SI9200080A - Pharmaceutical preparations containing compressed medicaments granules - Google Patents

Abstract

Tablet formulations having the structure of which it contains compressed granulate mixtures of the active substance and granular disintegrant that works inside the granule, granules that are pressed together into a granular tablet out - of - grain disintegrants and optionally with granular lubricators operating outside the granules and excipients. The invention thus provides pharmaceuticals tablets that disintegrate quickly and require reduced the amount of lubricator to compress.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING COMPRESSED GRANULATES OF THE MEDICINAL PRODUCT

The present invention relates to pharmaceutical forms for oral administration in the treatment of bacterial infections, and to methods for the preparation of such forms.

Formulations for oral administration are known in the form of granules that can be dispersed in water or tablets that can be swallowed or dispersed in water before swallowing.

In one of the known methods for making tablets, an intermediate granulate is prepared containing a granular disintegrant that acts inside the granule and an active substance such as an antibiotic. This granulate is then mixed with an intergranular disintegrator (and optionally with other additives including a lubricator) and compressed into tablets. Such a process, tablets and granules, for example, are described in EP 0281200A, CA 1199871 and JP 3240023A.

Such a solid form is desirable to be rapidly dispersed when immersed in water, for example by rapid disintegration of tablets.

New designs have now been discovered to help achieve some of the aforementioned desirable characteristics.

The invention therefore enables the manufacture of tablets having a structure containing compact granules; granules containing at least one compact drug of choice together with one granular disintegrant operating within the granule; granules which are compressed into tablet form together with a granular disintegrant operating outside the granule and optionally together with a granular lubricator operating outside the granule, provided that, if a lubricant is present, its amount is less than 0.5 % by weight of the total tablet.

In the tablets of the present invention, the granules may be in the crushed state resulting from the compression of the tablets, and as a consequence they may not have discrete boundaries, or may be internally divided or broken into smaller granules. The invention is intended to include tablets having such a structure containing crushed granules. It is desirable that the size of the granules is in the range of 100 µm to 2 min, with a suitable maximum dimension of about 1 mm ± 0.25 mm.

It is desirable that the active substance can be orally absorbed, especially the 3-lactam antibiotics in combination with the ^ -lactamase inhibitors. A priority antibiotic is amoxicillin, for example present in the form of a hydrate such as trihydrate. Amoxicillin may be used alone, or optionally in combination with other 3-lactam antibiotics and / or ZJ-lactamase inhibitors such as clavulanic acid or its salts (especially potassium salt), for example in a weight ratio equivalent to amoxicillin: clavulanic acid to the extent 12: 1 to 1: 1, like about 4: 1 or 2: 1. The desired antibiotic ratio in the tablets is 60-98% by weight of the total tablet, calculated in the case of amoxicillin trihydrate as the weight of the trihydrate. It is desirable that the antibiotic particles in the granules range in size from 1 to 300 µm, especially from 10 to 200 µm. Typical suitable distribution of antibiotic particles is: 200 to 5% or less, 200-100 to 5-15%, 100-50 to 7.5-15%, 50 to 75% or more.

Suitable granular disintegrants are starches such as maize starch and rice starch, crosslinked N-vinyl-2-pyrrolidone (CLPVP), sodium starch glycolate, croscarmellose sodium and formaldehyde-casein, or combinations thereof. A desirable granular disintegrator is CLPVP, such as the one on sale under the trade name Polyplasdone XL and Polyplasdone XL-10.

The granulate may consist, as a whole, of the antibiotic (s), optionally in the case of the / 3-lactam antibiotic combined with the inhibitor / 3-lactamase, and the granular disintegrant operating within the granule. Alternatively, especially when the granulate contains clavulanic acid and its salt, the granulate may contain a diluent such as silica gel (e.g., Syloid-Trade Mark). Granular disintegrants that work inside the granule, CLPVP and sodium starch glycolate are suitable for use with antibiotics. A typical granular disintegrator ratio in the granulate may be 0.1 - 10% by weight of granulate, preferably 1.0 - 8.0% by weight, as well as 1.25 - 3.5% by weight. A typical combination ratio of one antibiotic or antibiotic + inhibitor / 3-lactamase in the granulate may be 99.9-90% by weight, preferably 99-92% by weight, for example 99-95% by weight, such as 98.75-96.5 % by weight relative to the weight of the granulate. Where the granulate contains a diluent, it may contain up to 30% by weight of the granulate, but a weight ratio with the amount of clavulanic acid or its salt in the granulate is 1: 1. When the granulate contains a diluent, the granulate will contain a correspondingly lower antibiotic ratio or a combination of antibiotic + inhibitor / 3-lactamase, for example 70-99% by weight of granulate.

