Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders

Abstract

To provide an injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-β-cyclodextrin, and water.SOLUTION: The injectable ganaxolone formulation optionally includes a surfactant and a pH modifier. The ganaxolone and sulfobutyl ether-β-cyclodextrin may be in an inclusion complex. The disclosure also provides a lyophilized powder of the ganaxolone / sulfobutyl ether-β-cyclodextrin formulation that may be reconstituted in water for injection. The disclosure provides a method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, comprising administering an effective amount of the injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-β-cyclodextrin; and water. The disclosure also provides combination methods in which the injectable ganaxolone / sulfobutyl ether-β-cyclodextrin formulation is administered in combination with at least one additional active agent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an intravenous formulation of ganaxolone and a method for the treatment of status epilepticus and other seizure disorders. Regarding its use in therapy. [Background technology]

[0002] Status epilepticus (SE) is a severe seizure disorder in which the patient experiences seizures for up to 5 minutes. seizures lasting more than 5 minutes or more than one seizure lasting more than 5 minutes without recovery between seizures In some cases, seizures may last for days or even weeks. In the emergency department, status epilepticus is treated with conventional anticonvulsants. GABAergic drugs like benzaldehyde (BZs) A Receptor modulators are first-line treatments. For patients who do not respond to serotonin monotherapy, anesthetics or barbiturates are usually used in combination with BZs. Combined treatment: benzodiazepines and at least one additional anticonvulsant. Approximately 23% to 43% of patients with status epilepticus who receive antiepileptic drugs do not respond to treatment and are considered refractory. (Rossetti, AO and Lowenstein, L owenstein), DH, Lancet Neurol.(2011)10(1 0):922-930. At present, there are no reasonable treatment options for these patients. Mortality is high in patients with refractory status epilepticus (RSE), and the majority of RSE patients are Approximately 15% of patients hospitalized with SE have extremely refractory SE ( Patients in this group were divided into a subgroup of RSE patients called SRSE, in which the following symptoms occurred after the start of anesthesia treatment: Attacks lasting more than 24 hours or recurring frequently. SRSE is associated with high mortality and morbidity. Associated with morbidity (Shorvon, S., and Ferli si), M., Brain, (2011) 134(10):2802-2818.).

[0003] Parenteral allopregnanolone has been proposed as a treatment for refractory status epilepticus. (Rogawski, MA, et al., Epilep sia, (2013) 54: 93-98.) However, allopregnanolone has a half-life It is very short and is metabolized to the active steroid 5α-dihydroprogesterone. Allopregnanolone is not an ideal choice for treating RSE.

[0004] Another severe seizure disorder is PCDH19-related epilepsy (PCDH19-associated epilepsy), which affects women and children. DH19 female pediatric epilepsy, which affects approximately 1 in the United States. Affecting between 5,000 and 30,000 women, this genetic disorder usually begins within a few weeks. These are focal clusters of seizures that may last for years and are associated with seizure onset early in life. Mutations in the CDH19 gene are associated with reduced allopregnanolone levels, but For these reasons, treatment with regnanolone is not an ideal option. There are currently no approved treatments for PCDH19-related epilepsy in women and children. stomach. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Rossetti, AO and Lowenstein, DH, Lancet Neurol. (2011) 10(10):922-930. [Non-Patent Document 2] Shorvon, S., and Ferlisi, M., Brain, (2011) 134(10):2802-2818. [Non-Patent Document 3] Rogawski, MA, et al., Epilepsia, (2013) 54:93-98. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus and for seizure disorders such as PCDH19-related epilepsy in women and children. There is a need for alternative treatments. The present disclosure satisfies this need and provides the additional provides the advantages of: [Means for solving the problem]

[0007] The present disclosure relates to a method for the preparation of a composition comprising ganaxolone, sulfobutylether-β-cyclodextrin, and water. The present invention provides an injectable ganaxolone formulation comprising ganaxolone and sulfobutyl ether. Ter-β-cyclodextrin may be included in the inclusion complex. β-Cyclodextrin is available under the trade name CAPTISOL® (Ligand Phosphate). It is commercially available from Armaceuticals, Inc., with an average of 6 per cyclodextrin molecule. The present disclosure further provides a method for the preparation of a medicament for the preparation of a medicament for injection, comprising the steps of: Lyophilized powder of good ganaxolone / sulfobutylether-β-cyclodextrin formulation to provide.

[0008] The present disclosure further relates to a method of treating a patient suffering from a seizure disorder, stroke, or traumatic brain injury. The composition comprises ganaxolone, sulfobutyl ether-β-cyclodextrin, and water. The method includes administering an effective amount of an injectable ganaxolone formulation comprising the steps of:

[0009] The present disclosure provides methods of treatment in which ganaxolone is the only active agent, and methods of treatment in which ganaxolone / sulfo How to administer a butyl ether-β-cyclodextrin formulation in combination with another active agent Includes the law.

[0010] The present disclosure provides a ganaxolone / sulfobutyl ether-β-cyclodextrin formulation alone. The present invention also includes treatments comprising dosing regimens with or in combination with at least one additional active agent. [Brief description of the drawings]

[0011] [Figure 1] 1 is a plot of ganaxolone concentration (mg / mL) in solution versus CAPTISOL concentration (mg / mL) as measured by HPLC, showing that the weight:weight ratio of CAPTISOL:ganaxolone required to solubilize ganaxolone is 52:1. [Diagram 2] Figure 1 shows plasma exposure of ganaxolone in rats infused with ganaxolone-CAPTISOL solution. The ganaxolone:CAPTISOL ratio was 1:60 (w / w). [Figure 3A]Figure 15 min after SE onset, rats were treated with vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv). Mean FFT power is shown after subtracting baseline values ​​from subsequent values ​​in each animal and averaging; thus, baseline = 0 for each treatment. Each panel (A-F) shows the mean ± SEM of EEG power at the following time points: -135 min = baseline; -75 min = scopolamine; -45 min = pilocarpine; -15 min = status epilepticus onset; 0 min = post-dose (PD) 0-15 min; 15 min = PD 15-30 min; 30 min = PD 30-60 min; 60 min = PD 1-2 h; 120 min = PD 2-3 h; 180 min = PD 3-5 h. Vertical dashed lines = time points after first dose, 0-15 min. [Figure 3B] FIG. 15 shows rats receiving vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 15 min after the onset of SE. [Figure 3C] FIG. 15 shows rats receiving vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 15 min after the onset of SE. [Figure 3D] FIG. 15 shows rats receiving vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 15 min after the onset of SE. [Figure 3E] FIG. 15 shows rats receiving vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 15 min after the onset of SE. [Figure 3F] FIG. 15 shows rats receiving vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 15 min after the onset of SE. [Figure 4A]Rats were treated with vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg i.v.) 60 min after SE onset. Mean FFT power is shown after subtracting baseline values ​​from subsequent values ​​in each animal and averaging; thus, baseline = 0 for each treatment. Each panel (A-F) shows the mean ± SEM of EEG power at the following time points: -180 min = baseline; -120 min = scopolamine; -90 min = pilocarpine; -60 min = status epilepticus onset; 0 min = post-dose (PD) 0-15 min; 15 min = PD 15-30 min; 30 min = PD 30-60 min; 60 min = PD 1-2 h; 120 min = PD 2-3 h; 180 min = PD 3-5 h. Vertical dashed lines = time points after first dose, 0-15 min. [Figure 4B] FIG. 1 shows that rats were administered vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 60 min after the onset of SE. [Figure 4C] FIG. 1 shows that rats were administered vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 60 min after the onset of SE. [Figure 4D] FIG. 1 shows that rats were administered vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 60 min after the onset of SE. [Figure 4E] FIG. 1 shows that rats were administered vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 60 min after the onset of SE. [Figure 4F] FIG. 1 shows that rats were administered vehicle, allopregnanolone (15 mg / kg), or ganaxolone (12 or 15 mg / kg iv) 60 min after the onset of SE. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] [Definition] Unless otherwise stated herein, the recitation of a range of values ​​includes each and every value within the range. are only intended to serve as a shorthand method of referring to them individually; All of the above-mentioned categories are incorporated herein as if they were individually recited herein. The endpoints of the range are included within the range and are independently combinable. Unless otherwise expressly stated or clearly contradicted by context, all methods described herein are Any or all of the examples or exemplary language (e.g., The use of "such as" is intended as an example only and should not be construed as limiting the scope of the invention. Unless otherwise stated, no limitation should be construed as imposing limitations on the scope of the present invention. Nothing in this specification should be construed as indicating any element not claimed as essential to the practice of the invention. It shouldn't be.

[0013] As used herein, the terms "a" and "an" do not denote a limitation of quantity but rather This means that there is at least one item being referenced.

[0014] As used herein, the term "about" is equivalent to the term "approximately." As will be appreciated by those of skill in the art, the precise boundaries of "about" are determined by the composition of the composition. Illustratively, when the term "about" is used, a value may vary from the stated value. This suggests that the estimate is slightly off, i.e., plus or minus 0.1% to 10%. However, these values ​​are also valid and safe. Therefore, it is best to go slightly outside the ranges mentioned. Compositions in which the composition is formed are also encompassed within the scope of the present invention.

[0015] An "active agent" is any compound, element, or mixture, either alone or in combination with other agents. When administered in combination to a patient, they exert a direct or indirect physiological effect on the patient. When the active agent is a compound, salts, the free compound or the like, as well as various polymorphs of the compound, may be used. The term also includes solvates (including hydrates) of the compound or salt, as well as crystalline and non-crystalline forms. It may have one or more asymmetric elements such as a chiral center or a stereogenic axis, for example, an asymmetric carbon atom, Therefore, the compounds may exist in various stereoisomeric forms. In the case of compounds with two or more asymmetric elements, these The compounds may furthermore be mixtures of diastereomers. For compounds having asymmetric centers, It should be understood that all optical isomers in pure form and mixtures thereof are encompassed. In addition, compounds having carbon-carbon double bonds may occur in Z and E forms. All isomers of these compounds are included in the present invention. Enantiomers, i.e. optically active forms, can be produced by asymmetric synthesis, synthesis from optically pure precursors, or or by resolution of the racemate. Resolution of the racemate can be achieved, for example, by reaction in the presence of a resolving agent. or by conventional methods such as chiral HPLC column chromatography. This can also be achieved through legislation.

