WO1998025887A2 - Formulations et formes polymorphes de desferrioxamine et rpeparation de ces dernieres - Google Patents

Formulations et formes polymorphes de desferrioxamine et rpeparation de ces dernieres Download PDF

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Publication number
WO1998025887A2
WO1998025887A2 PCT/EP1997/006849 EP9706849W WO9825887A2 WO 1998025887 A2 WO1998025887 A2 WO 1998025887A2 EP 9706849 W EP9706849 W EP 9706849W WO 9825887 A2 WO9825887 A2 WO 9825887A2
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WIPO (PCT)
Prior art keywords
desferrioxamine
decanesulphonate
salt
crystal
acid
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PCT/EP1997/006849
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English (en)
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WO1998025887A3 (fr
Inventor
Erwin Marti
Andre Joseph Geoffroy
Hans Hirt
Andreas Burkhard
Ian Francis Hassan
Nicholas Lowther
Joanne Nicklin
Alan Steward
Peter Van Hoogevest
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Novartis Ag
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Priority claimed from GBGB9625878.5A external-priority patent/GB9625878D0/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to HU0000705A priority Critical patent/HUP0000705A2/hu
Priority to BR9713570-4A priority patent/BR9713570A/pt
Priority to EP97954727A priority patent/EP0944586A2/fr
Priority to AU59839/98A priority patent/AU5983998A/en
Priority to CA002274761A priority patent/CA2274761A1/fr
Priority to IL13020397A priority patent/IL130203A0/xx
Publication of WO1998025887A2 publication Critical patent/WO1998025887A2/fr
Publication of WO1998025887A3 publication Critical patent/WO1998025887A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to a new polymorphous crystal modification of desferrioxamine-1- decane-sulphonate, and the preparation thereof, as well as pharmaceutical compositions and the use of this crystal modification for therapeutic purposes and the preparation of pharmaceutical compositions; and also to other crystal forms. It generally also relates to new pharmaceutical compositions containing a desferrioxamine-B salt as active ingredient.
  • organo-chemical substances The morphology and polymorphy of organo-chemical substances is of immense importance in the chemical and pharmaceutical development thereof. Substances are known which only appear in a single crystal form, and similarly there are substances with two, three and even a higher number of polymorphous forms. This possible morphological and structural variety and the respective physico-chemical, especially thermodynamic stability relationships cannot be calculated or predicted on a scientific-mathematical basis. The relevant polymorphism of an organo-chemical substance is thus a surprise in respect of the number of forms and the stability thereof.
  • desferrioxamine-B and pharmaceutically acceptable salts thereof are described for example in US Patent No. 3,247,197.
  • the present invention provides a parenterally injectable composition comprising particles of a desferrioxamine-B salt of an aliphatic sulphonic acid having at least 8 carbon atoms suspended in a parenterally administrable oil.
  • EP 643690 discloses inter a//a the 1 -deca- nesulphonate of desferrioxamine-B as iron chelator. However, it is not written down whether there are further crystal modifications of desferrioxamine-1-decanesulphonate. Now, surprisingly, several new crystal forms of this substance have been found. The present invention therefore also concerns a new stable crystal modification of desferrioxamine-1- decanesulphonate and a process for the production thereof.
  • Fig. 1/3 shows an X-ray diagram of crystal modification A 2 of desferrioxamine-decane- sulphonate. Abscissa (x-axis): diffraction angle 2 ⁇ (range 3° to 30°); Ordinate (y-axis): relative intensity.
  • Fig 2/3 shows an X-ray diagram of crystal modification Ai of desferrioxamine-decane- sulphonate. Abscissa (x-axis): diffraction angle 2 ⁇ (range 3° to 30°); Ordinate (y-axis): relative intensity.
  • Fig. 3/3 shows an X-ray diagram of crystal modification B (mixture with modifications An to A 13 ) of desferrioxamine-decanesulphonate. Abscissa (x-axis): diffraction angle 2 ⁇ (range 3° to 30°); Ordinate (y-axis): relative intensity.
  • a first preferred embodiment of the invention relates to a parenterally injectable composition
  • a parenterally injectable composition comprising particles of a desferrioxamine-B salt of an aliphatic sulphonic acid having at least 8 carbon atoms suspended in a parenterally administrable oil.
  • the desferrioxamine-B salt may be, in general, a salt of an aliphatic sulphonic acid having 8 to 20 carbon atoms.
  • Such acids include hydrocarbyl sulphonic acids, for example alkanesul- phonic, alkenesulphonic and alkynesulphonic acids such as octane-1 -sulphonic acid, octa- ne-2-sulphonic acid, nonane-1 -sulphonic acid, nonane-2-sulphonic acid, n-decanesulphonic acid, n-dodecanesulphonic acid, tetradecanesulphonic acid, hexadecanesulphonic acid, octadecanesulphonic acid, octene-1 -sulphonic acid, decene-1 -sulphonic acid, dodecene-1 - sulphonic acid, tetradecene-1 -sulphonic acid, hexadecene
  • the desferrioxamine-B salt is a salt of an aliphatic sulphonic acid having 8 to 12, preferably 8 to 10 carbon atoms, especially a salt of n-octanesulphonic acid or n-decanesulphonic acid.
  • a preferred extraordinarily stable form of desferrioxamine-B n-decanesulpho- nate for use in the present invention is a crystal modification A 2 which is described in more detail below.
  • Another preferred form of desferrioxamine-B n-decanesulphonate for use in the present invention is a crystal form A T having a melting point range of 140 °C to 153°C determined by DSC and having the following characteristic diffraction lines (2 ⁇ in angular degrees + 0.1 °) in its X-ray diffraction pattern : 4.1 °, 6.3 °, 8.4 °, 10.5 °, 12.6 °, 16.9 °, 18.0 °, 19.8 °, 20.8 °, 22.1 °, 25.0 °, 25.6 ° and 26.4° (see below for more details).
