Pharmaceutical granulates containing an intragranular disintegrant

Abstract: Tablet formulations having a structure comprising compacted granulates of a mixture of a medicament and intra-granular disintegrant, the granulates being compacted together into a tablet with an extra-granular disintegrant and optional extra-granular lubricant and excipients.

Description: The present invention relates to pharmaceutical formulations for oral administration in the treatment of bacterial infections, and to processes for the manufacture of such formulations. It is known to provide formulations for oral administration in the form of water-dispersible granules or tablets which may be swallowed or dispersed in water prior to swallowing. In one known method of tablet manufacture, an intermediate granulate is prepared comprising an intragranular disintegrant and an active material such as an antibiotic. This granulate is then mixed with an intergranular disintegrant (and optional other additives including a lubricant) and compressed into tablets. Such a process, tablets and granulate are for example described in EP 0281200A, CA 1199871 and JP 3240023A. It is desirable that such solid formulations should rapidly disperse on immersion in water, for example by rapid disintegration of tablets. Novel formulations have now been discovered which assist in achieving some of the above-mentioned desirable features. The invention therefore provides a tablet formulation having a structure comprising at least 70% by weight of the tablet of compacted granulates; the granulates comprising amoxycillin and a salt of clavulanic acid in a weight ratio equivalent to amoxycillin:clavulanic acid in the range 12:1 to 1:1 and an intra-granular disintegrant which is cross linked N-vinyl-2-pyrrolidone (CLPVP), the amoxycillin and the salt of clavulanic acid comprising from 92 to 99% by weight of the granulate; the granulates being compacted together into a tablet form together with an extra-granular disintegrant and from 0 to 0.5% by weight of the total tablet of an extra-granular lubricant. In the tablets of this invention the granulates may be in a crushed state resulting from the compaction of the tablet, and consequently may not have discrete boundaries, or may be sub-divided or broken up into smaller granulates. The invention is intended to include tablets having such a structure containing crushed granulates. Preferably the size of the granulates is in the range 100µm to 2mm, suitably around 1mm ± 0.25mm, maximum dimension. A preferred antibiotic is amoxycillin, for example present as a hydrate such as the trihydrate. Amoxycillin may be used alone, or may optionally be used in combination with other β-lactam antibiotics and/or β-lactamase inhibitors such as clavulanic acid or salts (especially the potassium salt) thereof, for example in a weight ratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to 1:1 such as around 4:1 or 2:1. Preferably the proportion of the antibiotic in the tablet is 60-98% by weight of the total tablet, in the case of amoxycillin trihydrate calculated as the weight of the trihydrate. Preferably the particles of antibiotic in the granulates are in the size range 1µm to 300µm, especially 10µm to 200µm. A typical suitable size distribution of the antibiotic particles is : >200µ 5% or less, 200-100µ 5-15%, 100-50µ 7.5-15%, <50µ 70% or more. A preferred intra-granular disintegrant is CLPVP, for example as marketed under the trade names Polyplasdone XL and Polyplasdone XL-10. When the granulate contains clavulanic acid or a salt thereof, the granulate may also contain a diluent such as silica gel (eg Syloid-Trade Mark). A suitable intra-granular disintegrant for use with antibiotics is CLPVP. Typically the proportion of intra-granular disintegrant in the granulate may be 0.1 - 10wt % of the granulate, suitably 1.0 - 8.0wt %, such as 1.25 - 3.5wt %. Typically the proportion of an antibiotic or antibiotic + β-lactamase inhibitor combination in the granulate may be 99.9 - 90wt %, suitably 99 - 92wt %, e.g. 99 - 95wt %, such as 98.75 - 96.5wt % of the weight of the granulate. The intimate contact between the antibiotic and the intra-granular disintegrant in the granulate appears to assist in improved disintegration and dispersion of the granulate in contact with water to release antibiotic particles in the size range referred to above, and to provide finely dispersed suspensions. Problems are associated with preparation of granulates which include clavulanic acid or its salts, due to their hygroscopicity, and the granulate of the invention facilitates manufacture. In the tablet formulation the granulate may suitably comprise 70% or more, e.g. 80% or more, 90% or more or 95% or more of the total tablet weight so that a high proportion of medicament is present. The extra-granular disintegrant may be a conventional disintegrant for example starches such as maize-starch and rice starch, CLPVP, sodium starch glycollate, croscarmellose sodium, microcrystalline or microfine cellulose, low-substituted hydroxypropylcellulose (i.e. cellulose partially substituted with 2-hydroxypropyl groups, e.g. less than 25% substituted, preferably 7-16% substituted), cross-linked sodium carboxymethylcellulose, swellable