Intimate contact in the granulate between the antibiotic and the granular disintegrant acting inside the granule appears to help improve the disintegration and dispersion of the granulate in contact with water, which releases antibiotic particles within the aforementioned size range and allows finely dispersed suspensions. There are problems with the preparation of granulates that include clavulanic acid or its salts due to their hygroscopicity, and the granulate of the invention facilitates their production.

In tablet formulation, the granulate may conveniently represent 70% or more, e.g. 80% or more, 90% or more or 95% or more of the total weight of the tablets so that the active substance ratio is high.

The granular disintegrant acting outside the granule may be a conventional disintegrant, for example starches such as cornstarch and rice starch, CLPVP, sodium starch glycolate, croscarmellose sodium, microcrystalline or micronized cellulose, partially substituted hydroxypropylcellulose substrate (hydroxypropylcellulose substrate) , e.g., less than 25% substituted, preferably 7-16% substituted) cross-linked sodium carboxymethylcellulose, inflatable ion exchange resins, formaldehyde-casein, or alginates. Desirable granular disintegrants operating outside the granule are CLPVP, sodium starch glycolate, micronized cellulose and croscarmellose sodium, and combinations thereof. One example of a combination of a granular disintegrant operating outside the granule is a combination of microcrystalline or micronized cellulose with sodium starch glycolate, croscarmellose sodium, or CLPVP containing 80-90% by weight of cellulose.

The ratio of the granular disintegrant operating outside the granule to the total weight of the tablet may vary over a wide range, for example 0.1-25% by weight. For example, if a CLPVP or sodium starch glycolate is used as a granular disintegrant operating outside the granule, it may be suitably used in a ratio of 0.1-5.0% by weight, as such conveniently total

0.1-3.0% by weight, preferably 0.1-1.5% by weight of the tablet, if cellulose or a combination containing cellulose is used, e.g. as described above, containing about 80-90% by weight of cellulose, a granular disintegrant operating outside the granule may comprise 1-25% by weight, typically about 1-20% by weight of the total tablet.

Suitable lubricators are those common in the art, such as long-chain fatty acids such as stearic acid or a salt thereof, especially Group II metal salts such as magnesium or calcium.

The preferred lubricator is magnesium stearate. It is desirable to have a lubricator ratio as small as possible e.g. 0.35% by weight or lower, e.g. 0.275% or less, e.g. 0.25% or less, it is advisable not to use a lubricator at all.

The granulate may also contain a granular lubricator that operates inside the granule, which can be selected from the same compounds as a granular lubricator that operates outside the granule, such as magnesium stearate. But one advantage of new tablet manufacturing is that the granulate and the tablet do not need to contain any lubricant. This may allow better wetting and therefore improved tablet disintegration. Furthermore, a reduced lubricator ratio may reduce the weight of the tablet by a given dose of antibiotic and thus, in the case of dispersed forms, avoid the dirty appearance associated with a high lubricator ratio.

The tablet may also include conventional excipients, typically present up to about 10% of the total weight of the tablet. Taste corregents, for example, such as menthol, peppermint, vanilla, or fruit flavored, flavor flavors characterized by an amount of up to about 0.5-5% by weight of the total tablet, and sweeteners, e.g. . aspartame, the amount of which is approximately 15 mg per dosage unit. Excipients may also include coloring agents, protective agents, suspending agents and fillers such as silica, microcrystalline cellulose, bicalcium phosphate, lactose, sorbitol, calcium carbonate or magnesium carbonate. Preference is given to mixtures of such excipients with granular out-of-grain disinfectants and lubricators (if present). The ingredients present in the pills should have a low free moisture content and is better when pre-dried. In some cases, especially when the drug is an antibiotic and includes clavularic acid or its salts, it may be necessary to include an excipient that is a drying agent, such as silica gel, in a ratio of about 15% by weight of the antibiotic mixed in the granules with an antibiotic and a granular disintegrator that works inside the granule. The size of the excipient particles does not appear to be critical, but it is desirable to exclude agglomerates.

The tablet may also contain a couple of a known type, which makes it effervescent, such as solid acid and carbonate or bicarbonate of an alkali metal that, in contact with water, releases carbon dioxide, which helps disintegrate the tablet.

