EP0593443A1 - Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant

Info

Publication number
EP0593443A1
EP0593443A1 EP90916292A EP90916292A EP0593443A1 EP 0593443 A1 EP0593443 A1 EP 0593443A1 EP 90916292 A EP90916292 A EP 90916292A EP 90916292 A EP90916292 A EP 90916292A EP 0593443 A1 EP0593443 A1 EP 0593443A1
Authority
EP
European Patent Office
Prior art keywords
iron
compounds
acylated
albumins
ironsuccinylalbumin
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Withdrawn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
EP90916292A
Other languages
German (de)
English (en)
Inventor
Pietro Cremonesi
Roberto Barani
Ida Caramazza
Piero Del Soldato
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 EP0593443A1 publication Critical patent/EP0593443A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

  • the present invention relates to albumins acylated with dicarboxylic acid residues containing iron in a bioavailable form.
  • the Ironproteinsuccinylate derivative (obtained according to Italian Patent N°. 1,150,213) which is used for the appropriate pharmaceutical formulation and is nowadays commercially available contains 5% by weight iron.
  • albumins can be used in the preparation of the compounds of the invention, particularly preferred being highly pure bovine serum albumin and lactalbumin.
  • albumins are acylated with dicarboxylic acid residues such as, for instance, those deriving from succinic, glutaric, maleic, malic, malonic, aspartic, glutamic acids and the like.
  • residues from succinic acid which proved to be the most suitable for improving some protein characteristics, such as solubility and degradability by proteases.
  • the present invention relates to compounds comprising iron and succinylated bovine serum albumin, supporting iron amounts from 3 to 10% by weight, as well as compounds comprising iron and succinylated lactalbumin supporting iron amounts up to 20% by weight, both these compounds being highly soluble.
  • Said compounds can be obtained in aqueous medium by reacting the above mentioned succinylated or acylated albumins with iron ions at a pH ranging from 2 to 12, preferably from 3 to 7.
  • bovine serum albumin 20 g of bovine serum albumin are dissolved in 400 ml of water. pH is adjusted to 8.0 by adding NaOH. 24 g of succinic anhydride are added in small portions, under stirring, keeping pH from 7.5 to 8 by addition of 2N NaOH and constant temperature below 25°C, preferably at 20°C. The mixture is left to react for one hour, then pH is lowered to 3 ⁇ 0.5 by means of 2N HCl. A white precipitate forms which is recovered by centrifugation. The formed excess of succinic acid is removed by dissolving the precipitate in 400 ml of water at pH 8.0, adjusting the solution pH to 3 ⁇ 0.5 with 2N HCl. A white precipitate forms which is recovered by centrifugation.
  • a red-brown powder (19 g) is obtained which is insoluble in water and becomes soluble adjusting pH to about neutrality by addition of 2N NaOH.
  • the compound shows at the analysis an iron content of 6.1-6.2% by weight.
  • electrophoresis on cellulose acetate as described in item 4 below the compound moves as a unitary spot, in which iron can be determined.
  • the compound is prepared as described in Example 1, but adding 4.8 g of FeCl 3 .6H 2 O (equivalent to 0.922 g of Iron).
  • the compound moving under the electrophoretic field as a unitary spot in which iron can be determined, shows a 3.8-4.1% by weight Fe content.
  • the precipitation procedure at acid pH and the dissolution procedure at basic pH are repeated twice. Then the solution is slowly added with a solution of 578.5 g of FeCl 3 .6H 2 O in 10 1 of demineralized water keeping pH from 6.5 to 6.8 by addition of 5N NaOH. Then the mixture is stirred at pH 6.6-6.8 for 30 min., acidified to pH 3 with 6N HCl and left under stirring for 30 min.. The precipitate is centrifuged, thoroughly washed with demineralized water adjusting pH to 8.5 with 5N NaOH. After having kept at the pH of 8.5 for about one hour, the obtained solution is filtered through Celite (300 g). The precipitation procedure at acid pH and the dissolution procedure at basic pH are repeated for one time.
  • the solution is filtered on Celite (200 g), the product is precipitated at pH 3 with 6N HCl, stirring for 30 min., then it is centrifuged and thoroughly washed with demineralized water. The dark brown solid is sieved and dried under vacuum at 30°C, to obtain 1 kg of Ironsuccinylalbumin.
  • Example 2 The solution of the succinylated protein is added with 1.2 kg of FeCl 3 .6H 2 O in 10 1 of water, keeping pH from 6.5 to 6.9 by addition of 5N NaOH. The reaction is carried out as described in the above Example to obtain, at the end of the reaction, 1 kg of the title compound.
  • bovine serum albumin 10 g are dissolved in 200 ml of water and pH is adjusted to 7.2 by addition of
  • the iron compound is prepared as described in
  • Example 6 but using maleic anhydride as the acylating agent.
  • the iron compound is prepared as described in Example 6, but using glutaric anhydride as the acylating agent.
  • the solubility profile is taken from spectrophotometric measurements of the absorbance difference at 500 nm and 280 nm of solutions obtained treating 20 mg of Ironsuccinylalbumin with 50 ml of water, in a pH range from 2.0 to 7.0. 5 ml of the sample are diluted to 10 ml with water, centrifuged at 3,000 rpm during 10 min. and the supernatant is read at spectrophotometer.
  • Ironsuccinylalbumin is completely soluble at pH values equal or above 6.5, whereas it is insoluble at pH below 6.
