD concentration in the receptor compartment was kept below 10% of its solubility. The experimental conditions were the same as those shown in Table 5 of Example 13.

Example 16
Synthetic cannabidiol (CBD) formulations (Formulation Nos. 047-055) for transdermal delivery were prepared by mixing the ingredients shown in Table 10.

The above ingredients (Table 10) are stirred and blended for 18 hours, after which the matrix is spread onto a 20 x 36 cm (8 x 14 inch) sheet of release liner (such as 3M9744) using a commercially available bench top spreader. Spread evenly to a thickness of 0.5 mm. The sheet is then placed in a 30°C (86F) oven for 120 minutes to evaporate the ethyl acetate adhesive solvent. Next, to suppress photo- and oxidative degradation, an opaque backing film with low oxygen permeability (such as 3M9730NR film) is carefully applied by hand to avoid the formation of air bubbles or voids. A circular mold (4 cm (1.5 inch) in diameter) is used to cut out patches (1.76 square cm) for subsequent study. The drug-adhesive matrix after drying has a surface density of 2-30 mg/cm2 and contains 5% w/w CBD.

The prepared formulations were then subjected to release testing as follows. After weighing the patches (n=3), the release liner was removed and the patches were placed in a 20 ml scintillation vial with 15 ml of receptor medium. The receiving medium was a PBS solution containing 0.5% Brij® (O)20 at pH 7.4. The vial was placed on a roller overnight at 20 RPM. Samples were taken every 24 hours, up to every 48 hours, and the media was completely replaced each time. The samples were then analyzed by HPLC to determine the % release of CBD from the different formulations.

The prepared formulations are also analyzed for uniformity of drug content. Weigh the patches (n=3) for each formulation, remove the release liner, and place the patches (including release liner) into a 20 ml scintillation vial with 15 ml of IPA:ethanol (190 proof) (50:50) solution. Ta. The vial was then placed on a roller at 20 RPM and left overnight. To determine the drug content of each formulation, samples were taken from each vial and analyzed by HPLC.

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

Investigation of drug content showed that the recovery of CBD in the extracts was 96-107% for all formulations manufactured. Additionally, release testing showed that silicone adhesive 4501 exhibited greater than 90% release within the first 24 hours. Based on the release profile, the optimal adhesive for CBD formulations is: BIOPSA®-4501>2054=2194>2074>2516>2852=2287>9301.

Release studies show that functional groups and crosslinkers influence CBD release from acrylic adhesives. Current research has shown that acrylic adhesives containing -COOH functional groups along with crosslinkers release the most CBD from all acrylic adhesive patches.

Example 17
Additional synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation Nos. 057-064) were prepared by mixing the ingredients shown in Table 13.

Synthetic cannabidiol formulations (057-064) for transdermal delivery were prepared by the same procedure as described in Example 16.
The prepared transdermal formulations were then subjected to the following flux measurement tests. Human cadaver skin stored at -80°C was thawed at room temperature in phosphate buffered saline (PBS) and visually inspected for defects before use in the study. The transdermal flux was then measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment of 13 mL volume. The human cadaver skin was clamped between the two compartments with the dermal side facing the receptor compartment. The donor compartment was filled with the transdermal CBD formulation prepared as described above. The receptor compartment was filled with receptor medium and kept at a constant temperature and with constant stirring to collect the CBD that diffuses through the skin into the receptor compartment. It is important to ensure that the receptor fluid is in constant contact with the skin. The receptor compartment was emptied at 24-hour intervals for assay of CBD and replaced with fresh receptor solution. To maintain sink conditions in the receptor compartment, it is important to keep the CBD concentration in the receptor compartment below 10% of its solubility. The experimental conditions are shown in Table 14:

The flux of CBD through human cadaver skin was measured for a minimum period of 96 hours (4 days). The results of the flux measurements are shown in Table 15.
Once the flux test was completed, the used patch was carefully removed and the CBD was extracted from the used patch using IPA:ethanol (50:50). Human cadaver skin was also soaked in IPA:ethanol (50:50) to extract CBD therefrom. Samples were analyzed using HPLC. The data in Table 6 shows the amount of CBD present in the skin and remaining patch.

