Dantrolene preparations and methods of use thereof

Abstract

The present disclosure relates to liquid formulations of dantrolene, or pharmaceutically acceptable salts thereof, and methods of their use in the treatment of disease. [Selection diagram] None

Description

[Technical Field]

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 674,394, filed May 21, 2018, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to liquid formulations of dantrolene, or pharmaceutically acceptable salts thereof, and methods of their use in the treatment of disease. [Background technology]

[0003] Dantrolene (1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino}imidazolidine-2,4-dione) has the structure of formula (1) [ka] It has.

[0004] Dantrolene is the rescue agent of choice for the treatment of malignant hyperthermia (MH) and is widely available in most settings where anesthetic drugs are administered. First synthesized in 1967, dantrolene was first used to treat muscle spasms in 1975 and subsequently received FDA approval for the treatment of MH in 1979. Dantrolene is recognized as a potent muscle relaxant and a treatment for neurospasticity. Since its initial discovery, dantrolene has been explored for the prevention and treatment of other life-threatening conditions, such as overdose of recreational drugs such as ecstasy (N-methyl-3,4-methylenedioxyphenylisopropylamine), heatstroke, neuroleptic malignant syndrome, and ischemic disorders of the peripheral nervous system, and may play an important role in preventing sudden infant death syndrome (SIDS).

[0005] Dantrolene is very poorly soluble in water. Poor solubility of dantrolene significantly impairs administration. For example, DANTRIUM™ is dantrolene sodium supplied in a 20 mg vial, which must be reconstituted with 60 mL of sterile water before intravenous administration. The recommended dose of dantrolene to treat MH is 1 mg / kg to approximately 10 mg / kg. Therefore, a subject weighing 80 kg would require a rapid infusion of up to 2400 mL to treat MH.

[0006] In addition to poor solubility, dantrolene solutions have a high pH. DANTRIUM™ has a pH of approximately 9.5. RYANODEX®, an improved dantrolene sodium formulation that can be reconstituted to 50 mg / mL, significantly improves the rate of administration of dantrolene sodium. However, the pH of reconstituted RYANODEX® is also high, approximately 10.3. Due to its high pH, ​​dantrolene formulations currently cannot be administered subcutaneously or intramuscularly, but can only be administered intravenously. Indeed, care must be taken to prevent extravasation into surrounding tissues to avoid tissue necrosis.

[0007] New formulations of dantrolene with appropriate concentrations and pH levels suitable for intravenous administration are needed. The prior art documents relevant to the invention of this application are as follows (including documents cited in the international phase after the international filing date and documents cited when the application entered the national phase in other countries). (Prior art document) (Patent document) (Patent Document 1) U.S. Patent Application Publication No. 2017 / 143677 Summary of the Invention

[0008] The present disclosure relates to dantrolene, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and 1-6 This invention relates to non-aqueous or anhydrous pharmaceutical compositions having a pharmaceutically acceptable carrier comprising an alkyl alcohol, a polyol, a polyether, or a mixture thereof. Methods of using these compositions to treat disorders responsive to dantrolene are also described. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure may be more readily understood by reference to the following detailed description taken in conjunction with the accompanying figures and examples that form a part of this disclosure: It is to be understood that the present disclosure is not limited to the specific compositions, devices, methods, applications, conditions, or parameters described and / or illustrated herein, and that the terminology used herein is exemplary only and is for the purpose of describing particular embodiments and is not intended to limit the claimed disclosure.

[0010] As used in the specification, including the appended claims, the singular forms "a," "an," and "the" include the plural, and a reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise.

[0011] When a range of values ​​is expressed, exemplary embodiments include from one particular value and / or to the other particular value. All ranges are inclusive and combinable. Furthermore, reference to values ​​stated in a range includes all values ​​within that range. For example, the phrase "about 2 to about 4" also discloses a range of "2 to 4." When values ​​are expressed as approximations, by use of the preposition "about," it will be understood that the particular value forms another embodiment. The term "about," as used herein when referring to a measurable value, such as an amount, a temporal duration, or the like, is meant to encompass a reasonable variation of the value, e.g., ±10% from the specified value. For example, the phrase "about 50%" can include ±10% of 50, or 45% to 55%, inclusive.

[0012] It should be understood that certain features of the disclosure that are, for clarity, described herein in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any subcombination.

[0013] It should be understood that certain features of the present disclosure that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present disclosure that are described in the context of a single embodiment may also be provided separately or in any subcombination. Furthermore, references to values ​​stated in ranges include all values ​​within that range.

[0014] It should be understood that as used herein, the phrases "method of treating" and "method of treatment," by themselves or in combination with other terms, can be used interchangeably with the phrase "for use in treating" a particular condition.

[0015] As used herein, by itself or in combination with another term, "pharmaceutically acceptable" indicates that the specified entity, e.g., a pharmaceutically acceptable excipient, is generally chemically and / or physically compatible with the other ingredients in the composition and / or generally physiologically compatible with its recipient.

[0016] As used herein, the term "pharmaceutical composition" is intended to mean a composition suitable for administration to a human and comprising pharmaceutically acceptable excipients, such as, but not limited to, stabilizers, fillers, buffers, carriers, diluents, vehicles, solubilizers, and binders.

[0017] "Pharmaceutically acceptable excipient" means a substance that is non-toxic, biologically tolerable, and suitable for administration to a subject, e.g., an inert substance that can be added to a pharmacological composition or used as a vehicle, carrier, or diluent to facilitate administration of a drug, and is compatible with such substances. Examples of excipients are described, for example, in Remington's Pharmaceutical Sciences, 17 th They are listed in ed. (1985).

[0018] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed when the compound coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. When the compound contains a basic functional group, non-toxic organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, or oxalate are included.

[0019] As used herein, by itself or in combination with other terms, "subject," "individual," and "patient" refer to a mammal, including a human. The term human refers to and includes a human child, adolescent, or adult.

