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US20090123566A1 - Use of a phosphate adsorbent to combat vascular diseases - Google Patents

Use of a phosphate adsorbent to combat vascular diseases Download PDF

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Publication number
US20090123566A1
US20090123566A1 US12/351,882 US35188209A US2009123566A1 US 20090123566 A1 US20090123566 A1 US 20090123566A1 US 35188209 A US35188209 A US 35188209A US 2009123566 A1 US2009123566 A1 US 2009123566A1
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patient
adsorption material
phosphate
calcium
metal oxide
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US12/351,882
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Dietrich Seidel
Karl-Siegfried Boos
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for influencing the calcium level and, in particular, for treating or/and preventing atherosclerotic vascular diseases or/and disturbances of bone metabolism.
  • Substances which are known to possess phosphate-binding properties are calcium salts (e.g.: calcium acetate, calcium carbonate, calcium citrate, calcium alginate, calcium gluconate, calcium lactate and calcium sulfate), magnesium carbonate and magnesium hydroxide and also aluminum hydroxide and aluminum carbonate.
  • DE 28 15 811 C2 (1978) has disclosed a macroporous sorption agent which is characterized in that it is an organic cation exchanger which is loaded with ions of at least one metal whose phosphate is only sparingly soluble.
  • German patent application 42 39 442.2 describes the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for selectively eliminating inorganic phosphate from protein-containing liquids, in particular body fluids.
  • the agent is therefore outstandingly suitable for treating hyperphosphatemia.
  • this document does not report any effect on calcium concentration.
  • the adsorption material which has been modified with polynuclear metal oxide hydroxides decreases the calcium phosphate product significantly, e.g. by almost a third after a 28-day period of treatment.
  • the invention consequently relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for treating or/and preventing atherosclerotic vascular diseases or/and disturbances of bone metabolism.
  • the invention also relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for reducing the calcium phosphate product in the blood or serum.
  • the agent according to the invention is used in patients who are suffering from restricted renal function, in particular predialysis patients. Administration of the agent can in some cases result in a substantial, prolongation of the predialytic stage. In another preferred embodiment, the agent is administered to dialysis patients.
  • Administering the agent reduces the phosphate concentration while at the same time maintaining or, in many cases, even reducing the calcium concentration. This thereby prevents calcification of the blood vessels, in particular the coronary vessels, of patients and consequently increases their survival rate.
  • the adsorption materials which have been modified with polynuclear metal oxide, hydroxides are preferably employed in the form of pharmaceutical preparations which comprise the active compound in a form which is essentially not capable of being resorbed under physiological conditions.
  • the preparation of such insoluble adsorption materials is described in detail in German patent application 42 39 442.2, the disclosure of which is hereby incorporated by reference.
  • the preparation is particularly preferably effected by the unmodified adsorption material being brought into contact with a solution of an iron salt, e.g. iron(III) chloride, and then adjusting the pH to a value of >10, in particular >12, using a base, e.g. sodium hydroxide solution.
  • the resulting precipitate is then washed, where appropriate after having been aged, and can, if necessary, be sterilized once again before use.
  • the adsorption materials are preferably selected from soluble or insoluble materials possessing organic or/and inorganic hydroxyl functionalities.
  • organic supports such as natural, semisynthetic or synthetic, linear or branched, soluble or insoluble carbohydrates, organic polymers or copolymers, e.g. agarose, dextran, dextrin, starch, amylose, amylopectin, cellulose or/and polyvinyl alcohol, as the basal material.
  • inorganic supports in particular those based on silicon dioxide or/and silicate, such as glyceryl-modified glasses and glyceryl-modified silica gels.
  • Carbohydrates, such as dextrans are particularly preferred starting materials.
  • metals are suitable for being used as polynuclear metal oxide hydroxides, for example all transition metals, such as zirconium or else aluminum.
  • iron is used as a particularly preferred metal since, with the metal possibly becoming detached to a lesser extent, iron is the metal which is to be regarded as that which is the least harmful for the body.
  • trivalent iron is the metal which is most preferred even though other metals can also be used on account of their binding properties vis-à-vis the inorganic phosphate.
  • the adsorption materials which are used in accordance with the invention are distinguished by the fact that they do not to any significant extent release the polynuclear metal oxide hydroxide or metal ion, in particular the preferably employed iron(III) compound, which is bound covalently or coordinately to the support, even on contact with protein-containing liquids, such as whole blood and/or plasma, and consequently do not elicit any undesirable side effects, such as a disturbance of enteral iron resorption or of the cellular, and in particular the erythrocytic, iron metabolism in connection with the therapeutic extracorporeal or/and peroral use according to the invention.
  • the preparations can be administered in any suitable manner.
  • the preparations are administered orally for enteral adsorption or elimination of inorganic phosphate or/and calcium.
  • the oral preparations can be administered in the form of powders, tablets, capsules, etc., where appropriate coated with a gastric acid-resistant layer.
  • the materials according to the invention can also be employed in an extracorporeal perfusion system for treating whole blood, plasma or/and dialysis liquid.
  • an adsorption material which has already been pretreated with phosphate and which can be prepared by bringing the agent disclosed in German patent application 42 39 442.2 into contact with a phosphate-containing liquid, in particular an aqueous solution of phosphate.
  • This phosphate-pretreated adsorber is particularly suitable for selectively decreasing the calcium content and is therefore preferentially employed, where appropriate together with a phosphate adsorber which has not been pretreated, for oral applications.
  • the daily treatment dose can essentially be selected at will.
  • the treatment is preferably a long-term treatment and has to be carried out for a period of at least 6 months if it is to display its optimal effect.
  • the polynuclear iron(III) oxide hydroxide-carbohydrate complex which is used in this example is the preparation which is prepared as described in Example 1 in German patent application 42 39 442.
  • the contents (mean values) of phosphate (2.1 mmol/l) and calcium (2.5 mmol/l) were first of all determined in the serum derived from 13 dialysis patients who were being treated with customary phosphate binders (calcium carbonate, calcium acetate, phosphonorm, Renagel®), and the calcium-phosphate product (5.25) was calculated from these mean values.
  • the phosphate binders were discontinued for 7 days and the contents of phosphate (2.9 mmol/l) and calcium (2.2 mmol/l) were once again determined in serum and the calcium-phosphate product (6.38) calculated from these contents.
  • Treatment with the phosphate binder according to the invention (polynuclear Fe(III) oxide hydroxide-carbohydrate complex) then took place, initially at a daily dose of 4.6 g dry weight over a period of 14 days and then at a dose of 8.6 g for a further 14 days.
  • phosphate binder according to the invention surprisingly reduced the calcium-phosphate product by almost a third as compared with the phosphate binders which were previously employed.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for influencing the calcium level and, in particular, for treating or/and preventing atherosclerotic vascular diseases or/and disturbances of bone metabolism.