[0016] As used herein, the terms "comprising," "including," "including" and "containing" are not limiting. Unrecited elements may be present in embodiments claimed using these transitional phrases. "Comprising," "containing," or When "including" is used as a transitional phrase, the claims Other elements may be included within the scope of the present invention, and may form further embodiments. The end transitional phrase "comprising" is used to iate transitional phrase: "consisting essentially of "isting essentially of," and close-ended phrases se-ended phrase) "consisting of" Includes.

[0017] A "bolus dose" refers to a relatively large amount of a drug administered over a short period of time, e.g., 1 to 30 minutes. It is a quality product.

[0018] C max is the measured concentration of activity in plasma at the time of maximum concentration.

[0019] The term "inclusion complex" refers to a complex between a ganaxolone molecule and a cyclodextrin molecule. The ganaxolone molecule is intended to fit into the hydrophobic cavity of the cyclodextrin molecule. It is believed that the inclusion complex is partially intercalated. The body contains one ganaxolone molecule and one sulfobutylether-β-cyclodextrin It has a phosphorus molecule and is a mixture of ganaxolone and sulfobutyl ether-β-cyclodextrin. The ratio is 1:1.

[0020] Infusion is a parenteral route, usually intravenously, but may be administered via other parenteral routes, such as epidural administration. Oral administration routes are included in some embodiments. Infusion administration takes longer than bolus administration. For example, at least 15 minutes, at least 30 minutes, at least an hour, Each session lasts for at least two hours, at least three hours, or at least four hours.

[0021] A "patient" is a human or non-human animal in need of medical treatment. Treatment includes treatment of an existing condition, such as a disorder or injury. Treatment includes prophylactic or preventative treatment. This also includes diagnostic treatment.

[0022] "Reduced irritation" means irritation less than that caused by injectable ganaxolone formulations that are poorly solubilized. The reduced stimulation is tolerable to patients and is associated with patient compliance. Minor adverse reactions at the injection site or muscle site that do not adversely affect the immunization It is a mild to moderate irritant.

[0023] A "therapeutically effective amount" or "effective amount" is the amount of a pharmaceutical agent that provides a pharmacological effect. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. necessary to obtain the desired pharmacological effect or therapeutic improvement without undue adverse side effects. The effective amount of ganaxolone can be determined by one skilled in the art depending on the particular patient and disease. An "effective amount" or a "therapeutically effective amount" is an amount that is effective to inhibit the metabolism of ganaxolone, Age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and The dosage may vary from subject to subject, depending on variance in the dosage and the judgment of the prescribing physician.

[0024] "Treating" or "treatment" refers to inhibiting a disorder or disease, e.g., preventing or reducing a disorder or disease. is intended to prevent the onset of a disease, alleviate a disorder or disease, or promote the regression of a disorder or disease. to cause a disorder, to alleviate a condition caused by a disease or disorder, or or for any treatment of a disorder or disease, such as alleviating the symptoms of the disease or disorder. It mentions:

[0025] [Chemical Description] Ganaxolone (CAS Registry Number 38398-32-2, 3α-hydroxy, 3β-methyl 5α-pregnan-20-one) is useful in the treatment of epilepsy and other central nervous system disorders. It is a synthetic steroid with useful anticonvulsant activity. [ka] 3α-Hydroxy, 3β-methyl-5α-pregnan-20-one Ganaxolone

[0026] Ganaxolone has a relatively long half-life in human plasma after oral administration, approximately 20 hours. (Nohria, V. and Giller, E., Neurot herapeutics, (2007) 4 (1): 102-105). Ron is a short T max This means that therapeutic blood concentrations are reached quickly. Therefore, no initial bolus dose (loading dose) is required, which is Ganaxolone has shown advantages over treatment of epilepsy in adults and children. It is useful for treating seizures in a patient.

[0027] U.S. Patent Nos. 5,134,127 and 5,376,645 (Stel la) et al.) have reported sulfoalkyl ether cyclodextrin derivatives and their use in oral, nasal and A polymerizable composition for water-insoluble drugs for parenteral administration, including intracavitary administration, intravenous administration, and intramuscular administration. discloses its use as a solubilizing agent for water-insoluble drugs. Inclusion complexes of sulfoalkyl ether cyclodextrin derivatives and their inclusion complexes. The disclosed sulfoalkyl ether cyclode is a cyclopentadiene that is a cyclopentadiene. Examples of cyclodextrin derivatives include the mono-sulfobutyl ether of β-cyclodextrin and and monosulfopropyl ether of β-cyclodextrin. CAPTISOL, marketed by harmaceuticals, is a cyclodextrin. Sulfobutyl ethers with an average of 6-7 sulfobutyl ether groups per string molecule β-cyclodextrin. CAPTISOL is commercially available as an amorphous material. The average molecular weight is 2163 g / mol based on a substituent number of 6.5 per molecule.

[0028] [Injectable β-cyclodextrin-substituted ganaxolone formulation] The present disclosure provides injectable compositions, including formulations containing a CAPTISOL-ganaxolone inclusion complex. Substituted β-cyclodextrin ganaxolone formulations are provided. Injectable substituted beta-cyclodextrin ganaxolone formulations include intramuscular, intravenous, intraarterial, and spinal. Injectable formulations include those suitable for intrathecal and intrathecal injection. Suitable formulations for parenteral administration are included.

[0029] The present disclosure relates to a method for the preparation of substituted β-cyclodextrins such as CAPTISOL and ganaxolone. Injectable substituted β-cyclodextrin containing inclusion complex and pharma- ceutically acceptable carrier In certain embodiments, substituted β-cyclodextrin formulations of the present disclosure are provided. Stringanaxolone formulations shall be in the form of aqueous parenteral or injectable preparations. do.

[0030] Ganaxolone is very poorly soluble in water (<0.001 mg / mL) and therefore is not suitable for aqueous injection. It is difficult to formulate it as a bolus injection. The aqueous solubility of ganaxolone can be improved by complexing it with substituted β-cyclodextrins such as L. The company discovered that the activity of 1,2-dichlorophenyl 1,2-dichlorophenyl 2,3-dichlorophenyl 2,4-dichlorophenyl 2,5-dichlorophenyl 2,6-dichlorophenyl 2,7 ... The results showed that substituted β-cyclodextrins reduced the precipitation of ganaxolone at the injection site. This reduces irritation and allows for injection without unacceptable irritation at the injection site.

[0031] The injectable substituted β-cyclodextrin ganaxolone formulations provided herein are aqueous formulations. or an aqueous formulation, including a lyophilized formulation, which can be quickly dissolved in water to obtain an injectable formulation; The present disclosure relates to a lyophilized ganaxolone powder comprising ganaxolone and sulfobutyrate. The formulation contains ganaxolone 1.0% to 2.0%. Includes embodiments in which the percentage is by weight.

[0032] The present disclosure provides 0.25 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 1.5 mg / mL mL, 2.0mg / mL, 2.5mg / mL, 3.0mg / mL, 3.5mg / mL, 4 .0mg / mL, 4.5mg / mL, 5.0mg / mL, 5.5mg / mL, 6.0mg / mL, 6.5mg / mL, 7.0mg / mL, 7.5mg / mL, 8.0mg / mL, 8.5mg / mL, 9.0mg / mL, 10mg / mL, 11mg / mL, 12mg / m Injectable devices containing ganaxolone at a concentration of about 1.5 mg / mL, 13 mg / mL, or about 15 mg / mL. As an end point, a substituted β-cyclodextrin ganaxolone formulation is provided. All ranges including any two of the clodextrin concentrations are also included in this disclosure. For example, The present disclosure relates to a concentration of about 0.5 mg / mL to about 15 mg / mL, about 1.0 mg / mL to about 10 mg / mL, about 2.0mg / mL to about 8.0mg / mL, or about 4.0mg / mL to about 8. Substituted β-cyclodextrin ganaxolone formulation containing 100 mg / mL ganaxolone The present disclosure contains about 2.0 mg / mL to about 8.0 mg / mL of ganaxolone. For example, inclusion complexes of ganaxolone / sulfobutyl ether β-cyclodextrin for injection in water The present invention includes embodiments that include string formulations.

[0033] The substituted β-cyclodextrin is administered in a weight:weight ratio of about 10:1 to ganaxolone. 100:1, or from about 40:1 to about 80:1, or from about 52:1 to about 80:1, or 52:1 to about 85:1, or about 55:1 to about 70:1, or about 55:1 to about 65:1 or about 55:1. Precipitation of ganaxolone in the formulation or upon injection is The substituted β-cyclodextrins of ganaxolone required to inhibit or prevent The ratio of CA to β-cyclodextrin varies depending on the particular type of substituted β-cyclodextrin used. When PTISOL is used, the ratio of CAPTISOL:ganaxolone is about 52:1 to about 8. 5:1, or about 55:1 to about 70:1, or about 55:1 to about 65:1, or about 55 The substituted β-cyclodextrin helps solubilize ganaxolone. The ganaxolone may be present in an amount greater than that required for conjugation to the ganaxolone.

[0034] In all formulations disclosed herein, ganaxolone and sulfobutyl The ether-β-cyclodextrin may be included in an inclusion complex, the inclusion complex being A 1:1 complex of ganaxolone:sulfobutylether-β-cyclodextrin is also acceptable. stomach.

[0035] In certain embodiments, ganaxolone and sulfobutylether-β-cyclodextrin The phosphorus inclusion complex was prepared by sulfobutylether-β-cyclodextrin at a concentration of 30% w / When the amount of ganaxolone obtained from the complex was measured in water, the amount was at least 2.0 ml. ganaxolone at least 0.1 mg / mL, or at least 1.0 In certain embodiments, the resulting concentration is 1.5 mg / mL, or at least 1.5 mg / mL. The ganaxolone concentration is about 0.1 mg / mL to about 15 mg / mL, or about 1 mg / mL. L to about 10 mg / mL, or about 1 mg / mL to about 5 mg / mL.

[0036] In certain embodiments, ganaxolone is present in an amount of about 0.1 to about 100 mg / kg based on the total weight of the injectable formulation. In an amount of about 5% by weight, or about 0.2 to about 2.5% by weight, or about 0.5 to about 1.5% by weight , will be present in the aqueous injectable formulation.

