GB2314268A

GB2314268A - Pulmonary administration of desferrioxamine-B salts

Info

Publication number: GB2314268A
Application number: GB9612684A
Authority: GB
Inventors: Alan Steward
Original assignee: Ciba Geigy AG; Novartis AG
Current assignee: Novartis AG
Priority date: 1996-06-18
Filing date: 1996-06-18
Publication date: 1997-12-24
Also published as: GB9612684D0

Abstract

Desferrioxamine-B salts in the form of i) nebulizable aqueous suspensions or solutions or; ii) in admixture with a suitable aerosol propellant such as propane or fluorocarbon, e.g. tetrafluoroethane or; (iii) in powder form; are suitable for pulmonary administration via inhalation or intra-tracheal injection.

Description

Pharmaceutical Products This invention relates to pharmaceutical products containing a salt of desferrioxamine-B, and to inhalation devices containing such products.

The preparations of desferrioxaime-B and pharmaceutically acceptable addition salts thereof are described in U.S. Patent No. 3247197. The amine and salts thereof such as those described in the above mentioned U.S. patent exhibit a marked ability to form stable complexes with trivalent metal ions, especially Fe > . Consequently, desferrioxamine-B (especially administered as the methane sulphonate salt) is of immense importance as a pharmacological iron-chelator in the treatment of ironoverload diseases such as beta-thalassemia. As the only currently marketed drug which is available for the treatment of thalassemia, desferrioxamine-B is vital to the survival of patients suffering from this disease.

Administration of desferrioxamine-B (as the methane sulphonate salt) via slow (8 to 12 hour) subcutaneous infusion is now widely accepted as the route necessary to control transfusional iron overload in beta-thalassemics. However, such a mode of treatment is laborious, uncomfortable and inconvenient for the patient, and involves high costs. Patient compliance is poor: non-compliance with iron-chelation therapy has been suspected to be the most importance cause of death amongst thalassemics.

Hence there is a great need for simpler, more convenient and cheaper iron-chelation therapy.

This need has been apparent for a long time, and numerous attempts have been made over many years to obtain a form of desferrioxamine-B which is effective in ironoverload therapy when administered by more convenient methods. In WO 93/24451 there are described organic sulphonate salts of desferrioxamine-B which can be administered orally.

It has now been found, in accordance with the present invention, that desferrioxamine-B, particularly in the form of a salt thereof, can be administered in a highly efficacious manner by pulmonary delivery. A relatively low dose of desferrioxamine-B administered by the pulmonary route is effective over an extended period, the lung apparently acting as a slow release reservoir.

Accordingly the present invention provides, in one aspect, a pharmaceutical product comprising a pharmaceutically acceptable salt of desferrioxamine-B in a form adapted for pulmonary administration.

Pharmaceutically acceptable salts of desferrioxamine-B include, for example, salts with hydrohalic acids such as hydrochloric or hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, carboxylic acids such as acetic, propionic, glycollic, lactic, malonic, succinic, maleic, malic, tartaric, citric, ascorbic, benzoic, phenylacetic, salicyclic, or 4-aminebenzoic acids or methionine, lysine or arginine.

