CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION

Abstract: A solid, controlled release, pharmaceutical composition comprising an active ingredient incorporated in a controlled release matrix comprising a water soluble polydextrose. The controlled release matrix may also contain at least one of a digestible C₈-C₅₀ substituted or unsubstituted hydrocarbon, especially a C₁₂-C₃₆ fatty alcohol, and a polyalkylene glycol, especially polyethylene glycol. Optionally, the matrix may contain a cellulose ether, especially a hydroxyalkylcellulose or a carboxyalkylcellulose.

Description: The present invention relates to a solid controlled release pharmaceutical composition. A "controlled release pharmaceutical composition" is one that achieves slow release of a drug over an extended period of time and extends the duration of drug action over that achieved by conventional delivery. Preferably, such a composition maintains drug level in the blood or target tissue within the therapeutic range for 8 hours or more. A controlled (sustained) release pharmaceutical composition containing an active ingredient has many advantages over a normal release form of the same ingredient. These include a reduction of the frequency of administration, a decrease in side effects and the maintenance of effective concentrations of the active material in the blood. Accordingly, a large number of controlled release forms have been prepared in the past few years. For example, the composition may contain a large amount of an excipient that disintegrates slowly in the stomach or intestines. Alternatively, granules or tablets containing the active ingredient may be covered with a gastro-resistant coating or with a semipermeable membrane. A further device is to mix the active ingredient with a hydrophilic polymer. Of these controlled release forms, the use of hydrophilic polymers (in matrices for active ingredients) has been particularly successful. Amongst the most widely used of these hydrophilic polymers are hydroxyalkylcelluloses such as hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. It is an object of the present invention to provide a controlled release pharmaceutical composition containing a hydrophilic polymer that, in controlled release formulations, exercises better control over the release of the active ingredient than a hydroxyalkylcellulose. Other objects and advantages of the present invention will become apparent from the following detailed description thereof. According to the present invention, therefore, there is provided a solid, controlled release, pharmaceutical composition comprising an active ingredient incorporated in a controlled release matrix comprising a water-soluble polydextrose. Pharmaceutical compositions comprising an active ingredient and inter alia a polydextrose are known. US 4,459,280 describes a composition comprising psyllium hydrophilic mucilloid and polydextrose, with the polydextrose being present as a coating agent. EP 172984A1 describes a polydextrose/iodine complex for germicidal use by localised administration. Neither reference relates to the use of polydextrose in a controlled release composition. In the present specification, a "water soluble polydextrose" is a polydextrose that dissolves to a level of at least 1% (w/w) in water at 25°C. Although the polydextrose employed in the present composition may have an average molecular weight of between about 360 and 10⁶, preferably the polydextrose has a number average molecular weight between 1000 and 12000. Polydextrose is a non-nutritive polysaccharide, prepared by the condensation polymerisation of saccharides in the presence of polycarboxylic acid catalysts, under reduced pressure. Polydextrose is described in US Patents No. 3766165 and 3876794 and is available from Pfizer Inc., New York. Commercially available polydextrose polymer is generally a low molecular weight, water-soluble, randomly bonded polymer of glucose containing minor amounts of sorbitol end groups and citric acid residues attached to the polymer by mono- and di-ester bonds. The number average molecular weight of this commercially available material is 1500, ranging from about 360 to about 20,000. The amount of polydextrose present in the composition of this invention will be determined by a number of factors, including the active ingredient to be administered and the rate of drug release required. Preferably, however, the composition will contain between 1% and 80% (w/w), especially between 1% and 50% (w/w) of polydextrose, most especially between 2% and 40% (w/w) of polydextrose. In addition to the polydextrose, the present composition may also include further in gredients which can contribute to the control of the active