Patentamt

JEuropâischesEuropean Patent Office © Publication number: O 003 589

Office européen des brevets B 1

@ EUROPEAN PATENT SPECIFICATION

@ Date of publication of patent spécification: 11.04.84 @ Int. Cl.3: A 61 K 9/20 @ Application number: 79100337.9 @ Date offiling: 05.02.79

(54) tablet formulation.

(30) Priority: 06.02.78 GB 466978 @ Proprietor: THE WELLCOME FOUNDATION LIMITED 1 83-1 93 Euston Road (43) Date of publication of application: London NW1 2BP (GB) 22.08.79 Bulletin 79/1 7

@ Inventor: Harden, David (45) Publication of the grant of the patent: 25 Sandhurst Road 1 1 .04.84 Bulletin 84/1 5 Sidcup, Kent (GB) Inventor: Gayst, Stephen 19 Arthur Street @ Designated Contracting States: Double Bay New South Wales (AU) BE CH DE FR GB LU NL SE

(74) Representative: Berg, Wilhelm, Dr. etal, (§) References cited: Dr. Berg, Dipl.-lng. Stapf, Dipl.-Ing. Schwabe, Dr. FR - A - 2 007 475 Dr. Sandmair Patentanwalte Postfach 860245 FR - A - 2 230 341 D-8000 Miinchen 86 (DE) FR - A - 2 260 993 FR - A - 2 300 550 GB-A-1 057 940 US - A - 2 550 489 US-A-2 581 035 US-A-2 912 358

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1 ) European patent convention). Courier Press, Leamington Spa, England. The present invention relates to tablets FR-A-2,300,550, 2,260,993 and which rapidly disperse in solution and are useful 2,230,341 disclose tablets in which the for the treatment of gastric hyperacidity. The ingredient is present in high concentration and present invention also provides methods for in which a disintegrating agent having a preparing such tablets. swelling capacity of greater than 5 mg/g. Formulations used to combat gastric However the disclosures are concerned with the hyperacidity conventionally contain an insoluble provision of tablets having good disintegration base or an alkaline salt with a weak acid of times (eg less. than 15 minutes) and are not or or a mixture of such dispersible tablets nor would they exhibit the bases or salts. Occasionally insoluble bases or properties of a dispersible tablet. alkaline salts with weak acids of , cal- It is usual to include a mixture of insoluble cium and bismuth are also included in the metal compounds in the tablets of the present formulations together with the said magnesium invention but the invention also includes the and/or aluminium bases or salts. Thus typical case where only one such compound is formulations often contain aluminium included. The tablets contain 50 to 90%, hydroxide, or magnesium preferably 60 to 70% of the antacid carbonate. These antacid formulations act by component(s). neutralising excess acidity in the stomach. To Suitable insoluble metal compounds include give rapid relief of gastric hyperacidity it is those of , such as , of necessary that antacid formulations give rapid bismuth, such as bismuth carbonate and release of the active ingredients on dismuth subnitrate, of aluminium, such as administration. , aluminium oxide, Unfortunately, the formulations at present and aluminium glycinate, marketed are often deficient in this respect. and of magnesium, such as magnesium Antacid formulations currently available are hydroxide, and normally in tablet or suspension form and of magnesium silicate. Mixed bases and/or alkaline these the suspension form gives the most rapid salts, that is to say bases and/or salts formed release of active ingredients. A new form of from more than one metal such as sodium poly- antacid tablet has now been developed which hydroxy-aluminium monocarbonate, sodium not only gives a far more rapid release of magnesium aluminium silicate, magnesium ingredient than those antacid tablets which aluminium hydroxide and magnesium have gone before but also gives a more rapid aluminate, are also suitable. release of ingredients than some antacid Particularly suitable insoluble metal suspensions presently available. Such tablets compounds are those of aluminium and contain a disintegrating agent that has a magnesium. Thus, aluminium hydroxide is capacity to swell substantially in the presence of preferred compound for inclusion in the tablets water. of the present invention. Preferred magnesium Accordingly, the present invention provides a compounds include magnesium carbonate and, dispersible tablet for the treatment of gastric in particular, magnesium hydroxide. It has been hyperacidity, which comprises 50-90% of a found that a combination of aluminium conventional antacid component and 5-15% of hydroxide and magnesium hydroxide provides a a disintegrating agent having a swelling particularly favourable antacid component for capacity of between 5 and 100 ml/g. the tablets of the present invention. Suitably the All percentages herein are expressed as aluminium hydroxide and the magnesium weight/weight unless otherwise stated. hydroxide are in weight ratio of from 4:1 to 1:4 Antacid components suitable