WO2001003701A1

WO2001003701A1 - An oral composition having as a first active ingredient budesonide and as a second active ingredient an antibiotic, for use in intestinal conditions, especially crohn's disease

Info

Publication number: WO2001003701A1
Application number: PCT/SE2000/001467
Authority: WO
Inventors: Gordon Greenberg
Original assignee: Astrazeneca Ab
Priority date: 1999-07-12
Filing date: 2000-07-07
Publication date: 2001-01-18
Also published as: SE9902673D0; AU6194100A

Abstract

The invention provides a composition or kit having as a first active ingredient budesonide and as a second active ingredient an antibiotic, the use of the composition and kit in the treatment of intestinal conditions, especially Crohn's disease, and processes for preparation of the composition.

Description

AN ORAL COMPOSITION HAVING AS A FIRST ACTIVE INGREDIENT BUDESONIDE AND AS A SECOND ACTIVE INGREDIENT AN ANΗBIOTIC. FOR USE IN INTESTINAL CONDITIONS, ESPECIALLY CROHN'S DISEASE

Field of the Invention

The invention provides a new combination of pharmaceutically active substances which is 5 of use in the treatment of intestinal conditions such as inflammatory bowel diseases, particularly Crohn's disease.

Background to the Invention

Inflammatory bowel disease is the term generally applied to two diseases, namely 10 ulcerative colitis and Crohn's disease.

Ulcerative colitis is a chronic inflammatory disease of unknown aetiology afflicting only the large bowel and, except when very severe, limited to the bowel mucosa. The course of the disease may be continuous or relapsing, mild or severe. It is curable by total colectomv 15 which may be needed for acute severe disease or chronic unremitting disease. Most patients with ulcerative colitis are managed medically rather than surgically.

Crohn's disease is also a chronic inflammatory disease of unknown aetiology but. unlike ulcerative colitis, it can affect any part of the bowel. Although lesions may start 20 superficially, the inflammatory process extends through the bowel wall to the draining lymph nodes. As with ulcerative colitis, the course of the disease may be continuous or relapsing, mild or severe but, unlike ulcerative colitis it is not curable by resection of the involved segment of bowel. Most patients with Crohn's disease come to surgery at some time, but subsequent relapse is common and continuous medical treatment is usual.

25

Oral monotherapy treatment of ulcerative colitis and Crohn's disease in its different forms with budesonide is described in EP 0 502 092.

Improved treatments for these conditions are required. Description of the Invention

It has surprisinly been found that the composition of the present invention administered by the oral route is of great potential benefit in the treatment of intestinal conditions such as inflammatory bowel diseases, particularly Crohn's disease in its different stage.

The composition of the present invention for oral administration comprising:

(a) a first active ingredient which is budesonide; and

(b) a second active ingredient which is an antibiotic.

According to the invention there is further provided a kit comprising a composition as defined above, and instructions for the simultaneous, sequential or separate administration of the first and second active ingredients to a patient in need thereof.

A patient suffering from an intestinal condition such as inflammatory bowel disease, particularly Crohn's disease, can be treated by administering orally a composition according to the invention. Alternatively, such a patient can be treated by orally administering, simultaneously, sequentially or separately: (i) a dose of the first active ingredient; and (ii) a dose of the second active ingredient.

By the second active ingredient is meant one, two or more antibiotics.

The second active ingredient, which is an antibiotic, such as an antibacterial agent, preferably a quinolone, especially a fluoroquinolone, and/or an antiprotozoal agent. Suitable fluoroquinolone antibacterial agents include ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, amifloxacin, fleroxacin, levofloxacin, nadifloxacin, rufloxacin, sparfloxacin and/or tosufloxacin. Another suitable antibacterial agent may be clarithromycin or rifamycin derivatives such as rifampicin and rifabutin. Suitable antiprotozoal agents are 5-nitromidazoles, especially azanidazole, metronidazole, nimorazole, ornidazole, propenidazole, secnidazole, ternidazole and/or tinidazole. Preferably ciprofloxacin and/or metronidazole are used.

By the first active ingredient budesonide is included racemic budesonide and the 22R- epimer of budesonide.

Reference is made to the Merck Index, 12 Edition, S Budavari et al (ed.) for definitions and chemical names of the above- mentioned compounds. This is incorporated herein by reference.

The first active ingredient, budesonide, and the second active ingredient can be orally administered in one formulation or alternatively in two or more formulations, separately or sequentially to treat intestinal conditions. By sequential it is meant that the first and second active ingredients are administered one immediately after the other. They still have the desired effect if they are administered separately but less than about 12 hours apart, preferably less than about 6 hours apart, more preferably less than about 2 hours apart, even more preferably less than about 30 minutes apart.