[0037] The disclosure further provides a method for the preparation of a ganaxolone composition comprising administering to said patient a substituted β-cyclodextrin in an amount of about 52% or less. Substituted β-cyclodextrin at concentrations of 5mg / mL, 10mg / mL, as long as the pH is 1 or higher. , 50mg / mL, 100mg / mL, 150mg / mL, 200mg / mL, 250m g / mL, 300mg / mL, 350mg / mL, 400mg / mL, 450mg / mL , 500mg / mL, 550mg / mL, 600mg / mL, 650mg / mL, or We provide an injectable β-cyclodextrin substituted ganaxolone formulation containing 700mg / mL As the end point, a range including any two of the above substituted β-cyclodextrin concentrations is used. For example, the present disclosure includes a concentration of about 5 mg / mL to about 500 mg / mL. or about 50 mg / mL to about 500 mg / mL, or about 100 mg / mL to about 400 Substituted β-cyclodextrin ganaki containing 100 mg / mL of substituted β-cyclodextrin The present disclosure includes substituted β-cyclodextrin ganaxolone formulations having a ganaxolone concentration of about 25 Contains sulfobutyl ether-β-cyclodextrin at 400 mg / mL to approx. The present invention includes an embodiment having the above structure.

[0038] Ganaxolone forms a complex with substituted-β-cyclodextrin, The complex may be dissolved in water to form an injectable formulation. -Physical mixtures of cyclodextrins are within the scope of this disclosure.

[0039] The substituted-β-cyclodextrin-ganaxolone formulations of the present disclosure can be reconstituted with water and The dried physical properties of ganaxolone and substituted-β-cyclodextrins to form a potent injectable formulation. Alternatively, the aqueous injection may be formed from an aqueous mixture or a dried inclusion complex. The formulation may be lyophilized and subsequently reconstituted with water.

[0040] The present disclosure relates to a ganaxolone-sulfobutyl ether-β-cyclodextrin formulation. , and also acetic acid, citric acid, tartaric acid, phosphoric acid, or triethanolamine (TRIS) Buffer solutions such as buffers, containing acid or base buffers to adjust the pH to a desired level In some embodiments, the desired pH is between 2.5 and 11. 0, 3.5-9.0, or 5.0-8.0, or 6.0-8.0, or 6.8-7 0.6, or 6.80 to 7.10, or about 7.4. Examples of acid buffers useful in formulations of ganaxolone include oxalic acid, maleic acid, fumaric acid, lactic acid, and the like. Acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, methanesulfonic acid, histidine, These include succinic acid, toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, and the like. Acid salts of the above acids may also be used. Examples of base buffers useful in the formulation include sodium carbonate. and sodium bicarbonate, and sodium monohydrogen phosphate. and phosphate buffer systems such as sodium dihydrogen phosphate. In certain embodiments, the buffer is a phosphate buffered saline. In certain embodiments, the buffer is potassium dihydrogen phosphate or dibasic potassium phosphate. A mixture of monobasic and dibasic phosphate buffers such as basic phosphate buffers. The concentration of each component of the buffer system is about 5 mM to about 20 mM, about 10 mM to about 200 mM, or is about 20 mM to about 150 mM, or about 50 mM to about 100 mM.

[0041] The present disclosure relates to the ganaxolone-sulfobutyl ether-β-cyclodextrin formulation. The pH is about 6.9, 7.0, 7.1, 7.2, 7.3, or 7.4. nothing.

[0042] The formulation may contain electrolytes such as sodium or potassium. Includes embodiments in which the formulation is about 0.5% to about 1.5% sodium chloride (saline).

[0043] The formulation may contain a tonicity adjusting agent and is therefore isotonic with human plasma. Examples of tonicity adjusting agents useful in the preparation of pharmaceutical compositions include, but are not limited to, dextrose, mannitol, In certain embodiments, the tonicity agent is 0. It is .9% sodium chloride.

[0044] The injectable substituted cyclodextrin-ganaxolone formulation may contain a non-aqueous carrier. The non-aqueous carrier must be compatible with ganaxolone and provide the desired pharmacological properties of the dosage form. Any pharma- ceutically acceptable excipient capable of providing a release profile is included. Carrier materials include, for example, suspending agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, etc. "Pharmaceutically compatible carrier materials" include, but are not limited to, Acacia gum, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate Calcium, Maltodextrin, Glycerin, Magnesium Silicate, Polyvinylpyrrolide (PVP), cholesterol, cholesterol esters, sodium caseinate, soybean lactate Cytin, taurocholic acid, phosphotidylcholine e), sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, cellulose and Cellulose complex, sugar, sodium stearoyl lactylate, carrageenan, monoglyceride , diglycerides, pregelatinized starch, and the like.

[0045] The injectable substituted β-cyclodextrin-ganaxolone formulation may further contain ethanol. Any non-aqueous diluent, one or more polyhydric alcohols (e.g., glycerol, propylene glycol) The composition may contain a water-soluble glycerin (such as ethanol), an oil-based carrier, or any combination of the foregoing.

[0046] The injectable substituted β-cyclodextrin-ganaxolone formulation further comprises a preservative. The preservative may be used to inhibit bacterial growth. Preservatives Suitable for Parenteral Formulations Contains benzyl alcohol, chlorobutanol, 2-ethoxyethanol, paraben (methyl (ethyl, ethyl, propyl, butyl, and combinations thereof), benzoic acid, sorbic acid, chlorine Contains hexydene, phenol, 3-cresol, thimerosal, and phenylmercury salts. can be.

[0047] The above injectable substituted β-cyclodextrin-ganaxolone formulations are similar to CAPTISOL. Desired solubilization and flux of ganaxolone encapsulated in such substituted β-cyclodextrins. To ensure suitability, a coating agent or surfactant may optionally be included.

[0048] Surfactants include lecithin (a phospholipid), sorbitan trioleate, and other sol sorbitan esters, polyoxyethylene sorbitan fatty acid esters (e.g., monolauro Polyoxyethylene sorbitan phosphate (TWEEN 20, also known as polysorbate 20) (CAS registration number 9005-64-5) and polyoxyethylene monooleate sol Bitan (TWEEN 80, ICI Speciality Chemicals, Polys Commercially available TWEETS, also known as Rubet 80 (CAS Registry Number 9005-65-6) N), poloxamers (e.g., poloxamer 188 (PLURONIC F68) and poloxamer Roxama 338 (PLURONIC F108), which is a mixture of ethylene oxide and propylene and Poloxamer 407, a block copolymer of propylene oxide and poloxamer 407. It is a triblock copolymer consisting of polyethylene glycol and two blocks of polyethylene glycol. sodium cholesterol sulfate or other cholesterol salts, as well as deoxy Sodium cholate, sodium cholate, sodium glycolate sodium, salts of deoxycholic acid, salts of glycolic acid, These compounds include bile salts, such as the salts of chenodeoxycholic acid and lithocholic acid. can be.

[0049] In one embodiment, the present disclosure provides: (1) ganaxolone, 2 to about 8 mg / mL; (2) CAPTISOL, about 100 to about 400 mg / mL; (3) pH adjusted to about 7.0 to about 7.5 (4) a phosphate buffer for adjusting the concentration of substituted β-cyclodextrin for injection containing water The injectable β-cyclodextrin-ganaxolone formulation includes The injectable β-cyclodextrin may be sterilized by filtration using, for example, a 0.2 μm filtration membrane. Phosphoganexolone formulations must be autoclaved or lyophilized for storage and reconstitution. may be carried out.

[0050] The present disclosure relates to any injectable β-cyclodextrin as described herein and further comprising the following requirements: Dextrin-ganaxolone formulations are included. As long as a stable formulation is obtained, any of the following requirements may be met: These may also be combined. In both the bolus and injection formulations, ganaxolone and sulfobutyl ether-β-cyclodextrin were The kistrin is in the form of an inclusion complex.

[0051] (a) The injectable β-cyclodextrin-ganaxolone formulation contains a surfactant. The surfactant is a sorbitan ester or a polyoxyethylene sorbitan fatty acid ester. , poloxamers, cholesterol salts, or bile salts.

[0052] (b) The injectable β-cyclodextrin-ganaxolone formulation contains about 0.0% surfactant. It is 5 to about 15% by weight.

[0053] (c) The injectable β-cyclodextrin-ganaxolone formulation does not contain a surfactant. , where the surfactant is polysorbate 80.

[0054] (d) The injectable β-cyclodextrin-ganaxolone formulation contains a buffer.

[0055] (e) The injectable β-cyclodextrin-ganaxolone formulation has a pH of about 6.8 to about Contains 7.6 buffer.

[0056] (f) The injectable β-cyclodextrin-ganaxolone formulation contains a phosphate buffer. In certain embodiments, the phosphate buffer is phosphate buffered saline. The buffer solution is a combination of monobasic and dibasic phosphate buffers, where each phosphate The concentration of the acid buffer is 2 mM to 50 mM. In a particular embodiment, the phosphate buffer is , a combination of monobasic phosphate buffer and dibasic phosphate buffer, where each phosphate buffer The concentration of the solution is 2 mM to 50 mM.

[0057] (g) The injectable β-cyclodextrin-ganaxolone formulation contains ganaxolone in an amount of 2 mg / kg. Contains sulfobutyl ether-containing ganaxolone at a concentration of 500 mg / mL to 8 mg / mL The w / w ratio of β-cyclodextrin is from about 52:1 to about 90:1, or from about 52:1 to about 80:1, or in the range of about 55:1 to about 70:1, or at least 55:1; The preparation contains a buffer and has a pH of 6.7 to 7.3. % by weight of a surfactant, or about 1 to about 10% by weight of a surfactant, or about 10% by weight of a boundary layer. Contains surfactant.

[0058] (h) The above injectable sulfobutyl ether beta-cyclodextrin-ganaxolone formulation is ganaxolone at a concentration of 1 mg / mL to 5 mg / mL, and The weight percent of β-cyclodextrin is 20% to 40%, or 25% to 35%, or about 30% sulfobutyl ether β-cyclodextrin, and the formulation contains at least the following: Each of these is contained at 5% to 20%, 5% to 15%, or about 10% (by weight). In certain embodiments, the solvent may be selected from the group consisting of ethanol, glycerin, and propylene glycol. The formulation contains lecithin (phospholipids), sorbitan trioleate and other sorbitan Esters, polyoxyethylene sorbitan fatty acid esters (e.g., monolauric acid Polyoxyethylene sorbitan and polyoxyethylene sorbitan monooleate, etc. commercially available TWEEN), poloxamers (e.g., poloxamer 188 (PLURONIC F68) and Poloxamer 338 (PLURONIC F108), which are ethylene oxides. and poloxamer 40, a block copolymer of propylene oxide and poloxamer 7. This is a triblock copolymer consisting of propylene glycol and two-block polyethylene glycol. block copolymer), sodium cholesterol sulfate or other cholesterol salts, as well as a surfactant selected from bile salts.

