MXPA98007440A - Agglomerates containing beta-lact compounds - Google Patents

Abstract

Free agglomerates of auxiliary of a B-lactam antibiotic are described: a mixture of agglomerates of an active B-lactam antibiotic and a second pharmaceutically active agent, with or without auxiliaries, a tablet comprising compressed agglomerates of a B-lactam antibiotic. lactam optionally in admixture with pharmaceutically acceptable auxiliaries, and a tablet comprising compressed agglomerates of a B-lactam antibiotic in admixture with a second pharmaceutically active agent and with or without pharmaceutically acceptable auxiliaries

Description

AGGLOMERATES CONTAINING BETA-LACTAMA COMPOUNDS DESCRIPTION OF THE INVENTION This invention relates to agglomerates of β-lactam antibiotics, including, for example, penicillin V potassium, amoxicillin trihydrate, cephalexin monohydrate, which are suitable for direct tablet formation. The most important and most frequently used form for orally administering antibiotics and ß-lactam mixtures in addition to a second pharmaceutically active agent and optionally adjuvants, is a tablet or a film tablet. For the production of a film tablet or tablet, there are currently two known methods, namely granulation and direct tablet formation. During granulation, pharmaceutically active, generally fine-grained, powdery, cohesive, nonfree-flowing and non-compressible agents are granulated in a multi-step process to form thicker, free-flowing and compressible granules. In said process, the pharmaceutically active agents are mixed in a first step with a binder, compacted while wet or dry, and subsequently granulated in a second pass through a screen. The binder agent can be, for example, dissolved in a humectant liquid to wet and granulate the powder. In a wet granulation process, the drying of the granules is carried out including screening subsequent to the final grain size. In a dry granulation process, after granulation it is generally necessary to separate the particles that are too thick or too fine, and to recirculate these particles, the coarse grain particles are pulverized again and the fine particles are compacted again. The obtained granules can be mixed with auxiliaries, which are preferably pharmaceutically acceptable required for the formation of tablets and compress them to tablets. Granulation is generally very time-consuming and costly, and in this way can be extremely economical. The desired production procedures for a tablet require a considerable amount of apparatus and a high amount of valuation work, and with respect to the number of production steps there are many sources of error. The direct formation of tablets is a much easier procedure; the pharmaceutically active agents are easily mixed with auxiliaries (vehicles, binding agents, lubricants, etc.) and the mixture is compressed into tablets. However, until now, despite the economic advantages with respect to granulation, direct tablet formation can only be used to a limited extent, since it can generally only be done with, for example, the following conditions: Pharmaceutically active agents have to be sufficiently free flowing and compressible per se, and the proportion of pharmaceutically active agents per tablet should be a maximum of 100 mg or 25%. Under such conditions, good free flow capacity and good compressibility can only be obtained through the addition of large quantities of special auxiliaries (for example Tablettose®, Ludípress®, etc.). In the case of β-lactam antibiotic tablets, the proportion of the β-lactam antibiotic per tablet may be up to 80% and more (eg, 1 g and more), and the β-lactam antibiotics generally not sufficiently They are free flowing and compressible per se. For example, potassium penicillin V, potassium phenoxymethyl penicillin, amoxicillin trihydrate and cephalexin monohydrate are generally obtained during production in a grain size based on average volume of 10 μm to 30 μm with the following size distribution of Grain: 4 μm to 80 μm 80% > 125 μm 1% to 5% and having an overall density of 0.15 g / ml to 0.45 g / ml. These characteristics generally make it impossible to use the direct tablet formation procedure for β-lactam antibiotics. Mixtures containing ß-lactam antibioticsFor example a combination of amoxycillin trihydrate (antibiotic ß-lactam), for example an antibacterially active compound with a second pharmaceutically active agent, for example, a potassium salt of clavulanic acid (potassium clavulanate) as, for example, a beta-lactamase inhibitor are of great interest for the treatment of infections caused by gram-positive and gram-negative bacteria which have become resistant to amoxycillin as a result of the formation of beta-lactamase. The combinations of amoxicillin trihydrate / potassium clavulanate / auxiliaries are commercially available under the trade name Augmentin®. The most important pharmaceutical form for oral administration thereof is a tablet or a film tablet. So far, the preparation of tablets Augmentin® or film tablets has been particularly difficult because of the following problems in addition to the problems with tablet forming in the case of antibiotics ß-lactam as described above: - A clavulanate Potassium can be extremely sensitive to moisture and can degrade rapidly in the presence of water. A mixture of two pharmaceutically active agents in a defined ratio has to be produced, which can include the danger of disintegration of the two components during production due to, for example, the non-homogeneous contents of a pharmaceutically active agent in a tablet or a movie tablet. The total ratio of the two pharmaceutically active agents per tablet can be up to 80% and more and the ability of the active agents to be compressed into a tablet or film tablet can be determined almost exclusively through the physical properties of the ingredients active, that is, deformation behavior under pressure. Thus, when a tablet or a film tablet is produced with a combination of amoxicillin trihydrate and potassium clavulanate in a first granulation step it generally has to be performed, in order to ensure that the compressible mixture has a satisfactory capacity Free flow and compression; and to prevent the disintegration of the active ingredients. However, due to the extreme sensitivity of! potassium clavulanate to moisture, wet granulation with water-alcohol mixtures or agglutination agent solutions, or pure water, which is currently the usual way for the production of ß-lactam antibiotic tablets or tablets of film, may not be effected; since during the wetting and subsequent granulation of the amoxicillin trihydrate / potassium clavulanate / auxiliaries powder, as well as during the subsequent drying step of the granules, potassium clavulanate can be degraded due to water present to an unacceptable degree. During the practice, until now for the production of tablets or film tablets containing amoxicillin trihydrate and potassium clavulanate with sufficient uniformity there are only two alternative granulation processes, both can be complicated and extremely non-economic and non-ecological, particularly: - Wet granulation with organic solvents free of water: The active ingredients of amoxicillin trihydrate and potassium ciavulanate are mixed in a first step with a binder, the mixture is moistened with a water-free, organic solvent, granulated and dried. The agglutination agent can also be added dissolved in the solvent. The granules obtained can be screened to a final grain size and mixed with tablet-forming auxiliaries (binding agents, disintegrators, etc.) before being compressed into tablets. This procedure is non-economic and non-ecological, since the solvent has to be recirculated; special equipment is necessary, solvent losses arise, etc.

