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JP-7855629-B2 - Treatment of essential tremor with (R)-2-(4-isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridine-2-yl)ethyl)acetamide

JP7855629B2JP 7855629 B2JP7855629 B2JP 7855629B2JP-7855629-B2

Inventors

  • リー，マーガレット エス．
  • パパペトロプロス，スピリドン
  • ヒギン，ミシェル エス．
  • ドゥヴリ，ムラリクリシュナ
  • レーレンダー，ブルース エヌ．
  • ニューボールド，エヴァン

Assignees

  • カビオン・インコーポレイテッド

Dates

Publication Date
20260508
Application Date
20240424
Priority Date
20181003

Claims (19)

  1. A pharmaceutical composition comprising a Cav3 antagonist, to be administered orally once daily to a person having a motor disorder, for use in the treatment of the person, The aforementioned Cav3 antagonist is CX-8998 or a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprises a controlled-release component containing the Cav3 antagonist and an immediate-release component containing the Cav3 antagonist. When the pharmaceutical composition is administered to a human once daily, the maximum plasma concentration (Cmax) of the Cav3 antagonist, calculated by dividing it by the mean plasma concentration of the Cav3 antagonist 24 hours after administration, is ( The pharmaceutical composition is effective in maintaining the ratio between approximately 1.0 and approximately 5.0.
  2. The pharmaceutical composition according to claim 1 , wherein the plasma concentration of the Cav3 antagonist is the plasma concentration at a steady state.
  3. The pharmaceutical composition according to claim 1 or 2 , wherein the Cav3 antagonist is a hydrochloride salt.
  4. The pharmaceutical composition according to any one of claims 1 to 3 , wherein the controlled-release component comprises a plurality of particles containing the Cav3 antagonist or a pharmaceutically acceptable salt thereof, and comprises a coating containing a pH-sensitive enteric polymer .
  5. The pharmaceutical composition according to claim 4 , wherein the pH-sensitive enteric polymer has a dissolution pH of approximately 5.5 to 7.
  6. The pharmaceutical composition according to claim 5 , wherein the pH-sensitive enteric polymer has a dissolution pH of approximately 7.
  7. The pharmaceutical composition according to any one of claims 4 to 6 , wherein the particles in the controlled release component are beads.
  8. The pharmaceutical composition according to any one of claims 1 to 7 , wherein the pharmaceutical composition contains an immediate-release component comprising the Cav3 antagonist or a pharmaceutically acceptable salt thereof.
  9. The pharmaceutical composition according to claim 8 , comprising approximately 40% of the immediate-release component and approximately 60% of the controlled-release component.
  10. The pharmaceutical composition according to any one of claims 1 to 9 , wherein the immediate-release component comprises a plurality of particles containing the Cav3 antagonist or a pharmaceutically acceptable salt thereof, and optionally the particles in the immediate-release component are beads.
  11. The pharmaceutical composition according to any one of claims 8 to 10 , wherein each of the immediate-release component and the controlled-release component further comprises lactose monohydrate.
  12. The pharmaceutical composition according to any one of claims 1 to 11 , wherein the movement disorder is essential tremor or tremor associated with Parkinson's disease.
  13. The pharmaceutical composition according to claim 12 , wherein the aforementioned movement disorder is essential tremor.
  14. The pharmaceutical composition according to claim 12 , wherein the movement disorder is a tremor associated with Parkinson's disease.
  15. The pharmaceutical composition according to claim 14 , wherein the treatment is effective in reducing or eliminating tremors associated with Parkinson's disease.
  16. The pharmaceutical composition according to claim 1, administered within four hours of the patient's awakening.
  17. The pharmaceutical composition according to claim 1, wherein the human being is an adult.
  18. The pharmaceutical composition according to claim 14 , wherein the adult is 18 years of age or older.
  19. The pharmaceutical composition according to claim 1, wherein the unit dose of the pharmaceutical composition contains about 0.5 mg to about 20 mg of the Cav3 antagonist or a pharmaceutically acceptable salt thereof.

