WO2002080931A1 - Nouvelle utilisation de glyconjugues de glucocorticosteroides ayant comme cible le colon - Google Patents

Nouvelle utilisation de glyconjugues de glucocorticosteroides ayant comme cible le colon Download PDF

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Publication number
WO2002080931A1
WO2002080931A1 PCT/SE2002/000662 SE0200662W WO02080931A1 WO 2002080931 A1 WO2002080931 A1 WO 2002080931A1 SE 0200662 W SE0200662 W SE 0200662W WO 02080931 A1 WO02080931 A1 WO 02080931A1
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WO
WIPO (PCT)
Prior art keywords
sugar
gcs
butylidenedioxy
dione
compound according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/SE2002/000662
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English (en)
Inventor
Ralph Brattsand
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AstraZeneca AB
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AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2002080931A1 publication Critical patent/WO2002080931A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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 present invention relates to the use of glycoconjugates of glucocorticosteroids (GC) as a targeting to the colon, for example to colon of patients with irritable bowel syndrome (IBS), and pharmaceutical compositions containing said glycoconjugates.
  • GC glucocorticosteroids
  • IBS is an abdominal syndrome affecting 20% of the population, causing patients much discomfort and society large healthy care costs.
  • Current treatment of IBS is mainly antispasmodics, laxatives, loperamide and antidepressants.
  • the IBS symptoms arise from . altered gastrointestinal motility, increased visceral sensitivity and/or altered brain-bowel modulation. Even if the symptoms may vary, the common ground is a neuromuscular dysfunction, including increased visceral sensitivity with pain and altered bowel habits. Up to 30% of patients hit by bacterial gastro-enteritis (Salmonella, Campylobacter etc) develop IBS, suggesting that these infections provoke longstanding or chronic alterations of the colonic neuromuscular function.
  • Irritable bowel syndrome is a common disorder of the intestines that leads to crampy pain, gassiness, bloating, and changes in bowel habits.
  • Some people with IBS have constipation (difficult or infrequent bowel movements); others have diarrhoea (frequent loose stools, often with an urgent need to move the bowels); and some people experience both.
  • Sometimes the person with IBS has a crampy urge to move the bowels but cannot do so.
  • IBS Intra colitis and Morbus Crohn
  • IBD Intra colitis and Morbus Crohn
  • the only change reported is an enhanced number of mucosal mast cells in the colon and cecum (O 'Sullivan M et al Neurogastroenterology &Motility 2000;12:449-457; Yang Y et al. Chinese Journal of Internal Medicine 1997;36(4):231-233.
  • the IBD-diseases are immune- mediated illnesses characterized by a broad inflammation comprising most types of inflammatory and immune cells, and they lead to a marked remodelling of bowel tissue.
  • mast cell mediators may trigger nerve reflexes, inducing contractions of the deeper located circular and longitudinal muscle layers and with a possibility to signal pain/discomfort to CNS. Contrary can a stressed brain trigger neuropeptide discharge (e.g. Substance P and other peptides) from the mucosal EN-nerve endings, which may degranulate adjacent mast cells and by that trigger plasma leakage and pain signals.
  • neuropeptide discharge e.g. Substance P and other peptides
  • Other mucosal cells like enterochromaffine cells, containing tachykinins and CRF (Corticotrophin Releasing Factor) may contribute to these cellular-neural interactions.
  • a high steroid dose (dexamethasone 0.5 mg/kg given intraperitoneally) blunted nearly fully the neuromuscular hyperresponsiveness of rat jejunum, persisting after parasite infestation.
  • a new and better mode to selectively deliver steroid to colon mucosa of IBS-patients is the administration of glycoconjugates of selected steroids.
  • These steroidal prodrugs are inactive at the GC-receptor, they are very hydrophilic and are by that poorly absorbed by
  • a preferred glycoconjugate needs the following combination of properties:
  • the glycoconjugate should be slowly hydrolysed by the colon microbial flora, and mucosal glycosidases may also contribute. * The released, active steroid should have
  • the present invention relates to the use of a compound of the general formula
  • GCS. 1 is a glucocorticosteroid (GCS '-OH) with a hepatic first pass metabolism of at least 95%, selected from the group of formula I CH,
  • formulas Xj and X 2 being the same or different selected from the group consisting of hydrogen, fluoro, chloro or bromo, X 3 being a fluoro, chloro or bromo substituent, R being a hydrocarbon chain with 1-9 carbon atoms and in which formulas the 1,2-position is saturated or unsaturated, the Sugar 1 being the moiety of a monosaccharide, a disaccharide or an oligosaccharide, the GCS being linked in 21 -position to the sugar via a glycosidic bond as well as a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for dampening the neuromuscular hyperresponsiveness of bowel.