Dry granulation (compaction, briquette formation) The active ingredients, amoxicillin trihydrate and potassium clavulanate, can generally be mixed with an agglutination agent and compacted in a dry form. Compaction may be presented by compressing the pharmaceutically active agent / binder mixture either in a roller compactor to form the so-called "shells" or in a tablet press having large stamps to form the so-called "briquettes". Both the briquettes and the obtained briquettes are pulverized or broken in a mill or sieve in order to obtain an appropriate granulate. After granulation, it is generally necessary to separate the particles that are too coarse or too fine, and to recirculate these particles, the coarse-grained particles being pulverized again and the fine particles being compacted again (briquette formation). The granules thus obtained can be mixed with auxiliaries required for tablet formation (lubricants, disintegrating agents, etc.), which are preferably pharmaceutically acceptable, and the mixture can be compressed to form a tablet. Part of the lubricants or disintegrating agents (mixed with the active ingredient) can be incorporated prior to compaction / briquette formation. Said process of dry granulation production can be unfavorable since: - it is very time-consuming - it is expensive the losses of active ingredient can be practically unavoidable - it may require a considerable number of apparatuses - a great amount of work is necessary pre-assessment may require a large number of production steps - there is a considerable amount of error sources. Despite such disadvantages, said process is to be used for the production of amoxicillin trihydrate / potassium clavulanate film tablets, obviously due to the absence of alternative possibilities (for example, PCT application WO 95/28927). Surprisingly, ß-lactam agglomerates have been found, including penicillin V potassium, amoxicillin trihydrate, cephalexin monohydrate, which are free of auxiliaries and which have excellent flowability, and which can be compressed directly to tablets optionally after mixing these agglomerates with auxiliaries; and a process for the production of free-flowing, compressible, free-blowing, β-lactam antibiotic agglomerates from powders. Surprisingly, a mixture of pharmaceutically active agents including at least one β-lactam antibiotic, tai as a mixture of amoxicillin trihydrate and potassium clavulanate, optionally containing auxiliaries, suitable for the production of a tablet (or a tablet) has also been found. film) through the direct formation of tablets; a method for the direct formation of tablets of a mixture of pharmaceutically active agents including at least one β-lactam antibiotic, such as a mixture of amoxicillin trihydrate and potassium clavulanate, optionally containing auxiliaries that are pharmaceutically acceptable, avoiding the wetting of the mixture in very few steps of production than those according to the above procedures. The free agglomerates of auxiliaries of a β-lactam antibiotic are new and form part of the present invention. The free binder agglomerates of a β-lactam antibiotic, which have excellent flowability, and which can be directly tablet compressed optionally after mixing with auxiliaries, can be, for example, such as a grain based on the average volume of 200 μm to 1000 μm, most preferably 400 μm to 600 μm. The grain size distribution can be as follows: <100 μm: from 1% to 30%, for example from 5% to 20% 100 - 500 μm: from 10% to 80%, for example from 20% to 60% 500 - 1000 μm: from 10% to 80%, by example of 25% to 60% > 1000 μm: max. 30%, for example max. 15% > 2000 μm: max. 0.5%, for example max. 0.1% The overall density of the agglomerates can be, for example, in the range from about 0.4 g / ml to about 0.8 g / ml, for example, 0.4 g / ml to 0.8 g / ml; such as from about 0.5 g / ml to about 0.7 g / ml, for example 0.5 g / ml to 0.7 g / ml. The present invention therefore provides, in one aspect, free agglomerates of adjuvants of β-lactam antibiotics, especially penicillin potassium V amoxicillin trihydrate and cephalexin monohydrate; having, for example, a grain size based on the average volume of 100 μm to 1000 μm, preferably 400 μm to 600 μm, such as 200 μm to 600 μm; having, for example, the following grain size distribution: < 100 μm: from 1% to 30%, for example from 5% to 20% 100 μm - 500 μm: from 10% to 80%, for example from 20% to 60% 500 μm - 1000 μm: from 10% to 80%, for example from 25% to 60% > 1000 μm: max. 30%, for example max. 15% > 2000 μm: max. 0.5%, for example max. 0.1% and / or having an overall density of 0.4 g / ml to 0.8 g / ml, for example, from 0.5 g / ml to 0.7 g / ml. The auxiliary-free agglomerates according to the invention can be produced as follows: A solid β-lactam antibiotic, for example, potassium penicillin V, amoxicillin trihydrate and cephalexin monohydrate, for example, in the form of a powder, with a grain size based on average volume of 10 μm to 30 μm, with approximately the following grain size distribution: 4 μm to 80 μm 80% > 125 μm 1 to 5% and an overall density of 0.15 g / ml to 0.45 g / ml, as usually obtained in the production process for a β-lactam antibiotic, can be formed into a paste, for example, through of conventional methods, with a liquid in which the β-lactam antibiotic is insoluble or slightly soluble. This paste can be kneaded and extruded in a double screw extrusion having a specific mechanical energy input of 0.01 to 0.1 kilowatt-hours / kg, preferably 0.02 to 0.6 kilowatt-hours / kg.

