US2021244723A1PendingUtilityA1

Formulations and Pharmacokinetics of Deuterated Benzoquinoline Inhibitors of Vesicular Monoamine Transporter 2

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Assignee: AUSPEX PHARMACEUTICALS INCPriority: Sep 18, 2012Filed: Mar 25, 2021Published: Aug 12, 2021
Est. expirySep 18, 2032(~6.2 yrs left)· nominal 20-yr term from priority
Inventors:Andreas SommerChengzhi ZhangJohn CarterJohn ArthurMargaret BradburyThomas G. GantManouchehr Shahbaz
A61K 31/473A61K 9/4808C07D 455/06A61K 9/2018A61K 9/5073A61K 9/1676A61K 9/28A61K 9/2054A61K 9/2031A61K 45/06A61K 9/0065A61K 9/5078A61K 9/288A61K 9/5084A61K 9/5047A61K 9/2027A61K 31/4745A61K 9/284C07B 2200/05A61K 9/2866A61K 9/2013A61K 9/2846A61K 9/2072A61K 9/2077A61P 43/00A61P 25/14A61K 9/2095A61K 9/0053
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Claims

Abstract

The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating tardive dyskinesia or chorea associated with Huntington's disease in a human comprising administering to the human
 a solid oral dosage form comprising 6 mg of d 6 -tetrabenazine and between about 5% and about 30% by weight of the dosage form of a sustained-release polymer having a viscosity of up to 4,000 cPs and that is a poly(ethylene oxide) polymer, a hydroxypropyl methylcellulose (HPMC) polymer, a hydroxypropylcellulose (HPC) polymer, or a combination thereof,   wherein oral administration of the oral dosage form to a human results in a ratio of fed to fasted AUC inf  of a total combined amount of deuterated dihydrotetrabenazine of >1 to 1.2; and   wherein oral administration of the oral dosage form to a human in a fed state, results in
 an AUC inf  in plasma of a total combined amount of deuterated dihydrotetrabenazine of about 132 hr*ng/mL; or 
 a C max  in plasma of a total combined amount of deuterated dihydrotetrabenazine of about 15.5 ng/mL. 
   
     
     
         2 . The method of  claim 1 , wherein the AUC inf  of the total combined amount of deuterated dihydrotetrabenazine is about 132 hr*ng/mL; and
 the C max  of the total combined amount of deuterated dihydrotetrabenazine is about 15.5 ng/mL;   after the oral administration of the oral dosage form to the human in the fed state.   
     
     
         3 . The method of  claim 1 , wherein the polymer comprises a poly(ethylene oxide) polymer. 
     
     
         4 . The method of  claim 3 , wherein the poly(ethylene oxide) polymer comprises a poly(ethylene oxide) polymer having an approximate molecular weight of 2,000,000 and a viscosity of 2000-4000 cP. 
     
     
         5 . The method of  claim 3 , wherein the poly(ethylene oxide) polymer is a poly(ethylene oxide) polymer having an approximate molecular weight of 2,000,000 and a viscosity of 2000-4000 cP. 
     
     
         6 . The method of  claim 1 , wherein the polymer comprises a hydroxypropyl methylcellulose (HPMC) polymer. 
     
     
         7 . The method of  claim 6 , wherein the polymer comprises a HPMC polymer that is a hydroxypropyl methylcellulose having a molecular weight of about 400,000 and a viscosity of 4000 cPs, a hydroxypropyl methylcellulose having a molecular weight of about 120,000 dalton and a viscosity of 100 cPs, or a hydroxypropyl methylcellulose having a molecular weight of about 50,000 dalton and a viscosity of 15 cPs. 
     
     
         8 . The method of  claim 7 , wherein the polymer comprises a hydroxypropyl methylcellulose having a molecular weight of about 400,000 and a viscosity of 4000 cP. 
     
     
         9 . The solid oral dosage form of  claim 1 , wherein the sustained-release polymer has a viscosity of 6 cPs to 4,000 cPs, 15 cPs to 4,000 cPs, 100 cPs to 4,000 cPs, or 2,000 cPs to 4,000 cPs. 
     
     
         10 . The method of  claim 1 , for treating tardive dyskinesia. 
     
     
         11 . The method of  claim 1 , for treating chorea associated with Huntington's disease. 
     
     
         12 . A method of treating tardive dyskinesia or chorea associated with Huntington's disease in a human comprising administering to the human
 a solid oral dosage form comprising 12 mg of d 6 -tetrabenazine and between about 5% and about 30% by weight of the dosage form of a sustained-release polymer having a viscosity of up to 4,000 cPs that is a poly(ethylene oxide) polymer, a hydroxypropyl methylcellulose (HPMC) polymer, a hydroxypropylcellulose (HPC) polymer, or a combination thereof,   wherein oral administration of the oral dosage form to a human results in a ratio of fed to fasted AUC inf  of a total combined amount of deuterated dihydrotetrabenazine of >1 to 1.2; and   wherein oral administration of the oral dosage form to a human in a fed state, results in
 an AUC inf  in plasma of a total combined amount of deuterated dihydrotetrabenazine of about 289 hr*ng/mL; or 
 a C max  in plasma of a total combined amount of deuterated dihydrotetrabenazine of about 32.1 ng/mL. 
   
     
     
         13 . The method of  claim 12 , wherein
 the AUC inf  of the total combined amount of deuterated dihydrotetrabenazine is about 289 hr*ng/mL; and   the C max  of the total combined amount of deuterated dihydrotetrabenazine is about 32.1 ng/mL;   after the oral administration of the oral dosage form to the human in the fed state.   
     
     
         14 . The method of  claim 12 , wherein the polymer comprises a poly(ethylene oxide) polymer. 
     
     
         15 . The method of  claim 14 , wherein the poly(ethylene oxide) polymer comprises a poly(ethylene oxide) polymer having an approximate molecular weight of 2,000,000 and a viscosity of 2000-4000 cP. 
     
     
         16 . The method of  claim 14 , wherein the poly(ethylene oxide) polymer is a poly(ethylene oxide) polymer having an approximate molecular weight of 2,000,000 and a viscosity of 2000-4000 cP. 
     
     
         17 . The method of  claim 12 , wherein the polymer comprises a hydroxypropyl methylcellulose (HPMC) polymer. 
     
     
         18 . The method of  claim 17 , wherein the polymer comprises a HPMC polymer that is a hydroxypropyl methylcellulose having a molecular weight of about 400,000 and a viscosity of 4000 cP, a hydroxypropyl methylcellulose having a molecular weight of about 120,000 dalton and a viscosity of 100 cP, or a hydroxypropyl methylcellulose having a molecular weight of about 50,000 dalton and a viscosity of 15 cP. 
     
     
         19 . The method of  claim 18 , wherein the polymer comprises a hydroxypropyl methylcellulose having a molecular weight of about 400,000 and a viscosity of 4000 cP. 
     
     
         20 . The solid oral dosage form of  claim 12 , wherein the sustained-release polymer has a viscosity of 6 cPs to 4,000 cPs, 15 cPs to 4,000 cPs, 100 cPs to 4,000 cPs, or 2,000 cPs to 4,000 cPs. 
     
     
         21 . The method of  claim 12 , for treating tardive dyskinesia. 
     
     
         22 . The method of  claim 12 , for treating chorea associated with Huntington's disease.

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