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
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.