Pharmaceutical dosage forms comprising 6'-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine

Abstract

A pharmaceutical dosage form for administration twice daily, once daily or less frequently, which contains 6′-fluoro-(N-methyl- or N,N-dimethyl)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof.

1 . A pharmaceutical dosage form for use in the treatment of pain, which contains a pharmacologically active agent corresponding to formula (I) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 , 
         or a physiologically acceptable salt thereof, and 
         wherein the pharmaceutical dosage form is administered twice daily, once daily or less frequently. 
       
     
     
         2 . The pharmaceutical dosage form according to  claim 1 , wherein said dosage form provides immediate release in vitro of the pharmacologically active agent corresponding to formula (I) in accordance with Ph. Eur. 
     
     
         3 . The pharmaceutical dosage form according to  claim 1 , wherein the pharmacologically active agent corresponding to formula (I) is molecularly dispersed. 
     
     
         4 . The pharmaceutical dosage form according to  claim 1 , which comprises a liquid core encapsulated by a solid material, wherein the pharmacologically active agent corresponding to formula (I) is dispersed in the liquid core. 
     
     
         5 . The pharmaceutical dosage form according to  claim 1 , wherein said dosage form contains a self-emulsifying formulation giving (micro)emulsions with an average droplet size smaller than or equal 10 micrometers in presence of aqueous media. 
     
     
         6 . The pharmaceutical dosage form according to  claim 1 , further comprising a surfactant. 
     
     
         7 . The pharmaceutical dosage form according to  claim 6 , wherein
 the surfactant has a HLB value of at least 10; and/or   the content of the surfactant is at least 0.001 wt.-%, based on the total weight of the pharmaceutical dosage form.   
     
     
         8 . The pharmaceutical dosage form according to  claim 6 , wherein the surfactant is selected from the group consisting of polyoxyethylene fatty acid esters, partial fatty acid esters of polyoxyethylenesorbitan, and sulfuric acid esters. 
     
     
         9 . The pharmaceutical dosage form according to  claim 1 , wherein the pharmacologically active agent corresponding to formula (I) has a stereochemistry according to formula (I′) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 . 
       
     
     
         10 . The pharmaceutical dosage form according to  claim 1 , wherein the pharmacologically active agent corresponding to formula (I) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, or a physiologically acceptable salt thereof. 
     
     
         11 . The pharmaceutical dosage form according to  claim 1 , wherein under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 said dosage form releases after 30 minutes at least 80 wt.-% of the pharmacologically active agent corresponding to formula (I), based on the total amount of the pharmacologically active agent corresponding to formula (I) originally contained in the dosage form. 
     
     
         12 . The pharmaceutical dosage form according to  claim 1 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 10 μg to 50 μg. 
     
     
         13 . The pharmaceutical dosage form according to  claim 1 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 300 μg to 500 μg. 
     
     
         14 . The pharmaceutical dosage form according to  claim 1 , wherein:
 the pharmacokinetic parameter t max  is within the range of from 0.5 to 16 h; and/or   the ratio of the pharmacokinetic parameter AUC 0-t /dose is within the range of from 0.3 to 20 h/m 3 ; and/or   the ratio of the pharmacokinetic parameter C max /dose is within the range of from 0.04 to 2.00 m −3 .   
     
     
         15 . The pharmaceutical dosage form according to  claim 1 , wherein the pain is selected from the group consisting of acute pain, visceral pain, neuropathic pain, and chronic pain. 
     
     
         16 . A pharmaceutical dosage form for administration twice daily, once daily or less frequently, which contains a pharmacologically active agent corresponding to formula (I) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 , 
         or a physiologically acceptable salt thereof; and 
         wherein in accordance with Ph. Eur. under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 and 37±0.5° C. said dosage form releases after 30 minutes according to the paddle method with sinker at 100 rpm at least 50 wt.-% of the pharmacologically active agent, based on the total amount of the pharmacologically active agent originally contained in the pharmaceutical dosage form. 
       
     
     
         17 . The pharmaceutical dosage form according to  claim 16 , wherein the pharmacologically active agent corresponding to formula (I) is molecularly dispersed. 
     
     
         18 . The pharmaceutical dosage form according to  claim 16 , wherein said dosage form comprises a solid polymeric matrix material in which the pharmacologically active agent corresponding to formula (I) is dispersed. 
     
