Crystalline form of a vitamin D analogue

Details Crystalline form of a vitamin D analogue Crystalline form of a vitamin D analogue

1995-07-14

1998-06-09

Dees, Jose G.

Textiles: spinning, twisting, and twining

552653, A61K 3159, C07C40100

Patent

active

057634262

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/DK94/00011 filed Jan. 7, 1994.
The present invention relates to calcipotriol, hydrate--a new crystalline form of calcipotriol--with superior technical properties e.g. in the manufacture of crystal suspension formulations, and with superior stability properties.
Calcipotriol (INN) (calcipotriene (USAN), (1.alpha.,3.beta.,5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola-5,7,10(19), 22-tetraene-1,3,24-triol) is described in International patent application No. PCT/DK86/00081, filing date 14th Jul. 1986, publication No. WO 87/00834.
Calcipotriol possesses a remarkable profile of biological activity which has proved very useful e.g. in the topical treatment of psoriasis.
Due to the poor stability of calcipotriol in certain solutions it is in some formulations, in particular in creams and gels, preferred to use crystal suspensions.
In order to prepare suitable crystal suspension formulations it is mandatory to be able to control the crystal size, this parameter being important with regard to obtaining a reproducible release of the active compound from the formulation. The crystalline bulk drug is usually subjected to micronization or to a wet milling process in order to reduce the crystal size before the final suspension formulation is prepared.
In the case of calcipotriol a wet ball milling process has been used. However, it has turned out to be technically difficult to perform this process when using the anhydrous crystal form described in WO 87/00834. These crystals are not easily wetted and during the milling process they develop a stable foam which results in difficulties in obtaining a suitable small and uniform particle size.
It has now surprisingly been found that these technical problems can be avoided when a hitherto unknown crystalline form of calcipotriol, i.e. calcipotriol, hydrate, is used instead of the known anhydrous form. The hydrate is technically superior to the anhydrate; it is easily wetted and the wet ball milling process is running smoothly.
This novel product is the monohydrate of calcipotriol which is perfectly crystalline, stable and well suited for its use in modern therapy.
Stability studies have demonstrated that calcipotriol, hydrate is surprisingly stable, and this is illustrated by stability data at 40.degree. C.
The anhydrous form of calcipotriol shows a considerable degree of decomposition at this temperature and more than 30% degradation is seen after 12 months storage.
In contrast the compound of the present invention, calcipotriol hydrate, shows no degradation after 12 months storage at 40.degree. C.
Calcipotriol, monohydrate may be prepared by dissolving crystalline or non-crystalline calcipotriol in an organic solvent, e.g. ethyl acetate or acetone, followed by the addition of water and optionally a non polar solvent, e.g. hexane.
Calcipotriol, monohydrate shall form part of pharmaceutical preparations for topical use, such as creams, ointments, solutions, lotions or gels. The concentration of the active ingredient will generally be between 1 and 100 .mu.g/g.
The formulations will be applied one or more times daily.
The formulations prepared according to the present invention comprise the active compound in association with a pharmaceutically acceptable vehicle and optionally other therapeutic ingredient(s). The vehicle(s) must be "acceptable" in the sense of being compatible with the other ingredients of the preparations and not deleterious to the recipient thereof.
Preparations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, pastes or gels; or solutions or suspensions.
In addition to the aforementioned ingredients, the preparations of this invention may include one or more additional ingredients such as diluents, buffers, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
The invention will now be further descr

REFERENCES:
patent: 4435325 (1984-03-01), Jolly et al.
patent: 4866048 (1989-09-01), Calverley et al.
Thavarajah, et al: "1,25(OH).sub.2 D.sub.3 and Calcipotriol (MC903) Have Similar Effects on the Induction of Osteoclast-Like Cell Formation in Human Bone Marrow Cultures", Biochemical and Biophysical Research Commnications., vol. 171, No. 3, Sep. 28, 1990, pp. 1056-1063.
Bagot , et al: "Immunosuppressive Effects of 1.25-Dihyrixyvitamin D3 Analog (Calcipotriol) on Epidermal Cells", Chemical Abstracts, vol. 119, No. 5, Aug. 2, 1993, abstract No. 41719, p. 182, col. 1, see abstract & Proc.Workshop Vitam.D (8th) 1991 pp. 518-519.
Braeutigam, et al: "Effects of Calcipotroil (MC903) and Calcitriol After Topical Application on the Skin of Hairless Rats. Much Lower Effect of Calcipotriol on Systemic Calcium Homeostasis", Chemical Abstracts vol. 117, No. 21, Nov. 23, 1992, abstract #205159, p. 93, col. 1, see abstract & Skin Pharmacol. vol. 5, No. 2, 1992, pp. 87-92.
Kragblle et al: "Vitamin D Analogs in The Treatment of Psoriasis", Chemical Abstracts, vol. 116, No. 25, Jun. 22, 1992, abstract No. 248622, p. 90, col 1, see abstract & J.Cell.Biochem. vol. 49, No. 1, 1992, pp. 46-52.
Larsen, et al: "Structure and Absolute Configuration of a Monohydrate of Calcipotriol, (1.alpha.,3,5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola-5,7 10(19),22-tetraene-1,3,24-triol", Acta Crystallographica, Section C, Crystal Structure Communications, vol. C49, No. 3, 1993, pp. 618-621, se the hwole document.

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