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Dantrolene formulations and methods of their use

A technology for dantrolene and medicinal salts, applied to dantrolene preparations and the application field thereof, can solve the problems of only intravenous administration, not subcutaneous or intramuscular administration, and the like

Pending Publication Date: 2020-12-25
伊格尔制药公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to their high pH, ​​current dantrolene formulations cannot be administered subcutaneously or intramuscularly, only intravenously

Method used

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  • Dantrolene formulations and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1. Solubility and pH in PEG400

[0104] 11.2mg dantrolene acid was added to 224uL PEG400. The liquid was cloudy after vortexing, and some solid remained at the bottom of the Eppendorf tube, indicating that a saturated solution had been obtained. The tubes were centrifuged at 15,000 rpm for 5 min at room temperature to separate the samples into supernatant (dantrolene acid in solution) and precipitate (insoluble material). The supernatants were transferred to clean tubes and diluted 100, 200 and 400 times in 25% acetonitrile for analysis by UPLC as described below. The solubility of dantrolene acid in PEG400 was calculated to be ~15 mg / mL.

[0105] The pH of the supernatant was measured by making a 10-fold dilution of the supernatant in water. The pH was measured to be 4.88. The 10-fold dilution soon precipitated out.

Embodiment 2

[0106] Example 2. Solubility and pH in Propylene Glycol

[0107] To 326 uL of propylene glycol was added 16.3 mg dantrolene acid. The liquid was cloudy after vortexing, and some solid remained at the bottom of the Eppendorf tube, indicating that a saturated solution had been obtained. The tubes were centrifuged at 15,000 rpm for 5 min at room temperature to separate the samples into supernatant (dantrolene acid in solution) and precipitate (insoluble material). The supernatants were transferred to clean tubes and diluted 50, 100 and 200 times in 25% acetonitrile for analysis by UPLC as described below. The solubility of dantrolene acid in propylene glycol was calculated to be ~0.8 mg / mL.

[0108] The effective pH of the supernatant was measured by making a 10-fold dilution of the supernatant in water. The pH was measured to be 5.73. The 10-fold dilution slowly precipitated out.

Embodiment 3

[0109] Example 3. Changing ratios to determine formulation at physiological pH

[0110] Different 10 mg / mL dantrolene acid: pH of dantrolene sodium samples in PEG400. Dissolve 13.0 mg of dantrolene in 1.3 mL of PEG400, targeting 10 mg / mL of dantrolene. Dissolve 12.7 mg of dantrolene sodium in 1.27 mL of PEG400, targeting 10 mg / mL of dantrolene sodium. The liquid in the dantrolene acid sample was cloudy after vortexing, and some solid remained at the bottom of the Eppendorf tube, indicating that a saturated solution had been obtained. The dantrolene sodium sample was not cloudy, indicating that the dantrolene sodium was completely dissolved. Both tubes were centrifuged at 3,900 rpm for 5 min at room temperature to separate the samples into supernatant (dantrolene acid or dantrolene sodium in solution) and precipitate (insoluble material). The dantrolene acid sample had precipitate formation, but the dantrolene sodium sample did not. The supernatant of the dantrolene acid sa...

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Abstract

The disclosure is directed to liquid formulations of dantrolene, or a pharmaceutically acceptable salt thereof, and methods of their use in the treatment of disease.

Description

[0001] Cross References to Related Applications [0002] This application claims priority 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. technical field [0003] The present disclosure relates to liquid formulations of dantrolene or a pharmaceutically acceptable salt thereof and methods of their use in the treatment of disease. Background technique [0004] Dantrolene (1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino}imidazolidine-2,4-dione) has the structure of formula (1): [0005] [0006] Dantrolene is the rescue agent of choice in the treatment of malignant hyperthermia ("MH") and is available in most settings where anesthetics are delivered. First synthesized in 1967, dantrolene was first used in the treatment of muscle spasms in 1975 and was later approved by the FDA in 1979 for the treatment of MH. Dantrolene is considered a powerful muscle rela...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K47/10A61K9/19A61K31/4178
CPCA61K9/0019A61K9/19A61K31/4178A61K47/10
Inventor 查尔斯·韦斯科特吉尔·科兰
Owner 伊格尔制药公司