EP1539192A1 - Zusammensetzung und set zur behandlung von entzündlichen darmerkrankungen - Google Patents

Zusammensetzung und set zur behandlung von entzündlichen darmerkrankungen

Info

Publication number
EP1539192A1
EP1539192A1 EP02735862A EP02735862A EP1539192A1 EP 1539192 A1 EP1539192 A1 EP 1539192A1 EP 02735862 A EP02735862 A EP 02735862A EP 02735862 A EP02735862 A EP 02735862A EP 1539192 A1 EP1539192 A1 EP 1539192A1
Authority
EP
European Patent Office
Prior art keywords
heparin
chitosan
aqueous composition
sulfate
treatment
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.)
Withdrawn
Application number
EP02735862A
Other languages
English (en)
French (fr)
Inventor
Olle Medicarb AB Larm
Robert Lofberg
Leif Torkvist
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medicarb AB
Original Assignee
Medicarb 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 Medicarb AB filed Critical Medicarb AB
Publication of EP1539192A1 publication Critical patent/EP1539192A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/745—Polymers of hydrocarbons
    • A61K31/75—Polymers of hydrocarbons of ethene
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus

Definitions

  • This invention relates to the use of new pharmaceutical compositions for the inhibition of inflammation and infections and the acceleration, stimulation or promotion of the healing of wounds in the gastrointestinal tract.
  • the invention also includes processes for the preparation of such formulations
  • GAG glycosaminoglycans
  • the GAGs are heparin, the heparan sulfates, the chondroitin sulfates, hyaluronic acid, dermatan sulfate and eratan sulfate.
  • Other semisynthetical polysaccharides with similar biological activities are called heparinoids, for instance dextran sulfate.
  • Free heparin and heparan sulfate activates the plasmaprotein antithrombin, which in turn inhibits the serine proteases of the coagulation cascade in blood. This phenomenon has been clinically exploited and made heparin the most widely used blood- anticoagulant in the clinic. Most of the other GAGs and heparinoids also show blood anticoagulant activities, but these are less specific and prominent. Other documented biological functions of GAGs and heparinoids are their abilities to hinder inflammatory reactions.
  • heparin The ability of heparin to hinder inflammation is also used in the clinic. For instance if deep venous thrombosis is treated with heparin, there is not only an antithrombotic effect, but also an antiinflammatory effect; swelling is also decreased. Probably several mechanisms contribute to the antiinflammatory effect of heparin and GAGs but it is as yet unclear which one is the most important.
  • the negatively charged polysaccharides bind, mainly from their strongly anionic nature caused by their. sulfate and/or carboxyl functions, to a large number of proteins. Some of these are involved in the inflammatory system, for instance the complement factors. Investigators hypothesize that the endothelium, or the lining of blood vessels, plays a role in inflammatory responses.
  • endothelial cells coated with the molecule heparan sulfate (similar to heparin) bind with leukocytes, the white blood cells that proliferate during inflammation. This relationship is promoted by cytokines, chemicals secreted during inflammation.
  • heparin combats this inflammatory action in several ways. Heparin due to its structural similarity with heparin sulfate interferes with the attachment of inflammatory cells to endothelial cells. Furthermore, heparin is believed to interact with some cytokines that promote inflammation, such as tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • Heparin increases the effects of proteins that stimulate cell turnover and proliferation. This action can generate the repair of blood vessels, as well as the lining of the colon.
  • Yet other documented biological functions of GAGs and heparinoids are their abilities to inhibit microbial infections.
  • microbes for " example viruses in the Herpes family and bacteria in the Coli, Staphylococci, Streptococci families use GAGs on the surfaces of mammalian cells as acceptors. The microbes bind with high specificity to the GAGs and then start to infect the cells. By blocking the GAG-binding proteins on the surfaces of the microbes with GAG or heparinoid fragments, infections can be prevented.
  • the pathogenic bacterium Helicobacter pylori which causes active, chronic type B gastritis and peptic ulcer disease binds to the heparin-like GAG, heparan sulfate, on the epithelial cells.
  • HSBP heparin /heparan sulfate binding protein
  • IBD ulcerative colitis
  • the most common symptom of flammatory Bowel Disease is diarrhea.