ingredient's release and are compatible with polydextrose. Suitable materials are, (a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers and protein derived materials. Of these polymers, the cellulose ethers, especially hydroxyalkyl celluloses and carboxyalkylcelluloses, most especially hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose, are preferred. (b) Digestible, long chain (C₈-C₅₀, especially C₈-C₄₀), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils and waxes. Preferably the hydrocarbons have a melting point between 25° and 90°C. Of these long chain hydrocarbon materials, fatty alcohols, most especially C₁₄-C₂₂ fatty alcohols, such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol are preferred. (c) Polyalkylene glycols, especially polyethylene glycol. At least one of the materials within categories (b) and (c) is particularly preferred. When the polydextrose is combined with at least one of a digestible, C₈-C₅₀ substituted or unsubstituted hydrocarbon and a polyalkylene glycol, the matrix itself is novel. Thus, in another aspect of the present invention, there is provided a preparation for use in the production of a solid, controlled release pharmaceutical composition comprising a matrix of polydextrose and at least one of a digestible C₈-C₅₀ substituted or unsubstituted hydrocarbon and a polyalkylene glycol. Optionally, the matrix may also contain at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose. In a particularly preferred embodiment of the present composition, the matrix comprises polydextrose, at least one of a C₁₂-C₃₆ fatty alcohol and a polyalkylene glycol and, optionally, at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose. In such an embodiment the ratio of polydextrose/cellulose to fatty alcohol/glycol is preferably between 6 to 1 and 1 to 6, especially between 4 to 1 and 1 to 4. Preferably a C₁₄-C₂₂ fatty alcohol is employed. This matrix is also a novel composition and, therefore, according to a further aspect of the present invention, there is provided a preparation for use in the production of a solid, controlled release, pharmaceutical composition comprising a matrix of polydextrose, at least one of a C₁₂-C₃₆ fatty alcohol and a polyalkylene glycol and, optionally, at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose. Preferably the matrix comprises a C₁₄-C₂₂ fatty alcohol. In addition to the above materials, the present controlled release composition may also contain excipients such as binders, disintegrating agents, colours, flavours, preservatives, stabilisers, glidants and lubricants, the use of which will be known to those skilled in the pharmaceutical art. Although the present controlled release composition may be in any solid dosage form, for example, a suppository or a pessary, it is preferably adapted for oral administration. In the present specification "oral administration" incorporates buccal and sublingual administration. Thus, the preferred oral dosage forms include tablets, buccal tablets, sublingual tablets, pills, lozenges, capsules containing, for example, granules or pellets, and dragees. Any active ingredient that may be administered by the oral, buccal, sublingual, rectal or vaginal routes may be employed in the controlled release composition of this invention. Those medicaments having a biological half-life below about 8 hours, however, are particularly suitable for incorporation in the present composition. Examples of active ingredients that may advantageously be incorporated in the present composition are, 1) Anti-allergic drugs, such as cyclizine, dimethindene maleate and triprolidine hydrochloride, 2) Anti-diabetic drugs, such as chlorpropamide, glibenclamide, metformin and tolbutamide, 3) Hormones, 4) Antiarrhythmic agents, such as disopyramide, procainamide, propranolol and quinidine, 5) Anti-inflammatory agents, such as aspirin, diclofenac sodium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen and phenylbutazone, 6) Antiemetic drugs, such as metoclopramide, 7) Diuretics, such as amiloride, bendrofluazide, bumetanide, cyclopenthiazide, ethacrynic acid, frusemide, hydrochlorothiazide, triampterene, chlorthalidone and spironolactone, 8) Anti-anginal agents, such as nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, verapamil and diltiazem, 9) Vasodilators, such as nifedipine, naftidrofuryl oxalate, and nicardipine, 10) Antihypertensive agents, such as clonidine, indoramin, guanethidine, methyldopa, oxprenolol, captopril, hydralazine and propranolol, 11) Bronchodilators, such as salbutamol, isoprenaline and terbutaline, 12) CNS stimulants, such as caffeine and amphetamine, 13) Anti-histamines, such as clemastine fumarate, mepyramine, chlorpheniramine, brompheniramine, diphenhydramine. 