WO2001003703A1 - Composition orale comportant en tant que premier principe actif un rofleponide et en tant que second ingredient un antibiotique, destinee a traiter des troubles intestinaux tels que la maladie de crohn - Google Patents

Composition orale comportant en tant que premier principe actif un rofleponide et en tant que second ingredient un antibiotique, destinee a traiter des troubles intestinaux tels que la maladie de crohn Download PDF

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Publication number
WO2001003703A1
WO2001003703A1 PCT/SE2000/001469 SE0001469W WO0103703A1 WO 2001003703 A1 WO2001003703 A1 WO 2001003703A1 SE 0001469 W SE0001469 W SE 0001469W WO 0103703 A1 WO0103703 A1 WO 0103703A1
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WO
WIPO (PCT)
Prior art keywords
active ingredient
disease
composition
treatment
crohn
Prior art date
Application number
PCT/SE2000/001469
Other languages
English (en)
Inventor
Gunilla NYGÅRD
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU61943/00A priority Critical patent/AU6194300A/en
Publication of WO2001003703A1 publication Critical patent/WO2001003703A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention provides a new combination of pharmaceutically active substances which is of use in the treatment of intestinal conditions such as inflammatory bowel diseases, particularly Crohn's disease.
  • Inflammatory bowel disease is the term generally applied to two diseases, namely 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 colectomy 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 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.
  • 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.
  • composition of the present invention for oral administration comprising:
  • kits 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.
  • 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.
  • 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.
  • 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.
  • ciprofloxacin and/or metronidazole are used.
  • rofleponide By the first active ingredient rofleponide is included racemic rofleponinde and its esters and salts e.g rofleponide palmitate.
  • the chemical name of rofleponide is (22R)-16 ⁇ , ⁇ 7a- butylidenedioxy-6a,9a-difluoro-l l 9,21-dihydroxypregn-4-ene-3,20-dione, which compound is described in US 5, 674, 861.
  • the first active ingredient, rofleponide, 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.
  • 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.
  • the first and second active ingredients are used in a weight ratio of from 1 :200000 to 1 :5, preferably from 1 :1000 to 1 :50.
  • the first active ingredient is administered at a daily dosage of from 0.01 to 20 mg, more preferably from 0.1 to 5 mg, particularly preferably 2 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Listeson has been achieved).
  • CDAI Crohn's Disease Activity Index
  • rofleponide 2 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).
  • IBDQ life index

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à une composition ou à une trousse comportant en tant que premier ingrédient actif du rofléponide, ses esters et sels et en tant que second ingrédient actif un antibiotique. L'invention se rapporte également à l'utilisation de ladite composition et de ladite trousse pour le traitement de troubles intestinaux, et notamment de la maladie de Crohn. Elle se rapporte également à des procédés de préparation de ladite composition.
PCT/SE2000/001469 1999-07-12 2000-07-07 Composition orale comportant en tant que premier principe actif un rofleponide et en tant que second ingredient un antibiotique, destinee a traiter des troubles intestinaux tels que la maladie de crohn WO2001003703A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61943/00A AU6194300A (en) 1999-07-12 2000-07-07 An oral composition having as a first active ingredient rofleponide and as a second active ingredient an antibiotic, for use in intestinal conditions, especially crohn's disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9902674A SE9902674D0 (sv) 1999-07-12 1999-07-12 New composition
SE9902674-2 1999-07-12

Publications (1)

Publication Number Publication Date
WO2001003703A1 true WO2001003703A1 (fr) 2001-01-18

Family

ID=20416478

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2000/001469 WO2001003703A1 (fr) 1999-07-12 2000-07-07 Composition orale comportant en tant que premier principe actif un rofleponide et en tant que second ingredient un antibiotique, destinee a traiter des troubles intestinaux tels que la maladie de crohn

Country Status (3)

Country Link
AU (1) AU6194300A (fr)
SE (1) SE9902674D0 (fr)
WO (1) WO2001003703A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005519901A (ja) * 2002-01-19 2005-07-07 ザ・キュレーターズ・オブ・ザ・ユニバーシティ・オブ・ミズーリ 新規の置換ベンゾイミダゾール剤形とそれを使用する方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032089A1 (fr) * 1997-12-22 1999-07-01 Astrazeneca Ab Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032089A1 (fr) * 1997-12-22 1999-07-01 Astrazeneca Ab Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] PRANTERA C. ET AL.: "Use of antibiotics in the treatment of active Crohn's disease: Experience with metronidazole and ciprofloxacin", retrieved from 130:291127 accession no. STN International Database accession no. 1999:225244 *
ITAL. J. GASTROENTEROL. HEPATOL., vol. 30, no. 6, 1998, (ENGLISH), pages 602 - 606 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005519901A (ja) * 2002-01-19 2005-07-07 ザ・キュレーターズ・オブ・ザ・ユニバーシティ・オブ・ミズーリ 新規の置換ベンゾイミダゾール剤形とそれを使用する方法

Also Published As

Publication number Publication date
AU6194300A (en) 2001-01-30
SE9902674D0 (sv) 1999-07-12

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