  • ulcerative colitis the normal function of water re-absorption is impaired, resulting in many liquid stools. Since the lining of the colon also is ulcerated, the diarrhea often contains blood.
  • the colon is often narrowed and shortened, with decreased absorption of water, rectal urgency and poor control of bowel function.
  • Crohn's disease may prevent the proper absorption of food, resulting in diarrhea and the increased elimination of fat (steatorrhea) and other foodstuffs, leading to weight loss.
  • the intestine may become narrowed and obstructed in Crohn's disease.
  • Ulcerative colitis involves inflammation of the inner lining of the colon and the rectum that causes rectal bleeding and diarrhea. UC usually involves the last part of the ileum (terminal " ileiim), but can involve the large bowel iri about 30-50% of patients. When UC affects only the lowest part of the colon, the rectum, it is termed ulcerative proctitis. (UP).
  • CD Crohn's disease
  • Corticosteroids have been proven to be the most efficacious drugs in acute attacks of ulcerative colitis (UC), with an average obtained remission/improvement rate of nearly 70%. Around 20-30 % of the patients, however, respond poorly or not at all to corticosteroids in the acute phase.
  • Treatment with sulphasalazine or 5-amino salicylates has beneficial, although limited effect in the active phase of UC, and mainly has their advantage in long-term therapy for maintenance of remission, hnmunosuppressives, such as azathioprine and cyclosporine, have a role of induction and later, preservation of remission, particularly in the more severe cases, but may be associated with hazardous side effects. However, all these treatments may induce unwanted side- effects. Consequently, there is a need for the development of alternative, less toxic and more efficient treatments of IBD.
  • a more efficient administration of heparin may be achieved if the drug is applied directly to inflamed tissue, but as heparin is rapidly degrade in vivo, for the treatment of IBD, this requires a suitable drug delivery system.
  • an aqueous composition comprising chitosan in combination with a biologically active polysaccharide selected from heparin, heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate for the rectal treatment of inflammatory bowel diseases.
  • a biologically active polysaccharide selected from heparin, heparan sulfate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate for the rectal treatment of inflammatory bowel diseases.
  • Criitosan is a linear polysaccharide which is generally prepared by the alkaline deacetylation of chitin.
  • Chitin itself is a naturally occurring polysaccharide which can be obtained from a number of sources, but is generally obtained on an industrial scale from crustacean, e.g. crab or shrimp, shells.
  • Chitosan is composed of 1,4-beta-linked D-glucosamine and N-acetyl-D-glucosamine residues. Chitosans in their base form, and in particular those of high molecular weight and/or high degrees of N-deacetylation, are practically insoluble in water.
  • the average pKa of the glucosamine residues in chitosan is about 6.8 and chitosan forms salts with acids, e.g. HC1 and acetic acid.
  • the salts with monobasic acids tend to be water soluble.
  • Chitosan binds strongly to toxic and environmentally undesirable (heavy) metals, e.g. Hg, Cd and Pb, and transition metals, e.g. Cr, Ni, Mn and Cu.
  • chitosans include chitosan salts, for example with acids having pharmaceutically acceptable anions, especially organic acids, e.g. lower alkanoic acids such as acetic, formic, propionic, and butyric acids.
  • organic acids e.g. lower alkanoic acids such as acetic, formic, propionic, and butyric acids.
  • suitable organic acids include lactic, glycolic, citric, ascorbic and amino acids.
  • a suitable mineral acid is for example hydrochloric acid.
  • chitosan derivatives e.g. alkylated, N- carboxymethylated, N,O-carboxymethylated and cross-linked chitosans.
  • the cross- linked chitosans may be cross-linked by covalent or ionic bonds.
  • the chitosan may be any deacetylated chitin; however we prefer the chitosan to have a degree of deacetylation of greater than 50%, more preferably greater than 55% and especially greater than 60 %.
  • the degree of deacetylation is preferably less than 100 %, more preferably less than 95% and especially less than 90%. A degree of deacetylation between 85% and 95% is particularly preferred.
  • the chitosan prefferably has a viscosity of up to 15,000 mPas, preferably from 2 to 10,000, more preferably from 2 to 2,000, and most preferably from 2 to 1000 mPas when measured as a 1 % w/v solution in 1 % v/v aqueous acetic acid at a temperature of 25 degrees C.
