IL129900A - Use of budesonide for the preparation of a pharmaceutical composition for the treatment of cholestatic liver diseases - Google Patents

Abstract

It has been surprisingly discovered that budesonide is effective for treating cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and auto-immune cholangitis. The invention therefore concerns the use of budesonide for treating cholestatic liver diseases.

Description

129900/2 BUDESONIDE FOR THE TREATMENT OF CHOLESTATIC LIVER DISEASES Dr. Falk Pharma GmbH Budesonide for the treatment of cholestatic liver diseases The present invention relates to the use of the well known medicament budesonide for the treatment of certain liver diseases .

Therapy with immuno suppressives, e.g. corticosteroids such as prednisolone or budesonide is well known in the case of non-cholestatic hepatic diseases (Danielsson et al., Aliment. Pharmacol. Ther., 1994, 8, 585-590). Different in many aspects from non-cholestatic diseases, however, are cholestatic hepatic diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AC). It was the general belief in the art that the therapy with such immuno suppressives is not promising for the treatment of cholestatic diseases.

In particular, there were controlled clinical investigations whether prednisolone can be used for the treatment of the above mentioned diseases (Mitchison et al . , Hepatology, 1989, 4, 420-429; Mitchison et al., Hepatology, 1992, 15, 336-344), however, the therapy with prednisolone is controversially discussed. The activity of prednisolone is not without doubt and, furthermore, severe steroid-associated side effects were observed. For this reason, up to now a therapy of PBC, PSC and AC with glucocorticoids was not considered being helpful (Paumgartner & Beuers, In: Acute and chronic liver diseases, 1996* 96-106; Hepatologie (Ed. Gerok & Blum), 1995, page 435 and 439; Praktische Gastroenterologie, (Ed. Layer et al.), 1996, 397-398).

Budesonide is a steroid that is resorbed in the intestine to an extent of 52% to 79% within four to six hours. Its affinity to the corticoid receptors is 15 times higher than that of prednisolone. Budesonide has a first pass metabolism of 80 to 90% in the liver during the first liver pass. The systemic bioavailability is about 10%. Because of these properties budesonide belongs to the steroids having very low side effects, however, the very high first pass metabolism and the low systemic bioavailability of budesonide apparently exclude a treatment of cholestatic liver diseases.

Therefore, it is generally accepted in the art that the only way to achieve an effective medical therapy, in particular of PBC and PSC, is the administration of ursodeoxycholic acid, which however does not completely heal the disease (Aktuelle Wissenschaft fiir Klinik und Praxis, Satellitensymposium, "Aktuelle Hepatologie - Diagnostische und therapeutische Fortschritte 1997", Wiesbaden, April 5, 1997, page 3). Several compounds have been proposed to assist ursodeoxycholic acid, among others also budesonide (Aktuelle Wissenschaft fur Klinik und Praxis, Satellitensymposium, "Aktuelle Hepatologie Diagnostische und therapeutische Fortschritte 1997", Wiesbaden, April 5, 1997, page 3; U. Leuschner et al., Ursodeoxycholic acid in combination with prednisolone or budesonide in the therapy of primary biliary cirrhosis, In: Bile acids in Hepatobiliary Diseases: Basic Research and Clinical Application. pages 299-302. Kluwer Academic Publishers, Dordrecht, 1997). The use of budesonide alone and not as an assisting agent for ursodeoxycholic acid was not considered to be promising and therefore has not been proposed in the prior art.

Despite the success in the treatment of cholestatic hepatic diseases with ursodeoxycholic acid, there is need for further pharmaceutical compositions that show similarly good results in the treatment of cholestatic hepatic diseases. Therefore, one problem of the invention is to provide a pharmaceutical composition that can be used to successfully treat cholestatic hepatic diseases, in particular primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangitis.

The solution to this problem is based on the unexpected finding that the glucocorticoid budesonide which up to now was believed to act only in an assisting manner in the treatment of cholestatic diseases with ursodeoxycholic acid is also very effective against cholestatic hepatic diseases without concurrent administration of ursodeoxycholic acid. According to the present invention the use of budesonide is provided for the treatment of cholestatic hepatic diseases, in particular for the treatment of primary biliary cirrhosis, of primary sclerosing cholangitis and of autoimmune cholangitis.

According to the invention budesonide is not administered to assist in the treatment of a cholestatic hepatic disease with ursodeoxycholic acid but is itself the actual agent for the treatment of the diseases. Pharmaceutical compositions or therapy schedules that comprise the concurrent or timely shifted administration of budesonide and ursodeoxycholic acid in a way that budesonide and ursodeoxycholic acid act jointly, are therefore not subject matter of the invention.

Budesonide can be formulated to a pharmaceutical composition for the treatment of mammals, preferably humans in a per se known manner. In the pharmaceutical composition budesonide usually is in admixture with a pharmaceutically acceptable organic or inorganic carrier which is suitable for the enteral or parenteral application. The oral administration of the pharmaceutical compositions according to the invention such as by tablets, capsules, powders, liquids such as suspensions, solutions or emulsions or as a syrup are preferred.