Preferred pharmaceutically acceptable salts of desferrioxamine-B are organic sulphonate salts which may be, for example, aliphatic sulphonate salts, including salts of unsubstituted and substituted, e.g. hydroxy-, alkoxy-, acyloxy-, alkoxycarbonyl-, halogen- or amino-substituted alkanesulphonic acids, alkenesulphonic acids and alkyne sulphonic acids such as methanesulphonic, ethanesulphonic, propane-l-sulphonic acid, propane-2-sulphonic acid, butane-lsulphonic acid, 2-methyl-l-propanesulphonic acid, pentane-l-sulphonic acid, 3methyl-l-butanesulphonic acid, 2-methyl-l-butanesulphonic acid, pentane-2sulphonic acid, hexane-l-sulphonic acid, 2-ethyl-l-butanesulphonic acid, 4-methyl2-pentanesulphonic acid, hexane-2-sulphonic acid, heptane-l-sulphonic acid, heptane-2-sulphonic acid, octane- l-sulphonic acid, ocatane-2-sulphonic acid, nonane- l-sulphonic acid, nonane-2-sulphonic acid, decane- 1 -sulphonic acid, dodecane-l -sulphonic acid, tetradecane- 1 -sulphonic acid, hexadecane- 1 -sulphonic acid, octadecane-l-sulphonic acid, 2-hydroxypropane-l-sulphonic acid, 3 hydroxypropane- 1 -sulphonic acid, 1 -hydroxyoctane-2-sulphonic acid, 2ethoxyethane-l-sulphonic acid, 2-acetoxy-l-butanesulphonic acid, dioctyl sulphosuccinate, 3-chioropropane- 1 -sulphonic acid, 4bromobutane- 1 -sulphonic acid, l-aminopropane-2-sulphonic acid, 3-aminopropane-l-sulphonic acid, 2 aminopropane- l-sulphonic acid, l-aminobutane-2-sulphonic acid, 4aminobutane- 1 - sulphonic acid or 2-aminobutane-l-sulphonic acid, allylsulphonic acid, 2-methyl-2propene-l-sulphonic acid, hexene-l-sulphonic acid, octene-l-sulphonic acid, decenel-sulphonic acid, dodecene-l -sulphonic acid, tetradecene- 1 -sulphonic acid, hexadecene- 1 -sulphonic acid, methylacetylene sulphonic acid or decylacetylene sulphonic acid; cycloaliphatic sulphonate salts, for example salts of cyclopentanesulphonic acid, cyclohexanesulphonic acid, cyclopentene- l-sulphonic acid, cyclohexene-l-sulphonic acid, or l,3-cyclohexadiene-l-sulphonic acid; and aromatic sulphonate salts such as a benzenesulphonate, p-toluenesulphonate or sulphanilate.

Preferred organic sulphonate salts of desferrioxamine-B are C1 to C20 aliphatic sulphonate salts, more preferably C, to C12 aliphatic sulphonate salts.

The salts of desferrioxamine-B may be prepared by conventional salt-forming reactions. For example, the organic sulphonate salts may be prepared by reacting desferrioxamine-B with a sulphonic acid in a solvent from which the desired salt crystallises out. Desferrioxamine-B may be prepared as described in US Patent 3153621 or US Patent 3247197.

In one embodiment of the invention the desferrioxamine-B salt, particularly a C1 to C6 aliphatic sulphonate, is in the form of an aqueous solution for intratracheal injection, the dosage units for such injection preferably containing 3 to 15 ml of aqueous solution containing 50 to 250 mg of desferrioxamine salt per ml of solution.

In another embodiment of the invention, the desferrioxamine-B salt, preferably a C, to C6 aliphatic sulphonate and especially the methane sulphonate, is in the form of a nebulizable aqueous solution or suspension, containing the salt in a concentration suitable for administration by inhalation, preferably containing 50 to 250 mg of desferrioxamine salt per ml of solution or suspension.

Where the desferrioxamine-B salt is in the form of an aqueous solution adapted for administration by intratracheal injection or a nebulizable aqueous solution or suspension, the aqueous solution or suspension is preferably buffered to maintain a pH of 5.5 to 8, preferably 6.0 to 7.5. Suitable buffering salts include sodium and potassium bicarbonates, hydrogen phosphates and dihydrogen phosphates. The aqueous solution or suspension may also contain other metal salts, particularly alkali metal, calcium and magnesium halides and magnesium sulphate. A preferred buffered aqueous solution in which the desferrioxamine-B salt may be dissolved or suspended contains sodium bicarbonate, sodium dihydrogen phosphate, sodium, calcium and potassium chlorides, magnesium sulphate and glucose for example Krebs-Henseleit solution.

In a further embodiment of the invention, the desferrioxamine-B salt is in admixture with a pharmaceutically acceptable aerosol propellant in a pressurised aerosol composition. The desferrioxamine-B salt may be in solution in a solvent in admixture with the propellant but is preferably present in the aerosol composition in particulate form. Suitable propellants include hydrocarbons such as n-propane, nbutane or isobutane or mixtures of two or more such hydrocarbons, or halogenated hydrocarbons, for example fluorine-substituted methanes, ethanes, propanes, nbutanes, isobutanes, cyclopropanes or cyclobutanes, particularly tetrafluoroethane, trifluoroethane, difluoroethane and heptafluoropropane.

Such aerosol compositions, particularly where the desferrioxamine-B salt is a C, to C6 aliphatic sulphonate, may also contain buffering agents to increase the pH of a solution formed by contact of the salt with moisture in the pulmonary tract of a patient. Such aerosol compositions may also contain other excipients such as those conventionally used in pharmaceutical aerosols, including polar solvents such as ethanol, isopropanol, propylene glycol or glycerol and mixtures of two or more thereof and surfactants.