  • Crystal form At is less stable than crystal form A 2 , especially in the presence of water and polar solvents or mixtures thereof.
  • form A t is kinetically stable in the parenterally administrable oil of the composition of the invention.
  • Crystal modification A 2 may be prepared by adding an aqueous solution of an alkali metal salt of n-decanesulphonic acid gradually to an aqueous solution of desferrioxamine-B methanesulphonate at a temperature below room temperature, preferably at 0 to 5 °C. This mixture is then heated up to elevated temperatures, preferably to a termperature between room temperature and the boiling point of the mixture, more preferably from 30 °C to 80 °C.
  • Crystal form B has a melting point (determined by DSC) of about 142 °C and has the following characteristic diffraction lines (2 ⁇ in angular degrees + 0.1 °) in its X-ray diffraction pattern : 3.5 °, 7.1 °, 8.9 °, 9.9 °, 11.3 °, 12.3 °, 19.0 °, 21.7 °, 22.1 ° and 23.8 °. Crystal form B is less stable than A1 , being transformed, at a temperature increase rate of 10 °C/min, into crystal form Aj.
  • a mixture of the forms At and B can be prepared by reacting decane-1 -sulphonic acid with desferrioxamine-B free base as described in Example 1 of WO93/24451 to form the crude salt and recrystallising the latter by dissolving it in aqueous ethanol, filtering the resulting solution, and removing part of the ethanol under reduced pressure until the product is precipitated.
  • the desferrioxamine-B salt particles when suspended in the oil generally have a mean diameter of from 1 to 1000 microns, preferably from 3 to 500 microns, especially from 5 to 100 microns, most preferably from 5 to 10 microns.
  • the parenterally administrable oil may be any pharmaceutically acceptable oil or mixture of pharmaceutically acceptable oils having a viscosity suitable for delivery by injection.
  • oils include mineral oils, vegetable oils and animal oils and esters of fatty acids obtained from such oils, preferably vegetable oils or esters of fatty acids obtained from them, such as refined paraffin oil, castor oil, sesame oil, cottonseed oil, sunflower oil, coconut oil, palmker- nel oil, peanut oil, wheat germ oil, ethyl oleate, isopropyl myristate, esters of coconut and palmkernel fatty acids, i.e. caprylic and capric acids, with glycerol or propylene glycol, and mixtures of two or more thereof.
  • the parenterally administrable oil comprises ethyl oleate, a mixture of ethyl oleate with sesame oil or a triglyceride of a mixture of caprylic and capric acids.
  • the parenterally administrable oil comprises 25 to 100% by weight of ethyl oleate and 0 to 75% by weight of sesame oil, or the parenterally administrable oil comprises a triglyceride of a mixture of caprylic and capric acids, the weight ratio of caprylic acid to capric acid being from 10:9 to 13:6.
  • triglyceride is commercially available as Miglyol 812 from H ⁇ ls AG, Germany.
  • the desferrioxamine-B salt may be present generally in a therapeutically effective amount, usually in an amount of 0.05g to 0.4g per ml of the parenterally administrable oil, preferably in an amount of 0.1 g to 0.3g per ml of the oil.
  • the composition is conveniently in the form of a parenteral injection dosage unit, usually having a volume of 0.5 to 10ml, preferably 3 to 7ml, which may be in a conventional container such as a glass or plastic syringe or vial or polyethylene container.
  • the composition is preferably supplied in, and administered from, a prefilled syringe or a bottlepack polyethylene container.
  • a composition of the invention also contains a surfactant (emulsifying agent).
  • emulsifying agent emulsifying agent
  • Suitable surfactants include pharmaceutically acceptable non-ionic surfactants, preferably lipophilic surfactants such as sorbitan fatty acid esters, particularly sorbitan monoiaurate, sorbitan monooleate and sorbitan trioleate, polysorbates such as polyoxyethylene (20) sorbitan monoiaurate, polyoxyethylene (20)sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate and polyoxyethylene (20) sorbitan trioleate, C 10 to C 20 alkyl ethers of polyoxyethylene glycols such as polyoxyethylene (4) lauryl ether, and phospholipid surfactants such as soy lecithin.
  • non-ionic surfactants preferably lipophilic surfactants such as sorbitan fatty acid esters, particularly sorbitan monoiaurate, sorbitan monooleate and sorbitan trioleate
  • polysorbates such as polyoxyethylene (20) sorbitan monoiaurate, polyoxyethylene (20)sorbitan
  • compositions of the invention may also contain other excipients such as those used in conventional compositions to be administered by parenteral injection, for example tonicity agents such as dextrose and sodium chloride, preservatives such as benzyl alcohol, benzyl benzoate and methyl and propyl esters of p-hydroxy benzoic acids and antioxidants such as butylated cresols and tocopherols.
  • excipients such as those used in conventional compositions to be administered by parenteral injection, for example tonicity agents such as dextrose and sodium chloride, preservatives such as benzyl alcohol, benzyl benzoate and methyl and propyl esters of p-hydroxy benzoic acids and antioxidants such as butylated cresols and tocopherols.
  • the present invention also provides a method of preparing a composition of the invention as hereinbefore defined which comprises mixing particles of the desferrioxamine-B salt with the parenterally administrable oil and, where present, the surfactant.
  • the mixing is carried out in two stages in which (a) the salt is milled with part of the oil and (b) the remainder of the oil is added to the milled mixture, the surfactant, where present, being added in stage (a) and/or stage (b).
  • the oil comprises a mixture of oils of different viscosities, for example a mixture of sesame oil and ethyl oleate
  • the salt may conveniently be mixed with the more viscous oil before addition of less viscous oil.
