Process for preparing a clodronate preparation

Details Process for preparing a clodronate preparation Process for preparing a clodronate preparation

1996-08-06

1998-07-07

Page, Thurman K

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424 51, A01K 914

Patent

active

057764999

DESCRIPTION:

BRIEF SUMMARY
This application is a continuation of PCT/F194/00509 filed Nov. 11, 1994.
The object of the present invention is a process for preparing a clodronate preparation by dry granulation, where the crystalline phase of the clodronate raw material used is the stable and easy-to-handle tetrahydrate of the clodronic acid disodium salt (CH.sub.2 Cl.sub.2 O.sub.6 P.sub.2 Na.sub.2 4H.sub.2 O), with a definite crystal form.
Clodronate or the disodium salt of (dichloromethylene) bisphosphonic acid, tetrahydrate, is useful for instance in the treatment and prophylaxis of disorders of the calcium metabolism, such as bone resorption, hypercalcaemia and osteoporosis. Based on its ability to form a strong complex with a Ca.sup.2+ -ion, clodronate removes excessive calcium from the circulation, prevents calcium phosphate from dissolving from the bone and/or acts via cell-mediated mechanisms. However, it is necessary to administer clodronate in relatively large doses for a prolonged time. A problem with clodronate preparations has therefore been how to achieve a sufficiently high amount and concentration of the active agent in a capsule or tablet, without having to use capsule or tablet sizes which are unpleasantly large for the patient.
Due to the properties of clodronate, it has in practice turned out that untreated clodronate raw material is difficult to mix to a homogenous mixture with other excipients and active agents present in the preparation.
Processes previously used for the preparation of clodronate preparations have been disclosed for instance in the publication EP 275 468, which relates to a process for preparing a clodronate preparation by a wet granulation process. In the process the raw materials are mixed dry, a granulating liquid is added, the mixture is wet granulated and the granulate is dried.
Due to the properties of clodronate, the clodronate powder thus obtained is, however, inaccurate as regards its composition and obviously difficult to handle (sticky, very poor flow properties). It is thus extremely difficult in practice to mix it with other substances used in the preparation, as well as to further process it, wherefore for instance a relatively large amount of gliding agents is needed. From the unhomogenous raw powder an unhomogenous and poorly flowing product mass is then obtained, which affects also the accuracy of dosing of the final medicament.
In the absorption of clodronate, as well as of other bisphosphonates, phosphonates, great individual and diet-related differences have been observed, wherefore the homogenity of the drug and the pharmaceutical preparation is essential for the determination of a suitable dose and for the follow-up of the treatment.
The bulk volume of the clodronate raw material generally varies a great deal between different batches of preparation, due to the difficultly controlled crystallization process in the preparation of the raw material, where the four crystal waters must have time to take their positions in the crystal lattice in order to obtain a uniform and non-caking composition but where, on the other hand, a too slow crystallization leads to an unsuitably large crystal volume. In a wet granulation process this has the effect that the amount of granulating liquid has to be varied from one granulation batch to the next, depending on the quality of the raw clodronate, in order to obtain, as the end product, granules with the same bulk volume. As stated above, the wet granulation process is thus an extremely difficult and laborious process and the final result is often, however, unforeseeably inaccurate. The wet granulation process is always connected with time-consuming and expensive drying of the granules. In addition to the step of manufacturing the raw material, a second balancing regarding the four necessary crystal waters is required in the drying stage of the wet granulation process.
According to the invention it has now surprisingly been discovered that by crystallizing clodronate specifically in the form of stable and non-caking and non-sticky disodium cl

REFERENCES:
patent: 5525354 (1996-06-01), Posti

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