ion exchange resins, formaldehyde-casein, or alginates. Preferred extra-granular disintegrants are CLPVP, sodium starch glycollate, microfine cellulose and croscarmellose sodium, and combinations thereof. An example of an extra-granular disintegrant combination is a combination of microcrystalline or microfine cellulose with sodium starch glycollate, croscarmellose sodium, or CLPVP, containing 80-90% by weight cellulose. The proportion of extra-granular disintegrant to total tablet weight may vary between broad limits, for example 0.1-25 weight %. For example if CLPVP or sodium starch glycollate is used as extra-granular disintegrant it may suitably be used as such in a proportion 0.1-5.0 weight %, suitably 0.1 - 3.0 weight %, preferably 0.1-1.5 weight % of the total tablet weight. If cellulose or a combination containing cellulose is used, e.g. as described above containing around 80-90% by weight of cellulose, the extra-granular disintegrant may comprise 1-25 weight %, typically around 1-20 weight % of the total tablet. Suitable lubricants are those conventional to the art, such as long-chain fatty acids, such as stearic acid, or salts thereof, in particular Group II metal salts, such as of magnesium or calcium. A preferred lubricant is magnesium stearate. It is preferred to use a lubricant proportion as low as possible e.g. 0.35% by weight or preferably lower, e.g. 0.275% or less, e.g. 0.25% or less, preferably using no lubricant at all. An advantage of the present tablet formulation is that the granulate and tablet need not contain any lubricant. This can lead to improved wettability and hence improved disintegration of the tablet. Further a reduced lubricant proportion can lead to a lower tablet weight for a given dose of antibiotic and in the case of dispersible formulations can avoid the "smeared" appearance associated with higher lubricant proportions. The tablet may also include conventional excipients, typically present up to about 10% of the total tablet weight. These may include flavouring agents, for example flavourings such as menthol, peppermint, vanilla or fruit flavourings, flavouring agents typically being present up to around 0.5-5% by weight of the whole tablet, and sweeteners, e.g. aspartame, present of up to around 15mg per unit dose. Excipients may also include colouring agents, preservatives, suspending aids and fillers such as silicon dioxide, microcrystalline cellulose, dicalcium phosphate, lactose, sorbitol, calcium carbonate or magnesium carbonate. Such excipients are preferably mixed with the extra-granular disintegrant and lubricant (if present). The materials present in the tablets should have low free moisture content and preferably be pre-dried. In some cases, particularly when the medicament is an antibiotic, and includes clavulanic acid or its salts, it may be necessary to include a dessiccant diluent such as silica gel as an excipient, in a proportion of about 1-5% of the weight of the antibiotic, mixed with the antibiotic and intra-granular disintegrant in the granulates. The particle size of the excipients does not appear to be critical but it is desirable to exclude agglomerates. The tablet may also contain an effervescent couple of known type, e.g. a solid acid and an alkali metal carbonate or bicarbonate which generates carbon dioxide on contact with water to assist in disintegration of the tablet. The tablets may be film coated in a conventional manner, e.g. for cosmetic, palatability or production purposes. Suitable coatings include hydroxypropylcellulose, acrylate and/or methacrylate co-polymers, resins etc. Alternatively the coating may be an enteric coating, e.g. which is insoluble in acidic gastric juice but soluble in alkaline digestive juice. Such a coating enables the antibiotic to pass through the stomach into the duodenum, from where it is absorbed. Suitable enteric coatings include cellulose acetate phthalate. Preferred combinations of components for the tablets of this aspect of the invention therefore comprise: Granulate: Component wt% Example Medicament 70 - 99 Amoxycillin ± Pot.clavulanate Disintegrant 0.1 -4 CLPVP, Microcryst. cellulose, sodium starch glycollate Diluent 0 - 30 Silica gel Tablet: Component wt% Example Granulate 70+ above Disintegrant 0.1 - 25 CLPVP, Microcryst. cellulose, sodium starch glycollate. Lubricant 0 - 0.35 Magnesium stearate Excipients to 100 Aspartame, flavour, colour, silicon dioxide The invention also provides a process for the manufacture of a tablet in which granulates comprising a compacted mixture of at least one medicament such as a β-lactam antibiotic in combination with a β-lactamase inhibitor, together with an intra-granular disintegrant are mixed with an extra-granular disintegrant and optionally with an extra-granular lubricant and optionally with any excipients, provided that if a lubricant is present it amounts to less than 0.5% by weight of the mixture, and the mixture is compressed into tablets. Suitable and preferred antibiotics, intra- and extra-granular disintegrants, lubricants, excipients, granulate and particle sizes, and relative proportions thereof are as discussed above. The necessary granulate for the process of this aspect of the invention may be made in a further