EP1047434A2 - Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete - Google Patents

Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete

Info

Publication number
EP1047434A2
EP1047434A2 EP98956862A EP98956862A EP1047434A2 EP 1047434 A2 EP1047434 A2 EP 1047434A2 EP 98956862 A EP98956862 A EP 98956862A EP 98956862 A EP98956862 A EP 98956862A EP 1047434 A2 EP1047434 A2 EP 1047434A2
Authority
EP
European Patent Office
Prior art keywords
glycosaminoglycans
pharmaceutical preparations
sulfate
diabetes
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Withdrawn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
EP98956862A
Other languages
German (de)
English (en)
Inventor
Fokko Van Der Woude
Dieter Herr
Volker Laux
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.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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 Knoll GmbH filed Critical Knoll GmbH
Publication of EP1047434A2 publication Critical patent/EP1047434A2/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/70—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • glycosaminoglycans for the manufacture of pharmaceutical preparations for the treatment of eye diseases associated with diabetes
  • the invention relates to the use of glycosaminoglycans for the production of pharmaceutical preparations for the prevention or treatment of eye diseases associated with diabetes mellitus.
  • the invention further relates to pharmaceutical preparations suitable for the treatment of diabetes-associated eye diseases.
  • glycosaminoglycans and especially heparins and heparinoids for the manufacture of pharmaceutical preparations for the treatment of circulatory disorders is well known.
  • glycosaminoglycans in a number of other diseases has recently been described.
  • No. 5,236,910 claims the use of glycosaminoglycans in the treatment of diabetic nephropathy and neuropathy.
  • the use of low molecular weight heparins for the same indication is described by van der Pijl et al. (J. Americ. Soc. Nephrol. 1997, 8: 456-462).
  • Retinopathy is the most common and serious eye complication in diabetes mellitus. It is the main cause of blindness in industrialized countries. The risk of going blind is very difficult to assess in an individual diabetic. It depends on many factors such as age, type and duration of the diabetes. The current retina findings also play an important role in assessing the risk.
  • retinopathy The prevalence for retinopathy was 50.1% within the study patients, but only 2.2% had features at risk of loss of vision. In the "younger" group, the prevalence of moderate visual impairment was 1.4%. 3.2% were blind.
  • the disadvantage of this method is that the detoxified enzyme must first be obtained from the snake venom in a complex process and then detoxified. Only in combination with high-molecular heparin could animal retinopathy be treated with guinea pigs. Neither the heparin used nor the snake enzyme alone showed an effect in the treatment of retinopathy.
  • the object was therefore to provide agents for the treatment of retinopathy and / or macular degeneration which do not have the disadvantages mentioned above and can be used safely, easily and simply for the treatment of retinopathy and macular degeneration.
  • glycosaminoglycans for the production of pharmaceutical preparations for the prevention or treatment of eye diseases associated with diabetes.
  • the invention also relates to pharmaceutical preparations containing one or more substances selected from the group consisting of glycosaminoglycan, glycosaminoglycan derivatives, heparinoids, physiologically active salts of these substances or mixtures thereof, which are suitable for the treatment of " diabetes-associated eye diseases " .
  • the pharmaceutical preparations produced for the use according to the invention can contain the abovementioned compounds as free compounds, or in the form of their physiologically active salts, their tautomeric and / or isomeric forms or in the form of the combination of the free compounds and the various salts.
  • the Na, Ca or Mg salts may be mentioned as examples of advantageous physiologically active salts. Salts with organic bases such as diethylamine, triethylamine or triethanolamine are also suitable.
  • the pharmaceutical preparations can advantageously contain at least one free substance or at least one compound in the form of its salt or mixtures thereof.
  • uronic acid such as D-glucuronic acid or L -Iduronic acid
  • At least one of the sugars in the disaccharide has a negatively charged carboxylate or sulfate group, which can be bonded via an oxygen or nitrogen atom.