The tablets may be coated with the film in the usual manner, e.g. for cosmetic purposes, for taste or production purposes. Suitable coatings include hydroxypropylcellulose, acrylate and / or methacrylate co-polymers, resins i.t.d. Alternatively, the coating may be gastroresistant, e.g. one insoluble in acidic gastric juice but soluble in alkaline digestive juice. Such a coating allows the antibiotic to pass through the stomach into the duodenum from which it is absorbed. Suitable gastro-resistant coatings include acetate phthalate cellulose.

Preferred combinations of ingredients for the tablets of this aspect of the invention therefore include:

Granulate:

Ingredient Fat% Example Medication 70-99 Amoxicillin pot.clavulanate Disintegrator 0,1-4 CLPVP, Microcryst. cellulose sodium starch glycolate Thinner 0-30 Silica gel

Tablet:

Ingredient

Fat%

Example

Granulate 70+

Disintegrator 0.1-25

Lubricator 0-0,35

Excipients up to 100 previous

CLPVP, Microcryst. cellulose sodium starch glycolate

Magnesium stearate

Aspartame, taste, color, silica

The invention also provides a process for making tablets in which granules containing compressed mixtures of at least one drug such as / 3-lactam antibiotic or alone or in combination with a / 3-lactamase inhibitor, together with a granular disintegrant acting within the granule are mixed with a granular disintegrant operating outside the granule and optionally with a granular lubricator operating outside the granule and optionally with any excipient provided that, if lubricator ¹ is present, it is less than 0.5% by weight of the mixture and that the mixture is compressed into tablets.

suitable and desirable antibiotics, granular disintegrants operating inside and outside the granule, lubricators, excipients, granules and particle sizes, and their relative ratios have been discussed previously.

The necessary granulate for the process of this aspect of the invention can be prepared in a further process by mixing the drug in powder form with a granular disintegrant that operates inside the granule in a dry state and by compressing the mixture under pressure. This further process is believed to be novel as long as CLPVP granular disintegrant, sodium starch glycolate, caseinformaldehyde, croscarmellose sodium, or combinations thereof, is used as a further aspect of the present invention.

In this further process, it is desirable to grind and sift the antibiotic to obtain the desired particle size range. It is also desirable to grind and sift the granular disintegrant operating within the granule to a suitable particle size, for example in the case of CLPVP of about 30 μm, but the particle size does not appear to be critical.

Compressing the mixture into granules may be a common dry method of compacting, such as pressing, compression in a drum press, slow ejection of i.t.d. suitable pressure for the compacting process is 30-200 kN, e.g. 35-65 kN preferably 40-50. The granulate shapes described so far are particularly suitable for compression molding in a drum press. It may be necessary to grind and squeeze the compressed mixture after compression to obtain a suitable granulate fraction size. Compression into tablets may be carried out in the usual manner, e.g. using a conventional tablet machine. A further optional step may be tablet coating as described previously.

When the granulates described above contain as a drug / 3-lactam antibiotic such as amoxicillin in combination with an fb-lactamase inhibitor such as clavulanic acid and its salts (especially potassium clavulanate), these granulates are believed to be novel and a further aspect thereof. of the invention. We have previously discussed the suitable and desirable properties of these granules.

The granules described may be suitable for use in the preparation of other pharmaceutical forms as adjuncts to tablets, for example, they may be supplemented as free granular forms in bags containing suitable dosage units. They can also, for example, be dissolved in water together with excipients such as sweeteners, diluents, safeners and buffers such as sodium benzoate, sodium acetate and sodium citrate to form a syrup, for example for administration to young children.

The ability of the granules to form loose compacts and to disperse them quickly upon contact with water makes them particularly suitable for use in encapsulated forms. Therefore, a further aspect of the present invention provides a capsule form containing such granules. The capsule formulations may optionally include a granular lubricator that operates outside the granule, the amount of which, if present, is less than 0.5% by weight of the granules and is contained in a pharmaceutical capsule.

It is desirable that the active substance is such that it is capable of oral absorption, specifically the / 5-lactam antibiotic of choice in combination with the / 3-lactamase inhibitor. Suitable and desirable antibiotics, inhibitors / 3-lactamase, granular disintegrator, granule-acting, granular-lubricator, granule-extracellular, granulate and particle sizes, and their relative ratios for capsule production have been discussed previously, except that the desired ratio is lubricator 0.1-0.5%, especially 0.320.35% by weight of granulate.

