Therapeutic combinations, liquid pharmaceutical compositions, kits for their preparation, and methods of use thereof

Abstract

To provide therapeutic approaches for treating epileptogenesis associated with a brain insult, e.g., traumatic brain injury (TBI), stroke, or brain infection.SOLUTION: Provided are liquid pharmaceutical compositions including topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient, the liquid pharmaceutical compositions optionally further including, e.g., levetiracetam or brivaracetam and / or atorvastatin or a pharmaceutically acceptable salt thereof (e.g., atorvastatin sodium).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to liquid pharmaceutical compositions, kits for their preparation, and methods of their use. [Background technology]

[0002] background Pharmaceutical compositions provide a vehicle for the delivery of therapeutic substances.Non-oral pharmaceutical compositions are often liquid pharmaceutical compositions.For oral pharmaceutical dosage forms, liquid compositions can also be advantageous because they can be dosed by volume.This is also useful for patients who cannot swallow tablets or capsules, or when they can only tolerate the administration of liquids by stomach tube.

[0003] The need for liquid pharmaceutical compositions containing multiple therapeutic agents is particularly evident in parenteral administration, as administering multiple therapeutic agents in a single administration event can improve patient compliance and reduce waste caused by multiple parenteral administration devices. Accordingly, there is a need in the art for the development of liquid pharmaceutical compositions.

[0004] As an example, topiramate is a prescription drug used as a monotherapy for epilepsy and is typically available in solid pharmaceutical compositions, such as tablets and sprinkle capsules. Currently, there are no United States Food and Drug Administration (USFDA)-approved parenteral or oral liquid pharmaceutical compositions of topiramate. Furthermore, there are currently no USFDA-approved liquid (parenteral or oral) pharmaceutical compositions that combine topiramate with levetiracetam or brivaracetam as a dual combination, or with levetiracetam or brivaracetam and atorvastatin as a triple combination, in a single liquid pharmaceutical composition. Thus, there is a need for a parenteral or oral liquid composition comprising topiramate or a pharmaceutically acceptable salt thereof for patients with limited ability to swallow tablets or capsules.

[0005] Epilepsy is a chronic brain disorder characterized by spontaneous, recurrent seizures. Approximately 70 million people worldwide have epilepsy, making it one of the most common neurological disorders worldwide. Approximately 20% of all epilepsy cases are caused by acute brain injuries, such as traumatic brain injury (TBI), stroke, brain tumors, and infections. Acquired epilepsy is often difficult to treat and is accompanied by comorbidities such as depression, anxiety, and cognitive deficits. Being able to prevent or reduce the severity of epilepsy after brain injury represents a significant unmet need in neurology. Typically, an epileptogenic brain injury is followed by a seizure-free latency period, during which a process called epileptogenesis occurs that leads to the onset of epilepsy. Epileptogenesis is accompanied by brain changes such as blood-brain barrier disruption, inflammation, neurodegeneration, neuronal regeneration, new neuronal fiber sprouting, synapse formation, and neuronal hyperexcitability and increased synchronization, ultimately leading to spontaneous recurrent seizures and comorbidities. Acute brain injury, such as TBI, stroke, or infection, can induce epileptogenesis. The injury initiates processes that ultimately lead to the development of chronic epilepsy and related symptoms (epilepsy comorbidities). After such injury, epileptogenesis begins with a latency period during which no seizure activity can be recorded; at this time, the brain remodels and becomes epileptic. Clinical epilepsy develops after a latency period, which can be as short as a few days or as long as several years. This latency period provides an opportunity during which treatment can be used to modify the epileptogenic process and prevent the onset of epilepsy, or to modify epilepsy to be less severe, or to treat or reduce the severity of comorbid conditions.

[0006] Despite numerous clinical trials for the treatment of epileptogenesis, to the inventors' knowledge, no drugs have been shown to treat epileptogenesis after brain injury. Drugs that have failed clinical trials for the treatment of epileptogenesis include phenobarbital, phenytoin, their combinations, carbamazepine, valproate, and magnesium sulfate. One possible explanation for the failure of clinical trials to date is that epilepsy is considered a neuronal network disorder. Electrical firefighting and status epilepticus (SE) are typically used to induce epileptogenesis in rodents. Firefighting and SE do not cause the same type of brain injury as TBI, stroke, or brain infection. Therefore, the onset or worsening of epilepsy due to firefighting, SE, or seizures may be expected to differ from brain injury-induced epileptogenesis. Most preclinical studies of the effects of potential antiepileptogenic drugs have been conducted in rats or mice with SE models induced by either chemical or electrical means in healthy animals. SE is a rare cause of acquired epilepsy in humans and almost never occurs in healthy individuals. Therefore, preclinical data on the effects of disease-modifying or antiepileptogenic drugs in post-SE models of acquired epilepsy are unlikely to translate into clinically relevant causes of epileptogenesis associated with brain injury, such as TBI, stroke, or brain infection. To obtain translatable preclinical data, drug experiments in models of TBI, stroke, or brain infection are needed. There are few pharmacological trials (with single drug treatments) available for the treatment of epileptogenesis in models of TBI, stroke, or brain infection, and to the best of our knowledge, of these trials, few have observed some disease-modifying effects, but none have demonstrated any therapeutic effect on epileptogenesis.

[0007] Currently, there are no approved treatments for epileptogenesis after brain injury, such as TBI.

[0008] Thus, there is a need for therapeutic approaches to treat epileptogenesis associated with brain injury, such as TBI, stroke, or brain infection. Summary of the Invention

[0009] Generally, liquid pharmaceutical compositions of topiramate or a pharmaceutically acceptable salt thereof are disclosed.

[0010] In one aspect, a liquid pharmaceutical composition is disclosed comprising topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient.

[0011] In some embodiments, the composition comprises 1 mg / mL to 100 mg / mL (e.g., 1 mg / mL to 65 mg / mL, 10 mg / mL to 70 mg / mL, 20 mg / mL to 65 mg / mL, 4 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 9 mg / mL to 11 mg / mL, 4 mg / mL to 6 mg / mL) topiramate or a pharmaceutically acceptable salt thereof.

[0012] Liquid pharmaceutical compositions disclosed herein can include, for example, meglumine. In certain embodiments, the composition contains 1 mg / mL to 550 mg / mL (e.g., 1 mg / mL to 100 mg / mL, 1 mg / mL to 50 mg / mL, 5 mg / mL to 50 mg / mL, 10 mg / mL to 50 mg / mL, or 1 mg / mL to 30 mg / mL) of meglumine.

[0013] The liquid pharmaceutical compositions disclosed herein may contain, for example, levetiracetam. In certain embodiments, the compositions contain 5 mg / mL to 500 mg / mL of levetiracetam (e.g., 5 mg / mL to 150 mg / mL, 20 mg / mL to 150 mg / mL, 60 mg / mL to 120 mg / mL, or 30 mg / mL to 60 mg / mL). In further embodiments, the weight ratio of levetiracetam to topiramate is 15:1 or less (e.g., 10:1 or less). In still further embodiments, the weight ratio of levetiracetam to topiramate is at least 5:1. In other embodiments, the weight ratio of topiramate to atorvastatin is 5:1 to 15:1 (e.g., 5:1 to 10:1).

[0014] The liquid pharmaceutical composition disclosed herein may contain, for example, brivaracetam. In still further embodiments, the composition contains 0.5 mg / mL to 50 mg / mL (e.g., 2 mg / mL to 8 mg / mL, 4 mg / mL to 8 mg / mL, or 2 mg / mL to 4 mg / mL) of brivaracetam. In other embodiments, the weight ratio of brivaracetam to topiramate is 1:1 or less. In still other embodiments, the weight ratio of brivaracetam to topiramate is at least 1:4. In certain embodiments, the weight ratio of brivaracetam to topiramate is 1:4 to 1:1.

[0015] Liquid pharmaceutical compositions disclosed herein can include, for example, padosevonil. In still further embodiments, the composition contains 1 mg / mL to 100 mg / mL (e.g., 4 mg / mL to 16 mg / mL, 8 mg / mL to 16 mg / mL, or 4 mg / mL to 8 mg / mL) of padosevonil. In other embodiments, the weight ratio of padosevonil to topiramate is 2:1 or less. In still other embodiments, the weight ratio of padosevonil to topiramate is at least 1:4. In certain embodiments, the weight ratio of padosevonil to topiramate is 1:2 to 2:1.

[0016] The liquid pharmaceutical compositions disclosed herein may contain, for example, seletracetam. In still further embodiments, the compositions contain 0.1 mg / mL to 40 mg / mL (e.g., 0.8 mg / mL to 4 mg / mL, 2.4 mg / mL to 4 mg / mL, or 1.2 mg / mL to 2 mg / mL) of seletracetam. In other embodiments, the weight ratio of topiramate to seletracetam is 10:1 or less. In certain embodiments, the weight ratio of topiramate to seletracetam is at least 2.5:1. In further embodiments, the weight ratio of topiramate to atorvastatin is 2.5:1 to 10:1.

[0017] The liquid pharmaceutical compositions disclosed herein may contain, for example, atorvastatin or a pharmaceutically acceptable salt thereof. In still other embodiments, the compositions contain 0.1 mg / mL to 80 mg / mL (e.g., 0.1 mg / mL to 20 mg / mL, 0.1 mg / mL to 16 mg / mL, 0.2 mg / mL to 16 mg / mL, 0.4 mg / mL to 2 mg / mL, 1.2 mg / mL to 2 mg / mL, or 0.6 mg / mL to 1 mg / mL) of atorvastatin or a pharmaceutically acceptable salt thereof. In some embodiments, the weight ratio of topiramate to atorvastatin is 15:1 or less (e.g., 10:1 or less). In certain embodiments, the weight ratio of topiramate to atorvastatin is at least 5:1. In further embodiments, the weight ratio of topiramate to atorvastatin is 5:1 to 15:1 (e.g., 5:1 to 10:1). In certain embodiments, the composition comprises atorvastatin sodium.

[0018] The liquid pharmaceutical compositions disclosed herein can include, for example, a pharmaceutically acceptable excipient. In a further embodiment, the composition further includes an acidulant (e.g., acetic acid). In yet a further embodiment, the composition further includes an emulsifier (e.g., polyoxyethylene (20) sorbitan monooleate (polysorbate 80)). In yet a further embodiment, the composition includes 0.001% to 5.0% (w / v) of the emulsifier.

[0019] The liquid pharmaceutical compositions disclosed herein may contain, for example, a calcium sequestering agent. In further embodiments, the calcium sequestering agent is ethylenediaminetetraacetic acid (EDTA), egtazic acid (EGTA), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), or an alkali salt thereof. In still further embodiments, the composition contains 0.001% to 5.0% (w / v) of a calcium sequestering agent (e.g., EDTA, EGTA, BAPTA, or an alkali salt thereof). A preferred concentration range for the calcium sequestering agent (e.g., EDTA, EGTA, BAPTA, or an alkali salt thereof) is 0.005 to 0.5% (w / v). An even more preferred concentration is 0.01 to 0.1% (w / v). Some calcium sequestering agents may serve multiple functions; first, they may be used to sequester calcium ions, and second, they may function as an acidulant. Advantageously, in some embodiments, liquid pharmaceutical compositions comprising calcium sequestrants may include reduced amounts of emulsifiers, or in some cases may even be free of emulsifiers. The reduction or elimination of emulsifiers in the composition is advantageous due to the typically unfavorable toxicological profile of emulsifiers.

[0020] In other embodiments, the composition has a pH of 5.5 to 8.8 (eg, 6.5 to 8.5).

[0021] In other embodiments, the composition is formulated for parenteral administration (e.g., for intravenous, subcutaneous, or intramuscular administration), hi yet other embodiments, the composition is formulated for oral administration.

[0022] In some embodiments, the composition is in a dosage form. In certain embodiments, the composition is aqueous.

[0023] In another aspect, a kit is disclosed that includes a first container containing topiramate or a pharmaceutically acceptable salt thereof and a second container containing a pharmaceutically acceptable aqueous solution of meglumine.

[0024] Typically, the contents of the first container and the second container can be combined to provide, for example, a liquid pharmaceutical composition as described herein.

[0025] In some embodiments, topiramate or a pharmaceutically acceptable salt thereof is present in the first container in crystalline micronized form. In certain embodiments, topiramate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to provide a composition containing 1 mg / mL to 65 mg / mL of topiramate upon combination with the pharmaceutically acceptable aqueous solution of meglumine.

[0026] In certain embodiments, the pharmaceutically acceptable aqueous solution comprises 1 mg / mL to 550 mg / mL of meglumine.

[0027] In a further embodiment, the first container further comprises levetiracetam. In yet a further embodiment, the levetiracetam is present in an amount sufficient to provide a composition comprising 5 mg / mL to 500 mg / mL of levetiracetam in combination with the pharmaceutically acceptable aqueous solution of meglumine. In still a further embodiment, the weight ratio of levetiracetam to topiramate is 15:1 or less (e.g., 10:1 or less). In other embodiments, the weight ratio of levetiracetam to topiramate is at least 5:1. In other embodiments, the weight ratio of topiramate to atorvastatin is 5:1 to 15:1 (e.g., 5:1 to 10:1).

[0028] In a further embodiment, the first container further comprises brivaracetam. In yet a further embodiment, the brivaracetam is present in an amount sufficient to provide a composition comprising 0.5 mg / mL to 50 mg / mL of brivaracetam when combined with the pharmaceutically acceptable aqueous solution of meglumine. In still a further embodiment, the weight ratio of brivaracetam to topiramate is 1:1 or less. In yet other embodiments, the weight ratio of brivaracetam to topiramate is at least 1:4. In certain embodiments, the weight ratio of brivaracetam to topiramate is 1:4 to 1:1.

[0029] In further embodiments, the first container further comprises padosevonil. In still further embodiments, the padosevonil is present in an amount sufficient to provide a composition comprising 1 mg / mL to 100 mg / mL (e.g., 4 mg / mL to 16 mg / mL, 8 mg / mL to 16 mg / mL, or 4 mg / mL to 8 mg / mL) of padosevonil when combined with the pharmaceutically acceptable aqueous solution of meglumine. In still further embodiments, the weight ratio of padosevonil to topiramate is 2:1 or less. In yet other embodiments, the weight ratio of padosevonil to topiramate is at least 1:2. In certain embodiments, the weight ratio of padosevonil to topiramate is 1:2 to 2:1.

[0030] In further embodiments, the first container further comprises seletracetam. In still further embodiments, the seletracetam is present in an amount sufficient to provide a composition comprising 0.1 mg / mL to 40 mg / mL (e.g., 0.8 mg / mL to 4 mg / mL, 2.4 mg / mL to 4 mg / mL, or 1.2 mg / mL to 2 mg / mL) of seletracetam when combined with the pharmaceutically acceptable aqueous solution of meglumine. In still further embodiments, the weight ratio of topiramate to seletracetam is 10:1 or less. In certain embodiments, the weight ratio of topiramate to seletracetam is at least 2.5:1. In further embodiments, the weight ratio of topiramate to atorvastatin is 2.5:1 to 10:1.

[0031] In still other embodiments, the first container further contains atorvastatin or a pharmaceutically acceptable salt thereof. In yet other embodiments, the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to provide a composition containing 0.1 mg / mL to 80 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof, when combined with the pharmaceutically acceptable aqueous solution of meglumine. In some embodiments, the weight ratio of topiramate to atorvastatin is 15:1 or less (e.g., 10:1 or less). In certain embodiments, the weight ratio of topiramate to atorvastatin is at least 5:1. In further embodiments, the weight ratio of topiramate to atorvastatin is 5:1 to 15:1 (e.g., 5:1 to 10:1). In certain embodiments, the composition contains atorvastatin sodium.

[0032] In a further embodiment, the contents of the first container and the contents of the second container, when combined, result in a composition having a pH of 5.5 to 8.8 (eg, 6.5 to 8.5).

[0033] In still further embodiments, the kit further comprises an acidulant (e.g., acetic acid). In still further embodiments, the pharmaceutically acceptable aqueous solution of meglumine comprises an acidulant.

[0034] In other embodiments, the kit further comprises an emulsifying agent (e.g., polyoxyethylene (20) sorbitan monooleate (polysorbate 80)). In still other embodiments, the pharmaceutically acceptable aqueous solution of meglumine comprises an emulsifying agent. In still other embodiments, the emulsifying agent is present in an amount sufficient such that combination of the contents of the first container and the contents of the second container results in a composition comprising 0.001% to 5.0% (w / v) of the emulsifying agent.

[0035] In a further embodiment, the kit further comprises a calcium sequestering agent. In yet a further embodiment, the calcium sequestering agent is ethylenediaminetetraacetic acid (EDTA), egtazic acid (EGTA), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), or an alkali salt thereof. In yet a further embodiment, the calcium sequestering agent is present in an amount sufficient to result in a composition comprising 0.001% to 5.0% (w / v) of the calcium sequestering agent (e.g., EDTA, EGTA, BAPTA, or an alkali salt thereof). A preferred concentration range for the calcium sequestering agent (e.g., EDTA, EGTA, BAPTA, or an alkali salt thereof) is 0.005 to 0.5% (w / v). An even more preferred concentration is 0.01 to 0.1% (w / v).

[0036] In some embodiments, combining the contents of the first container with the contents of the second container produces a composition for parenteral administration.In certain embodiments, combining the contents of the first container with the contents of the second container produces a composition for intravenous administration, subcutaneous administration, or intramuscular administration.In certain embodiments, combining the contents of the first container with the contents of the second container produces a composition for oral administration.In further embodiments, combining the contents of the first container with the contents of the second container produces a dosage form.

[0037] In still further embodiments, the contents of the first container are solid (eg, lyophilized).

[0038] In yet another aspect, methods of treating a patient in need thereof by administering to the patient a therapeutically effective amount of a liquid pharmaceutical composition disclosed herein are disclosed.

[0039] In yet another aspect, a method of treating a patient in need thereof by combining the contents of a first container and the contents of a second container in a kit to form a liquid pharmaceutical composition and administering a therapeutically effective amount of the liquid pharmaceutical composition to the patient is disclosed.

[0040] In some embodiments, the therapeutically effective amount is 0.5 mg / kg / day to 20 mg / kg / day (e.g., 2 mg / kg / day to 15 mg / kg / day) of topiramate. In certain embodiments, the therapeutically effective amount is at least 40 mg / day (e.g., at least 200 mg / day) of topiramate. In certain embodiments, the therapeutically effective amount is 1200 mg / day or less (e.g., 400 mg / day or less) of topiramate.

[0041] In a further embodiment, the therapeutically effective amount is 2.5 mg / kg / day to 150 mg / kg / day (eg, 10 mg / kg / day to 75 mg / kg / day) of levetiracetam.

[0042] In yet a further embodiment, the therapeutically effective amount is 0.2 mg / kg / day to 10 mg / kg / day (eg, 0.5 mg / kg / day to 5 mg / kg / day) of brivaracetam.

[0043] In still further embodiments, the therapeutically effective amount is 0.1 to 1.5 mg / kg / day (eg, 0.2 to 2.0 mg / kg / day) of atorvastatin.

[0044] In other embodiments, the liquid pharmaceutical composition is administered parenterally (e.g., intravenously, subcutaneously, or intramuscularly), hi yet other embodiments, the liquid pharmaceutical composition is administered orally.

[0045] In still other embodiments, the patient is diagnosed with epilepsy, seizures, anoxia, stroke, traumatic brain injury, brain infection, brain abscess, aneurysm, subarachnoid hemorrhage, status epilepticus, refractory status epilepticus, refractory partial onset seizures (POS), addiction (e.g., gambling addiction or drug addiction), migraine, substance addiction, alcohol addiction, cocaine addiction, opioid addiction, nicotine addiction, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder. In some embodiments, the patient is in need of treatment for a disorder or condition selected from the group consisting of: rheumatoid arthritis, refractory generalized social phobia, Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet syndrome, bipolar disorder, obesity, post-traumatic stress disorder, headache (e.g., cluster headache or severe headache), and conditions caused by exposure to chemical warfare nerve agents.

[0046] In some embodiments, the patient is in need of neuroprotection. In such embodiments, the patient is in need of treatment for a disorder or condition selected from the group consisting of traumatic brain injury, stroke, brain infection, and subarachnoid hemorrhage. In certain embodiments, the patient is in need of treatment for traumatic brain injury. In further embodiments, the patient is in need of treatment for stroke. In still further embodiments, the patient is in need of treatment for brain infection. In still further embodiments, the patient is in need of treatment for encephalitis, meningoencephalitis, or brain abscess.

[0047] In one aspect, the present invention provides a method of treating epileptogenesis in a subject following a brain injury by administering to the subject a therapeutically effective amount of a therapeutic combination, wherein the therapeutic combination comprises two to five drugs selected from the group consisting of anti-inflammatory drugs, antioxidants, neuroprotective drugs, GABA potentiators, glutamate inhibitors, drugs having a presynaptic effect on neuronal excitability, drugs having a metabolic mechanism of action, and pharmaceutically acceptable salts thereof, with the proviso that the two to five drugs are all different.

[0048] In some embodiments, each anti-inflammatory drug is independently ibuprofen, celecoxib, parecoxib, sartans, atorvastatin, fingolimod, anakinra, or agmatine.In certain embodiments, each antioxidant is independently α-tocopherol, deferoxamine, N-acetylcysteine, sulforaphane, or melatonin.In certain embodiments, each neuroprotective drug is independently gabapentin, pregabalin, ifenprodil, perampanel, memantine, agmatine, celecoxib, or ceftriaxone.In further embodiments, each GABA enhancer and each glutamate inhibitor are independently topiramate, valproate, phenobarbital, deferoxamine, ceftriaxone, ifenprodil, perampanel, padosevonil, or memantine. In yet further embodiments, each drug having a presynaptic effect on neuronal excitability is independently levetiracetam, brivaracetam, etiracetam, padosevonil, gabapentin, pregabalin, or valproate. In yet further embodiments, each drug having a metabolic mechanism of action is independently stiripentol, 2-deoxy-D-glucose, 5-azacytidine, decitabine, β-hydroxybutyrate, or vorinostat.

[0049] In certain embodiments, the therapeutic combination is a combination of topiramate, levetiracetam, and deferoxamine, or pharmaceutically acceptable salts thereof. In certain embodiments, the therapeutic combination is a combination of topiramate, levetiracetam, and atorvastatin, or pharmaceutically acceptable salts thereof. In some embodiments, the therapeutic combination is a combination of topiramate and levetiracetam. In a further embodiment, the therapeutic combination is a combination of topiramate, levetiracetam, and ceftriaxone, or pharmaceutically acceptable salts thereof. In yet a further embodiment, the therapeutic combination is a combination of topiramate, levetiracetam, and gabapentin, or pharmaceutically acceptable salts thereof. In yet a further embodiment, the therapeutic combination is a combination of topiramate, levetiracetam, and pregabalin, or pharmaceutically acceptable salts thereof. In other embodiments, the therapeutic combination is a combination of levetiracetam, topiramate, and α-tocopherol. In yet other embodiments, the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin. In yet other embodiments, the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib. In some embodiments, the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, gabapentin, or a pharmaceutically acceptable salt thereof, or fingolimod, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In certain embodiments, the therapeutic combination is a combination of levetiracetam and perampanel, or a pharmaceutically acceptable salt thereof. In a further embodiment, the therapeutic combination is a combination of levetiracetam, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In yet a further embodiment, the therapeutic combination is a combination of levetiracetam, parecoxib, and anakinra. In yet a further embodiment, the therapeutic combination is a combination of levetiracetam and phenobarbital.

[0050] In other embodiments, the therapeutic combination is a combination of brivaracetam and topiramate. In yet other embodiments, the therapeutic combination is a combination of brivaracetam, topiramate, and ceftriaxone. In yet other embodiments, the therapeutic combination is a combination of brivaracetam and perampanel, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination is a combination of brivaracetam, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In certain embodiments, the therapeutic combination is a combination of topiramate, brivaracetam, and deferoxamine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of topiramate, brivaracetam, and atorvastatin, or a pharmaceutically acceptable salt thereof. In yet further embodiments, the therapeutic combination is a combination of topiramate, brivaracetam, and gabapentin, or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the therapeutic combination is a combination of topiramate, brivaracetam, and pregabalin, or a pharmaceutically acceptable salt thereof. In other embodiments, the therapeutic combination is a combination of brivaracetam, topiramate, and α-tocopherol. In still other embodiments, the therapeutic combination is a combination of brivaracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin. In yet other embodiments, the therapeutic combination is a combination of brivaracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib. In some embodiments, the therapeutic combination is a combination of brivaracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, gabapentin, or a pharmaceutically acceptable salt thereof, and fingolimod, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of brivaracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In a still further embodiment, the therapeutic combination is a combination of brivaracetam, parecoxib, and anakinra. In a still further embodiment, the therapeutic combination is a combination of brivaracetam and phenobarbital.

[0051] In other embodiments, the therapeutic combination is a combination of padosevonil and topiramate. In yet other embodiments, the therapeutic combination is a combination of padosevonil, topiramate, and ceftriaxone. In yet other embodiments, the therapeutic combination is a combination of padosevonil and perampanel, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination is a combination of padosevonil, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In certain embodiments, the therapeutic combination is a combination of topiramate, padosevonil, and deferoxamine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of topiramate, padosevonil, and atorvastatin, or a pharmaceutically acceptable salt thereof. In yet further embodiments, the therapeutic combination is a combination of topiramate, padosevonil, and gabapentin, or a pharmaceutically acceptable salt thereof. In yet further embodiments, the therapeutic combination is a combination of topiramate, padosevonil, and pregabalin, or a pharmaceutically acceptable salt thereof. In other embodiments, the therapeutic combination is a combination of padosevonil, topiramate, and α-tocopherol. In still other embodiments, the therapeutic combination is a combination of padosevonil, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin. In yet other embodiments, the therapeutic combination is a combination of padosevonil, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib. In some embodiments, the therapeutic combination is a combination of padosevonil, deferoxamine, or a pharmaceutically acceptable salt thereof, gabapentin, or a pharmaceutically acceptable salt thereof, and fingolimod, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of padosevonil, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In yet a further embodiment, the therapeutic combination is a combination of padosevonil, parecoxib, and anakinra. In yet a further embodiment, the therapeutic combination is a combination of padosevonil and phenobarbital.

[0052] In other embodiments, the therapeutic combination is a combination of seletracetam and topiramate. In yet other embodiments, the therapeutic combination is a combination of seletracetam, topiramate, and ceftriaxone. In yet other embodiments, the therapeutic combination is a combination of seletracetam and perampanel, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination is a combination of seletracetam, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In certain embodiments, the therapeutic combination is a combination of topiramate, seletracetam, and deferoxamine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of topiramate, seletracetam, and atorvastatin, or a pharmaceutically acceptable salt thereof. In yet further embodiments, the therapeutic combination is a combination of topiramate, seletracetam, and gabapentin, or a pharmaceutically acceptable salt thereof. In yet further embodiments, the therapeutic combination is a combination of topiramate, seletracetam, and pregabalin, or a pharmaceutically acceptable salt thereof. In other embodiments, the therapeutic combination is a combination of seletracetam, topiramate, and α-tocopherol. In still other embodiments, the therapeutic combination is a combination of seletracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin. In yet other embodiments, the therapeutic combination is a combination of seletracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib. In some embodiments, the therapeutic combination is a combination of seletracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, gabapentin, or a pharmaceutically acceptable salt thereof, and fingolimod, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic combination is a combination of seletracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone. In yet further embodiments, the therapeutic combination is a combination of seletracetam, parecoxib, and anakinra. In yet further embodiments, the therapeutic combination is a combination of seletracetam and phenobarbital.

[0053] In certain embodiments, the therapeutic combination is a combination of valproate or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and memantine or a pharmaceutically acceptable salt thereof.

[0054] In certain embodiments, the therapeutic combination includes three of the drugs. In further embodiments, the dose of each drug in the combination is the maximum tolerated dose for the individual patient when the drug is administered in the therapeutic combination. In still further embodiments, agmatine is administered at a dose of 3.56 g / day. In still further embodiments, anakinra is administered at a dose of 8 mg / kg / day. In some embodiments, brivaracetam is administered at a dose of 400 mg / day. In certain embodiments, padosevonil is administered at a dose of 800 mg / day. In certain embodiments, ceftriaxone is administered at a dose of 4 g / day. In still further embodiments, deferoxamine is administered at a dose of 62 mg / kg / day up to 6000 mg / day. In still further embodiments, fingolimod is administered at a dose of 1.25 mg / day. In still further embodiments, gabapentin is administered at a dose of 3,200 mg / day. In other embodiments, ifenprodil is administered at a dose of 40 mg / day. In still other embodiments, levetiracetam is administered at a dose of 55 mg / kg up to 6,000 mg / day. In still other embodiments, losartan is administered at a dose of 100 mg / day. In some embodiments, melatonin is administered at a dose of 20 mg / day. In certain embodiments, memantine is administered at a dose of 28 mg / day. In certain embodiments, N-acetylcysteine ​​is administered at a dose of 300 mg / kg / day. In further embodiments, perampanel is administered at a dose of 24 mg / day. In still further embodiments, phenobarbital is administered at a dose of 200 mg. In still further embodiments, sulforaphane is administered at a dose of 60 mg / day. In other embodiments, topiramate is administered at a dose of 400 mg / day. In still other embodiments, valproate is administered at a dose of 3,000 mg / day. In yet another embodiment, alpha-tocopherol is administered at a dose of 15 mg / day.

[0055] In some embodiments, the therapeutically effective dose is 50%-75% of the maximum approved dose for administration as monotherapy to humans. In certain embodiments, agmatine is administered at a dose of 1.78-2.67 g / day. In certain embodiments, anakinra is administered at a dose of 4-6 mg / kg / day. In further embodiments, brivaracetam is administered at a dose of 200-300 mg / day. In yet further embodiments, padosevonil is administered at a dose of 400 mg / day. In still further embodiments, ceftriaxone is administered at a dose of 2-3 g / day. In other embodiments, deferoxamine is administered at a dose of 31-4500 mg / kg / day. In yet other embodiments, fingolimod is administered at a dose of 0.625-0.94 mg / day. In yet other embodiments, gabapentin is administered at a dose of 1600-2400 mg / day. In some embodiments, ifenprodil is administered at a dose of 20-30 mg / day. In certain embodiments, levetiracetam is administered at a dose of 27.5-41 mg / kg / day up to 3000-4500 mg / day. In certain embodiments, losartan is administered at a dose of 50-75 mg / day. In further embodiments, melatonin is administered at a dose of 10-15 mg / day. In still further embodiments, memantine is administered at a dose of 14-21 mg / day. In still further embodiments, N-acetylcysteine ​​is administered at a dose of 150-225 mg / kg / day. In some embodiments, perampanel is administered at a dose of 12-18 mg / day. In certain embodiments, phenobarbital is administered at a dose of 100-150 mg / day. In certain embodiments, sulforaphane is administered at a dose of 30-45 mg / day. In a further embodiment, topiramate is administered at a dose of 200-300 mg / day. In yet a further embodiment, valproate is administered at a dose of 1500-2250 mg / day. In yet a further embodiment, alpha-tocopherol is administered at a dose of 7.5-11.25 mg / day.

[0056] In certain embodiments, the therapeutic combination has tolerability and efficacy that are greater than the expected additive tolerability and efficacy of the drugs in the therapeutic combination. In certain embodiments, the therapeutic combination is initially administered to a subject intravenously for 1 to 30 days. In certain embodiments, the therapeutic combination is administered to a subject intramuscularly, subcutaneously, orally, transdermally, sublingually, buccally, intranasally, by inhalation, or rectally. In further embodiments, after administration of the therapeutic combination is initiated, administration of the therapeutic combination is maintained by chronic oral or parenteral administration. In still further embodiments, administration of the therapeutic combination is maintained for 3 to 6 months after brain injury. In still further embodiments, at least two drugs are present in the same pharmaceutical composition. In other embodiments, at least three drugs are present in the same pharmaceutical composition. In still other embodiments, the administering step is initiated within 7 days after brain injury. In still other embodiments, the administering step is initiated within 48 hours after brain injury. In some embodiments, the administering step is initiated within 24 hours after brain injury. In certain embodiments, the administering step is initiated within 8 hours after the brain injury. In certain embodiments, the therapeutic combination is administered to the subject for a period of 3 days to 3 months after the injury. In further embodiments, the therapeutic combination is administered to the subject for 5 to 30 days after the brain injury.

[0057] In certain preferred embodiments, the therapeutic combination methods described herein involve administration of a liquid pharmaceutical composition described herein.

