Pharmaceutical ion exchange resin composition

Abstract: A process for the preparation of a pharmaceutical ion exchange resin composition that is readily dispersible in water comprising granulating an ion exchange resin, having a pharmacologically active ingredient bound to it, with a sugar or a sugar alcohol in the presence of sufficient water, aqueous alcohol or alcohol to allow granulation. Preferably the active ingredient is morphine or metoclopramide and the sugar alcohol is xylitol. Granulation, rather than mere mixing, enhances the rate at which the composition forms a suspension in water.

Description: The present invention relates to a pharmaceutical ion exchange resin composition and to a process of preparing the composition. According to the present invention there is provided a process for the preparation of a pharmaceutical ion exchange resin composition that is readily dispersible in water comprising granulating an ion exchange resin having a pharmacologically active ingredient bound thereto with a sugar or a sugar alcohol in particulate form, in the presence of sufficient ware, aqueous alcohol or alcohol to facilitate granulation the amount of water, aqueous alcohol or alcohol employed in the granulation is from 1% to 20% (by weight) of the combined weight of the drug-resin complex and the sugar or the sugar alcohol. EP-A2-0122219, FR-M-792, US-A-3138525, EP-A2-0225615 and GB-A-791281 all describe resin compositions in the form of standard tablet formulations and do not teach granule formulations for reconstitution. EP-A1-0022932 in Example 4 refers to granules prepared from hexoprenaline resinate, lactose, maize starch, collidone and glycerol palmistearate which are filled into capsules, there is no teaching of granulation with water, alcohol or aqueous alcohol as claimed in the present invention. DE-A-2810250 and DD-B-249634 relate to pharmaceutical compositions containing cholestyramine, a polystyrene-divinylbenzene copolymer anion exchange resin. These references are directed to obtaining an acceptable cholestyramine resin formulation which is effective in binding reflexed bile. GB 2218333A describes granules prepared by granulating a ranitidine resin adsorbate with a sugar alcohol (xylitol) using a solution of hydroxypropylmethyl cellulose in aqueous ethanol, there is no disclosure of the amount of granulating medium employed. In the present specification, the phrase "readily dispersible in water" means that the composition must disperse, with stirring in 20 times its own weight of water within 10 seconds. Any acidic or basic drug may be bound to the ion exchange resin. Preferably, however, active ingredients having a biological half life of 8 hours or less are used. Suitable ingredients include i. Narcotic analgesics, such as codeine, dihydrocodeine, hydromorphone, morphine, pentazocine and propoxyphene, ii. Sympathomimetics, such as norephedrine and pseudoephedrine, iii. Antitussives, such as dextromethorphan, iv. Analgesics, such as aspirin, v. Antiemetics, such as metoclopramide, vi. Anticholinergics, such as atropine, ipratropium bromide and scopolamine, vii. Muscle relaxants, such as cyclobenzaprine and papaverine, viii. Bronchodilators, such as salbutamol, terbutaline and theophylline, ix. Antibiotics, such as amoxycillin, ampicillin, azlocillin, bacampicillin, cefamandole, cefonicid, cefotaxime, cefotetan, cefoxitin, ceftriaxone, mezlocillin and piperacillin, x. Antidepressants, such as bupropion, nomifensine, and nortriptyline, xi. Antiasthmatics, such as cromolyn, xii. Antineoplastics, such as tamoxifen. xiii. Antiepileptics, such as valproic acid and phenytoin, xiv. Cardiovascular agents, such as propranolol. Acid addition salts or, if appropriate, alkali or alkaline earth metal salts of the above drugs would be particularly suitable for use in the present process. Similarly, a wide range of cationic (for the basic drugs) or anionic (for the acidic drugs) exchange resins may be used to bind the active ingredient. Suitable ion exchange resins have acrylic, methacrylic, phenol-formaldehyde or dextran matrices. However, a preferred cationic ion exchange resin is a gel styrene-divinyl benzene sulphonic acid resin, such as Amberlite IR 120 (Trade Mark), Amberlite XE 69 (Trade mark) and Dowex 50W (Trade Mark), whilst a preferred anionic ion exchange resin is a gel styrene-divinyl benzene quaternary ammonium resin, such as Dowex SBR (Trade Mark) and Dowex SAR (Trade Mark). The particle size and, if applicable, the degree of cross linking of the resin is determined by amongst other factors, the drug employed and the rate of drug release required. Preferably, however, the resin has a particle size of