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CA-3109769-C - USE OF RILUZOLE ORAL DISINTIGRATING TABLETS FOR TREATING DISEASES

CA3109769CCA 3109769 CCA3109769 CCA 3109769CCA-3109769-C

Abstract

Disclosed are methods of treating a disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of riluzole, or a pharmaceutically acceptable salt or prodrug thereof, in the form of an oral solid molded fast-dispersing dosage form. Pharmaceutical compositions and kits are also disclosed.

Inventors

  • Vladimir Coric

Assignees

  • BIOHAVEN THERAPEUTICS LTD.

Dates

Publication Date
20260505
Application Date
20190815
Priority Date
20180816

Claims (16)

  1. 34 CLAIMS What is claimed is: 1. A use of a pharmaceutical composition comprising a therapeutically effective amount of riluzole, or a pharmaceutically acceptable salt or prodrug thereof, in the form of an oral solid molded fastdispersing dosage form in order to provide a reduction of at least 10 Visual Analogue Scale (VAS) points as compared to administration of a placebo for treating social anxiety disorder and enhancing memory in a patient in need thereof, wherein the oral solid molded fast-dispersing dosage form comprises 50-70 weight% riluzole, pharmaceutically acceptable salt or prodrug thereof, 10-30 weight% fish gelatin, and 10-20 weight% of a filler, wherein the riluzole prodrug has the following formula: and pharmaceutically acceptable salts thereof, wherein: R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2.
  2. 2. The use of claim 1, wherein the dosage of riluzole in the oral solid molded fast dispersing tablet is from 20 to 50 mg.
  3. 3. The use of claim 2, wherein the dosage of riluzole in the oral solid molded fast dispersing tablet is about 35 mg.
  4. 4. The use of any one of claims 1 to 3, wherein the use provides a reduction of at least 12 VAS points.
  5. 5. The use of claim 4, wherein the use provides a reduction of at least 14 VAS points.
  6. 6. The use of any one of claims 1 to 3, wherein the use provides a reduction of from 10 to 25 VAS points.
  7. 7. The use of any one of claims 1 to 3, wherein the use provides a mean VAS Score of from 49 to 60.
  8. 8. The use of claim 7, wherein the use provides a mean VAS Score of from 52 to 58.
  9. 9. The use of claim 1, wherein the filler is mannitol.
  10. 10. The use of claim 1, wherein the riluzole prodrug has the following formula: .
  11. 11. A kit for treating social anxiety disorder and enhancing memory in a patient, the kit comprising: (a) a pharmaceutical composition comprising a therapeutically effective amount of riluzole, or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in the form of an oral solid molded fast dispersing tablet; and (b) instructions for administration of the pharmaceutical composition; wherein the therapeutically effective amount provides a reduction of at least 10 Visual Analogue Scale (VAS) points as compared to administration of a placebo, wherein the oral solid molded fast-dispersing dosage form comprises 50-70 weight% riluzole, pharmaceutically acceptable salt or prodrug thereof, 10-30 weight% fish gelatin, and 10-20 weight% of a filler, wherein the riluzole prodrug has the following formula: 36 and pharmaceutically acceptable salts thereof, wherein: R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2.
  12. 12. The kit of claim 11, wherein the riluzole prodrug has the following formula: .
  13. 13. A use of a pharmaceutical composition comprising riluzole, or a pharmaceutically acceptable salt or prodrug thereof, in the form of an oral solid molded fast-dispersing dosage form, and a pharmaceutically acceptable carrier, for treating social anxiety disorder in a patient in need thereof; wherein the riluzole prodrug is according to the following formula: and pharmaceutically acceptable salts thereof, wherein: R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2; and 37 wherein the dosage of riluzole in the oral solid molded fast dispersing dosage form is from 20 to 50 mg.
  14. 14. The use of claim 13, wherein the riluzole prodrug has the following formula: .
  15. 15. A kit for treating social anxiety disorder in a patient, the kit comprising: (a) a pharmaceutical composition comprising from 20 to 50 mg of riluzole, or a pharmaceutically acceptable salt or prodrug thereof in the form of an oral solid molded fast dispersing tablet, and a pharmaceutically acceptable carrier; and (b) instructions for administration of the pharmaceutical composition; wherein the riluzole prodrug has the following formula: and pharmaceutically acceptable salts thereof, wherein: R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2.
  16. 16. The kit of claim 15, wherein the riluzole prodrug has the following formula: .