[0058] The present disclosure also includes the following items: A1. A liquid pharmaceutical composition comprising topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient. A2. The liquid pharmaceutical composition of item A1, comprising 1 mg / mL to 550 mg / mL of meglumine. A3. The liquid pharmaceutical composition of item A1, comprising 1 mg / mL to 100 mg / mL of meglumine. A4. The liquid pharmaceutical composition of item A1, comprising 1 mg / mL to 50 mg / mL of meglumine. A5. The liquid pharmaceutical composition of item A1, comprising 5 mg / mL to 50 mg / mL of meglumine. A6. The liquid pharmaceutical composition of item A1, comprising 10 mg / mL to 50 mg / mL of meglumine. A7. The liquid pharmaceutical composition of item A1, comprising 1 mg / mL to 30 mg / mL of meglumine. A8. The liquid pharmaceutical composition of any of items A1 to A7, comprising 1 mg / mL to 100 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A9. The liquid pharmaceutical composition of any of items A1 to A7, comprising 1 mg / mL to 65 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A10. The liquid pharmaceutical composition according to any one of items A1 to A7, comprising 10 mg / mL to 70 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A11. The liquid pharmaceutical composition according to any one of items A1 to A7, comprising 20 mg / mL to 65 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A12. The liquid pharmaceutical composition according to any one of items A1 to A7, comprising 4 mg / mL to 30 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A13. The liquid pharmaceutical composition of any of items A1 to A7, comprising 4 mg / mL to 20 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A14. The liquid pharmaceutical composition of any of items A1 to A7, comprising 9 mg / mL to 11 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A15. The liquid pharmaceutical composition of any of items A1 to A7, comprising 4 mg / mL to 6 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. A16. The liquid pharmaceutical composition of any one of items A1 to A15, further comprising levetiracetam. A17. The liquid pharmaceutical composition of item A16, comprising 5 mg / mL to 500 mg / mL of levetiracetam. A18. The liquid pharmaceutical composition of item A16, comprising 5 mg / mL to 150 mg / mL of levetiracetam. A19. The liquid pharmaceutical composition of item A16, comprising 20 mg / mL to 150 mg / mL of levetiracetam. A20. The liquid pharmaceutical composition of item A16, comprising 60 mg / mL to 120 mg / mL of levetiracetam. A21. The liquid pharmaceutical composition of item A16, comprising 30 mg / mL to 60 mg / mL of levetiracetam. A22. The liquid pharmaceutical composition of any of items A16 to A21, wherein the weight ratio of levetiracetam to topiramate is 15:1 or less. A23. The liquid pharmaceutical composition of any of items A16 to A21, wherein the weight ratio of levetiracetam to topiramate is 10:1 or less. A24. The liquid pharmaceutical composition of any of items A16 to A23, wherein the weight ratio of levetiracetam to topiramate is at least 5:1. A25. The liquid pharmaceutical composition of any of items A1 to A15, further comprising brivaracetam. A26. The liquid pharmaceutical composition of item A25, comprising 0.5 mg / mL to 50 mg / mL of brivaracetam. A27. The liquid pharmaceutical composition of item A25, comprising 2 mg / mL to 10 mg / mL of brivaracetam. A28. The liquid pharmaceutical composition of item A25, comprising 2 mg / mL to 8 mg / mL of brivaracetam. A29. The liquid pharmaceutical composition of item A25, comprising 4 mg / mL to 10 mg / mL of brivaracetam. A30. The liquid pharmaceutical composition of item A25, comprising 4 mg / mL to 8 mg / mL of brivaracetam. A31. The liquid pharmaceutical composition of item A25, comprising 2 mg / mL to 4 mg / mL of brivaracetam. A32. The liquid pharmaceutical composition of any of items A25 to A31, wherein the weight ratio of brivaracetam to topiramate is 1:1 or less. A33. The liquid pharmaceutical composition of any of items A25 to A32, wherein the weight ratio of brivaracetam to topiramate is at least 1:4. A34. The liquid pharmaceutical composition of any of items A1 to A15, further comprising padosevonil. A35. The liquid pharmaceutical composition of item A34, comprising 1 mg / mL to 100 mg / mL of padosevonil. A36. The liquid pharmaceutical composition of item A35, comprising 4 mg / mL to 16 mg / mL of padosevonil. A37. The liquid pharmaceutical composition of item A35, comprising 8 mg / mL to 16 mg / mL of padosevonil. A38. The liquid pharmaceutical composition of item A35, comprising 4 mg / mL to 8 mg / mL of padosevonil. A39. The liquid pharmaceutical composition of any of items A34 to A38, wherein the weight ratio of padosevonil to topiramate is 2:1 or less. A40. The liquid pharmaceutical composition of any of items A34 to A38, wherein the weight ratio of padosevonil to topiramate is 1:2 to 2:1. A41. The liquid pharmaceutical composition of any of items A1 to A40, further comprising atorvastatin or a pharmaceutically acceptable salt thereof. A42. The liquid pharmaceutical composition of item A41, comprising 0.1 mg / mL to 80 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A43. The liquid pharmaceutical composition of item A41, comprising 0.1 mg / mL to 20 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A44. The liquid pharmaceutical composition of item A41, comprising 0.1 mg / mL to 16 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A45. The liquid pharmaceutical composition of item A41, comprising 0.2 mg / mL to 16 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A46. The liquid pharmaceutical composition of item A41, comprising 0.4 mg / mL to 2 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A47. The liquid pharmaceutical composition of item A41, comprising 1.2 mg / mL to 2 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A48. The liquid pharmaceutical composition of item A41, comprising 0.6 mg / mL to 1 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. A49. The liquid pharmaceutical composition of any of items A41 to A48, wherein the weight ratio of topiramate to atorvastatin is 15:1 or less. A50. The liquid pharmaceutical composition of any of items A41 to A48, wherein the weight ratio of topiramate to atorvastatin is 10:1 or less. A51. The liquid pharmaceutical composition of any of items A41 to A50, wherein the weight ratio of topiramate to atorvastatin is at least 5:1. A52. A liquid pharmaceutical composition according to any one of items A41 to A51, comprising atorvastatin sodium. A53. The liquid pharmaceutical composition of any of items A1 to A52, having a pH of 5.5 to 8.8. A54. The liquid pharmaceutical composition of item A53, having a pH of 6.5 to 8.5. A55. The liquid pharmaceutical composition of any one of items A1 to A54, further comprising an acidulant. A56. The liquid pharmaceutical composition of any of items A1 to A55, wherein the acidulant is acetic acid. A57. The liquid pharmaceutical composition of any of items A1 to A56, further comprising a calcium sequestering agent. A58. The liquid pharmaceutical composition of item A57, wherein the calcium sequestering agent is EDTA, EGTA, BAPTA, or an alkali salt thereof. A59. The liquid pharmaceutical composition of item A57 or A58, comprising 0.001% to 5.0% (w / v) of a calcium sequestering agent. A60. The liquid pharmaceutical composition of item A57 or A58, comprising 0.005% to 0.5% (w / v) of a calcium sequestering agent. A61. The liquid pharmaceutical composition of item A57 or A58, comprising 0.01% to 0.1% (w / v) of a calcium sequestering agent. A62. The liquid pharmaceutical composition of any of items A1 to A61, further comprising an emulsifier. A63. The liquid pharmaceutical composition of item A62, comprising 0.001% to 5.0% (w / v) of an emulsifier. A64. The liquid pharmaceutical composition of item A62 or A63, wherein the emulsifier is polyoxyethylene (20) sorbitan monooleate (polysorbate 80). A65. The liquid pharmaceutical composition of any of items A1-A64 formulated for parenteral administration. A66. The liquid pharmaceutical composition of item A65 formulated for intravenous, subcutaneous, or intramuscular administration. A67. The liquid pharmaceutical composition of any of items A1 to A66, formulated for oral administration. A68. The liquid pharmaceutical composition of any of items A1 to A67, which is a dosage form. A69. The liquid pharmaceutical composition of any of items A1 to A68, which is aqueous. A70. A kit comprising a first container and a second container, wherein the first container contains topiramate or a pharmaceutically acceptable salt thereof, and the second container contains a pharmaceutically acceptable aqueous solution of meglumine. A71. The kit of item A70, wherein the topiramate or a pharmaceutically acceptable salt thereof is present in the first container in crystalline micronized form. A72. The kit of item A70 or A71, wherein the pharmaceutically acceptable aqueous solution contains 1 mg / mL to 550 mg / mL of meglumine. A73. The kit of any of items A70-A72, wherein topiramate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 1 mg / mL to 65 mg / mL of topiramate upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A74. The kit of any of items A70-A72, wherein topiramate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 10 mg / mL to 70 mg / mL of topiramate upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A75. The kit of any of items A70-A72, wherein topiramate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 20 mg / mL to 65 mg / mL of topiramate upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A76. The kit of any of items A70-A72, wherein topiramate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 4 mg / mL to 20 mg / mL of topiramate upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A77. The kit of any of items A70-A72, wherein topiramate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 9 mg / mL to 11 mg / mL of topiramate upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A78. The kit of any of items A70-A77, wherein the first container further contains levetiracetam. A79. The kit of item A78, wherein the levetiracetam is present in an amount sufficient to result in a composition containing 5 mg / mL to 500 mg / mL of levetiracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A80. The kit of item A78, wherein the levetiracetam is present in an amount sufficient to result in a composition comprising 60 mg / mL to 120 mg / mL of levetiracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A81. The kit of item A78, wherein the levetiracetam is present in an amount sufficient to result in a composition comprising 60 mg / mL to 120 mg / mL of levetiracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A82. The kit of item A78, wherein the levetiracetam is present in an amount sufficient to result in a composition containing 30 mg / mL to 60 mg / mL of levetiracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A83. A kit according to any of items A78 to A82, in which the weight ratio of levetiracetam to topiramate is 15:1 or less. A84. A kit according to any of items A78 to A82, in which the weight ratio of levetiracetam to topiramate is 10:1 or less. A85. A kit according to any of items A78 to A84, wherein the weight ratio of levetiracetam to topiramate is at least 5:1. A86. The kit of any of items A70-A77, wherein the first container further contains brivaracetam. A87. The kit of item A86, wherein the brivaracetam is present in an amount sufficient to result in a composition containing 0.5 mg / mL to 50 mg / mL of brivaracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A88. The kit of item A86, wherein the brivaracetam is present in an amount sufficient to result in a composition containing 2 mg / mL to 10 mg / mL of brivaracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A89. The kit of item A86, wherein the brivaracetam is present in an amount sufficient to result in a composition containing 2 mg / mL to 8 mg / mL of brivaracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A90. The kit of item A86, wherein the brivaracetam is present in an amount sufficient to result in a composition containing 4 mg / mL to 10 mg / mL of brivaracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A91. The kit of item A86, wherein the brivaracetam is present in an amount sufficient to result in a composition containing 4 mg / mL to 8 mg / mL of brivaracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A92. The kit of item A86, wherein the brivaracetam is present in an amount sufficient to result in a composition containing 2 mg / mL to 4 mg / mL of brivaracetam upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A93. A kit according to any of items A86 to A92, wherein the weight ratio of brivaracetam to topiramate is 1:1 or less. A94. A kit according to any of items A86 to A93, wherein the weight ratio of brivaracetam to topiramate is at least 1:4. A95. The kit of any of items A70-A77, wherein the first container further contains padosevonil. A96. The kit of item A95, wherein the padosevonil is present in an amount sufficient to result in a composition containing 1 mg / mL to 100 mg / mL of padosevonil upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A97. The kit of item A95, wherein the padosevonil is present in an amount sufficient to result in a composition containing 4 mg / mL to 16 mg / mL of padosevonil upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A98. The kit of item A95, wherein the padosevonil is present in an amount sufficient to result in a composition containing 8 mg / mL to 100 mg / mL of padosevonil upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A99. The kit of item A95, wherein the padosevonil is present in an amount sufficient to result in a composition containing 4 mg / mL to 8 mg / mL of padosevonil upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A100. A kit according to any of items A95 to A99, in which the weight ratio of padosevonil to topiramate is 2:1 or less. A101. A kit according to any of items A95 to A100, wherein the weight ratio of padosevonil to topiramate is 2:1 or less. A102. A kit according to any one of items A95 to A99, in which the weight ratio of padosevonil to topiramate is 1:2 to 2:1. A103. The kit of any of items A70-A102, wherein the first container further comprises atorvastatin or a pharmaceutically acceptable salt thereof. A104. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition comprising 0.1 mg / mL to 80 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A105. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition comprising 0.1 mg / mL to 20 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A106. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition comprising 0.1 mg / mL to 16 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A107. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition comprising 0.2 mg / mL to 16 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A108. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 0.4 mg / mL to 2 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A109. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition containing 1.2 mg / mL to 2 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A110. The kit of item A103, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is present in an amount sufficient to result in a composition comprising 0.6 mg / mL to 1 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof upon combination with the pharmaceutically acceptable aqueous solution of meglumine. A111. The kit of any of items A103 to A110, wherein the weight ratio of topiramate to atorvastatin is 15:1 or less. A112. The kit of any of items A103 to A111, wherein the weight ratio of topiramate to atorvastatin is 10:1 or less. A113. The kit of any of items A103 to A112, wherein the weight ratio of topiramate to atorvastatin is at least 5:1. A114. The kit of any of items A103-A113, wherein the composition comprises atorvastatin sodium. A115. The kit of any of items A70-A114, wherein the contents of the first container and the contents of the second container, when combined, result in a composition having a pH of 6.5 to 8.5. A116. The kit of any of items A70 to A115, further comprising an acidulant. A117. The kit of item A116, wherein the pharmaceutically acceptable aqueous solution of meglumine includes an acidulant. A118. A kit of item A116 or A117, wherein the acidulant is acetic acid. A119. The kit of any of items A70 to A118, further comprising a calcium sequestering agent. A120. The kit of item A119, wherein the calcium sequestering agent is EDTA, EGTA, BAPTA, or an alkali salt thereof. A121. The kit of item A119 or A120, further comprising 0.001% to 5.0% (w / v) of a calcium sequestering agent. A122. The kit of item A119 or A120, further comprising 0.005% to 0.5% (w / v) of a calcium sequestering agent. A123. The kit of item A119 or A120, further comprising 0.01% to 0.1% (w / v) of a calcium sequestering agent. A124. The kit of any of items A119 to A123, comprising a calcium sequestering agent in a first container. A125. The kit of any of items A70 to A124, further comprising an emulsifier. A126. The kit of item A125, wherein the pharmaceutically acceptable aqueous solution of meglumine comprises an emulsifier. A127. The kit of item A125 or A126, wherein the emulsifier is present in an amount sufficient such that the combination of the contents of the first container and the contents of the second container results in a composition comprising 0.001% to 5.0% (w / v) of the emulsifier. A128. The kit of any of items A125 to A127, wherein the emulsifier is polyoxyethylene (20) sorbitan monooleate (polysorbate 80). A129. The kit of any of items A70-A128, wherein combining the contents of the first container with the contents of the second container provides a composition for parenteral administration. A130. The kit of item A129, wherein combining the contents of the first container with the contents of the second container provides a composition for intravenous, subcutaneous, or intramuscular administration. A131. The kit of any of items A70-A128, wherein combining the contents of the first container with the contents of the second container provides a composition for oral administration. A132. The kit of any of items A70-A131, wherein the contents of the first container and the contents of the second container are combined to provide the dosage form. A133. The kit of any of items A70 to A132, wherein the contents of the first container are solid. A134. The kit of item A133, wherein the contents of the first container are lyophilized. A135. A method of treating a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compositions of items A1-A69. A136. A method of treating a patient in need thereof, comprising combining the contents of a first container with the contents of a second container in a kit of any of items A70-A134 to form a liquid pharmaceutical composition, and administering a therapeutically effective amount of the liquid pharmaceutical composition to the patient. A137. The method of item A135 or A136, wherein the therapeutically effective amount is an amount that provides between 0.5 mg / kg / day and 20 mg / kg / day of topiramate. A138. The method of item A135 or A136, wherein the therapeutically effective amount is an amount that provides between 2 mg / kg / day and 15 mg / kg / day of topiramate. A139. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides at least 40 mg / day of topiramate. A140. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides at least 100 mg / day of topiramate. A141. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides at least 200 mg / day of topiramate. A142. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides 1200 mg / day or less of topiramate. A143. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides 600 mg / day or less of topiramate. A144. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides 400 mg / day or less of topiramate. A145. The method of any of items A135-A138, wherein the therapeutically effective amount is an amount that provides 300 mg / day or less of topiramate. A146. The method of any of items A135-A144, wherein the therapeutically effective amount is an amount that provides 2.5 mg / kg / day to 150 mg / kg / day of levetiracetam. A147. The method of any of items A135-A144, wherein the therapeutically effective amount is an amount that provides 10 mg / kg / day to 75 mg / kg / day of levetiracetam. A148. The method of any of items A135-A144, wherein the therapeutically effective amount is an amount that provides 13.75 mg / kg / day to 41 mg / kg / day of levetiracetam. A149. The method of any of items A135-A144, wherein the therapeutically effective amount is an amount that provides between 0.5 mg / kg / day and 10 mg / kg / day of brivaracetam. A150. The method of any of items A135-A144, wherein the therapeutically effective amount is an amount that provides between 0.5 mg / kg / day and 5 mg / kg / day of brivaracetam. A151. The method of any of items A135-A150, wherein the therapeutically effective amount is an amount that provides at least 100 mg / day of brivaracetam. A152. The method of any of items A135-A151, wherein the therapeutically effective amount is an amount that provides 400 mg or less of brivaracetam per day. A153. The method of any of items A135-A151, wherein the therapeutically effective amount is an amount that provides 300 mg or less of brivaracetam per day. A154. The method of any of items A135-A144, wherein the therapeutically effective amount is an amount that provides at least 400 mg / day of padosevonil. A155. The method of any of items A135-A154, wherein the therapeutically effective amount is an amount that provides 800 mg / day or less of padosevonil. A156. The method of any of items A135-A155, wherein the therapeutically effective amount is an amount that provides 600 mg / day or less of padosevonil. A157. The method of any of items A135-A156, wherein the therapeutically effective amount is an amount that provides 0.1-2.0 mg / kg / day of atorvastatin. A158. The method of any of items A135-A156, wherein the therapeutically effective amount is an amount that provides 0.2-1.5 mg / kg / day of atorvastatin. A159. The method of any of items A135-A158, wherein the therapeutically effective amount is an amount that provides at least 20 mg / day of atorvastatin. A160. The method of any of items A135-A159, wherein the therapeutically effective amount is an amount that provides 80 mg or less of atorvastatin per day. A161. The method of any of items A135-A159, wherein the therapeutically effective amount is an amount that provides 60 mg or less of atorvastatin per day. A162. The method of any of items A135-A161, wherein the liquid pharmaceutical composition is administered parenterally. A163. The method of item A162, wherein the liquid pharmaceutical composition is administered intravenously, subcutaneously, or intramuscularly. A164. The method of any of items A135-A161, wherein the liquid pharmaceutical composition is administered orally. A165. The patient has epilepsy, seizures, anoxia, stroke, traumatic brain injury, brain infection, brain abscess, aneurysm, subarachnoid hemorrhage, status epilepticus, refractory status epilepticus, refractory partial onset seizures (POS), addiction (e.g., gambling or drug addiction), migraine, substance addiction, alcohol addiction, cocaine addiction, opioid addiction, nicotine addiction, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder, refractory generalized social phobia, Tourette's disease, or flu-like illness. any of the methods of paragraphs A135-A164, wherein the patient is in need of treatment for a disorder or condition selected from the group consisting of: Parkinson's syndrome, levodopa-induced dyskinesia in Parkinson's disease, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet syndrome, bipolar disorder, obesity, post-traumatic stress disorder, headache (e.g., cluster headache or severe headache), and conditions caused by exposure to chemical warfare nerve agents. A166. The patient requires neuroprotection, using any of the methods described in items A135-A165. A167. The method of any of paragraphs A135-A165, wherein the patient is in need of treatment for a disorder or condition selected from the group consisting of traumatic brain injury, stroke, brain infection, and subarachnoid hemorrhage. A168. The method of item A167, wherein the patient is in need of treatment for a traumatic brain injury. A169. The method of item A167, wherein the patient is in need of treatment for a stroke. A170. The method of item A167, wherein the patient is in need of treatment for a brain infection. A171. The method of item A170, wherein the patient is in need of treatment for encephalitis, meningoencephalitis, or brain abscess.

[0059] The present disclosure also includes the following items: B1. A method of treating epileptogenesis in a subject following brain injury, the method comprising administering to the subject a therapeutically effective amount of a therapeutic combination, wherein the therapeutic combination comprises two to five drugs selected from the group consisting of anti-inflammatory drugs, antioxidants, neuroprotective drugs, GABA potentiators, glutamate inhibitors, drugs having a presynaptic effect on neuronal excitability, drugs having a metabolic mechanism of action, and pharmaceutically acceptable salts thereof, with the proviso that the two to five drugs are all different. B2. The method of section B1, wherein each anti-inflammatory drug is independently ibuprofen, celecoxib, parecoxib, a sartan, atorvastatin, fingolimod, anakinra, or agmatine. B3. The method of paragraph B1, wherein each antioxidant is independently alpha-tocopherol, deferoxamine, N-acetylcysteine, sulforaphane, or melatonin. B4. The method of section B1, wherein each neuroprotective agent is independently gabapentin, pregabalin, ifenprodil, perampanel, memantine, agmatine, celecoxib, or ceftriaxone. B5. The method of section B1, wherein each GABA enhancer and each glutamate inhibitor is independently topiramate, valproate, phenobarbital, padosevonil, deferoxamine, ceftriaxone, ifenprodil, perampanel, or memantine. B6. The method of paragraph B1, wherein each drug having a presynaptic effect on neuronal excitability is independently levetiracetam, brivaracetam, etiracetam, padosevonil, gabapentin, pregabalin, or valproate. B7. The method of section B1, wherein each drug having a metabolic mechanism of action is independently stiripentol, 2-deoxy-D-glucose, 5-azacytidine, decitabine, beta-hydroxybutyrate, or vorinostat. B8. The method of item B1, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and deferoxamine, or pharmaceutically acceptable salts thereof. B9. The method of item B1, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and atorvastatin, or pharmaceutically acceptable salts thereof. B10. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, ceftriaxone, and atorvastatin, or pharmaceutically acceptable salts thereof. B11. The method of item B1, wherein the therapeutic combination is a combination of topiramate and levetiracetam. B12. The method of item B1, wherein the fixed-dose therapeutic combination is a combination of topiramate, levetiracetam, and ceftriaxone, or pharmaceutically acceptable salts thereof. B13. The method of item B1, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and gabapentin, or pharmaceutically acceptable salts thereof. B14. The method of item B1, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and pregabalin, or pharmaceutically acceptable salts thereof. B15. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, topiramate, and α-tocopherol. B16. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin. B17. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib. B18. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, deferoxamine or a pharmaceutically acceptable salt thereof, gabapentin or a pharmaceutically acceptable salt thereof, and fingolimod or a pharmaceutically acceptable salt thereof. B19. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone. B20. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam and perampanel, or a pharmaceutically acceptable salt thereof. B21. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone. B22. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam, parecoxib, and anakinra. B23. The method of item B1, wherein the therapeutic combination is a combination of levetiracetam and phenobarbital. B24. The method of item B1, wherein the therapeutic combination is a combination of brivaracetam and topiramate. B25. The method of item B1, wherein the therapeutic combination is a combination of brivaracetam, topiramate, and ceftriaxone. B26. The method of item B1, wherein the therapeutic combination is a combination of brivaracetam, ceftriaxone, and atorvastatin. B27. The method of item B1, wherein the therapeutic combination is a combination of brivaracetam, ceftriaxone, and atorvastatin. B28. The method of item B1, wherein the therapeutic combination is a combination of brivaracetam and perampanel. B29. The method of item B1, wherein the therapeutic combination is a combination of brivaracetam, perampanel, and ceftriaxone. B30. The method of item B1, wherein the therapeutic combination is a combination of valproate or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and memantine or a pharmaceutically acceptable salt thereof. B31. The method of any of paragraphs B1-B30, wherein the therapeutic combination includes three of the drugs. B32. The method of any of paragraphs B1-B31, wherein the dose of each drug in the combination is the highest tolerated dose in the individual patient when the drugs are administered in a therapeutic combination. B33. The method of any of paragraphs B1-B31, wherein the therapeutically effective dose is 30% to 75% of the highest approved dose for administration as monotherapy to humans. B34. The method of any of paragraphs B1-B31, wherein the therapeutically effective dose is 50%-75% of the highest approved dose for administration as monotherapy to humans. B35. The method of item B1, wherein agmatine is administered at a dose of 0.89 to 3.56 g / day. B36. The method of item B1, wherein agmatine is administered at a dose of 0.89 to 2.67 g / day. B37. The method of item B1, wherein agmatine is administered at a dose of 1.78 to 2.67 g / day. B38. The method of item B1, wherein anakinra is administered at a dose of 2 to 8 mg / kg / day. B39. The method of item B1, wherein anakinra is administered at a dose of 2 to 6 mg / kg / day. B40. The method of item B1, wherein anakinra is administered at a dose of 4 to 6 mg / kg / day. B41. The method of item B1, wherein brivaracetam is administered at a dose of 100 to 400 mg / day. B42. The method of item B1, wherein brivaracetam is administered at a dose of 100 to 300 mg / day. B43. The method of item B1, wherein brivaracetam is administered at a dose of 200-300 mg / day. B44. The method of item B1, wherein padosevonil is administered at a dose of 200 to 800 mg / day. B45. The method of item B1, wherein padosevonil is administered at a dose of 200 to 600 mg / day. B46. The method of item B1, wherein padosevonil is administered at a dose of 400 mg / day. B47. The method of item B1, wherein ceftriaxone is administered at a dose of 1 to 4 g / day. B48. The method of item B1, wherein ceftriaxone is administered at a dose of 1 to 3 g / day. B49. The method of item B1, in which ceftriaxone is administered at a dose of 2 to 3 g / day. B50. The method of paragraph B1, wherein deferoxamine is administered at a dose of 15.5 to 62 mg / kg / day. B51. The method of item B1, wherein deferoxamine is administered at a dose of 15.5 to 46.5 mg / kg / day. B52. The method of paragraph B1, B50, or B51, wherein deferoxamine is administered at a dose of up to 6000 mg / day. B53. The method of paragraph B1, B50, B51, or B52, wherein deferoxamine is administered at a dose of up to 4500 mg / day. B54. The method of item B1, wherein fingolimod is administered at a dose of 0.31 to 1.25 mg / day. B55. The method of item B1, wherein fingolimod is administered at a dose of 0.31 to 0.94 mg / day. B56. The method of item B1, wherein fingolimod is administered at a dose of 0.625 to 0.94 mg / day. B57. The method of item B1, wherein gabapentin is administered at a dose of 800 to 3200 mg / day. B58. The method of item B1, wherein gabapentin is administered at a dose of 800 to 2400 mg / day. B59. The method of item B1, wherein gabapentin is administered at a dose of 1600 to 2400 mg / day. B60. The method of item B1, wherein ifenprodil is administered at a dose of 10 to 40 mg / day. B61. The method of item B1, wherein ifenprodil is administered at a dose of 10 to 30 mg / day. B62. The method of item B1, wherein ifenprodil is administered at a dose of 20 to 30 mg / day. B63. The method of item B1, in which levetiracetam is administered at a dose of 13.75 to 55 mg / kg / day. B64. The method of item B1, in which levetiracetam is administered at a dose of 13.75 to 41 mg / kg / day. B65. The method of item B1, in which levetiracetam is administered at a dose of 27.5 to 41 mg / kg / day. B66. The method of paragraph B1, B63, B64 or B65, wherein levetiracetam is administered at a dose of 6000 mg / day or less. B67. The method of paragraph B1, B63, B64 or B65, wherein levetiracetam is administered at a dose of 4500 mg / day or less. B68. The method of paragraph B1, B63, B64 or B65, wherein levetiracetam is administered at a dose of 3000 mg / day or less. B69. The method of item B1, B63, B64, B65, B66, B67, or B68, wherein levetiracetam is administered at a dose of at least 900 mg / day. B70. The method of item B1, B63, B64, B65, B66, B67, or B68, wherein levetiracetam is administered at a dose of at least 3000 mg / day. B71. The method of item B1, wherein losartan is administered at a dose of 25 to 100 mg / day. B72. The method of item B1, wherein losartan is administered at a dose of 25 to 75 mg / day. B73. The method of item B1, wherein losartan is administered at a dose of 50 to 75 mg / day. B74. The method of paragraph B1, wherein melatonin is administered at a dose of 5 to 20 mg / day. B75. The method of paragraph B1, wherein melatonin is administered at a dose of 5 to 15 mg / day. B76. The method of paragraph B1, wherein melatonin is administered at a dose of 10 to 15 mg / day. B77. The method of item B1, wherein memantine is administered at a dose of 7 to 28 mg / day. B78. The method of item B1, wherein memantine is administered at a dose of 7 to 21 mg / day. B79. The method of item B1, in which memantine is administered at a dose of 14 to 21 mg / day. B80. The method of item B1, wherein N-acetylcysteine ​​is administered at a dose of 75 to 300 mg / kg / day. B81. The method of item B1, wherein N-acetylcysteine ​​is administered at a dose of 75 to 225 mg / kg / day. B82. The method of item B1, wherein N-acetylcysteine ​​is administered at a dose of 150 to 225 mg / kg / day. B83. The method of item B1, in which perampanel is administered at a dose of 6 to 24 mg / day. B84. The method of item B1, in which perampanel is administered at a dose of 6 to 18 mg / day. B85. The method of item B1, in which perampanel is administered at a dose of 12 to 18 mg / day. B86. The method of item B1, in which phenobarbital is administered at a dose of 50 to 200 mg. B87. The method of item B1, in which phenobarbital is administered at a dose of 50 to 150 mg / day. B88. The method of item B1, in which phenobarbital is administered at a dose of 100 to 150 mg / day. B89. The method of paragraph B1, wherein sulforaphane is administered at a dose of 15 to 60 mg / day. B90. The method of paragraph B1, wherein sulforaphane is administered at a dose of 15 to 45 mg / day. B91. The method of paragraph B1, wherein sulforaphane is administered at a dose of 30 to 45 mg / day. B92. The method of item B1, wherein topiramate is administered at a dose of 100 to 400 mg / day. B93. The method of item B1, wherein topiramate is administered at a dose of 100 to 300 mg / day. B94. The method of item B1, wherein topiramate is administered at a dose of 200 to 300 mg / day. B95. The method of item B1, wherein valproate is administered at a dose of 750 to 3000 mg / day. B96. The method of item B1, wherein valproate is administered at a dose of 750 to 2250 mg / day. B97. The method of item B1, wherein valproate is administered at a dose of 1500 to 2250 mg / day. B98. The method of item B1, wherein alpha-tocopherol is administered at a dose of 3.75 to 15 mg / day. B99. The method of item B1, wherein alpha-tocopherol is administered at a dose of 3.75 to 11.25 mg / day. B100 The method of item B1, wherein alpha-tocopherol is administered at a dose of 7.5 to 11.25 mg / day. B101. The method of any of items B1-B34, wherein the therapeutic combination is administered as a liquid pharmaceutical composition of any of items A1-A69. B102. The method of any of paragraphs B1-B101, wherein the therapeutic combination has tolerability and / or efficacy that is greater than the expected additive tolerability and / or efficacy of the drugs in the therapeutic combination. B103. The method of any of paragraphs B1-B102, wherein the therapeutic combination is initially administered to the subject intravenously for 1 to 30 days. B104. The method of any of paragraphs B1-B103, wherein the therapeutic combination is administered to the subject intramuscularly, subcutaneously, orally, transdermally, sublingually, buccally, intranasally, by inhalation, or rectally. B105. The method of any of paragraphs B1-B104, wherein after administration of the therapeutic combination is initiated, administration of the therapeutic combination is maintained by chronic oral or parenteral administration. B106. The method of item B105, wherein administration of the therapeutic combination is maintained for 3 to 6 months after brain injury. B107. The method of any of items B1-B106, wherein at least two drugs are present in the same pharmaceutical composition. B108. The method of any of items B1-B106, wherein at least three drugs are present in the same pharmaceutical composition. B109. The method of any of paragraphs B1-B109, wherein the administering step is initiated within 7 days after brain injury. B110. The method of item B109, wherein the administering step is initiated within 48 hours after brain injury. B111. The method of item B109, wherein the administering step is initiated within 24 hours after brain injury. B112. The method of item B109, wherein the administering step is initiated within 8 hours after brain injury. B113. The method of any of paragraphs B1-B112, wherein the therapeutic combination is administered to the subject for a period of 3 days to 3 months after the injury. B114. The method of item B113, wherein the therapeutic combination is administered to the subject for 5 to 30 days after brain injury.

[0060] definition The term "α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist" as used herein refers to a compound that binds to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and blocks their activation. Non-limiting examples of AMPA receptor antagonists include perampanel, ilamphenel (dimethyl-(2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxyl]-ethyl)amine hydrochloride), and talampanel. AMPA antagonists are characterized by reducing / blocking glutamate-induced currents as assessed by whole-cell voltage clamp experiments in cells (cell lines or primary neuronal cells) expressing AMPA receptors. Compounds with an IC50 of less than 5 μM are exemplary selective AMPA antagonists. Perampanel, a non-competitive selective allosteric modulator of AMPA receptors, has an IC50 in the range of 0.56 μM.

[0061] The term "anti-inflammatory agent," as used herein, refers to a compound selected from the group consisting of cyclooxygenase (COX) inhibitors; HMGCR inhibitors; selective angiotensin II receptor antagonists (sartans); sphingosine-1-phosphate receptor 1 (S1P1-receptor) modulators; interleukin-1-receptor antagonists; and agmatine.

[0062] The term "antioxidant" as used herein refers to α-tocopherol, deferoxamine, N-acetylcysteine, sulforaphane, or melatonin.

[0063] The term "COX inhibitor," as used herein, refers to a compound that inhibits the cyclooxygenase (COX) enzyme. A COX inhibitor may inhibit cyclooxygenase 1 (COX1), cyclooxygenase 2 (COX2), or both. A COX inhibitor may be a selective COX inhibitor (e.g., a selective COX2 inhibitor). A COX inhibitor that binds to COX2 with at least 10-fold greater affinity than COX1 is a selective COX2 inhibitor. Non-limiting examples of COX inhibitors include ibuprofen, flurbiprofen, naproxen, ketoprofen, tiaprofenic acid, diclofenac, indomethacin, acemetacin, flufenamic acid, mefenamic acid, piroxicam, tenoxicam, meloxicam, lornoxicam, acetylsalicylic acid, celecoxib, parecoxib, etoricoxib, rofecoxib, valdecoxib, and lumiracoxib. A COX inhibitor is defined as a compound capable of inhibiting human cyclooxygenase activity at an IC50 concentration of 10 μM or less. Selective COX inhibitors exhibit an IC50 that is at least 10-fold lower for inhibiting one COX enzyme subtype (e.g., COX2) than another (e.g., COX1) subtype enzyme. Universally applicable multiplex COX inhibition assays have been reported for measuring COX inhibition. One example is the use of cell-free enzyme preparations to assess inhibition of the peroxidase activity of COX enzymes using clonally expressed COX enzyme preparations.