When budesonide is formulated as a tablet, usual carriers and excipients such as lactose, microcrystalline cellulose, starch and anhydrous silica, lubricants such as hydrogenated castor oil, magnesium stearate, sodium lauryl sulfate and talc as well as binders such as starch, glucose, gum arabicum and mannitol are used.

If the compositions according to the invention are to be administered in a liquid state, usual liquid carriers can be used. Preferred is a formulation of the pharmaceutical compositions of the invention as injection or infusion or as a suppository, as is known in the prior art and described in well known standard text books.

In a particularly preferred embodiment of the present invention, the budesonide containing pharmaceutical compositions are formulated with the excipients corn starch, lactose, aerosil, polyvinylpyrrolidone and magnesium stearate to tablets. In a further preferred embodiment of the present invention, the budesonide containing pharmaceutical compositions are formulated with the excipients corn starch, lactose, magnesium stearate and aerosil to capsules.

The budesonide containing compositions of the present invention can furthermore be formulated as sustained release preparations , as is known in the art .

The daily dose of budesonide is about 0.5 mg to 100 mg per day depending on the severity of the disease, the state of the patient, further diseases of the patient, the administration route and further parameters which are routinely taken into account by the treating doctor. Preferred are daily doses of 1 mg to 50 mg and particularly preferred are daily doses of 5 mg to 20 mg. The daily doses can be administered at one time per day or divided over the day, for example three times a day. According to the above mentioned daily doses, the formulations according to the invention comprise preferably 0.5 to 10 mg, particularly preferred 1 mg to 5 mg budesonide per unit dosage form.

The examples reported below illustrate the invention.

Formulation example 1: budesonide containing tablets (5 mg) Budesonide 50 g Corn starch 450 g Lactose 450 g Aerosil 50 g are mixed and wetted with Polyvinylpyrrolidone 100 g dissolved in 500 ml ethanol (70%).

The moist mass is passed through a 1 mm-sieve and dried. After renewed sieving of the dried mass Magnesium stearate 30 g are added.

The mixture is pressed into tablets of 120 mg.

Formulation example 2; budesonide containing capsules (3 ma) Budesonide 30 g Corn starch 300 g Lactose 200 g Magnesium stearate 30 g Aerosil 20 g are mixed and are filled into hardgelatine-capsules . The filling weight is 58 mg.

Formulation example 3: budesonide containing injection (3 mg/ml Budesonide 3 g is dissolved in Lecithin (USP 60 g The solution is instilled into 1000 ml of water (pH 3.5, citrate buffer, 50 mM) under strong shearing with an Ultraturrax. The resulting solution is filled into 1 ml phiols and sterilized for 20 min at 121 °C.

Formulation example 4; budesonide containing suppositories (10 ma¾ Budesonide (micronized) 10 g is suspended in Hard fat 2000 g which is melted to approximately 45 °C and is then poured into 2 g suppository molds. After cooling down the suppositories are taken out.

Experimental Example A female patient with the diagnosis; PBC was treated with 3 * 3 mg budesonide per day over a longer period of time. Prior to the therapy the clinical parameters were determined, and these parameters were followed during the therapy (table 1) . As clinical parameters the enzyme activities of GPT (Alanine-Aminotransferase) , AP (Alkaline Phosphatase), and LAP (Leucineaminopeptidase) were used. The GPT is an enzyme which has the highest activity in the liver. An increase in the serum activity of this enzyme (normal: up to 22 U/l) points to a damaged liver with a high specificity. An increase in the serum activity of the AP (normal: up to 170 U/l) occurs with all diseases of the liver and the biliary tract, which occur in combination with a cholestasis. A further parameter pointing to a cholestatic liver disease is the serum activity of the LAP. An increased value of the enzyme activity in the serum (normal: 11 - 35 U/1) points to a hepatic-biliary disease with obstructive and nonobstructive cholestasis.

As can be seen from table 1, prior to the treatment with budesonide all serum activities described above of the female patient with indicated PBC were higher than normal.

After treatment for only one month with a daily dose of 3 * 3 mg budesonide all parameters were significantly improved and did not increase again, even after a treatment of 12 months. No side effects were observed during the whole treatment period.

Table 1 This clearly shows that cholestatic liver diseases can successfully be treated with budesonide.

Claims (3)

129900/2 8 Claims

1. Use of budesonide for the production of a pharmaceutical composition as described in the specification for the treatment of cholestatic liver diseases.

2. Use according to claimi , wherein the cholestatic liver disease is primary biliary cirrhosis, primary sclerosing cholangitis or autommune cholangitis

3. Use according to claimi or 2, wherein the daily dose of budesonide in the pharmaceutical composition as prepared in claims 1 and 2 is 1 to 20 mg. FOR THE APPLICANT Dr. Yitzhak Hess & Partners