[0020] As used herein, by itself or in combination with another term, "treats," "treating," "treated," and "treatment" mean and include ameliorative, palliative, and / or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylactically. It is understood that "prevention" or a prophylactic use or result does not refer to or require absolute or complete prevention (i.e., a 100% preventative or protective use or result). As used herein, a prophylactic or preventative use or result means a use or result in which administration of a compound or composition results in lessening or reducing the severity of a particular condition, symptom, disorder, or disease described herein; a use or result in which the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein is reduced; or a use or result in which the onset or recurrence (recurrence) of a particular condition, symptom, disorder, or disease described herein is delayed; or any combination of the foregoing.

[0021] As used herein, by itself or in combination with another term, "therapeutically" and "therapeutically effective amount" refer to an amount of a compound or composition that (a) treats a specific condition, symptom, disorder, or disease described herein, (b) reduces, ameliorates, or eliminates one or more symptoms of a specific condition, symptom, disorder, or disease described herein, or (c) delays the onset or recurrence (recurrence) of a specific condition, symptom, disorder, or disease described herein. The terms "therapeutic" and "therapeutically effective" should be understood to encompass any of the foregoing effects (a)-(c), alone or in combination with any of the others (a)-(c).

[0022] As used herein, "ameliorate" refers to a lessening of the severity of the disorder or condition being treated in a particular subject or subject population.

[0023] The present disclosure relates to a liquid pharmaceutical composition having dantrolene (also referred to herein as "dantrolene acid"), or a pharmaceutically acceptable salt thereof, or a mixture thereof (i.e., a mixture of dantrolene and a pharmaceutically acceptable salt of dantrolene), and a pharmaceutically acceptable carrier. 1-6 The liquid carrier comprises an alkyl alcohol, a polyol, or a mixture thereof. In the most preferred embodiment, the composition is a solution, i.e., a liquid in which the solute is dissolved in the carrier.

[0024] The present disclosure also relates to lyophilized pharmaceutical compositions comprising a mixture of dantrolene (i.e., dantrolene acid) and a pharmaceutically acceptable salt of dantrolene. Preferred ratios of dantrolene to dantrolene salt in these lyophilized pharmaceutical compositions include, for example, 90:10 to 70:30, preferably 90:10, 80:20, 75:25, or 70:30. Preferably, in these embodiments, the lyophilized pharmaceutical composition has 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, or 70% (w / w) dantrolene, with the remainder being dantrolene salt (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, or 30% (w / w)), based on the total weight of dantrolene and dantrolene salt. 1-6 When reconstituted with a pharmaceutically acceptable carrier that is an alkyl alcohol, a polyol, a polyether, or a mixture thereof, the reconstituted lyophilized pharmaceutical composition has an effective pH of 4 to about 9, e.g., 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.49, 5.50, 5.51, 5.52, 5.53, 5.54, 5.55, 5.56, 5.57, 5.58, 5.59, 5.60, 5.61, 5.62, 5.63, 5.64, 5.65, 5.66, 5.67, 5.68, 5. Indicates a pH of 7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, or 9.5.

[0025] In some embodiments, the pharmaceutical composition comprises dantrolene and excludes pharmaceutically acceptable salts of dantrolene. In these embodiments, the pharmaceutical composition comprises greater than 95% (w / w) dantrolene based on the combined weight of dantrolene and dantrolene salts. Preferably, in these embodiments, the pharmaceutical composition comprises greater than 96, 97, 98, 99, or 99% (w / w) dantrolene based on the combined weight of dantrolene and dantrolene salts.

[0026] In some embodiments, the pharmaceutical composition comprises dantrolene and a pharmaceutically acceptable salt of dantrolene. In some embodiments, the pharmaceutical composition comprises dantrolene and dantrolene sodium. In these embodiments, the pharmaceutical composition can comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 95% (w / w) of dantrolene, based on the total weight of the dantrolene and the dantrolene salt. In other embodiments, the pharmaceutical composition can comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 95% (w / w) of the dantrolene salt. Preferred ratios of dantrolene:dantrolene salt include, for example, 90:10, 80:20, 75:25, 70:30. Other ratios of dantrolene:dantrolene salt include 60:40, 50:50, 40:60, 30:70, 25:75, 20:80, and 10:90.

[0027] In these embodiments, the pharmaceutical composition is a lyophilized pharmaceutical composition comprising a mixture of dantrolene and a pharmaceutically acceptable salt of dantrolene.

[0028] The preferred dantrolene salt is dantrolene sodium. Other dantrolene salts are within the scope of this disclosure.

[0029] The pharmaceutical compositions of the present disclosure are preferably non-aqueous. As used herein, "non-aqueous" refers to a composition having 10% (w / v) or less water. In a preferred embodiment, a "non-aqueous" composition has 5% (w / v) or less water. For example, a "non-aqueous" composition can contain 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10% (w / v) water.

[0030] In other embodiments, the pharmaceutical composition of the present disclosure is anhydrous.As used herein, "anhydrous" refers to a composition having less than 0.1% (w / v) water.For example, an "anhydrous" composition may contain water in an amount below the detection limit using conventional methods and equipment.

[0031] The pharmaceutical compositions of the present disclosure have an effective pH of 3 to 11.5. As used herein, "effective pH" refers to the pH of a non-aqueous or anhydrous composition as measured using the methods described herein. For example, the pharmaceutical compositions of the present disclosure have an effective pH of 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, or 11.5. In some embodiments, the effective pH of the pharmaceutical composition is 4 to 9. In other embodiments, the effective pH of the pharmaceutical composition is 5 to 8. In other embodiments, the effective pH of the pharmaceutical composition is approximately physiological pH, i.e., 7.4.

[0032] The pharmaceutical compositions of the present disclosure also include a pharmaceutically acceptable carrier. The carrier is a liquid carrier, 1-6The organic solvent may be an alkyl alcohol, a polyol, a polyether, or a mixture thereof. As used herein, a "polyol" is a liquid organic composition containing at least two hydroxyl (-OH) moieties. As used herein, a "polyether" is a liquid organic composition containing at least two alkenyl ether moieties.