A pharmaceutical capsule may be a completely conventional capsule capable of melting in the stomach by releasing its contents, for example, prepared from gelatin.

It is desirable that the forms described hereinbefore contain antibiotic dosage units, for example, 375, 500, 750, or 1000 mg amoxicillin per tablet or capsule. The tablets may be dispersed in water before administration, or alternatively chewed or swallowed whole.

X

The invention further provides pharmaceutical forms, such as those described above, for use as active therapeutic substances.

The invention further provides a pharmaceutical formulation as described wherein the medicament is a β-lactam antibiotic optionally in combination with a / 3-lactamase inhibitor for use in the treatment of bacterial infections.

The invention further provides a method of using a pharmaceutical form as described above wherein the drug / 3-lactam antibiotic is optionally combined with an inhibitor / 5-lactamase in the manufacture of a medicament for use in the treatment of bacterial infections.

The invention further provides a method of treating bacterial infections in a mammal comprising administering to the mammal an effective amount of a pharmaceutical formulation as previously described wherein the drug / 3-lactam antibiotic is optionally in combination with a 3-lactamase inhibitor.

The invention will now be described by way of example only.

Example 1: Granulate

Amoxicillin trihydrate was ground and sieved with a sieve of 0.04 or 0.027 inch (1.0-0.7 mm) sieve and mixed in a blender with dried crosslinked polyvinylpyrrolidone for about 15 minutes with a molecular weight of about 1 million and a density of 1 , 22 mg / cm3 (polyplasdone XL - Trade Mark), the mixture contained 3.4% CLPVP by weight.

The mixture was combined using a drum press at a controlled pressure of 50 kN. The compressed flakes were granulated in a mill or through a 1 mm sieve-balanced sieve to obtain an appropriate fraction size.

Example 2: Tablet

We have prepared tablets of the following composition:

Ingredient

Weight mg Weight%

Amoxicillin trihydrate CLPVP

Sodium starch glycolate (Primogel)

Magnesium stearate Aspartame

Microcrystalline Cellulose (Avicel PH102)

7501 78.95 as a granulate 26,0 2.73 of Example 1 21.6 2.27 2.0 0.21 additional 20,0 2.10 granulate 130,4 13,74

(1) expressed as free acid equivalent.

To prepare these tablets, dried sodium starch glycolate, magnesium stearate and microcrystalline cellulose were screened and then mixed with the granulate of Example 1. Subsequently, aspartame was added and the mixture stirred until homogeneous (5 minutes). The mixture was then compressed into tablets using t

conventional tableting machines.

Example 3: Granulate

The granulate was prepared by the procedure identical to Example 1, comprising 97% by weight of amoxicillin trihydrate and 3% by weight of XL polyploid and by a controlled pressure of 40-50 kN.

Example 4: Tablet

We have prepared tablets of the following composition:

Ingredient Mass mq Mass mq Mass mo Weight mq Weight% Amoxicillin 375 500 750 1000 83,00 CLPVP 17.5 23,33 35 46.65 3.78 Korigens z 3 4 6 7.99 0.65

flavored with peppermint

Aspartame 7.5 10 15 19,99 1.62 Magnesium 1 1.34 2 2.67 0.21

stearate (1) As 95% by weight of amoxicillin trihydrate.

(2) 3% as a granular disintegrant _r operating within the granule and

0.78 as a granular disintegrant operating outside the granule.

For the preparation of these tablets, the dried flavors of flavor, aspartame, magnesium stearate and CLPVP (polyplasdone XL) were mixed for 5 minutes, the mass of which corresponded to 0.78% by weight of the total weight of the mixture with the granulate of Example 3 to give the weight% previously indicated. The mixture was then compressed using a conventional tabletting machine.

Typical tablets in this example containing 750. mg of amoxicillin in the form of trihydrate had the following characteristics:

mass hardness time required for dispersion in water fineness presentation 17xl0x7mm

925 mg 5% kP minute 1%

Oval, tablets

Example 5: Granulate

The granulate was prepared by a procedure identical to that of Example 1 comprising 97.12% by weight of amoxicillin trihydrate together with 2.88% by weight of sodium starch glycolate (as Primogel) as a granular disintegrant operating inside the granule.