During the kneading process, the temperature of the pulp can be maintained on a scale from about 10 ° C to about 80 ° C, for example from 10 ° C to 80 ° C. Auxiliary-free agglomerates can be obtained, which can be dried, for example, as is conventional in a fluidized-bed dryer. In another aspect, the present invention provides a process for the production of free agglomerates of auxiliary of a β-lactam antibiotic, through the following steps: a) form a paste from a β-lactam antibiotic with a liquid , b) kneading the dough at a temperature of 10 ° C to 80 ° C, c) extruding the dough in a twin screw extruder having, for example, a specific mechanical energy input of 0.01 to 0.1 kilowatt-hours / kg , and, if desired, d) dry the obtained agglomerates. The β-lactam, for example in the form of a powder, can be placed in the extruder in an already wet form, or in a dry form. If the β-lactam antibiotic, for example in the form of a powder, is placed in the extruder in dry form, the liquid can be expelled in the extruder simultaneously with the β-lactam antibiotic. Suitable liquids include, for example, water, alcohols and mixtures thereof; as well as organic solvents such as acetone. An alcohol can preferably be ethanol or isopropanol.

The amount of liquids may be appropriate to result in a paste amenable to the β-lactam antibiotic and preferably it may be as follows (expressed as a percentage by weight, based on the paste): from about 3 to about 20, for example from 3 to 20, preferably from about 5 to about 10, for example 5 to 10 for the case that the active ingredient is slightly dissolved by the liquid; and from about 5 to about 35, for example from 5 to 35, preferably from about 10 to about 20, for example from 10 to 20 for the case in which the active ingredient is insoluble in the liquid. The optimum density of the agglomerates of β-lactam antibiotic can be such that the mechanical stability of the agglomerates is appropriate, ie, after drying, the agglomerates should not disintegrate into a powder as this could adversely affect the capacity of free flow. But the agglomerates must not be extremely stable mechanical (density too high), since during the formation of the tablet formation process said stable end agglomerates could not be able to mechanically form stable tablets which could not be produced in this way. Surprisingly, the optimum density in a process according to the present invention corresponds exactly to the maximum torque collection observed in the extrusion screw, which passes through during the extrusion as the amount of liquid flows through the extrusion. Increase In this way, the optimum density of the powder is very easily controllable.