  • the reversed precipitation curve obtained by acidifying the Ironsuccinylalbumin solution (20 mg of the compound in water at pH 7), shows the precipitation onset at pH 4.5.
  • the protein amount in the samples prepared according to Examples 1-8 was determined by titration of protein nitrogen (using the method described in
  • the found values range from a maximum of 85% (in the compound of Example 3) to a minimum of 65% (in the compound of Example 5).
  • Electrophoresis was carried out for 20 min. at 40 V/cm, using 0.05M Tris tricine buffer, pH 8.6, which detects bands at the same electrophoretic distance for the compounds of the invention and for the respective acylated proteins. No bands which can be attributed to the starting albumins can be evidenced. The presence of iron in the bands of the compounds of the invention can be detected by means of o-phenanthroline.
  • the distance of the spot from the origin is 37 mm.
  • the fluorescence emission spectra at 400 and 200 nm show a poor emission, equal to about 1/10 that of the starting protein.
  • the spectra were recorded both at room temperature and at -160°C with a spectrometer Varian E1D, and they are characterized by a single peak of 1200 G width between the maximum and minimum slope with a value of g
  • Electrophoresis was carried out on 7.5% polyaerylamide gel containing 1% by weight SDS.
  • the electrophoretic bands were evidenced with Comassie Brilliant Blue.
  • the following products were used as molecular weight standards: myosin (200 KD), beta-galactosidase (116 KD), phosphorylase b (97 KD), bovine albumin (68 KD), ovoalbumin (42 KD).
  • Ironsuccinylalbumin showed a single band corresponding to 100 KD molecular weight.
  • a similar electrophoretic behaviour was shown by Ironsuccinyl- ⁇ -lactalbumin, but the molecular weight thereof is 20 KD.
  • the acylation degree was determined both spectrophotometrically, according to the reaction of the protein free amino groups with ninhydrin and by fluorometric reaction with o-phthalaldehyde (G. Goodno et al., Anal. Biochem., 115, 203, 1981). Both these methods were used to evaluate localization of the acylation on the protein fraction constituting the prepared compounds.
  • Methyl succinate is determined under the following conditions, using methyl glutarate as the internal standard:
  • Figure 1 shows the dichroism spectrum of bovine serum albumin, of the corresponding acylated compound and of the compound of Example 3.
  • the spectrum shows signals at 15-70 ppm (aliphatic CH), 110-140 ppm (aromatic) and 180 ppm (carboxylic).
  • the amino acid profile is reported in Table 1.
  • the enzyme hydrolysis was carried out by treating 25 mg dissolved in 5 ml of 0.05M Tris-HCl buffer pH 7.6 with chymotrypsin (50 ⁇ g) and trypsin (50 ⁇ g). 1 ml is withdrawn from the reaction mixture at definite times; 2 ml of a 5% trichloroacetic acid (TCA) are added, the mixture is centrifuged at 3000 rpm for 110 min. and the supernatant is spectrophotometrically read at 280 nm against a TCA blank.
  • TCA 5% trichloroacetic acid
  • the absorbance change as a function of time represents the hydrolysis rate, which turns out to be comparable to that of the corresponding albumin used in the preparation, of the compound, to evidence that iron present in the compound does not inhibit the action of proteolytic enzymes.
  • Iron mobilization is tested by reaction with desferrioxamine, which is controlled as a function of time by measuring the absorbance increase, at 487 nm, of a solution containing 7.0 ul of desferrioxamine, 500 ug of Ironsuccinylalbumin previously neutralized at pH 7.4 in 20 mM Tris-HCl buffer.
  • the absorbance increase at 487 nm during time confirms that iron can be mobilized from Ironsuccinylalbumin.
  • the release rate is 2.2 mA for 5 min.
  • Ironsuccinylalbumin is dissolved in water at pH 8.
  • the obtained solutions are viscosimetrically analyzed with a capillary viscosimeter or a Brookfield viscosimeter.
  • FeCl, and FeSO 4 which are known to be capable of generating OH radicals, are used as the controls.
  • Groups of rats are treated intraperitoneally with Ironsuccinylalbumin and Ironproteinsuccinylate (prepared according to Italian Patent 1,150,213) (in amounts corresponding to 100 mg iron/kg), and with ferrous sulphate (in amounts corresponding to 25 mg/kg iron).
  • Plasma samples are collected after 2, 8 and 15 hours and the presence of iron is determined with the bleomycin test (see Table 3).
  • Ironsuccinylalbumin contrary to ferrous sulphate and Ironproteinsuccinylate, induces no free iron in plasma, thus proving to be free from the injuring effects induced by free radicals deriving from iron.
  • the animals were treated orally with Ironsuccinylalbumin (a sample prepared according to Example 3, which sample being significant due the high iron content thereof, and therefore being potentially more toxic) or ferrous sulphate at dose levels of 200 mg/kg.
  • the animals were killed at different times, up to 24 hours.
  • the examination of stomach and intestine showed that the intestinal and gastric injuries were significantly less marked after administration of Ironsuccinylalbumin than ferrous sulphate.
  • Ironsuccinylalbumin proves to be much less toxic than ferrous sulphate and does not induces toxicity symptoms up to 2000 mg/kg.
  • Subacute toxicity with repeated doses by the oral route was tested with doses of 100. 250, 600 mg/kg/die of the derivative (equivalent to 1, 2.5, 6 times the treatment with 10 mg/kg/die iron). No toxicity signs are evidenced during the treatment .
