MXPA99005663A - New treatment for joint inflammation - Google Patents

Abstract

The invention provides the use of a glucocorticoid substance which has a minimal systemic effect in the manufacture of a medicament for oral or rectal administration for non-topical use in the treatment of joint inflammation.

Description

NEW TREATMENT FOR CONTINUOUS INFLAMMATION Field of the Invention The present invention provides a new treatment for inflammation of the joints or joints.

BACKGROUND OF THE INVENTION The. Symptoms of joint inflammation are generally associated with spondyloatropathies (eg, ankylosing spondylitis, psoriatic arthropathy, reactive arthritis and saqroilitis,) and rheumatoid arthritis. The inflammation of the joints is localized for different joints in these different conditions. In ankylosing spondylitis, inflammation is localized in the spinal column, the sacroiliac joints, and also frequently in the large peripheral joints (for example, the knees, elbows, and ankles). In sacroilitis inflammation is isolated in the sacroiliac joints but some REF .: 30428 times also occurs in the peripheral joints. The other spondyloarthropathies have a similar clinical picture in that said joints are also inflamed. In rheumatoid arthritis, a symmetrical inflammation of the joints occurs.

Rheumatoid arthritis and spondyloarthropathies have in common a chronic inflammation of synovial and extrasynovial structures, such as tendons and ligaments. The inflammatory reaction of the joints or joints is dominated by certain inflammatory cells (for example neutrophils, activated lymphocytes and macrophages) which all contribute to the pain of the joints and the destruction of the joints. Drugs that have been used in the past to treat inflammation of the joints or joints are based on symptomatic anti-inflammatory treatments or treatments that modify the disease. The dominant drugs for symptomatic treatments are non-spheroidal anti-inflammatory drugs, orally active glucocorticosteroids with a mainly systemic effect, or intra-cerebral injections of glucocorticosteroids. Disease-modifying treatments include drugs which, by influencing the body's immune reactions, reduce inflammation of the joints. Examples of drugs that modify the disease include methotrexate, azathioprine, gold salts, cyclophosphamide and sulfasalazine. All these treatments unfortunately cause severe side effects and are not particularly effective. For example, the administration of glucocorticoids is generally directed against local inflammation / for example, it has been used to directly treat the inflammatory cells present in the inflammation of the joints or conjunctures. The routes used to administer such glucocorticoid treatment result in severe side effects in the body, including effects on the skeleton and muscles. It has now surprisingly been found that rectal oral Q administration of a glucocorticoid substance which has a minimal systemic effect is effective in controlling inflammation of the joints.

Brief Description of the Invention According to the invention, there is provided the use of a glucocorticoid substance having a minimal systemic effect, in the manufacture of a medicament for oral or rectal administration, for non-topical use in the treatment of inflammation of the joints or conjunctures. . According to the invention, there is further provided a method for the treatment of a mammal, human or non-human, suffering from inflammation of the joints, which comprises administration non-topically and orally or directly to the human or non-human mammal, of a therapeutically effective amount of a glucocorticoid substance which has a minimal systemic effect. According to the invention, there is also provided a pharmaceutical composition comprising a glucocorticoid substance which has a minimal systemic effect in association with a pharmaceutically acceptable diluent, adjuvant or carrier, whose composition is for non-topical use in the treatment of inflammation. of the joints or joints, Detailed Description of the Invention The invention is preferably used to treat a human or non-human mammal suffering from rheumatoid arthritis, peripheral oligoarthritis, peripheral arthropathies or spondyloarthropathy, especially ankylosing spondylitis, psoriatic arthropathy, reactive arthritis and sacroiliitis. This can also be used to treat human or non-human mammals suffering from conditions where inflammation of the joints or joints is associated with intestinal inflammation. The non-human mammals in which the invention can be used, include domestic animals such as cats, dogs, horses, sheep and cows. The glucocorticoid substance used in the present invention is preferably one having a first pass metabolism of at least £ 0%. The first-pass metabolism of a glucocorticoid substance can be measured by the method described by Andersson,?. and collaborators Xenobiotica (1987) 17: 35-44.