14) Analgesic agents, such as morphine, codeine, phenazocine, dihydrocodeine, hydromorphone, meptazinol, phenacetin, pethidine, paracetamol, oxycodone, diamorphine, nalbuphine, buprenorphine, and mefenamic acid, 15) Vitamins, such as Vitamin B1, Vitamin B2, Vitamin B6, Vitamin C and Vitamin E, 16) Antidepressants, such as lofepramine, amitriptyline, doxepin, maprotiline, imipramine, desipramine and mianserin, 17) Tranquilisers, such as chlordiazepoxide and diazepam, 18) Hematinic agents, such as ferrous fumarate, 19) Respiratory stimulants, such as nikethamide, 20) Antibacterial agents, such as polymyxin, streptomycin, sulphonamides, penicillins, erythromycin, cephalosporins, nalidixic acid, tetracyclines, hexamine salts, gentamicin and nitrofurantoin, 21) Hypnotic agents such as barbiturates, dichloral phenazone, nitrazepam and temazepam, 22) Antiviral agents, such as idoxuridine, 23) Vasoconstrictors, such as angiotensin amide, dihydroergotamine, and ergotamine, 24) Topical anaesthetics, such as benzocaine, 25) Anticholinergic agents, such as scopolamine, atropine and propantheline, 26) Adrenergic drugs, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride and pseudoephedrine, 27) Anthelmintic agents, such as diethylcarbamazine, 28) Corticosteroids, such as dexamethasone, prednisone, prednisolone and triamcinolone acetonide, 29) Inorganic drugs, such as lithium carbonate, potassium chloride and lithium sulphate, 30) Antacids, such as aluminium trisilicate and aluminium hydroxide, 31) Antiulcer agents, such as cimetidine and ranitidine, 32) Cofactors, such as nicotinic acid, 33) Antipsychotic agents, such as thioridazine, trifluoperazine, fluphenazine and haloperidol, 34) Laxatives, such as bisacodyl and magnesium hydroxide, 35) Antiperistaltic agents, such as diphenoxylate, 36) Anticoagulant agents, such as warfarin, 37) Haemostatic agents, such as epsilon-aminocaproic acid, 38) Antinauseant agents, such as metoclopramide, pyridoxine and prochlorperazine, 39) Anticonvulsant agents, such as sodium valproate and phenytoin sodium, 40) Neuromuscular drugs, such as dantrolene sodium, 41) Hypoglycaemic agents, such as chlorpropramide, glucagon and tolbutamide, 42) Thyroid dr , such as thyroxine, triiodothyronine and propylthiouracil, 43) Uterine relaxant, such as ritodrine, 44) Appetite suppressants, such as phentermine, diethylpropion HCl and fenfluramine HCl, 45) Erythropoietic substances,such as folic acid, calcium gluconate, and ferrous sulphate, 46) Expectorants, such as carbocisteine and, guiaphenesin, 47) Cough suppressants, such as noscapine, dextromethorphan and oxycodone, 48) Antiuricaemic drugs, such as allopurinol, probenecid and sulphinpyrazone, When the present controlled release matrix contains polydextrose, but no digestible, long chain substituted or unsubstituted hydrocarbon or polyalkylene glycol, the active ingredient is preferably a water-insoluble drug. In the present specification, a water insoluble drug is a drug that dissolves in water (pH 5) at 20°C to a concentration of less than 1.0mgml⁻¹, preferably less than 0.5mgml⁻¹. According to another feature of the present invention, the solid, controlled release, pharmaceutical composition is prepared by mixing an active ingredient with a water soluble polydextrose, optionally in the presence of one or more of the following excipients, a hydrophilic or hydrophobic polymer (other than polydextrose), a digestible long chain, substituted or unsubstituted hydrocarbon, a polyalkylene glycol, a binder, a disintegrating agent, a granulating aid, a colour, a flavour, a preservative, a stabiliser, a lubricant and a glidant. Preferably, the active ingredient is mixed with polydextrose and, at least, a C₁₂-C₃₆ fatty alcohol, especially a C₁₄-C₂₂ fatty alcohol such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol, and/or a polyalkylene glycol, especially polyethylene glycol. In a particularly preferred embodiment of this feature of the invention a solid, controlled release, pharmaceutical composition, in unit dosage form and for oral administration (as hereinbefore defined), is prepared by granulating an active ingredient with a water soluble polydextrose and, optionally, mixing with one or more of the following excipients, a hydrophilic or hydrophobic polymer (other than polydextrose), a digestible, long chain, substituted or unsubstituted hydrocarbon, a polyalkylene glycol, a binder, a disintegrating agent, a colour, a flavour, a preservative, a stabiliser, a lubricant, a glidant, to form granules and compressing the granules to give an oral, solid, unit dosage form containing a predetermined, therapeutically active, quantity of the active ingredient. Depending on the particular