[0064] The term "drug with a metabolic mechanism of action" as used herein refers to a compound selected from the group consisting of stiripentol, 2-deoxy-D-glucose, 5-azacytidine, decitabine, β-hydroxybutyrate, and vorinostat.

[0065] The term "drugs having presynaptic effects on neuronal excitability," as used herein, refers to compounds selected from the group consisting of levetiracetam, brivaracetam, padosevonil, seletracetam, known modulators of synaptic vesicle protein 2, and modulators of presynaptic calcium channels.

[0066] The terms "GABA potentiator" and "glutamate inhibitor," as used herein, refer to topiramate, valproate, phenobarbital, padosevonil, deferoxamine, ceftriaxone, ifenprodil, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or an N-methyl-D-aspartate receptor (NMDA) antagonist.

[0067] The term "HMGCR inhibitor" as used herein refers to a compound that inhibits 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase.Non-limiting examples of HMGCR inhibitors include atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.Selective inhibitors block the catalytic domain of HMBCR domain with an IC50 of at least 1 μM when assessed using human purified hydroxymethylglutaryl-coenzyme A reductase catalytic domain.Inhibition of enzyme activity can also be evaluated in rat and human liver microsomes because they are rich in HMGCR.

[0068] The term "interleukin-1 receptor antagonist" as used herein refers to a compound that binds to the interleukin-1 receptor. Non-limiting examples of interleukin-1 receptor antagonists include anakinra, a recombinant, slightly modified version of the human interleukin-1 receptor antagonist protein. Other agents include rilonacept, canakinumab, and gevokizumab, all of which are biopharmaceutical drugs (fusion proteins or monoclonal antibodies) that bind to the IL1 receptor without activating the receptor. The affinity of such biopharmaceutical drugs is expected to be in the low nanomolar or picomolar range, as measured by surface plasmon resonance assay using commercially available assays.

[0069] The term "presynaptic calcium channel modulator" as used herein refers to a compound that binds to presynaptic calcium channels. Non-limiting examples of presynaptic calcium channel modulators include gabapentin, pregabalin, and valproate. Other presynaptic calcium channel blockers bind to the α2-δ1 or α2-δ2 ​​subunit of the presynaptic calcium channel. 3 It binds with an affinity of less than 1 μM as measured by receptor binding assays using it as a competitive ligand for [H]-pregabalin binding.

[0070] The term "modulator of synaptic vesicle protein 2," as used herein, refers to a compound that binds to synaptic vesicle protein 2. Non-limiting examples of SV2 modulators, such as SV2A modulators, include levetiracetam, brivaracetam, etiracetam, seletracetam, and padosevonil. SV2 modulators are administered to purified SV2A protein preparations or clonally expressed SV2A protein as competitive ligands. 3 H]-levetiracetam binds with an affinity (IC50) of 1 μM or less.

[0071] The term "neuroprotective agent or drug that enhances regeneration and plasticity" as used herein refers to gabapentin, pregabalin, ifenprodil, perampanel, memantine, agmatine, celecoxib, or ceftriaxone.

[0072] The term "N-methyl-D-aspartate receptor (NMDA) antagonist" as used herein refers to a compound that binds to N-methyl-D-aspartate receptor (NMDA) and blocks its activity.Non-limiting examples of NMDA receptor antagonists include memantine ifenprodil, ketamine, dizocilpine, and dextromethorphan.NMDA antagonists are characterized by reducing / blocking the N-methyl-D-aspartate-induced current, as assessed by whole-cell voltage clamp experiments in cells (cell lines or primary neuronal cells) that express NMDA receptors.Compounds with an IC50 of less than 10 μM are selective NMDA antagonists.Both competitive and non-competitive NMDA antagonists are included.

[0073] The term "liquid pharmaceutical composition" as used herein refers to pharmaceutical compositions in the form of pharmaceutical solutions and pharmaceutical suspensions. Preferably, the liquid pharmaceutical composition (e.g., parenteral liquid pharmaceutical composition) is a liquid.

[0074] The term "pharmaceutically acceptable," as used herein, indicates that the compound, material, composition, and / or dosage form is suitable for contact with the tissues of an individual (e.g., human) without undue toxicity, irritation, allergic response, and other untoward complications, commensurate with a reasonable benefit / risk ratio.

[0075] The term "pharmaceutical composition" as used herein refers to a composition that contains one or more compounds described herein, is formulated with pharmaceutically acceptable excipients, and is typically manufactured or sold under the approval of a government regulatory agency as part of a therapeutic regimen for treating mammalian disease. Pharmaceutical compositions can be formulated, for example, into a unit dosage form for oral administration (e.g., oral solution or alternatively, tablet, capsule, caplet, gel cap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system that is free of particulate matter and suitable for intravenous use); or into any other formulation described herein.

[0076] The term "pharmaceutically acceptable salt" as used herein refers to a salt that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment, does not cause excessive toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. The salt can be prepared, for example, by reacting a free base group with a suitable organic acid in situ during the final isolation and purification of the compound described herein, or separately. Representative acid addition salts include, for example, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, and the like. Examples of salts that can be used include benzoate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, cocamidolate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate.Representative alkali metal or alkaline earth metal salts include, for example, sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Those skilled in the art will recognize that any reference to a drug compound includes within its scope pharmaceutically acceptable salts of the drug compound indicated.

[0077] The term "polysorbate," as used herein, typically refers to oleic acid esters of sorbitol and its anhydrides copolymerized with ethylene oxide. A preferred polysorbate is polysorbate 80 (poly(ethylene oxide)(80) sorbitan monolaurate).

[0078] The term "long-term," as used herein with respect to administration of a therapeutic combination, refers to long-term administration of the therapeutic combination for a period of at least three months.

[0079] The term "selective angiotensin II receptor antagonist" as used herein refers to a compound that binds to and blocks activation of angiotensin II receptor type 1, known as the AT1 receptor. Selective angiotensin II receptor antagonists are also known as sartans. Non-limiting examples of sartans include losartan, valsartan, irbesartan, telmisartan, candesartan, olmesartan, and azilsartan. Sartans bind to the AT1 receptor with at least 10-fold greater affinity than the AT2 receptor. Each compound is tested for in vitro AT receptor binding affinity by radiolabeling [the AT1 receptor and the AT2 receptor]. 125 AT antagonists are assessed by conventional ligand binding assays in competitive inhibition of the binding of [I]-angiotensin II to the receptor. 125I]-angiotensin II binding, which shows an affinity of less than 1 μM, expressed as an IC50 value, which is the concentration that inhibits 50% of the binding of angiotensin II.

[0080] The term "S1P1-receptor antagonist" as used herein refers to a compound that binds to the sphingosine-1-phosphate receptor 1. By binding to the S1P receptor, the receptor is degraded over time to an inactive state, which is the mechanism of action of this agent. Non-limiting examples of S1P1 antagonists include fingolimod, ozanimod, ponesimod, and laquinimod. Each S1P1 antagonist binds to the receptor at submicromolar concentrations, resulting in an EC50 of <0.1 μM as measured by the GTP-GammaS assay.

[0081] "Treatment" and "treating," as used herein, refer to the medical management of a subject with the intent to ameliorate, alleviate, stabilize, prevent, or cure a disease, disorder, or condition. This term includes active treatment (treatment directed at ameliorating the disease, disorder, or condition); causal treatment (treatment directed at the cause of the associated disease, disorder, or condition); palliative treatment (treatment designed to alleviate the symptoms of the disease, disorder, or condition); preventative treatment (treatment directed at minimizing or partially or completely preventing the onset of the associated disease, disorder, or condition); and symptomatic treatment (treatment used to supplement another therapy). "Treatment" and "treating," as used herein, also refer to disease modification, which means that the manifestations of a disease (e.g., post-traumatic epilepsy and central nervous system symptoms associated with post-traumatic epilepsy) are modified toward less severe manifestations, e.g., less severe or less frequent seizure occurrence, and / or less severe or complete suppression of central nervous system symptoms associated with the disease, e.g., anxiety disorders, depressive disorders, epilepsy, and seizure disorders, such as cognitive impairments, e.g., learning and memory deficits and sleep disorders, known to be associated with the disease. Non-limiting examples of diseases, disorders, and conditions that can be treated using the compositions, kits, and methods disclosed herein include, for example, epilepsy, seizures, anoxia, stroke, traumatic brain injury, brain infection, brain abscess, aneurysm, subarachnoid hemorrhage, status epilepticus, refractory status epilepticus, refractory partial onset seizures (POS), addiction (e.g., gambling addiction or drug addiction), migraine, substance addiction, alcohol addiction, cocaine addiction, opioid addiction, nicotine addiction, and the like. These conditions include addiction, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder, refractory generalized social phobia, Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet syndrome, bipolar disorder, obesity, post-traumatic stress disorder, headaches (e.g., cluster headaches or severe headaches), and conditions caused by exposure to chemical warfare nerve agents.Preferably, the disease, disorder, or condition is post-traumatic epilepsy and central nervous system conditions associated with post-traumatic epilepsy, epilepsy, subarachnoid hemorrhage, seizures, anoxia and anoxia-induced brain injury, stroke, traumatic brain injury, brain infection, brain abscess, status epilepticus, refractory status epilepticus, or refractory partial-onset seizures. [The present invention 1001] A liquid pharmaceutical composition comprising topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient. [The present invention 1002] 1001. A liquid pharmaceutical composition of the present invention comprising 1 mg / mL to 550 mg / mL of meglumine. [The present invention 1003] 1001. A liquid pharmaceutical composition of the present invention, comprising 1 mg / mL to 100 mg / mL of topiramate or a pharmaceutically acceptable salt thereof. [The present invention 1004] 1001. A liquid pharmaceutical composition according to claim 1001, further comprising levetiracetam. [The present invention 1005] 1004. A liquid pharmaceutical composition of the present invention comprising 5 mg / mL to 500 mg / mL of levetiracetam. [The present invention 1006] The liquid pharmaceutical composition of the present invention 1004, wherein the weight ratio of levetiracetam to topiramate is 5:1 to 15:1. [The present invention 1007] 1001. A liquid pharmaceutical composition according to claim 1001, further comprising brivaracetam. [The present invention 1008] 1007. A liquid pharmaceutical composition according to claim 10, comprising 0.5 mg / mL to 50 mg / mL of brivaracetam. [The present invention 1009] The liquid pharmaceutical composition of the present invention 1007, wherein the weight ratio of brivaracetam to topiramate is 1:4 to 1:1. [The present invention 1010] 1001. The liquid pharmaceutical composition of this invention, further comprising atorvastatin or a pharmaceutically acceptable salt thereof. [The present invention 1011] 10. The liquid pharmaceutical composition of the present invention, comprising 0.1 mg / mL to 80 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof. [The present invention 1012] 10. The liquid pharmaceutical composition of claim 10, wherein the weight ratio of topiramate to atorvastatin is 5:1 to 15:1. [The present invention 1013] 1001. A liquid pharmaceutical composition of the present invention having a pH of 5.5 to 8.8. [The present invention 1014] 1001. The liquid pharmaceutical composition of claim 1001, further comprising an acidulant. [The present invention 1015] 1001. The liquid pharmaceutical composition of claim 1001, wherein the acidulant is acetic acid. [The present invention 1016] 1001. The liquid pharmaceutical composition of claim 1001, further comprising a calcium sequestering agent. [The present invention 1017] 1016. The liquid pharmaceutical composition of claim 1016, wherein the calcium sequestering agent is EDTA, EGTA, BAPTA, or an alkali salt thereof. [The present invention 1018] 1001. The liquid pharmaceutical composition of claim 1001, further comprising an emulsifier. [The present invention 1019] 1018. A liquid pharmaceutical composition of the present invention comprising 0.001% to 5.0% (w / v) of an emulsifier. [The present invention 1020] 1018. The liquid pharmaceutical composition of claim 10, wherein the emulsifier is polyoxyethylene (20) sorbitan monooleate (polysorbate 80). [The present invention 1021] The liquid pharmaceutical composition of the present invention 1001, which is aqueous. [The present invention 1022] A kit comprising a first container and a second container, wherein the first container contains topiramate or a pharmaceutically acceptable salt thereof, and the second container contains a pharmaceutically acceptable aqueous solution of meglumine. [The present invention 1023] A method of treating a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition of the present invention. [The present invention 1024] A method of treating a patient in need thereof, comprising combining the contents of a first container and the contents of a second container in a kit of the present invention 1033 to form a liquid pharmaceutical composition, and administering a therapeutically effective amount of the liquid pharmaceutical composition to the patient. [The present invention 1025] The method of claim 1024, wherein the therapeutically effective amount is an amount that provides 0.5 mg / kg / day to 20 mg / kg / day of topiramate. [The present invention 1026] The method of claim 1024, wherein the therapeutically effective amount is an amount that provides at least 40 mg / day to 1200 mg / day of topiramate. [The present invention 1027] The method of claim 1024, wherein the therapeutically effective amount is an amount that provides 2.5 mg / kg / day to 150 mg / kg / day of levetiracetam. [The present invention 1028] The method of claim 1024, wherein the therapeutically effective amount is an amount that provides 0.2 mg / kg / day to 10 mg / kg / day of brivaracetam. [The present invention 1029] The method of claim 1024, wherein the therapeutically effective amount is an amount that provides 0.1 to 2.0 mg / kg / day of atorvastatin. [The present invention 1030] 1025. The method of claim 1024, wherein said liquid pharmaceutical composition is administered parenterally or orally. [The present invention 1031] 1024. The method of claim 1024, wherein said patient is in need of treatment for a disorder or condition selected from the group consisting of epilepsy, seizures, anoxia, stroke, traumatic brain injury, brain infection, brain abscess, aneurysm, subarachnoid hemorrhage, status epilepticus, refractory status epilepticus, refractory partial onset seizures (POS), gambling addiction, migraine, substance dependence, alcoholism, cocaine dependence, opioid dependence, nicotine dependence, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder, refractory generalized social phobia, Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet syndrome, bipolar disorder, obesity, post-traumatic stress disorder, headache, and conditions caused by exposure to chemical warfare nerve agents. [The present invention 1032] 1025. The method of claim 1024, wherein said patient is in need of neuroprotection. [The present invention 1033] The method of claim 1024, wherein said patient is in need of treatment for a disorder or condition selected from the group consisting of traumatic brain injury, stroke, and brain infection. [The present invention 1034] 1025. The method of claim 1024, wherein said patient is in need of treatment for a brain abscess. [This invention 1035] 1. A method of treating epileptogenesis in a subject following a brain injury, the method comprising the step of administering to the subject a therapeutically effective amount of a therapeutic combination, the therapeutic combination comprising two to five drugs selected from the group consisting of anti-inflammatory drugs, antioxidants, neuroprotective drugs, GABA potentiators, glutamate inhibitors, drugs having a presynaptic effect on neuronal excitability, drugs having a metabolic mechanism of action, and pharmaceutically acceptable salts thereof, with the proviso that the two to five drugs are all different. [The present invention 1036] 1035. The method of claim 1035, wherein each anti-inflammatory agent is independently ibuprofen, celecoxib, parecoxib, a sartan, atorvastatin, fingolimod, anakinra, or agmatine. [This invention 1037] The method of claim 1035, wherein each antioxidant is independently α-tocopherol, deferoxamine, N-acetylcysteine, sulforaphane, or melatonin. [The present invention 1038] 1035. The method of claim 1035, wherein each neuroprotective agent is independently gabapentin, pregabalin, ifenprodil, perampanel, memantine, agmatine, celecoxib, or ceftriaxone. [This invention 1039] 1035. The method of claim 1035, wherein each GABA enhancer and each glutamate inhibitor is independently topiramate, valproate, phenobarbital, deferoxamine, ceftriaxone, ifenprodil, perampanel, or memantine. [The present invention 1040] 1035. The method of claim 1035, wherein each drug having a presynaptic effect on neuronal excitability is independently levetiracetam, brivaracetam, etiracetam, padosevonil, gabapentin, pregabalin, or valproate. [This invention 1041] The method of claim 1035, wherein each drug having a metabolic mechanism of action is independently stiripentol, 2-deoxy-D-glucose, 5-azacytidine, decitabine, β-hydroxybutyrate, or vorinostat. [The present invention 1042] 1035. The method of claim 1035, wherein said therapeutic combination is a combination of topiramate, levetiracetam, and deferoxamine, or pharmaceutically acceptable salts thereof. [This invention 1043] 1035. The method of claim 10, wherein said therapeutic combination is a combination of topiramate, levetiracetam, and atorvastatin, or pharmaceutically acceptable salts thereof. [This invention 1044] 1035. The method of claim 10, wherein said therapeutic combination is a combination of topiramate and levetiracetam. [This invention 1045] 1035. The method of claim 10, wherein said therapeutic combination is a combination of topiramate, levetiracetam, and ceftriaxone, or pharmaceutically acceptable salts thereof. [The present invention 1046] 1035. The method of claim 10, wherein said therapeutic combination is a combination of topiramate, levetiracetam, and gabapentin, or pharmaceutically acceptable salts thereof. [This invention 1047] 1035. The method of claim 10, wherein said therapeutic combination is a combination of topiramate, levetiracetam, and pregabalin, or pharmaceutically acceptable salts thereof. [This invention 1048] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam, topiramate, and alpha-tocopherol. [This invention 1049] 1035. The method of claim 1035, wherein said therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin. [The present invention 1050] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib. [This invention 1051] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam, deferoxamine or a pharmaceutically acceptable salt thereof, gabapentin or a pharmaceutically acceptable salt thereof, and fingolimod or a pharmaceutically acceptable salt thereof. [This invention 1052] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone. [This invention 1053] The method of claim 1052, wherein at least one of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone is administered at a low dose. [This invention 1054] The method of claim 1053, wherein each of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone is administered at a low dose. [This invention 1055] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam and perampanel, or pharmaceutically acceptable salts thereof. [This invention 1056] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone. [This invention 1057] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam, parecoxib, and anakinra. [This invention 1058] 1035. The method of claim 10, wherein said therapeutic combination is a combination of levetiracetam and phenobarbital. [This invention 1059] 1035. The method of claim 1035, wherein said therapeutic combination is a combination of brivaracetam and topiramate. [The present invention 1060] 1035. The method of claim 1035, wherein said therapeutic combination is a combination of brivaracetam, topiramate, and ceftriaxone. [This invention 1061] 1035. The method of claim 10, wherein said therapeutic combination is a combination of brivaracetam and perampanel. [This invention 1062] 1035. The method of claim 10, wherein said therapeutic combination is a combination of brivaracetam, perampanel, and ceftriaxone. [This invention 1063] 1035. The method of claim 1035, wherein said therapeutic combination is a combination of valproate or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and memantine or a pharmaceutically acceptable salt thereof. [This invention 1064] 1035. The method of claim 1035, wherein said therapeutic combination comprises three of said drugs. [This invention 1065] The method of claim 1035, wherein the dose of each drug in said combination is the highest tolerated dose in said individual patient when that drug is administered in a therapeutic combination. [The present invention 1066] The method of claim 1035, wherein said therapeutic combination is initially administered to said subject intravenously for 1 to 30 days. [This invention 1067] The method of claim 1035, wherein said therapeutic combination is administered to said subject intramuscularly, subcutaneously, orally, transdermally, sublingually, buccally, intranasally, by inhalation, or rectally. [The present invention 1068] The method of claim 1035, wherein after administration of said therapeutic combination has been initiated, administration of said therapeutic combination is maintained by chronic oral or parenteral administration. [The present invention 1069] 1068. The method of claim 1068, wherein administration of said therapeutic combination is maintained for 3 to 6 months after said brain injury. [The present invention 1070] The method of claim 1035, wherein at least two of said drugs are present in the same pharmaceutical composition. [This invention 1071] The method of claim 1035, wherein at least three of said drugs are present in the same pharmaceutical composition. [This invention 1072] 1035. The method of claim 1035, wherein said administering step is initiated within 7 days after said brain injury. [This invention 1073] 1073. The method of claim 1072, wherein said administering step is initiated within 48 hours after said brain injury. [This invention 1074] 1073. The method of claim 1072, wherein said administering step is initiated within 24 hours after said brain injury. [This invention 1075] 1073. The method of claim 1072, wherein said administering step is initiated within 8 hours after said brain injury. [This invention 1076] 1035. The method of claim 1035, wherein said therapeutic combination is administered to said subject for a period of 3 days to 3 months after said injury. [This invention 1077] 1077. The method of claim 1076, wherein said therapeutic combination is administered to said subject for 5 to 30 days after said brain injury. [Brief explanation of the drawings]

[0082] [Figure 1] FIG. 1 is a graph showing the dependence of aqueous topiramate solubility (mg / mL) on meglumine concentration (mg / mL). DETAILED DESCRIPTION OF THE INVENTION

[0083] Detailed Description Generally, the present invention provides compositions and methods of use thereof, e.g., therapeutic combination therapy. The compositions and methods described herein can be used to treat subjects in need thereof, e.g., subjects suffering from epileptogenesis or epilepsy.

[0084] Therapeutic Combinations The present invention provides therapeutic combinations containing 2 to 5 (e.g., 2, 3, 4, or 5) drugs selected from the group consisting of anti-inflammatory drugs, antioxidants, neuroprotective drugs, GABA potentiators, glutamate inhibitors, drugs with presynaptic effects on neuronal excitability, drugs with metabolic mechanisms of action, and pharmaceutically acceptable salts thereof. The therapeutic combinations described herein are useful in treating epileptogenesis in subjects with brain injury (e.g., traumatic brain injury (TBI), stroke, or brain infection).

[0085] Advantageously, the therapeutic combinations described herein may reduce the occurrence of epileptic seizures in a subject (e.g., reducing the frequency of seizures and / or the severity of seizures), as well as reduce the occurrence of disease-related symptoms. The therapeutic combinations described herein may suppress epileptogenesis in a subject.

[0086] The following drugs may be used in therapeutic combinations: a) anti-inflammatory drugs, such as cyclooxygenase (COX) inhibitors; HMGCR inhibitors; sartans; sphingosine-1-phosphate receptor 1 (S1P1-receptor) modulators; interleukin-1-receptor antagonists; or agmatine; b) antioxidants, such as α-tocopherol, deferoxamine, N-acetylcysteine, sulforaphane, or melatonin; c) neuroprotective or regenerative and plasticity-enhancing drugs, such as gabapentin, pregabalin, ifenprodil, perampanel, memantine, agmatine, celecoxib, or ceftriaxone; d) GABA enhancers and glutamate inhibitors, such as topiramate, valproate, phenobarbital, padosevonil, deferoxamine, ceftriaxone, ifenprodil, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists or N-methyl-D-aspartate receptor (NMDA) antagonists; e) drugs with presynaptic effects on neuronal excitability, such as levetiracetam, known modulators of synaptic vesicle protein 2 or modulators of presynaptic calcium channels; and f) Drugs with a metabolic mechanism of action, such as stiripentol, 2-deoxy-D-glucose, 5-azacytidine, decitabine, β-hydroxybutyrate or vorinostat.

[0087] The therapeutic combinations described herein are useful for treating brain injury, such as traumatic brain injury, e.g., open or closed brain injury, cerebral contusion, brain injury as a result of brain surgery, hypoxic brain injury following thrombotic or hemorrhagic stroke, or brain injury resulting from a brain infection or brain injury resulting from a brain tumor.

[0088] Preferably, the therapeutic combination comprises topiramate and levetiracetam. A particularly preferred therapeutic combination is a combination of topiramate, levetiracetam, and a third drug. Preferably, the third drug is an anti-inflammatory drug (e.g., an anti-inflammatory drug that targets the early inflammatory component of epileptogenesis), such as atorvastatin, celecoxib, or deferoxamine. Another preferred third drug is gabapentin or pregabalin; each of these drugs adds presynaptic excitability modulation to topiramate and levetiracetam.

[0089] Alternate preferred therapeutic combinations are (i) a combination of levetiracetam and alpha-tocopherol; (ii) a combination of levetiracetam, deferoxamine, and melatonin; or (iii) a combination of levetiracetam, deferoxamine, and celecoxib.

[0090] Further preferred therapeutic combinations include combinations of (i) levetiracetam, deferoxamine, gabapentin, and fingolimod; (ii) levetiracetam, atorvastatin, and ceftriaxone; (iii) levetiracetam and perampanel; (iv) levetiracetam, parecoxib, and anakinra; or (iv) levetiracetam and phenobarbital.

[0091] Still further preferred therapeutic combinations include combinations of (i) brivaracetam and topiramate; (ii) brivaracetam and perampanel; or (iii) valproate, losartan, and memantine.

[0092] An important aspect of combination treatment is the proper timing of treatment. Treatment at a therapeutically effective dose is preferably initiated within one week after brain injury, more preferably within 48 hours after brain injury, even more preferably within 24 hours after brain injury, and most preferably within 8 hours after brain injury. Early treatment initiation can be important for the effectiveness of epileptogenic treatment.

[0093] Treatment is preferably continued for a predetermined period after initiation, even if no clinical signs of epileptogenesis are observed during the latent period of epileptogenesis. Currently, there are no known predictive markers of epileptogenesis that are useful for determining the initial treatment duration. Therefore, it is important to initiate treatment early and continue it for a sufficiently long period. A preferred initial treatment duration is at least 3 consecutive days (e.g., up to 3 months) after the initial brain injury; more preferably, the initial treatment duration is 5 to 30 days. This treatment duration can be adjusted to the individual severity or physical condition of the individual patient and / or the expected duration of the latent period of epileptogenesis in each case of brain injury. If clinical experience indicates that the latency period can be too long, the initial treatment of epileptogenesis may be extended beyond the first 30 days of treatment, or may be transitioned to long-term maintenance treatment, either with the same therapeutic combination or with a different therapeutic combination, in which drugs that target the early phase of epileptogenesis after brain injury, such as early inflammation, are removed or replaced from the therapeutic combination. Thus, the initial treatment of epileptogenesis and its consequences may be continued with a different therapeutic combination to further the treatment of epileptogenesis.

[0094] The route of administration for initial treatment (also referred to as initiation treatment) can be selected to ensure sufficient exposure and can be adjusted to the patient's condition. Preferably, the therapeutic combination is administered intravenously. Advantageously, intravenous administration can result in rapid and / or sufficient bioavailability of the therapeutic substance(s). Intravenous administration is also advantageous because it can be used for administration to outpatient subjects (e.g., by paramedics, in an emergency room, or in an intensive care unit), to subjects with a reduced level of consciousness, or to subjects with disrupted intestinal motility and absorption. Intravenous administration can be performed as a bolus injection or infusion. The dosing frequency of the infusion can depend on the pharmacokinetics of the therapeutic combination administered. Intravenous administration can be performed once daily, twice daily, three times daily, or by chronic infusion with or without a loading bolus. While the individual drugs can be administered separately, the therapeutic combination is preferably administered as a single pharmaceutical composition. Alternative routes of administration include oral (e.g., using an esophageal or gastric tube) and parenteral (e.g., subcutaneous, intramuscular) administration. Non-limiting examples of alternative routes of administration include rectal, nasal, inhalation, sublingual, buccal, and transdermal administration.

[0095] The dosage of each drug in the therapeutic combination can be selected as needed. Two separate strategies can be used for dose selection. The high-dose strategy aims to administer each of the combination partners of the therapeutic combination at the highest tolerated dose (or highest approved dose). This high-dose approach results in the maximum pharmacodynamic effect of each drug. This high-dose approach is particularly appropriate for the initial treatment period (first treatment) from immediately after injury up to 30 days. This approach is particularly useful for subjects with severe brain injury who have a high likelihood of epileptogenesis due to the severity or nature of their brain injury, as well as for subjects treated in emergency rooms and intensive care units. Advantageously and unexpectedly, the tolerability of a favorable combination can be comparable to that of the individual components. Without wishing to be bound by theory, the use of drugs that target different aspects of epileptogenesis may result in the elimination of enhanced drug-specific adverse effects.

[0096] In the methods disclosed herein, treatment at the maximum tolerated dose is typically not required for most subjects, but may be useful in some cases. Typically, due to the combination of various drugs, a therapeutic effect can be achieved with a low-dose approach. A low-dose approach typically involves administering 75% or less (e.g., 40-60%) of the maximum approved dose of each drug in the therapeutic combination.

[0097] Because the preferred route of administration for initial treatment is intravenous, any such dose, both high-dose and low-dose approaches, may require a loading dose at the beginning of intravenous administration to rapidly provide therapeutically effective plasma and tissue levels of the active ingredient(s). Such a loading dose may exceed the maximum approved dose of the drug by 2-5 times. Typically, the loading dose may be selected depending on the pharmacokinetics of each individual drug used in any given therapeutic combination. Furthermore, the approved high dose may be exceeded by as much as 100% for initial treatment, depending on factors related to each individual subject, such as the severity of the brain injury, general health, other comorbidities, body weight, and metabolic status.

[0098] In a high-dose approach, the following doses may be appropriate, being exemplary high doses: agmatine, 3.56 g / day; anakinra, 8 mg / kg / day; atorvastatin, 80 mg / day; brivaracetam, 400 mg / day; ceftriaxone, 4 g / day; deferoxamine, 62 mg / kg / day up to 6,000 mg / day; fingolimod, 1.25 mg / day; gabapentin, 3,200 mg / day; ifenprodil, 40 mg / day; levetiracetam, 55 mg / kg / day up to 6,000 mg / day; losartan, 100 mg / day; melatonin, 20 mg / day; memantine, 28 mg / day; N-acetylcysteine, 300 mg / kg / day; padosevonil, 800 mg / day; perampanel, 24 mg / day; phenobarbital, 200 mg / day; sulforaphane, 60 mg / day; topiramate, 400–600 mg / day; valproate, 3,000 mg / day; α-tocopherol, 15 mg / day; seletracetam, 100–160 mg / day.

[0099] In a low-dose approach for initial treatment, the therapeutically effective dose of each drug in the therapeutic combination may be 25-75% of the maximum approved dose when administered as monotherapy. For example, low doses include: agmatine, 0.89–2.67 g / day; anakinra, 2–6 mg / kg / day; atorvastatin, 20–60 mg / day; brivaracetam, 100–300 mg / day; ceftriaxone, 1.0–3 g / day; deferoxamine, 15.5–46.5 mg / kg / day up to a maximum dose of 4500 mg / day; fingolimod, 0.31–0.94 mg / day; gabapentin, 800–2400 mg / day; ifenprodil, 10–30 mg / day; levetiracetam, 13.75–41 mg / kg / day up to a maximum dose of 3000–4500 mg / day; losartan, 25–75 mg / day; melatonin, 5–15 mg / day; and memantine, 7–21 mg. mg / day; N-acetylcysteine, 75 to 225 mg / kg / day; padosevonil, 200 to 600 mg / day; perampanel, 6 to 18 mg / day; phenobarbital, 50 to 150 mg / day; seletracetam, 25 to 75 mg / day; sulforaphane, 15 to 45 mg / day; topiramate, 100 to 300 mg / day; valproate, 750 to 2250 mg / day; α-tocopherol, 3.75 to 11.25 mg / day.

[0100] The preferred administration route for initial treatment is intravenous, either as a single pharmaceutical composition containing the therapeutic combination, or as a series of pharmaceutical compositions containing one or more drugs of the therapeutic combination (e.g., bolus or infusion). Depending on the subject's physical condition, or based on the disease state and the subject's capacity, or based on the availability of formulations, other administration routes may be appropriate. For example, treatment may be initiated as intravenous or parenteral (e.g., intramuscular or subcutaneous) administration, and as the subject's compliance and capacity improve, the administration route may be switched to oral, but the initial treatment regimen may be maintained. The administration routes of the drugs of the therapeutic combination may be the same or different. For example, one agent may be administered intravenously, and another drug may be administered subcutaneously, intramuscularly, or orally.

[0101] An important aspect is the initial treatment after brain injury during the latency period of epileptogenesis. Typically, the initial treatment can last up to 30 days. Because the latency period may last longer than 30 days, depending on the individual brain injury and the subject's physical condition, the initial treatment should be followed by a maintenance treatment. Preferably, the maintenance treatment involves oral administration of an orally bioavailable drug. The maintenance treatment may be performed using the same therapeutic combination as the initial treatment, or a different therapeutic combination, in which drugs targeting the initial phase of epileptogenesis (e.g., inflammatory processes) are excluded from the therapeutic combination. The maintenance treatment may be continued for, for example, 3 to 6 months after the initial treatment, or may be continued long-term (e.g., to treat residual epileptogenic symptoms).

[0102] Dosage regimens and pharmaceutical formulations The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for in vivo administration. Pharmaceutical compositions typically contain one compound or, in the case of combination treatments as described herein, more than one compound in a fixed ratio, and a pharmaceutically acceptable excipient.

[0103] The individual compounds described herein can also be used in the form of a free base, a salt, a zwitterion, a solvate, or as a prodrug or pharmaceutical composition thereof. All forms are within the scope of the present invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof can be administered to patients in various forms depending on the selected route of administration, as will be understood by those skilled in the art. The various compounds administered in combination can be administered as fixed-dose combinations, in which two or more compounds can be formulated into a single dosage form or administered as individual formulated compounds, but can be administered to patients as a combined treatment. When more than two compounds are administered in a combination treatment, some or all of the compounds may be administered in one fixed-dose combination, while any remaining compounds to be administered may be administered as individual formulated compounds, or (e.g., in the case of four compounds, combined as two fixed-dose combinations with each compound, or as one single compound with a fixed-dose combination of three compounds, or as a fixed-dose combination of four compounds, or as four individually formulated compounds). The compounds and / or fixed-dose combinations of compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0104] One compound or any combination of compounds described herein may be administered alone or in admixture with a pharmaceutical carrier selected in accordance with the intended route of administration and standard pharmaceutical practice.The pharmaceutical compositions for use according to the present invention can therefore be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the compounds into pharmaceutically usable preparations.