Description

  • The invention relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for influencing the calcium level and, in particular, for treating or/and preventing atherosclerotic vascular diseases or/and disturbances of bone metabolism.
  • Clinical studies (e.g. G. A. Block et al., Am. J. Kidney Dis. 31 (1998), 607-617) performed on dialysis patients demonstrate that the relative risk of these patients dying increases as the calcium phosphate product in the serum increases, since elevated values of the calcium phosphate product promote calcification of the blood vessels, in particular the coronary vessels.
  • Lowering the calcium phosphate product could therefore increase the survival rate of dialysis patients, in particular.
  • Preference has previously been given to using perorally administrable phosphate binders, which are intended to prevent the phosphates present in the food in the gastrointestinal tract from being resorbed, as therapeutic agents for decreasing the phosphate concentration. Substances which are known to possess phosphate-binding properties are calcium salts (e.g.: calcium acetate, calcium carbonate, calcium citrate, calcium alginate, calcium gluconate, calcium lactate and calcium sulfate), magnesium carbonate and magnesium hydroxide and also aluminum hydroxide and aluminum carbonate.
  • Aside from these saliniform phosphate binders, DE 28 15 811 C2 (1978) has disclosed a macroporous sorption agent which is characterized in that it is an organic cation exchanger which is loaded with ions of at least one metal whose phosphate is only sparingly soluble.
  • Furthermore, Burt, H. M. et al. (J. Pharm. Sci. 75 (1978), 379-983) describes Dowex®-based anion exchangers which carry tertiary or quaternary amines as the functional group and adsorb inorganic phosphate in the intestinal tract.
  • However, these agents display substantial side effects in that the content of calcium in the patient serum is increased, which means that, despite a certain decrease in the phosphate concentration, only a relatively modest reduction in the calcium phosphate product is achieved.
  • German patent application 42 39 442.2 describes the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for selectively eliminating inorganic phosphate from protein-containing liquids, in particular body fluids. The agent is therefore outstandingly suitable for treating hyperphosphatemia. However, this document does not report any effect on calcium concentration.
  • It has been found, surprisingly, that, in contrast to previously employed phosphate binders, the adsorption material which has been modified with polynuclear metal oxide hydroxides decreases the calcium phosphate product significantly, e.g. by almost a third after a 28-day period of treatment.
  • The invention consequently relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for treating or/and preventing atherosclerotic vascular diseases or/and disturbances of bone metabolism.
  • The invention also relates to the use of an adsorption material which has been modified with polynuclear metal oxide hydroxides for reducing the calcium phosphate product in the blood or serum.
  • In a preferred embodiment, the agent according to the invention is used in patients who are suffering from restricted renal function, in particular predialysis patients. Administration of the agent can in some cases result in a substantial, prolongation of the predialytic stage. In another preferred embodiment, the agent is administered to dialysis patients.
  • Administering the agent reduces the phosphate concentration while at the same time maintaining or, in many cases, even reducing the calcium concentration. This thereby prevents calcification of the blood vessels, in particular the coronary vessels, of patients and consequently increases their survival rate.
  • The adsorption materials which have been modified with polynuclear metal oxide, hydroxides are preferably employed in the form of pharmaceutical preparations which comprise the active compound in a form which is essentially not capable of being resorbed under physiological conditions. The preparation of such insoluble adsorption materials is described in detail in German patent application 42 39 442.2, the disclosure of which is hereby incorporated by reference. The preparation is particularly preferably effected by the unmodified adsorption material being brought into contact with a solution of an iron salt, e.g. iron(III) chloride, and then adjusting the pH to a value of >10, in particular >12, using a base, e.g. sodium hydroxide solution. The resulting precipitate is then washed, where appropriate after having been aged, and can, if necessary, be sterilized once again before use.