case, the method of preparation of the granules may involve for example wet granulation or direct compression. Preferably, the active ingredient is granulated with polydextrose and the granules formed are mixed with a C₁₂-C₃₆ fatty alcohol, especially a C₁₄-C₂₂ fatty alcohol such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol, and/or a polyalkylene glycol, especially polyethylene glycol. Once the oral, solid unit dosage form has been prepared it may, if desired, be coated for example, with a gastro-resistant coating. In a further, particularly preferred embodiment of this feature of the invention a solid, controlled release, pharmaceutical composition in the form of a capsule is prepared by pelletising, spheronising or granulating an active ingredient with a water-soluble polydextrose and, optionally, one or more of the optional ingredients employed in the preparation of the oral, unit dosage form above, to form pellets, spheroids or granules and encapsulating the pellets, spheroids or granules to give a capsule containing a predetermined, therapeutically active, quantity of the active ingredient. Prior to filling the capsule with the pellets, the spheroids or the granules, the pellets/spheroids/granules may b e coated, for example with a gastro-resistant coating. According to another feature of the present invention, there is provided a process for the preparation of a matrix for admixture with an active ingredient to form a controlled release pharmaceutical composition comprising mixing a water soluble polydextrose with at least one of a digestible, C₈-C₅₀ substituted or unsubstituted hydrocarbon and a polyalkylene glycol. Preferably the polydextrose is mixed with at least one of a C₁₂-C₃₆ fatty alcohol (especially C₁₄-C₂₂) and a polyalkylene glycol, especially polyethylene glycol. The mixing stage is preferably a granulation step. Once the matrix has been granulated it can then be mixed with a predetermined amount of the active ingredient and, optionally compressed, to give a controlled release pharmaceutical composition according to this invention. Predetermined release patterns of unusually reliable and constant characteristics can be secured using the present composition. This is often very important medically, especially when treating patients having coronary diseases, such as angina pectoris, or related problems, such as circulatory disorders or abnormal blood pressure, or when treating psychotropic disorders, such as manic depression or schizophrenia or when treating bronchial disorders or moderate to severe pain. The present composition may also be extremely useful in the treatment of ulcerated tissues or mucous lesions and other conditions which arise from local hyperacidity or metabolic dysfunction in the physiological system. The present composition is therefore extremely versatile and adaptable giving a wide range of application and end use. The present solid, controlled release, pharmaceutical composition, together with methods for its preparation will now be described by way of example only, with particular reference to the Figures in which, Figure 1 illustrates the control exercised over theophylline release by polydextrose, as measured by in vitro dissolution, Figure 2 compares the release rates of two theophylline controlled release formulations, one containing hydroxyethylcellulose, the other polydextrose, Figure 3 compares the release rates of two pyridoxine hydrochloride controlled release formulations, one containing hydroxyethylcellulose, the other polydextrose, and Figure 4 compares the release rates of two metoclopramide hydrochloride controlled release formulations, one containing hydroxyethylcellulose, the other polydextrose. Example 1 (Comparative) Anhydrous theophylline (40gm) was dry mixed with anhydrous lactose (15gm), microcrystalline cellulose (5gm) and crosslinked carboxymethyl cellulose (2gm; Croscarmellose). The mixture was granulated with water until a wet granular mass was obtained. The wet material was then sieved through a 1.25mm (16 mesh) screen. The granules were then dried in a Fluid Bed Dryer (FBD) at 60°C. Finally, magnesium stearate (0.5gm) was added to and mixed with the granules, which were then compressed to give 100 tablets each containing, mg/tablet Theophylline anhydrous 400 Lactose anhydrous 150 Microcrystalline cellulose 50 Crosslinked carboxymethylcellulose 20 Magnesium stearate 5 Example 2 Anhydrous theophylline (40gm) was wet granulated with polydextrose (2.5gm) and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were then dried in an FBD at 60°C. Talc (1.0gm) and magnesium stearate (1.0gm) were then added and mixed with the granules. The granules were then compressed to give 100 tablets each