The ß-lactam agglomerates according to the present invention may be compressed, optionally after mixing with the ingredients, which are preferably pharmaceutically acceptable, such as polyvinylpyrrolidone, talc, magnesium stearate; directly to tablets of high unit weight, satisfactory mechanical stability and rapid release of the β-lactam antibiotic (active ingredient). Since no agglutination agent or binders between the particles of the active ingredient and an agglutination agent are generally present in the agglomerates as they are generally in the wet granulation processes, the release of the active ingredient from the tablets directly compressed according to the invention can be considerably faster than the tablets produced through granulation as usual. Compared with tablets produced through the multi-step wet granulation process as described above, the tablets produced according to the present invention through direct tabletting of the novel type agglomerates of the active ingredient have, for example, the following advantages: Due to the excellent free fl ow capacity of the agglomerates according to the present invention, the weight deviation of the tablets is lower. The optimum density of the agglomerates results in a high mechanical stability (a higher degree of hardness, lower friability), and, in spite of this, the release of the pharmaceutically active agent, ie the ß-lactam antibiotic, of the tablet is considerably faster. A mixture of the β-lactam antibiotic, such as amoxicillin trihydrate with a second pharmaceutically active agent, for example, potassium clavulanate, can be easily produced by mixing the agglomerates of a β-lactam antibiotic, for example, of amoxicillin trihydrate. , which are of a sufficiently free and compressible flow, such as the agglomerates that are obtained through the process of the present invention, with a second pharmaceutically active agent, which can be in general of insufficiently free flow and incomprimibies, such as , for example, potassium clavulanate having, for example, a grain size of about 5 μm to 100 μm, which may be a normal grain size in pharmaceutical powders, obtained during production. Surprisingly it has been found that the mixture has a sufficiently free and compressible flow for direct tablet formation, even if a high degree of potassium clavulanate is mixed with the b-lactam antibiotic agglomerates according to the present invention. The weight ratio of agglomerates of a β-lactam antibiotic, such as amoxicillin trihydrate and potassium clavulanate in the directly compressible mixture may be in the range of 12: 1 to 1: 1; for example from 7: 1 to 1: 1; such as from 4: 1 to 1: 1; for example 2: 1 to 1: 1. The mixture of the β-lactam antibiotic agglomerates with a second pharmaceutically active agent, for example potassium clavulanate, for example in the form of a powder, can be effected, for example in a forced flow or free-fall mixer. The agglomerates of a β-lactam antibiotic according to the present invention, for example the agglomerates of amoxicillipa trihydrate can function as a carrier for the second pharmaceutically active agent, for example, potassium clavulanate, for example in the form of a dust. The auxiliaries, which are preferably pharmaceutically acceptable, for example conventional auxiliaries in tabletting processes, such as, for example, lubricants, ie magnesium stearate; mold separation agents, for example, talc; binding or filling agents, for example polyvinylpyrrolidone, microcrystalline cellulose (Avicel), modified starch (Starch 1500 J); disintegrating agents, for example crosslinked carboxymethylcellulose (Ac-Di-Sol), crosslinked carboxymethyl starch (Primojel) or entangled polyvinylpyrrolidone (PVPP); they may be present in the mixture of the β-lactam antibiotic agglomerates and potassium clavulanate powder, preferably in small amounts since it was found that only small amounts may be necessary. The auxiliaries, optionally pre-dried, can be mixed in the mixture, for example, before, during or after the mixing of the agglomerates of the β-lactam antibiotic with the powder of potassium clavulanate. The water activity of a mixture is described in the literature and is generally described as being on a scale of 0.2 to 0.6 (the optimum being 0.4). It has surprisingly been found that the compressibility of the mixture according to the present invention is excellent even with a substantially low water activity of the mixture, mainly < 0.2, which is a major advantage due to the moisture sensitivity of, for example, potassium clavulanate. The activity of the water at 25 ° C of a mixture of amoxicillin trihydrate / potassium clavulanate according to the present invention can be < 0.1, preferably < 0.05. Mixtures of the agglomerates of a β-lactam antibiotic such as amoxicillin trihydrate, with a second pharmaceutically active agent, eg, potassium clavulanate, include particular scales preferred with respect to average grain size and grain size distribution. , mainly: The average grain size of 100 μm to 800 μm, preferably 200 to 600 μm, with the following grain size distribution: < 100 μm: from 1% to 50%, preferably from 10% to 50% 100 - 500 μm: from 20% to 90%, preferably from 30% to 70% 500 - 1000 μm: from 20% to 70%, preferably from 10% to 50% > 1000 μm: max. 15%, preferably max. 10% > 2000 μm: max. 0.1%, preferably max. 0.1% The overall density of the mixture can be, for example, in the range from about 0.3 g / ml to about 0.8 g / ml, for example from 0.3 g / ml to 0.8 g / ml; such as from about 0.4 g / ml to about 0.6 g / ml; for example from 0.4 g / ml to 0.6 g / ml. The response angle of the mixture, which is a measure for the flowability can be, for example, < 40 °, preferably < 35 °. Said mixtures are new and form part of the invention. In another aspect, the present invention provides a mixture of agglomerates of an active β-lactam, for example, amoxicillin trihydrate, for example having an average grain size of 100 μm to 800 μm, for example 200 μm to 600 μm; and a second active ingredient, for example a potassium salt of clavulanic acid, for example in the form of a powder, with or without auxiliaries; the mixture having, for example, the following grain size distribution: < 100 μm: from 1% to 50%, preferably from 10% to 50% 100 - 500 μm: from 20% to 90%, preferably from 30% to 70% 500 - 1000 μm: from 20% to 70%, preferably from 10% to 50% > 1000 μm: max. 15%, preferably max. 10% > 2000 μm: max. 0.1%, preferably max. 0.1%, the mixture having: for example, a density of 0.3 g / ml to 0.8 g / ml, preferably 0.4 g / ml to 0.6 g / ml for example, a resting angle of < 40 °, preferably < 351. Mixtures of agglomerates of a β-lactam antibiotic, for example, amoxicillin trihydrate and a second pharmaceutically active agent, for example potassium clavulanate in the form of a powder according to the present invention, optionally containing auxiliaries, can be directly compressed to tablets with a high uniformity of the content of active ingredients and a high uniformity of tablet weight, a satisfactory mechanical stability and a rapid release of the active ingredient. Since moisture is not necessary throughout the process of producing the tablets, potassium clavulanate is not degraded due to the effects of moisture, which also ensures a high stability of potassium clavulanate in the finished pharmaceutical preparation. In another aspect, the present invention provides the use of β-lactam antibiotic agglomerates free of auxiliary in the production of a mixture of a β-lactam antibiotic; and a second pharmaceutically active agent, with or without auxiliaries, having, for example, an average grain size of 100 μm to 800 μm; and in one more aspect; Free agglomerates of auxiliary β-lactam antibiotics, especially of phenoxymethyl penicillin potassium, amoxicillin trihydrate and cephalexin monohydrate, which is suitable for direct tablet formation, characterized in that the agglomerates have a grain size based on average volume of 200-1000 μm, preferably 400-600 μm, with the following grain size distribution: < 100 μm: 1 - 30% 100 - 500 μm: 10-80% 500 - 1000 μm: 10-80% > 1000 μm: max.30% > 2000 μm: max.0.5%, and an overall density of 0.4 to 0.8 g / ml; and in another aspect, A mixture suitable for direct tablet formation, containing amoxicillin trihydrate and the potassium salt of clavulanic acid as the essential components, wherein the amoxicillin trihydrate is present in the form of an agglomerate and the mixture it has an average grain size of 100-800 μm, preferably 200-600 μm, with the following grain size distribution: < 100 μm: 1-50%, preferably 10-50%, 100-500 μm: 20-90%, preferably 30-70%, 500-1000 μm: 20-70%, preferably 10-50% > 1000 μm: max. 15, preferably max. 10, > 2000 μm: max. 0.1, and having a global density of 0.3 g / ml - 0.8 g / ml, preferably 0.4 g / ml - 0.6 g / ml, and an angle of repose of < 40 °, preferably < 35 °. The tablets produced by the compression of a mixture of agglomerates of a β-lactam antibiotic, such as, for example, amoxicillin trihydrate, with a second pharmaceutically active agent, for example, potassium clavulanate, and optionally with auxiliaries, also they can be coated with a film with film suspensions, dispersions (aqueous or organic solvents) in a coating apparatus (drum, fluidized bed), for example, as is conventional. Tablets, for example, for oral administration comprising compressed agglomerates of a β-lactam antibiotic, such as, for example, potassium penicillin V, amoxicillin trihydrate, cephalexin monohydrate, optionally in admixture with pharmaceutically acceptable auxiliaries, are novel and they are also part of the present invention. In a further aspect, the present invention provides a tablet for, for example, oral administration, comprising compressed agglomerates of a β-lactam antibiotic optionally in admixture with pharmaceutically acceptable auxiliaries. Tablets, for example for oral administration, comprising compressed agglomerates of a β-lactam antibiotic, such as, for example, amoxicillin trihydrate in admixture with a second pharmaceutically active agent, for example potassium clavulanate, and optionally with pharmaceutically acceptable auxiliaries , they are new and also form part of the present invention. In a further aspect, the present invention provides a tablet, for example, for oral administration, comprising compressed agglomerates of a β-lactam antibiotic, such as, for example, amoxicillin trihydrate in admixture with the second pharmaceutically active agent, for example potassium clavulanate with or without pharmaceutically acceptable auxiliaries. The following examples illustrate the invention. All temperatures are given in degrees Celsius.