  • the desferrioxamine-B salt is added to the oil, or to a mixture of oil and surfactant, and the resulting mixture is homogenised by a pharmaceutically acceptable acceptable milling process, preferably in a colloid mill or the like, until the desired particle size of the salt is obtained.
  • the deferrioxamine salt may be micronised using an air jet mill, resuspended in the oil phase using an utraturrax mixer, followed by filling the desired container and sterilisation of the container and drug product by means of gamma or beta irradiation (10-100 kGy dose) or heat treatment.
  • the preparation of a sterile composition of the invention can be ensured by purifying the desferrioxamine-B salt under aseptic conditions, sterilizing the oil using conventional procedures, for example by filtration through a filter having a pore size of 0.22 ⁇ m or by heating it at 170 °C for at least 2 hours, and mixing the sterilised oil with the purified desferrioxamine-B salt under aseptic conditions.
  • compositions of this invention may be carried out, for example, by intramuscular or subcutaneous injection. After parenteral administration of the compositions, sustained release of desferrioxamine-B can occur over 48 hours.
  • the dosage of desferrioxamine-B salt administered to a patient may be up to about 4g per day, for example 500mg to 4g per day. This dosage is conveniently delivered by bolus injection once a day or once every two days.
  • the invention includes a method of treating iron-overload disease, aluminium overload, Alzheimer's disease, malaria, reperfusion injury or cancer which comprises parenterally injecting a composition of the invention as hereinbefore defined into a warm-blooded mammal, particularly a human, in need of such treatment.
  • the present invention also concerns a new stable crystal modification of desferrioxamine-1- decanesulphonate (that is preferably used in the compositions mentioned above and for their preparation) and a process for the production thereof.
  • the invention relates to a crystal modification of desferrioxamine-1-decanesul- phonate, which in DSC under nitrogen has a melting point range of 154°C to 158°C inclusive at a heating rate of 10°C/min and possesses the following characteristic diffraction lines (2 ⁇ in angular degrees ⁇ 0.1 °) in its X-ray pattern: 3.1 °, 4.2°, 7.3°, 8.4°, 9.4°, 10.5°, 13.7°, 16.8°, 17.4°, 18.0°, 18.4°, 19.6°, 20.1 °, 20.9°, 22.3°, 23.7°, 25.1 ° and 25.6°.
  • Crystal modification A 2 This new specific crystal form (referred to here as “crystal modification A 2 ”) has properties superior to all other known crystal modifications of desferrioxamine-1 -decanesulphonate.
  • Crystal modification A 2 is physico-chemically and thermodynamically more stable than the other known modifications in the customary temperature range, and for this reason is more suitable for production of the chemical substance in solid form, as well as the development and production of pharmaceutical formulations, and also for therapeutical application thereof.
  • all known crystal forms are metastable, when compared to crystal modification A 2 . Therefore only crystal modification A 2 will not show solid state transformation, independent of the dispersion phase in production, storage and during therapeutic application e.g. after depot injections.
  • crystal form A 2 is better to mill than crystal
  • the crystal modification A 2 is very stable with good thermal stability up to the melting range. It melts at a heating rate of 10°C/min in a range of 148°C to 162°C with a melting point range of 154°C to 158°C inclusive. Very preferred is the crystal modification A 2 displaying the x-ray diagram according to FIG. 1/3.
  • Crystal modification A has a melting point range of 140°C to 153°C. It corresponds to the form specified in the patent application EP 643690. By means of more precise Differential Scanning Calorimetry (DSC), it can be shown that it consists of four sub-forms An, Aj 2 , A 13 and A 14 with melting points 148°C, 150°C, 152°C and 153°C. These sub-modifications are obtained during the production of the substance in different quantity ratios and together form the crystal modification A ⁇ .
  • DSC Differential Scanning Calorimetry
  • Crystal modification B may similarly appear during the production of the desferrioxamine-1 - decanesulphonate.
  • the melting point thereof in DSC is approximately 142°C, and with a heating rate of 10°C/minute, a transformation into one or several sub-forms of crystal modifications A ⁇ , namely An to A 14 , may be observed.
  • the crystal modifications may also be distinguished by their X-ray powder patterns, in addition to their melting points.
  • X-ray powder patterns taken with a Guinier camera in transmission geometry and using Cu-K ⁇ radiation, are preferably employed to characterise solids of organic substances.
  • X-ray diffraction patterns are used successfully to determine the different crystal modifications of a substance.
  • the measurements are carried out at room temperature and the X-ray films evaluated in an angle range (2 ⁇ ) of 3° to 30° . All cited diffraction angles 2 ⁇ in the present disclosure are given in respect to the Cu-K ⁇ j radiation.
  • Tables 2 and 3 reproduce the X-ray diffraction patterns of the above-described crystal modification Ai and of crystal modification B.
  • the X-ray diffraction patterns confirm that the crystal modifications of desferrioxamine-1- decanesulphonate indicated by A ⁇ A 2 and B are completely distinct polymorphous forms. In contrast to the DSC method, in which four distinct melting points (see above) could be determined for the crystal modification Ai, the differences in the X-ray diffraction patterns are too small to show significant deviations of the 2 ⁇ values of the reflection angle corresponding to Table 2.
  • a further appropriate parameter for distinguishing the crystal modifications is frequently their hygroscopicity, from which conclusions may be drawn on the stability of a crystal modification, it is determined for example by weighing the water vapour absorption, whereby the water absorption by the substance to be tested is measured in an atmosphere, preferably a nitrogen atmosphere, of known relative moisture.
  • the present invention also relates to a process for the production of the crystal modification A 2 of desferrioxamine-1-decanesulphonate according to the invention.