Example 6: Tablet

We have prepared tablets of the following composition:

Ingredient% Weight mg_ Weight%

Amoxicillin 1 750 78.95 Sodium starch glycolate 21.6 2.27 as the granulate of Example 5 Magnesium stearate 2.0 0,2 ~ T additional Dried microcrystals- to 950 18,57 granulate.

Linear cellulose (Avicel PH102) (1) as free acid equivalent.

For the preparation of these tablets, the granulate of Example 5 was sieved using a 1 mm sieve and then stirred for 15 minutes with an appropriate amount of magnesium stearate (lubricator) and microcrystalline cellulose. The mixture was then compressed into a tablet having the following characteristics:

mass: 950 mg hardness: 12-16 kP Dispersion time in water: 10-15 seconds (37θΟ) 20-25 seconds (37θ (3)

These tablets may be supplied as previously uncoated, dispersed in water before swallowing, or film-coated for swallowing.

Example 7: Capsule Making

The granulate of Example 3 was made into a slight compact under gentle pressure, together with an amount of magnesium stearate lubricant, up to 0.34% by weight of the total compact. This slight compact was inserted into gelatin capsules containing the following mixture:

Ingredient_mass mg_mass%

Amoxicillin trihydrate 573.91 96.8

CLPVP 17 2.9

Magnesium stearate 2 0.34 (1) corresponds to 500 mg of amoxicillin as a free acid.

Example 8: Making a bag

Ingredient_mass mg Weight%

Potassium amoxicillin trihydrate 2711.1 76.12

Clavulanate / siloid AL-1 mixed 1: 1 granulate

Polypladon XL dried

Polypladon XL dried Dry lemon flavored corigens 13.5 408,0 0.38 11,45 Dry berries with berry flavor 132,0 3.71 Dry peach flavored corigens 102,0 2.86 Aspartame 45,0 1,26 Xantham gum 150,0 4.21

extra granulate

The granules were identical in manufacture to those of Example 1, i.e. by grinding and sieving the constituents of the granulate, followed by compression in a drum press (50 kN) and granulation. The granules may be made into a mixture suitable for presentation in the form of sacs with granular excipients acting outside the granules.

Example 9: Granulate

Ingredient Mass mq Weight% Amoxicillin trihydrate 581,41 64,0 Potassium clavulanate 152.42 16,8 as Siloid AL-1 152,4 16.8 Polyploid XL dried 22,0 2.2

granulate (1) corresponds to 500 mg of amoxilin in free acid form.

(2) corresponds to 125 mg of free clavulanic acid.

The granules were prepared with the aid of this mixture in a manner identical to that of Example 8. These granules are suitable for storage in bags together with flavor correction and sucrose in the following proportions relating to the aforementioned amount of granules per bag:

Dry Corigens Dry Corigens Dry Corigens Sucrose with lemon flavored berry flavored with peach

136.0 mg 44.0 mg 34.0 to 3500 mg

Bags containing different weights of amoxicillin, e.g. 250 or 125 mg may be made using proportional amounts of the abovementioned masses and supplemented to 1750 mg total weight by sucrose.

Example 10: Tablet

Ingredient Mass mq Weight% Amoxicillin trihydrate 581,41 61,2 Potassium clavulanate 152.42 16.0 as a granulate Siloid AL-1 152,4 16.0 Polyploid XL dried 17.4 1.83 Dry coriander flavors 6.0 0.63 ~ (peppermint or tangerine) Polypladon XL dried 25,0 2.63 additional Aspartame 5.0 1.58 granulate Dyes 5.0 0.53 Magnesium stearate 2.5 0.26

(1) corresponds to 500 mg of amoxilin as free acid.

(2) corresponds to 125 mg of free clavulanic acid.

The granules were prepared using this mixture in a manner identical to that of Example 8. The taste corregens, polyploid XL, colorant and magnesium stearate were sieved and then mixed with the granulate. Then aspartame was added and the mixture was compressed into tablets using a conventional tabletting machine. This tablet contains 625.0 mg of the combination amoxicillin: clavulanate, and the quantities used can be halved to make the tablet containing 312.5 mg.

Example 11: Tablet

Ingredient_mass mg_mass%

Amoxicillin trihydrate 290,71 46,3 Potassium clavulanate 152.42 24.3 Siloid AL-1 152,4 24.3 Polypladon XL dried 8.7 1.38 Dry coriander flavors 3.0 0.48 (peppermint or tangerine) Polypladon XL dried 12.5 2.00 Aspartame 7.5 1.19 Dye 2.5 0.39 Magnesium stearate 1,25 0.20

as granulate, the additional granulate (1) corresponds to 250 mg of amoxicillin as free acid.