[0105] The present invention also encompasses pharmaceutical compositions that may contain one or more pharmaceutically acceptable carriers.In preparing pharmaceutical compositions, active ingredients are typically mixed with excipients, diluted with excipients, or enclosed in such carriers, such as capsules, sachets, paper or other containers.For example, in the case of liquid preparations for parenteral administration, such containers can be glass or plastic vials or bottles, ampoules or other pharmaceutically acceptable containers for liquid drugs.When an excipient serves as a diluent, it can be a solid, semi-solid or liquid substance (e.g., normal saline) that serves as a vehicle, carrier or for the active ingredient.Therefore, the composition can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules.As is known in the art, the type of diluent can vary depending on the intended route of administration. The resulting composition may also contain additional agents, such as preservatives.

[0106] Excipient or carrier is selected based on mode and route of administration.Suitable pharmaceutical carrier and pharmaceutical requirements for use in pharmaceutical preparations are listed in the well-known reference textbook in this field: Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and USP / NF (United States Pharmacopeia and the National Formulary).The examples of suitable excipient are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may further comprise: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl- and propylhydroxy-benzoates; sweeteners; and flavoring agents. Other exemplary excipients are listed in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0107] Such pharmaceutical compositions can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing processes. Methods well known in the art for preparing formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York. Appropriate formulation depends on the selected route of administration. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. In preparing formulations, the active compound can be milled before being combined with other ingredients to obtain appropriate particle size. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, eg about 40 mesh.

[0108] Dosage The dosage of each compound or its pharmaceutically acceptable salt or prodrug, or pharmaceutical composition thereof, administered as a combination treatment used in the methods described herein may vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the recipient's age, health, and weight; the nature and severity of symptoms; the frequency of treatment, and the type of combination treatment, if any; and the clearance rate of the compound in the individual being treated.Those skilled in the art will be able to determine the appropriate dosage based on the above factors.The compounds used in the methods described herein can be initially administered at an appropriate dosage, and this dosage can be adjusted as necessary depending on the clinical response.In general, the appropriate daily dose of each compound in the combination is the minimum dose amount that each compound is effective in producing a therapeutic effect.Such an effective dose generally depends on the above factors.

[0109] Each compound may be administered to a patient, for example, in a single dose or multiple doses. For any such combination, the dosing frequency may be the same for each combined compound or may be selected individually for each individual combined compound. When administered in multiple doses, the doses may be separated from each other by, for example, 1 to 24 hours or 1 to 7 days. The compounds may be administered according to a schedule, or the compounds may be administered without a set schedule. The active compound may be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily, every second, third, fourth, fifth, or sixth day, or 1, 2, 3, 4, 5, 6, or 7 times weekly. For parenteral administration, e.g., intravenous or subcutaneous, each compound or combination may be administered once or several times daily (1 to 12 times daily) as a bolus, or as a slow bolus over 1 to 120 minutes for each individual bolus, or as a continuous infusion with or without a loading bolus. It will be understood that for any particular subject, specific dosage regimes will be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0110] An effective amount of each compound in the combination can be, for example, a total daily dosage of any compound described herein, e.g., 0.05 mg to 6000 mg. For some compounds, particularly those in the antioxidant compound family, the total daily dosage can be greater than 3000 mg, with the maximum dose reaching 10,000 mg. Alternatively, the dosage amount can be calculated using the patient's body weight. Such a dosage range can include, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of an individual compound is administered.

[0111] The period over which the therapeutic combination may be administered may be as described herein.

[0112] According to a preferred embodiment, treatment is administered within a defined time frame after the occurrence of traumatic brain injury. Initial treatment at an effective dose is initiated within 7 days after the brain injury, preferably within 48 or 24 hours after the brain injury, and most preferably within 8 hours after the brain injury. Initial treatment is continued for a period of 3 days to 3 months after the injury, preferably 5 to 30 days. The initial treatment is followed immediately by subsequent treatment with the same combination, either by a different route of administration or by the same route of administration. Such long-term treatment can be expected to continue for 3 to 6 months after the initial treatment, or, if epileptogenic relief is minimal, as long-term as medically indicated to treat residual symptoms, or until uncontrollable seizures occur, necessitating a change in treatment regimen.

[0113] formulation The compound identified in the compound combination of the present invention as capable of treating any of the conditions described herein when administered using any of the methods described herein can be administered to patients or animals in unit dosage form with a pharmaceutically acceptable diluent, carrier, or excipient.Chemical compounds for use in such therapeutic agents can be produced and isolated by any standard method known to those skilled in the art of pharmaceutical chemistry.Conventional pharmaceutical practice can be used to obtain suitable formulations or compositions for administering the identified compound to patients suffering from bacterial infections.Administration can begin before the patient shows symptoms.

[0114] The exemplary administration route of the compound described herein or its pharmaceutical composition used in the present invention includes oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation and topical administration.The compound is preferably administered with a pharmaceutically acceptable carrier.The pharmaceutical preparation of the compound described herein that is formulated for treating the disorders described herein also constitutes part of the present invention.

[0115] Formulations for oral administration Pharmaceutical compositions contemplated by the present invention include those formulated for oral administration ("oral dosage forms"), which may be in the form of, for example, a tablet, capsule, liquid solution or suspension, powder, or liquid or solid crystal containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. Such excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches such as potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives such as microcrystalline cellulose, starches such as potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0116] The preparation for oral administration can also be presented as chewable tablets, hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Powders, granules and pellets can be prepared in a conventional manner using the ingredients mentioned above in tablets and capsules, for example, using a mixer, fluidized bed equipment or spray drying equipment.

[0117] Controlled-release compositions for oral use can be constructed so that the active drug is released by controlled dissolution and / or diffusion of the active drug substance. Any of several strategies can be implemented to achieve controlled release and a target plasma concentration profile over time. In one example, controlled release is achieved by appropriate selection of various formulation parameters and components, such as various types of controlled-release compositions and coatings. Examples include single-use or repeat-use tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, the composition comprises a biodegradable pH- and / or temperature-sensitive polymer coating.

[0118] Dissolution- or diffusion-controlled release can be achieved by suitable coating of tablet, capsule, pellet, or granule formulations of the compound, or by incorporating the compound into a suitable matrix. The controlled-release coating can include one or more of the coating materials listed above and / or, for example, shellac, beeswax, glycowax, castor oil wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled-release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0119] Liquid forms into which the compounds and compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0120] Formulations for oral administration The dosage for oral or sublingual administration is typically 0.1 to 500 mg per single dose as needed. In practice, the attending physician will determine the most suitable actual dosage regimen for each individual patient, and the dosage will vary depending on the age, weight and response of the specific patient. The dosages above are exemplary of average cases, but there are individual cases where a higher or lower dosage is beneficial, and such cases are within the scope of the present invention.

[0121] For oral administration, the composition may take the form of tablets, lozenges, etc., formulated in a conventional manner. Liquid drug formulations suitable for use in nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices typically comprise a compound together with a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol, or perfluorocarbon. Optionally, another substance can be added to modify the aerosol properties of the compound solution or suspension. Desirably, this substance is a liquid, such as alcohol, glycol, polyglycol, or fatty acid. Other methods for formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Patent No. 5,112,598 and Biesalski, U.S. Patent No. 5,556,611, each of which is incorporated herein by reference).

[0122] Formulations for nasal or inhaled administration Compound can also be formulated for nasal administration.In addition, the composition for nasal administration can be easily formulated as aerosol, drops, gel and powder.Preparation can be provided in single dose form or multi-dose form.In case of dropper or pipette, administration can be carried out by patient administering appropriate predetermined volume of solution or suspension.In case of spray, this can be carried out by, for example, metered atomizing spray pump.

[0123] The compounds can also be formulated for aerosol administration, particularly to the respiratory tract via inhalation, for example, intranasal administration. The compounds generally have a small particle size, for example, of 5 micrometers or less. Such a particle size can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol can also conveniently contain a surfactant, such as lecithin. The dosage of the drug can be controlled by a metering valve. Alternatively, the active ingredient can be provided in dry powder form, for example, a powder mix of the compound in a suitable powder base, such as lactose, starch, and starch derivatives, for example, hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier forms a gel in the nasal cavity. The powder composition can be presented in unit dose form, for example, in capsules or cartridges of, for example, gelatin, or in blister packs, from which the powder can be administered by an inhaler.

[0124] Aerosol formulations typically contain a solution or fine suspension of an active substance in a physiologically acceptable aqueous or non-aqueous solvent, usually presented in a single or multiple doses in a sterile form in a sealed container, which may be in the form of a cartridge or refill for use in an atomizing device. Alternatively, the sealed container may be a unitary drug delivery device intended to be disposed of after use, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve. When the dosage form includes an aerosol dispenser, it contains a propellant, which may be a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon. Alternatively, the aerosol dosage form may be in the form of a pump-atomizer.

[0125] Formulations for parenteral administration The compounds described herein for use in the methods described herein can be administered in pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, or subcutaneous) formulations as described herein. Pharmaceutical formulations can also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutions that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. For example, to prepare such compositions, the compounds can be dissolved or suspended in parenterally acceptable liquid vehicles. Among acceptable vehicles and solvents that can be used are water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, or n-propyl p-hydroxybenzoate. Further information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0126] Parenteral formulations can be any of five general types of preparations recognized by the USP-NF as suitable for parenteral administration: (1) "Drug injection": a liquid preparation that is a drug substance (e.g., a compound or combination of compounds described herein) or a solution thereof; (2) "Injectable drug": a drug substance (e.g., a compound or combination of compounds described herein) as a dry solid combined with a sterile vehicle suitable for parenteral administration as a drug injection; (3) "Drug Injectable Emulsion": A liquid preparation of a drug substance (e.g., a compound or combination of compounds described herein) dissolved or dispersed in a suitable emulsion vehicle; (4) "Drug Injectable Suspension": A liquid preparation of a drug substance (e.g., a compound or combination of compounds described herein) suspended in a suitable liquid vehicle; and (5) "Drug for injectable suspension": A drug substance (e.g., a compound or combination of compounds described herein) as a dry solid combined with a sterile vehicle suitable for parenteral administration as a drug for injectable suspension.

[0127] Exemplary formulations for parenteral administration include the solution of compound prepared in water, preferably mixed with surfactant, such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO and their mixtures with or without alcohol, and in oil.Under normal storage and use conditions, these preparations can contain preservatives to prevent microbial growth.The routine procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and United States Pharmacopeia: National Formulary (USP 36 NF31), 2013 publication.

[0128] The formulation for parenteral administration may contain, for example, excipients, sterilized water, or physiological saline, polyalkylene glycols, such as polyethylene glycol, plant-derived oils, or hydrogenated naphthalene.Biocompatible biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymer can be used to control the release of the compound.Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.The formulation for inhalation may contain excipients, such as lactose, or may be an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be an oily solution for administration in the form of nasal drops or as a gel.

[0129] Parenteral formulations may be formulated for immediate release of the compound or for sustained / extended release. Exemplary formulations for parenteral release of the compound include, for example, aqueous solutions, powders for reconstitution, co-solvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymeric gels.

[0130] Preferred Pharmaceutical Compositions In some embodiments, the present invention provides a liquid pharmaceutical composition of topiramate or a pharmaceutically acceptable salt thereof. As demonstrated herein, it has surprisingly been found that a liquid pharmaceutical composition of topiramate can be prepared by including meglumine as a cosolvent in the composition. Such liquid pharmaceutical compositions disclosed herein comprise topiramate (or a pharmaceutically acceptable salt of topiramate), meglumine, and a pharmaceutically acceptable excipient. Preferably, the liquid pharmaceutical composition is aqueous.

[0131] Topiramate The pharmaceutical composition disclosed in this specification is, for example, 1 mg / mL~100 mg / mL(for example, 1 mg / mL~100 mg / mL、4 mg / mL~100 mg / mL、10 mg / mL~100 mg / mL、13 mg / mL~100 mg / mL、20 mg / mL~100 mg / mL、30 mg / mL~100 mg / mL、37 mg / mL~100 mg / mL mg / mL、40 mg / mL~100 mg / mL、50 mg / mL~100 mg / mL、60 mg / mL~100 mg / mL、65 mg / mL~100 mg / mL、70 mg / mL~100 mg / mL、80 mg / mL~100 mg / mL、90 mg / mL~100 mg / mL、1 mg / mL~90 mg / mL、4 mg / mL~90 mg / mL mg / mL、10 mg / mL~90 mg / mL、13 mg / mL~90 mg / mL、20 mg / mL~90 mg / mL、30 mg / mL~90 mg / mL、37 mg / mL~90 mg / mL、40 mg / mL~90 mg / mL、50 mg / mL~90 mg / mL、60 mg / mL~90 mg / mL、65 mg / mL~90 mg / mL、70 mg / mL~90 mg / mL、80 mg / mL~90 mg / mL mg / mL、1 mg / mL~80 mg / mL、4 mg / mL~80 mg / mL、10 mg / mL~80 mg / mL、13 mg / mL~80 mg / mL、20 mg / mL~80 mg / mL、30 mg / mL~80 mg / mL、37 mg / mL~80 mg / mL、40 mg / mL~80 mg / mL、50 mg / mL~80 mg / mL、60 mg / mL~80 mg / mL mg / mL、65 mg / mL~80 mg / mL、70 mg / mL~80 mg / mL、1 mg / mL~70 mg / mL、4 mg / mL~70 mg / mL、10 mg / mL~70 mg / mL、13 mg / mL~70 mg / mL、20 mg / mL~70 mg / mL、30 mg / mL~70 mg / mL、37 mg / mL~70 mg / mL、40 mg / mL~70 mg / mL、50 mg / mL mg / mL~70 mg / mL、60 mg / mL~70 mg / mL、65 mg / mL~70 mg / mL、1 mg / mL~65 mg / mL、4 mg / mL~65 mg / mL、10 mg / mL~65mg / mL、13 mg / mL~65 mg / mL、20 mg / mL~65 mg / mL、30 mg / mL~65 mg / mL、37 mg / mL~65 mg / mL、40 mg / mL~65 mg / mL、50 mg / mL~65 mg / mL、60 mg / mL~65 mg / mL、1 mg / mL~60 mg / mL、4 mg / mL~60 mg / mL mg / mL~60 mg / mL、13 mg / mL~60 mg / mL、20 mg / mL~60 mg / mL、30 mg / mL~60 mg / mL、37 mg / mL~60 mg / mL、40 mg / mL~60 mg / mL、50 mg / mL~60 mg / mL、1 mg / mL~50 mg / mL、4 mg / mL~50 mg / mL、10 mg / mL~50 mg / mL、13 mg / mL~50 mg / mL、20 mg / mL~50 mg / mL、30 mg / mL~50 mg / mL、37 mg / mL~50 mg / mL、40 mg / mL~50 mg / mL、1 mg / mL~40 mg / mL、4 mg / mL~40 mg / mL、10 mg / mL~40 mg / mL、13 mg / mL~40 mg / mL、20 mg / mL~40 mg / mL mg / mL、37 mg / mL~40 mg / mL、1 mg / mL~37 mg / mL、4 mg / mL~37 mg / mL、10 mg / mL~37 mg / mL、13 mg / mL~37 mg / mL、20 mg / mL~37 mg / mL、30 mg / mL~37 mg / mL、1 mg / mL~30 mg / mL、10 mg / mL~30 mg / mL mg / mL、13 mg / mL~30 mg / mL、20 mg / mL~30 mg / mL、1 mg / mL~20 mg / mL、4 mg / mL~20 mg / mL、10 mg / mL~20 mg / mL、13 mg / mL~20 mg / mL、1 mg / mL~13 mg / mL、4 mg / mL~13 mg / mL、10 mg / mL~13 mg / mL、1 mg / mL~10 mg / mL、4 mg / mL~10 mg / mL、or 1 mg / mL~4 mg / mL) may contain permissible salt.

[0132] Preferably, the liquid pharmaceutical composition disclosed herein contains topiramate or a pharmaceutically acceptable salt thereof at 10 mg / mL to 70 mg / mL (e.g., 13 mg / mL to 70 mg / mL, 20 mg / mL to 70 mg / mL, 30 mg / mL to 70 mg / mL, 37 mg / mL to 70 mg / mL, 40 mg / mL to 70 mg / mL, 50 mg / mL to 70 mg / mL, 60 mg / mL to 70 mg / mL, 65 mg / mL to 70 mg / mL, 10 mg / mL to 65 mg / mL, 13 mg / mL to 65 mg / mL, 20 mg / mL to 65 mg / mL, 30 mg / mL to 65 mg / mL, 37 mg / mL to 65 mg / mL, 40 mg / mL to 65 mg / mL, 50 mg / mL to 65 mg / mL, 60 mg / mL to 65 mg / mL, 10 mg / mL to 60 mg / mL, 13 mg / mL to 60 mg / mL, 20 mg / mL to 60 mg / mL, 30 mg / mL to 60 mg / mL, 37 mg / mL to 60 mg / mL, 40 mg / mL to 60 mg / mL, 50 mg / mL to 60 mg / mL, 10 mg / mL to 50 mg / mL, 13 mg / mL to 50 mg / mL, 20 mg / mL to 50 mg / mL, 30 mg / mL to 50 mg / mL, 37 mg / mL to 50 mg / mL, 40 mg / mL to 50 mg / mL, 10 mg / mL to 40 mg / mL, 13 mg / mL to 40 mg / mL, 20 mg / mL to 40 mg / mL, 30 mg / mL to 40 mg / mL, 37 mg / mL to 40 mg / mL, 10 mg / mL to 37 mg / mL, 13 mg / mL to 37 mg / mL, 20 mg / mL to 37 mg / mL, 三十mg / mL to 37 mg / mL, 10 mg / mL to 30 mg / mL, 13 mg / mL to 30 mg / mL, 20 mg / mL to 30 mg / mL, 10 mg / mL to 20 mg / mL, 13 mg / mL to 20 mg / mL, or 10 mg / mL to 13 mg / mL).

[0133] It should be noted that there seems to be an error in the original text where "三十mg / mL" is present. It should probably be "30 mg / mL". The translation is provided as accurately as possible based on the given text.More preferably, the liquid pharmaceutical compositions disclosed herein contain 20 mg / mL to 65 mg / mL (e.g., 30 mg / mL to 65 mg / mL, 37 mg / mL to 65 mg / mL, 40 mg / mL to 65 mg / mL, 50 mg / mL to 65 mg / mL, 60 mg / mL to 65 mg / mL, 20 mg / mL to 60 mg / mL, 30 mg / mL to 60 mg / mL, 37 mg / mL to 60 mg / mL, 40 mg / mL to 60 mg / mL, 50 mg / mL to 60 mg / mL, 20 mg / mL to 50 mg / mL, 30 mg / mL to 50 mg / mL, 37 mg / mL to 50 mg / mL, 40 mg / mL to 50 mg / mL, 20 mg / mL to 40 mg / mL, 30 mg / mL to 40 mg / mL, 37 mg / mL to 40 mg / mL, 20 mg / mL to 37 mg / mL, 30 mg / mL to 37 mg / mL, or 20 mg / mL to 30 mg / mL) of topiramate or a pharmaceutically acceptable salt thereof.

[0134] In some preferred embodiments (e.g., when low concentrations of meglumine are preferred, such as in liquid pharmaceutical compositions comprising combinations of therapeutic agents described herein), the liquid pharmaceutical compositions disclosed herein contain between 4 mg / mL and 30 mg / mL (e.g., between 10 mg / mL and 30 mg / mL, between 13 mg / mL and 30 mg / mL, between 20 mg / mL and 30 mg / mL, between 4 mg / mL and 20 mg / mL, between 10 mg / mL and 20 mg / mL, between 13 mg / mL and 20 mg / mL, between 4 mg / mL and 13 mg / mL, between 10 mg / mL and 13 mg / mL, or between 4 mg / mL and 10 mg / mL) of topiramate or a pharmaceutically acceptable salt thereof. In certain more preferred embodiments (e.g., when a low concentration of meglumine (e.g., 1 mg / mL to 50 mg / mL (preferably, 5 mg / mL to 50 mg / mL)) is preferred, such as in liquid pharmaceutical compositions comprising the therapeutic combinations described herein), the liquid pharmaceutical compositions disclosed herein contain 4 mg / mL to 20 mg / mL (e.g., 4 mg / mL to 9 mg / mL, 9 mg / mL to 20 mg / mL, 4 mg / mL to 7 mg / mL, 7 mg / mL to 15 mg / mL, or 8 mg / mL to 12 mg / mL) of topiramate or a pharmaceutically acceptable salt thereof. In even more preferred embodiments (e.g., when a low concentration of meglumine is preferred, such as in liquid pharmaceutical compositions comprising the therapeutic combinations described herein), the liquid pharmaceutical compositions disclosed herein contain 9 mg / mL to 11 mg / mL (e.g., 10 mg / mL) of topiramate or a pharmaceutically acceptable salt thereof. In an alternative preferred embodiment (e.g., a liquid pharmaceutical composition configured for administration in a high dosage volume (e.g., 40 mL to 50 mL), the liquid pharmaceutical composition disclosed herein comprises 4 mg / mL to 6 mg / mL (e.g., 5 mg / mL) of topiramate or a pharmaceutically acceptable salt thereof.

[0135] Meglumine The liquid composition disclosed in this specification is, for example, 1 mg / mL~550 mg / mL(for example, 1 mg / mL~500 mg / mL、1 mg / mL~400 mg / mL、1 mg / ml~300 mg / mL、1 mg / ml~250 mg / mL、1 mg / mL~200 mg / mL、1 mg / mL~150 mg / mL、1 mg / mL~100 mg / mL mg / mL~75 mg / ml、1 mg / mL~60 mg / mL、1 mg / mL~50 mg / mL、1 mg / mL~30 mg / mL、1 mg / mL~25 mg / mL、1 mg / mL~10 mg / mL、5 mg / mL~550 mg / mL、5 mg / mL~500 mg / mL、5 mg / mL~400 mg / mL、5 mg / mL~300 mg / mL mg / mL~250 mg / mL、5 mg / mL~200 mg / mL、5 mg / mL~150 mg / mL、5 mg / mL~100 mg / mL、5 mg / mL~75 mg / mL、5 mg / mL~60 mg / mL、5 mg / mL~50 mg / mL、5 mg / mL~30 mg / mL、5 mg / mL~25 mg / mL、5 mg / mL~10 mg / mL、10 mg / mL~550 mg / mL、10 mg / mL~500 mg / mL mg / mL、10 mg / mL~400 mg / mL、10 mg / mL~300 mg / mL、10 mg / mL~250 mg / mL、10 mg / mL~200 mg / mL、10 mg / mL~150 mg / mL、10 mg / mL~100 mg / mL、10 mg / mL~75 mg / mL、10 mg / mL~60 mg / mL、10 mg / mL~50 mg / mL mg / mL、10 mg / mL~30 mg / mL、10 mg / mL~25 mg / mL、25 mg / mL~550 mg / mL、25 mg / mL~500 mg / mL、25 mg / mL~400 mg / mL、25 mg / mL~300 mg / mL、25 mg / mL~250 mg / mL、25 mg / mL~200 mg / mL、25 mg / mL~150 mg / mL、25 mg / mL~100 mg / mL mg / mL、25 mg / mL~75 mg / mL、25 mg / mL~60 mg / mL、25 mg / mL~50 mg / mL、25 mg / mL~30 mg / mL、50 mg / mL~550mg / mL、50 mg / mL~500 mg / mL、50 mg / mL~400 mg / mL、50 mg / mL~300 mg / mL、50 mg / mL~250 mg / mL、50 mg / mL~200 mg / mL、50 mg / mL~150 mg / mL、50 mg / mL~100 mg / mL、50 mg / mL~75 mg / mL、50 mg / mL~60 mg / mL、60 mg / mL~550 mg / mL、60 mg / mL~500 mg / mL、60 mg / mL~400 mg / mL、60 mg / mL~300 mg / mL、60 mg / mL~250 mg / mL、60 mg / mL~200 mg / mL、60 mg / mL~150 mg / mL、60 mg / mL~100 mg / mL、60 mg / mL~75 mg / mL、75 mg / mL~550 mg / mL、75 mg / mL~500 mg / mL、75 mg / mL~400 mg / mL、75 mg / mL~300 mg / mL、75 mg / mL~250 mg / mL、75 mg / mL~200 mg / mL、75 mg / mL~150 mg / mL、75 mg / mL~100 mg / mL、100 mg / mL~550 mg / mL、100 mg / mL~500 mg / mL、100 mg / mL~400 mg / mL、100 mg / mL~300 mg / mL、100 mg / mL~250 mg / mL、100 mg / mL~200 mg / mL、100 mg / mL~150 mg / mL、150 mg / mL~550 mg / mL、150 mg / mL~500 mg / mL、150 mg / mL~400 mg / mL、150 mg / mL~300 mg / mL、150 mg / mL~250 mg / mL、150 mg / mL~200 mg / mL、200 mg / mL~550 mg / mL、200 mg / mL~500 mg / mL、200 mg / mL~400 mg / mL、200 mg / mL~300 mg / mL、200 mg / mL~250 mg / mL、250 mg / mL~550 mg / mL、250 mg / mL~500 mg / mL、250 mg / mL~400 mg / mL、250 mg / mL~300 mg / mL、300 mg / mL~550 mg / mL、300 mg / mL~500 mg / mL、300 mg / mL~400 mg / mL、400The meglumine concentration may be between 400 mg / mL and 500 mg / mL (500 mg / mL to 550 mg / mL, or 400 mg / mL to 500 mg / mL).

[0136] In this specification, the pharmaceutical composition described in this document is, for example, 1 mg / mL~100 mg / mL (for example, 1 mg / mL~90 mg / mL、1 mg / mL~80 mg / mL、1 mg / mL~70 mg / mL、1 mg / mL~60 mg / mL、1 mg / mL~50 mg / mL、1 mg / mL~40 mg / mL、1 mg / mL~30 mg / mL、1 mg / mL~25 mg / mL、1 mg / mL~20 mg / mL、1 mg / mL~15 mg / mL、1 mg / mL~10 mg / mL、1 mg / mL~5 mg / mL、2 mg / mL~100 mg / mL、2 mg / mL~90 mg / mL、2 mg / mL~80 mg / mL、2 mg / mL~70 mg / mL、2 mg / mL~60 mg / mL、2 mg / mL~50 mg / mL、2 mg / mL~40 mg / mL mg / mL、2 mg / mL~30 mg / mL、2 mg / mL~25 mg / mL、2 mg / mL~20 mg / mL、2 mg / mL~15 mg / mL、2 mg / mL~10 mg / mL、2 mg / mL~5 mg / mL、3 mg / mL~100 mg / mL、3 mg / mL~90 mg / mL、3 mg / mL~80 mg / mL、3 mg / mL~70 mg / mL、3 mg / mL~60 mg / mL mg / mL~50 mg / mL、3 mg / mL~40 mg / mL、3 mg / mL~30 mg / mL、3 mg / mL~25 mg / mL、3 mg / mL~20 mg / mL、3 mg / mL~15 mg / mL、3 mg / mL~10 mg / mL、3 mg / mL~5 mg / mL、4 mg / mL~100 mg / mL、4 mg / mL~90 mg / mL、4 mg / mL~80 mg / mL mg / mL、4 mg / mL~70 mg / mL、4 mg / mL~60 mg / mL、4 mg / mL~50 mg / mL、4 mg / mL~40 mg / mL、4 mg / mL~30 mg / mL、4 mg / mL~25 mg / mL、4 mg / mL~20 mg / mL、4 mg / mL~15 mg / mL、4 mg / mL~10 mg / mL、4 mg / mL~5 mg / mL、5 mg / mL~100 mg / mL mg / mL~90 mg / mL、5 mg / mL~80 mg / mL、5 mg / mL~70 mg / mL、5 mg / mL~60 mg / mL、5mg / mL~50 mg / mL、5 mg / mL~40 mg / mL、5 mg / mL~30 mg / mL、5 mg / mL~25 mg / mL、5 mg / mL~20 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~10 mg / mL、10 mg / mL~100 mg / mL、10 mg / mL~90 mg / mL、10 mg / mL~80 mg / mL、10 mg / mL~70 mg / mL、10 mg / mL~60 mg / mL、10 mg / mL~50 mg / mL、10 mg / mL~40 mg / mL、10 mg / mL~30 mg / mL、10 mg / mL~25 mg / mL、10 mg / mL~20 mg / mL、10 mg / mL~15 mg / mL、15 mg / mL~100 mg / mL、15 mg / mL~90 mg / mL、15 mg / mL~80 mg / mL、15 mg / mL~70 mg / mL、15 mg / mL~60 mg / mL、15 mg / mL~50 mg / mL、15 mg / mL~40 mg / mL、15 mg / mL~30 mg / mL、15 mg / mL~25 mg / mL、15 mg / mL~20 mg / mL、20 mg / mL~100 mg / mL、20 mg / mL~90 mg / mL、20 mg / mL~80 mg / mL、20 mg / mL~70 mg / mL、20 mg / mL~60 mg / mL、20 mg / mL~50 mg / mL、20 mg / mL~40 mg / mL、20 mg / mL~30 mg / mL、20 mg / mL~25 mg / mL、25 mg / mL~100 mg / mL、25 mg / mL~90 mg / mL、25 mg / mL~80 mg / mL、25 mg / mL~70 mg / mL、25 mg / mL~60 mg / mL、25 mg / mL~50 mg / mL、25 mg / mL~40 mg / mL、25 mg / mL~30 mg / mL、30 mg / mL~100 mg / mL、30 mg / mL~90 mg / mL、30 mg / mL~80 mg / mL、30 mg / mL~70 mg / mL、30 mg / mL~60 mg / mL、30 mg / mL~50 mg / mL、30 mg / mL~40 mg / mL、40 mg / mL~100 mg / mL、40 mg / mL~90 mg / mL、40 mg / mL~80 mg / mL、40 mg / mL~70mg / mL, 40 mg / mL-60 mg / mL, 40 mg / mL-50 mg / mL, 50 mg / mL-100 mg / mL, 50 mg / mL-90 mg / mL, 50 mg / mL-80 mg / mL, 50 mg / mL-70 mg / mL, 50 mg / mL-60 mg / mL, 60 mg / mL-100 mg / mL, 60 mg / mL-90 mg / mL, 60 mg / mL-80 mg / mL, 60 mg / mL-70 mg / mL, 70 mg / mL-100 mg / mL, 70 mg / mL-90 mg / mL, 70 mg / mL-80 mg / mL, 80 mg / mL-100 mg / mL, 80 mg / mL-90 mg / mL, or 90 mg / mL-100 mg / mL.

[0137] Preferably, the composition disclosed in this specification should be 1 mg / mL~50 mg / mL (for example, 1 mg / mL~40 mg / mL、1 mg / mL~30 mg / mL、1 mg / mL~25 mg / mL、1 mg / mL~20 mg / mL、1 mg / mL~15 mg / mL、1 mg / mL~10 mg / mL、1 mg / mL~50 mg / mL、2 mg / mL~50 mg / mL mg / mL~40 mg / mL、2 mg / mL~30 mg / mL、2 mg / mL~25 mg / mL、2 mg / mL~20 mg / mL、2 mg / mL~15 mg / mL、2 mg / mL~10 mg / mL、2 mg / mL~5 mg / mL、3 mg / mL~50 mg / mL、3 mg / mL~30 mg / mL、3 mg / mL~25 mg / mL mg / mL、3 mg / mL~20 mg / mL、3 mg / mL~15 mg / mL、3 mg / mL~10 mg / mL、3 mg / mL~5 mg / mL、4 mg / mL~50 mg / mL、4 mg / mL~40 mg / mL、4 mg / mL~30 mg / mL、4 mg / mL~25 mg / mL、4 mg / mL~20 mg / mL、4 mg / mL~15 mg / mL、4 mg / mL~10 mg / mL、4 mg / mL~5 mg / mL mg / mL、5 mg / mL~50 mg / mL、5 mg / mL~40 mg / mL、5 mg / mL~30 mg / mL、5 mg / mL~25 mg / mL、5 mg / mL~20 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~10 mg / mL、10 mg / mL~50 mg / mL、10 mg / mL~40 mg / mL、10 mg / mL~30 mg / mL mg / mL、10 mg / mL~25 mg / mL、10 mg / mL~20 mg / mL、10 mg / mL~15 mg / mL、15 mg / mL~50 mg / mL、15 mg / mL~40 mg / mL、15 mg / mL~30 mg / mL、15 mg / mL~25 mg / mL、15 mg / mL~20 mg / mL、20 mg / mL~50 mg / mL、20 mg / mL~40 mg / mL、20 mg / mL~30 mg / mL mg / mL、20 mg / mL~25 mg / mL、25 mg / mL~50 mg / mL、25 mg / mL~40 mg / mL、25The liquid pharmaceutical compositions disclosed herein contain meglumine at a concentration of 5 mg / mL to 30 mg / mL, 30 mg / mL to 50 mg / mL, 30 mg / mL to 40 mg / mL, or 40 mg / mL to 50 mg / mL. More preferably, the liquid pharmaceutical compositions disclosed herein contain meglumine at a concentration of 5 mg / mL to 50 mg / mL.

