2-methyl-thieno-benzodiazepine formulation

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

1998-09-30

2001-01-02

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S557000

Utility Patent

active

06169084

ABSTRACT:

FIELD OF THE INVENTION
This invention provides a pharmaceutically elegant formulation of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, (hereinafter referred to as “olanzapine”) or a pamoate salt or solvate thereof.
BACKGROUND OF THE INVENTION
Olanzapine has shown great promise in the treatment of psychotic patients and is currently being marketed for that purpose. Such psychotic patients are often non-compliant, making it difficult to assess whether or not a patient has received the proper dosage of medication. Applicants have discovered that it can be especially desired to formulate olanzapine in a depot formulation or as a quick intramuscular formulation to assure consistent and proper dosage of the drug substance and to assume compliance.
Such formulation must be carefully designed and selected due to olanzapine's tendency to be metastable, to undergo pharmaceutically undesired discoloration, and olanzapine's surprising potency which requires care to assure homogeneity and stability of the finished formulation.
Typically, the artisan would prepare an ester form of the active drug substance to provide sustained release. Unfortunately, the olanzapine molecule is not amenable to formation of the ester product.
In addition, Applicants have discovered that olanzapine undergoes undesirable discoloration when contacted with certain excipients including powder blends. The discoloration is exacerbated by ambient air conditions, at elevated temperatures, and by moist environments. Although the discoloration phenomenon may not produce an increase in the number of total related substances, the color change is not generally considered pharmaceutically acceptable for commercial purposes.
In addition, it is known that the pH of muscle tissue can vary with exercise, stress, and injury which can affect drug solubility, and thus the rate of absorption of injectable drugs. Therefore, it is desirable to find an injectable sustained release formulation in which the release rate of the active ingredient is minimally dependent on pH.
Applicants have discovered that a formulation comprising olanzapine or a pamoate salt or solvate thereof as an active ingredient, and one or more carriers, can address the long felt need for such stable, pharmaceutically elegant formulation with a controllable release rate which may be useful as a depot formulation or for fast acting intramuscular or subcutaneous use.
SUMMARY OF THE INVENTION
The present invention provides a formulation comprising olanzapine or a pamoate salt or solvate thereof, and an oleaginous or cholesterol microsphere carrier.
The present invention provides, in addition, novel pamoate salts of olanzapine. Such salts are especially useful in preparing a sustained release formulation in which the release rate is minimally dependent on the pH of the environment.
DETAILED DESCRIPTION OF THE INVENTION
Olanzapine may be used. However, Applicants have discovered that pamoate salts of olanzapine may be preferred in effecting duration of release from the above compositions. Different solvate forms of olanzapine or its pamoate salts may also be useful, including, for example, olanzapine dihydrates D, E and F, olanzapine pamoate, and the monohydrate, dimethanolate, THF (tetrahydrofuran) and acetone solvates of olanzapine pamoate. Bis(olanzapine) pamoate and its solvates may also be useful in the current invention. A preferred salt is olanzapine pamoate monohydrate. Bis(olanzapine) pamoate monohydrate is also a preferred salt.
The formulation may contain the most stable anhydrous form of olanzapine, referred to herein as Form II; however, other forms of olanzapine are contemplated.
