MXPA01009208A - Corticosteroid formulation - Google Patents

Abstract

A unit dose formulation comprising 0.25 to 2 mg of a corticosteroid. This small dose can be used to treat rheumatoid arthritis, especially if adapted to release at least 90%by weight of the corticosteroid, 2 to 8 hours after administration.

Description

FORMULATION OF CORTICOSTEROIDS DESCRIPTION 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. Glucocorticoids, and in particular prednisone and prednisolone, are widely used for the treatment of rheumatoid arthritis. The use of glucocorticoids may be effective but they have disadvantages, particularly in terms of side effects such as bone loss. To be generally recognized that it may be desirable to use low levels of, ie, prednisolone, in the treatment of rheumatoid arthritis. While it is clear that the low oral dose of prednisolone may be effective, there is some controversy over what is currently understood by a low dose. Kir an, New England J. Med. 333: 142-5 (1995), indicates that a daily dose 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-spheroidal anti-inflammatory drug (NSAID) involves a high initial dose and, when the condition is under control, reduced doses, decreasing to a "low maintenance" of 7.5 mg / day. Gotzsche and Johansen, B.M.J. 316: 811-818 (1998), investigated a variety of low dose prednisolone studies in the treatment of rheumatoid arthritis. Most of these studies report doses of at least 7.5 mg. There is a report, but a long time ago like 1967, of a dose of 2.5 mg. It is clear that, in clinical practice, rheumatologists lower the dose of glucocorticoids to as low a level as they can, before the symptoms return. There may be patients who are stable with less than 5 mg of prednisolone per day, but there is little or no clinical data to support that such a low dose is currently providing some benefit. This is important, since in many of these patients, prednisolone may only contribute to side effects. There is no evidence that any dose of prednisolone, less than that 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 synchronization of glucocorticoids in rheumatoid arthritis may be important to control the acute inflammatory aspects of the disease. In the reported study, patients are awakened at 2:00 a.m. and they are given 7.5 mg or 5 mg of prednisolone. United States Patent US-A-5792496 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 for 40-80 minutes, starting approximately 1-3 hours after the introduction 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 major symptoms of rheumatoid arthritis (which occur briefly before awakening) can in this way be treated more effectively. This is based on the same data as in Arvidson et al, supra, that is, using doses of 5 or 7.5 mg of prednisolone given at 2 a.m. 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 US Pat. No. 5,789,296), a much lower dose of the glucocorticoid is 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 dose comprises 0.25 to 2 mg of a corticosteroid. Preferably, such a dose is in the formation of a controlled release formulation of the general type or specifically described in U.S. Patent No. 5,759,296. Thus, according to the present invention, a controlled dose formulation of the drug is adapted to release the drug in a predetermined period of time after administration, or at a predetermined time. The advantages of the invention may include increased efficacy, reduced side effects, reduced Cmax and / or a reduced level of the active material. The intention behind the invention is that the active ingredient must be released at a predetermined time, for example, between midnight and 6 a.m., for example 2 a.m. and 4 a.m., or a predetermined time after administration. In this way, the user can take the formulation before going to sleep, but it has the full value of an effective dose of the drug during the night, or during sleep, in a dose that has minimal side effects. Accordingly, a predominant amount of the active ingredient, for example, at least 90% by weight, is released at least 2 or 3 hours after administration, and preferably not more than 6, 7 or 8 hours after administration .