[0033] In the pharmaceutical compositions of the present disclosure, dantrolene can be present at a concentration of about 1 mg / mL to about 200 mg / mL, preferably 5 mg / mL to about 125 mg / mL. In certain embodiments of the present disclosure, dantrolene is present at a concentration of about 5 mg / mL or greater. In certain embodiments of the present disclosure, dantrolene is present at a concentration of about 6 mg / mL or greater. In certain embodiments of the present disclosure, dantrolene is present at a concentration of about 7 mg / mL or greater. In certain embodiments of the present disclosure, dantrolene is present at a concentration of about 8 mg / mL or greater. In certain embodiments of the present disclosure, dantrolene is present at a concentration of about 9 mg / mL or greater. In certain embodiments of the present disclosure, dantrolene is present at a concentration of about 10 mg / mL or greater. In further embodiments, dantrolene is present at a concentration of about 10-25 mg / mL. In yet another embodiment, dantrolene is present at a concentration of about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, or 50 mg / mL. In yet another embodiment, dantrolene is present at a concentration of about 125 mg / mL, 150 mg / mL, 175 mg / mL, or about 200 mg / mL.

[0034] In certain embodiments, dantrolene is present at a concentration of about 55 mg / mL or greater. In further embodiments, dantrolene is present at a concentration of about 55 to 125 mg / mL. In certain embodiments, dantrolene is present at a concentration of about 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 105 mg / mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, or 125 mg / mL. In other embodiments, dantrolene is present at a concentration of about 75 mg / mL to 95 mg / mL, 80 mg / mL to 100 mg / mL, 90 mg / mL to 110 mg / mL, 95 mg / mL to 105 mg / mL, 95 mg / mL to 115 mg / mL, 100 mg / mL to 110 mg / mL, or 110 mg / mL to 125 mg / mL, including all ranges and subranges therebetween.

[0035] According to the present disclosure, C 1-6 The alkyl alcohol is an alcohol suitable for human administration. 1-6 The alkyl alcohol is ethanol. The carrier is C 1-6 Alkyl alcohol (or C 1-6 In these embodiments, the carrier may be composed of more than 95% (v / v) C 1-6 Alkyl alcohol (or C 1-6 Alkyl alcohol mixtures), e.g., 96, 97, 98, 99, or greater than 99% (v / v) C 1-6 Alkyl alcohol (or C 1-6 In other embodiments, the carrier comprises a C alkyl alcohol in combination with one or more polyols. 1-6 Alkyl alcohol (or C 1-6 In these embodiments, the carrier may have a concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) C 1-6 Alkyl alcohol (or C 1-6 The remainder may be a polyol.

[0036] According to the present disclosure, the polyol is suitable for human administration and is an alkylene glycol (preferably C 1-6 The alkyl glycol is preferably a mixture of alkylene glycols (e.g., propylene glycol). The preferred alkylene glycol is propylene glycol. Ethylene glycol is also within the scope of this disclosure.

[0037] According to the present disclosure, the polyether is suitable for human administration and is a liquid polyalkyl ether or a mixture of liquid polyalkyl ethers. A preferred polyalkylene ether is liquid polyethylene glycol (PEG), such as PEG200, PEG300, PEG400, PEG500, or PEG600. PEG400 is a particularly preferred PEG. In another embodiment, the polyether is a liquid "capped" polyalkylene glycol, i.e., a polyalkylene glycol terminated at one or both ends with a non-hydroxyl moiety. Capped PEGs within the scope of the present disclosure include polyalkylene glycol monomethyl ether and polyalkylene glycol dimethyl ether.

[0038] The carrier can be composed of a polyol or a polyether, i.e., an alkylene glycol, a liquid polyalkylene glycol, or a liquid capped polyalkylene glycol. Preferably, the carrier is composed of an alkylene glycol or a liquid polyalkylene glycol. In another embodiment, the carrier comprises a capped polyalkylene glycol.

[0039] In other embodiments, the carrier comprises a polyol and a polyether, such as a mixture of alkylene glycols, a mixture of polyalkylene glycols, a mixture of capped polyalkylene glycols, a mixture of alkylene glycols and polyalkylene glycols, a mixture of alkylene glycols and capped polyalkylene glycols, or a mixture of polyalkylene glycols and capped polyalkylene glycols. 1-6 In yet another embodiment, the carrier may comprise an alkyl alcohol, an alkyl glycol, and a liquid polyalkylene glycol. 1-6 It can have alkyl alcohols, alkyl glycols, and capped liquid polyalkylene glycols.

[0040] In those embodiments in which the carrier comprises a polyol, the carrier can have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) of the polyol or polyols. In other embodiments, the carrier can contain more than 95% (v / v) of the polyol or polyols, e.g., more than 96, 97, 98, 99, or 99% (v / v) of the polyol or polyols.

[0041] In those embodiments in which the carrier comprises an alkylene glycol or alkylene glycols, the carrier can have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) alkylene glycol or alkylene glycols. In other embodiments, the carrier can have more than 95% (v / v) alkylene glycol or alkylene glycols, e.g., more than 96, 97, 98, 99, or 99% (v / v) alkylene glycol or alkylene glycols. For example, in a preferred embodiment, the carrier comprises propylene glycol. In these embodiments, the carrier can have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) propylene glycol. In other embodiments, the carrier has more than 95% (v / v) propylene glycol, e.g., more than 96, 97, 98, 99, or 99% propylene glycol. In some embodiments, the carrier has 100% propylene glycol.