  • This process is characterised in that, in at least one process step, a suspension of desfer- rioxamine-1-decanesulphonate of unknown or unspecified morphological composition in a polar solvent is maintained at elevated temperature; or that in at least one process step, a concentrated solution of desferrioxamine-1-decanesulphonate in a polar solvent is prepared at elevated temperature and then crystallised at a cooling rate of 2°C or less per minute.
  • Polar solvents are for example polar organic compounds such as low alcohols, low ketones, low nitriles and low cyclic ethers, or water or mixtures thereof.
  • the term "low” indicates organic compounds which contain 1 to 4 inclusive carbon atoms and one or two hetero atoms such as oxygen, nitrogen and/or sulphur.
  • Preferred polar organic solvents are water-misci- ble organic solvents, such as methanol, ethanol, n-propanol, isopropanol, acetone, ethyl methyl ketone, acetonitriie, tetrahydrofuran or p-dioxane.
  • Especially advantageous for the production of the crystal modification A 2 according to the invention are water or mixtures of water-miscible organic solvents, especially methanol, ethanol, n-propanol and/or isopropanol, with water.
  • Water is most particularly preferred.
  • Elevated temperature indicates the temperature range from room temperature to boiling point of the solvent or solvent mixture, whereby the temperature range of 30°C to 80°C° inclusive is preferred, or up to boiling point of the polar solvent, which is also always lower, especially the temperature range of 35°C to 60°C.
  • Concentrated solution signifies that the solution contains such a quantity of dissolved substance that upon cooling of the solution to a lower temperature the dissolved substance partially crystallises.
  • Preferred concentrated solutions are saturated or slightly supersaturated solutions. Saturated or supersaturated solutions of a substance do not dissolve any further substance without raising the temperature. Supersaturated solutions may be prepared for example by rapid cooling of a saturated solution to a somewhat lower temperature. It is especially advantageous to use saturated solutions.
  • the preferred cooling rate of a solution is 2°C/minute or less. Cooling rates of 1 °C/minute or less are especially advantageous.
  • At least one seeding crystal is added.
  • Appropriate seeding crystals may be produced for example from a less stable form or a mixture of several less stable forms, by maintaining a suspension at an elevated temperature.
  • a solution of desferrioxamine methane sulphonate in a polar solvent is prepared, heated to the desired temperature, then one part of an equimolar quantity of a 1 -decanesulphonic acid salt in solution in the same or another polar solvent is added, at least one seeding crystal is added, maintained until the commencement of crystallisation, then the remainder of the equimolar quantity of the 1 -decanesulphonic acid salt in solution in the same or another polar solvent is slowly added, and then maintained at the desired temperature; or a hot-saturated solution of desferrioxamine- 1 -decanesulphonate in a polar solvent is produced at an elevated temperature, then after adding at least one seeding crystal it is cooled at a rate of 1 °C/minute or less to a lower elevated temperature, during which time crystallisation takes place, and the crystal suspension is maintained at this lower temperature.
  • the salts used as 1 -decanesulphonic acid salts may be for example all salts of 1 -decanesulphonic acid that have better solubility in the chosen polar solvent than desferrioxamine-1 - decanesulphonate.
  • These salts are salts with bases, such as corresponding alkali metal salts, e.g. sodium or potassium salts, or salts with ammonia or organic amines, such as cyclic amines, such as mono-, di- or tri-iower-alkylamines, such as hydroxy-lower-alkylamines, e.g.
  • Cyclic amines are e.g. morpholine, thiomorpholine, piperidine or pyrrolidine.
  • the mono-lower-alkylamines may be for example ethyl- and fe/T-butylamine.
  • the di-lower-alkylamines may be for example diethyl- and diisopropylamine, and the tri- iower-alkylamines may be for example trimethyl- and triethylamine.
  • hydroxy- lower-alkylamines are e.g. mono-, di- and triethanolamine; hydroxy-iower-alkyl-lower-alkyl- amines are e.g. N,N-dimethylamino- and N,N-diethylamino-ethanol, and polyhydroxy-lower- alkylamine may be e.g. glucosamine.
  • Working up may be effected in a basically known manner, by separating the crystallisate from the mother liquor, for example by filtration, with or without the assistance of pressure ⁇ nd/or vacuum, or by centrifugation, with subsequent drying.
  • the present invention also relates to pharmaceutical preparations comprising as active ingredient crystal modification A 2 of desferrioxamine-1 -decanesulphonate and a pharmaceutically acceptable carrier, preferably as described hereinbefore and hereinafter.
  • the invention also relates to the preparation of such a pharmaceutical preparation, preferably as described hereinbefore.
  • the invention also relates to the use of crystal modification A 2 of desferrioxamine-1 -decanesulphonate for the treatment of a disease selected from the group comprising iron-overload disease, aluminium overload, Alzheimer's disease, malaria, reper- fusion injury and cancer, especially thalassemia, or for the preparation of a pharmaceutical preparation for the treatment of such a disease.
  • the invention furthermore relates to a method of treatment of a disease selected from the group comprising iron-overload disease, aluminium overload, Alzheimer's disease, malaria, reperfusion injury and cancer, especially thalassemia, which comprises administering to a patient in need of such treatment a dose of crystal modification A 2 of desferrioxamine-1 -decanesulphonate that is pharmaceutically effective in the treatment of said disease.
  • a disease selected from the group comprising iron-overload disease, aluminium overload, Alzheimer's disease, malaria, reperfusion injury and cancer, especially thalassemia
  • the doses and percentages of the active ingredient are in accordance with the customary ones, especially those as described hereinbefore and hereinafter.
  • Desferrioxamine-B n-decansulphonate Preparation I used in the Examples is prepared as follows: An aqueous 10% solution of 1 -decanesulfonic acid sodium salt is added at 0-5 °C over 60 minutes to an aqueous 20% solution of desferrioxamine-B methanesulfonate, the molar ratio of the decanesulphonate salt to the methanesulphonate being 1 :1. Desferrioxamine-B n-decanesulfonate precipitates. The suspension is agitated for another 1 -2 hours at 0-5 °C before the product is collected by filtration. The product is washed with water, dried in vacuum at 40 °C for 20 hours and finally de-agglomerated over a sieve.