     
         19 . The pharmaceutical dosage form according to  claim 16 , wherein said dosage form comprises a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-polyvinylacetate copolymers, cellulose derivatives, polymethacrylates, polyethylene oxides, polyethylene glycols and any combinations thereof. 
     
     
         20 . The pharmaceutical dosage form according to  claim 16 , further comprising a surfactant. 
     
     
         21 . The pharmaceutical dosage form according to  claim 20 , wherein
 the surfactant has a HLB value of at least 10; and/or   the content of the surfactant is at least 0.001 wt.-%, based on the total weight of the pharmaceutical dosage form.   
     
     
         22 . The pharmaceutical dosage form according to  claim 20 , wherein the surfactant is selected from the group consisting of polyoxyethylene fatty acid esters, partial fatty acid esters of polyoxyethylenesorbitan, and sulfuric acid esters. 
     
     
         23 . The pharmaceutical dosage form according to  claim 16 , wherein the pharmacologically active agent corresponding to formula (I) has a stereochemistry corresponding to formula (I′) 
       
         
           
           
               
               
           
         
       
       wherein R is —H or —CH 3 . 
     
     
         24 . The pharmaceutical dosage form according to  claim 16 , wherein the pharmacologically active agent corresponding to formula (I) is (1r,40-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, or a physiologically acceptable salt thereof. 
     
     
         25 . The pharmaceutical dosage form according to  claim 16 , wherein under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 said dosage form releases after 30 minutes at least 80 wt.-% of the pharmacologically active agent corresponding to formula (I), based on the total amount of the pharmacologically active agent corresponding to formula (I) originally contained in the dosage form. 
     
     
         26 . The pharmaceutical dosage form according to  claim 16 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 10 μg to 50 μg. 
     
     
         27 . The pharmaceutical dosage form according to  claim 16 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 300 μg to 500 μg. 
     
     
         28 . The pharmaceutical dosage form according to  claim 16 , wherein
 the pharmacokinetic parameter t max  is within the range of from 0.5 to 16 h; and/or   the ratio of the pharmacokinetic parameter AUC 0-t /dose is within the range of from 0.3 to 20 h/m 3 ; and/or   the ratio of the pharmacokinetic parameter C max /dose is within the range of from 0.04 to 2.00 m −3 .   
     
     
         29 . A method of treating pain in a subject in need thereof, said method comprising administering to said subject twice daily, once daily or less frequently a pharmaceutical dosage form according to  claim 16 . 
     
     
         30 . A method according to  claim 29 , wherein the pain is selected from the group consisting of acute pain, visceral pain, neuropathic pain and chronic pain. 
     
     
         31 . A pharmaceutical dosage form for administration twice daily, once daily or less frequently, which contains a pharmacologically active agent corresponding to formula (I) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 , 
         or a physiologically acceptable salt thereof. 
       
     
     
         32 . The pharmaceutical dosage form according to  claim 31 , wherein said dosage form provides immediate release in vitro of the pharmacologically active agent corresponding to formula (I) in accordance with Ph. Eur. 
     
     
         33 . The pharmaceutical dosage form according to  claim 31 , wherein said dosage form is a tablet. 
     
     
         34 . The pharmaceutical dosage form according to  claim 31 , further comprising at least one pharmaceutical excipient selected from the group consisting of antiadherents, binders, disintegrants, fillers, diluents, glidants, lubricants and preservatives. 
     
     
         35 . The pharmaceutical dosage form according to  claim 31 , further comprising a surfactant. 
     
     
         36 . The pharmaceutical dosage form according to  claim 35 , wherein
 the surfactant has a HLB value of at least 10; and/or   the content of the surfactant is at least 0.001 wt.-%, based on the total weight of the pharmaceutical dosage form.   
     
     
         37 . The pharmaceutical dosage form according to  claim 35 , which is prepared by wet granulation from an aqueous granulating fluid containing the pharmacologically active agent corresponding to formula (I) and the surfactant. 
     
     
         38 . The pharmaceutical dosage form according to  claim 35 , wherein the surfactant is selected from the group consisting of polyoxyethylene fatty acid esters, partial fatty acid esters of polyoxyethylenesorbitan, and sulfuric acid esters. 
     
     
         39 . The pharmaceutical dosage form according to  claim 31 , wherein the pharmacologically active agent corresponding to formula (I) has a stereochemistry according to formula (I′) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 . 
       