[0042] In those embodiments in which the carrier comprises a polyalkylene glycol or polyalkylene glycols, the carrier can have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) of the polyalkylene glycol or polyalkylene glycols. In other embodiments, the carrier can have more than 95% (v / v) of the polyalkylene glycol or polyalkylene glycols, e.g., more than 96, 97, 98, 99, or 99% (v / v) of the polyalkylene glycol or polyalkylene glycols. For example, in preferred embodiments, the carrier comprises a liquid polyethylene glycol, e.g., PEG200, PEG300, PEG400, PEG500, or PEG600, or a combination thereof. In some embodiments, the carrier may have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) PEG. In some embodiments, the carrier may have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) PEG mixture. In other embodiments, the carrier has more than 95% (v / v) PEG or mixture of PEG, e.g., more than 96, 97, 98, 99, or 99% (v / v) PEG or mixture of PEG. In some embodiments, the carrier has 100% PEG, e.g., 100% PEG200, PEG300, PEG400, PEG500, or PEG600.

[0043] In those embodiments in which the carrier comprises one capped polyalkylene glycol or two or more capped polyalkylene glycols, the carrier can have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) of the capped polyalkylene glycol or capped polyalkylene glycols. In other embodiments, the carrier can have more than 95% (v / v) of the capped polyalkylene glycol or capped polyalkylene glycols, e.g., more than 96, 97, 98, 99, or 99% (v / v) of the capped polyalkylene glycol or capped polyalkylene glycols. In some embodiments, the carrier may have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) capped polyalkylene glycol. In some embodiments, the carrier may have 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) capped polyalkylene glycol mixture. In other embodiments, the carrier has more than 95% (v / v) capped polyalkylene glycol, or a mixture of capped polyalkylene glycols, e.g., more than 96, 97, 98, 99, or 99% (v / v) capped polyalkylene glycol, or more than 96, 97, 98, 99, or 99% (v / v) capped polyalkylene glycol. In some embodiments, the carrier has 100% capped polyalkylene glycol.

[0044] In some embodiments, the carrier comprises ethanol, propylene glycol, and PEG. In these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) ethanol, with the remainder comprising propylene glycol and PEG. In other embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) propylene glycol, with the remainder comprising ethanol and PEG. In other embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) PEG, with the remainder being ethanol and propylene glycol.

[0045] In some embodiments, the carrier comprises ethanol, propylene glycol, and capped PEG. In these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) ethanol, with the remainder comprising propylene glycol and capped PEG. In other embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) propylene glycol, with the remainder comprising ethanol and capped PEG. In other embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) capped PEG, with the remainder being ethanol and propylene glycol.

[0046] In some embodiments, the carrier comprises ethanol and propylene glycol. In these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) ethanol, with the remainder being propylene glycol. In other of these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) propylene glycol, with the remainder being ethanol.

[0047] In some embodiments, the carrier comprises ethanol and PEG. In these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) ethanol, with the remainder being PEG. In other of these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) PEG, with the remainder being ethanol.

[0048] In some embodiments, the carrier comprises propylene glycol and PEG. In these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) propylene glycol, with the remainder comprising PEG. In other of these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) PEG, with the remainder comprising propylene glycol.

[0049] In some embodiments, the carrier comprises propylene glycol and capped PEG. In these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) propylene glycol, with the remainder comprising capped PEG. In other of these embodiments, the carrier may comprise 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (v / v) capped PEG, with the remainder comprising propylene glycol.

[0050] In certain embodiments, the pharmaceutical composition of the present disclosure may further comprise an additional pharmaceutically acceptable excipient. For example, the pharmaceutical composition of the present disclosure may further comprise a stabilizer or two or more stabilizers. In yet another embodiment of the present disclosure, the stabilizer is selected from the group consisting of surfactants, polymers, cross-linked polymers, buffers, electrolytes, and non-electrolytes. In yet another embodiment of the present disclosure, the composition comprises a combination of two or more stabilizers selected from the group consisting of surfactants, polymers, cross-linked polymers, buffers, electrolytes, and non-electrolytes. In yet another embodiment of the present disclosure, the stabilizer is a surfactant, such as, but not limited to, polysorbate 80, polysorbate 20, poloxamer 188, polyethoxylated vegetable oil, lecithin, human serum albumin, and mixtures thereof. In certain embodiments of the present disclosure, the stabilizer is a polymer, such as polyvinylpyrrolidone (such as, but not limited to, povidone K12, povidone K17, and mixtures thereof), polyethylene glycol 3350, and mixtures thereof. In other embodiments of the present disclosure, the stabilizer is an electrolyte, such as, but not limited to, sodium chloride, calcium chloride, and mixtures thereof. In yet other embodiments of the present disclosure, the stabilizer is a non-electrolyte, such as, but not limited to, dextrose, glycerol, mannitol, benzyl benzoate, or mixtures thereof. In other embodiments of the present disclosure, the stabilizer is a cross-linked polymer, such as, but not limited to, sodium carboxymethylcellulose (CMC). In some embodiments of the present disclosure, the stabilizer is CMC 7LF, CMC 7MF, CMC 7HF, or mixtures thereof.

[0051] In further embodiments of the present disclosure, a combination of non-electrolyte stabilizers and electrolytic stabilizers can be used. In some embodiments, the combination of stabilizers can have two or more non-electrolyte stabilizers. In other embodiments, the combination of stabilizers can have two or more electrolytic stabilizers. In further embodiments, the combination of stabilizers can have one or more non-electrolyte stabilizers and one or more electrolytic stabilizers. In yet another embodiment, the combination of stabilizers can have two or more of mannitol, dextrose, and sodium chloride.

[0052] In certain embodiments of the present disclosure, a combination of surfactant stabilizers and polymer stabilizers can be used. In some embodiments, the combination of stabilizers can include two or more surfactant stabilizers. In other embodiments, the combination of stabilizers can include two or more polymer stabilizers. In further embodiments, the combination of stabilizers can include one or more surfactant stabilizers and one or more polymer stabilizers. In yet another embodiment, the combination of stabilizers can include two or more of polysorbate 80, polysorbate 20, and poloxamer 188. In yet another embodiment, the combination of stabilizers can include one or more of polysorbate 80, polysorbate 20, and poloxamer 188 with one or more of povidone K12, povidone K17, and polyethylene glycol 3350.