for inclusion in and preferably in a weight ratio of from 4:1 to the tablets of the present invention are, for 1:2. Tablets containing these ingredients may example, pharmaceutically acceptable metal suitably contain from 200 to 1000 mg of these bases or alkaline salts with weak acids conven- compounds per tablet, for example 400 to tionally used in antacid formulations (see, for 500 mg per tablet. A suitable dose for the example, Martindale, the Extra Pharmacopoeia, treatment of gastric hyperacidity in man is 1 to 27th Ed., for a list of conventional antacid 4 tablets repeated as required. formulations and their ingredients), which have As used herein, the swelling capacity of a a solubility in water of less than 1 part in 70 disintegrating agent is defined as the volume under neutral conditions. (ml) to which 1 g. of a test tablet containing GB-A-1,269,987 (=FR-A-2,007,475) 95% of the dry, disintegrating agent and 5% of discloses inter alia, solid antacid formulations polyvinylpyrollidone (K30) will swell when in which are claimed to revert to suspensions on contact with an excess of water at a contact with water. However the only disclosure temperature of 21°C. It is determined by of a compressed tablet formulation provides granulating the disintegrating agent (2 g) with products with unacceptable physical properties 10% polyvinylpyrollidone (K30) (1 ml) and and, in as far as could be determined, would drying the resultant granules at 60°C. not be a dispersible tablet. Compression of the granules to a hardness value of 12 kg. provides test tablets having a the antacid component will normally be diameter of 15 mm and a weight of below 100 pm and preferably below 50 µm. As approximately 900 mg. Each tablet is then used herein, the particle size of the antacid accurately weighed and placed on the bottom of component is defined in terms of the "weight a 25 ml. measuring cylinder. A nylon disc of median diameter" hereinafter referred to as 8 mm thickness and having two grooves W.M.D. Thus, each particle is considered as a provides a close, but sliding, fit in the measuring sphere having a volume identical with the actual cylinder, resting on the top of the tablet. The particle and the W.M.D. is that "diameter", grooves are disposed opposite each other on wherein 50% of these hypothetical spheres the circumference of the disc in a direction at have a larger diameter than that figure and 50% right angles to the plane thereof and allow for a a smaller diameter than that figure. The W.M.D. thin hypodermic needle to be inserted between may be determined using a Coulter counter in the disc and the glass wall of the measuring which the antacid component dispersed in an cylinder. A 5 g. weight is placed on the nylon electrolyte comprising an aqueous solution of, disc and water injected through one of the for example, sodium chloride, saturated with the grooves into the space surrounding the tablet; antacid component is passed through a small the other groove allowing for air to be displaced. orifice in a tube on either side of which is When the water level is above the top of the immersed an electrode. The changes in disc, the needle can be removed and water resistance as particles pass through the orifice added until it is in excess, e.g. 25 ml. The generate voltage pulses whose amplitudes are volume under the disc is then noted at periodic proportional to the volume of the particles. The intervals until there is no further increase in pulses are amplified, and the numbers counted absorption. In some cases, disintegrating agents at different threshold levels. From this data the absorb water to form viscous gels, and this distribution of the suspended particles and slows down the rate of absorption necessitating hence the W.M.D. may be determined. a longer interval, such as 48 hours, before The particle size of the antacid component maximum swelling is achieved. may readily be reduced, if desired, by On completion of swelling, the final volume is precipitation techniques or by grinding the read and corrected to the corresponding value particles with any apparatus or by any other for 1 g. of the tablet, i.e. the value for the method known in the art suitable for such swelling capacity. The whole operation should purposes. In particular, the hammer mill, which preferably be performed at an approximately can be used with either the rigid or the swing constant room temperature, for example 21 °C. hammer type and is conveniently combined Disintegrating agents which have a swelling with a fan and a cyclone for collecting the capacity greater than 5 ml/g. and less than material, is preferred. 