More preferably, the glucocorticoid substance is budesonide, rofleponide or a derivative thereof, beclomethasone dipropionate, beclomethasone monopropionate, ciclesonide, tipredane, flunisolide, triamcinolone-acetonide or fluticasone propionate. Budesonide is particularly preferred. The glucocorticoid substance is used non-topically and can be administered either orally or rectally. When administered orally, it is administered esophageally, generally in the form of tablets, pills, capsules, syrups, powders or granules; when administered rectally, it is optionally in the form of suppositories or enemas. This can be administered alone or as a pharmaceutical composition in association with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions that do not contain material capable of causing an adverse reaction, for example, an allergic reaction. The glucocorticoid substance can be mixed with an adjuvant or a carrier, for example lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes and / or paraffins, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, can be coated with a concentrated sugar solution which may contain eg gum arabic, gelatin, talc and / or titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer, dissolved in an easily volatile organic solvent. The tablets are preferably enteric coated to allow the release of the glucocorticoid substances in the lower intestine. Suitable capsules can be prepared by using the methods described in European Patent EP-A-502092, and International Patents Nos. 95/08323 or 97/27843. For the preparation of soft gelatine capsules, the glucocorticoid substance can be mixed, for example, with a vegetable oil or polyethylene glycol. The hard gelatin capsules may contain granules of the substance, using either the above-mentioned excipients for tablets, for example lactose, sucrose, sorbitol, mannitol, starches, and cellulose or gelatin derivatives. Also liquid or semi-solid formulations of the substance can be filled into hard gelatin capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the glucocorticoid substance, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent, or other excipients known to those of skill in the art. Formulations for rectal enema may be in the form of simple suspensions of the glucocorticoid substance in a pharmaceutically acceptable carrier or may be in the form of a rectal foam formulation, for example as described in European Patent EP-A-468555.

The glucocorticoid substance is preferably administered at a dose of 0.1 to 40 mg, more preferably 0.5 to 20 mg, more preferably 1 to 10 mg, either as a single dose or in divided doses of 2 to 4 times a day. The pharmaceutical composition for oral administration used in the present invention must be prepared in a manner such that the glucocorticoid substance is released in the lower part of the small intestine or in the upper part of the large intestine. Preferably, the composition should be prepared so that the substance is released in the lower third of the small intestine or in the upper fourth of the large intestine. The invention is illustrated by the following examples, wherein budesonide is orally administered using the Entocort ™ preparation as described in European Patent EP-A-502092.

Example 1 A 36-year-old man who had been suffering from sacroiliitis and peripheral oligoarthritis for more than 7 years had previously been treated with various anti-inflammatory drugs and disease modifiers (for example non-spheroidal anti-inflammatory drugs, prednisolone and methotrexate) without success. Before the start of treatment, this patient had a swollen left knee and ankle, clinical signs of inflamed sacroiliac joints and had been unable to work for 8 months. Your score of initial morning stiffness, joint index, or spinal movement and joint pain are shown in Table 1. This was initially treated with 9 mg of budesonide, once a day, for the first four weeks and then the dose was reduced to 6 mg per day. The result after 2 months of treatment are shown in Table 1. Two months after the withdrawal of the treatment according to the invention, its condition deteriorated.

Table 1 Test Before After Morning stiffness / minute 120 20 arthritic joint index 127 0 Spinal movement / cm 1 4 Joint pains: at rest / moving 5 / 9.5 1.5 / 1.5 The normal value of morning stiffness is 0 minutes. The joint arthritic index was measured using the Lansbury index whose normal value is 0. Spinal movement was measured using the Shober's Test, whose normal value is 5 to 6 cm. The value of the joint at rest and in movement was estimated using a VAS (visual analogue scale) where 0 represents no pain and 10 very severe pain.