EXAMPLE 1 Production of potassium agglomerates of phenoxymethylpenicillin (potassium of penicillin V) Potassium penicillin V wet isopropanol-potassium (10% to 20% isopropanol based on the wet mass) was agglomerated in a twin-screw extruder (process length 4D) at 100 kg / hr to a maximum torque collection of the extrusion screws from 25% to 30%. The screws were configured with conveyor elements, and right and left kneading blocks. After drying the extruded wet mass in a fluidized bed dryer, penicillin V potassium agglomerates were obtained (yield of 99.7% theory) having the following properties: Grain size distribution: < 100 μm: 12% 100 μm to 500 μm: 68% 500 μm to 1000 μm: 18% > 1000 μm: 2% Overall density: 0.58 g / ml; Stamping density: 0.70 g / ml EXAMPLE 2 Production of potassium agglomerates of phenoxymethylpenicillin (potassium of penicillin V) Potassium penicillin V powder, dry (BP, USP) was agglomerated in a twin-screw extruder (3D procedure length) with water (from 5 to 10% based on the wet mass) at 200 kg / hr. Maximum torque of the extrusion screws from 10% to 15%. The screws were configured with conveyor elements, and right kneading blocks. After drying the extruded wet mass in a fluidized bed dryer, penicillin V potassium agglomerates were obtained (yield of 99.8%) having the following properties: Grain size distribution: < 100 μm: 10% 100 μm to 500 μm: 39% 500 μm to 1000 μm: 52% > 1000 μm: 1% Overall density: 0.63 g / ml; Stamping density: 0.71 g / ml.