100 ml/g. and which therefore may be used in In order to reduce flatulence anti-foam the present invention include calcium carboxy agents, such as siloxanes for example poly- methyl celluloses, such as E.C.G. 505, low methyl-siloxane and polydimethylsiloxane, are viscosity sodium carboxy methyl celluloses, often included in conventional antacid formu- such as Copagel and Nymcel, guar based lations. Thus, in one preferred embodiment the vegetable gums, such as Supercol U and tablets of the present invention will also contain Supercol NG-1, a sodium alginate, such as an anti-foaming agent. Suitably the tablet will alginate YZ, cross-linked sodium carboxy- contain between 1 and 5% of an anti-foaming methyl-celluloses, such as CLD, cross-linked agent. It has been found that certain antacid polyvinyl-pyrollidones, such as Plasdone XL, low materials and particularly aluminium hydroxide substituted hydroxypropylcelluloses, such as L- inhibit the anti-foaming properties of poly- HPC, cation exchange resins, such as amberlite dimethylsiloxane (see J. Pharm. Sci, 55, 538, IRP-88, and sodium starch glycolates, such as 1966) and when such an antacid material is Primojel or Explotab (Trade Marks). The most incorporated into the tablets of the invention it preferred disintegrating agents are Primojel and has been found to be convenient to separate it Explotab. The disintegrating agents will from the anti-foaming agent. It has been found normally have a swelling capacity of less than that compression coating the anti-foaming 60 ml/g. agent with one of the other ingredients of the The percentage of disintegrating agent which tablets, for example magnesium hydroxide in the is incorporated in the tablets of the invention case where both aluminium and magnesium will depend to a large extent on the swelling hydroxides are used as the antacid component, capacity of the disintegrating agent. Thus, if the to give a central core around which the disintegrating agent is one which has a high aluminium hydroxide or other antacid material swelling capacity, such as Primojel or Explotab, may be formulated gives a satisfactory the amount of disintegrating agent present will separated product. Alternatively, a mixed normally be between 5 and 10%. However, if a granule system compressed as a conventional disintegrating agent of low swelling capacity is tablet gives satisfactory separation of the anti- used then it will normally be present in a greater foam agent. amount, i.e. between 8 and 15%. Other components which may be The particle size, as hereinafter defined, of incorporated in the tablets of the present invention include granulating agents, lubricating the resulting material compressed into tablets. agents and binder/disintegrants and The tablets of the present invention may pharmaceutical excipients conventionally used either be administered in tablet form or sucked in tablet formulations. Granulating agents will or alternatively may be placed in water to give a normally be included in the tablets and suitable finely dispersed suspension. All forms of granulating agents include starch in the form of administration give a very rapid onset of mucilage, starch derivatives, such as starch neutralising power together with a high "Snow Flake", cellulose derivatives, such as neutralisation capacity. The formulations of the methylcellulose, gelatin and polyvinyl- present invention have a radically different pyrollidone. Polyvinylpyrollidone is particularly therapeutic profile and far superior properties preferred. Lubricating agents are added to from antacid preparations on the market. prevent the tablets from adhering to the The following Examples, which illustrate the punches and dies of the automatic tabletting invention, should in no way be construed as a equipment. Magnesium Stearate, Magnesium limitation thereof. Lauryl Sulphate, and Sodium Lauryl Sulphate are convenient lubricating agents for inclusion Example 1 in the tablets. Binder-disintegrants, as the name implies, serve a dual purpose in holding the tablets together until they come into contact with aqueous media when they aid the tablets' disintegration. Avicel, a microcrystalline cellulose, and L-HPC are particularly suitable examples of such binder/disintegrants. Conven- tional pharmaceutical excipients such as dyes, flavourings, surfactants, preservatives and the like may be included. It has been found that the inclusion of mannitol and/or lactose in the tablets of the present invention results in particularly advantageous products. In another aspect of the present invention, there is provided a method of preparing a tablet as hereinbefore defined, which comprises the The granule contents were mixed together in compression on standard machinery of a formu- conventional manner, for example by using Z- lation containing 50-90% of a conventional blade mixer. The mixed granule ingredients antacid component, as hereinbefore defined and were wetted with a solution consisting of 5-15% of the disintegrating agent having a aqueous alcohol (alcohol, water content 50:50) swelling capacity of