  • glycosaminoglycans react strongly acidic. These acid-reacting groups can be naturally present and / or synthetically introduced into the compounds by, for example, sulfation.
  • An example of a sulfation method is US 5,013,724.
  • Examples of natural glycosaminoglycans are heparin, heparan sulfate, keratin sulfate, dermatan sulfate, chondroitin or chondroitin sulfate. Heparan sulfate corresponds to heparin, only that it has fewer N and 0 sulfate groups and more N acetyl groups.
  • glycosaminoglycans or heparinoids are advantageously selected from the group dermatan sulfate, heparan sulfate, dextran sulfate (US 5,541,166), xylan sulfate (such as pentosan polysulfate, EP-A-0 184 480, FR 835170), Heparin or derivatives of these substances are used. These substances are applied in an effective amount for the treatment of eye diseases.
  • Glycosaminoglycans can advantageously be isolated from tissues of animals such as the intestinal mucosa or from the ears of pigs or cattle.
  • the tissues used are, for example, autolyzed to isolate the glycosaminoglycans and extracted with alkali.
  • the protein is then left to coagulate and is precisioned, for example by acidification.
  • the precipitate has been taken up in a polar, non-aqueous solvent, such as ethanol or acetone, the fats are removed by extraction with an organic solvent.
  • the proteins are finally removed by proteolytic digestion and the glycosaminoglycans are thus obtained. Charles et al. (Biochem. J., Vol.
  • Coyne, E in Chemistry and Biology of Heparin (Elsevier Publishers, North Holland, NY, Lunblad, RL, eds., 1981) are methods of isolating, for example To take heparin.
  • glycosaminoglycans isolated from natural sources can advantageously also undergo derivatization, for example by polysulfation, as is described, for example, in US Pat. No. 5,013,724.
  • the glycosaminoglycans have a sulfur content of 6 to 15% by weight, preferably between 13 to 15% by weight.
  • Derivatives of the substances are to be understood as compounds which improve the application properties of the glycosaminoglycans used in terms of their action, their stability and their elimination from the body.
  • Low molecular weight heparins and / or dermatan sulfates, which can be polysulfated, in the form of the free acid or in the form of a salt with physiologically compatible bases or mixtures of these compounds are particularly advantageous.
  • Low molecular weight glycosaminoglycans for example low molecular weight heparins and / or dermatan sulfates, can be produced by a number of methods. The production of low molecular weight heparins via depolymerization using nitrous acid is described, for example, in EP-B-0 037 319 or in Biochemistry Vol. 15, 1976: 3932. Low molecular weight heparin or low molecular weight glycosaminoglycans can also be produced with enzymes (Biochem. J. Vol. 108, 1968: 647), with sulfuric acid and chlorosulfonic acid (FR No.
  • the invention further relates to combination preparations from pharmaceutical preparations which contain glycosaminoglycans such as low molecular weight heparins and / or dermatan sulfates and at least one antihypertensive active ingredient or at least one antihypertensive active ingredient or a combination thereof.
  • glycosaminoglycans such as low molecular weight heparins and / or dermatan sulfates and at least one antihypertensive active ingredient or at least one antihypertensive active ingredient or a combination thereof.
  • blood pressure lowering agents are, for example
  • inhibitors of the endothelin converting enzyme ECE
  • endothelin antagonists or inhibitors of the renin-angiotensin system or a combination thereof.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • Blood sugar-lowering active substances are understood to mean, for example, insulin, blood sugar-lowering agents for oral use, such as sulfonylureas or glucosidase inhibitors.
  • the combinations of the active substances mentioned can be administered in a common galenical form or in a time and space separate manner.
  • compositions produced and used according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a customary manner; oral or intravenous applications are preferred.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the glycosaminoglycans are advantageously applied in a dose of 0.1 to 500 mg / kg body weight / day.
  • the glycosaminoglycans are advantageously administered in a dose of 0.1 to 30 mg / kg of body weight / day, in the case of oral use in a dose of 0.2 to 500 mg / kg of body weight / day, the administered Dose administered in a single dose or in multiple doses can be.
