MXPA00008173A - Method and means for treating glomerulonephritis - Google Patents

Abstract

The invention provides the use of a glucocorticoid having a first pass metabolism in the liver of at least 90%as active substance, for the manufacturing of a medicament for oral or rectal administration in the treatment of glomerulonephritis by releasing the active substance in the intestine. The invention also provides a method for treatment of glomerulonephritis in a native kidney or a kidney transplant with the glucocorticoid as defined above. The invention also comprises a composition comprising the active substance and a pharmaceutically acceptable carrier, adjuvant or diluent designed for oral or rectal administration.

Description

METHOD AND MEANS TO TREAT GLOMERULONEFRITIS FIELD OF THE INVENTION The present invention relates to a method and means for treating glomerulonephritis.

BACKGROUND OF THE INVENTION Functional units of the kidney, such as glomeruli, may suffer from inflammation. An inflammatory attack in the glomeruli is called glomerulonephritis and can be classified into subgroups such as membranous glomerulonephritis, focal segmental glomerulosclerosis, proliferative glomerulonephritis, diffuse mesangial, endocapillary or extracapillary proliferative glomerulonephritis. Using histopathological techniques these subgroups vary with respect to the microscopic or immunohistochemical image. One cause of inflammation is due to the deposition of immunoglobulin A (IgA) in the glomeruli. This condition is called IgA nephropathy (1-3), and is the most common form of glomerulonephritis in a global perspective.

REF: 121219 The evaluation of the degree of severity of glomerulonephritis is based on different research results. The most important findings are 1) the degree of urinary excretion of the protein (proteinuria) and 2) the filtration function of the kidney, which can be evaluated by serum creatinine (s-creatinine). The histological examination of the material from the kidney (renal biopsy) produces information regarding the type of kidney damage as well as the severity of the damage. The effect of a glomerulonephritis is variable and is dependent on the histological and immunohistochemical findings in a renal biopsy. Patients with IgA nephropathy who have constant proteinuria often develop renal failure and uremia after 5 to 20 years of disease (4). Various treatments for glomerulonephritis are known. For example, substances that act on the immune system, for example cyclophosphamide, azathioprine and cyclosporin have been used. Glucocorticoids have also been used (mainly prednisone or prednisone acetate) that can be administered orally or by venous infusion (5, 6). Unfortunately, these treatments can cause severe and not particularly effective side effects. Other suggested treatments include ACE inhibitors (7), polyunsaturated fatty acid preparations (8) and vitamin E (9). The results of the treatment for these therapies for IgA nephropathy have been very disappointing and it has been concluded that basically an effective treatment against progressive IgA nephropathy is lacking (10). For this reason, a substantial number of patients with IgA nephropathy, 20-30%, will sooner or later develop renal insufficiency and uremia (1-4). The treatment available for uremia today is dialysis or kidney transplantation. Patients with kidney transplants who have been transplanted due to uremia due to glomerulonephritis frequently suffer from recurrence of glomerulonephritis in the transplant and subsequently a gradual loss of the function of the transplant (11, 12). This is more common with patients who previously suffered from IgA nephropathy. Today there is no effective treatment against the recurrence of glomerulonephritis in a transplant.

Glucocorticoids that have been used in IgA nephropathy and in other types of glomerulonephritis are characterized by a substantial gastrointestinal absorption after oral administration, aimed at exerting a direct effect on circulating leukocytes and cells that have infiltrated the body. kidney or kidney transplant, thus having a systemic effect. Such a systemic effect is also achieved if the glucocorticoids are administered as an intravenous infusion. The systemic administration of glucocorticoids may have influenced the effect of IgA nephropathy in some cases.

BRIEF DESCRIPTION OF THE INVENTION Surprisingly, it has now been found that the glucocorticoid which has a first pass metabolism in the liver of at least 90%, which minimizes the systemic effect, is effective in controlling glomerulonephritis and especially Iga nephropathy in a native kidney or in a Kidney transplant. The substance preferentially exerts its effect on the intestinal wall of a certain part of the intestine (the lower third of the small intestine and the upper fourth of the large intestine). A person skilled in the art could not have expected that the treatment of an apparently healthy intestine should have an effect on an inflamed kidney. This discovery represents an advance in the treatment of glomerulonephritis since it has the advantage of reducing the severe side effects on the body, such as effects on the skeleton, metabolism and muscles, caused by. therapy with systemic glucocorticoids used in prior art therapy.

