Solid pharmaceutical preparations of active form of vitamin D3 o

Details Solid pharmaceutical preparations of active form of vitamin D3 o Solid pharmaceutical preparations of active form of vitamin D3 o

1990-10-31

1992-10-27

Waddell, Frederick E.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

514960, 514970, A61K 3159

Patent

active

051589443

DESCRIPTION:

BRIEF SUMMARY
The Field of the Art

The present invention relates to a solid pharmaceutical preparation of active form of vitamin D.sub.3. Particularly, the present invention relates to a solid preparation of active form of vitamin D.sub.3 of improved stability wherein the preparation is composed of an active form of vitamin D.sub.3 composition containing active form of vitamin D.sub.3 dispersed in an excipient readily soluble in organic solvent, and a basic substance.


The Background of the Invention

The compounds which are typified by 1.alpha.-hydroxycholealciferol, 1.alpha.,25-dihydroxychlolecalciferol or 1.alpha.,24-dihydroxycholecalciferol have been known as active forms of vitamin D.sub.3 (Martin J. Calverley; Tetrahedron Vol. 43, No. 20, 4609-4619, 1987), and it has been clarified that these active forms of vitamin D.sub.3 distribute, after being absorbed in the living body, in intestinal tracts, kidney, parathyroid gland and bone tissues and bind to the receptors to develop their 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 forms of vitamin D.sub.3 have been 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 to heat, light and oxygen and means such as refrigeration, light shading or replacement with an inert gas are required for storage of these vitamin D.sub.3 themselves.
Therefore, it would be very useful that these active forms of vitamin D.sub.3 are provided in the form of a stabilized preparation.
Conventionally, as a method for stabilizing these active forms of vitamin D.sub.3 in the solid state, have been proposed the clathration of the vitamin D.sub.3 with cyclodextrin by the present inventors (Japanese Patent Application Laidopen No. 128417/'76), the clathration with bile acids (Japanese Patent Publication No. 41351/'86), the complex formation with sterols (Japanese Patent Publication No. 51948/'87), the dispersion in polyvinyl pyrrolidone (Japanese Patent Publication No. 46728/'88), the formation of the outer layer containing an active form of vitamin D.sub.3 and an excipient readily soluble in organic solvent, for example, polyvinyl pyrrolidone or hydroxypropyl cellulose on the inner layer comprising an excipient slightly soluble in organic solvent, for example, lactose or crystalline cellulose (Japanese Patent Publication No. 60007/'88) or the like.
The composition of the active form of vitamin D.sub.3 is usually mixed with other components, for example, known excipient, lubricant, binder, colorant, antioxidant or the like, formed into a solid preparation, for example, tablets, hard shell capsules, granules, powders and used for medical purposes.
The solid preparation of active form of vitamin D.sub.3 produced in such a manner has excellent stability for a long period of time under usual storage conditions, for example, at room temperature (at the ambient temperature indoor) and the tablets of 1.alpha.-hydroxycholecalciferol have been actually used over a wide range of the clinical fields.
The preparations are under suitable control, while they are in medical institution after being produced, further they are packed, thus their quality is guaranteed. After they are given to the patients, however, they are opened and taken out of the package, therefore, may be frequently exposed directly to unexpected drastic conditions, for example to high temperature and humidity. In the case of the preparations of active form of vitamin D.sub.3, it has become possible that the preparation which stands the long-term storage at room temperature is provided by converting the markedly unstable vitamin D.sub.3 itself into a stabilized composition by a variety of measures and techniques, but the reduction in

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"The Merck Index", 11th Edition, 1989, pp. 1578-1579, Rahway, N.J., US, Abstract Nos. 9928-9929: Vitamins D.sub.2, D.sub.3.

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