[0053] In certain embodiments of the present disclosure, the composition has one or more excipients at about 0.2 mg / mL to about 75 mg / mL, including all ranges and subranges therebetween. In certain embodiments of the present disclosure, the composition has one or more excipients at about 0.2-0.7 mg / mL, 0.5-1 mg / mL, 1-5 mg / mL, 2-8 mg / mL, 5-6 mg / mL, 5-10 mg / mL, 8-12 mg / mL, 10-15 mg / mL, 15-20 mg / mL, 20-30 mg / mL, 30-40 mg / mL, 40-50 mg / mL, 45-55 mg / mL, 50-60 mg / mL, or 60-75 mg / mL, including all ranges and subranges therebetween. In further embodiments of the disclosure, the composition has about 0.2 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 15 mg / mL, 17 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, or 75 mg / mL of one or more excipients.

[0054] The pharmaceutical compositions of the present disclosure can be administered intravenously. Pharmaceutical compositions administered intravenously are sterile. Alternatively, the pharmaceutical compositions of the present disclosure can be administered intramuscularly. Pharmaceutical compositions administered intramuscularly are sterile. In other embodiments, the pharmaceutical compositions of the present disclosure are administered subcutaneously. Pharmaceutical compositions administered subcutaneously are sterile. The pharmaceutical compositions of the present disclosure can also be administered orally. Pharmaceutical compositions administered orally can be sterile, but sterility is not required. In other embodiments, the pharmaceutical compositions of the present disclosure are administered intramuscularly, for example, via intranasal administration. Pharmaceutical compositions administered mucosally are sterile. In other embodiments, the pharmaceutical compositions of the present disclosure are administered intraosseously. Pharmaceutical compositions administered intraosseously are sterile.

[0055] The pharmaceutical compositions of the present disclosure can be administered "as is," i.e., without the addition of further diluents or other excipients. In other embodiments, the pharmaceutical compositions of the present disclosure are diluted with a pharmaceutically acceptable diluent prior to administration.

[0056] Some embodiments of the present disclosure relate to a non-aqueous or anhydrous pharmaceutical composition having dantrolene, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and 1-6 The present invention relates to pharmaceutically acceptable carriers comprising alkyl alcohols, polyols, polyethers, or mixtures thereof. Such carriers are described in more detail elsewhere herein. These pharmaceutical compositions exhibit an effective pH that is physiologically compatible with administration to humans. For example, the pharmaceutical compositions exhibit an effective pH between 4 and 9. The pharmaceutical compositions can be administered "as is," or they can be diluted with additional pharmaceutically acceptable carriers, e.g., aqueous carriers such as water for injection, sodium chloride injection, dextrose injection, Ringer's injection, etc., before being administered to a subject in a therapeutically effective amount using any of the administration routes described herein.

[0057] In some embodiments using a lyophilized pharmaceutical composition having dantrolene and pharmaceutically acceptable salts of dantrolene (preferably dantrolene and dantrolene sodium), the lyophilized pharmaceutical composition comprises C 1-6 The reconstituted lyophilized pharmaceutical compositions are reconstituted with a pharmaceutically acceptable carrier, which may be an alkyl alcohol, a polyol, a polyether, or a mixture thereof. Such carriers are described in more detail elsewhere herein. These reconstituted lyophilized pharmaceutical compositions exhibit an effective pH that is physiologically compatible with administration to humans. For example, the reconstituted lyophilized pharmaceutical compositions exhibit an effective pH between 4 and 9. The reconstituted lyophilized pharmaceutical compositions can be administered "as is," or they can be diluted with additional pharmaceutically acceptable carriers, e.g., aqueous carriers such as water for injection, sodium chloride injection, dextrose injection, Ringer's injection, etc., before being administered in a therapeutically effective amount to a subject using any of the administration routes described herein.

[0058] The pharmaceutical composition of the present disclosure can be used to treat disorders that respond to dantrolene.See, for example, U.S. Patent Nos. 7,758,890, 8,110,225, 8,685,460, 9,271,964, 9,603,840, 9,789,090, 9,884,044, and U.S. Provisional Application No. 62 / 554,049, filed September 5, 2017, the entire contents of which are incorporated herein by reference.In other embodiments, a subject in need of treatment can be administered a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

[0059] Disorders that are responsive to dantrolene include, for example, malignant hyperthermia, chronic spasticity, exertional heat stroke, cardiac arrhythmia, tachycardia, atrial fibrillation, cardiac arrest, myocardial infarction, heart failure, myocardial injury, cardiomyopathy, central nervous system disease, amyotrophic lateral sclerosis, rhabdomyolysis, Duchenne muscular dystrophy, ataxia, detrusor overactivity, overactive bladder, seizures, epilepsy, neuroleptic malignant syndrome, human stress disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, ischemia-reperfusion injury, nerve reperfusion injury, hypoxia, cerebral aneurysm, subarachnoid hemorrhage, stroke, hyperthermia associated with drug abuse, or hyperthermia associated with drug overdose.

[0060] In a preferred embodiment, the pharmaceutical compositions of the present disclosure are used to treat malignant hyperthermia in a subject.

[0061] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat chronic spasticity in a subject.

[0062] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat exertional heat stroke in a subject.

[0063] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat cardiac arrhythmia in a subject.

[0064] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat tachycardia in a subject.

[0065] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat atrial fibrillation in a subject.

[0066] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat cardiac arrest in a subject.

[0067] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat myocardial infarction in a subject.

[0068] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat heart failure in a subject.

[0069] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat myocardial injury in a subject.

[0070] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat cardiomyopathy in a subject.

[0071] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat a central nervous system disorder in a subject.

[0072] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat amyotrophic lateral sclerosis in a subject.

[0073] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat rhabdomyolysis in a subject.