The invention relates to the use of a glucocorticoid having a first pass metabolism in the liver of at least 90%, which gives a minimal systemic effect, for the manufacture of a medicament for oral or rectal administration for the treatment of glomerulonephritis . More specifically, the invention relates to the use of the glucocorticoid defined above for the manufacture of a medicament for the treatment of glomerulonephritis, especially in IgA nephropathy, in a native kidney or in a kidney transplant. The drug is provided in a form by which the active substance is released in a pharmacologically effective amount, in the apparently healthy intestine when it passes the lower third of the small intestine and the upper fourth of the large intestine. The invention also relates to a method for the treatment of glomerulonephritis, by oral and rectal administration of a pharmacologically effective amount of a glucocorticoid preparation having a first pass metabolism in the liver of at least 90%, minimizing the systemic effect. In the method according to the invention, the preparation is released in the intestine when the lower third of the small intestine and the upper fourth of the large intestine passes. The invention relates more specifically to the treatment of IgA nephropathy by administering 0.1 mg to 40 mg of the active substance daily to a subject in need thereof. According to the invention, there is further provided a pharmaceutical composition comprising the glucocorticoid, in association with a pharmaceutically acceptable diluent, adjuvant or carrier, whose composition is for use in the treatment of glomerulonephritis. For oral use, the composition is preferably administered in a selected form of the tablets, pills, capsules, syrups, suspensions, powders and granules. The solid forms of the preparation comprise a carrier and an enteric coating, and are more preferably in the form of a capsule comprising microcapsules. When rectal is used, the active substance is preferably administered in a selected form of foams, suppositories and enemas.

DETAILED DESCRIPTION OF THE INVENTION The medicament and method according to the invention is preferably used to treat a patient who suffers from acute or chronic glomerulonephritis. Glomerulonephritis can be divided into subtypes such as membranous glomerulonephritis, focal segmental proliferative glomerulonephritis, diffuse mesangioproli ferati a glomerulonephritis, endocapillary or extracapillary proliferous glomerulonephritis, depending on where the inflammation is located. The medicament and method according to this invention is preferably used to treat the type of IgA nephropathy of glomerulonephritis. The invention is particularly suitable for treating patients suffering from glomerulonephritis (particularly IgA nephropathy), who had a transplant, and who suffered from a recurrence of glomerulonephritis (particularly IgA nephropathy) in the transplanted kidney. The glucocorticoid used in the present invention is preferably one that has a first pass metabolism in the liver of at least 90%, minimizing systemic effects. . The first-pass metabolism in the liver of a glucocorticoid substance can be determined using the method described previously (13). More preferably, this is budesonide, rofleponide or derivatives thereof, beclomethasone dipropionate, beclomethasone monopropionate, ciclesonide, tipredane, flunisolide, triamcinolone acetonide or flut iscasone propionate. Budesonide, which is a 16, 17-butydendioxy-1-l-21-dihydroxy-1-diene-3, 20-dione, is particularly preferred. The glucocorticoid, when administered orally, is generally administered in the form of tablets, pills, capsules, powders or granules, especially in the form of capsules comprising microcapsules. Liquid preparations such as syrups and suspensions are also conceivable. When administered rectally, it is in the form of foams, suppositories or enemas. The glucocorticoid can be administered as such or as a pharmaceutical composition in combination 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 into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, and / or titanium dioxide. Alternatively, the tablet can be coated with a suitable polymer dissolved in an easily volatile organic solvent. The tablet preferably has an enteric coating to allow the release of the glucocorticoid substance in the lower intestine. Suitable capsules can be prepared by using the methods described in EP-A-502092, WO 97/27843 or WO 95/08323. For the preparation of soft gelatine capsules, the glucocorticoid substance can be mixed, for example, with a vegetable oil or polyethylene glycol. The hard gelatine capsules may contain granules of the substance using either the above-mentioned tablet excipients, for example, lactose, sucrose, sorbitol, mannitol, starches, cellulose derivatives or gelatin. Also the liquid or semi-solid formulations of the glucocorticoid substance can be filled into hard gelatin capsules. Liquid preparations of 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 skilled 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 rate 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, should preferably be prepared in such a way that the glucocorticoid substance is released during the passage of the lower third of the small intestine and the upper fourth of the large intestine. This is in order to achieve a high local concentration of the glucocorticoid in these parts of the intestine, so that the glucocorticoid exerts its effect, preferably through the intestinal wall of these parts of the intestine. The invention is illustrated by the following examples, where budesonide was orally administered by administering the Entocort ™ preparation (tablet form) to patients suffering from IgA nephropathy in native kidneys or in kidney transplants.

Example 1 A 52-year-old man fell ill with signs of kidney disorder, as indicated by proteinuria and erythrocytes in the urine in 1982.