[0059] (i) The injectable β-cyclodextrin-ganaxolone formulation contains a preservative. In certain embodiments, the preservative is benzyl alcohol, chlorobutanol, 2-ethylhexyl ether, Toxicethanol, Parabens (methyl, ethyl, propyl, butyl, and combinations thereof) (including benzoic acid, sorbic acid, chlorhexidene, phenol, 3-cresol, thime Rosal, or phenylmercuric salt.

[0060] (j) The sulfobutyl ether-β-cyclodextrin is in the form of an inclusion complex. where the sulfobutylether-β-cyclodextrin concentration is about 30% w / v in water. When the amount of ganaxolone obtained from the complex was measured, it was found that at least Both formulations yield 2.0 mg / mL ganaxolone.

[0061] (k) The injectable β-cyclodextrin-ganaxolone formulation may be prepared by dissolving in water or in a solvent such as ethanol, e.g. , 1-20% (volume / volume), 5-15% (v / v), or about 10% ethanol (v / v) Contains v).

[0062] (l) The injectable β-cyclodextrin-ganaxolone formulation contains a wetting agent. In certain embodiments, the solubilizer is, for example, 1 to 20% (volume / volume), 5 to 1 5% (v / v) or approximately 10% (v / v) glycerin or propylene glycol be.

[0063] [Lyophilized β-cyclodextrin-ganaxolone formulation] The present disclosure includes lyophilized forms of all formulations disclosed herein.

[0064] The present disclosure relates to a method for the preparation of substituted β-cyclodextrins such as CAPTISOL and ganaxolone. Injectable substituted β-cyclodextrin containing inclusion complex and pharma- ceutically acceptable carrier In certain embodiments, the substituted β-cyclodextrin is The nganaxolone formulation is a lyophilized dosage form that is dissolved in water and made into an aqueous solution prior to administration. The lyophilized ganaxolone formulation can be reconstituted with water to give a clear solution. The lyophilized dosage form may further comprise a bulking agent, a stabilizer, a buffer (or The formulation may contain a glycerol-containing glycerol (H adjuster), a tonicity adjuster, or any combination of the foregoing. In an embodiment, the lyophilized formulation comprises one or more surfactants, buffers, and preservatives. Yes.

[0065] The bulking agent contains a low concentration of the active ingredient, or in this case, a low concentration of the inclusion complex. Bulking agents include mannitol, lactose, sucrose, and glycerol. , trehalose, sorbitol, glucose, raffinose, glycine, histidine , polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP). do.

[0066] If the hydration shell is removed from the active agent during lyophilization, it may become unstable. In embodiments, the lyophilized dosage form contains a stabilizer. Stabilizers include, but are not limited to: It is not possible to measure the mechanical, chemical and thermal stresses of a single device, but they can be measured in a laboratory environment. These include substances that maintain the desired properties of the formulation over a period of time. Such properties include: Consistent particle size or homogeneity that provides a concentration consistent with labeled strength and maintains purity It includes quality.

[0067] Suitable stabilizers include sucrose, trehalose, glucose, and lactose. Contains sugars.

[0068] [Treatment method] The present disclosure relates to a method for treating status epilepticus, refractory status epilepticus, ultra-refractory status epilepticus, Treating PCDH19-related epilepsy and other seizure disorders in women and children The method comprises administering to a patient suffering from any of these seizure disorders an effective amount of the injectable The method includes administering a substituted β-cyclodextrin-ganaxolone formulation.

[0069] Seizure disorders that may be treated with the injectable substituted β-cyclodextrin-ganaxolone formulations Harm may include status epilepticus, e.g., convulsive status epilepticus, e.g., early onset of epilepsy Status epilepticus, established status epilepticus, refractory status epilepticus status epilepticus, e.g., superrefractory generalized status epilepticus; nonconvulsive status epilepticus Status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; seizures, e.g. For example, acute recurrent seizures, cluster seizures, infantile spasms, Lennox-Gastaut syndrome, West syndrome group, PCDH19-related epilepsy occurring in women and children, and catamenial epilepsy Included.

[0070] The injectable substituted β-cyclodextrin-ganaxolone formulation further has the following properties: hypoglycemia, electrolysis ataxia, high fever, brain infection (encephalitis, malaria, meningitis, toxoplasmosis, or amyotrophic lateral sclerosis) infections in the brain), adverse reactions to prescription drugs, or alcohol or It may also be used to treat induced seizures, such as those caused by a drug overdose.

[0071] The present disclosure further provides an injectable substituted β-cyclodextrin for treating traumatic brain injury and stroke. A method of using a dextrin-ganaxolone formulation to treat a patient who has recently suffered a traumatic brain injury. or a patient who has recently suffered a stroke, comprising administering an effective amount of the formulation.

[0072] The present disclosure further includes a method of treating seizures resulting from a neurodegenerative disorder. Degenerative disorders include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Hantzsch disease. The present disclosure includes methods for treating stroke resulting from inflammatory disorders such as multiple sclerosis. The present disclosure includes methods for treating Niemann-Pick disease type C, Tay-Sachs disease, Batten disease, Sandoz disease, and other conditions. Methods for treating seizure disorders resulting from lysosomal storage diseases, including Hoff's disease and Gaucher's disease Includes.

[0073] Treatment involves treating patients who have suffered a seizure, traumatic brain injury, or stroke with an injectable replacement beta - Treated with a single injection (bolus dose) of a cyclodextrin-ganaxolone formulation The single injection may be intramuscular or intravenous. The dosage per injection is about 1 mg / kg to about 20 mg / kg, about 2 mg / kg to about 15 mg / kg, about 2mg / kg to about 10mg / kg, or about 2mg / kg to about 8mg / kg The treatment method may further include administering the injectable β-cyclodextrin for a period of 1 to 10 days. The administration of multiple injections of the dextrin-ganaxolone formulation is included. The injectable substituted β-cyclodextrin-ganaxolotl may be administered at 24 hour intervals. Inject the drug every 1, 2, 4, 6, 8, 12, or 24 hours. The administration schedule for the injectable substituted β-cyclodextrin is included herein. Phospho-ganaxolone formulations injected for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days Such dosing schedules are contained herein.

[0074] Treatment options include treating a patient who has had a seizure, traumatic brain injury, or stroke with any of the medications listed in the previous paragraph. As reported, for a period of 1 to 10 days, one or more bolus doses of the ganaxolone formulation, followed by the injectable substituted β-cyclodextrin In certain embodiments, the method includes treating the patient with ganaxolone by intravenous infusion of a phospho-ganaxolone formulation. In the method, the bolus dose is about 1 to about 30, about 1 to about 15, about 1 to about 10, or about 1 ~5, or over a period of about 5 minutes, followed by 1, 2, 3, 4, or 5 hours Within a short time, intravenous infusion will be started.

[0075] In some embodiments, the injectable dose is administered with or without a preceding bolus dose. Substituted β-cyclodextrin-ganaxolone formulations are 1, 2, 3, 4, 5, 6, 7, 8, The drug is administered as an intravenous infusion for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. , 4, 5, 6, 7, 8, 9, or 10 mg / kg / hour, or approximately 1 mg / kg g / hour to about 10 mg / kg / hour or 2 mg / kg / hour to about 8 mg / kg / hour The composition may be administered at a rate within the range of 0.1 to 100 rpm.

[0076] In some embodiments, the infusion (whether or not a bolus dose is administered) After administration, the first step reduction dose and optionally the second step reduction dose and optionally A third stage of reduced dose infusion is administered. In some embodiments, the first stage The doses of the following stages are 95%, 90%, 85%, 80%, 75%, 70%, 65%, 80%, 90%, 85%, 85%, 80%, 90%, 95 ... %, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15 %, 10%, or 5%. In some embodiments, the first phase dosage is: 95-50%, 75-50%, 85-50%, 90-50%, 80-50% of the injection dose %, or between 75-100%. In one embodiment, the first phase dosage is: In some embodiments, the second phase dose is 75% of the injection dose. 95%, 90%, 85%, 80%, 75%, 70%, 65%, 6% of the first phase reduction dose 0%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 1 In some embodiments, the second phase dosage is 0% or 5%. Reduction in dosage steps: 95~30%, 75~30%, 85~30%, 60~30%, 70~ In one embodiment, the second The dose of the third stage is 50% of the injection dose. The doses of the first stage are 95%, 90%, 85%, 80%, 75%, 70%, 85%, 9 ...95%, 90%, 95%, 90 0%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 2 In some embodiments, the third stage is 0%, 15%, 10%, or 5%. The dosage is 50-5%, 40-5%, 30-5%, or 25-5% of the reduced dosage in the second stage. , 25-10%, 25-20%, or 25-40%. The third step reduction dose is 25% of the injection dose.

[0077] The present disclosure relates to a method for treating a seizure disorder, wherein the seizure disorder is a condition characterized by status epilepticus, refractory epilepsy, Status epilepticus, extremely refractory status epilepticus, or PCDH19-related seizures occurring in women and children A method for treating epilepsy, which comprises administering to a patient an effective amount of the ganaxolone / sulfonamide combination. The method includes administering a butyl ether-β-cyclodextrin formulation.

[0078] The present disclosure provides a method for treating a seizure disorder, stroke, or traumatic brain injury, comprising administering to a patient Administer an effective amount of the ganaxolone / sulfobutylether-β-cyclodextrin formulation. wherein the dose of ganaxolone is about 1 mg / kg to about 200 mg / kg. g.

[0079] In certain embodiments, the ganaxolone / sulfobutylether-β-cyclodextrin Strolin preparations are administered intramuscularly or intravenously.

[0080] The present disclosure relates to the ganaxolone / sulfobutyl ether-β-cyclodextrin formulation. , including embodiments in which the ganaxolone formulation is administered to the patient as a single bolus dose. In certain embodiments, the single bolus dose provides ganaxolone dosing in the patient. Plasma C max A sufficient amount of gas is required to obtain a concentration of about 100 ng / mL to about 1000 ng / mL. Naxolone is provided.

[0081] The present disclosure relates to the ganaxolone / sulfobutyl ether-β-cyclodextrin formulation. as a bolus dose, the bolus dose providing a therapeutically effective amount of ganaxolone in the patient. plasma C max A sufficient amount of ganaki to achieve a concentration of about 600ng / mL to about 900ng / mL This includes embodiments in which solon is provided.