Example 18
Effect of gelling agent and its concentration on the permeation of CBD through human cadaver skin. CBD gel formulations may be formulated using gels containing natural polymers such as, but not limited to, natural polymers, polysaccharides and their derivatives, including, but not limited to, (agar, alginic acid and derivatives, cassia, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan gum, copal, starch, chitosan, resins, etc.), synthetic polymers and their derivatives, including, but not limited to, carboxyvinyl polymers or carbomers (carbopol® 940, carbopol® 934, carbopol® 971), polyolefins, polystyrene ... The cannabidiol can be gelled with gelling agents such as clays such as silicates, polyvinyl alcohol, polyacrylamides, polyvinylpyrrolidone homopolymers and copolymers thereof (PVP, poloxamers), acrylic acid and its esters, polyacrylate copolymers, isobutylene, ethylene vinyl acetate copolymers, natural rubber, synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, isoprene block copolymers, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, and silicone-based pressure sensitive adhesives or "hot melt adhesives". Additionally, cannabidiol can be evaluated in other artificial membranes beyond human cadaver skin, including but not limited to cellulose membranes, silicone membranes (polydimethylsiloxane), liposome-coated membranes, solid-supported liquid membranes, lecithin organogel membranes, and the like. In addition to gel formulations of CBD, other dosage forms can be used, including but not limited to ointments, creams, emulsions, liposomes, and the like.

Example 19
The effect of enhancers or solubilizers on the flux of cannabidiol through human cadaver skin was evaluated. The desired optimal composition of the cannabidiol gel formulation is dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), lactic acid, Tween®-20, high purity diethylene glycol monoethyl ether (Transcutol P), dipropylene glycol, polyethylene glycol- 400, propylene glycol (PG), hexylene glycol (HG), and lauroglycol-90. Apart from the enhancers and/or solubilizers mentioned above, transdermal delivery of cannabidiol can be achieved using water, sulfoxides, and similar chemicals, such as, but not limited to (dimethyl sulfoxide, dimethylacetamide, dimethylformamide). , decylmethyl sulfoxide, dimethyl isosorbide, etc.), azone, pyrrolidones, such as, but not limited to, (N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), esters, such as, but not limited to, ( propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monooleate, glycerol monolaurate, lauryl laurate, etc.), fatty acids, e.g. Alcohols, aliphatic alcohols and glycols, such as, but not limited to (capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, etc.), oleyl alcohol, natanol, dodecanol, propylene glycol, glycerol, etc.), ethers such as, but not limited to (diethylene glycol monoethyl ether), urea, polyoxyethylene aliphatic alcohol ethers, polyoxyethylene fatty acid esters, aliphatic For example, without limitation, esters of alcohols, esters of long chain fatty acids with methyl, ethyl or isopropyl alcohol, esters of fatty alcohols with acetic acid, lactic acid, and diethanolamine oleate, essential oils, terpenes and terpenoids, (terpineol, limonene, thymol, cineole, etc.), surfactant-type promoters (polysorbate 80, polysorbate 20, etc.), liposomes, niosomes, transferomes, ethanosomes, polysorbates, such as, but not limited to (polysorbate 20) , polysorbate 40, polysorbate 60, polysorbate 80, etc.), spans, such as but not limited to (span 80, span 20, etc.), surfactants, such as (anionic, cationic, nonionic and amphoteric ), propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate, medium chain triglycerides, propylene glycol monolaurate type II, linoleoyl polyoxyl-6 glyceride, caprylic acid glyceride, oleoyl- Polyoxyl-6-glyceride, lauroylpolyoxyl-6-glyceride, polyglyceryl-3-diolate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, etc., cyclodextrins, polyhydric alcohols, especially 1,2-propanediol, butanediol , glycerol, polyethylene glycol (molecular weight greater than 100), dimethyl sulfoxide, dimethyl isosorbide, tetrahydrofurfuryl alcohol, diethyl tolumide, monoisopropylidene glycerin, and the like. may be affected by. Solubilizers, surfactants, emulsifiers, dispersants and similar compounds or chemicals known to those skilled in the art can be used alone or in combinations thereof.