  • Ironsuccinylalbumin is tolerated in the intestinal tract, has a low acute toxicity and it is not mutagenic, in comparison with ferrous sulphate which causes gastric ulcerations, is more toxic after single administration and has mutagenic properties.
  • Ironsuccinylalbumin In order to pharmacologically characterize Ironsuccinylalbumin, the following parameters were evaluated: iron release at the gastric level; iron absorption and kinetic, and the antianaemic effect after a prolonged treatment using ferrous sulphate as the control (in animals with experimentally induced anaemia).
  • the Ironsuccinylalbumin used for these tests is the one prepared in Example 3.
  • the sideremia values were measured in the anaemic rat at different times after a single oral treatment with ferrous sulphate and Ironsuccinylalbumin at a dose of 0.3 mg of Fe equivalents. The results show for both the compounds an iron absorption peak 1 hour after the treatment (see Table 6).
  • a prolonged treatment was carried out during 6 weeks, in the anaemic rat, by administering orally Ironsuccinylalbumin and ferrous sulphate as the control, at doses of 3, 10, 30 mg Fe/kg/die.
  • Ironsuccinylalbumin is a protein iron complex (the iron contents can vary from 3 to 20% by weight), the protein component of. which is albumin or lactalbumin extensively acylated, mainly at the lysine chain, as evidenced by comparative physico- chemical analysis, particularly electrophoresis, amino acid composition, succinic acid content, (NMR), with disorganized structure (CD-circular dichroism).
  • the protein can complex with high amounts of iron in form of a polynuclear hydrated complex (ESR) with amorphous structure, in which aquo-complexes are maintained in solution by the succinylated protein, thus forming an aggregate structure with molecular weights higher than 10 Daltons.
  • ESR polynuclear hydrated complex
  • the obtained compounds are highly insoluble in acid medium and highly soluble at neutral or basic pH values.
  • the compounds are characterized by a very low toxicity in the animal, due to the release of iron traces, which cannot give raise to free radicals.
  • the above mentioned effects are completely unforeseeable and they are due to the presence of albumin in the compound.
  • the present invention also relates to the use of the novel compounds as agents effective in the treatment of anaemias, as well as to all of the industrial aspects related thereto, including the use thereof in pharmaceutical compositions, which are a further specific object of the invention.
  • the compounds of the invention can be incorporated in pharmaceutical compositions, particularly in formulations suitable to the oral administration.
  • the compounds are formulated in form of tablets, dispersible powders, capsules, dragees, granulates, suspensions, syrups, elixirs or solutions.
  • the preparations for the oral use can contain one or more of the usual excipients, such as sweetening, flavouring, colouring, covering and preservative agents, in order to obtain a pleasant and palatable preparation.
  • Tablets can contain the active ingredient in admixture with the usual pharmaceutically acceptable excipients, for example inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, such as alginic acid and sodium carboxymethyl cellulose, binding agents such as starch, gelatin, gum arabic and polyvinylpyrrolidone, preservative agents such as methyl, ethyl, propyl, butyl, or alkali metals benzoates or hydroxybenzoates, and lubricants such as talc, magnesium stearate, stearic acid, glyceryl palmitostearate and the like.
  • excipients for example inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, such as alginic acid and sodium carboxymethyl cellulose, binding agents such as starch, gelatin, gum arabic and polyviny
  • Syrups, elixirs, suspensions and solutions are prepared according to known methods. Together with the active ingredient, they can contain suspending agents, such as propylene glycol, methylcellulose, hydroxyethylcellulose, tragacanth gum and sodium alginate, wetting agents, such as lecithin, polyoxyethylene stearate and polyoxymethylenesorbitan monooleate and the usual preservatives, surfactants, sweetening and buffering agents. The addition of an alkali metal hydroxide can sometimes be necessary.
  • the most preferred forms of said pharmaceutical formulations consist or drinkable ampoules and sachets, the content of which is extemporarily dissolved or suspended in water.
  • the active ingredient dosages can range within wide limits, depending on the nature of the used compound. Effective results are generally obtained by administering the compounds of the invention at daily dosages ranging from about 5 to about 50 mg/kg body weight.
  • the dosage pharmaceutical forms generally contain from about 300 to about 1500 mg fo the active ingredient together with one or more of the conventional solid or liquid pharmaceutical carriers ad they can be administered one or more times a day.
  • One tablet contains:
  • Ironsuccinylalbumin (Example 3) mg 400 mg 1200
  • One tablet contains:
  • Ironsuccinylalbumin (Example 1) mg 1200
  • One drinkable vial contains: Ironsuccinylalbumin
  • One drinkable vial contains:
  • Ironsuccinyl- ⁇ -lactalbumin (Example 5) mg 400
  • One drinkable vial contains:
  • One sachet contains:
  • Ironsuccinylalbumin (Example 3) mg 400 . mg 1200
  • One sachet contains:
  • Ironsuccinyl- ⁇ -lactalbumin (Esempio 5) mg 600
  • One sachet contains:

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Sont décrits des dérivés de fer-albumines, comprenant des albumines acylées à l'aide de résidus d'acide dicarboxylique, et contenant des quantités élevées de fer, insolubles au pH de l'acide gastrique, et hautement solubles au pH intestinal. Les dérivés sont caractérisés par une très faible gastrolésivité et toxicité, et par une biodisponibilité et une efficacité thérapeutique remarquables dans le traitement d'états anémiques.
EP90916292A 1989-11-16 1990-11-09 Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant Withdrawn EP0593443A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT02239989A IT1237783B (it) 1989-11-16 1989-11-16 Derivati di ferro-albumina biodisponibile, loro procedimento di preparazione e relative composizioni farmaceutiche.
IT2239989 1989-11-16
PCT/EP1990/001878 WO1991007426A1 (fr) 1989-11-16 1990-11-09 Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant

Publications (1)

Publication Number Publication Date
EP0593443A1 true EP0593443A1 (fr) 1994-04-27

Family

ID=11195773

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90916292A Withdrawn EP0593443A1 (fr) 1989-11-16 1990-11-09 Composes de fer-albumines biodisponibles, leur procede de preparation et compositions pharmaceutiques les contenant

Country Status (7)

Country Link
EP (1) EP0593443A1 (fr)
AU (1) AU7039691A (fr)
CA (1) CA2068655A1 (fr)
IE (1) IE904124A1 (fr)
IT (1) IT1237783B (fr)
PT (1) PT95904B (fr)
WO (1) WO1991007426A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1251702B (it) * 1991-10-16 1995-05-19 Mediolanum Farmaceutici Srl Complessi del ferro con la conalbumina e i suoi derivati
IT1251725B (it) * 1991-11-04 1995-05-23 Italfarmaco Spa Composti di ferro biodisponibile con ovotransferrina acilata o suoi derivati di idrolisi acilati
IT1291289B1 (it) * 1997-04-30 1999-01-07 Derivati Organici Lab Complessi costituiti da fe(iii) un composto poliidrossilato e ovalbumina

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1150213B (it) * 1982-03-02 1986-12-10 Italfarmaco Spa Derivati di ferro biodisponibile esenti da gastrolesivita',procentimento di preparazione e relative composizioni farmaceutiche
IT1222912B (it) * 1987-10-14 1990-09-12 Italfarmaco Spa Derivati polipeptidici a elevato tenore di ferro e altamente solubili atti alla terapia marziale procedimenti di preparazione e loro forme farmaceutiche

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9107426A1 *

Also Published As

Publication number Publication date
PT95904B (pt) 1998-01-30
IT8922399A0 (it) 1989-11-16
WO1991007426A1 (fr) 1991-05-30
IE904124A1 (en) 1991-05-22
AU7039691A (en) 1991-06-13
IT1237783B (it) 1993-06-17
PT95904A (pt) 1991-09-13
CA2068655A1 (fr) 1991-05-17

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