  • the viscosity of the solution is an indication of the average molecular weight of the chitosan, it being understood that chitosan is a polymeric material having a distribution of molecules of varying chain length.
  • the aqueous composition may eTor example a s l ⁇ tio_ ⁇ ⁇ ' d ⁇ spef sion " or " suspension. "
  • the " aqueous composition preferably has a pH of from 4.0 to 6.8. A pH between 4.5 and 5.5 is particularly preferred.
  • the viscosity of the aqueous composition will depend on the viscosity of the component chitosan and biologically active polysaccharide; however, it is preferably less than 50mPas, more preferably less than 10 mPas.
  • the weight ratio between the chitosan and the biologically active polysaccharide is from 100:1 to 1:1, more preferably 20:1 to 1 :1.
  • the particular ratio will depend on the nature of the chitosan, its degree of deacetylation and the nature of the polysaccharide.
  • the chitosan combines with the biologically active polysaccharide to form a complex with a net positive charge; accordingly, in general, the ratio will be such that the overall complex of chitosan and polysaccharide is positively charged, particularly in weakly acid aqueous media, eg at a pH of from 4.0 to 6.8.
  • a particularly preferred biologically active polysaccharide is heparin.
  • Low molecular weight heparins eg dalteparin, may also be specifically mentioned.
  • a particular preferred ratio for chitosan, eg with a deacetylation degree of 86% complexed with heparin is between 100:1 and 1:1
  • the pH of the aqueous composition is suitably maintained by the use of a pharmaceutically acceptable mineral or organic acid, eg HC1.
  • heparin has been found to be beneficial in some patients with inflammatory bowel disease (IBD) suffering also from thrombo-embolic disorders such as deep venous thrombosis in a leg or pulmonary embolus.
  • IBD inflammatory bowel disease
  • corticosteroids i.v. in severe active IBD
  • heparin The main mechanism of action of heparin in UC is unknown, although it has been considered to be the anticoagulant effects. Moreover it has been demonstrated in reports that heparin inhibits leukocyte recruitment and it can not be excluded that such a mechanism is also involved in the protective action of heparin. Due to the possible microbial pathogenesis of IBD, the ability of heparin to bind to a multitude of microbes and also its anti-inflammatory effect should be beneficial.
  • heparin-enema isused as an adjunct or alternative in UC-patients with a distal disease or UP.
  • heparin-chitosan complex By administering a heparin-chitosan complex directly to the site of the disease, many problems with systemic administration of heparin by intravenous injections can be circumvented. For instance, native heparin is rapidly degraded in vivo, a process that is delayed by complexing it with chitosan. Further, the heparin-chitosan complex adheres, due to its positive net charge, to living tissue and is consequently immobilised in the bowel area.
  • heparin-chitosan complex can easily be administrated by the patient at home.
  • topical treatment of inflammatory bowel disease may be effected using an aqueous composition as described above in the form of an enema, suppositories or rectal bottles.
  • compositions may be prepared by mixing an aqueous preparation of the chitosan with an aqueous preparation of the biologically active polysaccharide. Where necessary or desired, the resulting composition may be filled into a suitable container, such as a rectal bottle, eg a clysma.
  • the chitosan and the biologically active polysaccharide may be presented as separate components of a kit, comprising solutions of each component, to be mixed immediately prior to rectal administration.
  • a method of rectal treatment of inflammatory bowel disease which comprises administering a therapeutically effective amount of an aqueous composition comprising chitosan in combination with a biologically active polysaccharide selected from heparin, heparan suphate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate to a patient suffering from such a disease.
  • a biologically active polysaccharide selected from heparin, heparan suphate, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate and dextran sulfate.
  • Heparin was purchased from Pharmacia Hepar Inc., Franklin, Ohio, USA and had the anti Xa activity 185 IU/mg.
  • Chitosan (Chitech®) was supplied by Medicarb AB, Sweden.
  • aqueous solutions containing 0.054, 0.27 and 0.54 mg heparin/mL corresponding to 500, 2500 and 5000 IU (Anti-factor Xa) respectively was prepared.
  • Three solutions of chitosan powder were prepared by adding 0.12, 0.61 and 1.23 mg/mL to water (Aqua steril ad). The pH value was kept at 4.7 by addition of 4M HC1...