Example 2 A 43-year-old man who had suffered ankylosing spondylitis for 12 years had previously been treated with non-spheroidal anti-inflammatory drugs and disease-modifying drugs, for example sulfasalazine and methotrexate, without success. Initially, his left knee, both ankles and both sternoclavicular and sacroiliac joints were clinically inflamed and had the symptoms indicated in Table 2. He was treated with 9 mg of budesonide once a day and one month after the start of treatment the patient experienced an improvement remarkable in its symptoms as can be seen in Table 2. One month after the withdrawal of the treatment his condition had returned to how it was before the treatment had begun.

Table 2 Test Next After morning stiffness / minute 270 0 joint arthritic index 127 80 Spinal motion / cm 2.5 3.5 Joint pains: at rest / while moving 8/8 1 / 1.7 Rate ESR / mm / hour 85 30 C-reactive protein / (mg / l) 140 25 The tests were carried out in the same manner as in Example 1, except that the inflammatory activity in the laboratory was measured using the ESR (rate or sedimentation rate of erythrocytes) whose normal value is less than 5 mm / hour and the concentration plasma C-reactive protein which is usually less than 10 mg / liter.

Example 3 A 75-year-old woman who had developed inflammation of the small joints of the hands and feet, 18 months previously, initially had a symmetrical inflammation of both wrists, the joints of all the fingers and ankles. He was diagnosed as having rheumatoid arthritis. You were treated with 9 mg of budesonide once a day. Its initial symptoms and after 4 months of treatment are shown in Table 3.

Table 3 Test Before After Morning stiffness / minute 180 0 arthritic joint index 205 0 ESR / mm / hour rate 70 16 C-reactive protein / (mg / l) 41 10 The tests for the symptoms were carried out in the same way as the tests. Examples 1 and 2 Example 4 A 47-year-old male patient, who had previously been healthy and without any complaint or joint pain, developed an arthritic reaction in both the ankles and the midtarsal joints of both feet. Gradually it also developed inflammation of the left knee joint and tendinitis of both Achilles tendons. He was treated with non-spheroidal anti-inflammatory drugs and prednisolone, with some relief of joint pains. When admitted to the hospital four months later, the diagnosis was established as reactive arthritis associated with HLA-B27. After treatment with 9 mg of budesonide once a day for three weeks, the patient no longer had tendonitis of the Achilles tendons and experienced a marked improvement in his symptoms, as can be seen in Table 4.

Table 4 Test k.ntes After Morning stiffness / minute 120 60 joint arthritic index 112 6 Ritchie index 9 4 where the Ritchie index is an alternative arthritic index of the joints.

Example 5 A 22-year-old male patient had suffered from sacroilitis associated with HLA-B27 with peripheral arthropathies for 8 years. The patient had been previously treated with different drugs: methotrexate, sulfasalazine, gold salts and prednisolone, without any apparent disease-modifying effect. When admitted to the hospital he suffered from direct pain of the sacroiliac joints and inflammation of the left knee and left ankle. The sacroiliac radiogram showed sacroiliitis. After 2 weeks of treatment with 9 mg of budesonide per day it began to improve and in clinical follow-up 6 weeks after the start of treatment with budesonide, this condition was considerably improved as can be seen in Table 5.

Table 5 Test Before After Morning stiffness / minute 180 0 joint arthritic index 127 0 Spinal motion / cm 3 0 Joint pains: at rest / moving 9.5 / 8 0/0 E j empl o 6 A 48-year-old male patient had suffered from diffuse joint pains and morning stiffness for 10 months. His condition deteriorated and he was admitted to the hospital. The patient had prominent symmetrical synovial inflammations of the joints of the fingers (metacarpophalangeal joints and proximal interphalangeal joints) and of the right wrist.

The patient had a positive test for rheumatoid factor and the diagnosis was rheumatoid arthritis.

She was treated with 9 mg of budesonide per day and at follow-up 4 weeks later her condition was under control, as can be seen from the data in Table 6. Other 4 weeks later her condition had improved further and she was able to go back to work Table 6 Test after After Morning stiffness / minute 120 60 arthritic joint index 64 0 Ritchie's index 8 5 Example 7 A 37-year-old woman had suffered from swelling of the joints and joint pains for approximately 5 months. In the admission, there was symmetrical swelling of the joints of the fingers, both knees and the left ankle. He was under treatment with diclofenac. The rheumatoid factor test was positive and the diagnosis was rheumatoid arthritis. Treatment with diclofenacc was stopped and 9 mg of budesonide was administered per day. In the follow up until three weeks later, his condition was greatly improved as can be seen in Table 7.