[0074] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat Duchenne muscular dystrophy in a subject.

[0075] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat ataxia in a subject.

[0076] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat detrusor overactivity in a subject.

[0077] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat overactive bladder in a subject.

[0078] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat a stroke in a subject.

[0079] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat epilepsy in a subject.

[0080] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat neuroleptic malignant syndrome in a subject.

[0081] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat a human stress disorder in a subject.

[0082] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat Alzheimer's disease in a subject.

[0083] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat Huntington's disease in a subject.

[0084] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat multiple sclerosis in a subject.

[0085] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat Parkinson's disease in a subject.

[0086] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat ischemia-reperfusion injury in a subject.

[0087] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat nerve reperfusion injury in a subject.

[0088] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat hypoxia in a subject.

[0089] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat a cerebral aneurysm in a subject.

[0090] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat subarachnoid hemorrhage in a subject.

[0091] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat stroke in a subject.

[0092] In other embodiments, the pharmaceutical compositions of the present disclosure are used to treat hyperthermia associated with substance abuse (e.g., ecstasy (3,4-methylenedioxymethamphetamine) abuse) in a subject.

[0093] In other aspects, the pharmaceutical compositions of the present disclosure are used to treat acetylcholine accumulation in a subject.

[0094] In other embodiments, the compounds and / or pharmaceutical compositions of the present disclosure are used to treat neurotoxic nerve gas exposure, e.g., organophosphate agents such as sarin, soman, and VX, in a subject. As used herein, "neurotoxic nerve agent" or "nerve gas" refers to a compound that affects the transmission of nerve impulses in the nervous system. Nerve gases are organophosphate compounds, i.e., they are of the formula (R)P(O), where each R group can be the same or different. "G"-type nerve agents include O-pinacolylmethylphosphonofluoridate (soman, GD), ethyl N,N-dimethylphosphoramidocyanidate (tabun, GA), propan-2-ylmethylphosphonofluoridate (sarin, GB), cyclohexylmethylphosphonofluoridate (cyclosarin, GF), and 2-(dimethylamino)ethyl (GV). "V" type nerve agents include O-cyclopentyl S-(2-diethylaminoethyl)methyl phosphonothiolate (EA-3148), (S)-(ethyl{[2-(diethylamino)ethyl]sulfonyl}(ethyl)phosphonate), e.g., (S)-(ethyl{[2-(diethylamino)ethyl]sulfanyl}(ethyl)phosphinate) (VE), O,O-diethyl S-[2-(diethylamino)ethyl]phosphorothioate (VG), S-[2-(diethylamino)ethyl]O-ethylmethyl Nerve agents that are effective against nerve agents include phosphonothioate (VM), N,N-diethyl-2-(methyl-(methyl-(2-methylpropoxy)phosphoryl)sulfanyltanamine (VR), and ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate (VX). The methods described herein can be used to treat a subject exposed to one nerve agent. The methods described herein can also be used to treat a subject exposed to two or more nerve agents.

[0095] The amount of dantrolene or a pharmaceutically acceptable salt thereof that is therapeutically effective in treating a subject according to any of the described methods should be determined by a practitioner skilled in the art. In these embodiments in which the subject is a human, the therapeutically effective amount of dantrolene is 1 mg / kg to about 30 mg / kg, which can be administered in a single dose or in two or more doses. In other embodiments, the therapeutically effective amount of dantrolene is 1 mg / kg to about 20 mg / kg. In other embodiments, the therapeutically effective amount of dantrolene is about 5 mg / kg to about 30 mg / kg. In other embodiments, the therapeutically effective amount of dantrolene is about 10 mg / kg to about 30 mg / kg. In other embodiments, the therapeutically effective amount of dantrolene is about 15 mg / kg to about 30 mg / kg. In other embodiments, the therapeutically effective amount of dantrolene is about 20 mg / kg to about 30 mg / kg. In other embodiments, the therapeutically effective amount of dantrolene is about 5 mg / kg to about 20 mg / kg. In another embodiment, the therapeutically effective amount of dantrolene is about 5 mg / kg to about 15 mg / kg. In another embodiment, the therapeutically effective amount of dantrolene is about 5 mg / kg to about 10 mg / kg. In another embodiment, the therapeutically effective amount of dantrolene is about 10 mg / kg to about 20 mg / kg. In another embodiment, the therapeutically effective amount of dantrolene is about 2 mg / kg to about 10 mg / kg, preferably about 2 mg / kg to about 6 mg / kg. In another embodiment, the therapeutically effective amount of dantrolene is about 15 mg / kg to about 20 mg / kg. In another embodiment, the therapeutically effective amount of dantrolene is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or about 30 mg / kg. In some embodiments, a therapeutically effective amount of dantrolene for treating a human subject is greater than 30 mg / kg, e.g., 30 mg / kg to about 100 mg / kg, which can be administered in one or two doses. In some embodiments, a therapeutically effective amount of dantrolene for treating a human subject is about 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg / kg.

[0096] The following examples are provided to illustrate some of the concepts described within this disclosure. Each example is considered to provide a particular individual embodiment of the disclosure, but no example should be considered to limit the more general embodiments described herein. In the following examples, efforts have been made to ensure accuracy with respect to numbers used (amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0097] Example Example 1. Solubility in PEG400 and pH 11.2 mg of dantrolene was added to 224 μL of PEG400. After vortexing, the liquid became cloudy and solids remained at the bottom of the Eppendorf tube, indicating a saturated solution was obtained. The tube was centrifuged at 15,000 rpm for 5 minutes at room temperature to separate the sample into a supernatant (dantrolene in solution) and a pellet (insoluble material). The supernatant was transferred to a clean tube and diluted 100x, 200x, and 400x with 25% acetonitrile for analysis by UPLC as described below. The solubility of dantrolene in PEG400 was calculated to be ~15 mg / mL.

[0098] The pH of the supernatant was measured by diluting the supernatant 10 times in water. The pH was measured to be 4.88. The 10-fold dilution resulted in immediate precipitation.

