Pharmaceutical levothyroxine preparation

Details Pharmaceutical levothyroxine preparation Pharmaceutical levothyroxine preparation

2001-01-05

2002-12-10

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S464000, C424S489000, C514S774000, C514S781000, C514S970000, C514S961000, C514S951000

Reexamination Certificate

active

06491946

ABSTRACT:

The invention relates to a novel stable pharmaceutical preparation comprising levothyroxine sodium, potassium iodide, microcrystalline cellulose and binding agent, which is free of antioxidants or further auxiliaries.
Auxiliaries are substances which prevent formation of iodine, e.g. potassium hydroxide.
A thyroxine preparation stabilized with thiosulfate as an antioxidant is described in DE 195 41 128.
Another known thyroxine-containing commercial preparation Thyreocomb® N (Red List 1998, 74015) contains the auxiliary potassium hydroxide, which drives the comproportionation reaction of iodide and iodate to iodine to the starting material side. In this manner, production of iodine is suppressed.
A preparation comprising levothyroxine sodium and potassium iodide for the stabilization of the active compound levothyroxine sodium is disclosed in U.S. Pat. No. 5,635,209. For a low dose, the amount of potassium iodide needed for the stabilization of levothyroxine sodium is given in a ratio of 4:1, e.g. 25 &mgr;g of levothyroxine sodium and 100 &mgr;g of potassium iodide. For high doses, the ratio is described as 1.5:1, e.g. 300-450 &mgr;g of potassium iodide for 300 &mgr;g of levothyroxine sodium. 300 &mgr;g of potassium iodide were needed for the stabilization of 100 &mgr;g of levothyroxine sodium.
The active compound levothyroxine sodium (=levothyroxine-Na=LT4) is sensitive to light, heat and oxygen. On account of these known stability problems, pharmaceutical preparations are therefore overdosed by up to 20%.
If, in addition to the active compound levothyroxine-Na in a pharmaceutical preparation, iodide is additionally contained, this pharmaceutical preparation becomes discoloured on storage, since the anion iodide in potassium iodide can be oxidized to iodine or can comproportionate with potassium iodate to give iodine. Furthermore, the demands on the in-vitro release for levothyroxine-Na tablets have been increased. The draft monograph of the Pharmacopeial Forum (Pharm. Preview, 1995, 21, 1459-1461) intends, in addition to the valid test 1 (phosphate buffer pH 7.4, in 80 minutes >55%), to approve the test 2 (water in 45 minutes >70%).
The invention was based on the object of making available novel medicaments in the form of pharmaceutical preparations which have better properties than known medicaments which can be used for the same purposes.
This object was achieved by the discovery of the novel preparation.
The novel preparation according to the invention essentially shows no discolouration and has an improved stability. It can be used as a thyroid hormone combination preparation, owing to the high content of iodide as a second active compound, in euthyroid iodine deficiency goitre and/or in relapse prophylaxis after resection of an iodine deficiency goitre.
The active compound iodide can be contained as an anion only in the presence of a stabilizing cation, e.g. potassium (
+
), and thus as a salt in a pharmaceutical preparation. 130 &mgr;g of potassium iodide correspond to 100 &mgr;g of iodide.
Discolouration of the preparation according to the invention is avoided, since formation of free iodine is prevented.
This novel preparation furthermore has a very good release of active compound in vitro.
The invention preferably relates to a pharmaceutical preparation as described, characterized in that it contain 5 to 400 &mgr;g, of levothyroxine 300 &mgr;g, in particular 50 to 200 &mgr;g, of levothyroxine sodium and 5 to 400 &mgr;g, preferably 10 to 300 &mgr;g, in particular 25 to 200 &mgr;g, of potassium iodide.
The invention furthermore preferably relates to a pharmaceutical preparation as described, characterized in that it contains levothyroxine sodium in micronized form having a particle size of between 5 and 25 &mgr;m (to 95%), particularly preferably having a particle size of between 5 and 15 &mgr;m (to 95%).
