Corticosteroid formulation comprising less than 2.5 mg...

Details Corticosteroid formulation comprising less than 2.5 mg... Corticosteroid formulation comprising less than 2.5 mg...

2002-10-01

2004-01-13

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S180000

Reexamination Certificate

active

06677326

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a controlled-release formulation, and in particular to a formulation of a corticosteroid, suitable for use in the treatment of rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Glucocorticoids, and in particular prednisone and prednisolone, are widely used for the treatment of rheumatoid arthritis. The use of glucocorticoids may be efficacious but has disadvantages, particularly in terms of side-effects such as bone loss.
It appears to be generally recognized that it would be desirable to use low doses of, say, prednisolone, in the treatment of rheumatoid arthritis. While it is clear that low dose oral prednisolone can be efficacious, there is some controversy over what is actually meant by a low dose.
Kirwan, New England J. Med. 333:142-5 (1995), indicates that a daily dosage of 7.5 mg prednisolone is effective. This is supported by Boers et al., The Lancet 350:309-318 (1997). Boers et al. also reports that a typical treatment of rheumatoid arthritis following initial treatment with a non-steroidal anti-inflammatory drug (NSAID) involves a high initial dose and, when the condition is under control, reduced doses, down to a “low maintenance” of 7.5 mg/day.
Gotzsche and Johansen, B. M. J. 316:811-818 (1998), reviews a number of studies of low dose prednisolone in the treatment of rheumatoid arthritis. Most of these studies report doses of at least 7.5 mg. There is one report, but from as long ago as 1967, of a 2.5 mg dose.
It is evident that, in clinical practice, rheumatologists taper the dose of glucocorticoid to as a low a level as they can, before symptoms return. There may be patients who are stable on less than 5 mg prednisolone per day, but there is little or no clinical data to support that such a low dose is actually providing any benefit. This is important, because in many of these patients, prednisolone may be contributing only side-effects. There is no evidence that any dose of prednisolone, lower than those generally used, is effective when given chronically for the treatment of rheumatoid arthritis.
Arvidson et al., Annals of the Rheumatic Diseases 56:27-31 (1997), reports that the timing of glucocorticoid administration in rheumatoid arthritis may be important, in controlling the acute inflammatory aspects of the disease. In the reported study, patients were woken at 2.00 a.m. and given 7.5 mg or 5 mg prednisolone.
U.S. Pat. No. 5,792,496 claims a sustained-release formulation of a glucocorticoid such as prednisone or prednisolone. The formulation comprises 2.5-7 mg of the glucocorticoid and releases at least 90% of the drug during 40-80 minutes, starting about 1-3 hours after the entry of the drug into the small intestine. The intention is that the formulation should be taken immediately before the patient goes to sleep, that the drug should be released during sleep, and that the greatest secretion of cytokines (which occur shortly before waking) should thus be treated most effectively. This is based on the same data as in Arvidson et al., supra, i.e. using doses of 5 or 7.5 mg prednisolone given at 2 a.m.
BRIEF SUMMARY OF THE INVENTION
This invention is based on the discovery that, in a study designed to test the reproducibility of the results reported by Arvidson et al. (and in U.S. Pat. No. 5,792,496), a much lower dosage of the glucocorticoid was also effective. Given the state of the art and the known side-effects of corticosteroids, this increase in their therapeutic index is surprising.
According to the present invention, a unit dosage comprises less than 2.5 mg of prednisolone or an equivalent amount of a corticosteroid. Equivalence is in terms of potency. It will be understood that drugs vary in potency, and that doses can therefore vary, in order to obtain equivalent effects.
Thus, in accordance with the present invention, a controlled-dose formulation of the drug is adapted to release the drug at a predetermined period of time after administration, or at a predetermined time. Advantages of the invention may include enhanced efficacy, reduced side-effects and/or reduced C
max
. Further or in addition, chronotherapeutic administration allows the use of a reduced level of active material.


REFERENCES:
patent: 5792476 (1998-08-01), Hällgren
patent: WO 95/08323 (1995-03-01), None
Rote Liste, 1998, 31 037 Decortin H 1mg.
Buckley, L.M. et al., “Effects of Low Dose Corticosteroids on the Bone Mineral Density of Patients with Rheumatoid Arthritis”The Journal of Rheumatology,1995, pp. 1055-1059, vol. 22, No. 6.
Cash, J.M. et al. “Pituitary-Adrenal Axis Responsiveness to Ovine Corticotropin Releasing Hormone in Patients with Rheumatoid Arthritis Treated with Low Dose Prednisone”The Journal of Rheumatology,1992, pp. 1692-1696, vol. 19, No. 11.

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