  • the compound according to the invention is preferably used for dampening the activity of the mast cells and nerves belonging to the enteric nervous (EN) system.
  • EN enteric nervous
  • the most preferred use is for the prevention and/or treatment of irritable bowel syndrome (IBS), particularly post-infectious IBS.
  • IBS irritable bowel syndrome
  • a method for dampening the neuromuscular hyperresponsiveness of bowel by administering to a mammal including man in need of such a treatment a therapeutically effective amount of a compound of the general formula GCS'-O-Sugar 1 as described above.
  • a pharmaceutical formulation for use in dampening the neuromuscular hyperresponsiveness of bowel wherein a compound of the general formula GCS ] -O-Sugar ] as described above is used as active ingredient.
  • the sugar conjugated via a glycosidic bond to the steroid can be D-glucose, D-glucuronic acid, D-galactose, D-galacturonic acid, D-cellobiose, or D-lactose.
  • the sugar is ⁇ -linked D-glucuronic acid or D-glucose.
  • a preferred embodiment of the invention is the use of the compound according to claim 1 wherein the glucocorticosteroid (GCS'-OH) has a hepatic first pass metabolism of at least 97%.
  • Preferred steroids to be linked at the 21 -OH position with a sugar are (22R)-16 ⁇ ,17 ⁇ - butylidenedioxy-1 l ⁇ ,21-dihydroxypregna-l,4-diene-3,20 dione; (22R)-16 ⁇ ,17 ⁇ - butylidenedioxy-6 ⁇ ,9 -difluoro-l l ⁇ ,21-dihydroxy-4-pregnene-3,20-dione; or (22R)- 16 ⁇ ,17 ⁇ -butylidenedioxy-6 ,9 ⁇ -difluoro-l l ⁇ ,21-dihydroxy-l,4-pregnadiene-3,20 .
  • the compounds to be used according to the present invention may be prepared according to the methods described in WO 94/15947.
  • the glycoconjugate When the glycoconjugate is administered orally, it is administered oesophageally, generally administered in the form of tablets, pills, capsules, syrups, powders, or granules and when it is administered rectally, is in the form of suppositories or enemas.
  • glycoconjugates as well as a pharmaceutically acceptable salt and/or solvate thereof may be administered on its own or as a pharmaceutical formulation in combination with pharmaceutical acceptable diluent, adjuvant or carrier.
  • the glycoconjugate as well as a pharmaceutically acceptable salt and/or solvate thereof is preferably administered at a dosage of from 0.1 to 50 nig, more preferably from 0.5 to 25 mg, either as a single dose or in divided doses from to 2-4 times per day.
  • glycoconjugates have a very high water solubility.
  • a potential animal model is nematode-infested mice, which after expulsion of the parasites develop a persistent enteric muscle dysfunction with similarities to human postinfectious IBS and which has been described in Barbara G et al. Role of immunological factors and cyclooxygenase-2 in persistent post infective enteric muscle dysfunction in mice. Gastroenterology 2001; 120: 1729-1736.
  • Tablets are prepared by conventional compression methods with the following composition
  • the tablet from Example 1 is coated with
  • Budesonide 22R-epimer ⁇ -D-glucoside, budesonide 22R-epimer ⁇ -D-glucosiduronate, GCS 1 IN 22R-epimer ⁇ -D-glucoside or GCS 'IV 22R-epimer ⁇ -D-glucosiduronate (7.1 g) is mixed with 300 g lactose, 128 g microcrystalline cellulose, 75 g crosslinked polyvinylpyrrolidone and 25 g polyvinylpyrrolidone. The mixture is granulated with water and the wet mass is extruded and spheronized giving cores with approximate size of 1 mm. The cores are dried and sieved.
  • the cores are coated with a mixture of 255 g Eudragit ⁇ E30D, 77 g magnesium stearate and 250 g water in a fluid bed apparatus. Finally an enteric coating consisting of 11 g Eudragit L30D dispersion, 3 g triethylcitrate and 15 g talc is sprayed on the spheres. The pellets are dried in the fluid bed apparatus, sieved and filled in hard gelatine capsules.
  • Budesonide 22R-epimer ⁇ -D-glucoside or budesonide 22R-epimer ⁇ -D-glucosiduronate (6.6 g) is suspended in a solution of 1 g of hydroxypropylmethylcellulose in 50 ml of water. The mixture is sprayed on to 510 g sugar spheres in a fluid bed apparatus. Thereafter a mixture of 85 g guar gum, 30 g (solid content) Eudragit RL30D and 15 g talc in totally 900 g of a 1 : 1 mixture of water and isopropanol is sprayed on the spheres.
  • enteric coating consisting of 100 g Eudragit L30D dispersion, 3 g triethylcitrate and 15 g talc is sprayed on the spheres.
  • the pellets are dried in the fluid bed apparatus, sieved and filled into hard gelatine capsules.
  • GCS 1 IV 22R-epimer ⁇ -D-glucoside or GCS ! IV 22R-epimer ⁇ -D-glucosiduronate (6.8 g) is suspended in a mixture of 15 g locust bean gum, 5 g (solid content) Eudragit RL30D and 2 g talc in totally 220 g of a 1 : 1 mixture of water and isopropanol. This mixture is sprayed on to 510 g of sugar spheres in a fluid bed apparatus.