  • the heparin solutions containing 500, 2500 and 5000 IU were added to the chitosan solutions containing 0.123, 0.614 and 1.227 mg/mL respectively, during mixing.
  • the suspensions was dispensed in 50 mL portions into plastic HOPE rectal bottles, 135 mL PLM Langeskov, Denmark and labeled as in Table 1.
  • Clinical study The objective is to screen different compositions of heparin and chitosan to find suitable formulations for an initial study on patient with LBD/proctitis. Important parameters for the formulations and principle of selection is the amount of heparin, viscosity, dose, and administration.
  • Study drugs are available in a single-dose 50 ml soft-plastic tube for rectal application (clysma). Three different heparin concentrations containing 500, 2500, 5000 IU (Anti-factor Xa) were chosen (Table 1). The patients will receive heparin-enema daily b.i.d. for a period up to four weeks.
  • IBD-Q quality of life questionnaire
  • the different dosage packages were labelled similarly on an individual patient basis.
  • Patients on maintenance treatment (5-ASA, SASP, olsalazine) continue with unchanged doses.
  • Patients, who are treated with oral steroids but who respond poorly, or not at all, or experience deterioration during tapering, may gradually taper their prednisolone treatment by 5 mg/week down to zero, and the doses may be recorded in the CRF.
  • the primary clinical efficacy variable is the induction of remission, as measured as crude overall remission rate and time to remission.
  • Safety is measured through reporting of adverse events and follow-up of vital signs.
  • Remission is defined as an endoscopic score of ⁇ 1 according to the scoring system used by L ⁇ fberg et al, in combination with lack of macroscopic blood in stools and ⁇ 2 stools above patient's normal average.
  • a patient who shows an improvement (decrease of the endoscopic score and/or clinical activity score) compared with baseline, is considered as a responder.
  • a clinical symptom index composed of different variables including stool frequency, consistency, rectal bleeding, rectal or abdominal pain and urgency is used for assessment of clinical activity.
  • the assessment period is the three days immediately preceding the day of visit to the clinic.
  • Body-weight, pulse rate and blood pressure (5 min rest, sitting) is determined at each visit as well as an assessment of the patient's general well being.
  • the skin is inspected for detection of bleeding complications such as haematomas.
  • a flexible videoendoscopy (colonoscopy or sigmoidoscopy) or rigid sigmoidoscopy is carried out at entry of the study, and rigid sigmoidoscopy is performed after 2 weeks of treatment.
  • a flexible endoscopy or rigid sigmoidoscopy will be carried out at 4-week termination of study. The endoscope pattern will follow the regular practice at the clinic.
  • Score 1 Granularity, oedema, lack of vascular pattern
  • Two biopsies will be put in formalin, and after preparation including staining with routine H&E, assessed in a blinded fashion by the same pathologist. Mucosal inflammation is determined using a grading scale adopted from Selendrijk .
  • One to two biopsies from each site will be frozen immediately in -70° centigrade for analysis of myeloperoxidase activity and immunohistological leukocyte adhesion molecules expression.
  • a simple quality of life questionnaire developed for IBD-patients will be used for assessment at entry and at time of remission or at treatment end.
  • TPK Platelet count
  • ESR Erythrocyte sedimentation rate
  • CRP C-reactive protein
  • Urine sample for analysis of Haemoglobin, Leucocytes and Protein (U-Dipstick - if positive for blood: urinary sediment) and for analysis of U-leukotrien E4 will be taken at each visit.
  • the efficacy variables are monitored on individual basis for each patient. The determination of the same variables from the three-day pre-entry period will serve as a baseline.
  • An adverse event is defined as any untoward medical occurrence in a patient. The event does not necessarily have to have a causal relationship with the treatment.
  • the adverse event reporting period in this study begins upon starting the heparin chitosan treatment and ends 7 days after stopping the treatment. (After the last study visit, only spontaneous reports from the patients are collected.)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP02735862A 2002-04-24 2002-04-24 Zusammensetzung und set zur behandlung von entzündlichen darmerkrankungen Withdrawn EP1539192A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2002/002275 WO2003090763A1 (en) 2002-04-24 2002-04-24 Composition and kit for the treatment of inflammatory bowel diseases