Description

Cross-reference of related applications This application claims the benefit of U.S. Patent Application No. 62/740,755 filed on 3 October 2018 and U.S. Patent Application No. 62/780,000 filed on 14 December 2018. We assert the benefit of Article 49. The disclosure of the prior application is deemed to be part of the disclosure of this application (and is incorporated into the disclosure of this application by reference). The present invention relates to methods and materials for treating mammals that have or are at risk of developing one or more movement disorders (e.g., essential tremor, epilepsy, and/or Parkinson's disease). In particular, this specification relates to compositions comprising one or more T-type calcium channel antagonists (e.g., one or more Cav3 antagonists such as CX-8998), and for treating one or more movement disorders (e.g., essential tremor, epilepsy, and/or Parkinson's disease). The present invention relates to treating mammals that have or are at risk of developing a disease by administering a composition to such mammals. Essential tremor is one of the most common movement disorders in adults. In a 2010 meta-analysis, Louis et al. (1998 Movement Dis) Orders. 13(1):5-10) estimated the pooled prevalence (all ages) to be 0.9%, with statistically significant heterogeneity between studies (I² = 99%, p < 0.001). 6 The prevalence in adults aged 5 years and older was estimated at 4.6% (Louis and Ferre IRA, 2010 Mov Disord. 25(5):534-541). ET does not shorten lifespan, but it does affect activities of daily living (ADL, e.g., writing and eating) at home and in the workplace. It affects the patient's ability to perform the procedure and negatively impacts their quality of life, social interaction, and mental state (Lorenz et al., 2006 Mov Disord. 21(8)). :1114-1118; Louis et al. , 2015 Parkinsonis m Relat Disord. 21(7):729-735; George et a. l. , 1994 Psychosomatics. 35(6):520-523; and Z Esiewicz et al. , 2011 Neurology. 77(19):17 52-1755). There is a growing recognition that ET is not a single-symptom disorder (Berm). ejo-Pareja, 2011 Nature Reviews Neurology 7(5):273-282). The impact on cognitive function is heterogeneous, affecting attention, executive function, Impairments include those in verbal fluency, visuospatial function, memory, and working memory (Bermej). o-Pareja et al. , 2012 “V. Cognitive Feature es of Essential Tremor: A Review of the C Linical Aspects and Possible Mechanistic "Underpinnings", Tremor and Other Hyperki Page 2:0 in Netic Movements (Louis, ed.) 2012 2-74-541-1). Patients with ET also show more sleep disturbances and fatigue compared to their age-equivalent controls (Chandran et al., 2012 Act). a. Neurol Scand. 125:332-7). Essential tremor usually worsens over time and can become severe in some individuals. It is a significant impairment affecting many activities of daily living and can cause social embarrassment, phobias, depression, and anxiety. T-type calcium channels are members of the family of voltage-activated calcium channels (Cavs), each member distinguished by a unique pore-forming α-subunit with different physiological properties that can be further modulated by association with various accessory subunits (Zamponi et al., 2015 Pharmacol Rev. 67:82). 1-70). The intrinsic and differential properties of T-type calcium channels are their ability to be activated in response to small membrane depolarization at relatively low potentials, thereby enabling further membrane depolarization, activation of additional ion channel subtypes, and a surge in calcium influx into excitable cells that triggers the initiation of action potentials. Another important feature of this class of channels is their relatively rapid inactivation (the "T" in "T-type" stands for transient) and relatively slow functional recovery from this inactivated state. Together, these properties allow Cav3 channels to transiently respond to small changes in sensory input and then rapidly reset, thereby giving them a crucial role in setting the resting membrane potential and, therefore, a crucial role in the overall excitability and oscillatory activity of the cell (Iftinca et al., 200). 9 Trends Pharmacol Sci. 30:32-40). Cav3 is a T-type calcium channel, and its isoforms (Cav3.1, Ca v3.2, and Cav3.3), and their genes CACNA1G, CACNA1 H and CACNA1I were discovered and cloned in the early 1990s, and their functions as low threshold potential opening calcium channels were elucidated (Perez-Reyes). , 1998 Bioenerg Biomembr. 30:313-8; Cribbs et al. , 1998 Circ Res. 83:103-9; Lee et al. , 1999 J Neurosci. 19(6):1912-21). The isoforms of Cav3 include the thalamocortical tract, in which Cav3.1 is the most common isoform. It is expressed throughout the central nervous system (CNS) and peripheral nervous system (Ertel e (t al., 2000 Neuron. 25:533-5). The cerebellar nuclei, substantia nigra, external segment of the globus pallidus, internal segment of the globus pallidus, and subthalamic nucleus (STN) have b