reference:

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

Claims (22)

A transdermal and/or topical pharmaceutical composition comprising:
from about 0.1% to about 20% active agent selected from the group consisting of synthetic cannabidiol, natural cannabidiol, and combinations thereof;
about 35% to about 99% of at least one adhesive and/or polymer;
optionally from about 0.1% to about 30% of at least one penetration enhancer;
Optionally, a pharmaceutical composition comprising from about 0.1% to about 40% gelling agent. 2. A pharmaceutical composition according to claim 1, wherein the CBD or derivative thereof is produced by a synthetic route. The pharmaceutical composition of claim 1 or 2, wherein the active agent is a high-purity compound containing at least about 90% (w/w) cannabidiol (CBD). The adhesive and/or polymer may include hydroxylpropyl methylcellulose, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971pNF, polyethylene, and the like. Copolymers, clays, silicates, bentonites, silicon dioxide, polyvinyl alcohol, acrylic polymers, Eudragit, acrylic esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers, PVP, Kollidon® 30 , poloxamer, isobutylene, ethyl vinyl acetate copolymer, natural rubber, synthetic rubber, pressure sensitive adhesive, bio psa (registered trademark) 4302, bio-psa (registered trademark) 4501, 4202, acrylic pressure sensitive adhesive, duro-tak (registered trademark) 87-2156, duro-tak (registered trademark) 387-2287, polyisobutylene, low molecular weight polyisobutylene, medium molecular weight polyisobutylene, 35000 mw polyisobutylene, acrylic copolymer, rubber adhesive, hot melt adhesive, Pharmaceutical composition according to any one of claims 1 to 3, selected from the group consisting of styrene-butadiene copolymers, bentonites, all water and/or organic solvent swellable polymers, and combinations thereof. The at least one penetration enhancer is present, and is dimethyl sulfoxide, dimethylacetamide, dimethylformamide, decimethyl sulfoxide, dimethylisosorbide, 1,3-butanediol, azone, pyrrolidone, N-methyl-2-pyrrolidone, 2- Pyrrolidone, ester, fatty acid ester, propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monooleate, glycerol monolaurate, methyl laurate, laurin Acid lauryl, fatty acids, capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, alcohol, fatty alcohols and glycols, oleyl alcohol, natanol, dodecanol, propylene glycol, glycerol, ethers Alcohol, diethylene glycol monoethyl ether, urea, triglyceride, triacetin, polyoxyethylene fatty alcohol ether, polyoxyethylene fatty acid ester, ester of fatty alcohol, essential oil, surfactant-type accelerator, brij (registered trademark), lauryl sulfate Pharmaceutical composition according to any one of claims 1 to 4, selected from the group consisting of sodium, Tween®, polysorbates, terpenes, terpenoids and combinations thereof. The at least one gelling agent is present and is selected from the group consisting of natural polymers, polysaccharides and derivatives thereof, agar, alginic acid and derivatives, cassia, collagen, gelatin, gellum gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan gum, copal, starch, chitosan, resins, synthetic polymers and derivatives thereof, carboxyvinyl polymers or carbomers, carbopol® 940, carbopol® 934, carbopol® 971, polyethylene and copolymers thereof, clays, silicates, polyvinyl alcohols, and the like. The pharmaceutical composition according to any one of claims 1 to 5, which is selected from the group consisting of cholesteryl, polyacrylamide, polyvinylpyrrolidone homopolymer and polyvinylpyrrolidone copolymer, PVP, poloxamer, acrylic acid and its esters, polyacrylate copolymers, isobutylene, ethylene vinyl acetate copolymers, natural rubber, synthetic rubber such as styrene-diene copolymers, styrene-butadiene block copolymers, isoprene block copolymers, acrylonitrile butadiene rubber, butyl rubber, or neoprene rubber, silicone-based pressure sensitive adhesives, hot melt adhesives, and combinations thereof. The pharmaceutical composition according to any one of claims 1 to 6, further comprising an effective amount of a carrier or component selected from the group consisting of a solvent, a skin softener, a skin irritation reducing agent, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, an oxidizing agent, and combinations thereof. A pharmaceutical composition according to any one of claims 1 to 7, formulated as a transdermal patch. The pharmaceutical composition according to any one of claims 1 to 8, which is formulated as a transdermal patch, the transdermal patch being selected from the group consisting of reservoir patches, microreservoir patches, matrix patches, pressure-sensitive