  • The adsorption materials are preferably selected from soluble or insoluble materials possessing organic or/and inorganic hydroxyl functionalities. Thus, it is possible, for example, to use organic supports, such as natural, semisynthetic or synthetic, linear or branched, soluble or insoluble carbohydrates, organic polymers or copolymers, e.g. agarose, dextran, dextrin, starch, amylose, amylopectin, cellulose or/and polyvinyl alcohol, as the basal material. On the other hand, it is also possible to use inorganic supports, in particular those based on silicon dioxide or/and silicate, such as glyceryl-modified glasses and glyceryl-modified silica gels. Carbohydrates, such as dextrans, are particularly preferred starting materials.
  • A large number of metals are suitable for being used as polynuclear metal oxide hydroxides, for example all transition metals, such as zirconium or else aluminum. However, iron is used as a particularly preferred metal since, with the metal possibly becoming detached to a lesser extent, iron is the metal which is to be regarded as that which is the least harmful for the body. For physiological reasons, therefore, trivalent iron is the metal which is most preferred even though other metals can also be used on account of their binding properties vis-à-vis the inorganic phosphate.
  • The adsorption materials which are used in accordance with the invention are distinguished by the fact that they do not to any significant extent release the polynuclear metal oxide hydroxide or metal ion, in particular the preferably employed iron(III) compound, which is bound covalently or coordinately to the support, even on contact with protein-containing liquids, such as whole blood and/or plasma, and consequently do not elicit any undesirable side effects, such as a disturbance of enteral iron resorption or of the cellular, and in particular the erythrocytic, iron metabolism in connection with the therapeutic extracorporeal or/and peroral use according to the invention.
  • The preparations can be administered in any suitable manner. In a preferred embodiment, the preparations are administered orally for enteral adsorption or elimination of inorganic phosphate or/and calcium. The oral preparations can be administered in the form of powders, tablets, capsules, etc., where appropriate coated with a gastric acid-resistant layer. On the other hand, the materials according to the invention can also be employed in an extracorporeal perfusion system for treating whole blood, plasma or/and dialysis liquid.
  • In a particularly preferred embodiment, it is possible to use an adsorption material which has already been pretreated with phosphate and which can be prepared by bringing the agent disclosed in German patent application 42 39 442.2 into contact with a phosphate-containing liquid, in particular an aqueous solution of phosphate. This phosphate-pretreated adsorber is particularly suitable for selectively decreasing the calcium content and is therefore preferentially employed, where appropriate together with a phosphate adsorber which has not been pretreated, for oral applications.
  • Since the agent is physiologically tolerated and to a large extent not resorbed, the daily treatment dose can essentially be selected at will. Thus, it is possible, for example, to administer, without difficulty, 2-20 g, or even more, of the preparation daily over a relatively long period.
  • The treatment is preferably a long-term treatment and has to be carried out for a period of at least 6 months if it is to display its optimal effect.
  • In addition, the invention will be explained by means of the following example. The polynuclear iron(III) oxide hydroxide-carbohydrate complex which is used in this example is the preparation which is prepared as described in Example 1 in German patent application 42 39 442.
    • EXAMPLE
  • The contents (mean values) of phosphate (2.1 mmol/l) and calcium (2.5 mmol/l) were first of all determined in the serum derived from 13 dialysis patients who were being treated with customary phosphate binders (calcium carbonate, calcium acetate, phosphonorm, Renagel®), and the calcium-phosphate product (5.25) was calculated from these mean values.
  • After that, the phosphate binders were discontinued for 7 days and the contents of phosphate (2.9 mmol/l) and calcium (2.2 mmol/l) were once again determined in serum and the calcium-phosphate product (6.38) calculated from these contents.
  • Treatment with the phosphate binder according to the invention (polynuclear Fe(III) oxide hydroxide-carbohydrate complex) then took place, initially at a daily dose of 4.6 g dry weight over a period of 14 days and then at a dose of 8.6 g for a further 14 days.
  • After a 28-day period of therapy, the content of phosphate was 1.8 mmol/l while that of calcium was 2.1 mmol/l. The calcium-phosphate product was calculated to be 3.78.
    • Result
  • Using the phosphate binder according to the invention surprisingly reduced the calcium-phosphate product by almost a third as compared with the phosphate binders which were previously employed.

