Stabilized aqueous preparation of active form of vitamin D.sub.3

Details Stabilized aqueous preparation of active form of vitamin D.sub.3 Stabilized aqueous preparation of active form of vitamin D.sub.3

1990-05-25

1993-01-26

Schenkman, Leonard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

A61K 3159

Patent

active

051822741

DESCRIPTION:

BRIEF SUMMARY
THE FIELD OF THE ART

The present invention relates to a stabilized aqueous preparation of active form of vitamin D.sub.3.
Particularly, the present invention relates to an aqueous preparation of active form of vitamin D.sub.3 which is solubilized into water using a nonionic surface active agent, and stabilized with a combination of at least one selected from the group consisting of citric acid, tartaric acid and their metal salts with an antioxidant.


THE BACKGROUND OF THE INVENTION

It has been clarified that active form of vitamin D.sub.3, typified by 1.alpha.-hydroxycholecalciferol, 1.alpha.,25-dihydroxychole-calciferol or 1.alpha.,24-dihydroxycholecalciferol, is absorbed in the body, binds to the receptors distributing in intestinal tracts, kidney, parathyroid gland and bone tissues to develop its pharmacological actions such as Ca absorption from intestinal tracts, increase of serum Ca level, secretory inhibition of parathyroid hormone or bone formation. Thus, the active form of vitamin D.sub.3 is clinically applied to a variety of symptoms (hypocalcemia, tetany, bone ache, bone lesion, and so on) accompanied by dysbolism of vitamin D in chronic renal failure, hypoparathyroidism, vitamin D resistant rickets, and osteomalacia, as well as for treatment of osteoporosis.
These active forms of vitamin D.sub.3 are chemically unstable and cannot be clinically applied without establishment of production of stabilized preparations. And many methods have been proposed.
For example, Japanese patent specification No. 57-45415 (1982), Japanese patent specification No.61-41351 (1986), Japanese patent specification No. 62-51948 (1987), Japanese patent specification No. 58-206533 (1983), U.S. Pat No. 4,729,895 (Japanese patent specification laid-open No. 59-155309 (1984) disclosed the stabilization processes for oral preparations, and the soft capsules and tablets prepared from 1.alpha.-hydroxycholecalciferol, 1.alpha.,25-dihydroxycholecalciferol or 1.alpha.,24-dihydroxycholecalciferol by the disclosed techniques have been practically used in the clinical fields.
These techniques relates, however, to the stabilization of only non-aqueous liquid preparations or solid preparations.
Meanwhile, aqueous preparations, particularly stabilized preparations of active form of vitamin D.sub.3 have been strongly desired clinically for the intravenous administration to chronic renal failure or for continuous application to premature babies and infants with convenience of application enhanced and side-effects decreased.
As for such stabilization of aqueous preparation, U.S. Pat. No. 4,308,264 (Japanese patent specification 61-44845 (1986)) disclosed a method for stabilizing 1.alpha.,25-dihydroxycholecalciferol in injection preparations and oral liquid preparations. Japanese patent specification laid-open No. 62-17 (1987) described a method for stabilizing an active form of vitamin D.sub.3 in aqueous solution by admixing some kinds of amino acids.
The present inventors have found, however, in the course of their study of the production of aqueous preparations of active forms of vitamin D.sub.3, that these conventional arts include great problems from a practical point of view.
In other words, the method according to U.S. Pat. No. 4,308,264 has following 2 problems:
First, the method described in the patent is effective for stabilization of 1,25-dihydroxycholecalciferol, to be sure, but the stabilization effect is limited to the conditions in the presence of inert atmosphere, as the specification told it.
But, it should be recognized that the actual conditions for the aqueous preparations to be given clinically are not always kept as the preparation has been provided in an inert atmosphere, in other words, actual administration is not limited only to the case where a unit dosage form which has been prepared in an inert atmosphere is given only in intravenous or oral bolus, namely the whole amount of the unit dose is given in single application. For example, even in intravenous administration, when it is given together with other d

REFERENCES:
patent: 4308264 (1981-12-01), Conway et al.
patent: 4729895 (1988-03-01), Makino et al.
patent: 4836957 (1989-06-01), Nemoto et al.
Chemical Abstracts 97:163329f (1982).
Chemical Abstracts 96:57766r (1982).
Chemical Abstracts 100:91354n (1984).
Chemical Abstracts 95:121145w (1981).
Chemical Abstracts 92:64750b (1980).
Merck Index, 9th ed., 1976 2307.

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