between 5 and 100 ml/g. sifted and passed through a 1400,u sieve and In order to aid the compression of the the granules dried on a fluid bed drier until the formulation into a tablet the formulation will outlet temperature was 46°C. The dried normally be granulated before it is compressed. granules were passed through a 1000,a sieve. This granulation step comprises for example, The avicel (external) and magnesium stearate mixing the antacid component with the (sifted to 150 p) were blended with the dried disintegrating agent in a dry state at slow granules and the mixture compressed to give speed, for example around 15 rev/min in a tablets of hardness 7.9 Kg., which give a fine planetary mixer, followed by wet mixing for up dispersion (dispersion time 35-40 secs.) in to about 30 minutes with a granulating solution, water at room temperature. together with additional solvent, if necessary, for maintaining the consistency of the mass. Example 2 The material can then be milled and either tray- Tablets were prepared as described in dried or dried in a fluidised bed. The dry Example 1 except that the Primojel was granulated material is then sifted and a lubricant replaced by Explotab (50 g). The tablets had a added. The granules are then compressed on hardness of 8.8 kg and gave a fine dispersion standard machinery to the specified hardness in (dispersion time 30 secs.) in water at room the conventional manner. temperature. Whilst water may be used as the solvent in the granulating solution this may lead to a Example 3 reduction in the dispersion properties of the tablets. We have found that the combination of water with a water miscible organic solvent, such as alcohol, provides an acceptable solvent for the granulating solution. When the antacid component has good flow properties there may be no need to include a granulation step in which case the ingredients will be mixed together, a lubricant added and The granule ingredients were granulated by of between 5'and 100 ml/g. the method described in Example 1. The dried 2. A dispersible tablet as claimed in claim 1 granules were blended with magnesium characterised in that the antacid component stearate (8.2 g) and the mixture pressed into comprises a pharmaceutically acceptable metal tablets. The tablets had a hardness of 11.2 Kg base or alkaline salt thereof with a weak acid. and gave a fine dispersion (dispersion time 10 3. A dispersible tablet as claimed in either secs.) in water at room temperature. claim 1 or claim 2 characterised in that the antacid component has a solubility in water of Example 4 less than 1 part by weight in 70. 4. A dispersible tablet as claimed in any one of claims 1 to 3 characterised in that the antacid component is a compound of calcium, bismuth, aluminium or magnesium. 5. A dispersible tablet as claimed in any one of claims 1 to 4 characterised in that the antacid component is a compound of calcium or magnesium. 6. A dispersible tablet as claimed in any one of claims 1 to 5 characterised in that the antacid component is selected from one or more of aluminium hydroxide magnesium hydroxide, magnesium carbonate and magnesium silicat. 7. A dispersible tablet as claimed in any one of claims 1 to 6 characterised in that the antacid component comprises aluminium hydroxide and magnesium hydroxide in a weight ratio of 4:1 to 1:4. 8. A dispersible tablet as claimed in any one of claims 1 to 7 characterised in that the antacid component has a weight median diameter, as herein defined, of less than 100 pm. 9. A dispersible tablet as claimed in claim 8 characterised in that the weight median diameter is less than 5µ µm. 10. A dispersible tablet as claimed in any one of claims 1 to 9 characterised in that the disintegrating agent is selected from calcium carboxymethyl celluloses, low viscosity sodium carboxymethyl celluloses, guar based vegetable gums, a sodium alginate, cross-linked sodium carboxymethyl celluloses, cross-linked poly- vinylpyrrolidones, low substituted hydroxy- propyl celluloses, cation exchange resins and sodium starch glycolates. 11. A dispersible tablet as claimed in any one of claims 1 to 10 characterised in that the Part I and II are granulated separately as disintegrating agent is a sodium starch described in Example I, the simethicone being glycolate. incorporated in the granulating solvent for Part 12. A dispersible tablet as claimed in any one II. The granules were dried and sifted by the of Claims 1 to 11 characterised in that the procedure of Example 1. The two granulations disintegrating agent has a swelling capacity of mixed together, Part III added and tablets were less than 60 ml/g. compressed to give a hardness of 8 Kg and a 13. A dispersible tablet as claimed in any dispersion time of 32 seconds at room one of claims 1 to 11 characterised by temperature. comprising from 5 to 10% of disintegrating agent.