containing, mg/tablet Theophylline anhydrous 400 Polydextrose 25 Talc 10 Magnesium stearate 10 A comparison of the release rates of theophylline from tablets prepared as described in Examples 1 and 2 is shown in Figure 1. The dissolution rates were measured by the USP Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH 6.5). Example 3 (Comparative) Anhydrous theophylline (40gm) was wet granulated with hydroxyethylcellulose (2.5gm; Natrosol 250HX, Trade Mark) and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were then dried in a FBD at 60°C. To the warmed theophylline containing granules was added a molten mixture of polyethylene glycol (PEG) 6000 (5.0gm) and, cetostearyl alcohol (4.0gm). This mixture was allowed to air cool and then passed through a 1.25mm (16 mesh) screen. Talc (1.0gm) and magnesium stearate (1.0gm) were then mixed with the granules. The granules were compressed to give 100 tablets each containing, mg/tablet Theophylline anhydrous 400 Hydroxyethylcellulose 25 PEG 6000 50 Cetostearyl alcohol 40 Talc 10 Magnesium stearate 10 Example 4 The procedure of Example 3 was followed except that polydextrose replaced the hydroxyethylcellulose. This gave 100 tablets, each containing mg/tablet Theophylline anhydrous 400 Polydextrose 25 PEG 6000 50 Cetostearyl alcohol 40 Talc 10 Magnesium stearate 10 A comparison of the release rates of theophylline from tablets prepared as described in Examples 3 and 4 is shown in Figure 2. The dissolution rates were measured by the USP Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH 6.5). Example 5 (Comparative) Pyridoxine hydrochloride (10gm) and hydrogenated castor oil (1.5gm) were granulated with hydroxyethylcellulose (2.0gm, Natrosol 250HX) and the granules were sieved through a 1.25mm (16 mesh) screen and dried in a FBD at 60°C. To the pyridoxine HCl containing granules, molten cetostearyl alcohol (3.5gm) was added. This mixture was allowed to air cool and then passed through a 1.25mm (16 mesh) screen. Talc (0.3gm) and magnesium stearate (0.1gm) were mixed with the granules. This mixture was compressed to give 100 tablets each containing, mg/tablet Pyridoxine HCl 100 Hydroxyethylcellulose 20 Hydrogenated castor oil 15 Cetostearyl alcohol 35 Talc 3 Magnesium stearate 1 Example 6 The procedure of Example 5 was followed except that polydextrose replaced the hydroxyethylcellulose. This gave 100 tablets each containing, mg/tablet Pyridoxine HCl 100 Polydextrose 20 Hydrogenated castor oil 15 Cetostearyl alcohol 35 Talc 3 Magnesium stearate 1 A comparison of the release rates of pyridoxine HCl from tablets prepared as described in Examples 5 and 6 is shown in Figure 3. The dissolution rates were measured by the USP Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH 6.5). Example 7 (Comparative) Metoclopramide HCl (3gm) was wet granulated with anhydrous lactose (17gm) and hydroxyethylcellulose (2gm: Natrosol 250HX) and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were then dried in an FBD at 60°C. To the warmed metoclopramide containing granules was added molten cetostearyl alcohol (7gm). The mixture was allowed to air cool and then passed through a 1.25mm (16 mesh) screen. Talc (0.6gm) and magnesium stearate (0.4gm) were mixed with the granules. The granules were then compressed to give 100 tablets each containing, mg/tablet Metoclopramide HCl 30 Anhydrous lactose 170 Hydroxyethylcellulose 20 Cetostearyl alcohol 70 Talc 6 Magnesium stearate 4 Example 8 Anhydrous lactose (17gm) and polydextrose (2gm) were dry mixed. Molten cetostearyl alcohol (7gm) was added to the dry mixed powders. The mixture was allowed to cool and passed through a 1.25mm (16 mesh) screen. Metoclopramide HCl (3gm), talc (6gm) and magnesium stearate (4gm) were then mixed with the polydextrose/wax granules and then compressed to give 100 tablets each containing, mg/tablet Metoclopramide HCl 30 Anhydrous lactose 170 Polydextrose 20 Cetostearyl alcohol 70 Talc 6 Magnesium stearate 4 A comparison of the release rates of metoclopramide HCl from tablets prepared as described in Examples 7 and 8 is shown in Figure 4. The dissolution rates were measured by the USP Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH 6.5). Example 9 Anhydrous theophylline (40gm) was wet granulated with polydextrose (21.8gm) and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were dried in a FBD at 60°C. To the warmed theophylline containing granules was added a molten mixture of polyethylene glycol 6000 (2.9gm), polyethylene glycol 1000 (1.45gm) and cetostearyl alcohol (2.9gm). This mixture was allowed to air cool and then passed through a 1.25mm (16 mesh) screen. Talc (1.0gm) and magnesium stearate (0.45gm) were then mixed with the granules. The granules were