Preferably the first and second active ingredients are used in a weight ratio of from 1 :20000 to 1 :2.5, preferably from 1 :200 to 1:10, more preferably from 1:120 to 1:25, even more preferably from 1 :85 to 1 : 55, most preferably from 1 :50 to 1 :40.

Preferably the first active ingredient is administered at a daily dosage of from 0.1 to 40 mg, more preferably from 5 to 15 mg, particularly preferably 9 mg, as a single dose daily or in divided doses from 2 to 4 times per day, preferably as a single dose daily.

The second active ingredient is preferably administered at a dosage of from 2000 mg to 100 mg, more preferably from 1000 mg to 250 mg, particularly preferably from 750 mg to 500 mg either as a single dose or in divided doses 2, 3 or 4 times per day, preferably 2 times per day.

Oral administration can be in the form of tablets, pills, capsules, syrups, powders or granules.

When given separately, each active ingredient can be administered either on its own or as a pharmaceutical composition in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse event, e.g. an allergic reaction or increased symptoms.

The active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, 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 e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. The tablet may preferably has an enteric coating to allow release of the drug in the lower intestine.

For the preparation of soft gelatine capsules, budesonide may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol , mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules. Suitable capsules may be prepared by using the methods described in EP-A-502092.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the active compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

The composition or kit according to the invention can be used in the treatment of intestinal conditions such as inflammatory bowel disease. More particularly the composition or kit according to the invention can be used in the treatment of Crohn's disease. In Crohn's disease the composition can be used for the treatment of small and large intestine in their active phases and in their chronic phases as relapse preventing therapy (i.e. maintenance therapy once remisson has been achieved).

Experimental

Patients with active Crohn^'s disease, defined by a Crohn^'s Disease Activity Index (CDAI) greater than 200 are treated orally with budesonide 9 mg once daily and antibiotics, for instance metronidazole 500 mg twice daily and ciprofloxazine 500 mg twice daily. The treatment is continued for 8 weeks at a constant dose. During these 8 weeks study period patients are not permitted to use any other medical or nutritional therapies known or suspected to have activity against Crohn^'s disease. Treatment success, complete response, is defined as a reduction of the CDAI, following 8 weeks therapy, to below 150. Partial response is analyzed as a secondary outcome measure and is defined as a reduction of the CDAI by 100 points or more but final value of 150 or greater. Patients are also completed a specific quality of the life index questionnaire (IBDQ).

Claims

1. A composition for oral administration comprising: (a) a first active ingredient which is budesonide; and (b) a second active ingredient which is an antibiotic.

2. A composition according to claim 1 wherein the second active ingredient is an antibacterial agent.

3. A composition according to claim 1 wherein the antibiotic is an antibacterial agent in combination with an antiprotozoal agent.

4. A composition according to any one of claims 2 or 3 wherein the antibacterial agent is a quinolone, preferably a fluoroquinolone.

5. A composition according to claim 4 wherein the antibacterial agent is ciprofloxacin.

6. A composition according to claim 3, wherein the antibacterial agent is ciprofloxacin and the antiprotozoal agent is metronidazole.

7. A composition according to any one of claims 1-6, wherein the active ingredients are in one formulation.

8. Use of a composition according to any one of claims 1-7 in medicinal therapy.

9. Use of a composition according to any one of claims 1-7 in the manufacture of a medicament for use in the treatment of an intestinal condition.

10. Use according to claim 9 in the treatment of Crohn's disease.

1 1. A kit comprising a composition as defined in any one of claims 1-7, and instructions for the sequential or separate administration of the first and second active ingredients to a patient in need thereof.

12. Use of budesonide in the manufacture of a composition as defined in any one of claims 1-7 or of a kit as defined in claim 11 for use in the treatment of an intestinal condition.

13. Use according to claim 12 in the treatment of Crohn's disease.

14. Use of an antibiotic in the manufacture of a composition as defined in any one of claims 1-7 or of a kit as defined in claim 11 for use in the treatment of an intestinal condition.

15. Use according to claim 14 in the treatment of Crohn's disease.

16. A method of treating an intestinal condition which method comprises orally administering to a patient suffering from a said condition, sequentially or separately, a therapeutically effective amount of a composition according to any one of claims 1-7.

17. A method according to claim 16 of treating Crohn's disease.

18. A process for preparation of the composition as defined in any one of claims 1-7, whereby the first active ingredient (a) is incorporated into the same formulation as the second active ingredient (b).

19. A process for preparation of the composition as defined in any one of claims 1-6, whereby the first active ingredient (a) is in one formulation and the second active ingredient (b) is in a different formulation.