Claims (13)

1-13. (canceled)
14. A method of treating a patient suffering from atherosclerotic vascular disease and/or disturbances of bone metabolism, comprising orally administering to said patient an adsorption material modified with an iron (III) metal oxide hydroxide in an amount sufficient to reduce the calcium phosphate product in blood from said patient.
15. The method of claim 14, wherein said adsorption material is an insoluble adsorption material.
16. The method of claim 15, wherein said insoluble adsorption material is a carbohydrate.
17. The method of claim 16, wherein said carbohydrate is starch.
18. The method of claim 17, wherein said patient is a dialysis patient.
19. The method of claim 17, wherein said patient is a predialysis patient.
20. A method of treating a patient suffering from atherosclerotic vascular disease and/or disturbances of bone metabolism, comprising:
a) selecting a patient for treatment on the basis of suffering from atherosclerotic vascular disease and/or disturbances of bone metabolism; and
b) orally administering to said patient an adsorption material modified with an iron (III) metal oxide hydroxide in an amount sufficient to reduce the calcium phosphate product in blood from said patient.
21. The method of claim 20, wherein said adsorption material is an insoluble adsorption material.
22. The method of claim 21, wherein said insoluble adsorption material is a carbohydrate.
23. The method of claim 22, wherein said carbohydrate is starch.
24. The method of claim 23, wherein said patient is a dialysis patient.
25. The method of claim 23, wherein said patient is a predialysis patient.
US12/351,882 2001-06-13 2009-01-12 Use of a phosphate adsorbent to combat vascular diseases Abandoned US20090123566A1 (en)