compressed to give 100 tablets each containing, mg/Tablet Theophylline anhydrous 400 Polydextrose 218 PEG 6000 29 PEG 1000 14.5 Cetostearyl alcohol 29 Talc 10 Magnesium stearate 4.5 The in-vitro dissolution rate of these tablets were measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Results are shown in Table 1. In vitro Dissolution of Theophylline Tablets Time (Hours) % (by wt) Released 2 21.7 4 33.7 6 42.3 8 49.0 10 54.3 12 58.3 14 62.0 16 65.0 18 67.8 Example 10 Naproxen (50gm), dicalcium phosphate (16.4gm), lactose (2.5gm), polydextrose (2.0gm) and hydroxypropylmethylcellulose (2.0gm) were wet granulated and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were then dried in a FBD at 50°C. Talc (1.35gm) and magnesium stearate (0.75gm) were then added and mixed with the granules. The granules were then compressed to give 100 tablets each containing mg/tablet Naproxen 500 Dicalcium phosphate, anhydrous 164 Lactose monohydrate 25 Polydextrose 20 Hydroxypropylmethylcellulose 20 Talc 13.5 Magnesium stearate 7.5 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 7.2). Results are shown in Table 2. In Vitro Dissolution of Naproxen Tablets Time (Hours) % (by wt) Released 1 22.3 2 49.9 3 74.4 4 91.1 5 95.9 Example 11 Naproxen (50gm), lactose (11.25gm), polydextrose (0.75gm) and povidone (2.0gm) were wet granulated and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were dried in a FBD at 60°C. Talc (1.2gm) and magnesium stearate (0.6gm) were mixed with the granules. The granules were compressed to give 100 tablet cores each containing, The tablet cores were then coated with an aqueous formulation (100ml) containing polyvinylacetate phthalate (15gm) and 0.88 ammonia solution (0.18ml) until the cores were coated with about 20mg (dry weight) of coat. The in-vitro dissolution rate of these tablets was measured by placing the tablets in 0.1N hydrochloric acid for 2 hours and thereafter continuing the USP Paddle Method at 100rpm in 900ml of aqueous buffer pH 7.2. Results are shown in Table 3. Example 12 Polydextrose (28gm) was mixed with a mixture of molten cetostearyl alcohol (6gm) and polyethylene glycol 4000 (6gm). The granules were allowed to cool and sieved through a 0.9mm (20 mesh) screen. Theophylline (40gm) was granulated with a solution of povidone (1.2gm) in water. The granules were sieved through a 1.6mm (12 mesh) screen and dried in a fluid bed drier. The granules were then sieved through a 0.9mm (20 mesh) screen. The theophylline granules and the polydextrose/wax granules were dry mixed with purified talc (0.6gm). Prior to compression, magnesium stearate (0.6gm) and purified talc (0.6gm) were mixed with the granules. This mixture was then compressed to give 100 tablets each containing, mg/Tablet Theophylline 400 Povidone 12 Polydextrose 280 Cetostearyl Alcohol 60 Polyethylene Glycol 4000 60 Purified Talc 12 Magnesium Stearate 6 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Results are shown in TABLE 4. Example 13 The procedure of Example 12 was followed except that the amounts used were chosen such that each tablet contained, The in-vitro dissolution rate of these tablets was measured as described in Example 12. Results are given in TABLE 5. Example 14 The procedure of Example 12 was followed except that the amounts used were chosen such that each tablet contained, The in-vitro dissolutin rate of these tablets was measured as described in Exam ple 12. Results are given in TABLE 6. Example 15 The procedure of Example 12 was followed except that the amounts used were chosen such that each tablet contained, The in-vitro dissolution rate of these tablets was measured as described in Example 12. Results are given in TABLE 7. In Vitro Dissolution of Theophylline Tablets Time (Hours) % (by wt) Released 1 12.7 2 19.6 4 30.9 8 48.6 12 66.5 16 80.8 24 94.5 Example 16 Theophylline (40gm) and polydextrose (21.8gm) were mixed and granulated with water. The granules were dried in a fluid bed drier. The dried granules were sieved through a 1.25mm (16 mesh) screen. The dried granules were mixed with a molten (70°C) mixture of PEG 6000 (2.9gm) and octyl alcohol (2.0gm). The "waxed" granules were then cooled, before blending with talc (1.0gm) and magnesium stearate (0.4gm). Compression of the granules gave 100 tablets each containing, mg/Tablet Theophylline 400 Polydextrose 218 Polyethylene Glycol 6000 29 Octyl Alcohol 29 Purified Talc 10 Magnesium Stearate 4 Examples 17-22 The procedure of Example 16 was followed except that the octyl alcohol was replaced by, respectively, decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol and cetostearyl alcohol. Example 23 Polydextrose (12.6gm) was mixed with molten cetostearyl alcohol (5.4gm). The granules were