adhesive patches, sustained release transdermal films, liquid reservoir systems, microreservoir patches, matrix patches, pressure-sensitive adhesive patches, mucoadhesive patches, polymer adhesive matrix patches, and combinations thereof. The pharmaceutical composition according to any one of claims 1 to 9, which is adapted for the treatment and/or prevention and/or control of a seizure disorder in a patient, wherein the composition includes, for example, a complex Seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and Infantile spasms, drug-induced seizures, traumatic seizures, febrile seizures, and certain other epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant Pharmaceutical compositions including epilepsy, treatment-resistant childhood epilepsy, medial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. Once a day, twice a day, three times a day, once every 1 to 8 hours, once every 1 to 24 hours, once every 2 days, once every 3 days, once every 4 days, 5 A dosage regimen selected from the group consisting of once a day, once every 6 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 pharmaceutical composition according to any one of claims 1 to 10, which is formulated as a transdermal preparation that can be administered with. The pharmaceutical composition according to any one of claims 1 to 11, which can be formulated as a microneedle. Claims 1-12 co-administered with at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. The pharmaceutical composition according to any one of . The pharmaceutical composition of any one of claims 1 to 13, further comprising at least one additional antiepileptic agent selected from the group consisting of clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacosamide; valproic acid; zonisamide; perampanel; and fosphenytoin. A method for the treatment and/or prevention and/or control of a seizure disorder in a patient, the method comprising:
selecting patients in need of treatment and/or prevention and/or control of seizure disorders;
A method of treating and/or preventing and/or controlling a seizure disorder in a patient, comprising topically applying a pharmaceutical composition according to any one of claims 1 to 14. 16. The method of claim 15, wherein the seizure disorders include complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions. The seizure disorders include, for example, complex partial seizures, simple partial seizures, partial seizures with secondary generalization, generalized seizures (including absence, grand mal (tonic-clonic), status epilepticus, tonic, atonic, and myoclonic), neonatal and infantile convulsions, drug-induced seizures, traumatic seizures, febrile convulsions, and other specific epilepsy syndromes, such as juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex (TSC), treatment-resistant epilepsy, treatment-resistant 17. The method of claim 15 or 16, wherein the topical application of a transdermal patch for the treatment and/or prevention and/or control of a patient's seizure disorder, including childhood epilepsy, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, progressive myoclonic epilepsy, and seizures associated with CNS mass lesions, is selected from the group consisting of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once every 10 days up to 30 days. Once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. 18. The method of any one of claims 15-17, further providing a constant rate of delivery of the active ingredient of the transdermal patch over a period of time selected from the group consisting of: Once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. 19. The method of any one of claims 15-18, further providing a stable rate of absorption of the active ingredient of the transdermal patch over a period of time selected from the group consisting of: Once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. 20. The method of any one of claims 15-19, further achieving a constant therapeutic serum level of the active ingredient of the transdermal patch over a period of time selected from the group consisting of: Once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days. 21. The method of any one of claims 15 to 20, further achieving a reduction in dosage variation of the active ingredient of the transdermal patch over a period selected from the group consisting of times. The method of any one of claims 15 to 21, further providing a therapeutic plasma concentration of the active ingredient of the transdermal patch within the therapeutic range for a period selected from the group consisting of once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, and once every 10 days up to 30 days.