[0082] The present disclosure relates to the ganaxolone / sulfobutyl ether-β-cyclodextrin formulation. , administered as a bolus dose, the bolus dose being administered in less than 10 minutes; C max The administration is complete This includes embodiments occurring within one hour of completion.

[0083] The present disclosure relates to the ganaxolone / sulfobutyl ether-β-cyclodextrin formulation. The single bolus dose is about 1 mg / kg to about 20 mg / kg. g / kg of ganaxolone. The dose is about 2 mg / kg to about 15 mg / kg of ganaxolone, or about 4 mg / kg to about About 10 mg / kg of ganaxolone, or about 1 mg / kg to about 30 mg / kg of ganaxolone Contains ron.

[0084] The present disclosure relates to the ganaxolone / sulfobutyl ether-β-cyclodextrin formulation. In certain embodiments, including embodiments in which multiple bolus doses are administered to the patient, The multiple bolus doses may be administered at intervals of 1 to 24 hours over a period of 1 to 10 days. In certain embodiments, each bolus dose reduces the amount of ganaxolone in the patient. Plasma C max A sufficient amount of gas is required to obtain a concentration of about 100 ng / mL to about 1000 ng / mL. In certain embodiments, the interval between bolus doses is about 10 to 20 minutes. About 24 hours later, the first C max From that point on, ganaxolone plasma concentrations increased In certain embodiments, the IL-10 concentration does not fall below 100 ng / mL at any time between doses. The interval between bolus doses is 20 to 24 hours, and the first C max From the point where The patient's ganaxolone plasma concentration was max Not less than 25% of the total amount of the specific implementation In some embodiments, each bolus dose contains about 1 mg / kg to about 20 mg / kg of ganaxolone. Or, optionally, the single bolus dose is from about 2 mg / kg to about 15 mg / kg. g of ganaxolone, or about 4 mg / kg to about 10 mg / kg of ganaxolone, or about Contains 1 mg / kg to approximately 30 mg / kg of ganaxolone.

[0085] In certain embodiments, the method includes administering an initial bolus dose or not. 2. The patient was administered the ganaxolone / sulfobutylether-β-cyclodextrin formulation. In certain embodiments, the injection comprises administering an initial bolus dose of It is given at a rate of 1 to 10 mg / kg / hour for 1 to 10 consecutive days without administration.

[0086] In certain embodiments, the methods include administering from about 1 mg / kg to about 20 mg / kg of ganaxoxo The above ganaxolone / sulfobutyl ether-β-cyclodextrin formulations containing ganaxolone followed by an infusion of the ganaxolone formulation within 24 hours. This includes administering at a rate of 1 to 10 mg / kg / hour for 1 to 10 consecutive days.

[0087] In certain embodiments, the method further comprises administering to said patient a ganaxolone / sulfobutyl ether-β - administering an initial bolus dose of the cyclodextrin formulation, followed by an infusion; The initial bolus dose resulted in the initial plasma C ma x A sufficient amount of ganaxolone is required to achieve a concentration of about 100 ng / mL to about 1000 ng / mL. The patient's ganaxolone plasma concentration remains at the initial dose until the completion of subsequent infusions. C max This includes not being less than 25% of the

[0088] In certain embodiments, the method further comprises administering to said patient a ganaxolone / sulfobutyl ether-β administering an initial bolus dose of the cyclodextrin formulation, wherein the initial bolus dose The initial plasma C of ganaxolone in these patients was max is about 100 ng / mL A sufficient amount of ganaxolone is provided to give a total of about 1000 ng / mL of ganaxolone, and then the patient is The plasma concentration of ganaxolone in max A constant sufficient to be at least 40% of The patient is administered an injection of the ganaxolone formulation in a tapered dose, followed by an injection of ganaxolone in a tapered dose. whereby, upon completion of the infusion, the plasma concentration of ganaxolone in the patient is , C max This includes falling below 20% of the

[0089] [Combination therapy] The present disclosure includes embodiments in which ganaxolone is the only active agent as well as embodiments in which ganaxolone is one or more active agents. This includes embodiments in which the compound is administered in combination with another active agent as described above. When used, ganaxolone and the other active agent may be combined in the same formulation or Alternatively, the ganaxolone may be administered during administration of the other active agent. (co-administration) or administration of ganaxolone before or after administration of the other active agent. (continuous administration).

[0090] The present disclosure includes embodiments in which the additional active agent is an anticonvulsant. Anticonvulsants include GAB A A Receptor modulators, sodium channel blockers, GAT-1 GABA transporter modulators modulators, GABA transaminase modulators, voltage-dependent calcium channel blockers drugs, and peroxisome proliferator-activated alpha modulators.

[0091] The present disclosure relates to the administration of an anesthetic or sedative to said patient in combination with ganaxolone. The anesthetic or sedative agent is administered in a concentration or dosage sufficient to medically induce coma. is a concentration sufficient to cause the patient to lose consciousness, such as a concentration effective to induce general anesthesia. Alternatively, the anesthetic or sedative may be administered in a concentration of Smaller doses may be administered which are effective, but not sufficient, for sedation.

[0092] Patients are given one dose of an anesthetic drug such as propofol, pentobarbital, or thiopental. Medically induced coma when a single dose is administered to produce a temporary coma or deep unconsciousness General anesthesia is particularly useful because it causes sufficient loss of consciousness that patients do not perceive pain during surgery. Certain medicinal products are used for medically induced coma or general anesthesia. Drugs used include inhaled anesthetics and anaesthetics, including barbiturates and non-barbiturates. and anesthetics.

[0093] Inhalation anesthetics include desflurane, enflurane, ethyl chloride, halothane, and isoflurane. , methoxyflurane, sevoflurane, and trichloroethylene.

[0094] Intravenous nonbarbiturate anesthetics include atracurium, cisatracurium, and etomide. These include acetaminophen, ketamine, propofol, and rocuronium.

[0095] Barbiturates include amobarbital, methohexital, pentobarbital, These include phenobarbital, secobarbital, thiamylal, and thiopental. do.

[0096] Benzodiazepines are used both as anticonvulsants and as anesthetics. Benzodiazepines that are useful for this purpose include diazepam, flunitrazepam, lorazepam, and and midazolam.

[0097] The present disclosure relates to the administration of propofol in combination with ganaxolone to induce anesthesia. Propofol is administered in a range of doses or in the range of 0.5 to 50 mg / kg. Anesthesia is induced by an initial bolus dose of 10 to 50 mg / kg. The drug was then inactivated by additional intermittent bolus doses or 10-50 mg / kg. Anesthesia is further induced by infusion of propofol 3–18 mg / kg / min. may be maintained.

[0098] The present disclosure relates to the administration of ganaxoxostat via intravenous or intramuscular injection of sodium pentobarbital. Pentobarbital is used in adults to induce anesthesia. 100-500 mg or 100-200 mg intramuscularly or intravenously It may be administered as an injection or as a single 2-6 mg / kg IM dose for pediatric patients. Pentobarbital may be administered as an IV injection to patients in status epilepticus. High doses may be given to induce coma, after which ganaxolone is combined with pentobarbital. They may be administered in combination to treat refractory seizures. Used to induce coma Pentobarbital doses ranged from 5 to 15 mg / kg administered over 1 to 2 hours. loading dose of 10-35 mg / kg, followed by 1 mg / kg / hour to 5 mg / kg / hour Maintenance dose to be administered for 12 to 48 hours between attacks, and 0.25 every 12 hours from the time seizures cease This involves tapering the dose by ~0.5mg / kg / hour.

[0099] The present disclosure includes administering thiopental sodium in combination with ganaxolone. Thiopental is administered as a bolus of 3-5 mg / kg, followed by elimination of seizures. Additional boluses of 1-2 mg / kg may be administered every 3-5 minutes until the drug is no longer effective, with a maximum total dose of The dose should be up to 10 mg / kg. Thiopental should be given at a maximum bolus dose of 10 mg / kg. Once this is achieved, thiopental can be infused at 3-5 mg / kg / hour.

[0100] The present disclosure includes administering midazolam in combination with ganaxolone. is administered as a loading dose of 0.5 mg / kg to 5 mg / kg, followed by 1 to 5 μg / kg / hour infusion is possible.

[0101] In each embodiment in which another active agent is administered to induce coma, anesthesia, or sedation, Ganaxolone is administered as an injectable substituted-β-cyclodextrin ganaxolone formulation. and, either simultaneously or sequentially, another active agent is administered, such as ganaxolotl as specified herein. The drug is administered according to any of the dosing schedules for administration of the drug.

[0102] The injectable substituted-β-cyclodextrin ganaxolone formulations of the present disclosure may be administered in combination with another anticonvulsant. Anticonvulsants include many drug classes and may be administered in combination with ganaxolone. There is some overlap with the coma-inducing anesthetics and sedatives that may be used. Anticonvulsants that may be used in combination with substituted-β-cyclodextrin ganaxolone preparations aldehydes such as paraldehyde; aromatic aryl alcohols such as stiripentol; Barbital; including methylphenobarbital and barbexacrone as well as the above. Rubituric acid series: alprazolam, bretazenil, bromazepam, brotizolam, chloramate Diazepoxide, cinolazepam, clonazepam, clorazepate, clobazam, clothiazepam Pam, Cloxazolam, Delorazepam, Diazepam, Estazolam, Etizolam, Lofla Ethyl azepam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazepam Zolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Midazolam, Nimetazepam Zepam, nitrazepam, nordazepam, oxazepam, phenenazepam, pinazepam, proazepam Razepam, premazepam, pyrazolam, quazepam, temazepam, tetrazepam, and Benzodiazepines, including triazolam; bromides, such as potassium bromide; carbamazepine carboxamides such as carbazepine, oxcarbazepine, and eslicarbazepine acetate; fatty acids such as valproic acid, sodium valproate, and divalproex sodium; Fructose derivatives such as pyramate; GABs such as gabapentin and pregabalin A analogues, such as ethotoin, phenytoin, mephenytoin, and fosphenytoin hydantoins; other neurosteroids such as allopregnanolone, paramethadione, oxazolidinediones such as rimethadione, ethadione, and propionamides such as beclamide Pyrimidinediones such as primidone, brivaracetam, levetiracetam, and pyrrolidines such as seletracetam, ethosuximide, pensuximide, and meth Succinimides such as succinimide; acetazolamide, sulthiame, methazolamide, and Sulfonamides such as zonisamide; triazines such as lamotrigine; ureas, such as phenacemide and phenacemide; NMDA antagonists, such as felbamate; Valproylamides, such as lupromide and valnoctamide; and perampanel. In certain embodiments, the present disclosure provides an injectable sulfobutyl ether β-cyclodextrin This includes the use of a ganaxolone preparation in combination with diazepam. Sulfobutyl ether beta-cyclodextrin for injection - may be combined with ganaxolone For example, the present disclosure provides a method for administering the compound of the present invention in a dosage form ranging from 1 mg / mL to 10 mg / mL. / mL ganaxolone, 25% to 35% (by weight) sulfobutyl ether β-cyclodextrin Kistrin, and 1 mg / mL to 40 mg / mL diazepam, or about 2 mg / mL ~An injectable sulfobutyl ether β-cyclodextrin containing approximately 20 mg / mL of diazepam Contains strin-ganaxolone preparations. EXAMPLES