     
     
         40 . The pharmaceutical dosage form according to  claim 31 , wherein the pharmacologically active agent corresponding to formula (I) is (1r,40-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, or a physiologically acceptable salt thereof. 
     
     
         41 . The pharmaceutical dosage form according to  claim 31 , wherein under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 said dosage form releases after 30 minutes at least 80 wt.-% of the pharmacologically active agent corresponding to formula (I), based on the total amount of the pharmacologically active agent corresponding to formula (I) originally contained in the dosage form. 
     
     
         42 . The pharmaceutical dosage form according to  claim 31 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 10 μg to 50 μg. 
     
     
         43 . The pharmaceutical dosage form according to  claim 31 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 300 μg to 500 μg. 
     
     
         44 . The pharmaceutical dosage form according to  claim 31 , wherein
 the pharmacokinetic parameter t max  is within the range of from 0.5 to 16 h; and/or   the ratio of the pharmacokinetic parameter AUC 0-t /dose is within the range of from 0.3 to 20 h/m 3 ; and/or   the ratio of the pharmacokinetic parameter C max /dose is within the range of from 0.04 to 2.00 m −3 .   
     
     
         45 . A method of treating pain in a subject in need thereof, said method comprising administering to said subject twice daily, once daily or less frequently a pharmaceutical dosage form according to  claim 31 . 
     
     
         46 . A method according to  claim 45 , wherein the pain is selected from the group consisting of acute pain, visceral pain, neuropathic pain and chronic pain. 
     
     
         47 . A pharmaceutical dosage form for administration once daily containing a pharmacologically active agent corresponding to formula (I) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 , 
         or a physiologically acceptable salt thereof, and 
         wherein said dosage form:
 provides immediate release in vitro of the pharmacologically active agent corresponding to formula (I) in accordance with Ph. Eur.; 
 contains the pharmacologically active agent corresponding to formula (I) in a dose of from 10 μg to 190 μg; and 
 exhibits a pharmacokinetic parameter t max  within the range of from 0.5 to 16 h. 
 
       
     
     
         48 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 25 μg to 80 μg. 
     
     
         49 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 10 μg to 50 μg. 
     
     
         50 . The pharmaceutical dosage form according to  claim 47 , wherein the pharmacologically active agent corresponding to formula (I) has a stereochemistry corresponding to formula (I′) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 . 
       
     
     
         51 . The pharmaceutical dosage form according to  claim 47 , wherein the pharmacologically active agent corresponding to formula (I) is (1r,40-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, or a physiologically acceptable salt thereof. 
     
     
         52 . The pharmaceutical dosage form according to  claim 47 , wherein under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 said dosage form releases after 30 minutes at least 80 wt.-% of the pharmacologically active agent corresponding to formula (I), based on the total amount of the pharmacologically active agent corresponding to formula (I) originally contained in the dosage form. 
     
     
         53 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in an amount that is sub-therapeutic with regard to a single administration of the dosage form. 
     
     
         54 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a quantity that is sub-therapeutic with regard to acute pain treatment. 
     
     
         55 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a quantity such that initial dose titration is not required. 
     
     
         56 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form has a pharmacokinetic parameter t max  within the range of from 2 to 10 h. 
     
     
         57 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form has a pharmacokinetic parameter AUC 0-t /dose within the range of from 0.3 to 20 h/m 3 . 
     
     
         58 . The pharmaceutical dosage form according to  claim 47 , wherein said dosage form has a pharmacokinetic parameter C max /dose within the range of from 0.04 to 2.00 m −3 . 
     
     
         59 . The pharmaceutical dosage form according to  claim 47 , wherein after once daily administration of the pharmaceutical dosage form to a subject for at least 5 consecutive days, said dosage form produces in said subject a highest plasma concentration of the pharmacological agent within the range from 10 to 120 μg/m 3 . 
     
     
         60 . The pharmaceutical dosage form according to  claim 59 , wherein the highest plasma concentration of the pharmacological agent reached after once daily administration of the pharmaceutical dosage form to said subject for at least 5 consecutive days is within the range from 20 to 80 μg/m 3 . 
     
     
         61 . The pharmaceutical dosage form according to  claim 59 , wherein the time to reach the highest plasma concentration of the pharmacological agent reached after once daily administration of the pharmaceutical dosage form for at least 5 consecutive days is within the range of from 2 to 6 h. 
     