Description

USE OF RILUZOLE ORAL DISINTIGRATING TABLETS FOR TREATING DISEASES BACKGROUND OF THE INVENTION FIELD OF lNVE..1'1TION The present invention relates to riluzole oral disintegrating tablets and their use in 10 treating various diseases. BRIEF DESCRIPTION OF RELATED ART Glutamate is a predominant excitatory neurotransmitter responsible for regulating signaling in normal brain function. While research on glutamate signaling has been priniarily focused on the central nervous system (CNS), 0th.er investigations have highlighted their 15 functional role in peripheral tissues. See, e.g., Skerry T, Genever P, Glutamate signaling in non-neuronal tissues. Trends Pharmacol. Sci. 2001, 22:174-181 and Frati C, Marchese C, Fisichella G, Copani A, Nasca MR, Storto M, Nicoletti F, Expression of functional mGlu5 metabotropic glutamate receptors in humanmelanocytes. J. Cell. Physiol. 2000, 183:364-372. Glutamate can exert its signaling abilities by acting on glutamate receptors, which are 20 located on the cell surface. Glutamate receptors exist as either ionotropic receptors (iGluRs) or metabotropic glutamate receptors (mGluRs). iGluRs are ligand-gated ion channels, which include N-methyl-d-aspartate (NMDA) receptors and non-NMDA receptors [a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] (iGluRl-4) and kainite (KA) subfamilies (iGluR5-7, KAI, and KA2). mGluRs are domain receptors that mediate their signal 25 by coupling to guanosine triphosphate (GTP)-binding proteins (G-proteins) and stimulate second messengers such as inositol 1,4,5-triphosphate (IP3), diacylglycerol (DAG), and cyclic adenosine monophosphate (cAMP). Various mGluR subtypes have been identified and grouped according to their sequence homology, pharmacologic response, and intracellular second messengers. Upon binding of the ligand, Group I receptors, which are comprised of 30 mGluRl and mGluR5, couple via Gq to phospholipase C (PLC) leading to the formation of IP3 and DAG. Group II comprises mGluR2 and mGluR3, and Group III comprises mGluR4, mGluR6, mGluR7, a11dmGluR8. Both Group II and III are negatively coupled via Gvo to adenyl cyclase leading to cAMP fom1ation. See, e.g., Teh J, Chen S, Metabotrobic glutamate receptors and cancerous growth, WIRE.); Membr. Transp. Signal. 2012, l :211-220; doi: 10.1002/wmts.21, 35 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Volume 1, March/April 2012. Date Rei;ue/Date Received 2023-01-13 WO 2020/037152 PCT/0S2019/046709 Glutamate can also be transported. Glutamate transporters have been cloned from the mammalian central nervous system. Two are expressed predominantly in glia [glial glutamate and aspartate transporter (GLAST) and glial glutamate transporter (GLT)J and three in neurons !EAACl, excitatory amino acid transporter (E.AAT)4 and EAAT5]. See, e.g., Seal, R, Amara, 5 S, (1999) Excitatory amino acid transporters: a family in flmc Annu. Rev. Pharmacol. Toxicol. 39: 431-456. Further information concerning glutamate transpmt can be found in the literature. See, e.g, Meldrum B, Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology, .J. Nutr. l30:1007S-1015S, 2000. Glutamate can also be metabolized. Glutamate metabolism reactions can be catalyzed 10 by enzymes that are regulated by activators and inhibitors. For instance, conversion of Lglutamate to N-acety1 L-glutamate in presence of N-acetylglutamate synthase (NAG:S) is activated by L-arginine and inhibited by succinate, coenzyme A, N-acetyl-L-aspartate and Nacetyl- L-glutamate. See, e.g., Shigesada K, Tatibana M, N-acetylglutamate synthetase from rat-liver mitochondria. Partial purification and catalytic properties. Eur. J. Biochem. 1978; 15 84:285-291; doi: 10.1111/j.14321033.1978, tb12167.x. Similarly, glutamine to glutamate conversion can be catalyzed by enzymes, which include glutaminase (GLS/GLS2), phosphoribosy 1 pyrophosphate amidotransforase (PP AT) and glutamine-fructose-6-phosphate transaminase (GFPTl and GFPT2). See, e.g., Holmes E, Wyngaarden J, Kelley W, Human glutamine phosphoribosylpyrophosphate amidotransfcrase. Two molecular fonns 20 interconvertible by purine ribonucleotides and phosphoribosylpyrophosphate . .J. Biol. Chem. 1973 ;248: 6035-6040, and Hu C, et al. Molecular enzymology of mammalian Deltal-pyrroline- 5-carboxy late synthase. Alternative Splice donor Utilization Generates Isofom1s with Different Sensitivity to Omithine Inhibition. J Biol. Chem. 1999; 274:6754-6762; doi: 10. l 074.(jbc.274. l 0.6754. 25 Glutamine, which serves as a precursor of glutamate is known to protect the body from nutrient depletion, oxidative stress and tumor stress. See, e.g., Shamvare N, et al., Glutamine: pleiotropic roles in tumor growth and stress resistance. J. ,viol. Afed (Berl.) 2011;89:229---236; doi: 10. 1007 /sOO 10901107319. Reports have shown that ammonia released from glutan1ine by the action of glutaminases regulates autophagy in cancer cells through a process known as 30 glutaminolysis. See, e.g.