  • Mixtures of, for example, at least one low molecular weight heparin and / or its polysulfated derivative and / or at least one low molecular weight dermatan sulfate and / or its polysulfated derivative are also used in a dose of 0.1 to 30 mg / kg body weight / day in the case of parenteral administration or in one Dose of 0.2 to 500 mg / kg / day administered orally.
  • compositions which contain glycosaminoglycans for the treatment of eye diseases caused by diabetes mellitus or combinations of these polysaccharides with other of the above-mentioned active ingredients are, in principle, all galenic administration forms customary for oral or parenteral use, whether solid or liquid, such as tablets, film-coated tablets, Capsules, powders, granules, coated tablets, suppositories, solutions or suspensions. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
  • the combinations according to the invention are generally administered orally, e.g. administered in the form of tablets, coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the active ingredients can be administered in the form of preparations which contain both active ingredients together, such as tablets or capsules, or separately as an ad-hoc combination of individual substances which can be administered simultaneously or at different times.
  • a combination according to the invention with pharmaceutically inert, inorganic or organic excipients can be processed to produce tablets, coated tablets, coated tablets and hard gelatin capsules.
  • Lactose and corn starch can be used as such excipients for tablets, coated tablets and hard gelatin capsules or derivatives thereof, talc, stearic acid or their salts.
  • Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
  • Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like.
  • Suitable excipients for injection solutions are water, alcohols, polyols, glycerin, vegetable oils. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients for suppositories.
  • the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
  • Consequential diseases e.g. retinopathy, nephropathy
  • streptozotozin rats at a dose of 60 mg / kg IV. administered once.
  • This treatment led to the destruction of the ß cells of the pancreatic islets of Langerhans.
  • the blood sugar level in these rats increased significantly compared to animals not treated with streptozotozin, and the animals lost weight due to the inability to use the glucose due to the lack of insulin, which is necessary for the uptake of the blood glucose into the cells .
  • Reviparin 5 low molecular weight heparin, average molecular weight 4000 Dalton
  • a dose of 1 mg / kg intravenously or 5 mg / kg orally significantly prevented the development of diabetic retinopathy in the rat compared to placebo can be ascertained semiquantitatively with the help of a score as early as possible by increasing the vascular permeability.
  • FIG. 1 shows the effect of Reviparin ' - (1 mg / kg subcutaneously) on vascular permeability in STZ diabetes rats.
  • FIG. 2 shows the effect of Reviparin (5 mg / kg orally) on vascular permeability in STZ diabetes rats.
  • Type I or Type II diabetes mellitus 0 Type I or Type II diabetes mellitus, mild or moderate non-proliferative retinopathy, ages 18-80 years
  • ___ Thrombocytopenia known allergy to heparin and sulphates, gastrointestinal bleeding (patients with a history of gastrointestinal bleeding should be treated with H2 blockers or with omeprazole), pregnancy or desire to have a pregnancy, patients of childbearing age must carry out a safe conception (hormone replacement)
  • the demographic data of the patients are as follows:
  • the blood pressure was examined by means of 24-hour blood pressure measurement before and at the end of the therapy phase and at the end of the follow-up phase.
  • the papilla was defined as the nasal margin mark in order to be able to compare the same image sections with one another in all control examinations. Images were taken with the best possible area coverage taking into account an optimal image quality.
  • the fluorescence angiography was based on qualitative criteria
  • Table II Flowchart (points in time for evaluating the ' safety variables ' )
  • ASAT aspar bronzeininotransferase Table III: Laboratory values before the start of therapy (TO) and after 12 weeks of therapy (Tl) with Reviparin. Average values (M) and standard deviation (SE) are given.
  • Table IV Outpatient 24-hour blood pressure measurement before the start of therapy (TO) and after 12 weeks of therapy (Tl) with Reviparin.
  • TO start of therapy
  • Tl 12 weeks of therapy
  • the mean values of the registration period for the systolic and diastolic blood pressure and for the pulse of the individual patients are given; below are the mean of all measurements and the standard deviation.