Publications (1)

Publication Number Publication Date
EP1539192A1 true EP1539192A1 (de) 2005-06-15

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EP02735862A Withdrawn EP1539192A1 (de) 2002-04-24 2002-04-24 Zusammensetzung und set zur behandlung von entzündlichen darmerkrankungen

Country Status (4)

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EP (1) EP1539192A1 (de)
CN (1) CN1627948A (de)
AU (1) AU2002309180A1 (de)
WO (1) WO2003090763A1 (de)

Cited By (1)

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US7556905B2 (en) 2005-12-27 2009-07-07 Konica Minolta Business Technologies, Inc. Electrostatic charge image developing toner

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US9241953B2 (en) 2008-05-13 2016-01-26 Apharm S.R.L. Glycosaminoglycan oral use and compositions
WO2009138843A1 (en) * 2008-05-13 2009-11-19 Hertek S.A. Glycosaminoglycan oral use and compositions
BRPI1009741A2 (pt) * 2009-06-10 2016-03-15 Exthera Ab composição, método para prevenir ou tratar a mucosite em paciente mamífero, composição farmacêutica para adminstração tópica, e uso de uma composição
ITMI20131467A1 (it) 2013-09-06 2015-03-07 Sofar Spa Uso di una composizione comprendente microrganismi per aumentare la produzione intestinale di acido butirrico, di acido folico o di niacina e/o per diminuire la produzione intestinale di acido succinico
MA39710A (fr) * 2014-04-23 2015-10-29 Sofar Spa Composition topique destinée à être utilisée dans le traitement d'une maladie inflammatoire de l'intestin
IT201600083376A1 (it) 2016-08-08 2018-02-08 Sofar Spa Uso di probiotici per aumentare l’assorbimento proteico
ITUA20164188A1 (it) 2016-06-08 2017-12-08 Sofar Spa Nuovo uso medico di probiotici
IT201600122724A1 (it) 2016-12-02 2018-06-02 Sofar Spa Exopolysaccharides and uses thereof
IT201600127498A1 (it) 2016-12-16 2018-06-16 Sofar Spa Probiotici per uso nella diverticolosi e malattia diverticolare
CN110312937B (zh) * 2017-01-19 2023-01-10 和田孝一郎 诊断肠黏膜通透性的诊断药、诊断方法及诊断装置
US11751597B2 (en) 2019-11-05 2023-09-12 Alfasigma S.P.A. Compositions comprising bacterial strains for use in increasing the bioavailability of amino acids derived from proteins, and related food product methods and systems

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US7556905B2 (en) 2005-12-27 2009-07-07 Konica Minolta Business Technologies, Inc. Electrostatic charge image developing toner

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AU2002309180A1 (en) 2003-11-10
WO2003090763A1 (en) 2003-11-06
CN1627948A (zh) 2005-06-15

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