process by mixing the medicament in a powdered form with the intra-granular disintegrant in a dry state, and compacting the mixture under pressure. Insofar as this further process uses as intra-granular disintegrant CLPVP, it is believed to be novel, and is a further aspect of this invention. In this further process, it is desirable to mill and sieve the antibiotic to achieve the desired particle size range. It is also desirable to mill and sieve intra-granular disintegrant to a suitable particle size, for example in the case of CLPVP about 30µ, but particle size does not appear to be critical. The compaction of the mixture into granulates may be by conventional dry compaction means, for example pressing, rolling, slugging extrusion etc, and a suitable pressure for the compaction process is 30-200KN, e.g. 35-65KN preferably 40-50 KN. The above-described granulate formulations are particularly suited to formation by roller compaction. It may be necessary to mill and sieve the compacted mixture after compaction so as to achieve a suitable size fraction of the granulate. Compression into tablets may be carried out in a conventional manner, e.g. on a conventional tabletting machine. As an optional further step the tablets may be coated as described above. When the granulates described above contain as a medicament a β-lactam antibiotic such as amoxycillin together in combination with a β-lactamase inhibitor such as clavulanic acid or its salts (especially potassium clavulanate) these granulates are believed to be novel and are a further aspect of this invention. Suitable and preferred features of these granules are as discussed above. The formulations described above preferably contain unit doses of antibiotic, for example 375, 500, 750 or 1000mg of amoxycillin per tablet or capsule. The tablets may be dispersed in water prior to ingestion, or may alternatively be chewed or swallowed whole. The invention further provides a pharmaceutical formulation as described above, for use as an active therapeutic substance. The invention further provides a pharmaceutical formulation as described above, in which the medicament is a β-lactam antibiotic in combination with a β-lactamase inhibitor, for use in the treatment of bacterial infections. The invention futher provides a method of use of a pharmaceutical formulation as described above in which the medicament is a β-lactam antibiotic in combination with a β-lactamase inhibitor in the manufacture of a medicament for use in the treatment of bacterial infections. The invention further provides the use according to the present invention for the treament of bacterial infections in mammals which comprises the administration to the mammal of an effective amount of a pharmaceutical formulation as described above, in whcih the medicament is a β-lactam antibiotic, in combination with a β-lactamase inhibitor. The invention will now be described by way of example only. Reference Example 1: Granulate. Amoxycillin trihydrate was milled and sieved using an 0.04 or 0.027 inch (1.0 - 0.7 mm) aperture sieve, and was mixed for 15 minutes in a blender with dried cross-linked polyvinylpyrrolidone having a molecular weight of approximately 1 million and a density of 1.22 mg/cm 3 (polyplasdone XL - Trade Mark), the mixture containing 3.4% of CLPVP by weight. The mixture was consolidated using a roller compacter at a controlled pressure of 50KN. The compacted flakes were granulated in a mill, or granulated through a sieve fitted with a 1mm mesh to obtain a suitable size fraction. Example 1 : Tablet Formulation Amox: clav 4 : 1 4 : 1 2 : 1 7 : 1 Component weight (mg) w+% Granulate 751.9 376.0 452.1 1201.3 70.90 Dry Flavour 6.0 3.0 3.0 8.0 0.48 - 0.63 Poliplasdone XL) dried ) 100.0 50.0 66.5 110.0 8.1 - 10.7 Aspartame 15.0 7.5 7.5 15.0 1.1-1.6 Colouring 4-5 2 - 2.5 2-2.5 4-5 0.3-0.55 Mag. Stearate Silicon Dioxide ) 2.5 1.25 1.25 3.4 0.19 - 0.26 Syloid AL - 1 ) to 950 475 628 1350 to 100 The granulate was prepared using the procedure of Reference Example 1. The granulate was prepared using the procedure of Reference Example 1. The other excipients except aspartame were sieved and blended then mixed with the granulate. The aspartame was then added, and this mixture was then compressed into tablets in a conventional tabletting machine. This tablet contained 625 mg of the amoxycillin : clavulante blend. Tablets of different strengths could be formulated correspondingly, eg containing 1000, 375 or 312.5 mg of the amoxycillin : clavulanate combination. Example 2 : Tablet Formulation Component Weight (mg) w +% Granulate (Amox.Kclav) ) 4:1 or 7:1 + 3% PVP ) 751.9 376.0 188.0 1201.3 71-83 Magnesium stearate Ph. Eur 2.6 1.3 0.65 3.9 0.25-0.27 Silicon Dioxide USP /NF) (Syloid AL-1) ) 44.0 22.0 11.0 44.0 3-4.25 Microcrystalline cellulose) Avicel pH 112 dried ...to..) 850.0 425.0 212.5 1275.0 1.8-5 Organic film coating yes yes yes yes to 100 Actual weight 1050.0 - - 1450.0 (1) amox : clav expressed as free acid. The tablet was made up in a manner identical to that of example 1. The weights and relative proportions of the components of examples 1 and 2 could be varied about the figures listed, but suitably are within ± 10% of those listed, desirably within ± 5%, especially ± 2.5%.