(2) corresponds to 125 mg of free clavulanic acid.

The tablets were made from this mixture by a procedure identical to that of Example 10.

Example 12: Making a bag or syrup

Ingredient Mass mq m +% Amoxicilintkali clavulanate 4: 1 w: w + 3 wt% CLPVP granulate ^ 2255,6 63,3 CLPVP 13.5 0.38 Dry lemon flavored corigens 408,0 11,46 Dry berries with berry flavor 132,0 3.71 Dry peach flavored corigens 102,0 2.86 USNF silica (Syloid AL-1) 450,0 12,64 Aspartame 45,0 1,26 Xantham gum 150,0 4.21 The whole mass 3561,6 100,0

(1) Amox: clav expressed as free acid.

The granulate was prepared by the method of Example 8. This form may be stored in a bag or may be made in the form of a syrup, for example at concentrations of 3561.6 mg / 60 ml or 7123.2 mg / 60 ml or 7123.2 mg / 60 ml (= 156.25 and 312.5 mg amoxicillin: clavulanate / 5 ml, respectively). Aerosil 200, succinic acid and / or the E-15 methocel (dry) may be used to adjust the appropriate viscosity and pH of the syrup.

Example 13: Making a bag

Ingredient_ Weight mg_m +%

Granulate (Amox: Kklavl

4: 1 or 7: 1 Dry Corigens taste + z 3% PVP) lemon 500 136 250 68 125 34 875 136) 7-25 Dry Corigens z strawberries 44 22 11 44) 3-6,1 taste Dry Corigens z peach 34 17 8.5 34) taste USNF silica 150 75 37.5 150 2, 1-4,3 (Syloid AL-1; 1 Sucrose to 3500 1750 1750 3500 to 100

(1) Masses and Amox / Cclav are expressed as free acid.

The granulate was prepared by the procedure of Example 8 and then mixed with other excipients.

Example 14: Making tablets

Amox: clav Ingredient 4: 1 4: 1 Mass 2: 1 mq 7: 1 m +% Granulate 2 751,9 376,0 452,1 1201,3 70.90 Dry flavors of flavor3 6.0 3.0 3.0 8.0 .48-0, .63 Polypladon XL (dry; ) 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 Dye 4-5 2-2, 5 2-2, 4-5 0.3 - 0.55 Magnesium stearate 2.5 1,25 1,25 3.4 0.19- 0.26 Silica (Syloid AL-1) to 950 475 628 1350 do 100

(1) Amox: clav is expressed as mass by weight amoxicillin: clavulanate as free acid.

(2) Granulate = amox: clav + 3% CLPVP.

(3) Peppermint or tangerine.

The granulate was prepared according to the procedure of Example 9. Excipients other than aspartame were screened and mixed and then mixed with the granulate. Subsequently, aspartame was added and the mixture was compressed into tablets using a conventional tabletting machine. Each tablet contains 625 mg of a mixture of amoxicillin: clavulanate. Different strength tablets may be suitably formulated, e.g., containing 1000, 375, or 312.5 mg of the combination amoxicillin: clavulanate.

Example 15: Making tablets

Ingredient_mass mg_m +%

Granulate (Amox: Kklav) 1 751.9 4: 1 or 7: 1 + 3% PVP

Magnesium stearate 2.6

Ph. Eur. _

Silica USP / NF 44.0 / Syloid AL-1) _

Avicel Microcrystalline Cellulose pH 12 Dried to .... _

Organic film coating

Current mass

850,0 yes

1050,0

376,0 '188,0 1201,3 71-83 1.3 0.65 3.9 0.25-0.27 22,0 11,0 44,0 3-4,25 425,0 212.5 1275,0 1,8-5 Yes Yes Yes do 100 o » 1450,0

1) amox: clav expressed as free acid.

The tablet is made in a manner identical to that of the example

14.

The weights and relative ratios of the constituents of Examples 1 to 15 may vary within the limits of the values indicated, but are appropriate in the range of 10% of the above, preferably in the range of 5%, especially 2.5%.