1. A tablet comprising a conventional antacid component as herein defined characterised in 1. Comprimé comprenant un composant that the tablet is dispersible, the antacid antiacide classique tel que défini ci-dessus, component is present in an amount of from 50 caractérisé en ce que le comprimé est to 90%, by weight, and the tablet additionally dispersable, le composant antiacide est présent comprising from 5 to 15% by weight of a en une quantité de 50 à 90% en poids et le disintegrating agent having a swelling capacity comprimé comprend, en outre, 5 à 15% en poids d'un agent de désintégration ayant une désintégration. capacité de gonflement située entre 5 et 100 ml/g. 2. Comprimé dispersable suivant la revendication 1, caractérisé en ce que le 1. Tablette, die einen herkömmlichen anta- composant antiacide comprend une base ciden Bestandteil gemäß hierin befindlicher De- métallique pharmaceutiquement acceptable ou finition enthält, dadurch gekennzeichnet, daß un sel alcalin de celle-ci issu d'un acide faible. die Tablette dispersibel ist, der antacide 3. Comprimé dispersable suivant la Bestandteil in einer Menge von 50 bis 90 Gew.-% revendication 1 ou 2, caractérisé en ce que le verhanden ist, und die Tablette zusätzlich 5 composant antiacide a une solubilité dans l'eau bis 15 Gew.-% eines Zersetzungsmittels mit inférieure à 1 partie en poids dans 70. einer Schwellkapazität von zwischen 5 und 4. Comprimé dispersable suivant l'une quel- 100 ml/g enthält. conque des revendications 1 à 3, caractérisé en 2. Dispersible Tablette nach Anspruch 1, da- ce que le composé antiacide est un composé du durch gekennzeichnet, daß der antacide calcium, du bismuth, de l'aluminium ou du Bestandteil eine pharmazeutisch verträgliche magnésium. Metallbase oder ein Alkalisalz davon mit einer 5. Comprimé dispersable suivant l'une schwachen Säure umfaßt. quelconque des revendications 1 à 4, caracté- 3. Dispersible Tablette nach Anspruch 1 oder risé en ce que le composant antiacide est un Anspruch 2, dadurch gekennzeichnet, daß der composé du calcium ou du magnésium. antacide Bestandteil eine Löslichkeit in Wasser 6. Comprimé dispersable suivant l'une quel- von weniger als 1 Gew.-Teil in 70 aufweist. conque des revendications 1 à 5, caractérisé en 4. Dispersible Tablette nach einem der ce que le composant antiacide comprend un ou Ansprüche 1 bis 3, dadurch gekennzeichnet, plusieurs composés choisis entre l'hydroxyde daß der antacide Bestandteil eine Verbindung d'aluminium, l'hydroxyde de magnésium, le von Calcium, Wismut, Aluminium oder Magne- carbonate de magnésium et le silicate de sium ist. magnésium. 