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Application Number Priority Date Filing Date Title
US12/351,882 US20090123566A1 (en) 2001-06-13 2009-01-12 Use of a phosphate adsorbent to combat vascular diseases

Applications Claiming Priority (5)

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DE10128511.6 2001-06-13
DE10128511A DE10128511A1 (en) 2001-06-13 2001-06-13 Treating or preventing atherosclerosis and/or bone metabolism disorders, especially in dialysis patients, using polynuclear metal oxide-modified adsorption material
PCT/EP2002/006465 WO2002100419A1 (en) 2001-06-13 2002-06-12 Use of a phosphate adsorbent to combat vascular diseases
US10/480,476 US7553482B2 (en) 2001-06-13 2002-06-12 Use of a phosphate adsorbent to combat vascular diseases
US12/351,882 US20090123566A1 (en) 2001-06-13 2009-01-12 Use of a phosphate adsorbent to combat vascular diseases

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PCT/EP2002/006465 Continuation WO2002100419A1 (en) 2001-06-13 2002-06-12 Use of a phosphate adsorbent to combat vascular diseases
US10/480,476 Continuation US7553482B2 (en) 2001-06-13 2002-06-12 Use of a phosphate adsorbent to combat vascular diseases

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EP (1) EP1401455B1 (en)
AT (1) ATE289513T1 (en)
DE (2) DE10128511A1 (en)
ES (1) ES2236539T3 (en)
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WO (1) WO2002100419A1 (en)

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KR101277028B1 (en) * 2006-06-29 2013-06-24 제이 파마 가부시끼가이샤 Preventive remedial therapeutic agent for phosphorus impairment, oral agent for adsorbing phosphate ion contained in food, beverage and chemical, and process for producing them
US8231790B2 (en) * 2006-06-29 2012-07-31 Createrra Inc. Process for producing an anion adsorbent and anion adsorbent produced by said process
ES2526171T3 (en) * 2006-12-14 2015-01-07 Novartis Ag Iron (III) -carbohydrate phosphate adsorbent
WO2010045558A1 (en) * 2008-10-17 2010-04-22 Fresenius Medical Care Holdings, Inc. Method of determining a phosphorus binder dosage for a dialysis patient
EP2548562A1 (en) * 2011-07-18 2013-01-23 SeBo GmbH Combination therapy with iron-based phosphate absorbers
CN107397758A (en) * 2016-05-19 2017-11-28 欣凯医药化工中间体（上海）有限公司 A kind of phosphate binder and preparation method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103126A (en) * 1992-11-24 2000-08-15 Sebo Gmbh Process for the selective elimination of inorganic phosphate from liquids by means of absorbent materials modified with polynuclear metal oxyhydroxides

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DE4239441A1 (en) 1992-11-24 1994-05-26 Fichtel & Sachs Ag Low-density friction materials, esp. for dry clutch linings - by press-moulding and heating a blank contg. gas-producing, density-reducing additives, e.g., bicarbonate, organic blowing agent, water, etc.
JP2003508446A (en) * 1999-09-02 2003-03-04 アコロジックス インコーポレイテッド Methods and compositions for lowering serum phosphate levels

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103126A (en) * 1992-11-24 2000-08-15 Sebo Gmbh Process for the selective elimination of inorganic phosphate from liquids by means of absorbent materials modified with polynuclear metal oxyhydroxides

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EP1401455B1 (en) 2005-02-23
DE50202331D1 (en) 2005-03-31
ATE289513T1 (en) 2005-03-15
ES2236539T3 (en) 2005-07-16
US7553482B2 (en) 2009-06-30
PT1401455E (en) 2005-05-31
US20040186073A1 (en) 2004-09-23
EP1401455A1 (en) 2004-03-31
DE10128511A1 (en) 2002-12-19
WO2002100419A1 (en) 2002-12-19

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