Claims (21)

PATENT APPLICATIONS A tablet form, characterized in that it has a structure which contains compressed granules; granules containing at least one compressed drug of choice, together with a granular disintegrant operating within the granule; granules pressed together in tablet form, together with a granular disintegrant acting outside the granule and optionally also together with a granular lubricator acting outside the granule, where, if a lubricator is present, its amount should be less than 0 , 5% by weight of the total tablet. Tablet formulation according to claim 1, characterized in that it contains the active ingredient / 3-lactam antibiotic, optionally in combination with the inhibitor / 3-lactamase. Tablet formulation according to claim 2, characterized in that the antibiotic contains amoxicillin, optionally in combination with clavulanic acid or a salt thereof, in an equivalent ratio of amoxicillin: clavulanic acid in the range of 12: 1 to 1: 1. Tablet formulation according to claim 1, 2 or 3, characterized in that the granular disintegrant operating within the granule is selected from corn starch, rice starch, crosslinked N-vinyl-2-pyrrolidone (CLPVP), sodium starch glycolate, croscarmellose sodium, formaldehyde decase, or combinations thereof. Tablet formulation according to any one of the preceding claims, characterized in that the ratio of the granular disintegrant operating within the granule is 0.1 to 10% by weight of the weight of the granulate. A tablet formulation according to any one of claims 1 to 6, characterized in that the granulate contains an active ingredient which is amoxicillin or amoxicillin + clavulanic acid or a salt thereof in combination, a granular disintegrant operating within a CLPVP granule or sodium starch glycolate, and optionally one or more diluents in the ratio of 70-99% by weight of the drug, 1-5% by weight of the disintegrant and up to 30% by weight of the diluent. Tablet formulation according to any one of the preceding claims, characterized in that the granulate contains 70% or more by weight of the tablet. Tablet formulation according to any one of the preceding claims, characterized in that the granular disintegrant operating outside the granule is selected from corn starch, rice starch, CLPVP, sodium starch glycolate, croscarmellose sodium, microcrystalline or micronized cellulose, micronized cellulose, partially substituted sodium carboxymethylcellulose, inflatable ion exchange resin, formaldehyde-casein, or alginates. Tablet formulation according to any one of the preceding claims, characterized in that the ratio of the granular disintegrant operating outside the granule in the tablet is between 0.1 - 25% by weight of the total weight of the tablet. Tablet formulation according to any one of the preceding claims, characterized in that it contains 0 - 0.35% by weight of lubricant. 11. Pharmaceutical form of granulate, characterized in that it contains the active substance, which is a β-lactam antibiotic in combination with an inhibitor (b-lactamase. 12. The formulation of claim 11, wherein the active ingredient is amoxicillin in combination with clavulanic acid or a salt equivalent to amoxicillin: clavulanic acid in the range of 12: 1 to 1: 1. A form according to claim 11 or 12, characterized in that the form further includes a granular disintegrant operating within the granule. A form according to claim 13, characterized in that the disintegrant is selected from corn starch, CLPVP, sodium starch glycolate, croscarmellose sodium, formaldehyde-casein or combinations thereof. 15. A form according to claim 13 or 14, characterized in that the ratio of the granular disintegrant operating within the granule is 0.1 to 10% by weight of the form. 16. Form according to claim 11, characterized in that the granulate contains an active ingredient, which is amoxicillin + clavulanic acid or a salt thereof in combination, a granular disintegrator operating inside a granule which is CLPVP or sodium starch glycolate, and optionally one or more diluents in the ratio of 70-99% by weight of the drug, 1-5% by weight of the disintegrant and up to 30% by weight of the diluent. A form according to any one of claims 11 to 16; or a granulate as defined in claim 1 or a granulate as defined in claim 1 when inserted into a pharmaceutical capsule. 18. A method for manufacturing a pharmaceutical tablet, characterized in that the granules containing at least one compressed active ingredient, optionally together with the granular disintegrant, which operates inside the granule, are mixed with the granular disintegrator, which operates outside the granule, and optionally with a granular lubricator , which operates outside the granules and excipients, but must be satisfied, if a lubricator is present, that its amount is less than 0.5% by weight of the mixture and that the mixture is compressed into tablets. 19. Process for the production of a pharmaceutical granulate, \ characterized in that the active ingredient, which is a / 5-lactam antibiotic, together with a / 3-lactamase inhibitor, is compressed under pressure, optionally together with a granular disintegrant that acts within the granule. A method according to claim 19, characterized in that the compression is carried out by means of compression in a drum press. 21. A pharmaceutical formulation according to any one of claims 1 to 17 for use as an active therapeutic substance.