from 0.045 to 1mm, especially from 0.045 to 0.5mm. If applicable, the preferred degree of cross-linking is from 2% to 16%, especially from 8% to 12%. The amount of drug bound to the resin is also determined by the choice of drug, as well as by the resin employed. Preferably the weight ratio of bound drug to resin is from 1:3 to 2:1, especially from 2:3 to 3:2. Adsorption of the drug onto the ion exchange resin particles is a well known technique as shown in GB 824337, GB 1218102 and US 2990332 and demonstrated in the examples below. In general, the drug is mixed with an aqueous suspension of the resin and the complex is then dried. Adsorption of the drug onto the resin is detected by an assay of the suspending fluid. Preferably the sugar or the sugar alcohol has a molecular weight of from 90 to 550, especially from 150 to 370. Suitable sugars/sugar alcohols are sucrose, dextrose, maltose, fructose, lactose, mannitol, sorbitol or, which is preferred, xylitol. The sugar/sugar alcohol is preferably finely divided, all of the sugar/sugar alcohol preferably having particle sizes of 0,6mm (600 microns) or less (30 mesh sieve). In a particularly preferred embodiment of the present process, at least 90% (by weight) of the sugar/sugar alcohol will have particle sizes of 0,25mm (250 microns) or less (60 mesh sieve). The concentration of the sugar/sugar alcohol in the composition formed by the present process must be high enough to allow the composition to disperse readily in water. This means that there must be enough sugar/sugar alcohol present to allow the composition to disperse (within 10 seconds) when added with stirring to 20 times its weight of water. Generally, the composition will contain from 25% to 99%, preferably from 70% to 95%, (by weight) of the sugar/sugar alcohol. The drug-resin complex and the sugar/sugar alcohol are granulated in the presence of sufficient water, aqueous alcohol or alcohol to facilate granulation. The most suitable alcohols are C₁-C₄ aliphatic alcohols, especially those having a boiling point, at 760mm Hg, of 100°C or less. Preferred alcohols are ethanol and isopropanol. Preferably, the amount of granulating medium employed is from 1 to 20%, especially from 2 to 7%, by weight of the weight of the complex/sugar, sugar alcohol mix. In a particularly preferred embodiment of the present process the mixture is granulated until the particle size of the sugar/sugar alcohol matches the resin particle size. In the present specification, "matches" means that at least 80% (by wt) of the sugar/sugar alcohol has a particle size between 0.5 and 1.5 times the mean particle size of the drug-resin complex. Once the drug-resin complex and the sugar/sugar alcohol have been granulated, the granules formed are then dried, preferably, until their water content is below 3% (by weight) (when measured by the Karl Fischer method of moisture analysis). Optionally, the drug-resin complex or the granules may be film coated with a material that permits release of the drug from the composition at a controlled rate. The film coat will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol, (b) shellac or zein, (c) a water insoluble cellulose derivative, especially ethyl cellulose, (d) a polymethacrylate, especially Eudragit (Trade Mark). Preferably, the film coat comprises a mixture of the water insoluble material and a water soluble material. The ratio of water insoluble to water soluble material is determined by, amongst other factors, the release rate required and the solubility characteristics of the materials selected. The water soluble material may be, for example, triacetin, propylene glycol, polyethylene glycol, polyvinylpyrrolidone or, which is preferred, a water soluble cellulose, such as hydroxypropyl cellulose, or especially, hydroxypropylmethyl cellulose. Suitable combinations of water insoluble and water soluble materials for the film coat include shellac and polyvinylpyrrolidone or, which is preferred, ethyl cellulose and hydroxypropylmethyl cellulose. Once the above processing is complete, the composition may then be presented in a suitable dosage form, such as a capsule or a sachet. This is done simply by filling the capsule/sachet with the finished composition. The present process and compositions prepared by the present process will now be described by way of example only, Example 1 Morphine Sulphate (Pentahydrate, 30gm), was added to purified water (EP, 110gm) and mixed until all of the powder was evenly wetted. With continuous mixing a cationic exchange resin (Dowex W50x8-200, Trade Mark, hydrous approx 50% (by wt) water, 60mg) was added to the morphine suspension. The stirring was continued for 24 hours at a