[0138] In certain preferred embodiments (e.g., liquid pharmaceutical compositions comprising two or more therapeutic agents described herein), the liquid pharmaceutical compositions disclosed herein provide a concentration of 1 mg / mL to 30 mg / mL (e.g., 1 mg / mL to 25 mg / mL, 1 mg / mL to 20 mg / mL, 1 mg / mL to 15 mg / mL, 1 mg / mL to 10 mg / mL, 1 mg / mL to 5 mg / mL, 2 mg / mL to 30 mg / mL, 2 mg / mL to 25 mg / mL, 2 mg / mL to 20 mg / mL, 2 mg / mL to 15 mg / mL, 2 mg / mL to 10 mg / mL, 2 mg / mL to 5 mg / mL, 3 mg / mL to 30 mg / mL, 3 mg / mL to 25 mg / mL, 3 mg / mL to 20 mg / mL, 3 mg / mL to 15 mg / mL, 3 mg / mL to 10 mg / mL, 3 mg / mL to 5 mg / mL, 4 mg / mL to 30 mg / mL, 4 mg / mL to 40 mg / mL, 4 mg / mL to 5 ... mg / mL~25 mg / mL, 4 mg / mL~20 mg / mL, 4 mg / mL~15 mg / mL, 4 mg / mL~10 mg / mL, 4 mg / mL~5 mg / mL, 5 mg / mL~30 mg / mL, 5 mg / mL~25 mg / mL, 5 mg / mL~20 mg / mL, 5 mg / mL~15 mg / mL, 5 mg / mL~10 mg / mL, 10 mg / mL~30 mg / mL, 10 mg / mL~25 mg / mL, 10 mg / mL~20 mg / mL, 10 mg / mL~15 mg / mL, 15 mg / mL~30 mg / mL, 15 mg / mL~25 mg / mL, 15 mg / mL~20 mg / mL, 20 mg / mL~30 mg / mL, 20 mg / mL~25 mg / mL, or 25 mg / mL~30 Contains meglumine (mg / mL).

[0139] In further preferred embodiments (e.g., in liquid pharmaceutical compositions described herein comprising topiramate as the only therapeutic agent), the liquid pharmaceutical compositions disclosed herein provide a bolus of 10 mg / mL to 50 mg / mL (e.g., 10 mg / mL to 40 mg / mL, 10 mg / mL to 30 mg / mL, 10 mg / mL to 25 mg / mL, 10 mg / mL to 20 mg / mL, 10 mg / mL to 15 mg / mL, 15 mg / mL to 50 mg / mL, 15 mg / mL to 40 mg / mL, 15 mg / mL to 30 mg / mL, 15 mg / mL to 25 mg / mL, 15 mg / mL to 20 mg / mL, 20 mg / mL to 50 mg / mL, 20 mg / mL to 40 mg / mL, 20 mg / mL to 30 mg / mL, 20 mg / mL to 25 mg / mL, 25 mg / mL to 50 mg / mL, 25 mg / mL to 40 Contains meglumine at concentrations of 25 mg / mL, 25 mg / mL to 30 mg / mL, 30 mg / mL to 50 mg / mL, 30 mg / mL to 40 mg / mL, or 40 mg / mL to 50 mg / mL.

[0140] Further therapeutic substances Levetiracetam The liquid pharmaceutical compositions disclosed herein may contain one or more additional therapeutic agents in addition to topiramate or a pharmaceutically acceptable salt thereof.

[0141] Preferably, the liquid pharmaceutical composition disclosed herein further comprises levetiracetam. For example, the liquid pharmaceutical composition disclosed herein may contain from 5 mg / mL to 500 mg / mL (e.g., 5 mg / mL to 400 mg / mL, 5 mg / mL to 300 mg / mL, 5 mg / mL to 250 mg / mL, 5 mg / mL to 200 mg / mL, 5 mg / mL to 150 mg / mL, 5 mg / mL to 100 mg / mL, 5 mg / mL to 75 mg / mL, 5 mg / mL to 60 mg / mL, 5 mg / mL to 50 mg / mL, 5 mg / mL to 30 mg / mL, 5 mg / mL to 25 mg / mL, 5 mg / mL to 10 mg / mL, 10 mg / mL to 500 mg / mL, 10 mg / mL to 400 mg / mL, 10 mg / mL to 300 mg / mL, 10 mg / mL to 250 mg / mL, 10 mg / mL to 200 mg / mL, 10 mg / mL to 150 mg / mL, 10 mg / mL to 100 mg / mL, 10 mg / mL to 75 mg / mL, 10 mg / mL to 60 mg / mL, 10 mg / mL to 50 mg / mL, 10 mg / mL to 30 mg / mL, 10 mg / mL to 25 mg / mL, 25 mg / mL to 500 mg / mL, 25 mg / mL to 400 mg / mL, 25 mg / mL to 300 mg / mL, 25 mg / mL to 250 mg / mL, 25 mg / mL to 200 mg / mL, 25 mg / mL to 150 mg / mL, 25 mg / mL to 100 mg / mL, 25 mg / mL to 75 mg / mL, 25 mg / mL to 60 mg / mL, 25 mg / mL to 50 mg / mL, 25 mg / mL to 30 mg / mL, 50 mg / mL to 500 mg / mL, 50 mg / mL to 400 mg / mL, 50 mg / mL to 300 mg / mL, 50 mg / mL to 250 mg / mL, 50 mg / mL to 200 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 50 mg / mL to 75 mg / mL, 50 mg / mL to 60 mg / mL, 60 mg / mL to 500 mg / mL, 60 mg / mL to 400 mg / mL, 60 mg / mL to 300 mg / mL, 60 mg / mL to 250 mg / mL, 60 mg / mL to 200 mg / mL, 60 mg / mL to 150mg / mL、60 mg / mL~100 mg / mL、60 mg / mL~75 mg / mL、75 mg / mL~500 mg / mL、75 mg / mL~400 mg / mL、75 mg / mL~300 mg / mL、75 mg / mL~250 mg / mL、75 mg / mL~200 mg / mL、75 mg / mL~150 mg / mL、75 mg / mL~100 mg / mL mg / mL、100 mg / mL~500 mg / mL、100 mg / mL~400 mg / mL、100 mg / mL~300 mg / mL、100 mg / mL~250 mg / mL、100 mg / mL~200 mg / mL、100 mg / mL~150 mg / mL、150 mg / mL~500 mg / mL、150 mg / mL~400 mg / mL mg / mL、150 mg / mL~300 mg / mL, 150 mg / mL-250 mg / mL, 150 mg / mL-200 mg / mL, 200 mg / mL-500 mg / mL, 200 mg / mL-400 mg / mL, 200 mg / mL-300 mg / mL, 200 mg / mL-250 mg / mL, 250 mg / mL-500 mg / mL, 250 mg / mL-400 mg / mL, 250 mg / mL-300 mg / mL, 300 mg / mL-500 mg / mL, 300 mg / mL-400 mg / mL, or 400 mg / mL-500 mg / mL).

[0142] In certain preferred embodiments, the liquid pharmaceutical compositions disclosed herein comprise a concentration of 5 mg / mL to 150 mg / mL (e.g., 5 mg / mL to 100 mg / mL, 5 mg / mL to 75 mg / mL, 5 mg / mL to 60 mg / mL, 5 mg / mL to 50 mg / mL, 5 mg / mL to 30 mg / mL, 5 mg / mL to 25 mg / mL, 5 mg / mL to 10 mg / mL, 10 mg / mL to 150 mg / mL, 10 mg / mL to 100 mg / mL, 10 mg / mL to 75 mg / mL, 10 mg / mL to 60 mg / mL, 10 mg / mL to 50 mg / mL, 10 mg / mL to 30 mg / mL, 10 mg / mL to 25 mg / mL, 25 mg / mL to 150 mg / mL, 25 mg / mL to 100 mg / mL, 25 mg / mL to 75 mg / mL, 25 mg / mL to 60 mg / mL, 25 mg / mL to 60 mg / mL, 25 mg / mL to 60 mg / mL, 25 mg / mL to 60 mg / mL, 25 mg / mL to 60 mg / mL, 25 mg / mL to 150 mg / mL, 25 mg / mL to 100 mg / mL, 25 mg / mL to 75 mg / mL, 25 mg / mL to 60 ...25 mg / mL, 25 mg / mL to 150 mg / mL, 25 mg / mL to 100 mg / mL, 25 mg / mL to 75 mg / mL, 25 mg / mL to 60 mg / mL mg / mL~50 mg / mL, 25 mg / mL~30 mg / mL, 50 mg / mL~150 mg / mL, 50 mg / mL~100 mg / mL, 50 mg / mL~75 mg / mL, 50 mg / mL~60 mg / mL, 60 mg / mL~150 mg / mL, 60 mg / mL~100 mg / mL, 60 mg / mL~75 mg / mL, 75 mg / mL to 150 mg / mL, 75 mg / mL to 100 mg / mL, or 100 mg / mL to 150 mg / mL) of levetiracetam. In some more preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain 20 mg / mL to 150 mg / mL of levetiracetam (e.g., 20 mg / mL to 120 mg / mL, 20 mg / mL to 100 mg / mL, 20 mg / mL to 60 mg / mL, 20 mg / mL to 50 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 120 mg / mL, 50 mg / mL to 100 mg / mL, 50 mg / mL to 60 mg / mL, 100 mg / mL to 150 mg / mL, 100 mg / mL to 120 mg / mL, or 120 mg / mL to 150 mg / mL). In an even more preferred embodiment, the liquid pharmaceutical compositions disclosed herein contain 60 mg / mL to 120 mg / mL of levetiracetam.In an alternative even more preferred embodiment (e.g., in liquid pharmaceutical compositions configured for administration in high dosage volumes (e.g., 40 mL to 50 mL)), the liquid pharmaceutical compositions disclosed herein contain 30 mg / mL to 60 mg / mL of levetiracetam.

[0143] Brivaracetam In an alternative preferred embodiment, the liquid pharmaceutical composition disclosed herein further comprises brivaracetam. For example, the liquid pharmaceutical compositions disclosed herein may be 0.5 mg / mL to 50 mg / mL (e.g., 0.5 mg / mL to 40 mg / mL, 0.5 mg / mL to 30 mg / mL, 0.5 mg / mL to 25 mg / mL, 0.5 mg / mL to 20 mg / mL, 0.5 mg / mL to 15 mg / mL, 0.5 mg / mL to 10 mg / mL, 0.5 mg / mL~7.5 mg / mL, 0.5 mg / mL~5 mg / mL, 0.5 mg / mL~2.5 mg / mL, 2.5 mg / mL~50 mg / mL, 2.5 mg / mL~40 mg / mL, 2.5 mg / mL~30 mg / mL, 2.5 mg / mL~25 mg / mL, 2.5 mg / mL~20 mg / mL, 2.5 mg / mL~15 mg / mL, 2.5 mg / mL~10 mg / mL, 2.5 mg / mL~7.5 mg / mL, 2.5 mg / mL~5 mg / mL, 5 mg / mL~50 mg / mL, 5 mg / mL~40 mg / mL, 5 mg / mL~30 mg / mL, 5 mg / mL~25 mg / mL, 5 mg / mL~20 mg / mL, 5 mg / mL~15 mg / mL, 5 mg / mL~10 mg / mL, 5 mg / mL~7.5 mg / mL, 7.5 mg / mL~50 mg / mL, 7.5 mg / mL~40 mg / mL, 7.5 mg / mL~30 mg / mL, 7.5 mg / mL~25 mg / mL, 7.5 mg / mL~20 mg / mL, 7.5 mg / mL~15 mg / mL, 7.5 mg / mL~10 mg / mL, 10 mg / mL~50 mg / mL, 10 mg / mL~40 mg / mL, 10 mg / mL~30 mg / mL, 10 mg / mL~25 mg / mL, 10 mg / mL~20 mg / mL, 10 mg / mL~15 mg / mL, 15 mg / mL~50 mg / mL, 15 mg / mL~40 mg / mL, 15 mg / mL~30 mg / mL, 15 mg / mL~25 mg / mL, 15 mg / mL~20 mg / mL, 20 mg / mL~50 mg / mL, 20 mg / mL~40 mg / mL, 20 mg / mL~30 mg / mL, 20 mg / mL~25 mg / mL, 25 mg / mL~50 mg / mL, 25 mg / mL~40 mg / mL, 25 mg / mL~30 mg / mL, 30 mg / mL~50 mg / mL, 30 5 mg / mL to 10 mg / mL). In certain preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain 0.5 mg / mL to 10 mg / mL of brivaracetam (e.g., 0.5 mg / mL to 7.5 mg / mL, 0.5 mg / mL to 5 mg / mL, 0.5 mg / mL to 2.5 mg / mL, 2.5 mg / mL to 10 mg / mL, 2.5 mg / mL to 7.5 mg / mL, 2.5 mg / mL to 5 mg / mL, 5 mg / mL to 10 mg / mL, 5 mg / mL to 7.5 mg / mL, or 7.5 mg / mL to 10 mg / mL). In even more preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain 2 mg / mL to 8 mg / mL of brivaracetam. In an even more preferred embodiment, the liquid pharmaceutical compositions disclosed herein contain 4 mg / mL to 8 mg / mL of brivaracetam. In an alternative even more preferred embodiment (e.g., in liquid pharmaceutical compositions configured for administration in high dosage volumes (e.g., 40 mL to 50 mL)), the liquid pharmaceutical compositions disclosed herein contain 2 mg / mL to 4 mg / mL of brivaracetam.

[0144] Seletracetam In an alternative preferred embodiment, the liquid pharmaceutical compositions disclosed herein further comprise seletracetam. For example, the liquid pharmaceutical compositions disclosed herein may be 0.2 mg / mL to 20 mg / mL (e.g., 0.2 mg / mL to 15 mg / mL, 0.2 mg / mL to 12 mg / mL, 0.2 mg / mL to 10 mg / mL, 0.2 mg / mL to 7.5 mg / mL, 0.2 mg / mL to 5 mg / mL, 0.2 mg / mL to 3.3 mg / mL, 0.2 mg / mL~2.5 mg / mL, 0.2 mg / mL~1 mg / mL, 0.1 mg / mL~0.5 mg / mL, 1 mg / mL~20 mg / mL, 1 mg / mL~15 mg / mL, 1 mg / mL~12 mg / mL, 1 mg / mL~10 mg / mL, 1 mg / mL~7.5 mg / mL, 1 mg / mL~5 mg / mL, 1 mg / mL~3.3 mg / mL, 1 mg / mL~2 mg / mL, 1 mg / mL~1.5 mg / mL, 2 mg / mL~20 mg / mL, 2 mg / mL~15 mg / mL, 2 mg / mL~12 mg / mL, 2 mg / mL~10 mg / mL, 2 mg / mL~7.5 mg / mL, 2 mg / mL~5 mg / mL, 2 mg / mL~3.3 mg / mL, 3.3 mg / mL~20 mg / mL, 3.3 mg / mL~15 mg / mL, 3.3 mg / mL~10 mg / mL, 3.3 mg / mL~7.5 mg / mL, 3.3 mg / mL~5 mg / mL, 5 mg / mL~20 mg / mL, 5 mg / mL~15 mg / mL, 5 mg / mL~12 mg / mL, 5 mg / mL~10 mg / mL, 5 mg / mL~7.5 mg / mL, 7.5 mg / mL~20 mg / mL, 7.5 mg / mL~15 mg / mL, 7.5 mg / mL~12 mg / mL, 7.5 The formulation may contain seletracetam at concentrations of 10 mg / mL to 10 mg / mL, 10 mg / mL to 20 mg / mL, 10 mg / mL to 15 mg / mL, or 15 mg / mL to 20 mg / mL.In certain preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain 0.2 mg / mL to 5 mg / mL (e.g., 0.2 mg / mL to 4 mg / mL, 0.2 mg / mL to 2.5 mg / mL, 0.2 mg / mL to 1 mg / mL, 0.2 mg / mL to 0.5 mg / mL, 1 mg / mL to 3.3 mg / mL, 1 mg / mL to 3.3 mg / mL, or 1 mg / mL to 2 mg / mL) of seletracetam. In even more preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain 0.8 mg / mL to 3 mg / mL of seletracetam. In even more preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain 1.6 mg / mL to 3 mg / mL of seletracetam. In an alternative even more preferred embodiment (e.g., in liquid pharmaceutical compositions configured for administration in high dosage volumes (e.g., 40 mL to 50 mL)), the liquid pharmaceutical compositions disclosed herein contain 0.8 mg / mL to 1.6 mg / mL of seletracetam.

[0145] Padosevonil In a preferred alternative embodiment, the liquid pharmaceutical composition disclosed herein further comprises pdsevonil. For example, the liquid pharmaceutical composition disclosed herein may contain from 1 mg / mL to 100 mg / mL, from 1 mg / mL to 100 mg / mL (e.g., from 1 mg / mL to 90 mg / mL, from 1 mg / mL to 80 mg / mL, from 1 mg / mL to 70 mg / mL, from 1 mg / mL to 60 mg / mL, from 1 mg / mL to 50 mg / mL, from 1 mg / mL to 40 mg / mL, from 1 mg / mL to 30 mg / mL, from 1 mg / mL to 25 mg / mL, from 1 mg / mL to 20 mg / mL, from 1 mg / mL to 15 mg / mL, from 1 mg / mL to 10 mg / mL, from 1 mg / mL to 5 mg / mL, from 2 mg / mL to 100 mg / mL, from 2 mg / mL to 90 mg / mL, from 2 mg / mL to 80 mg / mL, from 2 mg / mL to 70 mg / mL, from 2 mg / mL to 60 mg / mL, from 2 mg / mL to 50 mg / mL, from 2 mg / mL to 40 mg / mL, from 2 mg / mL to 30 mg / mL, from 2 mg / mL to 25 mg / mL, from 2 mg / mL to 20 mg / mL, from 2 mg / mL to 15 mg / mL, from 2 mg / mL to 10 mg / mL, from 2 mg / mL to 5 mg / mL, from 3 mg / mL to 100 mg / mL, from 3 mg / mL to 90 mg / mL, from 3 mg / mL to 80 mg / mL, from 3 mg / mL to 70 mg / mL, from 3 mg / mL to 60 mg / mL, from 3 mg / mL to 50 mg / mL, from 3 mg / mL to 40 mg / mL, from 3 mg / mL to 30 mg / mL, from 3 mg / mL to 25 mg / mL, from 3 mg / mL to 20 mg / mL, from 3 mg / mL to 15 mg / mL, from 3 mg / mL to 10 mg / mL, from 3 mg / mL to 5 mg / mL, from 4 mg / mL to 100 mg / mL, from 4 mg / mL to 90 mg / mL, from 4 mg / mL to 80 mg / mL, from 4 mg / mL to 70 mg / mL, from 4 mg / mL to 60 mg / mL, from 4 mg / mL to 50 mg / mL, from 4 mg / mL to 40 mg / mL, from 4 mg / mL to 30 mg / mL, from 4 mg / mL to 25 mg / mL, from 4 mg / mL to 20 mg / mL, from 4 mg / mL to 15 mg / mL, from 4 mg / mL to 10 mg / mL, from 4 mg / mL to 5 mg / mL, from 5 mg / mL to 100mg / mL、5 mg / mL~90 mg / mL、5 mg / mL~80 mg / mL、5 mg / mL~70 mg / mL、5 mg / mL~60 mg / mL、5 mg / mL~50 mg / mL、5 mg / mL~40 mg / mL、5 mg / mL~30 mg / mL、5 mg / mL~25 mg / mL、5 mg / mL~20 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~10 mg / mL、10 mg / mL~100 mg / mL、10 mg / mL~90 mg / mL、10 mg / mL~80 mg / mL、10 mg / mL~70 mg / mL、10 mg / mL~60 mg / mL、10 mg / mL~50 mg / mL、10 mg / mL~40 mg / mL、10 mg / mL~30 mg / mL、10 mg / mL~25 mg / mL、10 mg / mL~20 mg / mL、10 mg / mL~15 mg / mL、15 mg / mL~100 mg / mL、15 mg / mL~90 mg / mL、15 mg / mL~80 mg / mL、15 mg / mL~70 mg / mL、15 mg / mL~60 mg / mL、15 mg / mL~50 mg / mL、15 mg / mL~40 mg / mL、15 mg / mL~30 mg / mL、15 mg / mL~25 mg / mL、15 mg / mL~20 mg / mL、20 mg / mL~100 mg / mL、20 mg / mL~90 mg / mL、20 mg / mL~80 mg / mL、20 mg / mL~70 mg / mL、20 mg / mL~60 mg / mL、20 mg / mL~50 mg / mL、20 mg / mL~40 mg / mL、20 mg / mL~30 mg / mL、20 mg / mL~25 mg / mL、25 mg / mL~100 mg / mL、25 mg / mL~90 mg / mL、25 mg / mL~80 mg / mL、25 mg / mL~70 mg / mL、25 mg / mL~60 mg / mL、25 mg / mL~50 mg / mL、25 mg / mL~40 mg / mL、25 mg / mL~30 mg / mL、30 mg / mL~100 mg / mL、30 mg / mL~90 mg / mL、30 mg / mL~80 mg / mL、30 mg / mL~70 mg / mL、30 mg / mL~60 mg / mL、30 mg / mL~50 mg / mL、30mg / mL~40 mg / mL, 40 mg / mL~100 mg / mL, 40 mg / mL~90 mg / mL, 40 mg / mL~80 mg / mL, 40 mg / mL~70 mg / mL, 40 mg / mL~60 mg / mL, 40 mg / mL~50 mg / mL, 50 mg / mL~100 mg / mL, 50 mg / mL~90 mg / mL, 50 mg / mL~80 mg / mL, 50 mg / mL~70 mg / mL, 50 mg / mL~60 mg / mL, 60 mg / mL~100 mg / mL, 60 mg / mL~90 mg / mL, 60 mg / mL~80 mg / mL, 60 mg / mL~70 mg / mL, 70 mg / mL~100 mg / mL, 70 mg / mL~90 mg / mL, 70 mg / mL~80 mg / mL, 80 mg / mL~100 mg / mL, 80 In certain preferred embodiments, the liquid pharmaceutical compositions disclosed herein contain padosevonil at 4 mg / mL to 16 mg / mL (e.g., 4 mg / mL to 8 mg / mL or 8 mg / mL to 16 mg / mL).

[0146] Atorvastatin Additionally or alternatively, the liquid pharmaceutical compositions disclosed herein may further comprise, for example, atorvastatin or a pharmaceutically acceptable salt thereof. For example, the liquid pharmaceutical compositions disclosed herein may be 0.1 mg / mL to 80 mg / mL (e.g., 0.1 mg / mL to 70 mg / mL, 0.1 mg / mL to 60 mg / mL, 0.1 mg / mL to 50 mg / mL, 0.1 mg / mL to 40 mg / mL, 0.1 mg / mL to 30 mg / mL, 0.1 mg / mL to 20 mg / mL, 0.1 mg / mL~15 mg / mL, 0.1 mg / mL~13 mg / mL, 0.1 mg / mL~12 mg / mL, 0.1 mg / mL~11 mg / mL, 0.1 mg / mL~10 mg / mL, 0.1 mg / mL~9 mg / mL, 0.1 mg / mL~8 mg / mL, 0.1 mg / mL~7 mg / mL, 0.1 mg / mL~6 mg / mL, 0.1 mg / mL~5 mg / mL, 0.1 mg / mL~4 mg / mL, 0.1 mg / mL~3 mg / mL, 0.1 mg / mL~2 mg / mL, 0.1 mg / mL~1 mg / mL, 0.1 mg / mL~0.8 mg / mL, 0.1 mg / mL~0.5 mg / mL, 0.1 mg / mL~0.4 mg / mL, 0.1 mg / mL~0.3 mg / mL, 0.1 mg / mL~0.2 mg / mL, 0.2 mg / mL~80 mg / mL, 0.2 mg / mL~70 mg / mL, 0.2 mg / mL~60 mg / mL, 0.2 mg / mL~50 mg / mL, 0.2 mg / mL~40 mg / mL, 0.2 mg / mL~30 mg / mL, 0.2 mg / mL~20 mg / mL, 0.2 mg / mL~15 mg / mL, 0.2 mg / mL~13 mg / mL, 0.2 mg / mL~12 mg / mL, 0.2 mg / mL~11 mg / mL, 0.2 mg / mL~10 mg / mL, 0.2 mg / mL~9 mg / mL, 0.2 mg / mL~8 mg / mL, 0.2 mg / mL~7 mg / mL, 0.2 mg / mL~6 mg / mL, 0.2 mg / mL~5 mg / mL, 0.2 mg / mL~4 mg / mL, 0.2 mg / mL~3 mg / mL, 0.2 mg / mL~2 mg / mL, 0.2 mg / mL~1 mg / mL, 0.2 mg / mL~0.8 mg / mL, 0.2mg / mL~0.5 mg / mL、0.2 mg / mL~0.4 mg / mL、0.2 mg / mL~0.3 mg / mL、0.3 mg / mL~80 mg / mL、0.3 mg / mL~70 mg / mL、0.3 mg / mL~60 mg / mL、0.3 mg / mL~50 mg / mL、0.3 mg / mL~40 mg / mL、0.3 mg / mL~30 mg / mL、0.3 mg / mL~20 mg / mL、0.3 mg / mL~15 mg / mL、0.3 mg / mL~13 mg / mL、0.3 mg / mL~12 mg / mL、0.3 mg / mL~11 mg / mL、0.3 mg / mL~10 mg / mL、0.3 mg / mL~9 mg / mL、0.3 mg / mL~8 mg / mL、0.3 mg / mL~7 mg / mL、0.3 mg / mL~6 mg / mL、0.3 mg / mL~5 mg / mL、0.3 mg / mL~4 mg / mL、0.3 mg / mL~3 mg / mL、0.3 mg / mL~2 mg / mL、0.3 mg / mL~1 mg / mL、0.3 mg / mL~0.8 mg / mL、0.3 mg / mL~0.5 mg / mL、0.3 mg / mL~0.4 mg / mL、0.4 mg / mL~80 mg / mL、0.4 mg / mL~70 mg / mL、0.4 mg / mL~60 mg / mL、0.4 mg / mL~50 mg / mL、0.4 mg / mL~40 mg / mL、0.4 mg / mL~30 mg / mL、0.4 mg / mL~20 mg / mL、0.4 mg / mL~15 mg / mL、0.4 mg / mL~13 mg / mL、0.4 mg / mL~12 mg / mL、0.4 mg / mL~11 mg / mL、0.4 mg / mL~10 mg / mL、0.4 mg / mL~9 mg / mL、0.4 mg / mL~8 mg / mL、0.4 mg / mL~7 mg / mL、0.4 mg / mL~6 mg / mL、0.4 mg / mL~5 mg / mL、0.4 mg / mL~4 mg / mL、0.4 mg / mL~3 mg / mL、0.4 mg / mL~2 mg / mL、0.4 mg / mL~1 mg / mL、0.4 mg / mL~0.8 mg / mL、0.4 mg / mL~0.5 mg / mL、0.5 mg / mL~80 mg / mL、0.5 mg / mL~70 mg / mL、0.5 mg / mL~60 mg / mL、0.5mg / mL~50 mg / mL、0.5 mg / mL~40 mg / mL、0.5 mg / mL~30 mg / mL、0.5 mg / mL~20 mg / mL、0.5 mg / mL~15 mg / mL、0.5 mg / mL~13 mg / mL、0.5 mg / mL~12 mg / mL、0.5 mg / mL~11 mg / mL、0.5 mg / mL~10 mg / mL、0.5 mg / mL~9 mg / mL、0.5 mg / mL~8 mg / mL、0.5 mg / mL~7 mg / mL、0.5 mg / mL~6 mg / mL、0.5 mg / mL~5 mg / mL、0.5 mg / mL~4 mg / mL、0.5 mg / mL~3 mg / mL、0.5 mg / mL~2 mg / mL、0.5 mg / mL~1 mg / mL、0.5 mg / mL~0.8 mg / mL、1 mg / mL~80 mg / mL、1 mg / mL~70 mg / mL、1 mg / mL~60 mg / mL、1 mg / mL~50 mg / mL、1 mg / mL~40 mg / mL、1 mg / mL~30 mg / mL、1 mg / mL~20 mg / mL、1 mg / mL~15 mg / mL、1 mg / mL~13 mg / mL、1 mg / mL~12 mg / mL、1 mg / mL~11 mg / mL、1 mg / mL~10 mg / mL、1 mg / mL~9 mg / mL、1 mg / mL~8 mg / mL、1 mg / mL~7 mg / mL、1 mg / mL~6 mg / mL、1 mg / mL~5 mg / mL、1 mg / mL~4 mg / mL、1 mg / mL~3 mg / mL、1 mg / mL~2 mg / mL、2 mg / mL~80 mg / mL、2 mg / mL~70 mg / mL、2 mg / mL~60 mg / mL、2 mg / mL~50 mg / mL、2 mg / mL~40 mg / mL、2 mg / mL~30 mg / mL、2 mg / mL~20 mg / mL、2 mg / mL~15 mg / mL、2 mg / mL~13 mg / mL、2 mg / mL~12 mg / mL、2 mg / mL~11 mg / mL、2 mg / mL~10 mg / mL、2 mg / mL~9 mg / mL、2 mg / mL~8 mg / mL、2 mg / mL~7 mg / mL、2 mg / mL~6 mg / mL、2 mg / mL~5 mg / mL、2 mg / mL~4 mg / mL、2 mg / mL~3 mg / mL、3mg / mL~80 mg / mL、3 mg / mL~70 mg / mL、3 mg / mL~60 mg / mL、3 mg / mL~50 mg / mL、3 mg / mL~40 mg / mL、3 mg / mL~30 mg / mL、3 mg / mL~20 mg / mL、3 mg / mL~15 mg / mL、3 mg / mL~13 mg / mL、3 mg / mL~12 mg / mL、3 mg / mL~11 mg / mL、3 mg / mL~10 mg / mL、3 mg / mL~9 mg / mL、3 mg / mL~8 mg / mL、3 mg / mL~7 mg / mL、3 mg / mL~6 mg / mL、3 mg / mL~5 mg / mL、3 mg / mL~4 mg / mL、4 mg / mL~80 mg / mL、4 mg / mL~70 mg / mL、4 mg / mL~60 mg / mL、4 mg / mL~50 mg / mL、4 mg / mL~40 mg / mL、4 mg / mL~30 mg / mL、4 mg / mL~20 mg / mL、4 mg / mL~15 mg / mL、4 mg / mL~13 mg / mL、4 mg / mL~12 mg / mL、4 mg / mL~11 mg / mL、4 mg / mL~10 mg / mL、4 mg / mL~9 mg / mL、4 mg / mL~8 mg / mL、4 mg / mL~7 mg / mL、4 mg / mL~6 mg / mL、4 mg / mL~5 mg / mL、5 mg / mL~80 mg / mL、5 mg / mL~70 mg / mL、5 mg / mL~60 mg / mL、5 mg / mL~50 mg / mL、5 mg / mL~40 mg / mL、5 mg / mL~30 mg / mL、5 mg / mL~20 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~13 mg / mL、5 mg / mL~12 mg / mL、5 mg / mL~11 mg / mL、5 mg / mL~10 mg / mL、5 mg / mL~9 mg / mL、5 mg / mL~8 mg / mL、5 mg / mL~7 mg / mL、5 mg / mL~6 mg / mL、6 mg / mL~80 mg / mL、6 mg / mL~70 mg / mL、6 mg / mL~60 mg / mL、6 mg / mL~50 mg / mL、6 mg / mL~40 mg / mL、6 mg / mL~30 mg / mL、6 mg / mL~20 mg / mL、6 mg / mL~15 mg / mL、6 mg / mL~13mg / mL、6 mg / mL~12 mg / mL、6 mg / mL~11 mg / mL、6 mg / mL~10 mg / mL、6 mg / mL~9 mg / mL、6 mg / mL~8 mg / mL、6 mg / mL~7 mg / mL、7 mg / mL~80 mg / mL、7 mg / mL~70 mg / mL、7 mg / mL~60 mg / mL、7 mg / mL~50 mg / mL、7 mg / mL~40 mg / mL、7 mg / mL~30 mg / mL、7 mg / mL~20 mg / mL、7 mg / mL~15 mg / mL、7 mg / mL~13 mg / mL、7 mg / mL~12 mg / mL、7 mg / mL~11 mg / mL、7 mg / mL~10 mg / mL、7 mg / mL~9 mg / mL、7 mg / mL~8 mg / mL、8 mg / mL~80 mg / mL、8 mg / mL~70 mg / mL、8 mg / mL~60 mg / mL、8 mg / mL~50 mg / mL、8 mg / mL~40 mg / mL、8 mg / mL~30 mg / mL、8 mg / mL~20 mg / mL、8 mg / mL~15 mg / mL、8 mg / mL~13 mg / mL、8 mg / mL~12 mg / mL、8 mg / mL~11 mg / mL、8 mg / mL~10 mg / mL、8 mg / mL~9 mg / mL、9 mg / mL~80 mg / mL、9 mg / mL~70 mg / mL、9 mg / mL~60 mg / mL、9 mg / mL~50 mg / mL、9 mg / mL~40 mg / mL、9 mg / mL~30 mg / mL、9 mg / mL~20 mg / mL、9 mg / mL~15 mg / mL、9 mg / mL~13 mg / mL、9 mg / mL~12 mg / mL、9 mg / mL~11 mg / mL、9 mg / mL~10 mg / mL、10 mg / mL~80 mg / mL、10 mg / mL~70 mg / mL、10 mg / mL~60 mg / mL、10 mg / mL~50 mg / mL、10 mg / mL~40 mg / mL、10 mg / mL~30 mg / mL、10 mg / mL~20 mg / mL、10 mg / mL~15 mg / mL、10 mg / mL~13 mg / mL、10 mg / mL~12 mg / mL、10 mg / mL~11 mg / mL、11 mg / mL~80 mg / mL、11 mg / mL~70mg / mL、11 mg / mL~60 mg / mL、11 mg / mL~50 mg / mL、11 mg / mL~40 mg / mL、11 mg / mL~30 mg / mL、11 mg / mL~20 mg / mL、11 mg / mL~15 mg / mL、11 mg / mL~13 mg / mL、11 mg / mL~12 mg / mL、12 mg / mL~80 mg / mL mg / mL~70 mg / mL、12 mg / mL~60 mg / mL、12 mg / mL~50 mg / mL、12 mg / mL~40 mg / mL、12 mg / mL~30 mg / mL、12 mg / mL~20 mg / mL、12 mg / mL~15 mg / mL、12 mg / mL~13 mg / mL、13 mg / mL~80 mg / mL、13 mg / mL~70 mg / mL mg / mL、13 mg / mL~60 mg / mL、13 mg / mL~50 mg / mL、13 mg / mL~40 mg / mL、13 mg / mL~30 mg / mL、13 mg / mL~20 mg / mL、13 mg / mL~15 mg / mL、15 mg / mL~80 mg / mL、15 mg / mL~70 mg / mL、15 mg / mL~60 mg / mL、15 mg / mL~50 mg / mL mg / mL~40 mg / mL、15 mg / mL~30 mg / mL、15 mg / mL~20 mg / mL、20 mg / mL~80 mg / mL、20 mg / mL~70 mg / mL、20 mg / mL~60 mg / mL、20 mg / mL~50 mg / mL、20 mg / mL~40 mg / mL、20 mg / mL~30 mg / mL、30 mg / mL~80 mg / mL mg / mL、30 mg / mL~70 mg / mL、30 mg / mL~60 mg / mL, 30 mg / mL~50 mg / mL, 30 mg / mL~40 mg / mL, 40 mg / mL~80 mg / mL, 40 mg / mL~70 mg / mL, 40 mg / mL~60 mg / mL, 40 mg / mL~50 mg / mL, 50 mg / mL~80 mg / mL, 50 mg / mL~70 mg / mL, 50 mg / mL~60 mg / mL, 60 mg / mL~80 mg / mL, 60 mg / mL~70 mg / mL, or 70 mg / mL~80The liquid pharmaceutical composition may contain atorvastatin or a pharmaceutically acceptable salt thereof in an amount of 100 mg / mL. Among the liquid pharmaceutical compositions containing atorvastatin, preferred are those containing atorvastatin sodium.