The formulation of the invention is proposed for the treatment of disorders associated with the release of cytosines. In particular, the invention is suitable for the treatment of inflammatory diseases, and more especially rheumatoid arthritis, asthma, inflammatory bowel disease and atopic dermatitis. Accordingly, the drug that is used in the formulation can be chosen. Examples are glucocorticoids and other corticosteroids, for example budesonide, methylprednisolone, deflazacort, prednisone and prednisolone. If desired, the active ingredient can be formulated as a prodrug, such that the active component is released in vivo. The preferred route of administration of a formulation of this invention is oral. However, it will be readily apparent to those skilled in the art that other routes of administration may be used, for example, with respect to the nature of the condition being treated and the most effective means of achieving delayed release. The drug can be administered in some conventional formulation that provides delayed release, via any suitable route of administration. Conventional dosage parameters can be adopted, ie those that are known to or adapted for the practice of those skilled in the art. The daily dose is usually at least 0.25 or 0.5 mg, for example 1 2 mg, but will be chosen according to the age, weight and health of the subject, and other factors that are routinely considered by the person skilled in the art. A formulation of the invention can be a unit dose such as a tablet, capsule, vial, vial or suspension. A controlled release formulation can be in matrix, coating, reservoir, osmotic form, ion exchange or density exchange. This may comprise a coating of soluble polymer which dissolves or erodes after administration. Alternatively, there may be an insoluble coating, for example, of a polymer, through which the active ingredient permeates, as from a reservoir, it diffuses, for example through a porous matrix, or undergoes osmotic exchange. An additional option for a controlled release formulation involves density exchange, for example, in the case where the formulation is altered upon administration, for example, from microparticles to a gel, such that the active ingredient is diffused or permeates Ion-based resins, the active component that is released by ion exchange, and wherein the rate of release can be controlled using the cationic or anionic forms of the drug can also be used. Another type of controlled release formulation involves dosing driven. Additional examples are given in the United States Patent US-A-5792496. An example of a controlled dose of active ingredient is dosing with a tablet containing 1.2 mg prednisolone. In this example, a patient taking a controlled dose of 1.25 mg of prednisolone takes the tablet a number of hours before due to the release. The time zero on the graph (Fig. 1) denotes the earliest time at which the active ingredient is released, probably midnight. The plasma levels achieved by the release of the active ingredient at different times are shown (2, 4 and 6 a.m.). It can be seen that the range for Cmax obtained from the 125 mg dose of prednisolone is from about 20 to 50 ng / ml (the total prednisolone which includes the bound protein and the unbound active) depending on how quickly it absorbs a patient the active ingredient. The time for Cmax or Tmax is usually between 1 and 3 hours. Where absorption is particularly rapid, the Cma? it can be 100 ng / ml of total prednisolone or more (which is not shown in the graph). The following study provides the basis of the present invention. Study design The study is a blind comparison of evaluators of the effects of two doses of prednisolone (1 mg and 5 mg) given at 02:00. Patients enter the hospital at night but are free to leave or be around the hospital during the day. At 2.00 a.m. on the appropriate days patients are gently awakened, they are given prednisolone, and they are allowed to return to sleep. Blood samples and clinical evaluations are taken at 8:30 and additional clinical evaluations related to the symptoms on the day of administration of the drug at 12.00 and 8.30 the following day (except the final day when this last evaluation is done before to leave the hospital). Patients are admitted on Monday and have a night of "control" in the afternoon without prednisolone but with a full evaluation on the next day. In the following every three nights, prednisolone is administered. Patients return home on Friday afternoon but return on Monday to repeat the procedure. The placement of 1 mg or 5 mg of prednisolone in the first or second week is randomized in sealed covers. Neither the patient nor the evaluator are aware of what dose is given. Clinical: The consequence is measured at 8.30 each day for: swollen joint count (n = 28); sensitive articulation account (n = 28); pain (0.100 mm, VAS). The consequence is measured at 12.00 each day for: morning stiffness (minutes); opinion of the condition by the patient (0-100 mm, VAS); the opinion of the condition by the doctor (0-100 mm, VAS). The following day's consequence is measured: if arthritis worsens in the morning or afternoon on the previous day (-1 morning, 0 equal, +1 afternoon). Serological: Serum samples are obtained at 8. 30, are kept on ice for up to one hour, separated and stored at -70 ° C to measure: C-reactive protein (CRP); IL-6 concentration; concentration of the soluble IL-6 receptor (IL-6sR); hyaluronate concentration (HA). Procedure Patients act as their own control and take each dose of prednisolone for three consecutive nights. They are located randomly by cards kept in sealed covers for both 1 mg of prednisolone on the three consecutive nights by 5 mg on the three consecutive nights, or the opposite sequence. The evaluator is not aware of the location of the treatment order (and probably remains blind), but placebo tablets are not used and the patient may not be blind. Patients are invited to take part in the study that has the following characteristics: -more than 18 years of age -he has rheumatoid arthritis by the American College of Rheumatology criteria; see Arnett et al, Arthritis Rheum. 31: 315-324 (1988). - you have active disease as evidenced by 3 or more swollen or tender joints - you are not taking glucocorticoid medication - you do not have intra-articular glucocorticoid injections in the previous three weeks. -Does not have medical conditions which, in the opinion of the investigator, may contraindicate the therapy of low doses of prednisolone. The informed consent and prescription of the patient written by a doctor not associated with the evaluation of the test is obtained. The medication is given at 2 a.m. on each day of treatment after gently waking the patient. The patient is instructed to lie down again to sleep immediately. On the morning before the medication and every morning on the day of the medication, the blood samples are taken at 8.30 a.m. and the evaluations of the solutions are recorded later, and at night, as indicated above. Evaluation Symptoms, signs and laboratory results are compared within and between patients, but the primary evaluation is visual inspection of the total response pattern.