rate that kept the resin suspended. The resin was then washed with purified water and dried in a fluid bed dryer. Xylitol (500gm, 90% (by wt) having a particle size less than 200um) was mixed with the morphine-resin complex (40gm) and xanthan gum (20gm) in a granulator. With continuous mixing, purified water was added to the mixture until evenly wetted light granules were formed. Generally the amount of water added was 2.0 - 5.0% (by wt) of the xylitol/complex/xanthan gum weight. The moist granules were then dried in a fluid bed dryer until the water content was below about 3.0% (by wt, Karl Fischer). Each unit dose of this composition had the following formulation, mg/unit dose Morphine Sulphate (absorbed on the resin as morphine base) 20 Dowex W50x8-200 (Trade Mark) 20 Xylitol 500 Xanthan Gum 20 Example 2 The process of Example 1 was repeated to form a composition having the following formulation: mg/unit dose Metoclopramide Hydrochloride (absorbed on the resin as metoclopramide base) 15 Dowex W50x8-200 (Trade Mark) 15 Xylitol 500 Xanthan Gum 20 Example 3 The process of Example 1 was repeated to form a composition having the following formulation, mg/unit dose Hydromorphone Hydrochloride (absorbed on the resin as hydromorphone base) 4 Dowex W50x16-100 (Trade Mark) 12 Xylitol 500 Xanthan Gum 20 Example 4 The process of Example 1 was repeated to form a composition having the following formulation, mg/unit dose Theophylline Sodium (absorbed on the resin as theophylline base) 100 Dowex 2x8-200 (Trade Mark) 200 Xylitol 870 Xanthan Gum 45 Polyoxy 40-stearate (Trade Mark) 5 Comparative Example The process of Example 1 was repeated except that the xylitol/morphine-resin complex/xanthan gum were dry mixed to form a powder, rather than wet granulated. Dispersibility of Resin Compositions in Water Unit doses of the granular and powder products, produced according to Example 1 and the comparative Example respectively, were added to 10ml of water with continuous mixing. The granular product immediately (within 10 seconds) formed an aqueous suspension of the resin. By contrast, the powder product formed a wetted mass that took a number of minutes to disperse in the aqueous medium (and thereby form a resin suspension). Furthermore, whilst the granulated product gives a homogeneous product in which the drug substance is dispersed uniformly throughout the composition, the dry mixed powder was non-homogeneous, the drug substance being non-uniformly distributed throughout the composition.

Claims: A process for the preparation of a pharmaceutical ion exchange resin composition that is readily dispersible in water comprising granulating an ion exchange resin, having a pharmacologically active ingredient bound thereto, with a sugar or a sugar alcohol in particulate form, in the presence of sufficient water, aqueous alcohol or alcohol to facilitate granulation, the amount of water, aqueous alcohol or alcohol employed in the granulation is from 1% to 20% (by weight) of the combined weight of the drug-resin complex and the sugar or the sugar alcohol. A process according to claim 1 characterised in that the sugar or the sugar alcohol comprises sucrose, dextrose, maltose, fructose, lactose, mannitol, sorbitol or xylitol, preferably xylitol. A process according to either claim 1 or claim 2 characterised in that all of the sugar or the sugar alcohol particles have a particle size of 0.6mm (600 microns) or less. A process according to claim 3 characterised in that at least 90% (by wt) of the sugar or the sugar alcohol particles have a particle size of 0.25mm (250 microns) or less. A process according to any of claims 1 to 4 characterised in that the amount of water, aqueous alcohol or alcohol employed in the granulation is from 2% to 7% (by weight) of the combined weight of the drug-resin complex and the sugar or the sugar alcohol. A process according to any one of claims 1 to 5 characterised in that the granulation is continued until the particle size of the sugar or the sugar alcohol matches the particle size of the ion exchange resin. A process according to any one of claims 1 to 6 characterised in that subsequent to the granulation, the granules are dried until their water content is below 3% (by weight). A process according to any one of claims 1 to 7 characterised in that a capsule or a sachet is filled with the composition.

Inventors: BUXTON IAN RICHARD, MALKOWSKA SANDRA THERESE ANTOI, NORMAN ALISON ANNE, PRATER DEREK ALLAN, BUXTON, IAN RICHARD, MALKOWSKA, SANDRA THERESE ANTOINETTE, NORMAN, ALISON ANNE, PRATER, DEREK ALLAN
Applicants: EURO CELTIQUE SA, EUROCELTIQUE S.A.
Application year: 1989
Main classification: A61K9
IPC codes: A61K9, A61K47