EXAMPLE 3 Production of agglomerates of amoxicillin trihydrate Amoxicillin trihydrate moistened in acetone (10% to 15% acetone based on the wet mass) was agglomerated in a twin screw extruder (3D procedure length) at 150 kg / hr to a maximum torque pickup of the screws of extrusion from 25% to 35%. The screws were configured with conveyor elements, and right and left kneading blocks. After drying the extruded wet mass in a fluidized bed dryer, amoxicillin trihydrate agglomerates were obtained (yield 99.9%) having the following properties: Grain size distribution: < 100 μm: 13% 100 - 500 μm: 71% 500 - 1000 μm: 12% > 1000 μm: 4% Overall density: 0.56 g / ml; Stamping density: 0.67 g / ml.

EXAMPLE 4 Production of agglomerates of cephalexin monohydrate Dry cephalexin monohydrate in powder form was agglomerated in a twin-screw extruder (4D process length) with 50% aqueous ethanol (from 5% to 15% based on the mass of moisture) at 200 kg / hr. Maximum torque of the extrusion screws from 12% to 18%. The screws were configured with conveyor elements, and right kneading blocks. After drying the extruded wet mass in a fluidized bed dryer, agglomerates of cephalexin monohydrate (yield 99.7%) were obtained having the following properties: Grain size distribution: < 100 μm: 7% 100 μm to 500 μm: 43% 500 μm to 1000 μm: 47% > 1000 μm: 3% Overall density: 0.60 g / ml; Stamping density: 0.71 g / ml.

EXAMPLE 5 Preparation of tablets from agglomerated penicillin V potassium The ingredients of the tablet are as follows: Penicillin V potassium, agglomerated according to Example 1 150.0 kg Polyvinylpyrrolidone K25 6.0 kg Talc 6.9 kg Polyethylene glycol 6000 2.6 kg Magnesium stearate 2.2 kg Auxiliaries were screened through a 1.0 mm sieve and subsequently mixed for approximately 10 minutes at 20 rpm in a free fall mixer (200 liters, Rhonerad) with potassium of penicillin V agglomerate according to the Example 1. This mixture was compressed in a rotary press (KILLIAN LX 18) at a rate of 100,000 tablets per hour. Average weight of the tablet: 705 mg Relative normal weight deviation: 0.5% Tablet hardness (Pharmatest - rupture resistance tester P58200): between 100 N and 130 N Friability (400 rpm, Roche Friabilator): 0.6% . The tablets disintegrate in water at 37 ° C in 6 minutes. 100% of the penicillin V potassium in one tablet was dissolved after 15 minutes in a phosphate pH regulator, pH 6.8, a 37 ° C (Paddel model, 50 rpm).

EXAMPLE 6 Preparation of agglomerated amoxicillin trihydrate tablets The ingredients of the tablet are as follows: Amoxicillin trihydrate, agglomerate according to Example 3 172.2 kg Polyvinylpyrrolidone 3.75 kg Carboxymethyl starch 6.0 kg Cellulose (microcrystalline), pH 10.2 16.2 kg Magnesium stearate 1.5 kg Auxiliaries were sieved through a 1.0 mm sieve and subsequently mixed for about 10 minutes at 20 rpm in a free fall mixer (300 liters, Rhonerad) with agglomerated amoxicillin trihydrate according to Example 3. This mixture was compressed on a rotary press (KILLIAN LX 18) at a rate of 85,000 tablets per hour. Average weight of the tablet: 665 mg Relative normal deviation of weight: 0.4% Hardness of the tablets (determined as in Example 5): between 130 N and 160 N Friability (determined as in Example 5): 0.7% (400 revolutions). The tablets disintegrate in water at 37 ° C in 3 minutes, and, after 20 minutes, 100% of the amoxicillin trihydrate in the tablet dissolves.

EXAMPLE 7 Mixture of amoxicillin trihydrate and agglomerate and clavulanic acid in the form of a potassium salt Total mixture - 4 kg Amoxicillin trihydrate was agglomerated according to Examples 1 to 4. Composition (% w / w) Agglomerated amoxicillin trihydrate, (calculated as free from water in the free acid form) 77 (+/- 10) Clavulanic acid in the form of potassium salt, (calculated as the free acid) 33 (+/- 10) The agglomerates of amoxicillin trihydrate and potassium clavulanate were mixed for 10 minutes at 20 rpm in a dry atmosphere in a free fall mixer (Rhonerad, and the 10 liter milling drum); the average grain size of the mixture being 320 μm. Grain size distribution: < 100 μm 34% 100 μm at 500 μm 50% 500 μm at 1000 μm 13% > 1000 μm 3% > 2000 μm 0% Overall density: 0.43 g / ml. The mixture is free flowing. Angle of rest (Pfrengle determination method): 34 +/- 2 ° Water activity (see, for example, P. H. Stahl, Feuchtigkeit und Trocknen in der pharmazeutischen Technologie, UTB Steinkopff): < 0.1 to 25 ° C.