5. Dispersible Tablette nach einem der 7. Comprimé dispersable suivant l'une Ansprüche 1 bis 4 dadurch gekennzeichnet, daß quelconque des revendications 1 à 6, caracté- der antacide Bestandteil eine Verbindung von risé en ce que le composant antiacide comprend Calcium, oder Magnesium ist. de l'hydroxyde d'aluminium et de l'hydroxyde de 6. Dispersible Tablette nach einem der magnésium dans un rapport pondéral de 4:1 à Ansprüche 1 bis 5 dadurch gekennzeichnet, daß 1:4. der antacide Bestandteil under einer oder 8. Comprimé dispersable suivant l'une mehreren der Verbindungen Aluminium- quelconque des revendications 1 à 7, caracté- hydroxid, Magnesiumhydroxid, Magnesium- risé en ce que le composant antiacide à un carbonat und Magnesiumsilikat ausgewählt ist. diamètre médian en poids, tel que défini ci- 7. Dispersible Tablette nach einem der dessus, inférieur à 1µµ µm. Ansprüche 1 bis 6, dadurch gekennzeichnet, 9. Comprimé dispersable suivant la daß der antacide Bestandteil Aluminium- revendication 8, caractérisé en ce que le hydroxid und Magnesiumhydroxid in einem diamètre médian en poids est inférieur à 5µ µm. Gewichtsverhältnis von 4:1 bis 1:4 enthält. 10. Comprimé dispersable suivant l'une 8. Dispersible Tablette nach einem der quelconque des revendications 1 à 9, Ansprüche 1 bis 7, dadurch gekennzeichnet, caractérisé en ce que l'agent de désintégration daß der antacide Bestandteil einen Gewichts- est choisi parmi les carboxyméthylcelluloses mitteldurchmesser (weight median diameter) calciques, les carboxyméthylcelluloses sodiques gemäß der hierin befindlichen Definition von à basse viscosité, les gommes végétales à base weniger als 100,um besitzt. de cyamopsis, un alginate de sodium, les 9. Dispersible Tablette nach Anspruch 8, da- carboxyméthylcelluloses sodiques réticulées, les durch gekennzeichnet, daß der Gewichtsmittel- polyvinylpyrrolidones réticulées, les hydroxy- durchmesser weniger als 50,um beträgt. propylcelluloses à faible substitution, les résines 10. Dispersible Tablette nach einem der échangeuses de cations et les amidons Ansprüche 1 bis 9 dadurch gekennzeichnet, daß glycolates de sodium. das Zersetzungsmittel unter Calciumcarboxy- 11. Comprimé dispersable suivant l'une methylcellulosen, Natriumcarboxymethyl- quelconque des revendications 1 à 10, caracté- cellulosen niedriger Viskosität, pflanzlichen risé en ce que l'agent de désintégration est un Kautschuken auf Guar-Basis, einem Natrium- amidon glycolate de sodium. alginat, vernetzten Natriumcarboxymethyl- 12. Comprimé dispersable suivant l'une quel- cellulosen, vernetzten Polyvinylpyrrolidonen, conque des revendications 1 à 11, caractérisé niedrig substituierten Hydroxypropylcellulosen, en ce que l'agent de désintégration a une Kationenaustauscherharzen und Natrium- capacité de gonflement de moins de 60 ml/g. Stärkeglykolaten ausgewählt ist. 13. Comprimé dispersable suivant l'une quel- 11. Dispersible Tablette nach einem der conque des revendications 1 à 11, caractérisé Ansprüche 1 bis 10, dadurch gekennzeichnet, en ce qu'il comprend 5 à 10% d'agent de daß das Zersetzungsmittel ein Natrium- Stärkeglykolat ist. kapazität von weniger als 60 ml/g besitzt. 12. Dispersible Tablette nach einem der 13. Dispersible Tablette nach einem der Ansprüche 1 bis 11, dadurch gekennzeichnet, Ansprüche 1 bis 11, dadurch gekennzeichnet, daß das Zersetzungsmittel eine Schwell- daß sie 5 bis 10% Zersetzungsmittel enthält.