  • Desferrioxamine-B n-decansulphonate Preparation II used in the Examples is prepared as follows: Desferrioxamine-B methanesulphonate (12.3 parts) is dissolved in water (47 parts) at 30-40 °C. A solution of sodium n-decanesulphonate (0.7 parts) in water (12.0 parts) is added at 50 °C over a few minutes.
  • the solution is seeded by the addition of desferrioxamine-B n-decanesulphonate (0.08 parts) and, after stirring the resulting suspension for 30 min at 50 °C, a further solution of sodium n-decanesulphonate (3.8 parts) in water (64 parts) is added slowly with stirring over 3 to 4 hours at 50-52 °C.
  • the suspension obtained is stirred for a further 1 -2 hours at 50-52 °C and then cooled overnight to 40 °C.
  • the product is collected by filtration, washed with water, dried under vacuum at 50 °C for 20 hours and then de-agglomerated over a sieve.
  • Desferrioxamine-B n-decansulphonate, Preparation III used in the Examples is prepared as follows: Crude desferrioxamine-B n-decanesulphonate prepared by reacting n-decanesulphonic acid with desferrioxamine-B free base as described in Example 1 of WO93/24451 (548g) is dissolved in a mixture of ethanol (3000ml) and water (600ml) at 40 °C. The solution is filtered and the filtrate concentrated by distillation at 40 °C under reduced pressure (40 mbar). The thick suspension obtained is diluted with water (3000ml) and the product is collected by filtration, washed with water, dried in a vacuum at 50°C/20mbar for 20 hours and de-agglomerated over a sieve.
  • Example 1 Composition A
  • Desferrioxamine-B n-decansulphonate, Preparation I (1g) is mixed with sesame oil (3.75ml) and polyoxyethylene (20) sorbitan mono-oleate (0.02ml) until a lump-free suspension is obtained. Ethyl oleate (1.25ml) is added to the resulting suspension and mixed thoroughly therewith using pestle and mortar. Result: Mean particle diameter of 59.18 ⁇ m; particle size distribution: 90% less than 1 13.19 ⁇ m, 50% less than 55.08 ⁇ m and 10% less than 5.41 ⁇ m.
  • Example 1 is repeated, using 2.5ml of sesame oil and 2.5ml of ethyl oleate instead of the amounts used in Example 1.
  • Result Mean particle diameter of 66.34 ⁇ m; particle size distribution: 90% less than 121.78 ⁇ m, 50% less than 62.34 ⁇ m and 10% less than 6.49 ⁇ m.
  • Example 1 is repeated, using 1.25ml of sesame oil and 3.75ml of ethyl oleate instead of the amounts used in Example 1.
  • Result Mean particle diameter of 68.97 ⁇ m; particle size distribution: 90% less than 119.31 ⁇ m, 50% less than 66.97 ⁇ m and 10% less than 7.97 ⁇ m.
  • Example 2 is repeated, using 0.043ml of polyoxyethylene (20) sorbitan mono-oleate instead of the amount used in Example 2.
  • Result Mean particle diameter of 57.02 ⁇ m; particle size distribution: 90% less than 107.45 ⁇ m, 50% less than 54.65 ⁇ m and 10% less than 4.99 ⁇ m.
  • Example 2 is repeated, but omitting the polyoxyethylene (20) sorbitan mono-oleate. Result: Mean particle diameter of 60.04 ⁇ m; particle size distribution: 90% less than 112.84 ⁇ m, 50% less than 56.42 ⁇ m and 10% less than 5.25 ⁇ m.
  • Example 6 Composition F
  • Example 1 is repeated, using 2.5ml of sesame oil, 2.5ml of ethyl oleate and 0.043ml of polyoxyethylene (20) sorbitan mono-oleate instead of the amounts used in that Example, and additionally mixing the ingredients with sorbitan trioleate (0.057m! in the first stage of the procedure.
  • Result Mean particle diameter of 60.36 ⁇ m; particle size distribution: 90% less than 109.36 ⁇ m, 50% less than 58.14 ⁇ m and 10% less than 5.12 ⁇ m.
  • Example 2 is repeated, replacing the polyoxyethylene (20) sorbitan mono-oleate used in that Example by soy lecithin (0.011 g) .
  • Result Mean particle diameter of 43.13 ⁇ m; particle size distribution: 90% less than 93.62 ⁇ m, 50% less than 34.26 ⁇ m and 10% less than
  • Example 7 is repeated, using 0.027g of soy lecithin, instead of the amount used in that Example. Result: Mean particle diameter of 52.07 ⁇ m; particle size distribution: 90% less than 117.62 ⁇ m, 50% less than 39.98 ⁇ m and 10% less than 5.99 ⁇ m.
  • Desferrioxamine-B n-decansulphonate, Preparation II (1g) is mixed with sesame oil (2.5ml) and polyoxyethylene (20) sorbitan mono-oleate (0.02ml) until a lump-free suspension is obtained. Ethyl oleate (2.5ml) is added to the resulting suspension, and mixed thoroughly therewith. Result: Mean particle diameter of 41.48 ⁇ m and the following particle size distribution: 90% less than 99.19 ⁇ m, 50% less than 26.31 ⁇ m and 10% less than 5.24 ⁇ m.
  • Example 9 is repeated, using 0.004ml of polyoxyethylene (20) sorbitan mono-oleate in place of the amount used in that Example. Result: Mean particle diameter of 43.60 ⁇ m; particle size distribution: 90% less than 104.1 1 ⁇ m, 50% less than 26.63 ⁇ m and 10% less than 5.22 ⁇ m.