[0103] <Example 1> [Preparation of injectable ganaxolone formulations] The solubility of ganaxolone in aqueous CAPTISOL was determined by constructing a solubility phase diagram. It was first identified by The ganaxolone solution was added to the solution and shaken for 42 hours to reach equilibrium. The filtrate was filtered through a 0.45 μm syringe filter into a vial. The ganaxolone concentration in the CAPTI solution was quantitatively analyzed. The results are summarized in Table 1. The moles of ganaxolone in solution were plotted against the moles of SOL. The solubility of RON was observed to increase linearly with the addition of CAPTISOL. This suggests that ganaxolone and CAPTISOL form a 1:1 complex. Proportion of weight of ganaxolone (mg) in solution versus weight of CAPTISOL (mg) From the results (Figure 1), the amount of ganaxolone required for solubilization at equilibrium was The weight:weight ratio of CAPTISOL to 100% was shown to be approximately 52:1.

[0104] [Table 1]

[0105] To prepare the injectable solution, an overdose of ganaxolone is added to 400 mg / mL CAPTISOL. The solution is shaken at least overnight and passed through a 0.45 micron filter. Filter. The ganaxolone concentration of the filtered solution is determined by HPLC. SOLON / CAPTISOL solution (7.68m in 400mg / mLCAPTISOL aqueous solution) g / mL) was diluted with saline to 3.84 mg / mL, 0.7 mg / mL, and 1.0 mg / mL in 0.9% saline. ganaxolone solutions of 7 mg / mL and 0.39 mg / mL were obtained. All solutions were After freezing and thawing, the ganaxolone solution was clear and free of any precipitate. , no precipitate was observed.

[0106] <Example 2> [Preparation of Ganaxolone-CAPTISOL Solution for Injection (5 mg / mL)] First, ganaxolone (0.50 g) was manually dispensed into sterile water for injection using a spatula. Mix with a small amount (approximately 20 mL) of 30% w / v CAPTISOL solution to form a homogeneous paste. An additional volume of 30% w / v CAPTISOL solution (approximately 40 mL) was then added to the suspension. The suspension was stirred for 20 minutes using a magnetic stirrer. The suspension was sonicated for 2 hours using a probe sonicator. During sonication, the total volume of the CAPTISOL solution was kept at 99.58 mL. Additional 30% w / v CAPTISOL solution was added at 68°C. The stirred formulation was then mixed at 68°C for 12 hours. Heat at 5° C. for about 2.5 hours to give a solution. Remove heat and stir the solution at room temperature for about 2 hours. The volume lost by evaporation was replenished with water. The clear solution was filtered through a 0.2 μm nylon membrane. The solution was sterilized by filtration through a filter.

[0107] <Example 3> [Preparation of freeze-dried ganaxolone-CAPTISOL powder] Dissolve 42.6 mg of ganaxolone in 6.6 mL of 40% w / v CAPTISOL. A solution of Xolon-CAPTISOL was prepared and stirred for 1 hour (a small amount of undissolved Gana was The xolone was removed by filtration through a 0.45 μm syringe filter and the clarified The solution was frozen in a dry ice / acetone bath and lyophilized for 2 days. The freeze-dried powder contained 2.859 g of a free-flowing white powder. The concentration was quantitatively analyzed by HPLC and found to be 1.26% by weight, which is lower than the theoretical value. The lyophilized powder was reconstituted with water to give a clear solution. .

[0108] <Example 4> [Buffered Ganaxolone-CAPTISOL Solution] Potassium phosphate monobasic (19.6 mg) and sodium phosphate dibasic heptahydrate ( 93.3 mg) in 20 mL of 30% Captisol with an initial pH of 4.53. 3 mg / mL ganaxolone solution was added. The mixture was sonicated for 1 minute and adjusted to pH 6.95. Approximately 10 mL of this solution was added to a non-buffered counter solution in a sealed glass vial. The sample was stirred with a magnetic stirrer at 80°C together with the reference solution. The remaining 10 mL was kept at 5°C as a control. Aliquots were taken at 67 hours and on the fifth day. These samples were quantitatively analyzed by HPLC, and the results are shown in Table 2.

[0109] [Table 2]

[0110] <Example 5> [Ganaxolone for injection - 30% CAPTISOL solution containing polysorbate 80] 500 μL of 10% polysorbate 80 in water in a 20 mL scintillation vial Powdered ganaxolone (50 mg) was mixed in. The mixture was stirred to wet the ganaxolone. Next, add enough solid Captisol to form a 30% Captisol solution. (3.2 g) was added to the vial and the vial contents were mixed. Next, deionized water (8 0.0 g) was added and the mixture was stirred vigorously at room temperature overnight to give a cloudy solution. The solution was filtered through a 0.2 μm syringe filter and the ganaxolone concentration was quantified by HPLC. The concentration was analyzed and found to be 4.28 mg / mL.

[0111] The following injectable ganaxolone-30% Captisol solution was prepared by the method of this example: Prepared. (a) Ganaxolone-30% Captisol solution containing ethanol. Ganaxolone in 30% Captisol was incubated overnight in the presence of 10% v / v ethanol. The mixture was stirred thoroughly to give a 3.16 mg / mL ganaxolone solution. (b) Ganaxolone-30% Captisol solution containing glycerin Ganaxolone in 30% Captisol was incubated overnight in the presence of 10% v / v glycerol. The mixture was stirred thoroughly to give a 3.45 mg / mL ganaxolone solution. (c) Ganaxolone-30% Captisol solution containing propylene glycol Ganaxolone in 30% Captisol, 10% v / v propylene glycol The mixture was stirred vigorously overnight at room temperature to give a 2.53 mg / mL ganaxolone solution.

[0112] <Example 6> [Ganaxolone using a pre-dried mixture of ganaxolone and CAPTISOL Preparation of 30% CAPTISOL solution Powdered ganaxolone (125 mg) was placed in a 100 mL beaker. ol powder (7.9 g) was added to the beaker. The mixture was stirred for 5 minutes with a magnetic stirrer. Stir for 10 minutes to mix. Deionized water (20.1 g) was measured into a plastic cup. Approximately half of the water was added to the beaker and the contents were stirred vigorously for 30 minutes to obtain a homogenous mixture. Water was added and the beaker was covered with paraffin film. The contents were vigorously incubated at room temperature overnight. Stirring gave a 4.61 mg / mL ganaxolone solution. After stirring for 90 hours, the ganaxolone There was no change in the concentration of

[0113] <Example 7> [Ganaxolone-CAPTISOL SOLUTION INJECTED AND INFURNACED RATS] Plasma concentration of Male and female Crl:CD (SD) rats, 100-300 g (Charles River Laboratories, Raleigh, North Carolina Group 1 was administered ganaxolone-CAPTISOL solution in sterile water for injection for 8 to 24 hours. The mice were administered intravenous infusion (ganaxolone:CAPTISOL=1:60, w / w). Group 1 Group 1 was infused at a rate of 1 mg / kg / hour. Group 2 was infused at a rate of 2.5 mg / kg / hour. In the third group, male rats were infused at a rate of 3.5 mg / kg / h and females at 1.5 mg / kg / h. The patient received an infusion of 1.75 mg / kg / hour. The plasma concentration profile of ganaxolone over time was The file is shown in Figure 2.

[0114] <Example 8> [Effects of ganaxolone on pilocarpine-induced status epilepticus in rats] The study consisted of CAPTISOL-1 administered intravenously (IV) at 12 or 15 mg / kg. Ganaxolone (GNX) formulations improve pilocarpine-induced status epilepticus (S The study was designed to determine whether allopregnatamine has an inhibitory effect on the function of the steroid hormone, acetylcholinesterase (AH). Allo (15 mg / kg IV) was also evaluated. , administered 15 or 60 minutes after the onset of SE and compared with vehicle (30% Captisol). It was.

[0115] Cortical EEG activity in rats before and after administration of pilocarpine to induce SE Animals were given LiCl and pinpoint concentration to enhance and improve the reliability of seizure induction. Scopolamine was administered in advance to reduce the peripheral cholinergic side effects of rocarpine. After the onset of SE, EEG activity was recorded for 5 hours, and the frequency range of 0.3–96 Hz was Anticonvulsant activity was measured by determining changes in EEG power over the course of the study.

[0116] [Test compound] The compounds listed in Table 3 were used in the study of pilocarpine-induced status epilepticus. Used for.

[0117] [Table 3]

[0118] [animal] Male Sprague-Dawley rats were used in the study. The rats were equipped with EEG electrodes and A jugular vein catheter was surgically implanted. The mean body weight at the time of recording was 321 ± 3 g (26 9~351g).

[0119] EEG electrodes were surgically implanted in anesthetized rats. Animals were also given anti-inflammatory medication prior to surgery. Painkillers (RIMADYL, (Carprofen)) and subcutaneous local anesthetic were administered. Stainless steel screw electrodes were chronically attached to the skull so that the tips of the screws were flush with the inner surface of the skull. (0-80 × 1 / 4”, Plastics-One, Roanoke, VA One electrode was located 3.0 mm anterior to the bregma and 2 mm left of the midline, and two The eyes were positioned 4.0 mm posterior to the bregma and 2.5 mm right of the midline. The skull surface was sealed with super glue and dental acrylic, and EEG electrode leads were attached. The wire was attached to a plastic base that was attached to the skull using dental acrylic. The wound edge was then covered with a triple antibiotic cream (zinc bacitra, The patient was treated with 100 mg of 10 ... Afterwards, the animals were administered antibiotics (ampicillin, 50 mg / kg at 0.4 mL / kg I P), and a chewable dose (approximately 10 mg) of Rimadyl was administered after surgery. The animals were allowed one week to recover from the EEG surgery.