Claims: A pharmaceutical granulate comprising amoxycillin and a salt of clavulanic acid in a weight ratio equivalent to amoxycillin:clavulanic acid in the range 12:1 to 1:1 and an intra-granular disintegrant which is cross linked N-vinyl-2-pyrrolidone (CLPVP), the amoxycillin and the salt of clavulanic acid comprising from 92 to 99% by weight of the granulate. A pharmaceutical granulate as claimed in claim 1 in which amoxycillin and the salt of clavulanic acid comprise from 95 to 99% by weight of the granulate. A pharmaceutical granulate as claimed in claim 1 or 2 in which amoxycillin is present as amoxycillin trihydrate. A pharmaceutical granulate as claimed in any one of claims 1 to 3 in which the salt of clavulanic acid is potassium clavulanate. A pharmaceutical granulate as claimed in claim 3 or 4 in which amoxycillin trihydrate and potassium clavulanic are present in a weight ratio equivalent to amoxycillin: clavulanic acid of 2:1 or 4:1. A pharmaceutical granulate as claimed in any one of claims 1 to 5 in which the intra-granular disintegrant is present in from 1.0 to 8.0% by weight of the granulates. A pharmaceutical granulate as claimed in any one of claims 1 to 6 in which the intra-granular disintegrant is present in the range 1.25 to 3.5 wt%. A pharmaceutical granulate as claimed in any one of claims 1 to 7 in which the granulate further comprises silica gel present in from 1 to 5% by weight of amoxycillin and a salt of clavulanic acid. A pharmaceutical granulate as claimed in any one of claims 1 to 8 in which the granulate comprises no lubricant. A tablet formulation comprising at least 70% by weight of the tablet of compacted granulates as defined in any one of claims 1 to 9 together with an extra-granular disintegrant and from 0 to 0.5% by weight of the total tablet of an extra-granular lubricant. A tablet formulation as claimed in claim 10 in which the granulates comprise at least 80% of the total tablet weight. A tablet formulation as claimed in claim 10 in which the granulates comprise at least 90% of the total tablet weight. A tablet formulation as claimed in claim 10 in which the granulates comprise at least 95% of the total tablet weight. A tablet formulation as claimed in any one of claims 10 to 13 in which the proportion of extra-granular lubricant in the tablet is between 0 and 0.35 wt % of the total tablet weight A tablet formulation as claimed in any one of claims 10 to 14 in which the proportion of extra-granular disintegrant in the tablet is between 0.1 - 25 wt % of the total tablet weight. A process for preparing a granulate as claimed in any one of claims 1 to 9 which comprises the steps of compacting the ingredients thereof using dry compaction means to form granulates. A process as claimed in claim 16 in which the dry compaction means is a roller compactor. A process for preparing a tablet as as claimed in any one of claims 10 to 15 which comprises the steps of admixing the granulates prepared as defined in claim 16 or 17 with extra-granular excipients and then compacting to form a tablet.

Inventors: MARTIN LUIS, ROMERO JUAN DEDIOS, MARTIN, LUIS, ROMERO, JUAN DEDIOS, MARTIN, LUIS CARVAJAL C/O CIP CN925.1, Romero, Juan Dedios, c/o CIP CN925.1
Applicants: BEECHAM LAB SA, LABORATORIOS BEECHAM SA
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61K9