  • Example 11 Composition K
  • Example 9 is repeated, using 0.043ml of polyoxyethylene (20) sorbitan mono-oleate in place of the amount used in that Example. Result: Mean particle diameter of 30.60 ⁇ m; particle size distribution: 90% less than 73.40 ⁇ m, 50% less than 17.18 ⁇ m and 10% less than 5.22 ⁇ m.
  • Example 9 is repeated, but omitting the polyoxyethylene (20) sorbitan mono-oleate used in that Example. Result: Mean particle diameter of 43.75 ⁇ m and the following particle size distribution: 90% less than 104.80 ⁇ m, 50% less than 25.32 ⁇ m and 10% less than 5.36 ⁇ m.
  • Example 9 is repeated, using 3.75ml of sesame oil and 1.25ml of ethyl oleate instead of the amounts used in that Example and omitting the polyoxyethylene (20) sorbitan mono-oleate used in that Example. Result: Mean particle diameter of 50.52 ⁇ m; particle size distribution: 90% less than 118.97 ⁇ m, 50% less than 31.87 ⁇ m and 10% less than 6.91 ⁇ m.
  • Example 9 is repeated, using 1.25ml of sesame oil and 3.75ml of ethyl oleate instead of the amounts used in that Example and omitting the polyoxyethylene (20) sorbitan mono-oleate used in that Example. Result: Mean particle diameter of 35.83 ⁇ m; particle size distribution: 90% less than 86.60 ⁇ m, 50% less than 19.85 ⁇ m and 10% less than 5.92 ⁇ m.
  • Example 9 is repeated, but omitting the polyoxyethylene (20) sorbitan mono-oleate used in that Example. Result: Mean particle diameter of 39.50 ⁇ m; particle size distribution: 90% less than 96.33 ⁇ m, 50% less than 22.08 ⁇ m and 10% less than 6.23 ⁇ m.
  • Example 9 is repeated, using 5.00ml of ethyl oleate instead of the amount used in that
  • Example 17 Plasma Levels in hamsters I
  • Desferrioxamine-B n-decansulphonate, Preparation I (1g) is ground in a triple roll mill with a mixture of sesame oil (2.5ml), ethyl oleate (2.5ml), polyoxyethylene (20) monoiaurate (0.057ml) and polyoxyethylene (20) sorbitan mono-oleate (0.043ml) which is added slowly to the salt.
  • the resulting parenterally injectable suspension is tested for in vivo release of the desferrioxamine-B salt as follows:
  • mice Male golden Syrian hamsters weighing 100g + 20g are injected subcutaneously in the nape of the neck with the suspension at a dosage of 1 ml per kg. At various time intervals the animals are terminally anaesthetised, and blood samples are obtained by cardiac puncture, the blood being collected in heparinised syringes and centrifuged. The plasma is removed and the combined concentration of desferrioxamine-B and metabolite B in the plasma is determined by immunoassay. The results, expressed as the average results for 3 animals for each time interval, are as follows:
  • the immunoassay is done by a solid phase enzyme based immunoassay that is capabe of detecting the presence of the iron chelating compound DesferalTM and its major metabolite, Metabolite B, in biological fluids such as plasma and urine.
  • a polyclonal rabbit antibody was developed. It can distinguish between the parent molecule desferriox- amine (DFO) and the chelated form, Ferrioxamine (FO).
  • DFO desferriox- amine
  • FO Ferrioxamine
  • the principle of the method is as follows: FO is coated onto wells of a 96 well-plate (Nunc Maxisorb) via a biotin/streptavidin link.
  • a standard curve of DFO or Metabolite B is prepared in the diluted (1/20 in buffer) biological fluid (serum, urine etc.) containing ferric citrate (1 mM) as the iron source. Test samples are diluted accordingly in the same fluid. Appropriately diluted anti-ferrioxamine antibody is added and allowed to react. Unbound antibody is removed by washing. Bound antibody is detected using a goat anti-rabbit IgG Fc horseradish peroxidase conjugated antibody and a peroxidase substrate. The amount of colour produced is inversely proportional to the amount of DFO/MetB in the sample.
  • the antibody is produced as follows:
  • Immunogenic bovine serum albumin (BSA)/desferrioxamine conjugate is produced according to standard procedures (activation of BSA with N-succinimidyl 3-(2-pyridyldithio)- proprionate (SPDP), removal of the DPDP excess by dialysis, reduction with dithiothreitol to obtain BSA with attached sulfhydryl groups, dialysis, then addition of SPDP, DFO and N- methyimorpholine, after 1 h centrif ugation at 1000 g for 5 min and dialysis against PBS at 4 °C for 17 h, storing the resulting solution at -80 °C.
  • SPDP N-succinimidyl 3-(2-pyridyldithio)- proprionate
  • a keyhole limpet hemocyanin (KLH)/DFO conjugate is obtained in an analogous way. These conjugates are then injected s.c. into Dutch rabbits (Harlan-Olac) with alternating BSA-DFO and KLH conjugates mixed (1 :1) with incomplete Freund's adjuvant (450 ⁇ g BSA-DFO month 0, 300 ⁇ g KLH-DFO month 1 , 250 ⁇ g BSA-DFO month 2, 150 ⁇ g KLH-DFO month 3, 150 ⁇ g BSA-DFO month 6, 150 ⁇ g KLH-DFO month 10). Blood is isolated and serum prepared and stored at -20 °C. The antibodies are isolated over protein A-agarose by routine methods.
  • Biotin-FO/DFO conjugate is prepared by reaction of biotin-LC-NHS in water/dimethylform- amide with FO in the presence of N-Methylmorpholine.
