Pharmaceutical dosage form for immediate release of an indolinone derivative
The present invention relates to a pharmaceutical dosage form delivering an immediate release profile containing the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.
1. A pharmaceutical dosage form which is a viscous lipid suspension formulation comprising:
10 to 50 wt. % of the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylenel]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate,
10 to 70 wt. % of medium chain triglycerides;
10 to 30 wt. % of hard fat; and
0.25 to 2.5 wt. % of lecithin,
which delivers an immediate release profile in which not less than 70% (Q65%) of the active substance is dissolved in 60 minutes in vitro under the following in vitro dissolution conditions according to European Pharmacopeia 6.2: Apparatus 2 (paddle), dissolution medium with 0.1 M HCl (pH 1) and stirring speed of 50 to 150 rpm, at a temperature of 37° C.
2. The pharmaceutical dosage form according to claim 1 , wherein it is an orally deliverable dosage form.
3. The pharmaceutical dosage form according to claim 2 , wherein it is in the form of a capsule.
4. The pharmaceutical dosage form according to claim 3 in the form of a soft gelatine capsule comprising 50 mg of active substance free base equivalent selected from the group consisting of compositions A, B and C:
Formulation
Formulation
Formulation
A
B
C
mg per
mg per
mg per
Ingredients
capsule
capsule
capsule
Active
60.20
60.20
60.20
Substance*
Triglycerides,
40.95
53.70
54.00
Medium-chain
Hard fat
38.25
25.50
25.50
Lecithin
0.60
0.60
0.30
Gelatin
72.25
72.25
72.25
Glycerol 85%
32.24
32.24
32.24
Titanium
0.20
0.20
0.20
dioxide
Iron oxide A
0.32
0.32
0.32
Iron oxide B
0.32
0.32
0.32
Total Capsule Weight
245.33
245.33
245.33.
5. The pharmaceutical dosage form according to claim 3 in the form of a soft gelatine capsule comprising 75 mg of active substance free base equivalent selected from the group consisting of A, B and C:
Formulation
Formulation
Formulation
A
B
C
mg per
mg per
mg per
Ingredients
capsule
capsule
capsule
Active
90.3
90.3
90.3
Substance*
Triglycerides,
61.425
80.55
80.1
Medium-chain
Hard fat
57.375
38.25
38.25
Lecithin
0.9
0.9
1.35
Gelatin
107.11
107.11
107.11
Glycerol 85%
46.84
46.84
46.84
Titanium
0.35
0.35
0.35
dioxide
Iron oxide A
0.058
0.058
0.058
Iron oxide B
0.16
0.16
0.16
Total Capsule Weight
364.518
364.518
364.518.
6. The pharmaceutical dosage form according to claim 3 in the form of a soft gelatine capsule comprising 100 mg of active substance free base equivalent selected from the group consisting of compositions A, B and C:
Formulation
Formulation
Formulation
A
B
C
mg per
mg per
mg per
Ingredients
capsule
capsule
capsule
Active
120.40
120.40
120.40
Substance*
Triglycerides,
81.90
107.40
106.8
Medium-chain
Hard fat
76.50
51.00
51.00
Lecithin
1.20
1.20
1.80
Gelatin
111.58
111.58
111.58
Glycerol 85%
48.79
48.79
48.79
Titanium
0.36
0.36
0.36
dioxide
Iron oxide A
0.06
0.06
0.06
Iron oxide B
0.17
0.17
0.17
Total Capsule Weight
440.96
440.96
440.96.
7. The pharmaceutical dosage form according to claim 3 in form of a soft gelatine capsule comprising 125 mg of active substance free base equivalent, selected from the group consisting of compositions A, B and C:
Formulation
Formulation
Formulation
A
B
C
mg per
mg per
mg per
Ingredients
capsule
capsule
capsule
Active Substance*
150.50
150.50
150.50
Triglycerides,
102.375
134.25
133.5
Medium-chain
Hard fat
95.625
63.75
63.75
Lecithin
1.50
1.50
2.25
Gelatin
142.82
142.82
142.82
Glycerol 85%
62.45
62.45
62.45
Titanium dioxide
0.47
0.47
0.47
Iron oxide A
0.08
0.08
0.08
Iron oxide B
0.22
0.22
0.22
Total Capsule Weight
556.04
556.04
556.04.
8. The pharmaceutical dosage form according to claim 3 in form of a soft gelatine capsule comprising 150 mg of active substance free base equivalent selected from the group consisting of compositions A, B and C:
Formulation
Formulation
Formulation
A
B
C
mg per
mg per
mg per
Ingredients
capsule
capsule
capsule
Active Substance*
180.60
180.60
180.60
Triglycerides,
122.85
161.10
160.20
Medium-chain
Hard fat
114.75
76.50
76.50
Lecithin
1.80
1.80
2.70
Gelatin
142.82
142.82
142.82
Glycerol 85%
62.45
62.45
62.45
Titanium dioxide
0.47
0.47
0.47
Iron oxide A
0.08
0.08
0.08
Iron oxide B
0.22
0.22
0.22
Total Capsule Weight
626.04
626.04
626.04.
9. The pharmaceutical dosage form according to claim 3 in form of a soft gelatine capsule comprising 200 mg of active substance free base equivalent selected from the group consisting of compositions A, B and C:
Formulation
Formulation
Formulation
A
B
C
mg per
mg per
mg per
Ingredients
capsule
capsule
capsule
Active
240.80
240.80
240.80
Substance*
Triglycerides,
163.30
214.80
216.00
Medium-chain
Hard fat
153.50
102.00
102.00
Lecithin
2.40
2.40
1.20
Gelatin
203.19
203.19
203.19
Glycerol 85%
102.61
102.61
102.61
Titanium
0.57
0.57
0.57
dioxide
Iron oxide A
0.90
0.90
0.90
Iron oxide B
0.90
0.90
0.90
Total Capsule Weight
868.17
868.17
868.17.
10. The pharmaceutical dosage form according to claim 1 , comprising dose-range values of between 25 to 300 mg of the active substance.