allowed to cool and sieved through 0.9mm (20 mesh) screen. Metoclopramide HCl (3.0gm) was dry mixed with the polydextrose/alcohol granules and purified talc (0.21gm). Prior to compression, magnesium stearate (0.21gm) and purified talc (0.21gm) were mixed with the granules. This mixture was then compressed to give 100 tablets each containing, mg/Tablet Metoclopramide HCl 30 Polydextrose 126 Cetostearyl Alcohol 54 Purified Talc 4.2 Magnesium Stearate 2.1 Example 24 The procedure of Example 23 was followed except that the amounts used were chosen such that each tablet contained, mg/Tablet Metoclopramide HCl 30 Polydextrose 210 Cetostearyl Alcohol 90 Purified Talc 6.6 Magnesium Stearate 3.3 Example 25 The procedure of Example 23 was followed except that the amounts used were chosen such that each tablet contained, mg/Tablet Metoclopramide HCl 30 Polydextrose 420 Cetostearyl Alcohol 180 Purified Talc 12.6 Magnesium Stearate 6.3 Example 26 Salbutamol sulphate (0.964gm), equivalent to 0.8gm base salbutamol was wet granulated with anhydrous lactose (20.8gm), polydextrose (1.25gm) and povidone (0.3gm) and the granules were sieved through a 1.25mm (16 mesh) screen. The granules were then dried in a FBD at 60°C. To the warmed salbutamol containing granules was added molten cetostearyl alcohol (5.5gm). The mixture was allowed to air cool and then passed through a 1.25mm (16 mesh) screen. Talc (0.8gm) and magnesium stearate (0.4gm) were mixed with the granules. The granules were then compressed to give 100 tablets each containing, mg/Tablet Salbutamol Sulphate 9.64 Lactose, anhydrous 208 Polydextrose 12.5 Povidone (K30) 3 Cetostearyl Alcohol 55 Talc 8 Magnesium Stearate 4 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Results are given in TABLE 8. In Vitro Dissolution of Salbutamol Tablets Time (Hours) % (by wt) Released 1 49.5 2 62.4 3 73.2 4 79.1 5 85.5 6 91.0 Example 27 The procedure of Example 26 was followed except that the amounts used were chosen such that each tablet contained, mg/Tablet Salbutamol Sulphate 9.64 Lactose, anhydrous 190.36 Polydextrose 30 Povidone (K30) 3 Cetostearyl Alcohol 55 Talc 8 Magnesium Stearate 4 The in-vitro dissolution rate of the tablets was measured as described in Example 26. Results are given in TABLE 9. Example 28 The procedure of Example 26 was followed except that the amounts used were chosen such that each tablet contained, The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Results are given in TABLE 10. In Vitro Dissolution of Salbutamol Tablets Time (Hours) % (by wt) Released 1 41.0 2 57.8 3 68.0 4 74.6 5 81.0 6 83.1 Example 29 Quinidine polygalacturonate (41.25gm), lactose (4.5gm), hydroxypropylmethyl cellulose (1.25gm) and polydextrose (4.5gm) were granulated with water. The granules were sieved through a 1.25mm (16 mesh) screen and dried in a fluid bed drier. The granules were mixed with molten cetostearyl alcohol (9.0gm) and allowed to cool. The granules were sieved through a 1.25mm (16 mesh) screen and blended with purified talc (1.0gm). The granules were compressed to give 100 tablets each containing, mg/Tablet Quinidine Polygalacturonate 412.5 Lactose 45 Hydroxypropylmethyl cellulose 12.5 Polydextrose 45 Cetostearyl Alcohol 90 Purified Talc 10 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of buffer (pH 6.5). Results are given in TABLE 11. In Vitro Dissolution of Quinidine Tablets Time (Hours) % (by wt) Released 1 15.2 2 26.0 4 41.5 8 60.1 12 72.5 16 79.9 20 89.9 Example 30 Nifedipine (2.0gm), lactose (8.0gm) and polydextrose (2.0gm) were mixed and granulated with aqueous povidone solution (0.7gm Povidone K30). The granules were dried in a fluid bed drier. The dried granules were sieved through a 0.9mm (20 mesh) screen before blending with purified talc (0.4gm) and magnesium stearate (0.2gm). The granules were compressed to give 100 tablets each containing, mg/Tablet Nifedipine 20 Lactose, anhydrous 80 Polydextrose 20 Povidone K30 7 Purified Talc 4 Magnesium Stearate 2 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml aqueous isopropyl alcohol (4:1 (v/v), water; i-PrOH). Results are given in TABLE 12. In Vitro Dissolution of Nifedipine Tablets Time (Hours) % (by wt) Released 1 8.9 2 18.9 3 54.0 4 87.7 5 96.1 6 99.2 CLINICAL STUDIES A pharmacokinetic study in 3 healthy volunteers was performed on tablets prepared as described in Example 9. Samples were analysed by enzyme immunoassay. Mean plasma theophylline concentrations are given in TABLE 13. Time (Hours) Mean Plasma Theophylline Concentration (ug/ml) 0 0.0 1 0.7 2 1.6 3 2.1 4 2.7 5 3.3 6 3.3 7 3.0 8 3.0 10 2.5 12 2.1 24 1.4 It can therefore be seen that the composition of Example 9 exhibits excellent control over the release of theophylline in vivo .