After renal biopsy and histological analysis of renal tissue, he was diagnosed with nephropathy due to IgA He was treated with various antihypertensive drugs but proteinuria increased and in 1990 he had developed renal failure, and after that year he developed uremia, which in turn required dialysis treatment. In 1993 he received a kidney from a deceased person. The transplanted kidney was working satisfactorily for the first 24 months and the patient was treated with glucocorticoid substance with systemic effect (prednisolone) as well as with an immunosuppressant drug (Ciclosporin). In 1995, the first signs of renal disorder of the transplanted kidney were detected, such as increased proteinuria and reduced renal function, as measured by changes in serum creatinine concentrations. After the renal biopsy of the transplant, followed by histological analysis, it showed that the tissue was affected by IgA nephropathy. At this stage, treatment with budesonide (Entocort ™, 9 mg / day) was started. Before the treatment began, the patient had considerable proteinuria (3.1 g of albumin / day, normal range 0.3 g / day) and reduced renal filtration capacity (serum creatinine 264 μmol / 1, normal range 80-115 μmol / day). 1) . After treatment with budesonide, proteinuria and renal function were significantly improved as shown in Table 1.

Table 1 Time U - albumin S - creatinine (weeks) (mg / 24 h) (μmol / 1) 0 3089 264 6 624 213 12 347 203 Example 2 A 29-year-old female patient with IgA nephropathy, where the histological examination of the material from a kidney biopsy described irregular widening of the mesangium and a slight increase in the mesangial matrix, but no cell proliferation. She had been previously treated with immunosuppressant and antihypertensive drugs, with no success with respect to improving renal function or decreasing proteinuria. Treatment with budesonide (9 mg / day) was initiated and after three months of treatment a 50% reduction in proteinuria was detected as described in Table 2.

Table 2 Time u - albumin S - creatinine (weeks) (mg / 24 h) (μmol / 1) 0 899 85 6 745 75 12 421 75 Example 3 A 47-year-old male patient suffered from IgA nephropathy, who was diagnosed in August 1996. The histological examination of the material from the renal biopsy showed a mild to moderate widening of the mesangium, slight increase in the mesangial matrix and slight mesangial proliferation. . In addition, focal chronic inflammation was present in the interstitium and there was focal fibrosis and partial atrophic tubules were present. Treatment with budesonide (9 mg / day) was started and after 12 weeks of treatment, proteinuria was reduced and renal function (serum creatinine) was improved as shown in Table 3.

Table 3 Time U - albumin S - creatinine (weeks) (mg / 24 h) (μmol / 1) 0 1349 147 6 1050 142 • *. 12 1067 129 Example 4 A 37-year-old male patient with IgA nephropathy, where the histological examination of the renal biopsy showed that 2 of 15 glomeruli were sclerotic and the other glomeruli had mensangial proliferative changes. A slight focal interstitial fibrosis and tubular atrophy could also be demonstrated. Treatment with budesonide (9 mg / day) was initiated and after 12 weeks of treatment the proteinuria was reduced and the renal function remained basically unchanged as shown in Table 4.

Table 4 Time U - albumin S - creatinine (weeks) (mg / 24 h) (μmol / 1) 0 1244 116 6 964 113 12 1078 112 Example 5 A 52-year-old female patient with IgA nephropathy, where the histological examination of the kidney biopsy material showed substantial segmental sclerotic changes in 2-4 / 15 glomeruli, and slight mensangial proliferative changes in the rest of the glands. There was also slight interstitial fibrosis and present tubular atrophy. Treatment with budesonide (9 mg / day) was initiated and after 12 weeks of treatment, proteinuria was reduced and renal function was possibly improved as shown in Table 5.

Table 5 Time u - albumin S - creatinine (weeks) (mg / 24 h) (μmol / 1) 0 634 106 6 516 107 12 431 100 Example 6 A 26-year-old male patient with IgA nephropathy was studied before and during treatment with budesonide (9 mg / day). After 12 weeks of treatment, the proteinuria was reduced as shown in Table 6.

Table 6 Time U - albumin s - creatinine (weeks) (mg / 24 h) (μmol / 1) 0 1449 91 6 1398 97 12 1100 90 Example 7 A 27-year-old female patient with IgA nephropathy, where the histological examination of the material from the renal biopsy showed an irregular widening of the mesangium and a focal increase of the mesangial matrix, and a slight mesangial proliferation. The interstitium, the tubules, and the vessels had normal appearances. Treatment with budesonide (9 mg / day) was started and after 12 weeks of treatment, proteinuria was reduced as shown in Table 7.

Table 7 Time U - albumin S - creatinine (weeks) (mg / 24 h) (μmol / 1). 0 311 82 6 212 81 12 167 81 Example A 36-year-old male patient with IgA nephropathy, where the histological examination of the material from the renal biopsy showed that 12/28 glomeruli were completely sclerotic and in the rest of the other glomeruli there was a widening of the mesangium and a slight proliferation mesangial and an increase of the mesangial matrix. A focal fibrosis was also found in the interstitium. Treatment with budesonide (9 mg / day) was initiated and after 6 weeks of treatment, proteinuria was reduced and renal function was improved as shown in Table 8.

