Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1995-11-15
1997-07-22
Krass, Frederick
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424468, 424480, 424482, 424470, 424474, 514960, A61K 4738, A61K 920, A61K 3166
Patent
active
056501684
DESCRIPTION:
BRIEF SUMMARY
The invention concerns tablets with improved bioavailability of the active substance dichloromethylenediphosphonic acid (clodronic acid) or of a physiologically tolerated salt thereof and an additive of microcrystalline cellulose as a pharmaceutical auxiliary substance, pharmaceutical packs containing these tablets, the use of dichloromethylenediphosphonic acid together with microcrystalline cellulose for the production of a tablet with improved bioavailability as well as the process for producing this tablet.
It is known that the substance dichloromethylenediphosphonic acid, which is also known under the name clodronate, is used in pharmaceutical agents to treat osteolysis resulting from bone metastases of solid tumours as well as to treat hypercalcaemia (cf. e.g. DE-18 13 659). In the meantime it has also turned out that biphosphonates such as e.g. clodronic acid or their physiologically tolerated salts can be used successfully in the treatment of osteoporosis and osteoporotic pain.
In order to treat osteolysis the compound has to be administered in a relatively high dosage over a long period in order to develop its effect. The preparation Ostac.RTM. capsules contains the active substance in the form of its sodium salt (clodronic acid, disodium salt x 4 H.sub.2 O; MW: 360 g/mol) in an amount of 500 mg per capsule. With respect to the active substance clodronic acid (MW=244.9 g/mol) this corresponds to an amount of about 340 mg. The intake of four capsules daily and in severe cases up to eight capsules per day is necessary for the treatment. This corresponds to a daily dose to be administered of 1360-2720 mg clodronic acid.
Due to this high dosage of the active substance that is required, forms of administration were developed first of all which contain the highest possible content of active substance in order to make the individual form of administration as small as possible. Such formulations are described in EP 0 275 468 with a content of active substance of 80-95%. The preparation Ostac.RTM. has a percentage content of the active substance disodium-clodronate tetrahydrate of about 500 mg (corresponding to 91%) with a total weight of capsule filling material of about 550 mg.
It is difficult for some patients, due to their state of health, to swallow capsules of such a size between 550-570 mg filling mass several times daily over a long period of time.
On the other hand in order to improve the patient's compliance with the mode of administration it would be desirable to reduce the daily intake of four to eight capsules since experience shows that for example a single or double administration is adhered to more resolutely than a multiple administration. With regard to the required total dose of about 1400 mg and in severe cases of about 2700 mg clodronate which has to be administered daily, this would therefore require two relatively large capsules each with a total weight of at least 1100 mg. However, such capsules are disadvantageous due to their size.
The object of the invention was to provide a form of administration of the active substance clodronic acid with increased bioavailability which enables the total dose that has to be administered daily to the patient to be reduced and thus also the number of forms of administration to be taken daily or which enables smaller forms of administration such as tablets to be used with the same frequency of administration.
It was surprisingly found that when tablets to which microcrystalline cellulose has been added are used as the form of administration, the bioavailability of the active substance is higher compared to capsules when administered to humans. This enables the daily dose of clodronic acid to be administered to be reduced to lower values. In particular it was found that the tablets according to the invention enable the total daily dose of clodronic acid to be reduced to values of up to 60%. This means that for example instead of the usual amount of 1360 mg clodronic acid, a daily total dose of about 820 mg clodronic acid has a comparable therapeutic
REFERENCES:
patent: 4840799 (1989-06-01), Appelgren et al.
patent: 4859472 (1989-08-01), Demmer et al.
patent: 4980171 (1990-12-01), Fels et al.
Chemical Abstracts 1975:175208, "Dissolution Rate and Bioavailability of Griseofulvin from A Ground Mixture With Microcrystalline Cellulose" 1975.
Gabel Rolf-Dieter
Musel Bernd
Neugebauer Gunther
Preis Walter
Boehringer Mannheim GmbH
Krass Frederick
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