  • the competition assay relies on the drug in the sample competing with the bound drug for the binding of the antibody which is then detected with a horseradish peroxidase conjugated anti-species antibody.
  • concentration of drug is measured using a standard curve of DFO and a standard curve of Metabolite B (MetB) (at molar equivalent concentrations) diluted in the appropriate biological fluid/buffer mix.
  • the antibody recognizes only the iron bound forms of DFO or any of the iron chelating metabolites, which are converted in situ by addition of 1 mM ferriccitrate to the sample buffer.
  • the assay is performed in two different buffers, 0.3 M PBS pH 6.4 or 0.3 M Borate pH 7.4.
  • the plasma or urine samples are also converted to the iron bound form by the addition (1/2) of 1 mM ferric citrate.
  • Streptavidin is diluted to 1 ⁇ g/ml in 0.1 M carbonate coating buffer pH 9.6, added to the wells of a microtiter plate (100 ⁇ l/well) and incubated overnight at 22 °C. The wells are washed four times with PBS/Tween (Tween 20, Sigma, Poole, Dorset). Residual adsorption sites on the plate are saturated by incubation with 200 ⁇ l of PBS containing 0.1% casein for 1 h at 37 °C. The wells are washed four times with PBS/Tween.
  • Biotin-FO (427 ⁇ g/ml) is diluted (1 ng/ml) in PBS/casein and incubated in the wells (100 ⁇ l/well) for 2 h at 22 °C.
  • the wells are washed four times with PBS/Tween.
  • DFO and MetB standards range 2.80500 to 0.00273 /0.00000 ⁇ M
  • the rabbit anti- ferrioxamine antibody is diluted 1/800 in either pH 6.4 or 7.4 buffer and added (50 ⁇ l/well) to the same set of wells, mixed in a micro shaker for 30 seconds and incubated for 2 h at 22 °C.
  • the samples are diluted in either buffer and treated the same way as the FO standards.
  • the wells are washed four times with PBS/Tween.
  • a horseradish peroxidase conjugated anti-rabbit IgG Fc antiseru (Biogenesis, Poole, Dorset) is diluted 1/2500 and incubated in the wells (100 ⁇ l/well) overnight at 4 °C.
  • the wells are washed four times with PBS/Tween.
  • the enzyme conjugated antiserum that has remained bound after washing is developed by incubating the plate with 100 ⁇ l/well o-phenylendiamine dihydrochloride for 20 min in the dark.
  • the reaction is stopped with the addition of 100 ⁇ l/well 1 M HCI.
  • the colour is measured using a Dynatech MR600 colourimeter at 490 nm.
  • Example 18 Plasma levels in hamsters II
  • Example 17 is repeated, but grinding the salt with the other components of the suspension using an agate pestle and mortar instead of the tiple roll mill used in Example 17.
  • the resulting parenterally injectable suspension is tested as in Example 17. The results are as follows:
  • Example 19 Plasma levels in hamsters III
  • Example 17 is repeated, using Desferrioxamine-B n-decansulphonate, Preparation III (1 g) instead of the Desferrioxamine-B Salt I used in that Example.
  • the resulting parenterally injectable suspension is tested as in Example 17. The results are as follows:
  • Example 20 Plasma levels in hamsters IV
  • Example 18 is repeated, using Desferrioxamine-B n-decansulphonate, Preparation III (1 g) instead of the Desferrioxamine-B Salt I used in that Example.
  • the resulting parenterally injectable suspension is tested as in Example 17. The results are as follows:
  • Example 21 Plasma levels in hamsters V
  • Desferrioxamine-B n-decansulphonate, Preparation III (1 g) is ground, using an agate pestie and mortar, with a mixture of sesame oil (2.5ml), ethyl oleate (2.5ml), sorbitan trioleate (0.075ml) and polyoxyethylene-4-lauryl ether (0.025ml) which is added slowly to the salt.
  • the resulting parenterally injectable suspension is tested as in Example 17. The results are as follows:
  • Example 22 is repeated using 19.8 parts of Desferrioxamine-B n-decansulphonate, Preparation II and 99 parts of Miglyol 812 instead of the amounts used in that Example.
  • the resulting parenterally injectable suspension is tested for its effect on iron excretion in bile duct cannulated rats. After collecting control bile and urine samples for 3 hours, the rats (male Fischer) are injected subcutaneously with the suspension (591 ⁇ l/kg, corresponding to a desferrioxamine dosage of 117 mg/kg). Bile samples are then collected at 3 hour intervals and their iron content determined. The results for rats injected with the suspension are shown below (average for 3 animals):
  • the resulting material is mixed in the oil phase (ratio and ingredients as in example 22 or 23).
  • the homogeneous suspension is filled in a container (glass vial, prefilled syringe or bottelpack container) and sterilized by gamma or beta irradiation of heat treatment
  • a mixture of sesame oil (2.0ml), ethyl oleate (2.0ml), sorbitan trioleate (75 ⁇ l) and poiyoxy- ethylene-4-lauryl ether (25 ⁇ l) is added slowly to desferrioxamine-B n-octanesulphonate (1 g), while grinding with an agite pestle and mortar, to give a parenterally injectable suspension.
  • the suspension is tested for its affect on iron elimination in male golden Syrian hamsters iron-loaded by intravenous injection of 59 Fe labelled ferritin (100 ⁇ l).
  • the suspension under test is administered by subcutaneous injection, at a desferrioxamine dosage of 150 ⁇ mol/kg, one hour after administration of the ferritin.
  • the 59 Fe content of urine and faeces is determined using a gamma-counter after 24 hours and 48 hours.