[0120] One week after EEG surgery, rats were implanted with a jugular vein catheter (JVC). The rat was given an anti-inflammatory / analgesic drug, then anesthetized and placed in a supine position. A skin incision was made on the right ventral lateral aspect of the neck. The external jugular vein was then exposed and subsequently dissected free from the surrounding fascia. The vein was ligated anteriorly to prevent venous obstruction during venous dissection and catheter insertion. The vein was loosely ligated posteriorly to keep the vessel taut. After the vein was incised, a PE catheter was inserted. A catheter (3Fr) was inserted into the vein and advanced about 30 mm toward the heart. The tip was then connected to the descending vena cava and the right vena cava. The catheter was placed at the atrial junction. After blood sampling, the catheter was patency confirmed and the posterior ligature was performed. Release the catheter and flush it with "heparin lock" solution (5 units heparin / mL saline). The catheter was then inserted through the subcutaneous tissue and a sterilized stainless steel pin was inserted. The catheter was then externalized between the shoulder blades and behind the head. Finally, the catheter was sutured to the skin. All wounds were then closed with sutures or wound clips. Immediately after surgery, the animals The patient was awakened and the catheter was inspected for patency. Therefore, animals were given a chewable dose (approximately 10 mg) of Rimadyl after surgery.

[0121] The animals were allowed to recover from the JVC surgery for one week. The jugular venous catheter was relocated to maintain patency. The catheter was flushed once daily with 0.1 mL of heparin solution (5 units / mL). The lavage fluid contained ampicillin-sulbactam (50 mg / kg). If catheter flushing becomes difficult, record the animal number and date and remove the animal. or, if possible, assigned to a vehicle group.

[0122] [EEG recording procedure] For EEG recording, each rat was administered LiCl in the afternoon before recording and placed in a recording container ( recording container) (30×30×30cm with wire mesh ceiling) Before scopolamine administration, the animals were not fasted and had free access to food and water. The food was removed when scopolamine was administered. The test piece was placed in a sound-attenuating cabinet equipped with a well light, and a video camera.

[0123] Cortical EEG signals were fed through a connected cable to a rectifier (Plastics-On e, Roanoke, VA) and then to an amplifier (AM Systems mod el1700;1000×gain), bandpass filtered (0.3~ 1000Hz), and finally, National Instruments (Austin Data acquisition software (Labview 5.1) and hardware (PC ICELUS acquisition device / sleep evaluation software operated by I-MIO-16E-4) Ware (sleep scoring software) (M. Opp, U. Mich 512 samples per second were digitized using a digital multimeter.

[0124] [Drug administration group] Table 4 shows the drug administration groups used in this study. All injections were performed via the jugular catheter. These animals were injected via the tail vein. He was shot.

[0125] [Table 4]

[0126] Seizure induction, treatment, and recording procedures Animals were evaluated in one session per day for three consecutive days. The test schedule is shown in Table 5. The time of SE onset was recorded as determined by observation, and animals were included within 15 or 20 days after SE onset. After 60 minutes, the mice were administered either vehicle, allopregnanolone, or ganaxolone. The subjects were randomly assigned to receive pilocarpine injections at approximately 2, 15, 30, 60, 120, and 240 minutes after administration. Animals were euthanized 5 hours after treatment, after recordings were completed.

[0127] [Table 5]

[0128] [Preictal, intraictal, and postictal EEG analysis] EEG power (mV 2 / Hz) using the ICELUS software, 1 to 96 H Analyzed by Fourier analysis (Fast Fourier Transform, FFT) at 1 Hz frequency bins of z (The lowest frequency bin is suggested to be "0 to 5 Hz", but technically The lowest frequency recorded was 0.3 Hz. The frequency range is as follows: Available: Delta, 0~5Hz (0.3~4.99Hz), Theta 5~10Hz, Beta 10 ~30Hz, Gamma-30~50Hz, Gamma-2 50~70Hz, Gamma-3 70 ~96Hz. EEG power analysis determines the average power value over consecutive 5-minute intervals. To minimize biased results due to large amplitude, low frequency EEG activity, F FT amplitudes were log-transformed. The period from the start of recording to scopolamine administration was used as the baseline EE G, and all animals were assumed to be in a similar state of activity during this period. To normalize the baseline, the EEG power was normalized for the entire baseline period. The logarithmic FFT values ​​over the entire frequency range (0 to 96 Hz) are summed to produce a single Normalization constant K norm Obtained:

[0129]

number

[0130] For the following analysis, K norm , all FFT power values ​​(at each frequency and at all times) This procedure subtracted the total baseline EEG power for each animal. This results in the mean of the baseline for all subsequent animals being equal to 0. The frequency curves will closely overlap.

[0131] EEG power data were first averaged at the following task time points: baseline , scopolamine, pilocarpine, SE (time between SE onset and treatment), and post-administration Absence duration: 0-15, 15-30, 30-60 minutes, 1-2 hours, 2-3 hours, and 3-5 time.

[0132] [result] Table 6 shows the results when allopregnanolone or ganaxolone was administered 15 minutes after the onset of a seizure. A summary of the treatment effects is shown in Table 7. 4 is a summary of the therapeutic effect when administered 2 min later.

[0133] Regardless of the frequency range, EE from the time of administration to approximately 2 hours after administration in the vehicle group There was almost no decrease in G power, but the EEG power decreased 2 to 5 minutes after administration. The decrease was consistent with the increase in the frequency of the 100-fold increase in ... It was remarkable.

[0134] Allopregnanolone 15 mg / kg, administered 15 minutes after seizure onset, After 2 hours of administration, the SE in this group was significantly decreased, and the effect gradually weakened. After a 60-minute delay, the SE in the first 15 minutes after administration returned to nearly the same level as in the vehicle group. There was a significant decrease in SE in the frequency ranges of 0-5 and 5-10 Hz. In the 2-hour post-dose period, SE returned to vehicle levels and remained at those levels. At 30 Hz, the decline in SE lasted less than an hour, and at higher frequencies it lasted only about 15 minutes. Statistically, allopregnanolone was initially more effective when administered 60 minutes after the onset of SE. When administered 60 minutes later, the SE was suppressed for only 15 minutes, whereas when administered 60 minutes later, the SE was suppressed for less than 30 Hz. Suppression was observed for 2 to 3 hours at 30 Hz and for up to 1 hour at >30 Hz.

[0135] When ganaxolone was administered at 12 and 15 mg / kg, there was no significant difference in the efficacy of either dose. Both treatments produced qualitatively equivalent results producing very significant reductions in overall SE amplitude.

[0136] When administered 15 min after the onset of SE, GNX reduced serotonin levels across the full frequency range and for up to 5 h. Reduced EEG power to baseline levels or below baseline levels. 5 At ~70 Hz, EEG power decreased to near baseline levels until 5 hours after administration. At 0–5 Hz, EEG power remained at baseline for approximately 90 min. At 70–96 Hz, EEG power was below baseline for the entire 5 h period. However, EEG power above 30 Hz remained below the threshold for 2–5 h. There were no differences from the vehicle group, which was not significantly different from baseline EEG power levels. It is also noteworthy that in the higher frequency range, the EE of the solvent group is G power returned to baseline after 2 hours, thus showing no significant difference between the GNX and vehicle groups. There was no significant difference.

[0137] When administered 60 min after SE onset, it produced a similarly large reduction in EEG power, but The frequency range from 70 to 96H was not below the baseline level. In the z group, EEG power decreased below baseline from 1 to 4 hours after administration. The effect of administering GNX 60 minutes after the onset of symptoms was significantly different from that of administering it 15 minutes after the onset of symptoms. The main differences were: (1) higher frequencies (>30 Hz), most noticeable during the first 15 minutes after administration; and (2) the drugs showed no significant reduction in the 2-3 h response, especially at higher frequencies. The effect appeared to be stronger at the time points in between. Again, the EEG power levels were The EEG levels in the vehicle group remained at baseline levels for up to 5 hours after administration, but the EEG levels in the vehicle group also increased at 30 The drug had no effect as frequencies in the > 50 Hz range returned to baseline levels In contrast, at 0–5 Hz, EEG power remained at a high level in the vehicle group and GNX showed a significant decrease in the 12 mg / kg group.

[0138] [Table 6]

[0139] [Table 7]

Claims

1. a) Ganaxolone and sulfobutylether-β-cyclodextrin in an inclusion complex and b) water 1. An aqueous, injectable ganaxolone formulation comprising:

2. 2. The formulation of claim 1, wherein the ganaxolone and sulfobutyl ether-β- The cyclodextrin-containing complex is ganaxolone:sulfobutylether-β-cyclodextrin. A formulation characterized in that the dextrin comprises a 1:1 complex.

3. 3. The formulation of claim 1 or 2, wherein the concentration of ganaxolone is about 0.1 mg / mL. The formulation is characterized in that the dosage form has a concentration of from about 100 mg / mL to about 15 mg / mL.

4. The formulation according to any one of claims 1 to 3, further comprising 0.5% to 10% glycerin in the formulation. A formulation characterized in that it contains sodium chloride at a concentration of 1.5%.

5. 5. The formulation according to any one of claims 1 to 4, wherein the The w / w ratio of sulfobutylether-β-cyclodextrin is about 52:1 or greater. A formulation characterized by:

6. 5. The formulation according to any one of claims 1 to 4, wherein the Sulfobutylether-β-cyclodextrin w / w ratio of about 52:1 to about 80:1 The formulation is characterized in that the range of

7. 7. The formulation of claim 6, wherein the sulfobutyl ether to the ganaxolone - a formulation characterized in that the w / w ratio of β-cyclodextrin is about 55:

1.

8. The formulation according to any one of claims 1 to 7, which has a concentration of 5 mg / mL to 800 mg / mL The sulfobutyl ether-β-cyclodextrin of formula L is contained in the composition. Agent.

9. The formulation according to any one of claims 1 to 8, characterized in that it contains a surfactant. A preparation that exhibits the following characteristics.

10. 10. The formulation of claim 9, wherein the surfactant is a sorbitan ester, a polyoxyethylene ester, Ethylene sorbitan fatty acid esters, poloxamers, cholesterol salts, or bile salts A formulation characterized by:

11. 11. The formulation of claim 10, wherein the surfactant is present in an amount of from about 0.5 to about 15 wt. A formulation characterized in that the amount of

12. 12. The formulation of claim 11, wherein the surfactant is polysorbate 80. A formulation characterized by:

13. 13. The formulation according to any one of claims 1 to 12, wherein the pH is from about 2.5 to 11.