[0099] Example 2. Solubility in propylene glycol and pH 16.3 mg of dantrolene was added to 326 μL of propylene glycol. After vortexing, the liquid became cloudy and solids remained at the bottom of the Eppendorf tube, indicating a saturated solution was obtained. The tube was centrifuged at 15,000 rpm for 5 minutes at room temperature to separate the sample into a supernatant (dantrolene in solution) and a pellet (insoluble material). The supernatant was transferred to a clean tube and diluted 50x, 100x, and 200x with 25% acetonitrile for analysis by UPLC as described below. The solubility of dantrolene in propylene glycol was calculated to be ~0.8 mg / mL.

[0100] The effective pH of the supernatant was determined by diluting the supernatant 10 times in water. The pH was measured to be 5.73. The 10 times dilution resulted in a slow precipitation.

[0101] Example 3. Various ratios for determining formulation at physiological pH pH of various 10 mg / mL dantrolene acid PEG400:dantrolene sodium samples. 13.0 mg of dantrolene acid was dissolved in 1.3 mL of PEG 400 to target a 10 mg / mL dantrolene acid concentration. 12.7 mg of dantrolene sodium was dissolved in 1.27 mL of PEG 400 to target a 10 mg / mL dantrolene sodium concentration. The liquid in the dantrolene acid sample became cloudy after vortexing, with some solids remaining at the bottom of the Eppendorf tube, indicating a saturated solution had been achieved. The dantrolene sodium sample was clear, indicating complete dissolution of the dantrolene sodium. Both tubes were centrifuged at 3,900 rpm for 5 minutes at room temperature to separate the samples into a supernatant (dantrolene acid or dantrolene sodium in solution) and a pellet (insoluble material). The dantrolene acid sample formed a pellet, while the dantrolene sodium sample did not. The supernatant from the dantrolene acid sample was transferred to a clean tube. Dantrolenic acid supernatants and dantrolene sodium solutions were diluted 100- and 200-fold with 25% acetonitrile and analyzed by UPLC as described below.

[0102] The effective pH of the dantrolene acid supernatant and dantrolene sodium samples was determined by diluting 10-fold in water according to the method described elsewhere herein. The pH of the dantrolene acid supernatant was determined to be 4.95. The pH of the dantrolene sodium was determined to be 9.67.

[0103] Dantrolenic acid supernatant and dantrolene sodium solution were mixed at various ratios of acid:base (sodium) based on volume. Four separate samples with different ratios were made. 90:10 (180 uL dantrolene acid + 20 uL dantrolene sodium) 80:20 (160 uL dantrolene acid + 40 uL dantrolene sodium) 75:25 (150 uL dantrolene acid + 50 uL dantrolene sodium) 70:30 (140 uL dantrolene acid + 60 uL dantrolene sodium)

[0104] The effective pH of each sample was measured by diluting it 10 times with water. The pH values ​​were recorded as follows: 90:10 pH5.58 80:20 pH 6.72 75:25 pH7.34 70:30 pH9.00

[0105] A 100-fold and 200-fold dilution of each of the four samples was performed using 25% acetonitrile before injection into the UPLC for analysis, as described below. The dantrolene concentration in each sample was approximately 9–10 mg / mL.

[0106] Example 4. Freeze-drying of dantrolene sodium 43.5 mg of dantrolene sodium was slurried in 43.5 mL of water in a conical tube. The initial pH of the slurry was 9.89.

[0107] The pH of the slurry was then adjusted to 7.4 by slowly adding aliquots of 1 M HCl and 1 M NaOH solutions.

[0108] Once the pH reached 7.4, the conical tube was vortexed and the pH was read (repeated a total of five times with a central pH calibration to ensure the meter was providing reliable measurements). The pH value should be in the range of 7.2–7.6, which is close to physiological pH.

[0109] The top of the conical tube was covered with parafilm and holes were poked through to prepare the sample for lyophilization. The sample was flash-frozen using liquid nitrogen and then placed in the freeze dryer. The sample remained in the freeze dryer for a total of 4 days.

[0110] Example 5. Reconstitution of lyophilized dantrolene sodium in PEG 400 0.9 mg of lyophilized dantrolene sodium powder from Example 4 was reconstituted with 112 μL of PEG400. After vortexing on and off, the sample went into solution within a few minutes. The sample was spun at 15,000 rpm at room temperature for 5 minutes to separate the supernatant (dantrolene sodium in solution) from the pellet (insoluble material). A small pellet formed after spinning. The supernatant was transferred to a clean tube and diluted 80-fold and 160-fold with 25% acetonitrile for analysis by UPLC as described herein. The solubility of dantrolene in PEG400 was calculated to be ~5 mg / mL.

[0111] The pH of the supernatant was measured by diluting the supernatant 10-fold in water. The pH was measured to be 5.02. The 10-fold dilution resulted in immediate precipitation.

[0112] Example 6. Reconstitution of lyophilized dantrolene sodium in propylene glycol 1.2 mg of lyophilized dantrolene sodium powder from Example 4 was reconstituted with 150 μL of propylene glycol. After vortexing on and off, the sample became cloudy within a few minutes. The sample was spun at 15,000 rpm at room temperature for 5 minutes to separate the supernatant (dantrolene sodium in solution) from the pellet (insoluble material). A large pellet formed after spinning. The supernatant was transferred to a clean tube, diluted 50-fold and 100-fold with 25% acetonitrile, and analyzed by UPLC as described below. The solubility of dantrolene acid in propylene glycol was calculated to be ~0.6 mg / mL.

[0113] The pH of the supernatant was measured by diluting the supernatant 10-fold in water. The pH was measured to be 6.63. The 10-fold dilution resulted in a slow precipitation.