EXAMPLE 8 Mixture of agglomerated amoxicillin trihydrate and clavulanic acid in the form of a potassium salt Total mixture: 5 kg The amoxicillin trihydrate was agglomerated according to the Examples 1 to 4. Composition (% w / w) Agglomerated amoxicillin trihydrate, (calculated as free from water in the free acid form) 80 (+/- 10) Clavulanic acid in the potassium salt form, (calculated as the free acid) 20 (+/- 10) The agglomerates of amoxicillin trihydrate and potassium clavulanate were mixed for 3 minutes at 90 rpm in a dry atmosphere in a forced flow mixer (Stephan UHC, 15 liters); the average grain size of the mixture being 340 μm. Grain size distribution: < 100 μm 26% 100 μm to 500 μm 51% 500 μm to 1000 μm 14% > 1000 μm 9% > 2000 μm 0% Overall density: 0.54 g / ml. The mixture is free flowing. Angle of rest (Pfrengle determination method): 32 +/- 2 ° Water activity (see, for example, P. H. Stahl, Feuchtigkeit und Trocknen in der pharmazeutischen Technologie, UTB Steinkopff): < 0.1 to 25 ° C.

EXAMPLE 9 Mixture of agglomerated amoxicillin trihydrate and clavulanic acid in the form of a potassium salt Total mixture: 5 kg The amoxicillin trihydrate was agglomerated according to Examples 1 to 4. Composition (% w / w) Agglomerated amoxicillin trihydrate, (calculated as free from water in the free acid form) 87.5 (+/- 10) Clavulanic acid in the form of potassium salt, (calculated as the free acid) 12.5 (+/- 10) The agglomerates of amoxicillin trihydrate and potassium clavulanate were mixed for 10 minutes at 20 rpm in a dry atmosphere in a free fall mixer (Rhonerad, 10 liter milling drum); the average grain size of the mixture being 450 μm. Grain size distribution: < 100 μm 14% 100 μm to 500 μm 46% 500 μm to 1000 μm 38% > 1000 μm 12% > 2000 μm 0% Overall density: 0.61 g / ml. The mixture is free flowing. 'Angle of repose (Pfrengle determination method): 31 +/- 2 ° Water activity (see, for example, P. H. Stahl, Feuchtigkeit und Trocknen in der pharmazeutischen Technologie, UTB Steinkopff): < 0.1 to 25 ° C.

EXAMPLE 10 Tablet of a mixture of agglomerated amoxicillin trihydrate and clavulanic acid in the form of a potassium salt Composition Agglomerated amoxicillin trihydrate, (% w / w of the total weight of the mixture) (calculated as free water in the free acid form) 77 (+/- 10) Clavulanic acid in the form of the potassium salt (% w / w of the total weight of the mixture) (calculated as the free acid) 33 (+/- 10) Polyvinylpyrrolidine K25 (KOLLIDON 25R) 0.15 kg Talc 0.19 kg Magnesium stearate 0.12 kg Croscarmellose sodium (AcDiSolR) 0.20 kg Microcrystalline cellulose (AVICEL, pH 102) 0.50 kg Auxiliaries were screened through a 1.0 mm sieve and subsequent were mixed under a dry atmosphere for 10 minutes at 20 rpm in a free fall mixer, (Rhonerad, 10 liter milling drum) with the agglomerates of amoxicillin trihydrate and the potassium clavulanate as obtained according to Example 7 .

This mixture was compressed on a rotary press (PHARMA I) at a rate of 50,000 tablets per hour. Average weight of the tablet: 635 mg Relative normal deviation of weight: 0.4% Hardness of the tablets (determined as in Example 5): between 1 10 N and 142 N Friability (determined as in Example 5): 0.7% (400 revolutions). The tablets disintegrated in water at 37 ° C in 8.5 minutes, and after 30 minutes, 100% of the amoxicillin trihydrate and the potassium clavulanate in the tablets were dissolved (Paddel model, water at 37 ° C, 75 rpm). The content of amoxicillin per tablet (average of 20 tablets): 97 to 103% theory. Content of clavulanic acid per tablet (average of 20 tablets): from 96 to 102% theory. This shows a high uniformity of the content of the two active ingredients per tablet.