[0147] Preferably, the composition described in this specification is 0.1 mg / mL~20 mg / mL(eg,0.1 mg / mL~15 mg / mL、0.1 mg / mL~13 mg / mL、0.1 mg / mL~12 mg / mL、0.1 mg / mL~11 mg / mL、0.1 mg / mL~10 mg / mL、0.1 mg / mL~9 mg / mL、0.1 mg / mL~8 mg / mL mg / mL、0.1 mg / mL~7 mg / mL、0.1 mg / mL~6 mg / mL、0.1 mg / mL~5 mg / mL、0.1 mg / mL~4 mg / mL、0.1 mg / mL~3 mg / mL、0.1 mg / mL~2 mg / mL、0.1 mg / mL~1 mg / mL、0.1 mg / mL~0.8 mg / mL、0.1 mg / mL~0.5 mg / mL、0.1 mg / mL~0.4 mg / mL、0.1 mg / mL~0.3 mg / mL、0.1 mg / mL~0.2 mg / mL、0.2 mg / mL~20 mg / mL、0.2 mg / mL~15 mg / mL、0.2 mg / mL~13 mg / mL、0.2 mg / mL~12 mg / mL、0.2 mg / mL~11 mg / mL、0.2 mg / mL~10 mg / mL mg / mL~9 mg / mL、0.2 mg / mL~8 mg / mL、0.2 mg / mL~7 mg / mL、0.2 mg / mL~6 mg / mL、0.2 mg / mL~5 mg / mL、0.2 mg / mL~4 mg / mL、0.2 mg / mL~3 mg / mL、0.2 mg / mL~1 mg / mL、0.2 mg / mL~0.8 mg / mL mg / mL、0.2 mg / mL~0.5 mg / mL、0.2 mg / mL~0.4 mg / mL、0.2 mg / mL~0.3 mg / mL、0.3 mg / mL~20 mg / mL、0.3 mg / mL~15 mg / mL、0.3 mg / mL~13 mg / mL、0.3 mg / mL~12 mg / mL、0.3 mg / mL~11 mg / mL、0.3 mg / mL~10 mg / mL、0.3 mg / mL~10 mg / mL mg / mL~9 mg / mL、0.3 mg / mL~8 mg / mL、0.3 mg / mL~7 mg / mL、0.3 mg / mL~6 mg / mL、0.3 mg / mL~5 mg / mL、0.3 mg / mL~4 mg / mL、0.3 mg / mL~3mg / mL、0.3 mg / mL~2 mg / mL、0.3 mg / mL~1 mg / mL、0.3 mg / mL~0.8 mg / mL、0.3 mg / mL~0.5 mg / mL、0.3 mg / mL~0.4 mg / mL、0.4 mg / mL~20 mg / mL、0.4 mg / mL~15 mg / mL、0.4 mg / mL~13 mg / mL、0.4 mg / mL~12 mg / mL、0.4 mg / mL~11 mg / mL、0.4 mg / mL~10 mg / mL、0.4 mg / mL~9 mg / mL、0.4 mg / mL~8 mg / mL、0.4 mg / mL~7 mg / mL、0.4 mg / mL~6 mg / mL、0.4 mg / mL~5 mg / mL、0.4 mg / mL~4 mg / mL、0.4 mg / mL~3 mg / mL、0.4 mg / mL~2 mg / mL、0.4 mg / mL~1 mg / mL、0.4 mg / mL~0.8 mg / mL、0.4 mg / mL~0.5 mg / mL、0.5 mg / mL~20 mg / mL、0.5 mg / mL~15 mg / mL、0.5 mg / mL~13 mg / mL、0.5 mg / mL~12 mg / mL、0.5 mg / mL~11 mg / mL、0.5 mg / mL~10 mg / mL、0.5 mg / mL~9 mg / mL、0.5 mg / mL~8 mg / mL、0.5 mg / mL~7 mg / mL、0.5 mg / mL~6 mg / mL、0.5 mg / mL~5 mg / mL、0.5 mg / mL~4 mg / mL、0.5 mg / mL~3 mg / mL、0.5 mg / mL~2 mg / mL、0.5 mg / mL~1 mg / mL、0.5 mg / mL~0.8 mg / mL、1 mg / mL~20 mg / mL、1 mg / mL~15 mg / mL、1 mg / mL~13 mg / mL、1 mg / mL~12 mg / mL、1 mg / mL~11 mg / mL、1 mg / mL~10 mg / mL、1 mg / mL~9 mg / mL、1 mg / mL~8 mg / mL、1 mg / mL~7 mg / mL、1 mg / mL~6 mg / mL、1 mg / mL~5 mg / mL、1 mg / mL~4 mg / mL、1 mg / mL~3 mg / mL、1 mg / mL~2 mg / mL、2 mg / mL~20 mg / mL、2 mg / mL~15 mg / mL、2 mg / mL~13 mg / mL、2mg / mL~12 mg / mL、2 mg / mL~11 mg / mL、2 mg / mL~10 mg / mL、2 mg / mL~9 mg / mL、2 mg / mL~8 mg / mL、2 mg / mL~7 mg / mL、2 mg / mL~6 mg / mL、2 mg / mL~5 mg / mL、2 mg / mL~4 mg / mL、2 mg / mL~3 mg / mL、3 mg / mL~20 mg / mL、3 mg / mL~15 mg / mL、3 mg / mL~13 mg / mL、3 mg / mL~12 mg / mL、3 mg / mL~11 mg / mL、3 mg / mL~10 mg / mL、3 mg / mL~9 mg / mL、3 mg / mL~8 mg / mL、3 mg / mL~7 mg / mL、3 mg / mL~6 mg / mL、3 mg / mL~5 mg / mL、3 mg / mL~4 mg / mL、4 mg / mL~20 mg / mL、4 mg / mL~15 mg / mL、4 mg / mL~13 mg / mL、4 mg / mL~12 mg / mL、4 mg / mL~11 mg / mL、4 mg / mL~10 mg / mL、4 mg / mL~9 mg / mL、4 mg / mL~8 mg / mL、4 mg / mL~7 mg / mL、4 mg / mL~6 mg / mL、4 mg / mL~5 mg / mL、5 mg / mL~20 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~13 mg / mL、5 mg / mL~12 mg / mL、5 mg / mL~11 mg / mL、5 mg / mL~10 mg / mL、5 mg / mL~9 mg / mL、5 mg / mL~8 mg / mL、5 mg / mL~7 mg / mL、5 mg / mL~6 mg / mL、6 mg / mL~20 mg / mL、6 mg / mL~15 mg / mL、6 mg / mL~13 mg / mL、6 mg / mL~12 mg / mL、6 mg / mL~11 mg / mL、6 mg / mL~10 mg / mL、6 mg / mL~9 mg / mL、6 mg / mL~8 mg / mL、6 mg / mL~7 mg / mL、7 mg / mL~20 mg / mL、7 mg / mL~15 mg / mL、7 mg / mL~13 mg / mL、7 mg / mL~12 mg / mL、7 mg / mL~11 mg / mL、7 mg / mL~10 mg / mL、7 mg / mL~9 mg / mL、7 mg / mL~8 mg / mL、8It contains atorvastatin or a pharmaceutically acceptable salt thereof in the range of [[mg / mL~20 mg / mL, 8 mg / mL~15 mg / mL, 8 mg / mL~13 mg / mL, 8 mg / mL~12 mg / mL, 8 mg / mL~11 mg / mL, 8 mg / mL~10 mg / mL, 8 mg / mL~9 mg / mL, 9 mg / mL~20 mg / mL, 9 mg / mL~15 mg / mL, 9 mg / mL~13 mg / mL, 9 mg / mL~12 mg / mL, 9 mg / mL~11 mg / mL, 9 mg / mL~10 mg / mL, 10 mg / mL~20 mg / mL, 10 mg / mL~15 mg / mL, 10 mg / mL~13 mg / mL, 10 mg / mL~12 mg / mL, 10 mg / mL~11 mg / mL, 11 mg / mL~20 mg / mL, 11 mg / mL~15 mg / mL, 11 mg / mL~13 mg / mL, 11 mg / mL~12 mg / mL, 12 mg / mL~20 mg / mL, 12 mg / mL~15 mg / mL, 12 mg / mL~13 mg / mL, 13 mg / mL~20 mg / mL, 13 mg / mL~15 mg / mL, or 15 mg / mL~20 mg / mL]].

[0148] More preferably, the liquid pharmaceutical composition disclosed in this specification is 0.1 mg / mL to 16 mg / mL (for example, 0.1 mg / mL to 15 mg / mL, 0.1 mg / mL to 13 mg / mL, 0.1 mg / mL to 12 mg / mL, 0.1 mg / mL to 11 mg / mL, 0.1 mg / mL to 10 mg / mL, 0.1 mg / mL to 9 mg / mL, 0.1 mg / mL to 8 mg / mL, 0.1 mg / mL to 7 mg / mL, 0.1 mg / mL to 6 mg / mL, 0.1 mg / mL to 5 mg / mL, 0.1 mg / mL to 4 mg / mL, 0.1 mg / mL to 3 mg / mL, 0.1 mg / mL to 2 mg / mL, 0.1 mg / mL to 1 mg / mL, 0.1 mg / mL to 0.8 mg / mL, 0.1 mg / mL to 0.5 mg / mL, 0.1 mg / mL to 0.4 mg / mL, 0.1 mg / mL to 0.3 mg / mL, 0.1 mg / mL to 0.2 mg / mL, 0.2 mg / mL to 16 mg / mL, 0.2 mg / mL to 15 mg / mL, 0.2 mg / mL to 13 mg / mL, 0.2 mg / mL to 12 mg / mL, 0.2 mg / mL to 11 mg / mL, 0.2 mg / mL to 10 mg / mL, 0.2 mg / mL to 9 mg / mL, 0.2 mg / mL to 8 mg / mL, 0.2 mg / mL to 7 mg / mL, 0.2 mg / mL to 6 mg / mL, 0.2 mg / mL to 5 mg / mL, 0.2 mg / mL to 4 mg / mL, 0.2 mg / mL to 3 mg / mL, 0.2 mg / mL to 2 mg / mL, 0.2 mg / mL to 1 mg / mL, 0.2 mg / mL to 0.8 mg / mL, 0.2 mg / mL to 0.5 mg / mL, 0.2 mg / mL to 0.4 mg / mL, 0.2 mg / mL to 0.3 mg / mL, 0.3 mg / mL to 16 mg / mL, 0.3 mg / mL to 15 mg / mL, 0.3 mg / mL to 13 mg / mL, 0.3 mg / mL to 12 mg / mL, 0.3 mg / mL to 11 mg / mL, 0.3 mg / mL to 10 mg / mL, 0.3 mg / mL to 9 mg / mL, 0.3 mg / mL to 8 mg / mL, 0.3 mg / mL to 7 mg / mL, 0.3 mg / mL to 6 mg / mL, 0.3 mg / mL to 5 mg / mL, 0.3 mg / mL to 4 mg / mL, 0.3 mg / mL to 3mg / mL、0.3 mg / mL~2 mg / mL、0.3 mg / mL~1 mg / mL、0.3 mg / mL~0.8 mg / mL、0.3 mg / mL~0.5 mg / mL、0.3 mg / mL~0.4 mg / mL、0.4 mg / mL~16 mg / mL、0.4 mg / mL~15 mg / mL、0.4 mg / mL~13 mg / mL、0.4 mg / mL~12 mg / mL、0.4 mg / mL~11 mg / mL、0.4 mg / mL~10 mg / mL、0.4 mg / mL~9 mg / mL、0.4 mg / mL~8 mg / mL、0.4 mg / mL~7 mg / mL、0.4 mg / mL~6 mg / mL、0.4 mg / mL~5 mg / mL、0.4 mg / mL~4 mg / mL、0.4 mg / mL~3 mg / mL、0.4 mg / mL~2 mg / mL、0.4 mg / mL~1 mg / mL、0.4 mg / mL~0.8 mg / mL、0.4 mg / mL~0.5 mg / mL、0.5 mg / mL~16 mg / mL、0.5 mg / mL~15 mg / mL、0.5 mg / mL~13 mg / mL、0.5 mg / mL~12 mg / mL、0.5 mg / mL~11 mg / mL、0.5 mg / mL~10 mg / mL、0.5 mg / mL~9 mg / mL、0.5 mg / mL~8 mg / mL、0.5 mg / mL~7 mg / mL、0.5 mg / mL~6 mg / mL、0.5 mg / mL~5 mg / mL、0.5 mg / mL~4 mg / mL、0.5 mg / mL~3 mg / mL、0.5 mg / mL~2 mg / mL、0.5 mg / mL~1 mg / mL、0.5 mg / mL~0.8 mg / mL、1 mg / mL~16 mg / mL、1 mg / mL~15 mg / mL、1 mg / mL~13 mg / mL、1 mg / mL~12 mg / mL、1 mg / mL~11 mg / mL、1 mg / mL~10 mg / mL、1 mg / mL~9 mg / mL、1 mg / mL~8 mg / mL、1 mg / mL~7 mg / mL、1 mg / mL~6 mg / mL、1 mg / mL~5 mg / mL、1 mg / mL~4 mg / mL、1 mg / mL~3 mg / mL、1 mg / mL~2 mg / mL、2 mg / mL~16 mg / mL、2 mg / mL~15 mg / mL、2 mg / mL~13 mg / mL、2mg / mL~12 mg / mL、2 mg / mL~11 mg / mL、2 mg / mL~10 mg / mL、2 mg / mL~9 mg / mL、2 mg / mL~8 mg / mL、2 mg / mL~7 mg / mL、2 mg / mL~6 mg / mL、2 mg / mL~5 mg / mL、2 mg / mL~4 mg / mL、2 mg / mL~3 mg / mL、3 mg / mL~16 mg / mL、3 mg / mL~15 mg / mL、3 mg / mL~13 mg / mL、3 mg / mL~12 mg / mL、3 mg / mL~11 mg / mL、3 mg / mL~10 mg / mL、3 mg / mL~9 mg / mL、3 mg / mL~8 mg / mL、3 mg / mL~7 mg / mL、3 mg / mL~6 mg / mL、3 mg / mL~5 mg / mL、3 mg / mL~4 mg / mL、4 mg / mL~16 mg / mL、4 mg / mL~15 mg / mL、4 mg / mL~13 mg / mL、4 mg / mL~12 mg / mL、4 mg / mL~11 mg / mL、4 mg / mL~10 mg / mL、4 mg / mL~9 mg / mL、4 mg / mL~8 mg / mL、4 mg / mL~7 mg / mL、4 mg / mL~6 mg / mL、4 mg / mL~5 mg / mL、5 mg / mL~16 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~13 mg / mL、5 mg / mL~12 mg / mL、5 mg / mL~11 mg / mL、5 mg / mL~10 mg / mL、5 mg / mL~9 mg / mL、5 mg / mL~8 mg / mL、5 mg / mL~7 mg / mL、5 mg / mL~6 mg / mL、6 mg / mL~16 mg / mL、6 mg / mL~15 mg / mL、6 mg / mL~13 mg / mL、6 mg / mL~12 mg / mL、6 mg / mL~11 mg / mL、6 mg / mL~10 mg / mL、6 mg / mL~9 mg / mL、6 mg / mL~8 mg / mL、6 mg / mL~7 mg / mL、7 mg / mL~16 mg / mL、7 mg / mL~15 mg / mL、7 mg / mL~13 mg / mL、7 mg / mL~12 mg / mL、7 mg / mL~11 mg / mL、7 mg / mL~10 mg / mL、7 mg / mL~9 mg / mL、7 mg / mL~8 mg / mL、8It contains atorvastatin or a pharmaceutically acceptable salt thereof in the range of mg / mL~16 mg / mL, 8 mg / mL~15 mg / mL, 8 mg / mL~13 mg / mL, 8 mg / mL~12 mg / mL, 8 mg / mL~11 mg / mL, 8 mg / mL~10 mg / mL, 8 mg / mL~9 mg / mL, 9 mg / mL~16 mg / mL, 9 mg / mL~15 mg / mL, 9 mg / mL~13 mg / mL, 9 mg / mL~12 mg / mL, 9 mg / mL~11 mg / mL, 9 mg / mL~10 mg / mL, 10 mg / mL~16 mg / mL, 10 mg / mL~15 mg / mL, 10 mg / mL~13 mg / mL, 10 mg / mL~12 mg / mL, 10 mg / mL~11 mg / mL, 11 mg / mL~16 mg / mL, 11 mg / mL~15 mg / mL, 11 mg / mL~13 mg / mL, 11 mg / mL~12 mg / mL, 12 mg / mL~16 mg / mL, 12 mg / mL~15 mg / mL, 12 mg / mL~13 mg / mL, 13 mg / mL~16 mg / mL, 13 mg / mL~15 mg / mL, or 15 mg / mL~16 mg / mL).

[0149] More preferably, the liquid pharmaceutical composition disclosed in the present specification is 0.2 mg / mL to 16 mg / mL (for example, 0.2 mg / mL to 15 mg / mL, 0.2 mg / mL to 13 mg / mL, 0.2 mg / mL to 12 mg / mL, 0.2 mg / mL to 11 mg / mL, 0.2 mg / mL to 10 mg / mL, 0.2 mg / mL to 9 mg / mL, 0.2 mg / mL to 8 mg / mL, 0.2 mg / mL to 7 mg / mL, 0.2 mg / mL to 6 mg / mL, 0.2 mg / mL to 5 mg / mL, 0.2 mg / mL to 4 mg / mL, 0.2 mg / mL to 3 mg / mL, 0.2 mg / mL to 2 mg / mL, 0.2 mg / mL to 1 mg / mL, 0.2 mg / mL to 0.8 mg / mL, 0.2 mg / mL to 0.5 mg / mL, 0.2 mg / mL to 0.4 mg / mL, 0.2 mg / mL to 0.3 mg / mL, 0.3 mg / mL to 16 mg / mL, 0.3 mg / mL to 15 mg / mL, 0.3 mg / mL to 13 mg / mL, 0.3 mg / mL to 12 mg / mL, 0.3 mg / mL to 11 mg / mL, 0.3 mg / mL to 10 mg / mL, 0.3 mg / mL to 9 mg / mL, 0.3 mg / mL to 8 mg / mL, 0.3 mg / mL to 7 mg / mL, 0.3 mg / mL to 6 mg / mL, 0.3 mg / mL to 5 mg / mL, 0.3 mg / mL to 4 mg / mL, 0.3 mg / mL to 3 mg / mL, 0.3 mg / mL to 2 mg / mL, 0.3 mg / mL to 1 mg / mL, 0.3 mg / mL to 0.8 mg / mL, 0.3 mg / mL to 0.5 mg / mL, 0.3 mg / mL to 0.4 mg / mL, 0.4 mg / mL to 16 mg / mL, 0.4 mg / mL to 15 mg / mL, 0.4 mg / mL to 13 mg / mL, 0.4 mg / mL to 12 mg / mL, 0.4 mg / mL to 11 mg / mL, 0.4 mg / mL to 10 mg / mL, 0.4 mg / mL to 9 mg / mL, 0.4 mg / mL to 8 mg / mL, 0.4 mg / mL to 7 mg / mL, 0.4 mg / mL to 6 mg / mL, 0.4 mg / mL to 5 mg / mL, 0.4 mg / mL to 4 mg / mL, 0.4 mg / mL to 3 mg / mL, 0.4 mg / mL to 2 mg / mL, 0.4 mg / mL to 1mg / mL、0.4 mg / mL~0.8 mg / mL、0.4 mg / mL~0.5 mg / mL、0.5 mg / mL~16 mg / mL、0.5 mg / mL~15 mg / mL、0.5 mg / mL~13 mg / mL、0.5 mg / mL~12 mg / mL、0.5 mg / mL~11 mg / mL、0.5 mg / mL~10 mg / mL、0.5 mg / mL~9 mg / mL、0.5 mg / mL~8 mg / mL、0.5 mg / mL~7 mg / mL、0.5 mg / mL~6 mg / mL、0.5 mg / mL~5 mg / mL、0.5 mg / mL~4 mg / mL、0.5 mg / mL~3 mg / mL、0.5 mg / mL~2 mg / mL、0.5 mg / mL~1 mg / mL、0.5 mg / mL~0.8 mg / mL、1 mg / mL~16 mg / mL、1 mg / mL~15 mg / mL、1 mg / mL~13 mg / mL、1 mg / mL~12 mg / mL、1 mg / mL~11 mg / mL、1 mg / mL~10 mg / mL、1 mg / mL~9 mg / mL、1 mg / mL~8 mg / mL、1 mg / mL~7 mg / mL、1 mg / mL~6 mg / mL、1 mg / mL~5 mg / mL、1 mg / mL~4 mg / mL、1 mg / mL~3 mg / mL、1 mg / mL~2 mg / mL、2 mg / mL~16 mg / mL、2 mg / mL~15 mg / mL、2 mg / mL~13 mg / mL、2 mg / mL~12 mg / mL、2 mg / mL~11 mg / mL、2 mg / mL~10 mg / mL、2 mg / mL~9 mg / mL、2 mg / mL~8 mg / mL、2 mg / mL~7 mg / mL、2 mg / mL~6 mg / mL、2 mg / mL~5 mg / mL、2 mg / mL~4 mg / mL、2 mg / mL~3 mg / mL、3 mg / mL~16 mg / mL、3 mg / mL~15 mg / mL、3 mg / mL~13 mg / mL、3 mg / mL~12 mg / mL、3 mg / mL~11 mg / mL、3 mg / mL~10 mg / mL、3 mg / mL~9 mg / mL、3 mg / mL~8 mg / mL、3 mg / mL~7 mg / mL、3 mg / mL~6 mg / mL、3 mg / mL~5 mg / mL、3 mg / mL~4 mg / mL、4 mg / mL~16mg / mL、4 mg / mL~15 mg / mL、4 mg / mL~13 mg / mL、4 mg / mL~12 mg / mL、4 mg / mL~11 mg / mL、4 mg / mL~10 mg / mL、4 mg / mL~9 mg / mL、4 mg / mL~8 mg / mL、4 mg / mL~7 mg / mL、4 mg / mL~6 mg / mL、4 mg / mL~5 mg / mL、5 mg / mL~16 mg / mL、5 mg / mL~15 mg / mL、5 mg / mL~13 mg / mL、5 mg / mL~12 mg / mL、5 mg / mL~11 mg / mL、5 mg / mL~10 mg / mL、5 mg / mL~9 mg / mL、5 mg / mL~8 mg / mL、5 mg / mL~7 mg / mL、5 mg / mL~6 mg / mL、6 mg / mL~16 mg / mL、6 mg / mL~15 mg / mL、6 mg / mL~13 mg / mL、6 mg / mL~12 mg / mL、6 mg / mL~11 mg / mL、6 mg / mL~10 mg / mL、6 mg / mL~9 mg / mL、6 mg / mL~8 mg / mL、6 mg / mL~7 mg / mL、7 mg / mL~16 mg / mL、7 mg / mL~15 mg / mL、7 mg / mL~13 mg / mL、7 mg / mL~12 mg / mL、7 mg / mL~11 mg / mL、7 mg / mL~10 mg / mL、7 mg / mL~9 mg / mL、7 mg / mL~8 mg / mL、8 mg / mL~16 mg / mL、8 mg / mL~15 mg / mL、8 mg / mL~13 mg / mL、8 mg / mL~12 mg / mL、8 mg / mL~11 mg / mL、8 mg / mL~10 mg / mL、8 mg / mL~9 mg / mL、9 mg / mL~16 mg / mL、9 mg / mL~15 mg / mL、9 mg / mL~13 mg / mL、9 mg / mL~12 mg / mL、9 mg / mL~11 mg / mL、9 mg / mL~10 mg / mL、10 mg / mL~16 mg / mL、10 mg / mL~15 mg / mL、10 mg / mL~13 mg / mL、10 mg / mL~12 mg / mL、10 mg / mL~11 mg / mL、11 mg / mL~16 mg / mL、11 mg / mL~15 mg / mL、11 mg / mL~13 mg / mL、11 mg / mL~12atorvastatin or a pharmaceutically acceptable salt thereof.

[0150] Even more preferably, the liquid pharmaceutical composition disclosed herein contains 0.4 mg / mL to 2 mg / mL (e.g., 0.4 mg / mL to 1.6 mg / mL, 0.4 mg / mL to 1 mg / mL, 0.4 mg / mL to 0.8 mg / mL, 0.4 mg / mL to 0.5 mg / mL, 0.5 mg / mL to 2 mg / mL, 0.5 mg / mL to 1.6 mg / mL, 0.5 mg / mL to 1 mg / mL, 0.5 mg / mL to 0.8 mg / mL, 1 mg / mL to 2 mg / mL, 1 mg / mL to 1.6 mg / mL, or 1.6 mg / mL to 2 mg / mL) of atorvastatin or a pharmaceutically acceptable salt thereof. Particularly preferred among liquid pharmaceutical compositions containing atorvastatin or a pharmaceutically acceptable salt thereof are compositions containing 1.2 mg / mL to 2.0 mg / mL. In an alternative particularly preferred embodiment (e.g., in liquid pharmaceutical compositions configured for administration in high dosage volumes (e.g., 40 mL to 50 mL)), the liquid pharmaceutical compositions disclosed herein contain 0.6 mg / mL to 1.0 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof.

[0151] excipients The liquid pharmaceutical compositions disclosed herein may further comprise one or more pharmaceutically acceptable excipients, such as antioxidants, emulsifiers, tonicity agents, acidulants, calcium sequestrants, or combinations thereof. Other pharmaceutically acceptable excipients may be colorants, flavoring agents, sweeteners, taste masking agents, thickeners, etc.

[0152] Antioxidants are pharmaceutically acceptable excipients typically used for their ability to reduce oxidation-related degradation of pharmaceutical composition components. Non-limiting examples of antioxidants include citric acid, α-tocopherol (e.g., D,L-α-tocopherol), monothioglycerol, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium sulfite, sodium bisulfite, sodium thiosulfate, p-aminobenzoic acid, glutathione, propyl gallate, and combinations thereof. Liquid pharmaceutical compositions disclosed herein may contain, for example, 0.001% (w / v) to 1% (w / v) (e.g., 0.01% (w / v) to 0.5% (w / v)) of antioxidant.

[0153] Emulsifiers are pharmaceutically acceptable excipients that can be used to stabilize pharmaceutical compositions against mechanical stresses such as agitation, shear and / or crystallization. Non-limiting examples of pharmaceutically acceptable emulsifiers include poloxamers (e.g., low molecular weight poloxamers (e.g., poloxamers having an average molecular weight of less than 10 kDa, such as Poloxamer 188), polysorbates, polyoxyethylene alkyl ethers (Brij), alkylphenyl polyoxyethylene ethers (Triton-X), sodium dodecyl sulfate (SDS), polyvinylpyrrolidone (PVP), 1,2-propylene glycol, Cremophor EL, Cremophor RH40, lecithin, tert-butanol, ethanol, or polyoxyethylene stearate. A preferred emulsifier is polysorbate. For example, polysorbate 80 may be used in intravenous liquid pharmaceutical compositions (e.g., solutions) at a concentration of, for example, 0.0001% (w / v) to 0.5% (w / v).The liquid pharmaceutical compositions disclosed herein may be formulated to a concentration of, for example, 0.0001% (w / v) to 5% (w / v) (e.g., 0.001% (w / v) to 4% (w / v), 0.001% (w / v) to 3% (w / v), 0.001% (w / v) to 2% (w / v), 0.001% (w / v) to 1% (w / v), 0.001% (w / v) to 0.5% (w / v), 0.001% (w / v) to 0.3% (w / v), 0.001% (w / v) to 0.1% (w / v), 0.003% (w / v) to 5% (w / v), 0. 003%(w / v)~4%(w / v), 0.003%(w / v)~3%(w / v), 0.003%(w / v)~2%(w / v), 0.003%(w / v)~1%(w / v), 0.003%(w / v)~0.5%(w / v), 0.003%( w / v)~0.3%(w / v), 0.003%(w / v)~0.1%(w / v), 0.1%(w / v)~5%(w / v), 0.1%(w / v)~4%(w / v), 0.1%(w / v)~3%(w / v), 0.1%(w / v)~2%(w / v) , 0.1%(w / v)~1%(w / v), 0.1%(w / v)~0.5%(w / v), 0.1%(w / v)~0.3%(w / v), 0.3%(w / v)~5%(w / v), 0.3%(w / v)~4%(w / v), 0.3%(w / v)~3% (w / v), 0.3%(w / v)~2%(w / v), 0.3%(w / v)~1%(w / v), 0.3%(w / v)~0.5%(w / v), 0.5%(w / v)~5%(w / v), 0.5%(w / v)~4%(w / v), 0.5%(w / v)~ The emulsion may contain an emulsifier at 3% (w / v), 0.5% (w / v) to 2% (w / v), 0.5% (w / v) to 1% (w / v), 1% (w / v) to 5% (w / v), 1% (w / v) to 4% (w / v), 1% (w / v) to 3% (w / v), 1% (w / v) to 2% (w / v), 2% (w / v) to 5% (w / v), 2% (w / v) to 4% (w / v), 2% (w / v) to 3% (w / v), 3% (w / v) to 5% (w / v), 3% (w / v) to 4% (w / v), or 4% (w / v) to 5% (w / v)). Alternatively, liquid pharmaceutical compositions disclosed herein (e.g., those containing propylene glycol, tert-butanol, ethanol, or a combination thereof as an emulsifier) ​​can contain, for example, 1% (w / v) to 40% (w / v) (e.g., 1% (w / v) to 15% (w / v)) of the emulsifier.Liquid pharmaceutical compositions disclosed herein (e.g., those containing ethanol as an emulsifier) ​​may contain, for example, 1% (w / v) to 15% (w / v) of an emulsifier. Emulsifiers are particularly advantageous for liquid pharmaceutical compositions containing pharmaceutically acceptable salts of atorvastatin, because aqueous solutions of certain pharmaceutically acceptable salts of atorvastatin may precipitate on standing.

[0154] An isotonicity agent is a pharmaceutically acceptable excipient typically used to adjust the tonicity of a liquid pharmaceutical composition. Tonicity is generally related to the osmotic pressure of a solution and is typically assessed relative to that of human serum. The liquid pharmaceutical compositions disclosed herein can be hypotonic, isotonic, or hypertonic. The liquid pharmaceutical composition is preferably isotonic. An isotonic liquid pharmaceutical composition is a liquid that has the same tonicity as a reference solution, such as isotonic saline or serum. Non-limiting examples of tonicity agents include pharmaceutically acceptable salts (e.g., alkaline salts, such as alkaline halides (e.g., sodium chloride and / or potassium chloride)), amino acids, and sugars. Preferred tonicity agents are sodium chloride, trehalose, sucrose, and arginine. Non-limiting examples of amino acid tonicity agents include arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, and proline.

[0155] Acidulants are pharmaceutically acceptable excipients typically used to adjust the pH of liquid pharmaceutical compositions. The liquid pharmaceutical composition may contain an amount of acidulant sufficient to have a pH of 5.5 to 8.8. A preferred pH range is 6.5 to 8.5. Typical acidulants included in the liquid pharmaceutical compositions of the present invention are weak Bronsted acids, e.g., acids with a pKa of 3 to 8. Non-limiting examples of acidulants include acetic acid, maleic acid, ascorbic acid, lactic acid, malic acid, and phosphoric acid.

