Stabilized medicaments containing thyroid hormones

Details Stabilized medicaments containing thyroid hormones Stabilized medicaments containing thyroid hormones

1998-04-08

1999-09-28

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

424451, 424464, 424484, 424488, 514557, 562447, 562602, A61K 31195, A61K 920

Patent

active

059589795

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to stabilised medicaments containing thyroid hormones and processes for preparing the same.
Thyroid hormones within the meaning of the present invention are hormones suitable for therapeutic application, especially those of natural or synthetic origin bearing two to four iodine atoms in the molecule such as levothyroxin, liothyronin, dextrothyroxin, triiodoacetic acid, thyroid (dried thyroid), thyroglobulin, diiodotyrosin, and analogues and salts thereof.
Thyroid hormones of the above-mentioned type are used therapeutically for thyroid diseases of various origins, especially hyperthyroidism, hypothyrosis, iodine deficiency and related secondary diseases but also for prophylactic substitution both as monosubstances and in combination with each other or with other active ingredients such as iodine salts. Levothyroxin and liothyrinin, which are used in the form of their salts or as free acids, have attained special significance in this respect.
Thyroid hormones of the above type, especially the salts commonly used as medicaments, are very susceptible to temperature, humidity and oxidation. They are decomposed by various reaction mechanisms. In addition, they react with many of the pharmaceutical excipients commonly used so that it is difficult to prepare medicaments wherein the active ingredient remains effective for a sufficient period of time under regular storage conditions within the limits applicable for pharmaceutical agents, i.e. without special precautions.
In the normal central European climate (climatic zone I, i.e. a mean temperature of 21.degree. C.), conventional levothyroxin sodium tablets, for example, remain active for a maximum of three years at the still tolerable level of at least 90% of the active ingredients declared, but at higher temperature and humidity levels (climatic zones II to IV) stability cannot be maintained over this period of time. This disadvantageously cuts the time span during which the medicament may be sold. A decrease of the active ingredient level by 10% until the end of marketability which is tolerated for the climatic zone I must also be regarded as critical, because, as a rule, little is known about the type and activity of the resulting degradation products, especially with regard to their toxicity.
There has been no lack of attempts to stabilise thyroid hormones in medicament form, especially levothyroxin for oral administration to humans which determines any therapy. U.S. Pat. No. 5,225,204 (Chen et al.), for example, proposes to prepare a levothyroxin-sodium complex together with polyvinyl pyrrolidone and a cellulose component for stabilisation. Without the degree of stabilisation being explained in greater detail in this publication, the process described there has the disadvantage of a costly process for preparing the complex. Especially the use of organic solvents is considered disadvantageous both for cost and ecological reasons.
It was the object of the present invention to prepare medicaments containing thyroid hormones in such a manner that their stability is guaranteed for more than three years in the climatic zone I and at least three years in the climatic zones II to IV without special storage precautions and to provide a simple, ecologically safe process for preparing the same.
According to general consensus, the climatic zones are defined as follows ("The regulation of medicaments within the European Community", Volume III, EC Commission, Jan. 1989):


TABLE 1 ______________________________________ Zone III Zone II hot/dry or Zone IV Climatic Zone I Mediterranean hot/moderate very/hot conditions moderate (subtropical) humidity humid ______________________________________ Annual mean <20.5.degree. C. 20.5-24.degree. C. >24.degree. C. >24.degree. C. temperature Kinetic mean 21.degree. C. 26.degree. C. 31.degree. C. 31.degree. C. temperature (virtual temp.) Average of 45% 60% 40% 70% relative humidity p.a. ______________________________________
It has now been found that sodium thiosul

REFERENCES:
patent: 4154820 (1979-05-01), Simoons
patent: 5225204 (1993-07-01), Chen et al.
Chemical Patents Indesx, Basic Abstracts Journal, Sec. B, Derwent Publications, Ltd., London (Jun. 19, 1985), No. 85-102741/17; JP 0048937 A.
Chemical Abstracts, vol. 121, No. 18, Abstract Number: 213005, 1994.
Chemical Patents Index, Documentation Abstracts Journal, Sec. B, Derwent Publications, Ltd., London (Jun. 19, 1991). No. 91-112628/16; JP 3052814 A.
Chemical Patents Index, Basic Abstracts Journal, Sec. D. Derwent Publications, Ltd., London (Sep. 21, 1988). No. 88-209830/30; JP 3146829 A .

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