  • the results for hamsters injected with the suspension (average for 6 animals) and control hamsters receiving no iron chelator (average for 5 animals) are shown below:

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Abstract

L'invention concerne une composition pouvant être injectée par voie parentérale. Cette composition comprend des particules d'un sel desferrioxamine-B d'un acide sulfonique aliphatique comprenant au moins 8 atomes de carbone en suspension dans une huile pouvant être administrée par voie parentérale. L'invention concerne également de nouvelles modifications cristallines de sel décanésulfonique de desferrioxamine B, et une forme cristalline avec une meilleure stabilité.
PCT/EP1997/006849 1996-12-10 1997-12-08 Formulations et formes polymorphes de desferrioxamine et rpeparation de ces dernieres WO1998025887A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
HU0000705A HUP0000705A2 (hu) 1996-12-12 1997-12-08 A deferrioxamin készítményei és polimorf formái, valamint eljárás előállításukra
BR9713570-4A BR9713570A (pt) 1996-12-10 1997-12-08 Formulações e formas polimórficas de desferrioxamina e a sua preparação.
EP97954727A EP0944586A2 (fr) 1996-12-10 1997-12-08 Formulations et formes polymorphes de desferrioxamine et rpeparation de ces dernieres
AU59839/98A AU5983998A (en) 1996-12-10 1997-12-08 Formulations and polymorphic forms of desferrioxamine and the preparation thereof
CA002274761A CA2274761A1 (fr) 1996-12-10 1997-12-08 Formulations et formes polymorphes de desferrioxamine et preparation de ces dernieres
IL13020397A IL130203A0 (en) 1996-12-10 1997-12-08 Formulations and polymorphic forms of desferrioxamine and the preparation thereof

Applications Claiming Priority (4)

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CH302496 1996-12-10
CH3024/96 1996-12-10
GB9625878.5 1996-12-12
GBGB9625878.5A GB9625878D0 (en) 1996-12-12 1996-12-12 Compositions

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6670399B2 (en) * 1999-12-23 2003-12-30 Neurochem (International) Limited Compounds and methods for modulating cerebral amyloid angiopathy
EP1769791A3 (fr) * 2001-07-19 2007-07-11 Isis Innovation Limited Strategies therapeutiques pour la prevention et le traitement de la maladie d'alzheimer
WO2017068089A2 (fr) 2015-10-23 2017-04-27 Vifor (International) Ag Nouveaux inhibiteurs de la ferroportine
WO2018192973A1 (fr) 2017-04-18 2018-10-25 Vifor (International) Ag Sels inhibiteurs de ferroportine
WO2020201305A1 (fr) 2019-04-01 2020-10-08 Vifor (International) Ag Dérivés d'acide 4-(2,4-bis (2-hydroxyphényl)-1h-imidazol-1-yl) benzoïque en tant que nouveaux chélateurs du fer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10223913A1 (de) * 2002-05-29 2003-12-11 Bayer Cropscience Ag Verfahren zur Herstellung spezifischer Kristallmodifikationen polymorpher Substanzen

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1898M (fr) * 1961-04-07 1963-07-08 Ciba Geigy Nouvelle substance utilisable en thérapeutique.
US3247197A (en) * 1959-09-25 1966-04-19 Ciba Geigy Corp Tetrahydro-3:6-diodo-1:2-oxazines
WO1993024451A1 (fr) * 1992-06-03 1993-12-09 Ciba-Geigy Ag Sels de desferrioxamine-b et leur utilisation comme chelateurs de fer a efficacite orale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3247197A (en) * 1959-09-25 1966-04-19 Ciba Geigy Corp Tetrahydro-3:6-diodo-1:2-oxazines
FR1898M (fr) * 1961-04-07 1963-07-08 Ciba Geigy Nouvelle substance utilisable en thérapeutique.
WO1993024451A1 (fr) * 1992-06-03 1993-12-09 Ciba-Geigy Ag Sels de desferrioxamine-b et leur utilisation comme chelateurs de fer a efficacite orale

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6670399B2 (en) * 1999-12-23 2003-12-30 Neurochem (International) Limited Compounds and methods for modulating cerebral amyloid angiopathy
EP1769791A3 (fr) * 2001-07-19 2007-07-11 Isis Innovation Limited Strategies therapeutiques pour la prevention et le traitement de la maladie d'alzheimer
US8343926B2 (en) 2001-07-19 2013-01-01 Isis Innovation Ltd. Therapeutic strategies for prevention and treatment of alzheimer's disease
US8921321B2 (en) 2001-07-19 2014-12-30 Isis Innovation Ltd. Therapeutic strategies for prevention and treatment of alzheimer's disease
WO2017068089A2 (fr) 2015-10-23 2017-04-27 Vifor (International) Ag Nouveaux inhibiteurs de la ferroportine
US10364239B2 (en) 2015-10-23 2019-07-30 Vifor (International) Ag Ferroportin inhibitors
US10738041B2 (en) 2015-10-23 2020-08-11 Vifor (International) Ag Ferroportin inhibitors
US11001579B2 (en) 2015-10-23 2021-05-11 Vifor (International) Ag Ferroportin inhibitors
US11066399B2 (en) 2015-10-23 2021-07-20 Vifor (International) Ag Ferroportin inhibitors
WO2018192973A1 (fr) 2017-04-18 2018-10-25 Vifor (International) Ag Sels inhibiteurs de ferroportine
US11129820B2 (en) 2017-04-18 2021-09-28 Vifor (International) Ag Ferroportin-inhibitor salts
WO2020201305A1 (fr) 2019-04-01 2020-10-08 Vifor (International) Ag Dérivés d'acide 4-(2,4-bis (2-hydroxyphényl)-1h-imidazol-1-yl) benzoïque en tant que nouveaux chélateurs du fer

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AU5983998A (en) 1998-07-03
TR199901260T2 (xx) 1999-10-21
CA2274761A1 (fr) 1998-06-18
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CZ204499A3 (cs) 1999-09-15
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BR9713570A (pt) 2000-03-14

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