     
         62 . A method of treating neuropathic pain in a subject in need thereof, said method comprising administering once daily to said subject a pharmaceutical dosage form according to  claim 47 . 
     
     
         63 . A pharmaceutical dosage form for administration once daily and containing a pharmacologically active agent corresponding to formula (I) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 , 
         or a physiologically acceptable salt thereof, and 
         wherein said dosage form
 provides immediate release in vitro of the pharmacologically active agent corresponding to formula (I) in accordance with Ph. Eur.; and 
 contains the pharmacologically active agent corresponding to formula (I) in a dose of from 150 μg to 800 μg; and 
 has a pharmacokinetic parameter t max  within the range of from 0.5 to 16 h. 
 
       
     
     
         64 . The pharmaceutical dosage form according to  claim 63 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 200 μg to 600 μg. 
     
     
         65 . The pharmaceutical dosage form according to  claim 64 , wherein said dosage form contains the pharmacologically active agent corresponding to formula (I) in a dose of from 300 μg to 500 μg. 
     
     
         66 . The pharmaceutical dosage form according to  claim 63 , wherein the pharmacologically active agent corresponding to formula (I) has a stereochemistry corresponding to formula (I′) 
       
         
           
           
               
               
           
         
         wherein R is —H or —CH 3 . 
       
     
     
         67 . The pharmaceutical dosage form according to  claim 63 , wherein the pharmacologically active agent corresponding to formula (I) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, or a physiologically acceptable salt thereof. 
     
     
         68 . The pharmaceutical dosage form according to  claim 63 , wherein under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 said dosage form releases after 30 minutes at least 80 wt.-% of the pharmacologically active agent corresponding to formula (I), based on the total amount of the pharmacologically active agent corresponding to formula (I) originally contained in the dosage form. 
     
     
         69 . The pharmaceutical dosage form according to  claim 63 , wherein said dosage form has a pharmacokinetic parameter t max  within the range of from 2 to 10 h. 
     
     
         70 . The pharmaceutical dosage form according to  claim 63 , wherein said dosage form has a pharmacokinetic parameter AUC 0-t /dose within the range of from 0.3 to 20 h/m 3 . 
     
     
         71 . The pharmaceutical dosage form according to  claim 63 , wherein said dosage form has a pharmacokinetic parameter C max /dose within the range of from 0.04 to 2.00 m −3 . 
     
     
         72 . A method of treating nociceptive pain in a subject in need thereof, said method comprising administering once daily to said subject a pharmaceutical dosage form according to  claim 63 . 
     
     
         73 . The method according to  claim 72 , wherein said nociceptive pain is selected from the group consisting of acute nociceptive pain and chronic nociceptive pain. 
     
     
         74 . The method according to  claim 72 , wherein said nociceptive pain is selected from the group consisting of somatic pain and visceral pain. 
     
     
         75 . The pharmaceutical dosage form according to  claim 33 , wherein the pharmacologically active agent is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof, and wherein the tablet further comprises one or more fillers in an amount from 0.001 to 90 wt.-% and one or more binders in an amount from 0.1 to 25 wt.-%. 
     
     
         76 . The pharmaceutical dosage form according to  claim 75 , wherein the tablet further comprises from one or more antiadherents in an amount from 0.001 to 5.0 wt.-%, one or more lubricants in an amount from 0.001 to 5 wt.-%, and/or one or more disintegrants in an amount from 0.001 to 5 wt.-%. 
     
     
         77 . The pharmaceutical dosage form according to  claim 76 , wherein the tablet comprises about 50 μg, about 200 μg, about, 400 μg, or about 600 μg of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or physiologically acceptable salt. 
     
     
         78 . The pharmaceutical dosage form according to  claim 77 , wherein
 the T max  is within the range of from 0.5 to 16 h; and/or   the ratio of the pharmacokinetic parameter AUC 0-t /dose is within the range of from 0.3 to 20 h/m 3 ; and/or   the ratio of the pharmacokinetic parameter C max /dose is within the range of from 0.04 to 2.00 m −3 .   
     
     
         79 . A method of treating pain in a subject in need thereof, said method comprising administering to said subject twice daily, once daily or less frequently a pharmaceutical dosage form according to  claim 77 . 
     
     
         80 . A method according to  claim 79 , wherein the pain is selected from the group consisting of chronic nociceptive pain, chronic neuropathic pain and acute pain.