In a further embodiment of the invention, the desferrioxamine-B salt is in the form of a dry powder having a particle size suitable for inhalation, optionally in admixture with a pharmaceutically acceptable solid carrier in powder form. The solid carrier may be, for example, a material which is known as a carrier or diluent in dry powder inhalation compositions. Such materials include saccharides, e.g. monosaccharides such as arabinose or glucose, disaccharides such as sucrose, lactose or maltose and polysaccharides such as starches or dextran. An especially preferred carrier is lactose, which may be used in commercially available coarse form having a particle size up to 2OOtim or may be ground to smaller particle size, for example 30 to 80 clam, using conventional methods. The dry powder may be in capsules of gelatin or plastic or in blisters for use in a dry powder inhalation device, preferably in dosage units of 20 to 50mg of the desferrioxamine-B salt.

In the dry powder embodiment of the invention, and in the aerosol composition where the desferrioxamine-B salt is present in particulate form, the desferrioxamine B salt preferably has an average particle diameter of up to 10 tim, for example 1 to Stem. The particle size of the salt can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation from solution, spray drying, lyophilisation or recrystallisation from supercritical media.

A composition of the invention may also contain one or more pharmaceutically acceptable flavouring agents, such agents being chosen in accordance with the physical form of the composition. Suitable flavouring agents include menthol, thymol and saccharin.

The present invention provides, in another aspect, a pharmaceutical product comprising a pharmaceutically acceptable salt of desferrioxamine-B, in a form adapted for administration by inhalation as hereinbefore described, in association with an inhalation device.

In a further aspect, the present invention provides an inhalation device containing a pharmaceutical product comprising a pharmaceutically acceptable salt of desferrioxamine-B as hereinbefore described.

Where the desferrioxamine-B salt is in the form of a nebulizable aqueous solution or suspension, the inhalation device may be a known nebulizer, for example a pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer. The nebulizer may contain from 5 to 50 ml of the aqueous solution or suspension containing from 50 to 250 mg of the desferrioxamine-B salt per ml of solution or suspension.

Where the desferrioxamine-B salt is in a pressurised aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, e.g. 25 to 100z1, of the composition. Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy.

When the desferrioxamine-B salt is to be administered as a dry powder, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dosage unit of the dry powder or a multidose dry powder inhalation device adapted to deliver, for example, 25 mg of dry powder per actuation. Suitable such dry powder inhalation devices are well known.

A pharmaceutical product of the invention as hereinbefore described may be used for the treatment of indications such as aluminium overload, Alzheimer's disease, malaria, reperfusion injury, cancer and particularly for the treatment of iron-overload diseases. The present invention therefore further provides a method of treating one or more of the above indications which comprises administration to a patient by pulmonary delivery of desferrioxamine-B or a salt thereof as hereinbefore described.

The invention is illustrated by the following Examples.

Example 1 Desferrioxamine-B methanesulphonate (0.0984g) is dissolved in lml of Krebs Henseleit solution, an aqueous containing sodium chloride (6.9g/l), sodium bicarbonate (2.1gel), glucose (2g/l), calcium chloride (0.37g/l), potassium chloride (0.35g/l) magnesium sulphate (0.29g/l) and potassium dihydrogen phosphate (0. 16gun), to give an aqueous solution having a pH of 6.8 suitable for intratracheal injection.

The above desferrioxamine-B salt solution is tested in a hamster model with [59Fe] ferritin sequestered into hepatocytes, the hamster being selected on the basis of its desferrioxamine plasma stability and metabolism being similar to that of humans.

The [59Fe] ferritin is isolated from rat liver as follows: Male Wistar rats weighing 300 + 50g are given a single intraperitoneal injection of 15 mg of iron dextran. One week later the jugular vein is chronically cannulated under 1-3% halothane anaesthesia and the rats allowed 24 hours recovery period. The animals are then slowly infused intravenously (i.v.) with 2ml of packed rat erythrocytes (diluted with lml of saline) per 100g bodyweight. The following day 0.4ml (2mg) of a ferric citrate solution is given intravenously (i.v.) 10 minutes before the 250 pCi of 59Fe- ferric citrate (the [59Fe] ferric chloride is converted to 59Fe-ferric citrate just prior to dosing). The animals are then injected with an overdose of pentobarbitone 24 hours later and the livers removed. Isolation and purification of the 59Fe-ferritin is carried out by centrifugation and selective ammonium sulphate precipitation. Purity is determined using polyacrylamide gel electrophoresis and autoradiography. Iron content is determined colorimetrically using bathophenanthroline sulphonate. The solution is diluted with phosphate buffered saline to give about 100,000 cpm in 100cull as determined on a Packard Sy-counter which represents 18-501lg of iron.