The invention furthermore preferably relates to a pharmaceutical preparation as described, characterized in that it contains a hydroxypropyl-methylcellulose and/or gelatine as a binding agent.
A pharmaceutical preparation is particularly preferably described, characterized in that it is a solid preparation in the form of tablets.
Particularly preferred embodiments contain 50, 75 or 100 &mgr;g of levothyroxine sodium and 100 &mgr;g each of iodide, 100 &mgr;g of iodide corresponding to an amount of 130 &mgr;g of potassium iodide. A very particularly preferred embodiment contains 100 &mgr;g of levothyroxine sodium and 100 &mgr;g of iodide.
On account of the known instability of levothyroxine-Na, this active compound is overdosed to 5% in the formulations.
The preparation according to the invention has a surprising stability when hydroxypropylmethyl-cellulose and/or gelatine is used as a binding agent. At the same time, formation of iodine is surprisingly suppressed without admixture of antioxidants or further auxiliaries being necessary.
The data of the stability investigations are indicated in Tables I and II as exemplified by batches 005204 (13/97) and 004609 (3/96). Based on the results, it can be seen that the tablets according to the invention which contain levothyroxine sodium (100 &mgr;g) and iodide (100 &mgr;g) are stable for at least 2 years if they are stored at temperatures below 30° C. Likewise, no brown colouration of the pharmaceutical preparation is observed in this period, i.e. no formation of iodine.
Furthermore, the release of the active compound levothyroxine sodium is favoured if the active compound is employed in micronized form. Levothyroxine sodium is customarily soluble with great difficulty both in water and in ethanol. With a particle size of between 5 and 25 &mgr;m (to 95%), particularly preferably between 5 and 15 &mgr;m, however, a release of the active compound which corresponds to both test systems takes place (Tables I and II).
TABLE I
Stability and release of batch 005204 (13/97);
levothyroxine-Na (LT4) 100 &mgr;g/iodide 100 &mgr;g tablets;
prepared analogously to Example 1:
PP tube 25°/60%
Release
Release
Water content
Period
Content
Content
with
with
according
Disintegration
Date (storage)
of LT4
of iodide
buffer
water
to KF
time
Friability
Date (investigation)
[&mgr;g]
[&mgr;g]
[%]
[%]
[%]
[sec]
[N]
Starting value
108.3
99.5
30 min: 94.3
15 min: 91.3
2.51
43-55
42-50
60 min: 99.2
30 min: 93.5
80 min. 100.6
45 min: 95.1
13 weeks
106.9
104.2
15 min: 85.9
3.28
50-60
48-55
18.07.1997
30 min: 89.9
13.02.1998
45 min: 91.2
26 weeks
102.1
102.8
15 min: 89.5
3.14
50-68
41-48
17.10.1997
30 min: 91.6
21.02.1998
45 min: 95.1
39 weeks
100.6
103.2
15 min: 84.6
3.28
49-60
41-49
19.01.1998
30 min: 88.1
45 min: 89.3
52 weeks
100.9
103.2
15 min: 84.6
3.50
40-55
41-49
30 min: 87.2
45 min: 89.5
Comments: 5% overdosage of LT4
TABLE II
Stability and release of batch 004609 (3/96);
levothyroxine-Na (LT4) 100 &mgr;g/iodide 100 &mgr;g tablets;
prepared analogously to Example 1:
PP blister 25°/60%
Release
Release
Water content
Period
Content
Content
with
with
according
Disintegration
Date (storage)
of LT4
of iodide
buffer
water
to KF
time
Friability
Date (investigation)
[&mgr;g]
[&mgr;g]
[%]
[%]
[%]
[sec]
[N]
Starting value
108.3
103.6
30 min: 105.3
15 min: 101.0
3.18
60 min: 105.3
30 min: 102.9
80 min: 103.1
45 min: 106.1
13 weeks
104.9
100.2
15 min: 94.6
4.8
23.12.1996
30 min: 96.3
45 min: 96.7
26 weeks
104.8
103.6
15 min: 96.1
5.34
10.04.1997
30 min: 97.2
24.02.1998
45 min: 97.4
52 weeks
101.5
102.7
15 min: 94.1
6.26
37-50
39-44
29.09.1997
30 min: 95.3
45 min: 95.8
78 weeks
99.72
104.6
15 min: 95.8
5.69
30-38
35-40
24.02.1998
30 min: 97.5
45 min: 98.6
Comments: 5% overdosage of LT4
The analytical data are determined according to customary and known methods.
The invention also relates to a process for the production of a pharmaceutical preparation comprising levothyroxine sodium and potassium iodide, characterized in that levothyroxine sodium and potassium iodide, which are present in suspended

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