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

Abstract

L'invention concerne l'utilisation de glycosaminoglycanes pour la fabrication de préparations pharmaceutiques destinées à la prévention ou au traitement de maladies des yeux associées au diabète. L'invention concerne d'autre part des préparations pharmaceutiques appropriées pour le traitement de maladies des yeux associées au diabète.
EP98956862A 1997-10-24 1998-10-22 Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete Withdrawn EP1047434A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19747195 1997-10-24
DE19747195A DE19747195A1 (de) 1997-10-24 1997-10-24 Verwendung von Glykosaminoglykanen zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von mit Diabetes assoziierten Augenkrankheiten
PCT/EP1998/006703 WO1999021538A2 (fr) 1997-10-24 1998-10-22 Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete

Publications (1)

Publication Number Publication Date
EP1047434A2 true EP1047434A2 (fr) 2000-11-02

Family

ID=7846613

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98956862A Withdrawn EP1047434A2 (fr) 1997-10-24 1998-10-22 Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete

Country Status (13)

Country Link
EP (1) EP1047434A2 (fr)
JP (1) JP2001520987A (fr)
KR (1) KR20010024550A (fr)
CN (1) CN1277554A (fr)
AU (1) AU749673B2 (fr)
BR (1) BR9813098A (fr)
CA (1) CA2306379A1 (fr)
DE (1) DE19747195A1 (fr)
HU (1) HUP0004647A3 (fr)
IL (1) IL135171A0 (fr)
NO (1) NO20001895D0 (fr)
WO (1) WO1999021538A2 (fr)
ZA (1) ZA989665B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI991503A1 (it) * 1999-07-08 2001-01-08 Bidifarm S R L Uso di metaboliti oligosaccaridici di proteoglicani come maker in fluidi biologici di diagnosi del biabete e delle complicanze patologiche c
CN101584704B (zh) * 2008-05-23 2010-12-15 鲁南制药集团股份有限公司 肝素、低分子肝素可药用盐或其衍生物的医药用途
JPWO2011122321A1 (ja) * 2010-03-29 2013-07-08 国立大学法人名古屋大学 ヘパリン結合性蛋白に対する生理活性阻害剤
CN107137421A (zh) * 2017-05-25 2017-09-08 青岛市中心医院 硫酸葡聚糖在制备抑制角膜血管新生药物中的应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2597484B1 (fr) * 1986-04-17 1988-12-23 Sanofi Sa Glycosaminoglycanes de type heparine ou heparane-sulfate dotes d'une activite sur la division et la differentiation cellulaires, leur preparation et leurs applications therapeutiques.
JPH03500168A (ja) * 1988-06-27 1991-01-17 ライナー　ローラント 医薬の製造の為のグリコースアミノグリカンの使用
US5135920A (en) * 1988-11-16 1992-08-04 Takeda Chemical Industries, Ltd. Angiostatic agents
PT93847A (pt) * 1989-04-24 1990-11-20 Harvard College Processo para a preparacao de oligossacaridos de baixo peso molecular derivados de heparina ou de sulfato de heparano despolimerizados e de composicoes farmaceuticas que os contem
AU7520394A (en) * 1993-08-13 1995-03-14 Glycomed Incorporated Bridged oligosaccharides and sulfated derivatives thereof
AU700451B2 (en) * 1993-10-07 1999-01-07 Glycomed Incorporated Highly sulfated maltooligosaccharides with heparin-like properties
US5643892A (en) * 1995-06-07 1997-07-01 Baker Norton Pharmaceuticals, Inc. Method of treating chronic progressive vascular diseases
WO1999004801A1 (fr) * 1997-07-28 1999-02-04 Rijks Universiteit Leiden Utilisation de glycosaminoglycanes sulfates dans le traitement de la retinopathie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9921538A2 *

Also Published As

Publication number Publication date
AU1335599A (en) 1999-05-17
HUP0004647A3 (en) 2002-01-28
WO1999021538A3 (fr) 1999-08-05
HUP0004647A2 (hu) 2001-05-28
ZA989665B (en) 2000-04-25
KR20010024550A (ko) 2001-03-26
DE19747195A1 (de) 1999-04-29
WO1999021538A2 (fr) 1999-05-06
CA2306379A1 (fr) 1999-05-06
AU749673B2 (en) 2002-07-04
BR9813098A (pt) 2000-08-15
NO20001895L (no) 2000-04-12
JP2001520987A (ja) 2001-11-06
IL135171A0 (en) 2001-05-20
CN1277554A (zh) 2000-12-20
NO20001895D0 (no) 2000-04-12

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