Standard deviations and means are used to define the proportions of variation and to calculate the test size for future studies. A total evaluation of the practice and the potential for more frequent blood collection (but less volume) is done by discussion between the staff and the patients involved. Results Three patients are able to take part in the study in the time available. It is given to a patient (3) without warning the first dose of treatment in the second week on the first night of the hospital. Patient 3 takes prednisolone for the next two nights and stays in the hospital for a fourth night without prednisolone treatment. These evaluations of the patient have been included normally in the first week, but in the second week they have been used in a different way. Here, these patient results have been included with those of other patients according to the dose of prednisolone received. This final evaluation of the patient (without prednisolone the night before), therefore appears as an extra day after the other patients under study. The results for 5 mg of prednisolone place the patients in this pilot study well within the range of discovery published by Arvidson et al and reinforce the conclusions which can be represented in that paper. The results from 1 mg of prednisolone increase the possibility that even in this dose there may be an appreciable effect on the symptoms. Statistically significantly reduced pain, EMS, patient opinion and the opinion of the doctor, even with only three patients in the study. CRP and IL-6 are significantly reduced with 5 mg of prednisolone and there is a tendency for the reduction in 1 mg of prednisolone. Table 1 - mean and confidence intervals of 95% for each variable day dose Artic. Artic. More pain or EMS Op. Op. CRP HA IL-6 IL-6sR painful swelling less pac Med 0 0 20.3 21.0 37.7 -1.0 70.0 31.3 3 .3 0.5 345.1 44.1 31557.8 1 1 18.7 20.0 26.0 -0.7 55.0 23.7 28.7 35.5 241.9 28.1 31959.9 2 1 18.7 20.3 20.3 -0.7 51.7 26.7 29.3 31.2 320.3 31.1 31468.0 3 1 18.3 20.3 16.7 0.0 40.0 12.7 16.3 25.8 372.5 22.8 30898.9 0 12.3 15.3 25.0 -0.3 40.0 24.3 23.3 15.0 396.3 19.3 22937.2 11 5 18.0 19.0 19.7 -0.3 30.0 19.3 27.7 36.6 322.5 30.3 42328.2 12 5 17.3 19.7 15.7 -0.3 20.0 11.7 15.7 31.1 339.5 18.5 35331.6 13 5 14.0 19.7 16.0 -0.7 33.3 13.3 11.7 19.1 193.9 13.8 36172.7 14 0 12.0! 0 0.0 0.0 0.0 0.0 8.0 19.5 363.5 107.1 32180.5 Results of 95% CI day dose Artic. Artic. More pain or EMS Op. Op. CRP HA IL-6 IL-6sR painful swelling less pac Med 0 0 0.7 5.7 24.9 0.0 19.6 20.3 14.1 17.1 213.0 18.1 8838.9 1.3 7.4 25.2 0.7 9.8 15.4 10.3 23.0 152.3 18.1 10225.5 3. 5 7.7 20.3 0.7 8.6 5.7 10.5 27.5 321.8 32.7 10220.9 3. 6 9.1 16.9 1.1 9.8 12.9 4.6 25.3 96.7 28.4 11329.4 . 2 19.2 31.8 48.0 30.2 29.6 22.8 718.7 23.3 27617.3 3. 9 9.1 21.1 1.3 29.4 20.1 13.6 29.1 148.6 24.1 23485.3 6. 5 9.6 15.4 0.7 19.6 11.6 1.7 26.0 221.4 23.6 8919.1 6. 9 10.3 7.8 0.7 6.5 6.2 4.6 18.2 113.3 13.3 7069.5

Claims (16)

1. CLAIMS 1. A unit dose formulation characterized in that it comprises 0.25 to 2 mg of a corticosteroid.
2. 2. A formulation according to claim 1, characterized in that it comprises 0.5 to 2 mg of the corticosteroid.
3. 3. A formulation according to claim 2, characterized in that it comprises 1 to 1.25 mg of the corticosteroid. .
4. A formulation according to any preceding claim, adapted to release at least 90% by weight of the corticosteroid, 2 to 8 hours after administration.
5. 5. A formulation according to any preceding claim, characterized in that the corticosteroid is a glucocorticoid.
6. 6. A formulation according to any preceding claim, characterized in that the corticosteroid is selected from prednisone, budesonide, methylprednisolone, prednisolone and deflazacort.
7. 7. A formulation according to claim 6, characterized in that the corticosteroid is prednisolone.
8. 8. The use of 0.25 to 2 mg of a corticosteroid for the manufacture of a controlled release dosage unit formulation, characterized for use in the treatment of rheumatoid arthritis.
9. 9. The use according to claim 8, characterized in that the formulation comprises 0.5 to 2 mg of the corticosteroid.
10. 10. The use according to claim 9, characterized in that the formulation comprises 1 to 1.25 mg of the corticosteroid.
11. The use according to any of claims 8 to 10, characterized in that the formulation is adapted to release at least 90% by weight of the corticosteroid, 2 to 8 hours after administration.
12. 12. The use according to any of claims 8 to 11, characterized in that the corticosteroid is a glucocorticoid.
13. 13. The use according to claim 8 to 12, characterized in that the corticosteroid is selected from prednisone, budesonide, methylprednisolone, prednisolone and deflazacort.
14. 14. The use according to claim 13, characterized in that the corticosteroid is prednisolone.
15. 15. A controlled release formulation according to claim 4, characterized in that the corticosteroid is selected from prednisone, methylprednisolone and prednisolone.
16. 16. The use according to claim 11, characterized in that the corticosteroid is selected from prednisone, methylprednisolone and prednisolone.