Table 7 Test Before After Morning stiffness / minute 210 15 joint arthritic index 112 15 Spinal motion / c 19 5 Joint pains: at rest / moving 10/5 0/0 Example 8 A 73-year-old man had suffered from 2 months of rapidly progressive swelling of the joints of the fingers of both hands (metacarpophalangeal joints, proximal interphalangeal joints) and wrists. The diagnosis was rheumatoid arthritis. After the administration of 9 mg of budesonide once a day he began to feel better after 14 days and in the first clinical follow-up three weeks after the start of treatment with budesodine his condition had begun to normalize (see data for the arthritic index). of the joints and the Ritchie index in Table 8). In a second follow-up three weeks later the condition was further improved by clinical and laboratory measurements (see data on joint pains in Table 8).

Table 8 Test Before After Arthritic index of the joint 90 0 Ritchie index 16 2 Joint pains: at rest / moving 7/7 1/1 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (21)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The use of a glucocorticoid substance that has minimal systemic effect, in the manufacture of a drug for esophageal or rectal administration for non-topical use in the treatment of inflammation of the joints or joints.

2. The use according to claim 1, wherein the medicament is for use in the treatment of rheumatoid arthritis or spondyloarthropathy.

3. The use according to claim 1 or 2, wherein the medicament is for use in the treatment of ankylosing spondylitis.

4. The use according to any one of claims 1 to 3, wherein the glucocorticoid substance is budesonide or a derivative thereof.

5. The use according to any of claims 1 to 3, wherein the glucocorticoid substance is rofleponide or a derivative thereof.

6. The use according to any one of claims 1 to 3, wherein the medicament comprises a glucocorticoid substance in an amount that provides a daily dose of 0.1 to 0 mg.

7. The use according to claim 6, wherein the medicament is administered as a single daily dose or in 2 to 4 divided doses.

8. A method for the treatment of a patient suffering from inflammation of the joints, characterized in that it comprises the non-topical and esophageal or rectally administration to the patient of a therapeutically effective amount of a glucocorticoid substance which has a minimal systemic effect.

9. A method according to claim 8, characterized in that the patient is suffering from rheumatoid arthritis or spondyloarthropathy.

10. A method according to claim 8 or 9, characterized in that the patient is suffering from ankylosing spondylitis.

11. A method according to any of claims 8 to 10, characterized in that the glucocorticoid substance is budesonide or • a derivative thereof.

12. A method according to any of claims 8 to 10, characterized in that the glucocorticoid substance is rofleponide or a derivative thereof.

13. A method according to any of claims 8 to 12, characterized in that the administration of the glucocorticoid substance is in an amount that provides a daily dose of 0.1 to 40 mg.

14. A method according to claim 13, characterized in that the glucocorticoid substance is administered in a single daily dose or in 2 to 4 divided doses.

15. A pharmaceutical composition for esophageal or rectal administration for non-topical use in the treatment of inflammation of the joints or joints, characterized in that it comprises a giucocorticoid substance having a minimal systemic effect in association with a pharmaceutically acceptable diluent, adjuvant or carrier .

16. A composition according to claim 15, characterized in that it is for use in the treatment of rheumatoid arthritis or spondyloarthropathy.

17. A composition according to claim 15 or 16, characterized in that it is for use in the treatment of ankylosing spondylitis.

18. A composition according to any one of claims 15 to 17, characterized in that the glucocorticoid substance is budesonide or a derivative thereof.

19. A composition according to any of claims 15 to 17, characterized in that the glucocorticoid substance is rofleponide or a derivative thereof.

20. A composition according to any of claims 15 to 19, characterized in that it comprises a giucpcorticoid substance in an amount that provides a daily dose of 0.1 to 40 mg.

21. A composition according to claim 20, characterized in that the medicament is administered as a single daily dose or in 2 to 4 divided doses.