0. The formulation is characterized in that the range of

14. The formulation according to any one of claims 1 to 13, further comprising a buffer. A formulation characterized by:

15. The formulation according to claim 14, characterized in that the pH is from about 6.8 to about 7.

6. A formulation.

16. 16. The formulation according to claim 14 or 15, wherein the buffer is a phosphate buffer. A formulation characterized by:

17. 17. The formulation of claim 16, wherein the buffer is phosphate buffered saline. Characteristic formulation.

18. 17. The formulation of claim 16, wherein the buffer is a monobasic phosphate buffer and a dibasic phosphate buffer. A combination of phosphate buffers, wherein the concentration of each phosphate buffer is 2 mM to 50 mM. The formulation is characterized in that it is at mM.

19. 2. The formulation of claim 1, the concentration of the ganaxolone is 2 mg / mL to 8 mg / mL; The sulfobutylether-β-cyclodextrin w / The w ratio is in the range of about 52:1 to about 90:1; the formulation contains a buffer and has a pH of 6.7 to 7.3; The formulation contains 0.5 to 15% by weight of a surfactant; A formulation characterized in that

20. 2. The formulation of claim 1, the concentration of the ganaxolone is 1 mg / mL to 5 mg / mL; The weight percentage of the sulfobutylether-β-cyclodextrin is 25% to 35% %; The formulation may contain a surfactant, ethanol, glycerin, or propylene glycol. Contains 5% to 15% (by weight) of at least one of the following: A formulation characterized in that

21. The formulation according to any one of claims 1 to 19, further comprising a preservative. A formulation characterized by:

22. 21. The formulation of claim 20, wherein the preservative is benzyl alcohol, chlorobutanone ethanol, 2-ethoxyethanol, parabens (methyl, ethyl, propyl, butyl, and (including combinations thereof), benzoic acid, sorbic acid, chlorhexidene, phenol, 3-chlorhexidine, 2. A formulation comprising phenylmercuric acid, thimerosal, or phenylmercuric acid salt.

23. 23. The formulation of claim 22, wherein the inclusion complex is sulfobutylether-β-cyano. Ganaxolone obtained from the complex in water with a clodextrin concentration of about 30% w / v and providing at least 2.0 mg / mL of ganaxolone when measured in an amount of A formulation.

24. Lyophilized solution containing ganaxolone and sulfobutylether-β-cyclodextrin A dried ganaxolone formulation, said ganaxolone formulation comprising 1.0% to 1.5% ganaxolone. %.

25. A freeze-dried product comprising a ganaxolone formulation according to any one of claims 1 to 23. A dried ganaxolone formulation.

26. 26. The lyophilized ganaxolone formulation of claim 25, further comprising a surfactant, a buffer, and one or more preservatives.

27. 27. The lyophilized ganaxolone formulation of any one of claims 24 to 26, Lyophilized ganaxolone formulations can be reconstituted with water to give a clear solution. A lyophilized ganaxolone formulation comprising:

28. 28. The lyophilized ganaxolone formulation of claim 27, further comprising a bulking agent. A lyophilized ganaxolone formulation comprising:

29. 29. The lyophilized ganaxolone formulation of claim 28, wherein the bulking agent is mannitol. , lactose, sucrose, trehalose, sorbitol, glucose, raffinose, Glycine, histidine, polyethylene glycol (PEG), or polyvinylpyrrolide 1. A lyophilized ganaxolone formulation comprising polyvinyl phosphate (PVP).

30. A method of treating a patient suffering from a seizure disorder, stroke, or traumatic brain injury comprising administering to said patient a compound according to claim 1 or 2.

29. The method of claim 1, further comprising administering a therapeutically effective amount of a ganaxolone formulation according to any one of claims 1 to 29. A method comprising:

31. 31. The method of claim 30, wherein the seizure disorder is status epilepticus, refractory seizures, Status epilepticus, extremely refractory status epilepticus, or PCDH1 in women and children 9-associated epilepsy.

32. 32. The method of claim 30 or 31, wherein the dose of ganaxolone is about 1 mg / kg to about 200 mg / kg.

33. 33. The method of any one of claims 30 to 32, wherein the ganaxolone formulation is The method comprises administering the compound intramuscularly or intravenously.

34. 34. The method of any one of claims 30 to 33, comprising administering to the patient the ganaxolotl. The method comprises administering a single bolus dose of the formulation.

35. 35. The method of claim 34, wherein the bolus dose reduces the amount of GANA in the patient. Xolon Plasma C ｍａｘ is about 100 ng / mL to about 1000 ng / mL The method of claim 1, wherein a sufficient amount of ganaxolone is provided.

36. 35. The method of claim 34, wherein the bolus dose reduces the amount of GANA in the patient. Xolon Plasma C ｍａｘ is about 600 ng / mL to about 900 ng / mL The method of claim 1, wherein an amount of ganaxolone is provided.

37. 37. The method of any one of claims 34 to 36, wherein the bolus dose is administered over 10 minutes. Administered at less than C ｍａｘ occurs within 1 hour after administration is completed.

38. 35. The method of claim 34, wherein the single bolus dose is from about 1 mg / kg to about 2 mg / kg. 0 mg / kg of ganaxolone.

39. 34. The method of any one of claims 30 to 33, comprising administering to the patient the ganaxolotl. The method comprises administering multiple bolus doses of the formulation.

40. 40. The method of claim 39, wherein the multiple bolus doses are administered over a period of 1-10 days. and the administration is at intervals of 1 to 24 hours.

41. 40. The method of claim 39, wherein each bolus dose reduces ganaki activity in the patient. Solon's Plasma C ｍａｘ is about 100 ng / mL to about 1000 ng / mL The method of claim 1, wherein an amount of ganaxolone is provided.

42. 42. The method of claim 41, wherein the interval between the bolus doses is from about 10 to about 24 hours. And the first C ｍａｘ From that point on, the plasma concentration of ganaxolone increases The method is characterized in that the amount does not fall below 100 ng / mL at any time between doses.

43. 42. The method of claim 41, wherein the interval between the bolus doses is about 20 to about 24 hours. And the first C ｍａｘ From that point on, the patient's plasma concentration of ganaxolone is At any time between bolus doses, the first C ｍａｘ The characteristic of this method is that it is not less than 25% of the How to do it.

44. 44. The method of any one of claims 39 to 43, wherein each bolus dose is about 1 ml The method comprises administering to a patient in need thereof from about 20 mg / kg to about 20 mg / kg of said ganaxolone.

45. 33. The method of any one of claims 30 to 32, comprising administering an initial bolus dose. administering to said patient an intravenous infusion of said ganaxolone formulation with or without administration of A method comprising:

46. 46. ​​The method of claim 45, wherein the intravenous infusion is performed without administering an initial bolus dose. at a rate of 1 to 10 mg / kg / hour for 1 to 10 consecutive days. How to do this.

47. 46. ​​The method of claim 45, comprising administering from about 1 mg / kg to about 20 mg / kg of ganaxolone. followed by an initial bolus dose of the ganaxolone formulation intravenously within 24 hours. infusions at a rate of 1-10 mg / kg / hour for 1-10 consecutive days. The method of the present invention.

48. 48. The method of claim 47, wherein the initial bolus dose induces a decrease in the concentration of Initial plasma C ｍａｘ is about 100 ng / mL to about 1000 ng / mL and providing a sufficient amount of ganaxolone to maintain the patient's The plasma concentration of ganaxolone was ｍａｘ is not less than 25% of 。

49. 48. The method of claim 47, wherein the initial bolus dose induces a decrease in the concentration of The initial plasma C ｍａｘ is about 100 ng / mL to about 1000 ng / mL and then administering to the patient a sufficient amount of ganaxolone to the patient. The plasma concentration of Ron is C ｍａｘ A sufficient amount of said ganaxol to be at least 40% of The patient is administered an intravenous infusion of the ganaxolone formulation followed by intravenous administration of tapered doses of the ganaxolone formulation. administering an intravenous infusion, whereby upon completion of administration of the intravenous infusion, The plasma concentration of ganaxolone is ｍａｘ The method according to claim 1, wherein the concentration of the ion exchange resin is less than 20%.

50. 50. The method of any one of claims 30-49, wherein the ganaxolone formulation comprises: A first active agent, which is administered simultaneously or sequentially with at least one other active agent. The method according to claim 1,

51. 51. The method of claim 50, wherein the at least one additional active agent is an anticonvulsant or or an anesthetic / sedative.

52. 52. The method of claim 51, wherein the at least one additional active agent is GABA. Ａ Receptor modulators, sodium channel blockers, GAT-1 GABA transporter modulators GABA aminotransferase modulators, voltage-dependent calcium channel blockers, and peroxisome proliferator-activated alpha modulators. A method characterized in that

53. 52. The method of claim 51, wherein the at least one additional active agent is an inhalational anesthetic. (Desflurane, Enflurane, Ethyl chloride, Halothane, Isoflurane, Methoxyflurane , sevoflurane, and trichloroethylene), intravenous nonbarbiturate anesthetics Medications (atracurium, cisatracurium, etomidate, ketamine, propofol, and rocuronium), barbiturates (amobarbital, methohexidine, ethanol, pentobarbital, phenobarbital, secobarbital, thiamylal, and thiopental), and benzodiazepine anesthetics (diazepam, flunilate, anesthetic / sedative selected from the group consisting of azepam, lorazepam, and midazolam; A method comprising:

54. 52. The method of claim 51, wherein the additional active agent is an anesthetic / sedative agent, administering to the patient a dose of said anesthetic / sedative sufficient to induce coma. How to do it.

55. 55. The method of claim 54, wherein the additional active agent is a barbiturate. The method comprising:

56. 55. The method of claim 54, wherein the additional active agent is pentobarbital or thiamine. The method is characterized in that the compound is openthal.

57. 55. The method of claim 54, wherein the additional active agent is propofol. The method of the present invention.

58. 51. The method of claim 50, wherein a first additional active agent is an anticonvulsant and a second additional active agent is an anticonvulsant. wherein the active agent is an anesthetic / sedative.

59. 59. The method of claim 58, wherein the anticonvulsant is carbamazepine, tiagabine, levothyroxine, Betiracetam, lamotrigine, pregabalin, gabapentin, or phenytoin wherein the anesthetic / sedative is pentobarbital, thiopental, or propofol. The method according to claim 1,

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