[0114] Example 7. Reconstitution of lyophilized dantrolene sodium in a 50:50 mixture of propylene glycol:PEG400 1.1 mg of lyophilized dantrolene sodium powder from Example 4 was reconstituted with 68.7 μL of propylene glycol and 68.7 μL of PEG400. After vortexing on and off, the sample became cloudy within a few minutes. The sample was spun at 15,000 rpm at room temperature for 5 minutes to separate the supernatant (dantrolene sodium in solution) from the pellet (insoluble material). A large pellet formed after spinning. The supernatant was transferred to a clean tube, diluted 50-fold and 100-fold with 25% acetonitrile, and analyzed by UPLC as described below. The solubility of dantrolene acid in a 50:50 mixture of propylene glycol:PEG400 was calculated to be ~2 mg / mL.

[0115] The pH of the supernatant was measured by diluting the supernatant 10-fold in water. The pH was measured to be 5.04. The 10-fold dilution resulted in immediate precipitation.

[0116] Example 8. Dissolution of dantrolene sodium in propylene glycol Dantrolene sodium (6.4 mg) was weighed into a glass vial and propylene glycol (0.128 mL) was added using a positive displacement pipette to achieve a target concentration of 50 mg / mL dantrolene sodium. The contents of the vial were mixed with the positive displacement pipette. Visual inspection confirmed that the solution was clear. The sample was a stable solution at room temperature for approximately 2 days, after which a precipitate formed. The precipitate was determined to be 99.9% dantrolene using HPLC.

[0117] Addition of 50 μL of water resulted in precipitation.

[0118] Example 9. Dissolution of dantrolene sodium in PEG 400 Dantrolene sodium (6.2 mg) was weighed into a glass vial and PEG400 (0.124 mL) was added using a positive displacement pipette to achieve a target concentration of 50 mg / mL dantrolene sodium. The contents of the vial were mixed with the positive displacement pipette. Visual inspection confirmed that the solution was clear. The sample was a stable solution at room temperature for approximately 2 days, after which a precipitate formed. The precipitate was determined to be 99.9% dantrolene using HPLC.

[0119] Addition of 50 μL of water resulted in precipitation.

[0120] Example 10. Concentration measurement by UPLC The analysis was performed using an Agilent UPLC system equipped with a diode array detector and an Agilent C18 Zorbax column. Samples were analyzed using a gradient method with mobile phase A containing 0.1% trifluoroacetic acid in water and mobile phase B containing 0.1% trifluoroacetic acid in acetonitrile. The column was equilibrated with 75% mobile phase A. The percentage of mobile phase A was decreased to 57% A over the first 4 minutes. The column was then washed with 30% A for 2 minutes, returned to 75% A in 0.1 minutes, and re-equilibrated at 75% A in 3.9 minutes, for a total analysis time of 10 minutes. A 10 μL sample was injected, and the analytes were detected by UV at 385 nm. Dantrolene eluted at approximately 2.3 minutes. Peak areas were determined by manual integration.

[0121] A standard curve was prepared by dissolving 1.0 mg of dantrolene sodium in 1 mL of 25% acetonitrile. This stock solution was further diluted with 25% acetonitrile to prepare standard solutions at concentrations of 100, 50, 25, 12.5, and 6.25 μg / mL. A linear standard curve of peak area versus concentration was used to determine the concentrations of unknown samples. To account for the difference in molecular weight between dantrolene acid (314 g / mole) and dantrolene sodium (336 g / mole), the curve concentration values ​​were adjusted to 5.84, 11.68, 23.36, 46.72, and 93.45 μg / mL.

[0122] Example 11. Effective pH measurement Effective pH measurements were performed at ambient room temperature using a Thermo Scientific Orion Star A111 pH benchtop meter. The instrument was calibrated within one day of the effective pH measurement using phosphate buffers of pH 4, 7, and 10 (Hydrion Tri-Chek Buffer Capsule set).

[0123] Samples were prepared by diluting non-aqueous / anhydrous samples 10-fold with water. The diluted samples were vortexed for approximately 10-15 seconds. The effective pH was measured immediately after vortexing using a pre-calibrated pH benchtop meter.

[0124] After each effective pH measurement, the pH valve was rinsed with an appropriate rinse solution to remove all test sample from the valve.

Claims

1. 1. An anhydrous pharmaceutical composition suitable for intramuscular or subcutaneous administration, which is a solution having dantrolene, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier having PEG 400, propylene glycol, or a mixture thereof, said composition having an effective pH of 4 to 9.

2. 2. The pharmaceutical composition of claim 1, having an effective pH of 5 to 8, more preferably 7.

4.

3. The pharmaceutical composition according to any one of claims 1 to 2, comprising dantrolene.

4. 3. The pharmaceutical composition according to claim 1, comprising dantrolene sodium.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising dantrolene and dantrolene sodium.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the carrier comprises propylene glycol.

7. 7. The pharmaceutical composition according to claim 1, wherein the carrier comprises PEG 400.

8. 8. The pharmaceutical composition according to any one of claims 1 to 7, further comprising an additional pharmaceutically acceptable excipient.

9. 9. A pharmaceutical composition according to any one of claims 1 to 8 for use in treating a disorder responsive to dantrolene in a subject by intramuscular or subcutaneous administration.

10. 10. The pharmaceutical composition for use of claim 9, wherein the disorder is malignant hyperthermia, chronic spasticity, exertional heat stroke, cardiac arrhythmia, tachycardia, atrial fibrillation, cardiac arrest, myocardial infarction, heart failure, myocardial injury, cardiomyopathy, central nervous system disease, amyotrophic lateral sclerosis, rhabdomyolysis, Duchenne muscular dystrophy, ataxia, detrusor overactivity, overactive bladder, seizures, epilepsy, neuroleptic malignant syndrome, human stress disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, ischemia-reperfusion injury, nerve reperfusion injury, hypoxia, cerebral aneurysm, subarachnoid hemorrhage, stroke, hyperthermia associated with drug abuse, hyperthermia associated with drug overdose, exposure to a nerve agent, or acetylcholine accumulation.

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