Oral 2-methyl-thieno-benzodiazepine formulation

Details Oral 2-methyl-thieno-benzodiazepine formulation Oral 2-methyl-thieno-benzodiazepine formulation

2001-01-19

2004-08-24

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S482000, C424S494000, C424S495000, C424S497000, C514S772300, C514S781000

Reexamination Certificate

active

06780433

ABSTRACT:

BACKGROUND OF THE INVENTION
The compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine compound has useful central nervous system activity. Certain tablet formulations of olanzapine are known, as described in U.S. Pat. No. 5,229,382. However, improved oral formulations were desired in light of the moisture sensitive, polymorphic nature of olanzapine, the tendency of olanzapine to undesirably discolor in the known tablet formulation, and due to the surprisingly potent nature of olanzapine.
SUMMARY OF THE INVENTION
The presently claimed invention provides a pharmaceutically elegant solid oral formulation for comprising olanzapine intimately mixed with a bulking agent providing satisfactory hardness, friability, and disintegration time, binder, disintegrant, a dry binder to provide friability, and a lubricant; wherein such solid oral formulation is coated with polymer selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmacracrylate copolymer, methylcellulose, and ethylcellulose.
A method for preparing pharmaceutically elegant, stable solid oral olanzapine formulations having a polymer coat selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmacracrylate copolymer, methylcellulose, and ethylcellulose, comprised of using a high shear aqueous wet granulation with fluid bed drying process.
DETAILED DESCRIPTION OF THE INVENTION
Olanzapine, a potent compound having desired central nervous system activity has a tendency to undergo undesired polymorphic transformation, pharmaceutically undesired discoloration, and demands care to assure homogeniety of the finished solid formulation.
Applicants have discovered that olanzapine undergoes undesirable discoloration when contacted with certain excipients including powder blends. Further, the discoloration was exacerbated by ambient air conditions, at elevated temperatures, and by moist environments. Although the discoloration phenomenon does not produce in increase in the number of total related substances, the browning and mottling appearance is not generally considered pharmaceutically acceptable for commercial purposes.
Applicants have discovered that coating the solid oral formulation with a polymer selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmacracrylate copolymer, methylcellulose, and ethylcellulose as a coating or subcoating provides a uniform, physical stability and effectively prevents the undesired discoloration phenomenon.
Most preferred polymer coats are hydroxypropyl methyl cellulose, hydroxypropylcellulose, methylcellulose, and ethylcellulose. An especially preferred polymer coat is hydroxypropyl methylcellulose.
Applicants have discovered that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (olanzapine), which is a compound of the formula I:
exists as two anhydrous forms which are clearly distinguishable by x-ray powder diffractometry.
Unfortunately, anhydrous Form II olanzapine is metastable and is therefore not well suited for commercial use in pharmaceutical formulations. Applicants have discovered that the pharmaceutically elegant anhydrous Form I olanzapine can be formulated in its substantially pure form as a stable solid oral preparation. Such formulation provides assurance of a uniform pharmaceutically elegant product substantially free of Form II impurity in order to comply with regulatory requirements.
The Form I anhydrous 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine is the most stable form of the compound; however, Applicants have discovered that the Form I anhydrous olanzapine is subject to undesired crystalline transformations in the presence of certain solvents. Further certain excipients exacerbate physical instability. For commercial pharmaceutical development and compliance with regulatory guidelines, it is important to assure that marketed formulations comprise a uniform pharmaceutically elegant substantially pure anyhydrous Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine compound as the active ingredient and most preferably the formulation is free from undesired discolorations.
The substantially pure crystalline anhydrous Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (Form I) has a typical X-ray powder diffraction pattern substantially as follows, using a Sieman's D5000 diffractometer equipped with a copper radiation source, wherein d represents the interplaner spacing:
d
I/I
1
10.2689
100.00
8.577
7.96
7.4721
1.41
7.125
6.50
6.1459
3.12
6.071
5.12
5.4849
0.52
5.2181
6.86
5.1251
2.47
4.9874
7.41
4.7665
4.03
4.7158
6.80
4.4787
14.72
4.3307
1.48
4.2294
23.19
4.141
11.28
3.9873
9.01
3.7206
14.04
3.5645
2.27
3.5366
4.85
3.3828
3.47
3.2516
1.25
3.134
0.81
3.0848
0.45
3.0638
1.34
3.0111
3.51
2.8739
0.79
2.8102
1.47
2.7217
0.20
2.6432
1.26
2.6007
0.77
Form II olanzapine (Form II) has a typical X-ray powder diffraction pattern substantially as follows, using a Sieman's D5000 diffractometer equipped with a copper radiation source, wherein d represents the interplaner spacing:
d
I/I
1
9.9463
100.00
8.5579
15.18
8.2445
1.96
6.8862
14.73
6.3787
4.25
6.2439
5.21
5.5895
1.10
5.3055
0.95
4.9815
6.14
4.8333
68.37
4.7255
21.88
4.6286
3.82
4.533
17.83
4.4624
5.02
4.2915
9.19
4.2346
18.88
4.0855
17.29
3.8254
6.49
3.7489
10.64
3.6983
14.65
3.5817
3.04
3.5064
9.23
3.3392
4.67
3.2806
1.96
3.2138
2.52
3.1118
4.81
3.0507
1.96
2.948
2.40
2.8172
2.89
2.7589
2.27
2.6597
1.86
2.6336
1.10
2.5956
1.73
The x-ray powder diffraction patterns set forth herein were obtained with a copper K of wavelength =1.541A. The interplanar spacings in the column marked “d” are in Angstroms. The typical relative intensities are in the column marked “I/I
1
”. The detector was a Kevex silicon lithium solid state detector.
As used herein “substantially pure” shall refer to anhydrous Form I associated with <5% Form II; and most preferably it shall refer to <2% Form II. It is further preferred that “substantially pure” shall refer to <0.5% non-Form I polymorph.
As used herein “substantially pure” shall refer to anhydrous Form I associated with about <5% Form II; and most preferably it shall refer to about <2% Form II. It is further preferred that “substantially pure” shall refer to <0.5% related substances. When the Form I polymorph is formulated as a pharmaceutical composition, “substantially pure” shall preferably refer to about <15% Form II polymorph; more preferably, the term shall refer to about <10% Form II polymorph when the Form I polymorph is formulated as a pharmaceutical, and it is especially preferred that the term shall refer to about <5% Form II polymorph when the substantially pure substance is formulated.
As used herein, the term “2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine” refers to a technical grade of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine when no specific solvate or polymorph is named. Typically, the technical grade olanzapine contains less than about 5% undesired related substances and may be a mixed polymorph. Such technical grade olanzapine may contain less than about 1% undesired related substances.
The term “crude” refers to a form of olan

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