[0156] Calcium sequestrants are chelating agents capable of binding calcium ions. Non-limiting examples of calcium sequestrants include ethylenediaminetetraacetic acid (EDTA); ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (also known as egtazic acid or EGTA); 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA); and alkaline (e.g., sodium or potassium) salts thereof. Certain calcium sequestrants, such as EDTA, EGTA, or BAPTA in their free acid form, are acidic and can therefore function as acidulants. Calcium sequestrants can be used at concentrations of, for example, 0.0001% (w / v) to 0.5% (w / v).The liquid pharmaceutical compositions disclosed herein may be used in a range of concentrations, for example, from 0.0001% (w / v) to 5% (w / v) (e.g., 0.001% (w / v) to 4% (w / v), 0.001% (w / v) to 3% (w / v), 0.001% (w / v) to 2% (w / v), 0.001% (w / v) to 1% (w / v), 0.001% (w / v) to 0.5% (w / v), 0.001% (w / v) to 0.3% (w / v), 0.001% (w / v) to 0.1% (w / v), 0.003% (w / v) to 5% (w / v), 0.0 03%(w / v)~4%(w / v), 0.003%(w / v)~3%(w / v), 0.003%(w / v)~2%(w / v), 0.003%(w / v)~1%(w / v), 0.003%(w / v)~0.5%(w / v), 0.003%(w / v)~0.3%(w / v), 0.003%(w / v)~0.1%(w / v), 0.1%(w / v)~5%(w / v), 0.1%(w / v)~4%(w / v), 0.1%(w / v)~3%(w / v), 0.1%(w / v)~2%(w / v), 0. 1%(w / v)~1%(w / v), 0.1%(w / v)~0.5%(w / v), 0.1%(w / v)~0.3%(w / v), 0.3%(w / v)~5%(w / v), 0.3%(w / v)~4%(w / v), 0.3%(w / v)~3%(w / v) ), 0.3%(w / v)~2%(w / v), 0.3%(w / v)~1%(w / v), 0.3%(w / v)~0.5%(w / v), 0.5%(w / v)~5%(w / v), 0.5%(w / v)~4%(w / v), 0.5%(w / v)~3%(w / The calcium sequestering agent may be present in an amount of 0.5% (w / v), 0.5% (w / v) to 2% (w / v), 0.5% (w / v) to 1% (w / v), 1% (w / v) to 5% (w / v), 1% (w / v) to 4% (w / v), 1% (w / v) to 3% (w / v), 1% (w / v) to 2% (w / v), 2% (w / v) to 5% (w / v), 2% (w / v) to 4% (w / v), 2% (w / v) to 3% (w / v), 3% (w / v) to 5% (w / v), 3% (w / v) to 4% (w / v), or 4% (w / v) to 5% (w / v).Preferred liquid pharmaceutical compositions disclosed herein have a concentration of 0.005% (w / v) to 0.5% (w / v), for example, 0.005% (w / v) to 0.01% (w / v); 0.005% (w / v) to 0.02% (w / v); 0.005% (w / v) to 0.05% (w / v); 0.005% (w / v) to 0.1% (w / v); 0.005% (w / v) to 0.2% (w / v); 0.01% (w / v) to 0.02% (w / v); 0.01% (w / v) Other preferred liquid pharmaceutical compositions disclosed herein may contain between 0.01% (w / v) and 0.1% (w / v) of a calcium sequestering agent.

[0157] Advantageously, in some embodiments, liquid pharmaceutical compositions comprising calcium sequestrants may include reduced amounts of emulsifiers, or in some cases may even include no emulsifiers. The reduction or elimination of emulsifiers in the compositions is advantageous due to the typically unfavorable toxicological profile of emulsifiers.

[0158] Administration The liquid pharmaceutical compositions disclosed herein may be for parenteral administration, such as intravenous, intraperitoneal, subcutaneous, intramuscular, or intrathecal administration. Parenteral administration may be by continuous infusion over a period of time. Alternatively, the liquid pharmaceutical compositions disclosed herein may be for oral administration.

[0159] For example, the liquid pharmaceutical composition for parenteral administration can be provided in one or more containers.This container can be, for example, vial, bottle, ampoule, or other pharmaceutically acceptable container for liquid pharmaceutical composition.Alternatively, the container can be a pre-filled dosage system, for example, a pre-filled syringe, a pre-filled infusion bottle, or a pre-filled infusion bag.

[0160] Alternatively, the liquid pharmaceutical compositions disclosed herein can be prepared immediately prior to administration (e.g., at the time of use or within, e.g., 24-48 hours of preparation). Such liquid pharmaceutical compositions can be prepared using the kits disclosed herein. Typically, the kits disclosed herein include a first container and a second container, wherein the first container contains topiramate (e.g., topiramate as the sole therapeutic agent; topiramate and levetiracetam; topiramate and brivaracetam; topiramate, levetiracetam and atorvastatin; or topiramate, brivaracetam and atorvastatin) or a pharmaceutically acceptable salt thereof, and the second container contains a pharmaceutically acceptable aqueous solution of meglumine. The kits disclosed herein are configured to provide the liquid pharmaceutical compositions disclosed herein.

[0161] The liquid pharmaceutical composition disclosed herein can be used in a method for treating a patient in need thereof. The method includes administering to the patient a therapeutically effective amount of the liquid pharmaceutical composition described herein. The liquid pharmaceutical composition can be prepared in a kit. Thus, the method can include combining the contents of a first container and a second container in the kit described herein to form a liquid pharmaceutical composition, and administering to the patient a therapeutically effective amount of the liquid pharmaceutical composition.

[0162] A therapeutically effective amount can be, for example, an amount resulting in 0.5 mg / kg / day to 20 mg / kg / day (e.g., 2 mg / kg / day to 15 mg / kg / day) of topiramate. For example, a therapeutically effective amount can be, for example, an amount resulting in at least 40 mg / day (e.g., at least 200 mg / day) of topiramate. Additionally or alternatively, a therapeutically effective amount can be, for example, an amount resulting in 1200 mg / day or less (e.g., 400 mg / day or less) of topiramate. A therapeutically effective amount can be, for example, an amount resulting in 2.5 mg / kg / day to 150 mg / kg / day (e.g., 10 mg / kg / day to 75 mg / kg / day) of levetiracetam. A therapeutically effective amount can be, for example, an amount resulting in 0.2 mg / kg / day to 10 mg / kg / day (e.g., 0.5 mg / kg / day to 5 mg / kg / day) of brivaracetam. Additionally or alternatively, a therapeutically effective amount may be, for example, an amount resulting in 50 mg / day to 400 mg / day (e.g., 50 mg / day to 200 mg / day or 200 mg / day to 400 mg / day) of brivaracetam.A therapeutically effective amount may be, for example, an amount resulting in 0.1 mg / kg / day to 2.0 mg / kg / day (e.g., 0.2 to 1.5 mg / kg / day) of atorvastatin.

[0163] Liquid pharmaceutical compositions can be administered, for example, parenterally (e.g., intravenously, subcutaneously, or intramuscularly). Liquid pharmaceutical compositions can be administered, for example, orally.

[0164] When a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof as the only therapeutic agent is administered, the method may further comprise administering (i) levetiracetam or brivaracetam and / or (ii) atorvastatin or a pharmaceutically acceptable salt thereof. Levetiracetam may be administered as the only additional therapeutic agent or in combination with atorvastatin or a pharmaceutically acceptable salt thereof. When levetiracetam is administered in combination with atorvastatin or a pharmaceutically acceptable salt thereof, the two therapeutic agents may be administered in the same pharmaceutical composition or in different pharmaceutical compositions. When levetiracetam is administered in combination with atorvastatin or a pharmaceutically acceptable salt thereof, the two therapeutic agents may be administered by the same or different routes of administration. A pharmaceutical composition containing levetiracetam may be administered by the same route of administration as a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof. Alternatively, a pharmaceutical composition containing levetiracetam may be administered by a different route of administration than a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof. Brivaracetam may be administered as the only additional therapeutic agent or in combination with atorvastatin or a pharmaceutically acceptable salt thereof. When brivaracetam is administered in combination with atorvastatin or a pharmaceutically acceptable salt thereof, the two therapeutic agents may be administered by the same or different routes of administration. A pharmaceutical composition containing brivaracetam may be administered by the same route of administration as a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof. Alternatively, a pharmaceutical composition containing brivaracetam may be administered by a different route of administration than a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing atorvastatin or a pharmaceutically acceptable salt thereof may be administered by the same route of administration as a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof.Alternatively, the pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof may be administered by a different route of administration than the liquid pharmaceutical composition comprising topiramate or a pharmaceutically acceptable salt thereof.

[0165] When the method involves administering a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and levetiracetam as the only therapeutic agents, the method may further include administering atorvastatin or a pharmaceutically acceptable salt thereof. The pharmaceutical composition containing atorvastatin or a pharmaceutically acceptable salt thereof may be administered by the same route of administration as the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and levetiracetam. Alternatively, the pharmaceutical composition containing atorvastatin or a pharmaceutically acceptable salt thereof may be administered by a different route of administration than the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and levetiracetam.

[0166] When the method involves administering a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and brivaracetam as the only therapeutic substances, the method may further include administering atorvastatin or a pharmaceutically acceptable salt thereof. The pharmaceutical composition containing atorvastatin or a pharmaceutically acceptable salt thereof may be administered by the same route as the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and brivaracetam. Alternatively, the pharmaceutical composition containing atorvastatin or a pharmaceutically acceptable salt thereof may be administered by a different route than the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and brivaracetam.

[0167] When the method involves administering a liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof as the only therapeutic substances, the method may further include administering levetiracetam or brivaracetam. The pharmaceutical composition containing levetiracetam may be administered by the same route as the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition containing levetiracetam may be administered by a different route than the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof. The pharmaceutical composition containing brivaracetam may be administered by the same route as the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition containing brivaracetam may be administered by a different route of administration than the liquid pharmaceutical composition containing topiramate or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof.

[0168] treatment The patient may be suffering from a condition requiring treatment, for example, epilepsy, seizures, anoxia, stroke, traumatic brain injury, brain infection, brain abscess, aneurysm, subarachnoid hemorrhage, status epilepticus, refractory status epilepticus, refractory partial onset seizures (POS), addiction (e.g., gambling or drug addiction), migraine, substance dependence, alcohol dependence, cocaine dependence, opioid dependence, nicotine dependence, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder, refractory generalized social phobia, Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet syndrome, bipolar disorder, obesity, post-traumatic stress disorder, headache (e.g., cluster headache or severe headache), and conditions caused by exposure to chemical warfare nerve agents. Preferably, the patient is in need of treatment for post-traumatic epilepsy and central nervous system symptoms associated with post-traumatic epilepsy, epilepsy, seizures, anoxia and anoxia-induced brain injury, stroke, traumatic brain injury, brain infection, subarachnoid hemorrhage, brain abscess, status epilepticus, refractory status epilepticus, or refractory partial onset seizures. The patient may be in a condition requiring neuroprotection, for example. More preferably, the patient is in need of treatment for traumatic brain injury, stroke, or brain infection. The patient may be in a condition requiring treatment for, for example, a brain abscess.

[0169] Each compound may be administered to a patient, for example, in a single dose or multiple doses. For any such combination, the dosing frequency may be the same for each combined compound or may be selected individually for each individual combined compound. When administered in multiple doses, the doses may be separated from each other by, for example, 1 to 24 hours or 1 to 7 days. The compounds may be administered according to a schedule, or the compounds may be administered without a set schedule. The active compound may be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily, every second, third, fourth, fifth, or sixth day, or 1, 2, 3, 4, 5, 6, or 7 times weekly. For parenteral administration, e.g., intravenous or subcutaneous, each compound or combination may be administered once or several times daily (1 to 12 times daily) as a bolus, or as a slow bolus over 1 to 120 minutes for each individual bolus, or as a continuous infusion with or without a loading bolus. It will be understood that for any particular subject, specific dosage regimens will be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0170] The period over which the therapeutic combination may be administered may be as described herein.

[0171] According to a preferred embodiment, treatment is administered within a defined time frame after the occurrence of traumatic brain injury. Initial treatment at an effective dose is initiated within 7 days after the brain injury, preferably within 48 or 24 hours after the brain injury, and most preferably within 8 hours after the brain injury. Initial treatment is continued for a period of 3 days to 3 months after the injury, preferably 5 to 30 days. The initial treatment is followed immediately by subsequent treatment with the same combination, either by a different route of administration or by the same route of administration. Such long-term treatment can be expected to continue for 3 to 6 months after the initial treatment, or, if epileptogenic relief is minimal, as long-term as medically indicated to treat residual symptoms, or until uncontrollable seizures occur, necessitating a change in treatment regimen.

[0172] preparation When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (e.g., isotonic saline or aqueous meglumine) that acts as a vehicle, carrier, or medium for the therapeutic substance.

[0173] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (if water soluble) or sterile powders for the extemporaneous preparation of sterile injectable solutions. In all cases, the form must be sterile and fluid to the extent that easy needle penetration exists. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of emulsifying agents. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, such as sugars or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using agents delaying absorption, such as aluminum monostearate and gelatin, in the composition.

[0174] Sterile injectable solution is prepared by incorporating the required amount of active compound into suitable solvent with various other components as listed above as necessary, and then sterilizing by filtration (for example, using a microfilter with a typical pore size of about 0.22 μ m or less).Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains the dispersion medium of the base and the other components that are required as listed above.When preparing sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying or freeze-drying together with any other desired components.

[0175] Alternative sterile preparation techniques include autoclaving or ionizing radiation sterilization (i.e., gamma radiation sterilization) of the individual components and primary packaging or the entire formulation. In the case of sterilization of the individual components and primary packaging, the individual components must be handled in a manner that avoids contamination, i.e., may be handled in a sterile environment to limit contamination during handling, mixing, and filling into the primary packaging, e.g., vials, bottles, or infusion bags.

[0176] It is particularly advantageous to formulate parenteral compositions into unit dosage form for ease of administration and uniformity of dosage.Unit dosage form as used herein refers to the physically separate unit that is suitable for administration as a dosage unit to the mammalian subject being treated; each unit contains a predetermined amount of active substance calculated to produce desired therapeutic effect together with required pharmaceutical carrier.

[0177] The main active ingredient is formulated in an effective amount with a suitable pharmaceutically acceptable carrier into the unit dosage form described herein for convenient and effective administration.The unit dosage form can be prepared, for example, using the kit described herein.The dosage of some therapeutic substances described herein can be determined by referring to the usual dosage and administration mode of the component.

[0178] These pharmaceutical compositions can be prepared by methods known in the art, for example, by conventional mixing, dissolving, levigating, emulsifying, encapsulating, encapsulating or lyophilizing processes.The methods known in the art for preparing pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York.The appropriate formulation depends on the selected route of administration.

[0179] The dosage of each compound or its pharmaceutically acceptable salt or pharmaceutical composition administered as a combination treatment used in the methods described herein can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the recipient's age, health, and weight; the nature and severity of symptoms; the frequency of treatment, and the type of combination treatment, if any; and the clearance rate of the compound in the individual being treated.Those skilled in the art will be able to determine the appropriate dosage based on the above factors.The compound used in the methods described herein can be initially administered at an appropriate dosage, and this dosage can be adjusted as needed depending on clinical response.In general, the appropriate daily dose of each compound in the combination is the minimum dose amount that each compound is effective in producing a therapeutic effect.Such an effective dose generally depends on the above factors.

[0180] Compounds identified as being capable of treating any of the conditions described herein when administered in a combination of compounds using any of the methods described herein can be administered to patients or animals as liquid pharmaceutical compositions (e.g., in unit dosage forms). Chemical compounds for use in such therapeutic agents can be made and isolated by any standard method known to those skilled in the art of medicinal chemistry. Conventional pharmaceutical practice can be used to obtain suitable pharmaceutical compositions for administering the identified compounds to patients suffering from traumatic brain injury, brain infection, brain abscess, stroke, cerebral ischemia, e.g., ischemic stroke, status epilepticus, and brain tumors. Treatment is initiated after the occurrence / diagnosis of the respective injury and is aimed at treating epileptogenesis. Administration can be initiated before the patient exhibits symptoms.

[0181] Exemplary administration routes of liquid pharmaceutical compositions include oral, intranasal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intrathecal, and intraperitoneal.The compound is preferably administered with a pharmaceutically acceptable carrier.The liquid pharmaceutical compositions described herein that are formulated for the treatment of the disorders described herein are also part of the present invention.

[0182] The liquid pharmaceutical compositions described herein include those formulated for oral administration. Oral liquid pharmaceutical compositions can be, for example, in the form of a liquid solution or suspension containing an active ingredient(s) in a mixture with a pharmaceutically acceptable excipient, such as those described herein. Preferably, oral liquid pharmaceutical compositions are liquids.

[0183] Liquid pharmaceutical compositions may also include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions, as well as edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0184] Principles useful in formulating liquid pharmaceutical compositions and kits therefor are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and United States Pharmacopeia: National Formulary (USP 36 NF31), published 2013.

[0185] The following examples are intended to illustrate the invention, but are not intended to limit the invention in any way. [Example]

[0186] Example 1: Preclinical evaluation of fixed-dose combinations in a rat model of TBI The drug combinations described herein are evaluated for antiepileptogenic or disease-modifying activity in a rat model of fluid percussion injury (FPI)-induced TBI, where rostral parasagittal FPI in rats reliably induces perilesional epileptic lesions in the neocortex within weeks of injury.

[0187] In this model, male Sprague-Dawley rats (32-36 days old) undergo mechanical ventilation under halothane anesthesia. A 3 mm diameter craniotomy is performed, centered 2 mm posterior to bregma and 3 mm from the midline. The animal is then removed from the ventilator, and an 8 ms pressure pulse (3.4 or 3.7 atm) is applied via the FPI device. Ventilation is resumed after a uniform 10 s period of post-traumatic apnea. Epidural electrodes for seizure monitoring are incorporated into an acrylic headset firmly fixed to the skull. Five epidural electrodes are implanted using a procedure designed to avoid damage to the underlying neocortex. The entire EEG recording assembly is placed in dental acrylic and fixed to the skull. Video-electrocorticography (ECoG) monitoring is performed throughout the procedure and for up to 3 months after the end of treatment, including the first 4 weeks and drug-free period after treatment. Drug combination treatment begins 15 minutes to 8 hours after injury and continues for 3 to 4 weeks, the latency period before epilepsy develops in this model. Drug-treated rat groups are compared to a vehicle ("placebo")-treated group using a randomized, blinded protocol.

[0188] Only drug combinations that are effective in the TBI rat model will be included in clinical trials. Antiepileptogenic efficacy of drug treatment will be defined by a significant difference in the incidence of seizure-free rats between drug-treated rat groups versus vehicle-treated rat groups using stand statistical methods. Seizure activity will be assessed using EEG measurements performed after the end of treatment. Disease-modifying efficacy of drug treatment will be defined by a significant reduction in one or more of the following parameters: frequency, severity, or duration of spontaneous seizures in the drug-treated group compared to the vehicle-treated group. In rat studies, plasma drug levels will be measured to enable drug dose selection for clinical trials.

[0189] Example 1a The above model was applied to a combination of topiramate, levetiracetam, and deferoxamine. The following doses were administered: levetiracetam, 200 mg / kg, three times daily (tid) via the intraperitoneal route (ip), topiramate, 30 mg / kg iptid, and deferoxamine, 40 mg / kg iptid. Treatment began 60 minutes after fluid injury and continued for 21 days. Electrographic seizure activity was recorded 1 and 5 weeks after the end of treatment. The selected doses were in accordance with the high-dose treatment scheme described above. The administration route was intraperitoneal for the first 5 days, followed by oral administration for the remainder of the treatment period.

[0190] The same combinations are also tested using a low dose treatment scheme: levetiracetam: 100 mg / kg tid, topiramate 15 mg / kg tid, deferoxamine 20 mg / kg qd.

[0191] Example 1b The above model is applied to a combination of topiramate, levetiracetam, and atorvastatin. The following doses are administered: levetiracetam 200 mg / kg ipid, topiramate 30 mg / kg ipid, and atorvastatin 10 mg / kg ip or po, tid. Treatment begins 60 minutes after fluid injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal.

[0192] The same combinations are also tested using a low dose treatment scheme: levetiracetam: 100 mg / kg tid, topiramate 15 mg / kg tid, atorvastatin 5 mg / kg tid.

[0193] Administration of a high-dose regimen of 200 mg / kg levetiracetam, 30 mg / kg topiramate, and 10 mg / kg atorvastatin was well tolerated. After fluid percussion injury (FPI) in vehicle-treated rats (15 rats injured), one rat died within 1 hour of the injury (6.67% mortality rate). The remaining animals survived and were counted as survivors from 1 week onward.

[0194] In the treatment group, animals were exposed to FPI, and treatment began 1 hour after injury and was administered three times daily. Two animals in this group died within 1 hour of the injury; these deaths were unrelated to treatment. All treated animals exhibited normal grooming behavior and activity levels. No animals were observed to be in distress. It was concluded that this combination was well tolerated. Analysis of plasma samples from animals administered this combination revealed that three doses per day resulted in therapeutic anticonvulsant plasma exposures for levetiracetam and topiramate, as measured by the area under the plasma level-time curve. For atorvastatin, exposure duration was demonstrated for 24 hours. Mean plasma levels reached 26,800, 1,900, and 8.5 ng / ml for levetiracetam, topiramate, and atorvastatin, respectively, 8 hours after the first dose (just before the next dose).

[0195] After FPI, animals were evaluated for electrographic seizure frequency and total seizure duration four weeks after one week of treatment. One week of treatment with the triple combination resulted in a reduction in the number of electrographic seizures per animal and the total seizure duration per animal, indicating that short-term treatment with the triple combination starting after injury provides antiepileptogenic effects in a predictive animal model of traumatic brain injury.

[0196] Example 1c The above model is applied to the combination of topiramate and levetiracetam. The following doses are administered: levetiracetam 200 mg / kg iptid, topiramate 30 mg / kg iptid. Treatment begins 60 minutes after fluid injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme as described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0197] Example 1d The above model can be applied to the combination of topiramate, levetiracetam, and ceftriaxone. The following doses are administered: levetiracetam 200 mg / kg iptid, topiramate 30 mg / kg iptid, and ceftriaxone 200 mg / kg iptid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0198] Example 1e The above model can be applied to a combination of topiramate, levetiracetam, and gabapentin. The following doses will be administered: levetiracetam 200 mg / kg iptid, topiramate 30 mg / kg iptid, and gabapentin 200 mg / kg iptid. Treatment will begin 60 minutes after the fluid percussion injury and continue for 21 days. Electrographic seizure activity will be recorded 1 and 5 weeks after the end of treatment. The selected dose will be a high-dose treatment scheme as described above. The route of administration will be intraperitoneal. The same combination will also be tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regimen. The gabapentin in this combination may be replaced by a high dose of the gabapentin derivative pregabalin at 100 mg / kg iptid.

[0199] Example 1f The above model is applied to a combination of topiramate, levetiracetam, and pregabalin. The following doses are administered: levetiracetam 200 mg / kg iptid, topiramate 30 mg / kg iptid, and pregabalin 60 mg / kg iptid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0200] Example 1g The above model is applied to a combination of topiramate, levetiracetam, and ceftriaxone. The following doses are administered: levetiracetam 200 mg / kg iptid, topiramate 30 mg / kg iptid, and ceftriaxone 200 mg / kg iptid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0201] Example 1h The above model is applied to a combination of topiramate, levetiracetam, and α-tocopherol. The following doses are administered: levetiracetam 200 mg / kg ipid, topiramate 30 mg / kg ipid, and α-tocopherol 250 mg / kg subcutaneously tid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The selected dose is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, in which each dose is administered at 50% of the high-dose regime.

[0202] Example 1i The above model is applied to a combination of levetiracetam, deferoxamine, and melatonin. The following doses are administered: levetiracetam 200 mg / kg iptid, deferoxamine 40 mg / kg iptid, and melatonin 10 mg / kg sctid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0203] Example 1j The above model is applied to a combination of levetiracetam, deferoxamine, and celecoxib. The following doses are administered: levetiracetam 200 mg / kg iptid, deferoxamine 40 mg / kg iptid, and celecoxib 10 mg / kg sctid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0204] Example 1k The above model was applied to a combination of levetiracetam, deferoxamine, gabapentin, and fingolimod. The following doses were administered: levetiracetam 200 mg / kg iptid, deferoxamine 40 mg / kg iptid, gabapentin 200 mg / kJ sc, and fingolimod 1 mg / kg iptid. Treatment began 60 minutes after the fluid percussion injury and continued for 21 days. Electrographic seizure activity was recorded 1 and 5 weeks after the end of treatment. The selected doses were the high-dose treatment scheme described above. The route of administration was intraperitoneal. The same combinations were also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0205] Example 1l The above model is applied to a combination of levetiracetam, deferoxamine, and ceftriaxone. The following doses are administered: levetiracetam 200 mg / kg iptid, deferoxamine 40 mg / kg iptid, and ceftriaxone 200 mg / kg tid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0206] Example 1m The above model is applied to the combination of levetiracetam and perampanel. The following doses are administered: levetiracetam: 200 mg / kg iptid and perampanel: 2 mg / kg tid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0207] Example 1n The above model is applied to a combination of levetiracetam, perampanel, and ceftriaxone. The following doses are administered: levetiracetam 200 mg / kg iptid, perampanel 2 mg / kg iptid, and ceftriaxone 200 mg / kg tid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0208] Example 1o The above model is applied to a combination of levetiracetam, parecoxib, and anakinra. The following doses are administered: levetiracetam 200 mg / kg iptid, parecoxib 1 mg / kg iptid, and anakinra 100 mg / kg tid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The selected dose is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, in which each dose is administered at 50% of the high-dose regime.

[0209] Example 1p The above model is applied to the combination of levetiracetam and phenobarbital. The following doses are administered: levetiracetam: 200 mg / kg ipid and phenobarbital: 15 mg / kg twice daily (bid) ip after an initial bolus dose of 25 mg / kg ip. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0210] Example 1q The above model is applied to the combination of levetiracetam and agmatine. The following doses are administered: levetiracetam 200 mg / kg iptid and agmatine 100 mg / kg iptid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0211] Example 1r The above model is applied to a combination of levetiracetam, melatonin, perampanel, atorvastatin, and gabapentin. The following doses are administered: levetiracetam 200 mg / kg iptid, melatonin 10 mg / kg sctid, perampanel 2 mg / kg iptid, atorvastatin 10 mg / kg ip or po tid, and gabapentin 200 mg / kg iptid. Gabapentin in this combination may be replaced with a higher dose of the gabapentin derivative pregabalin at 100 mg / kg ietid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The selected dose is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combinations are also tested using a low dose treatment scheme in which each dose is administered at 50% of the high dose regime.

[0212] Example 1s The above model was applied to a combination of levetiracetam, N-acetylcysteine, ceftriaxone, losartan, and gabapentin. The following doses were administered: levetiracetam 200 mg / kg iptid, N-acetylcysteine ​​300 mg / kg iptid, ceftriaxone 200 mg / kg iptid, losartan 10 mg / kg iptid, and gabapentin 200 mg / kg iptid. The gabapentin in this combination may be replaced with a higher dose of the gabapentin derivative pregabalin at 100 mg / kg iptid. Treatment began 60 minutes after the fluid percussion injury and continued for 21 days. Electrographic seizure activity was recorded 1 and 5 weeks after the end of treatment. The selected dose was the high-dose treatment scheme described above. The route of administration was intraperitoneal. The same combinations are also tested using a low dose treatment scheme in which each dose is administered at 50% of the high dose regime.

[0213] Example 1t The above model is applied to a combination of levetiracetam, sulforaphane, perampanel, losartan, and gabapentin. The following doses are administered: levetiracetam 200 mg / kg iptid, sulforaphane 5 mg / kg iptid, perampanel 10 mg / kg iptid, losartan 10 mg / kg iptid, and gabapentin 200 mg / kg iptid. In this combination, gabapentin may be replaced with a higher dose of the gabapentin derivative pregabalin at 100 mg / kg iptid. Treatment begins 60 minutes after the fluid percussion injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The selected dose is the high-dose treatment scheme described above. The route of administration is intraperitoneal. The same combination is also tested using a low-dose treatment scheme, with each dose administered at 50% of the high-dose regime.

[0214] Example 1u The above model is applied to a combination of levetiracetam, ceftriaxone, and atorvastatin according to a low-dose regimen. The following doses are administered: levetiracetam (60 mg / kg tid), atorvastatin (3 mg / kg tid), and ceftriaxone (60 mg / kg tid). Treatment begins 60 minutes after fluid injury and continues for 21 days. Electrographic seizure activity is recorded 1 and 5 weeks after the end of treatment. The dose selected is a low-dose treatment scheme. The route of administration is intraperitoneal. The same combination is also tested using a high-dose treatment scheme: 200 mg / kg levetiracetam, 10 mg / kg atorvastatin, and 200 mg / kg ceftriaxone.

[0215] Example 1v The above model is applied according to Examples 1a-1t, where levetiracetam at a dose of 200 mg / kg iptid is replaced by brivaracetam at 10 mg / kg iptid or etiracetam at 200 mg / kg iptid.The same combinations are also tested using a low-dose treatment scheme, where each compound is administered at 50% of the high-dose regime.

[0216] Brivaracetam, etiracetam, and padosevonil may be used in place of levetiracetam in all the above examples, with the respective doses adjusted accordingly.

[0217] Example 2: Evaluation of combination therapy in the controlled cortical impact (CCI) model Ex vivo assessment of epileptogenic potential in neocortical slices after controlled cortical impact (CCI) injury in young rats is also an appropriate model for evaluating the potential effects of drug combinations on epileptogenesis. In this model, rats are subjected to a severe CCI injury (2.0 mm deep) and then a single dose of a triple combination of levetiracetam 200 mg / kg, topiramate 30 mg / kg, and atorvastatin 10 mg / kg is administered immediately after injury. Control animals are also subjected to CCI injury but receive only vehicle injections at the same volume. Two to three weeks after injury, cortical hyperexcitability and epileptiform activity are assessed by in vitro and ex vivo electrophysiological recordings of neocortical brain slices from treated and control animals. Coronal slices of somatosensory cortex (400 μm; 5 slices / rat) are prepared from areas adjacent to the injury site and maintained at 31.0 ± 1.0 °C in an interface recording chamber. Slices are examined for epileptiform activity by intracellular and extracellular recordings obtained from cortical layer V. Evoked responses are elicited by a single, brief electrical stimulus (200 μs) applied to layer VI.

[0218] Post-lesion administration of a single dose of the triple combination of levetiracetam, topiramate, and atorvastatin suppressed post-traumatic epilepsy in the rat neocortex after CCI injury. Slices from treated rats showed much fewer episodes of evoked and spontaneous epileptiform activity than slices from sham-treated control rats.

[0219] Evoked epileptiform discharges were observed in slices from all (100%) sham-treated rats, and at least one slice from each animal showed epileptiform activity. Spontaneous epileptiform discharges were recorded in slices from 75% of sham-treated animals. In comparison, significantly fewer treated animals had evoked epileptiform activity in their slices, and spontaneous epileptiform discharges were almost completely suppressed.

[0220] The combination of levetiracetam (60 mg / kg), atorvastatin (3 mg / kg) and ceftriaxone (60 mg / kg) was also effective in this model.

[0221] Example 3: Preclinical Evaluation of Fixed-Dose Combinations in the Controlled Cortical Impact (CCI) Mouse Model of TBI Drug combinations are also evaluated in a controlled cortical impact (CCI) mouse model of TBI. Male and female adult mice are subjected to severe CCI injury. Mice are anesthetized with 3% isoflurane, their heads shaved, and secured in a stereotaxic frame (Kopf, Tujunga, CA) on a heating pad to maintain body temperature. Mice are maintained under 3% isoflurane delivered via a nose cone. A 3 mm craniotomy is performed in the right motor cortex using a handheld dental drill. Bone powder is removed, and the bone flap is then carefully removed without damaging the dura mater. The injury is produced using a 2 mm stainless steel piston attached to a CCI device (Leica Biosystems, model number 39463920) at a speed of 4 m / s, a depth of 1.2 mm, and an impact duration of 300 ms. After injury, the skin is sutured using Vicryl sutures (Ethicon, Mokena, IL, USA). Within an 8-12 week delay period, 30-50% of all injured mice develop spontaneous generalized seizures at a rate of 1-3 seizures per day. Antiepileptogenic efficacy of drug treatment is defined by a significant difference in the incidence of seizure-free mice between drug-treated versus vehicle-treated groups. Disease-modifying efficacy of drug treatment is defined by a significant reduction in the frequency, severity, or duration of spontaneous seizures in drug-treated groups compared with vehicle-treated groups.

[0222] This model will be used to test preferred combinations as described in Examples 1a-u, as well as other preferred combinations. The doses used in mice in this study will correspond to those used in rat studies and are expressed as mg / kg body weight.

[0223] Example 4: Clinical evaluation of drug combinations The drug combinations described herein (see Examples 1a-d) are evaluated for anti-epileptogenic or disease-modifying activity in patients with traumatic brain injury (TBI) who are at high risk of developing epilepsy after traumatic brain injury (post-traumatic epilepsy, PTE).

[0224] In the first safety ("Phase 1") study, the safety and tolerability of the described combination will be tested in patients at high risk (20-30%) for developing PTE after TBI. These patients are those whose TBI resulted in intracranial hemorrhage (single or multiple sites), skull fracture (single or multiple sites), or entry of a traumatic object (e.g., a gunshot) or skull fragments into the brain, and who have "early" seizures after TBI. Early onset of seizures is defined as seizures occurring within 7 days after injury. These patients will be treated with the described drug combination. The selected drug doses correspond to the high-dose regimens described above. Thus, levetiracetam will be administered at doses ranging from 55 mg / kg to a maximum of 6,000 mg / day, topiramate at 400 mg / day, and deferoxamine at doses ranging from 62 mg / kg / day to a maximum of 6,000 mg / day. If atorvastatin is used in place of deferoxamine, the atorvastatin dose is 80 mg / day.

