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WO1993008830A1 - Composes de fer biodisponible et d'ovotransferrine acylee ou de ses derives d'hydrolyse acyles - Google Patents

Composes de fer biodisponible et d'ovotransferrine acylee ou de ses derives d'hydrolyse acyles Download PDF

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Publication number
WO1993008830A1
WO1993008830A1 PCT/EP1992/002489 EP9202489W WO9308830A1 WO 1993008830 A1 WO1993008830 A1 WO 1993008830A1 EP 9202489 W EP9202489 W EP 9202489W WO 9308830 A1 WO9308830 A1 WO 9308830A1
Authority
WO
WIPO (PCT)
Prior art keywords
iron
acylated
compounds
ovotransferrin
derivatives
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/EP1992/002489
Other languages
English (en)
Inventor
Roberto Barani
Ivano Carioni
Alberto Sala
Gianni Gromo
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.)
Italfarmaco SpA
Original Assignee
Italfarmaco SpA
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 Italfarmaco SpA filed Critical Italfarmaco SpA
Publication of WO1993008830A1 publication Critical patent/WO1993008830A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins

Definitions

  • the present invention relates to compounds of bioavailable iron with acylated ovotransferrin or with acylated hydrolysis derivatives thereof.
  • Iron which is present in all the body tissues, plays a paramount physiological role. The iron requirement is satisfied partially by the use of endogenous iron, deriving from the degradation of old erythrocytes, and partially from the absorption of exogenous iron. Exogenous iron is absorbed along all the duodenum and the upper part of jejunum and it is accumulated mainly in the liver.
  • the first pathological symptom of iron deficiency is hypochromic sideropenic anemia, whose primary causes can be of various origin: chronic hemorrhages occurring in case of gastroduodenal ulcers or neoplasias; an insufficient diet or a bad absorption, as in the case with diarrhoea; increased requirements, for example during pregnancy, lactation, infectious diseases and the like; impaired metabolic utilization; particular treatments, such as with ACTH or cortisones.
  • the ferro-dextran complex has been suggested for the intramuscular administration, whereas the ferro- dextrin complex is used for the intravenous administration.
  • the side effects of both said complexes can be allergic reactions, temperature rises, tachycardia, leukocytosis, lymphoadenopathy, in the case of intramuscular treatment, and even anaphylactic shock, thrombophlebitis and circulatory collapse in the case of intravenous treatment.
  • formulations are used based on organic salts (citrate, cholinate, aspartate, gluconate, glycinate, lactate, oxalate, succinate etc.) or inorganic salts (ferric chloride, ferrous sulfate, ferric phosphate etc.) which generally lead to gastrointestinal lesions with necrosis and perforation of the mucous membranes in the most serious cases, and diarrhoea and vomiting.
  • organic salts citrate, cholinate, aspartate, gluconate, glycinate, lactate, oxalate, succinate etc.
  • inorganic salts ferrric chloride, ferrous sulfate, ferric phosphate etc.
  • ferritin is a ferric globulin representing the most important iron- containing protein in mammals.
  • the commercial product- is extracted from horse spleen as a raw material.
  • Ferritin has a 20% iron content in terms of dry weight, it is water soluble and suitable for the oral administration.
  • Ferritin based treatment does not involve the ⁇ astrointestinal side effects arisin ⁇ during the use of the above mentioned iron derivatives, but it has severe restrictions deriving both from the very high cost of the raw material and mainly from the limited availability of extraction sources.
  • ferro-protein derivatives whose therapeutic interest is undermined by a series of negative characteristics, including: the insolubility of the derivatives obtained when the percentage of iron linked to the protein reaches values greater than 0.5%; the difficulty or even the impossibility of evaluating what fraction of the total iron content, under such conditions of insolubility, is actually linked to the protein and what fraction is co-precipitated in the form of hydrated oxides which may cause severe gastric lesions;
  • Patent n. 1150213 in the Applicant's name that, by carrying out a succinylation of the above mentioned proteins and reacting them with iron, ferroprotein derivatives could be obtained which have a fairly good iron content, are stable and sufficiently soluble at pH values above 5, and are able to supply therapeutically acceptable iron concentrations when administered orally.
  • said proteins have a varying composition, it is very difficult to obtain compounds having a constant iron content.
  • compounds can theoretically be obtained with a fairly good iron content (up to 20%) , such an iron content involves an increase in the viscosity of the solution of said products, therefore up to now such products are commercialized having an iron content of only 5% by weight.
  • WO 91/07426 discloses a very soluble iron-acylated albumin compound, but, even though the use of different types of albumin is stated to be effective, the best results are achieved with bovine serum-albumin, which yields a compound with a 10% iron content, above which value the solubility of the compound decreases, thus lowering the therapeutic value.
  • bovine serum-albumin which yields a compound with a 10% iron content, above which value the solubility of the compound decreases, thus lowering the therapeutic value.
  • BSE bovine spongiform enkephalitis
  • the present invention relates to compounds of bioavailable iron with acylated ovotransferrin or with acylated hydrolysis derivatives thereof.
  • the acyl moiety of the compound consists of a dicarboxylic acid derivative such as malonic, succinic, methylmalonic, ethylmalonic, acetylmalic, acetylglutamic, acetylaspartic, glutaric acids and the like.
  • Preferred carboxylic acid derivatives are the succinic and acetylaspartic acid derivatives.
  • the compounds of the present invention have an iron content from 3 to 20% by weight. Preferably the iron content of said compounds is 11% by weight at least.
  • Said compounds are suitable as active ingredients for the preparation of pharmaceutical compositions which can be used in the oral treatment of anemias and in all the pathological conditions caused by an iron lack-in mammals and in man. Therefore another object of the invention is provided by the use of the present compounds for the preparation of medicaments useful in said pathologies.
  • Pharmaceutical forms suitable for the oral administration of the compounds of the present invention are, for example, tablets, sugar-coated tablets, capsules, powders, granulates, syrups, suspensions and solutions. The present invention is illustrated in further detail by the following non-limiting example.
  • Said solution having a very high viscosity, is added with a solution of ferric chloride so as to obtain a weight ratio of succinylated protein to Fe of 10:1.
  • pH decreases to 2.6 and a precipitate forms which is recovered by filtration, then redissolved in water and added with NaOH until complete dissolution (pH 7.5).
  • the solid product is recovered by lyophilization.
  • the compound yield is 33% by weight of the starting protein and the iron content is 11%.
  • the product of the above example was administered orally to groups of rats with strong sideropenic anemia, experimentally induced by feeding the animals with an iron-free diet from the pre-natal time to the one of the test.
  • the administered compound dose was 1 g/kg iron.
  • a group was treated with placebo.
  • One or two hours after the treatment the animals were killed with ether, the blood was collected, the serum was prepared and sideremia was evaluated by means of a commercial kit.
  • the table below summarizes the means ⁇ S.E. of the values obtained in 6 animals.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Composés de fer biodisponible et d'ovotransferrine acylée ou de ses dérivés d'hydrolyse acylés, utilisés dans le traitement de carences en fer.
PCT/EP1992/002489 1991-11-04 1992-10-30 Composes de fer biodisponible et d'ovotransferrine acylee ou de ses derives d'hydrolyse acyles Ceased WO1993008830A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI912914A IT1251725B (it) 1991-11-04 1991-11-04 Composti di ferro biodisponibile con ovotransferrina acilata o suoi derivati di idrolisi acilati
ITMI91A002914 1991-11-04