Table 8 Time U-albumin S-creatinine (weeks) (mg / 24 h) (μmol / 1) 0 829 171 6 596 152 References 1. Clarkson and collaborators. In diseases of the Kidney, Braun & Co, 1988, pp. 2061-2090. 2. Alarmaatine and collaborators. Clin Nephfrol 34 (2): 45, 1990 3. Lai et al., Int Artif Organs 17 (9): 457, 1994. 4. Scheinman et al., Nephron 75: 251, 1997. 5. Shu et al., Clin Nephrol 44: 86, nineteen ninety five. 6. Goomanos et al., NDT 10: 1173, 1995. 7. Schmidt et al., Curr Op Nephrol Hypertension 5: 552, 1996. 8. Donadio et al., NEJM 3: 1194, 1994. 9. Trachtman et al., Ped Res 40: 620, 1996. 10. Feehally et al., Curr Op Nephrol Hypertension 5: 442, 1996. 11. Frohnert et al., Clin Transpl. 11: 127, 1997. 12. Odum et al., NDT 9: 309, 1994. 13. Anderson P et al. Xenobiotica 17: 5, 1987.

It is noted that in relation to this, date the best method known to the applicant to carry out the said invention, is that which is clear from the present description of the invention.

Claims (22)

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

1. The use of a glucocorticoid having a first pass metabolism in the liver of at least 90% for the manufacture of a medicament for the treatment of glomerulonephritis by oral or rectal administration of a pharmacologically effective amount thereof, for release in the intestine.

2. The use according to claim 1, wherein the glucocorticoid is selected from budesonide, rofleponide, beclomethasone monopropionate, beclomethasone dipropionate, ciclesonide, tipredane, flunisolide, tria mcinolone acetonide and fluticasone propionate.

3. The use according to claim 2, wherein the glucocorticoid is budesonide.

4. The use according to any of claims 1 to 3, wherein the daily pharmacologically effective amount is from 0.1 mg to 40 mg, preferably from 0.5 mg to 20 mg, more preferably from 1 mg to 10 mg, administered as a single dose or in divided doses 2 to 4 times a day.

5. The use according to any of claims 1-4, wherein the medicament is designed for oral administration.

6. The use according to claim 5, of the medicament in a selected form of tablets, pills, capsules, powders, syrups, solutions and granules, and wherein the solid forms comprise a carrier and an enteric coating.

7. The use according to claim 6, wherein the medicament is in the form of a capsule comprising microcapsules.

8. The use according to claims 5 to 7, wherein the pharmacologically effective amount of the glucocorticoid is released when the lower third of the small intestine and the upper fourth of the large intestine passes.

9. The use according to any of claims 1-4, wherein the medicament is designed for rectal administration.

10. The use according to claim 9, wherein the medicament is selected from enemas, suppositories and foams.

11. The use according to any of claims 1 to 10, of the medicament for the treatment of IgA nephropathy in a native kidney or in a kidney transplant.

12. A pharmaceutical composition for the treatment of glomerulonephritis, characterized in that it comprises a pharmacologically effective amount of a glucocorticoid having a metabolism of. first step in the liver of at least 90% and a pharmaceutically acceptable carrier, adjuvant, or diluent designed for oral or rectal administration, for release into the intestine.

13. The composition according to claim 12, characterized in that the glucocorticoid is selected from budesonide, rofleponide, beclomethasone monopropionate, beclomethasone dipropionate, ciclesonide, tipredane, flunisolide, triamcinolone acetonide and fluticasone propionate.

14. The composition according to claim 13, characterized in that the glucocorticoid is budesonide.

15. The composition according to claim 12, characterized in that the glucocorticoid is administered in a selected form of tablets, pills, capsules, powders, syrups, solutions and granules.

The composition according to claim 15, characterized in that the tablets, pills, capsules or granules comprise a carrier and uric enteric coating and are preferably in the form of capsules comprising microcapsules.

17. The composition according to any of claims 12 to 14, characterized in that the glucocorticoid is administered rectally in a selected form of suppositories, foams, and enemas.

18. The composition according to any of claims 12 to 17, characterized in that the medicament comprises glucocorticoid, preferably budesonide in an amount that provides a daily dose of 0.1 to 40 mg, preferably 0.5 mg to 20 mg, more preferably 1 mg to 10 mg.

19 The composition according to claim iß, characterized in that it is administered as a single daily dose or from 2 to 4 divided doses.

20. The composition according to claim 12, for use in the treatment of a patient who has had a kidney transplant.

21. The composition according to claim 12 to 14, for use in the treatment of a patient suffering from recurrence of glomerulonephritis in a kidney transplant.

22. The composition according to claim 12, for use in the treatment of IgA nephropathy.