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A solid, controlled release, pharmaceutical composition for oral, rectal or vaginal administration comprising an active ingredient incorporated in a controlled release matrix characterised in that the matrix comprises a water soluble polydextrose. A composition according to claim 1 characterised in that the matrix comprises a polydextrose and at least one of a digestible C₈-C₅₀ subsituted or unsubstituted hydrocarbon, especially a C₁₂-C₃₆ fatty alcohol, and a polyalkylene glycol, especially polyethylene glycol. A composition according to claim 2 characterised in that the hydrocarbon comprises a C₁₄-C₂₂ fatty alcohol, especially cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol. A composition according to any one of claims 1 to 3 characterised in that the matrix further comprises a cellulose ether, especially a hydroxyalkylcellulose or a carboxyalkylcellulose. A composition according to claim 4 characterised in that the ratio of polydextrose/cellulose ether to hydrocarbon/polyalkylene glycol in the composition is between 6 to 1 and 1 to 6, especially between 4 to 1 and 1 to 4. A composition according to any one of claims 1 to 5 characterised in that the composition contains between 1% and 80% (w/w), especially between 1% and 50% (w/w), of polydextrose. A composition according to claim 6 characterised in that the composition contains between 2% and 40% (w/w) of polydextrose. A composition according to any one of claims 1 to 7 characterised in that the active ingredient comprises theophylline, metoclopramide or naproxen. A preparation for use in the production of a solid, controlled release, pharmaceutical composition for oral, rectal or vaginal administration comprising an active ingredient incorporated in a matrix of a water soluble polydextrose and at least one of a digestible C₈-C₅₀ substituted or unsubstituted. hydrocarbon, especially a C₁₂-C₃₆ fatty alcohol, and a polyalkylene glycol, especially polyethylene glycol. A preparation according to claim 9 characterised in that the hydrocarbon comprises a C₁₄-C₂₂ fatty alcohol, especially cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol. Claims for the following Contracting States : AT, ES, GR A process for the preparation of a solid, controlled release, pharmaceutical composition for oral, rectal or vaginal administration characterised by mixing an active ingredient with a water soluble polydextrose to form a controlled release matrix incorporating the active ingredient. A process according to claim 1 characterised in that before, during or after the active ingredient is mixed with the water soluble polydextrose, the polydextrose is also mixed with at least one of a digestible C₈-C₅₀ substituted or unsubstituted hydrocarbon, especially a C₁₂-C₃₆ fatty alcohol, and a polyalkylene glycol, especially polyethylene glycol. A process according to either claim 1 or claim 2 characterised in that before, during or after the active ingredient is mixed with the water soluble polydextrose, the polydextrose is also mixed with a cellulose ether, especially a hydroxyalkylcellulose or a carboxyalkylcellulose. A process according to any one of claims 1 to 3 characterised in that the ratio of polydextrose/cellulose ether to hydrocarbon/polyalkylene glycol in the composition is between 6 to 1 and 1 to 6, especially between 4 to 1 and 1 to 4. A process according to claim 4 characterised in that the composition contains between 1% and 80% (w/w), especially between 1% and 50% (w/w), of polydextrose. A process according to any one of claims 1 to 5 characterised in that the active ingredient comprises theophylline, metoclopramide or naproxen. A process for the preparation of a solid, controlled release, pharmaceutical composition, in unit dosage form, for oral administration, characterised by granulating an active ingredient with a water soluble polydextrose to form granules and compressing the granules to give an oral, solid, unit dosage form containing a predetermined, therapeutically active, quantity of the active ingredient. A process for the preparation of a solid, controlled release, pharmaceutical composition for oral, rectal or vaginal administration in the form of a capsule characterised by pelletising, spheronising or granulating an active ingredient with a water soluble polydextrose to form pellets, spheroids or granules and encapsulating the pellets, spheroids or granules to give a capsule containing a predetermined, therapeutically active, quantity of the active ingredient. A process for the preparation of a matrix for admixture with an active ingredient to form a controlled release pharmaceutical composition for oral, rectal or vaginal administration characterised by mixing a water soluble polydextrose with at least one of a digestible, C₈-C₅₀ substituted or unsubstituted hydrocarbon and a polyalkylene glycol to form a controlled release matrix.

Inventors: ELGER, GORDON ANTHONY, LESLIE, STEWART THOMAS, MALKOWSKA, SANDRA THERESE ANTOINETTE, MILLER, RONALD BROWN, NEALE, PHILIP JOHN
Applicants: EUROCELTIQUE SA
Application year: 1987
Main classification: A61K9
IPC codes: A61K9, A61K47