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

Abstract

La présente invention concerne l'utilisation de glycoconjugués de glucocorticostéroïdes (GC) ayant comme cible le côlon, par exemple, le côlon de patients souffrant du syndrome du côlon irritable (IBS), et les compositions pharmaceutiques contenant ces glycoconjugués.
PCT/SE2002/000662 2001-04-04 2002-04-02 Nouvelle utilisation de glyconjugues de glucocorticosteroides ayant comme cible le colon Ceased WO2002080931A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0101220A SE0101220D0 (sv) 2001-04-04 2001-04-04 New use
SE0101220-2 2001-04-04

Publications (1)

Publication Number Publication Date
WO2002080931A1 true WO2002080931A1 (fr) 2002-10-17

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PCT/SE2002/000662 Ceased WO2002080931A1 (fr) 2001-04-04 2002-04-02 Nouvelle utilisation de glyconjugues de glucocorticosteroides ayant comme cible le colon

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SE (1) SE0101220D0 (fr)
WO (1) WO2002080931A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US12134631B2 (en) 2017-11-07 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
US12227538B2 (en) * 2021-03-23 2025-02-18 Eli Lilly And Company Glucocorticoid receptor agonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5908833A (en) * 1993-01-08 1999-06-01 Aktiebolaget Astra Colon or ileum-specific steroid derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5908833A (en) * 1993-01-08 1999-06-01 Aktiebolaget Astra Colon or ileum-specific steroid derivatives

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US12377159B2 (en) 2016-11-08 2025-08-05 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12589101B2 (en) 2017-05-18 2026-03-31 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12134631B2 (en) 2017-11-07 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US12497460B2 (en) 2018-05-09 2025-12-16 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US12227538B2 (en) * 2021-03-23 2025-02-18 Eli Lilly And Company Glucocorticoid receptor agonists

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