A typical example of an x-ray diffraction pattern for Form II is as follows wherein d represents the interplanar spacing and intensity represents the typical relative intensities as set forth in Table 1:
TABLE 1
d-spacings
Intensity
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
The x-ray diffraction patterns set out above were obtained using a Siemens D5000 x-ray powder diffractometer having a copper K
a
radiation source of wavelength, l=1.541 Å.
An especially preferred olanzapine pamoate solvate is the pamoate monohydrate having a typical x-ray powder diffraction pattern as represented by the following interplanar d-spacings and relative intensities as set forth in Table 2.
TABLE 2
Olanzapine Pamoate Monohydrate
d-spacing
Intensity
10.76 
98
9.20
62
8.38
85
8.18
24
7.62
20
6.67
18
6.56
18
6.51
20
6.44
20
6.11
26
5.88
22
5.64
15
5.38
100 
4.90
11
4.72
12
4.64
17
4.48
18
4.35
23
4.29
31
4.24
32
4.09
71
4.02
84
3.98
73
3.81
23
3.62
14
3.52
30
3.39
11
3.25
12
2.90
15
2.85
13
Another especially preferred olanzapine pamoate solvate is pamoate dimethanolate having a typical x-ray powder diffraction pattern as represented by the following interplanar d-spacings and relative intensities as set forth in Table 3.
TABLE 3
Olanzapine Pamoate Dimethanolate
d-spacing
Intensity
11.17 
73
9.37
17
8.73
40
8.29
23
7.77
14
7.22
24
6.84
31
6.66
54
6.42
11
6.40
11
6.17
26
5.87
12
5.56
100 
4.84
11
4.66
17
4.57
26
4.48
22
4.35
19
4.28
19
4.12
94
4.03
91
3.89
52
3.62
44
3.54
11
3.29
16
3.13
16
Yet another preferred olanzapine pamoate solvate is the pamoate THF solvate having a typical x-ray powder diffraction pattern as represented by the following interplanar d-spacings and relative intensities as set forth in Table 4.
TABLE 4
Olanzapine THF Solvate
d-spacing
Intensity
14.59 
100 
7.78
16
7.24
56
7.00
19
6.37
12
6.04
11
6.01
11
4.85
19
4.69
42
4.39
25
4.28
19
3.95
13
3.84
20
Still another especially preferred olanzapine pamoate solvate is the bis(olanzapine) pamoate acetone solvate having a typical x-ray powder diffraction pattern as represented by the following interplanar d-spacings and relative intensities as set forth in Table 5.
TABLE 5
Olanzapine Pamoate Acetone Solvate
d-spacing
Intensity
16.87 
32
9.58
35
8.88
80
8.40
16
8.19
35
7.85
16
7.34
29
7.22
25
7.04
30
6.87
18
6.77
11
6.73
11
6.65
21
6.36
12
6.26
26
5.76
31
5.58
79
5.53
100 
5.45
61
5.32
42
5.19
39
5.02
55
4.91
69
4.87
51
4.85
57
4.69
44
4.61
68
4.44
23
4.34
14
4.18
17
4.07
36
3.99
28
3.93
65
3.81
23
3.78
24
3.77
20
3.65
23
3.59
28
3.45
13
3.32
19
3.25
26
An additional especially preferred olanzapine pamoate solvate is bis(olanzapine) pamoate monohydrate having a typical x-ray powder diffraction pattern as represented by the following interplanar d-spacings and relative intensities as set forth in Table 6.
TABLE 6
Bis(Olanzapine) Monohydrate
d-spacing
Intensity
15.77 
26
10.44 
23
9.64
24
9.31
13
8.27
23
8.17
14
8.13
14
7.84
27
7.81
30
7.41
60
7.12
40
7.00
13
6.96
13
6.55
45
6.18
53
5.87
38
5.80
19
5.59
89
5.25
26
5.00
34
4.96
31
4.88
61
4.85
73
4.71
34
4.52
19
4.33
11
4.19
100 
4.12
48
4.05
39
3.97
30
3.89
31
3.80
29
3.72
20
3.70
21
3.58
33
3.45
27
3.04
13
2.84
16
The X-Ray powder diffraction patterns for the pamoate salts and solvates were collected on a Siemens D5000 Diffractometer, using Cu K&agr; radiation at a wavelength of 1.5406 Å. Instrumental conditions: stepsize 0.01°; scan rate 1.0 seconds/step; range 4°-35° 2&thgr;; 0.6 mm divergence slit; 1.0 mm scattered radiation slit; 0.2 mm receiving slit; 50 kV; 40 mA; Kevex solid state detector. Samples were packed into recessed sample holders for analysis.
The formulation of the invention may contain substantially pure Form II as the active ingredient. As used herein “substantially pure” refers to Form II associated with less than about 15% undesired polymorphic form of olanzapine (herein referred to as “Undesired Form”), preferably less than about 5% Undesired Form, and more preferably less than about 2% Undesired Form. Further

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