[0225] Treatment with the above drug combination is initiated within 8 hours of injury as the preferred intervention timeframe, although a delay of up to 24-48 hours after injury is also acceptable. Treatment with the above drug combination is continued for 28 days. Medications are administered intravenously for the first 1-7 days of treatment. Medication is then administered intravenously, orally, nasogastricly, or by other treatment routes, depending on the patient's state of consciousness and health. Blood levels of the drug are determined and compared to those observed in animals with positive FPI tests. Evaluation of the outcome of the study may include side effects of the described combination and blood levels of the drug.

[0226] This phase of the study will establish the safety and tolerability of the drug combination and, using human equivalent dosing, may confirm whether the blood levels of the drug achieved in patients with TBI are comparable to those of animals that performed well in preclinical FPI / PTE studies.

[0227] Based on the results of the safety study, dosage adjustments may be made; if tolerated, a useful dose is tested in a larger patient population in an efficacy study (a pivotal "Phase 3" efficacy study). Such a Phase 3 study is one of several studies to test the efficacy, safety, and tolerability of the combination described herein. Patients at high risk (e.g., 20-30%) for developing PTE after TBI are evaluated. These patients are typically TBI patients whose TBI resulted in intracranial hemorrhage (single or multiple sites), skull fracture (single or multiple sites), or entry of a traumatic object (e.g., a bullet) or skull fragment into the brain, and who have an "early" seizure following TBI, defined as a seizure occurring within 7 days of injury.

[0228] Such patients are treated with the drug combination described herein or a placebo. This Phase 3 study may follow a standard Phase 3 design of a double-blind, placebo-controlled, randomized trial. Patients are randomized in a double-blind fashion to receive treatment with either the drug combination described or a placebo. Treatment begins within 8 hours of injury as a preferred time frame, although this time frame may be extended to 24-48 hours after injury. Treatment is typically administered over a period of 1-3 months.

[0229] The drug is administered intravenously for the first 1 to 7 days of treatment, after which the drug is administered intravenously, orally, nasogastricly, or by other treatment routes depending on the patient's individual health condition.

[0230] Because most PTEs (e.g., 80%) begin within two years of injury, patients are evaluated after treatment has ended, for example, up to two years after injury. Evaluation of study outcomes may include the incidence of PTEs at one and two years after injury, treatment side effects, discontinuation of treatment due to side effects, mortality, and drug blood levels. These outcomes are compared between patients treated with the described drug combination and patients treated with a placebo. Standard statistical procedures will be used to evaluate study outcomes. The described drug combination will be considered effective in preventing epilepsy, i.e., antiepileptogenic, if the incidence of PTEs at two years after injury is statistically reduced in patients treated with the drug combination compared to patients treated with a placebo, or if the presence of validated biomarkers of PTE is statistically reduced in patients treated with the drug combination compared to patients treated with a placebo.

[0231] The severity of epilepsy in TBI patients who develop epilepsy may also be assessed. The severity of epilepsy will be determined by the frequency of seizures per unit time (e.g., 28 days) and by seizure type, defined in order of increasing severity as focal seizures without loss of consciousness, focal seizures with loss of consciousness, and focal seizures with loss of consciousness and secondary generalized tonic-clonic seizures. The severity of epilepsy in TBI patients who develop epilepsy will be compared using standard statistical procedures between TBI patients treated with the drug combination and TBI patients treated with a placebo. A drug combination will be considered to have disease-modifying properties if the severity of PTE is statistically significantly lower in TBI patients treated with the drug combination compared to TBI patients treated with a placebo.

[0232] Example 4a The above model will be applied to a combination of topiramate, levetiracetam, and deferoxamine. The following doses will be administered: levetiracetam 55 mg / kg / day up to a maximum of 6,000 mg / patient / day; topiramate 400 mg / day and deferoxamine 62 mg / kg / day up to a maximum of 6,000 mg / day. The same combination will also be tested using a lower-dose treatment scheme: levetiracetam 30 mg / kg / day, topiramate 100 mg / day, and deferoxamine 30 mg / kg / day. Treatment will preferably begin within 8 hours of injury, but if 8 hours is deemed unfeasible, it may be initiated 24 to 48 hours after injury. Treatment will be continued for 1 to 3 months. Treatment will be administered intravenously for the first 1 to 7 days of treatment. Treatment will be administered intravenously, orally, nasogastricly, or by other routes of treatment, depending on the patient's individual health status, after the initial 1-7 days of treatment. Patients may continue to be evaluated after treatment has ended for a total of two years from injury. Study outcome assessments may include the incidence and severity of PTE at one and two years post-injury, treatment side effects, treatment discontinuation due to side effects, mortality, and drug blood levels. These outcomes will be compared between patients treated with the described drug combination and those treated with placebo. Standard statistical procedures will be used to evaluate study outcomes.

[0233] Example 4b The above model will be applied to a combination of topiramate, levetiracetam, and atorvastatin. The following doses will be administered: levetiracetam 55 mg / kg / day up to a maximum of 6,000 mg / patient / day, topiramate 400 mg / day, and atorvastatin 80 mg / day. The same combination will also be tested using a lower-dose treatment scheme of levetiracetam 30 mg / kg / day, topiramate 100 mg / day, and atorvastatin 20 mg / day. Treatment will preferably begin within 8 hours of injury, but if 8 hours is deemed unfeasible, it may be initiated 24 to 48 hours after injury. Treatment will be continued for 1 to 3 months. Treatment will be administered intravenously for the first 1 to 7 days. After the first 1 to 7 days, treatment will be administered intravenously, orally, nasogastricly, or by other routes depending on the patient's individual health status. Patients may continue to be evaluated after treatment has ended for a total of two years from injury. Study outcome assessments may include the incidence and severity of PTE at one and two years post-injury, treatment side effects, discontinuation of treatment due to side effects, mortality, and drug blood levels. These outcomes will be compared between patients treated with the described drug combination and those treated with placebo. Standard statistical procedures will be used to assess study outcomes.

[0234] Example 4c The above model will be applied to the combination of topiramate and levetiracetam, administered at the following doses: levetiracetam: 55 mg / kg / day up to a maximum of 6,000 mg / patient / day, and topiramate: 400 mg / day. The same combination will also be tested using a lower-dose treatment scheme: levetiracetam: 30 mg / kg / day and topiramate: 100 mg / day. Treatment will preferably begin within 8 hours of injury, but if 8 hours is deemed unfeasible, it may begin 24-48 hours after injury. Treatment will be continued for 1-3 months. Treatment will be administered intravenously for the first 1-7 days of treatment. After the first 1-7 days of treatment, treatment will be administered intravenously, orally, nasogastricly, or by other routes depending on the patient's individual health status. Patients may continue to be evaluated after completion of treatment for a total of 2 years from injury. The outcome assessment of the study may include the incidence and severity of PTE at 1 and 2 years after injury, side effects of treatment, discontinuation of treatment due to side effects, mortality, and blood levels of drug.These outcomes will be compared between patients treated with the drug combinations described and patients treated with placebo.Standard statistical procedures will be used to assess the outcome of the study.

[0235] Example 4d The above model will be applied to a combination of topiramate, levetiracetam, and ceftriaxone. The following doses will be administered: levetiracetam: 55 mg / kg / day up to a maximum of 6,000 mg / patient / day; topiramate: 400 mg / kg / day; and ceftriaxone: 4 g / day. The same combination will also be tested using a lower-dose treatment scheme: levetiracetam: 30 mg / kg / day, topiramate: 100 mg / day, and ceftriaxone: 2 g / day. Treatment will preferably begin within 8 hours of injury, but if 8 hours is deemed unfeasible, it may be initiated 24 to 72 hours after injury. Treatment will be continued for 1 to 3 months. Treatment will be administered intravenously for the first 1 to 7 days. After the first 1 to 7 days, treatment will be administered intravenously, orally, nasogastricly, or by other routes depending on the patient's individual health status. Patients may continue to be evaluated after treatment has ended for a total of two years from injury. Study outcome assessments may include the incidence and severity of PTE at one and two years post-injury, treatment side effects, discontinuation of treatment due to side effects, mortality, and drug blood levels. These outcomes will be compared between patients treated with the described drug combination and those treated with placebo. Standard statistical procedures will be used to assess study outcomes.

[0236] Examples 4e to 4u Each preferred combination according to Examples 1e-1u is also tested in patients as described in Examples 4a-4d. The doses at which the individual drugs administered in the combination in these studies are best tolerated in individual patients are listed below. The respective doses were agmatine 3.56 g / day; anakinra 8 mg / kg / day; brivaracetam 400 mg / day; ceftriaxone 4 g / day; deferoxamine 62 mg / kg / day up to 6000 mg / day; fingolimod 1.25 mg / day; gabapentin 3200 mg / day; ifenprodil 40 mg / day; levetiracetam 55 mg / kg up to 6000 mg / day; losartan 100 mg / day; melatonin 20 mg / day; memantine 28 mg / day; N-acetylcysteine ​​300 mg / kg / day; padevonil 800 mg / day; perampanel 24 mg / day; phenobarbital 200 mg; sulforaphane 60 mg / day; and topiramate 400 mg. mg / day; valproate, 3,000 mg / day; and α-tocopherol, 15 mg / day. In the low-dose approach, the effective dose of each member of the fixed-dose combination is selected to be 50-75% of the maximum approved dose for administration to humans as a single drug.The respective doses were as follows: agmatine, 1.78–2.67 g / day; anakinra, 4–6 mg / kg / day; brivaracetam, 200–300 mg / day; ceftriaxone, 2–3 g / day; deferoxamine, 31–4500 mg / kg / day; fingolimod, 0.625–0.94 mg / day; gabapentin, 1600–2400 mg / day; ifenprodil, 20–30 mg / day; levetiracetam, 27.5–41 mg / kg / day up to 3000–4500 mg / day; losartan, 50–75 mg / day; melatonin, 10–15 mg / day; memantine, 14–21 mg / day; N-acetylcysteine, 150–225 mg / kg / day; and padosevonil, 200 mg. mg / day; perampanel, 12–18 mg / day; phenobarbital, 100–150 mg / day; sulforaphane, 30–45 mg / day; topiramate, 100–300 mg / day; valproate, 1500–2,250 mg / day; and α-tocopherol, 7.5–11.25 mg / day.

[0237] Example 5: Preparation of a liquid (aqueous) solution of topiramate using meglumine solution as a vehicle Meglumine (CAS No. 6284-40-8) solutions ranging in concentration from 0.3% (w / v) to 5% (w / v) were prepared using purified water by placing the required amount of meglumine in a 25 mL glass graduated cylinder and adding purified water to a final volume of 25 mL. For the 0.3% (w / v) solution, 75 mg of meglumine powder was dissolved in purified water to a final volume of 25 mL. For the 5% (w / v) solution, 1250 mg of meglumine powder was dissolved in purified water to a final volume of 25 mL. Meglumine dissolved immediately in water. The solution was stirred or shaken before use to ensure homogeneous distribution.

[0238] To prepare the topiramate solution, topiramate was weighed into a 25 mL glass beaker at the amount per 10 mL volume shown in the table below. The meglumine solution was added to approximately the final volume (approximately 9.5 mL), and the solution was stirred using a magnetic stirrer for approximately 20 minutes until a clear solution was obtained.

[0239] [Table 1] 1 Dissolution was attempted by constant stirring and moderate heat (50°C) application for 30 minutes. Near complete dissolution was achieved at the end of the 30-minute stirring period, but the solution was not stable and precipitation occurred after cooling and overnight storage at 2-8°C.

[0240] The data clearly demonstrate that meglumine solubilizes topiramate in a concentration-dependent manner. The solubility of topiramate is directly proportional to the meglumine concentration, as shown in the figure.

[0241] After dissolution, the pH of Formulations 5.2–5.5 was acidified by adding a few drops of acetic acid or 0.1 M hydrochloric acid (HCl) under constant stirring while the pH was continuously monitored using a pH meter. The pH was easily adjusted to reach values ​​between 6.5 and 8.5. The amount of HCl required was proportional to the concentration of meglumine used; the highest amount of HCl was required to prepare a 5% (w / v) meglumine solution, while a few drops per 10 mL was sufficient for Formulation 5.2. After pH adjustment, the volume was adjusted to 10 mL with the respective meglumine vehicle solution.

[0242] The solutions were then filtered through a 0.2 μm sterile filter prior to administration to ensure sterility prior to use. After preparation and pH adjustment, Formulations 5.1-5.5 were found to be stable with no precipitation within 48 hours whether stored at room temperature or 2-8°C. Long-term storage over a 4-week period showed no precipitation within 4 weeks whether stored at 2-8°C or at room temperature.

[0243] Example 6: Preparation of an aqueous solution of topiramate using a solution of meglumine and polysorbate 80 as a vehicle Polysorbate 80 (CAS No. 9005-65-6) was further used in the preparation of liquid formulations of topiramate. In this example, the solubility of topiramate was investigated. The solubility of topiramate solutions was also investigated in the presence of 0.3% (w / v) polysorbate 80 solution.

[0244] The following procedure was followed: A solution of 0.3% meglumine (CAS No. 6284-40-8) and 0.3% polysorbate 80 (CAS No. 9005-65-6) in purified water was prepared by placing 75 mg of meglumine in a 25 mL glass graduated cylinder and adding purified water to a final volume of approximately 25 mL. 75 mg of polysorbate 80 was then added, and the solution was carefully shaken to allow for complete dissolution. The glass cylinder was filled to 25 mL with purified water. The solution was stirred or shaken before use to ensure homogeneity.

[0245] A 10 mg / mL topiramate solution was prepared using the above solution. To this end, 100 mg of topiramate was added to a glass vial, and a solution of 0.3% meglumine and 0.3% polysorbate 80 was added to a final volume of 10 mL. The solution was stirred until all the topiramate dissolved within a few minutes. The pH of the solution (approximately pH 8.0) was adjusted to a range of 6.5–8.5 with a few drops of 0.1 M HCl solution or acetic acid. The solution was stable for several days at room temperature or 2–8°C without crystallization or precipitation.

[0246] Example 7: Preparation of aqueous solutions of topiramate and levetiracetam using meglumine as a vehicle with or without polysorbate 80 The following procedure was followed: A solution of 0.3% meglumine (CAS No. 6284-40-8) in purified water was prepared by adding 75 mg of meglumine to a 25 mL glass graduated cylinder and adding purified water to a final volume of approximately 25 mL. The glass cylinder was filled with purified water to a final volume of 25 mL. In a separate vial, a solution of 0.3% meglumine and 0.3% polysorbate 80 was prepared by mixing 75 mg of meglumine and 75 mg of polysorbate 80 with 25 mL of purified water. The solution was stirred or shaken before use to ensure homogeneity.

[0247] Using the above solution, a 10 mg / mL topiramate solution containing 50–75 ng / mL levetiracetam was prepared. To this end, 100 mg of topiramate and 500, 670, or 750 mg of levetiracetam were added to a glass vial. Then, 0.3% meglumine solution or a 0.3% meglumine + 0.3% polysorbate 80 solution was added to a final volume of 10 mL. The solution was carefully stirred until the substance was completely dissolved. Levetiracetam dissolved quickly, while topiramate took several minutes to dissolve. The pH of the solution (close to pH 8.0) was adjusted to the range of 6.5–8.5 with a few drops of 0.1 M HCl solution or acetic acid. The solution was stable for several days at room temperature or 2–8°C without crystallization or precipitation.

[0248] [Table 2]

[0249] In Formulations 7.1 to 7.6, levetiracetam may be replaced with brivaracetam. The brivaracetam dose is less than the levetiracetam dose. For example, 30 to 50 mg / 10 mL of brivaracetam may be used instead of 500 mg / 10 mL of levetiracetam; 45 to 67 mg / 10 mL of brivaracetam may be used instead of 670 mg / 10 mL of levetiracetam; and 50 to 75 mg / 10 mL of brivaracetam may be used instead of 750 mg / 10 mL of levetiracetam. Brivaracetam is water-soluble.

[0250] The formulation was stable for several days at room temperature and at 2-8° C. No precipitation was observed in meglumine solutions with or without polysorbate 80.

[0251] Example 8: Preparation of aqueous solutions of topiramate, levetiracetam, and atorvastatin sodium with a vehicle containing meglumine, with or without polysorbate 80 In further experiments, a solution containing topiramate (10 mg / mL), levetiracetam (75 mg / mL), and atorvastatin sodium (3.47 mg / mL), equivalent to an atorvastatin concentration of 3.33 mg / mL, was prepared and evaluated, along with a 3% (w / v) meglumine solution and a 0.3% (w / v) meglumine + 0.3% (w / v) polysorbate 80 solution.

[0252] Meglumine and meglumine plus polysorbate 80 solutions were prepared as described in Example 7.

[0253] In two separate glass beakers, 100 mg of topiramate, 750 mg of levetiracetam, and 34.7 mg of atorvastatin sodium were mixed. The meglumine solution was added to the first beaker until the total volume reached 10 mL, and the meglumine + polysorbate 80 solution was added to the second beaker until the total volume reached 10 mL. In the first beaker, the solid dissolved after approximately 20 minutes of stirring. Dissolution was faster in the second beaker, with the solution becoming clear after approximately 5 minutes of stirring. In two follow-up experiments, the atorvastatin concentration was lowered to 2 mg / mL, which resulted in faster overall dissolution for both formulations.

[0254] [Table 3]

[0255] After approximately 20 hours of storage under ambient conditions, precipitation was observed in Formulations 8.1, 8.6, 8.7, and 8.8, regardless of meglumine concentration. Such observations indicate that meglumine did not improve the solubility of atorvastatin. Similar precipitation was observed in Formulation 8.5, indicating that atorvastatin precipitates after approximately 20 hours of dissolution in water.

[0256] Polysorbate 80 (formulations 8.2 and 8.4) improved the stability of the solutions. In formulation 8.2, no precipitation was observed for 48 hours, followed by slight precipitation, whereas in formulation 8.4, which contained less atorvastatin, the solution remained stable at room temperature for several days. The effect of adding 0.1% polysorbate 80 was less pronounced. It improved the dissolution rate, but the first precipitation was still observed after approximately 24 hours (formulation 8.9).

[0257] In Formulations 8.1-8.4 and 8.6-8.9, levetiracetam may be replaced with brivaracetam. The brivaracetam dose is typically less than the levetiracetam dose. For example, 30-50 mg / 10 mL of brivaracetam may be used instead of 500 mg / 10 mL of levetiracetam; 45-67 mg / 10 mL of brivaracetam may be used instead of 670 mg / 10 mL of levetiracetam; and 50-75 mg / 10 mL of brivaracetam may be used instead of 750 mg / 10 mL of levetiracetam. Brivaracetam is water-soluble.

[0258] The pH of formulations 8.1, 8.2, 8.3, 8.3., and 8.9 was adjusted to 6.5-8.5 with a few drops of 0.1% HCl or acetic acid. The pH of formulations 8.6, 8.7, and 8.8 was adjusted to approximately 8.5.

[0259] Example 9 Formulations 9.1-9.10 shown in Table 4 can be prepared by combining topiramate, levetiracetam, and atorvastatin in the required proportions. For example, approximately 0.3% (w / v) meglumine can be used to dissolve a 100 mg / mL concentration of topiramate, so the formulations can be prepared as aqueous solutions containing 0.3% (w / v) or more meglumine. For example, the meglumine concentration can range from 0.3% (w / v) to 2.5% (w / v). The polysorbate 80 concentration can vary from 0.0% (i.e., no polysorbate 80) to 1% (w / v), which can aid in the dissolution rate and stability of the resulting solution. Atorvastatin is an optional component of the formulation.

[0260] If a high dosage volume is preferred, the formulation can be prepared in a higher volume, such as 20 or 25 mL, instead of 10 mL. Alternatively, if a high dosage volume is preferred, the formulation can be prepared in a higher volume, such as up to 250 mL (e.g., 20 mL, 25 mL, 40 mL, 50 mL, 60 mL, 75 mL, 80 mL, 100 mL, 120 mL, 125 mL, 140 mL, 150 mL, 160 mL, 175 mL, 180 mL, 200 mL, 220 mL, 225 mL, 240 mL, or 250 mL). The amount of each compound can be reduced proportionally, and the concentration of meglumine can also be reduced proportionally. For example, for such a high-volume formulation, the active ingredients in Formulation 9.1 can be, for example: Topiramate: 100 mg / 20 mL or 100 mg / 25 mL; Levetiracetam: 750 mg / 20 mL or 750 mg / 25 mL; and Atorvastatin: 20 mg / 20 mL or 20 mg / 25 mL It could be.

[0261] Alternatively, the formulation may be diluted after preparation with an acceptable diluent, such as purified water or purified water containing 0.1-1% (w / v) meglumine.

[0262] In each case, the pH may be adjusted to a range of 5.5 to 8.5, preferably 6.5 to 8.5.

[0263] [Table 4] * The unit is mg.

[0264] Example 10 Formulations 10.1 to 10.10 can be prepared by combining topiramate, brivaracetam, and atorvastatin in the required ratios. For example, approximately 0.3% (w / v) meglumine can be used to dissolve 100 mg / mL of topiramate, so the formulations can be prepared as aqueous solutions containing 0.3% (w / v) or more meglumine. For example, the meglumine concentration can range from 0.3% (w / v) to 2.5% (w / v). The polysorbate 80 concentration can vary from 0.0% (no polysorbate 80) to 1% (w / v).

[0265] If a high dosage volume is preferred, the formulation can be prepared in a higher volume, such as 20 or 25 mL, instead of 10 mL. Alternatively, if a high dosage volume is preferred, the formulation can be prepared in a higher volume, such as up to 250 mL (e.g., 20 mL, 25 mL, 40 mL, 50 mL, 60 mL, 75 mL, 80 mL, 100 mL, 120 mL, 125 mL, 140 mL, 150 mL, 160 mL, 175 mL, 180 mL, 200 mL, 220 mL, 225 mL, 240 mL, or 250 mL). The amount of each compound can be reduced proportionally, and the concentration of meglumine can also be reduced proportionally. For example, for such a high-volume formulation, the active ingredients in formulation 10.1 can be, for example: Topiramate: 100 mg / 20 mL or 100 mg / 25 mL; Brivaracetam: 50 mg / 20 mL or 50 mg / 25 mL; Atorvastatin: 20 mg / 20 mL or 20 mg / 25 mL It could be.

[0266] Alternatively, the formulation may be diluted after preparation with an acceptable diluent, such as purified water or purified water containing 0.1-1% (w / v) meglumine.

[0267] In each case, the pH may be adjusted to a range of 5.5 to 8.5, preferably 6.5 to 8.5.

[0268] [Table 5] * The unit is mg.

[0269] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 835,707, filed April 18, 2019, and U.S. Provisional Patent Application No. 62 / 926,130, filed October 25, 2019, the contents of which are incorporated herein by reference in their entireties.

[0270] Other Aspects Various modifications and variations of the invention as described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it will be understood that the invention as claimed should not be unduly limited to such specific embodiments.

[0271] Other embodiments are within the scope of the following claims.

Claims

1. A liquid pharmaceutical composition comprising topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient.

2. 10. The liquid pharmaceutical composition of claim 1, comprising 1 mg / mL to 550 mg / mL of meglumine.

3. 10. The liquid pharmaceutical composition of claim 1, comprising 1 mg / mL to 100 mg / mL of topiramate or a pharmaceutically acceptable salt thereof.

4. 10. The liquid pharmaceutical composition of claim 1, further comprising levetiracetam.

5. 5. The liquid pharmaceutical composition of claim 4, comprising 5 mg / mL to 500 mg / mL of levetiracetam.

6. 5. The liquid pharmaceutical composition according to claim 4, wherein the weight ratio of levetiracetam to topiramate is 5:1 to 15:

1.

7. 10. The liquid pharmaceutical composition of claim 1, further comprising brivaracetam.

8. 8. The liquid pharmaceutical composition of claim 7, comprising 0.5 mg / mL to 50 mg / mL of brivaracetam.

9. 8. The liquid pharmaceutical composition according to claim 7, wherein the weight ratio of brivaracetam to topiramate is 1:4 to 1:

1.

10. 10. The liquid pharmaceutical composition of claim 1, further comprising atorvastatin or a pharmaceutically acceptable salt thereof.

11. 11. The liquid pharmaceutical composition of claim 10, comprising 0.1 mg / mL to 80 mg / mL of atorvastatin or a pharmaceutically acceptable salt thereof.

12. 11. The liquid pharmaceutical composition of claim 10, wherein the weight ratio of topiramate to atorvastatin is 5:1 to 15:

1.

13. 10. The liquid pharmaceutical composition of claim 1, having a pH of 5.5 to 8.

8.

14. 10. The liquid pharmaceutical composition of claim 1, further comprising an acidulant.

15. 10. The liquid pharmaceutical composition of claim 1, wherein the acidulant is acetic acid.

16. 10. The liquid pharmaceutical composition of claim 1, further comprising a calcium sequestrant.

17. 17. The liquid pharmaceutical composition of claim 16, wherein the calcium sequestering agent is EDTA, EGTA, BAPTA, or an alkali salt thereof.

18. 10. The liquid pharmaceutical composition of claim 1, further comprising an emulsifier.

19. 19. The liquid pharmaceutical composition of claim 18, comprising 0.001% to 5.0% (w / v) of an emulsifier.

20. 19. The liquid pharmaceutical composition of claim 18, wherein the emulsifier is polyoxyethylene (20) sorbitan monooleate (polysorbate 80).

21. 10. The liquid pharmaceutical composition of claim 1, which is aqueous.

22. A kit comprising a first container and a second container, wherein the first container contains topiramate or a pharmaceutically acceptable salt thereof, and the second container contains a pharmaceutically acceptable aqueous solution of meglumine.

23. 10. A method of treating a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the composition of claim 1.

24. 34. A method of treating a patient in need thereof, comprising combining the contents of a first container and the contents of a second container in the kit of claim 33 to form a liquid pharmaceutical composition, and administering a therapeutically effective amount of the liquid pharmaceutical composition to the patient.

25. 25. The method of claim 24, wherein the therapeutically effective amount is an amount that provides between 0.5 mg / kg / day and 20 mg / kg / day of topiramate.

26. 25. The method of claim 24, wherein the therapeutically effective amount is an amount that provides at least 40 mg / day to 1200 mg / day of topiramate.

27. 25. The method of claim 24, wherein the therapeutically effective amount is an amount that provides 2.5 mg / kg / day to 150 mg / kg / day of levetiracetam.

28. 25. The method of claim 24, wherein the therapeutically effective amount is an amount that provides 0.2 mg / kg / day to 10 mg / kg / day of brivaracetam.

29. 25. The method of claim 24, wherein the therapeutically effective amount is an amount that provides 0.1 to 2.0 mg / kg / day of atorvastatin.

30. 25. The method of claim 24, wherein the liquid pharmaceutical composition is administered parenterally or orally.

31. 25. The method of claim 24, wherein the patient is in need of treatment for a disorder or condition selected from the group consisting of epilepsy, seizures, anoxia, stroke, traumatic brain injury, brain infection, brain abscess, aneurysm, subarachnoid hemorrhage, status epilepticus, refractory status epilepticus, refractory partial onset seizures (POS), gambling addiction, migraine, substance dependence, alcoholism, cocaine dependence, opioid dependence, nicotine dependence, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder, refractory generalized social phobia, Tourette's syndrome, levodopa-induced dyskinesia in Parkinson's disease, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet syndrome, bipolar disorder, obesity, post-traumatic stress disorder, headache, and conditions caused by exposure to chemical warfare nerve agents.

32. 25. The method of claim 24, wherein the patient is in need of neuroprotection.

33. 25. The method of claim 24, wherein the patient is in need of treatment for a disorder or condition selected from the group consisting of traumatic brain injury, stroke, and brain infection.

34. 25. The method of claim 24, wherein the patient is in need of treatment for a brain abscess.

35. 1. A method of treating epileptogenesis in a subject following a brain injury, the method comprising the step of administering to the subject a therapeutically effective amount of a therapeutic combination, the therapeutic combination comprising two to five drugs selected from the group consisting of anti-inflammatory drugs, antioxidants, neuroprotective drugs, GABA potentiators, glutamate inhibitors, drugs having a presynaptic effect on neuronal excitability, drugs having a metabolic mechanism of action, and pharmaceutically acceptable salts thereof, with the proviso that the two to five drugs are all different.

36. 36. The method of claim 35, wherein each anti-inflammatory agent is independently ibuprofen, celecoxib, parecoxib, a sartan, atorvastatin, fingolimod, anakinra, or agmatine.

37. 36. The method of claim 35, wherein each antioxidant is independently alpha-tocopherol, deferoxamine, N-acetylcysteine, sulforaphane, or melatonin.

38. 36. The method of claim 35, wherein each neuroprotective agent is independently gabapentin, pregabalin, ifenprodil, perampanel, memantine, agmatine, celecoxib, or ceftriaxone.

39. 36. The method of claim 35, wherein each GABA enhancer and each glutamate inhibitor is independently topiramate, valproate, phenobarbital, deferoxamine, ceftriaxone, ifenprodil, perampanel, or memantine.

40. 36. The method of claim 35, wherein each drug having a presynaptic effect on neuronal excitability is independently levetiracetam, brivaracetam, etiracetam, padosevonil, gabapentin, pregabalin, or valproate.

41. 36. The method of claim 35, wherein each drug having a metabolic mechanism of action is independently stiripentol, 2-deoxy-D-glucose, 5-azacytidine, decitabine, beta-hydroxybutyrate, or vorinostat.

42. 36. The method of claim 35, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and deferoxamine, or pharmaceutically acceptable salts thereof.

43. 36. The method of claim 35, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and atorvastatin, or pharmaceutically acceptable salts thereof.

44. 36. The method of claim 35, wherein the therapeutic combination is a combination of topiramate and levetiracetam.

45. 36. The method of claim 35, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and ceftriaxone, or pharmaceutically acceptable salts thereof.

46. 36. The method of claim 35, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and gabapentin, or pharmaceutically acceptable salts thereof.

47. 36. The method of claim 35, wherein the therapeutic combination is a combination of topiramate, levetiracetam, and pregabalin, or pharmaceutically acceptable salts thereof.

48. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, topiramate, and alpha-tocopherol.

49. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and melatonin.

50. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, deferoxamine, or a pharmaceutically acceptable salt thereof, and celecoxib.

51. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, deferoxamine or a pharmaceutically acceptable salt thereof, gabapentin or a pharmaceutically acceptable salt thereof, and fingolimod or a pharmaceutically acceptable salt thereof.

52. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone.

53. 53. The method of claim 52, wherein at least one of levetiracetam, atorvastatin, or a pharmaceutically acceptable salt thereof, and ceftriaxone is administered at a low dose.

54. 54. The method of claim 53, wherein each of the levetiracetam, atorvastatin, or pharmaceutically acceptable salts thereof, and ceftriaxone is administered at a low dose.

55. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam and perampanel, or pharmaceutically acceptable salts thereof.

56. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, perampanel, or a pharmaceutically acceptable salt thereof, and ceftriaxone.

57. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam, parecoxib, and anakinra.

58. 36. The method of claim 35, wherein the therapeutic combination is a combination of levetiracetam and phenobarbital.

59. 36. The method of claim 35, wherein the therapeutic combination is a combination of brivaracetam and topiramate.

60. 36. The method of claim 35, wherein the therapeutic combination is a combination of brivaracetam, topiramate, and ceftriaxone.

61. 36. The method of claim 35, wherein the therapeutic combination is a combination of brivaracetam and perampanel.

62. 36. The method of claim 35, wherein the therapeutic combination is a combination of brivaracetam, perampanel, and ceftriaxone.

63. 36. The method of claim 35, wherein the therapeutic combination is a combination of valproate or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and memantine or a pharmaceutically acceptable salt thereof.

64. 36. The method of claim 35, wherein the therapeutic combination comprises three of the drugs.

65. 36. The method of claim 35, wherein the dose of each drug in the combination is the highest tolerated dose in the patient individually when the drug is administered in a therapeutic combination.

66. 36. The method of claim 35, wherein said therapeutic combination is initially administered to said subject intravenously for 1 to 30 days.

67. 36. The method of claim 35, wherein said therapeutic combination is administered to said subject intramuscularly, subcutaneously, orally, transdermally, sublingually, buccally, intranasally, by inhalation, or rectally.

68. 36. The method of claim 35, wherein after administration of the therapeutic combination is initiated, administration of the therapeutic combination is maintained by chronic oral or parenteral administration.

69. 69. The method of claim 68, wherein administration of said therapeutic combination is maintained for 3 to 6 months after said brain injury.

70. 36. The method of claim 35, wherein at least two of said drugs are present in the same pharmaceutical composition.

71. 36. The method of claim 35, wherein at least three of said drugs are present in the same pharmaceutical composition.

72. 36. The method of claim 35, wherein said administering is initiated within 7 days after said brain injury.

73. 73. The method of claim 72, wherein said administering is initiated within 48 hours after said brain injury.

74. 73. The method of claim 72, wherein said administering is initiated within 24 hours after said brain injury.

75. 73. The method of claim 72, wherein said administering is initiated within 8 hours after said brain injury.

76. 36. The method of claim 35, wherein said therapeutic combination is administered to said subject for a period of from 3 days to 3 months after said injury.

77. 77. The method of claim 76, wherein said therapeutic combination is administered to said subject for 5 to 30 days after said brain injury.

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