Chronic cannulation of the jugular vein of male golden Syrian hamsters weighing 100 + 20g is carried out using 401l1 Hypnorm (fentanyl and fluanisone) dosed intramuscularly as premedication and 2-3% halothane anaesthesia The animals are allowed a day to recover. Prior to dosing, the hamsters are starved overnight. They are sedated with 401l1 Hypnorm and then dosed with lOOttl of S9Fe-ferritin followed one hour later by the desferrioxamine-B salt solution to deliver desferrioxamine at iOmg per kg. The intratracheal dosing is performed under 1% halothane anaesthesia after exposing the trachea and the wound is closed with sutures prior to recovery.

The dose of the desferioxamine-B salt solution is given rapidly through a 23 G needle (1all1 per ig bodyweight) and followed with an injection of 0.5ml of air. Six hours after dosing with desferrioxamine the animals are given an overdose of pentobarbitone. Blood is removed by cardiac puncture and tissues are removed for assay for 59Fe content using a Packard y-counter. Biliary excretion is determined by radioisotope counting of the intestines and their contents. The percentage of the S9Fe dose eliminated in the bile is 6.15%.

Example 2 Desferrioxamine-B methanesulphonate (0.0984g) is dissolved in 1 ml of Krebs Henseleit solution as used in Example 1 to give a nebulizable aqueous solution having a pH of 6.8 suitable for administration to a patient by inhalation using an airjet nebulizer.

Example 3 Desferrioxamine-B hexanesulphonate (0.109g) is dissolved in 1 ml of Krebs Henseleit solution as used in Example 1 to give a nebulizable aqueous solution suitable for administration to a patient by inhalation using an airjet nebulizer.

Claims

1. A pharmaceutical product comprising a pharmaceutically acceptable salt of desferrioxamine-B in a form adapted for pulmonary administration.

2. A product according to claim 1, in which the salt is an organic sulphonate salt.

3. A product according to claim 2, in which the salt is a C, to C, aliphatic sulphonate salt.

4. A product according to claim 3, in which the salt is a C, to C,2 alkanesulphonate salt.

5. A product according to any one of the preceding claims, in which the salt is in the form of an aqueous solution in a dosage unit thereof suitable for intratracheal injection.

6. A product according to any one of claims 1 to 4, in which the salt is in the form of a nebulizable aqueous solution or suspension containing the salt in a concentration suitable for administration by inhalation.

7. A product according to claim 6, in which the salt is a C, to C6 aliphatic sulphonate of desferrioxamine-B.

8. A product according to claim 5, 6 or 7, in which the aqueous solution or suspension is buffered to maintain a pH of 5.5 to 8.

9. A product according to claim 8, in which the aqueous solution or suspension is buffered to maintain a pH of 6.5 to 7.5.

10. A product according to any one of claims 6 to 9, in which the aqueous solution or suspension contains the desferrioxamine-B salt in an amount of 50 to 250 mg per ml of solution or suspension.

11. A product according to any one of claims 1 to 4, in which the salt is in admixture with a pharmaceutically acceptable aerosol propellant in a pressurised aerosol composition.

12. A product according to any one of claims 1 to 4, in which the salt is in the form of a dry powder having a particle size suitable for inhalation, optionally in admixture with a pharmaceutically acceptable solid carrier in powder form.

13. A product according to claim 12, which is in a capsule of gelatin or plastic or in a blister.

14. A product according to any one of claim 11 to 13, in which the salt has an average particle size diameter of up to 1011m.

15. A product according to claim 14, in which the salt has an average particle diameter of 1 to 5calm.

16. A product according to any one of the preceding claims in association with an inhalation device suitable for delivery of said product.

17. An inhalation device containing a product according to any one of claims 1 to 4and6to 15.

18. A method of treating an iron-overload disease, aluminium overload, Alzheimer's disease, malaria, reperfusion injury or cancer which comprises administration to a patient by pulmonary delivery of desferrioxamine-B or a salt thereof.

19. A method according to claim 18, in which the salt is as specified in any one of claims 1 to 15.

20. A product according to claim 1, substantially as described in any of the Examples.