Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1997-07-24
1999-01-05
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514 58, A61K 31195, A61K 31715
Patent
active
058563598
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP96/05275 filed Nov. 28, 1996.
Thyroxine containing pharmaceutical compositions with improved aqueous solubility, stability and enhanced membrane permeation have been prepared by formulating thyroxine with cyclodextrins. These thyroxine/cyclodextrin complexes can further be transformed into different dosage forms (oral tablets, injectables, transdermal patches, hydrogels, ointments, suppositories etc.) by employing known, common pharmaceutical additives.
The present invention relates to complexes of thyroxine and cyclodextrin and pharmaceutical compositions thereof suitable for oral, and parenteral or transdermal administration. In the present invention thyroxine stands for L-thyroxine or D-thyroxine or a pharmaceutical acceptable salt thereof or any racemate thereof.
Deficiency of thyroid activity, whether occurring spontaneously or resulting from surgical removal of thyroid gland, thyroiditis, or decreased function secondary to pituitary degeneration results in clinical hypothyroidism. Whatever the cause, the symptom is treated by replacement therapy using thyreoglobulin or salts of thyroxine, like Levothyroxine-sodium.
Levothyroxine (L-thyroxine) {0-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodotyrosine} is an iodinated aminoacid of the thyroid gland that exerts a stimulating effect on metabolism (Kendall, J. Am. Med. Assoc. 64. 2042. 1915.). Levothyroxine sodium as drug has been used mainly in tablet form with a unit dose of around 0.1 mg per tablet.
Dextrothyroxine (D-throxine) is the D-configuration of the natural occuring thyroid gland hormone and exhibits cholesterol and lipid lowering effects.
Cyclodextrins (CDs) are prepared from starches using CD-glucosyl transferase enzyme. There are three different kinds of CDs, i.e. the .alpha.-, .beta.- and .gamma.-CD, which consists of 6, 7 or 8 glucopyranose units connected with -1.4 glucosidic bonds. The three cyclodextrins differ in molecular weight, water-solubility and in cavity-diameter. Accordingly they are able to form inclusion complexes with most of compounds, but the inclusion complexes of the same compound are formed with different kinds of CD having very different properties. There is a possibility to carry out further modifications in the CD molecule with suitable substitutions. For example in case of heptakis-2,6-di-0-methyl-.beta.-CD (DIMEB) two hydroxyl groups of every glucose unit are methylated, while in case of randomly methylated .beta.-CD (RAMEB) the hydroxy groups are substituted randomly by methoxy groups, however the average degree of methylation is around 1,8. The hydroxyalkylation of cyclodextrins also results in improved aqueous solubility as known for hydroxypropylated and hydroxyethylated cyclodextrine derivatives (Szejtli, J. Cyclodextrin Technology, Kluwer Academic Publ. 1988. page 51.).
The solubility of these chemically modified cyclodextrins reaches the value of about 400-500 mg/ml at room temperature and their complex-forming capacity also differs from the unsubstituted CDs.
The interaction of thyroxine with cyclodextrins has not yet been reported. Thyroxine/cyclodextrin inclusion complexes as ingredients of any pharmaceutical formulations have never been previously described in any paper or patent.
The U.S. Pat. No.4,121,975 (Ullman, E.; Lavine, F. and Joel, E.) deals with the analytical determination of serum thyroxine levels in patients by competitive protein-binding or immunoassay, employing also .gamma.-cyclodextrin for the selective removal of interfering components (mainly blood lipids) present in the blood samples.
There is a lot of literature--both publications and patents--which describes the enhancement of poorly soluble drugs with cyclodextrins and with the concomitant consequences, like improved bioavailability, chemical and/or physical stability of the cyclodextrin complexed drug (Szejtli, J.: Cyclodextrin Technology, Kluwer Academic Publ., Dordrecht, Holland, 1988, p. 186-197). Summarizing the available data it can be stated that in most cases the .beta.-CD is the best complexing agent for hy
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Szente, Lajos et al., "Spontaneous Opalescence of Aqueous .gamma.-Cyclodextrin Solutions: Complex Formations or Self-Aggregation?", 14 pages, (Unpublished).
Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, pp. 41-42, 1986.
Bracher Daniel
Fischer Wilfried
Henley III Raymond
Hexal AG
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