Publications (1)

Publication Number Publication Date
WO1993008830A1 true WO1993008830A1 (fr) 1993-05-13

Family

ID=11361015

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/002489 Ceased WO1993008830A1 (fr) 1991-11-04 1992-10-30 Composes de fer biodisponible et d'ovotransferrine acylee ou de ses derives d'hydrolyse acyles

Country Status (3)

Country Link
AU (1) AU2891192A (fr)
IT (1) IT1251725B (fr)
WO (1) WO1993008830A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0537634A3 (fr) * 1991-10-16 1994-05-04 Mediolanum Farmaceutici Srl
WO2000051447A1 (fr) * 1999-03-01 2000-09-08 Societe Des Produits Nestle S.A. Systeme d'enrichissement en fer
US6994876B1 (en) 1999-03-01 2006-02-07 Nestec S.A. Iron fortification system
US10905748B2 (en) * 2018-04-16 2021-02-02 Vets Plus, Inc. Ovotransferrin treatment for the reproductive tract

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4493829A (en) * 1982-03-02 1985-01-15 Italfarmaco S.P.A. Bio-available succinylated protein-iron derivatives which do not cause gastric lesions, method of preparation and related pharmaceutical compounds
EP0319664A1 (fr) * 1987-10-14 1989-06-14 ITALFARMACO S.p.A. Dérivés polypeptidiques solubles contenant du fer, leur préparation, et leur utilisation comme médicament
WO1991007426A1 (fr) * 1989-11-16 1991-05-30 Italfarmaco S.P.A. Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4493829A (en) * 1982-03-02 1985-01-15 Italfarmaco S.P.A. Bio-available succinylated protein-iron derivatives which do not cause gastric lesions, method of preparation and related pharmaceutical compounds
EP0319664A1 (fr) * 1987-10-14 1989-06-14 ITALFARMACO S.p.A. Dérivés polypeptidiques solubles contenant du fer, leur préparation, et leur utilisation comme médicament
WO1991007426A1 (fr) * 1989-11-16 1991-05-30 Italfarmaco S.P.A. Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BIOCHEMISTRY vol. 4, no. 6, June 1965, EASTON, PA US pages 998 - 1005 H. BUTTKUS, 'Chemical modifications of amino groups of transferrins: ovotransferrin, human serum transferrin and human lactotransferrin.' *
BIOCHIM. BIOPHYS. ACTA vol. 181, 1969, pages 295 - 304 A. BEZKOROVAINY, 'Some physical-chemical properties of succinylated transferrin, conalbumin and orosomucoid.' *
POULTRY SCIENCE vol. 61, no. 6, 1982, pages 1041 - 1046 H.R. BALL, 'Acylation of egg white proteins with acetic anhydride and succinic anhydride.' *
STN INTERNATIONAL, KARLSRUHE. FILE 'CA', CHEMICAL ABSTRACTS. AN=CA75(6):40408u. T. NAGASAWA, 'Enzymic hydrolysis of iron conalbuminate'. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0537634A3 (fr) * 1991-10-16 1994-05-04 Mediolanum Farmaceutici Srl
WO2000051447A1 (fr) * 1999-03-01 2000-09-08 Societe Des Produits Nestle S.A. Systeme d'enrichissement en fer
US6994876B1 (en) 1999-03-01 2006-02-07 Nestec S.A. Iron fortification system
US10905748B2 (en) * 2018-04-16 2021-02-02 Vets Plus, Inc. Ovotransferrin treatment for the reproductive tract
US12083167B2 (en) 2018-04-16 2024-09-10 Vets Plus, Inc. Ovotransferrin treatment for the reproductive tract

Also Published As

Publication number Publication date
IT1251725B (it) 1995-05-23
ITMI912914A1 (it) 1993-05-04
ITMI912914A0 (it) 1991-11-04
AU2891192A (en) 1993-06-07

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