EXAMPLE 11 Tablet of a mixture of agglomerated amoxicillin trihydrate and clavulanic acid in the form of a potassium salt Composition Agglomerated amoxicillin trihydrate, (% w / w of the total weight of the mixture) (calculated as free water in the form of the acid free) 87.5 (+ / - 10) Clavulanic acid in the form of the potassium salt (% w / w of the total weight of the mixture) (calculated as the free acid) 12.5 (+/- 10) Polyvinylpyrrolidine K25 (KOLLIDON 25R) 0.53 kg Highly dispersed silicon dioxide (AEROSIL 200R) 0.18 kg Magnesium stearate 0.20 kg Croscarmellose sodium (AcDiSoIR) 0.40 kg Microcrystalline cellulose (AVICEL, pH 102) 1.20 kg The auxiliaries were sieved through a 1.0 mm sieve and subsequently mixed under a dry atmosphere for 10 minutes at 20 rpm in a free fall mixer, (Rhonerad, 15 liter milling drum) with the agglomerates of amoxicillin trihydrate and the potassium clavulanate as obtained according to Example 9. This The mixture was compressed in a rotary tablet press (KILIAN Eifel RUH 3) at a rate of 80,000 tablets per hour.

Average weight of the tablet: 1065 mg Relative normal deviation of the weight: 0.76% Hardness of the tablets (determined as in Example 5): between 149 N and 178 N Friability (determined as in Example 5): 1.1% (400 revolutions). The tablets disintegrated in water at 37 ° C in 9.05 minutes, and after 30 minutes, more than 90% of the amoxicillin trihydrate and more than 90% of the potassium clavuiate in the tablets were dissolved (Paddel model, water at 37 ° C 75 rpm). The content of amoxicillin per tablet (average of 20 tablets): 96 to 102% theory. Clavulanic acid content per tablet (average of 20 tablets): from 95 to 103% theory. This shows a high uniformity of the content of the two active ingredients per tablet.

Claims (10)

1. - Free agglomerates of auxiliary of a β-lactam antibiotic.

2. The auxiliary-free agglomerates according to claim 1, characterized in that they have an average grain size with a volume base of 100 μm to 1000 μm.

3. The auxiliary free agglomerates according to any of claims 1 to 2, characterized in that they have the following grain size distribution: < 100 μm: 1% to 30% 100 μm to 500 μm: 10% to 80% 500 μm to 1000 μm: 10% to 80% > 1000 μm: max. 30% > 2000 μm max. 0.5% 4.- The free agglomerates of auxiliary of a β-lactam antibiotic having an overall density of 0.4 to 0.8 g / ml. 5. The auxiliary-free agglomerates according to any of claims 1 to 4, wherein the β-lactam is selected from the group including penicillin V potassium, amoxicillin trihydrate, or cephalexin monohydrate. 6.- A procedure for the production of free agglomerates of auxiliary of a β-lactam antibiotic, characterized by the following steps: a) form a paste from a β-lactam antibiotic with a liquid, b) knead the paste at a temperature of 10 ° C to 80 ° C, c) extruding the paste in a twin-screw extruder, and, if desired, d) drying the obtained agglomerates. 7. A mixture of agglomerates of an active β-lactam antibiotic; and a second pharmaceutically active agent, with or without auxiliaries. 8. A mixture according to claim 7, having an average grain size of 100 μm to 800 μm and having the following grain size distribution: < 100 μm: 1% to 50% 100 μm to 500 μm: 20% to 90% 500 μm to 1000 μm: 20% to 70% > 1000 μm: max. 1 5% > 2000 μm max. 0.1%. 9. A mixture of agglomerates of a β-lactam antibiotic, and a second pharmaceutically active agent, with or without auxiliaries, having an overall density of 0.3 g / ml to 0.8 g / ml. 10. A mixture according to any of claims 7 to 9, or a tablet according to any of claims 12 to 13, wherein the β-lactam antibiotic is amoxicillin trihydrate and the second pharmaceutically active agent is acidic. clavulanic acid in the form of the potassium salt. 1 1 .- The use of agglomerates of free β-lactam antibiotic to aid in the production of a mixture of a β-lactam antibiotic; and a second pharmaceutically active agent, with or without auxiliaries. 12. A tablet comprising compressed agglomerates of a β-lactam antibiotic optionally in admixture with pharmaceutically acceptable auxiliaries. 13. A tablet comprising compressed agglomerates of a β-lactam antibiotic in admixture with a second pharmaceutically active agent and with or without pharmaceutically acceptable auxiliaries. 14.- Free agglomerates of auxiliary of β-lactam antibiotics, especially of phenoxymethylpenicillin potassium, amoxicillin trihydrate and cephalexin monohydrate, which are suitable for the direct formation of tablets, characterized in that the agglomerates have an average grain size based on in the volume of 200-1000 μm, preferably 400-600 μm, with the following grain size distribution: < 100 μm: 1-30% 100 μm to 500 μm: 10-80% 500 μm to 1000 μm: 10-80% > 1000 μm: max. 30% > 2000 μm max. 0.5% and an overall density of 0.4 to 0.8 g / ml. 15. A suitable mixture for the direct formation of tablets, which contains amoxicillin trihydrate and the potassium salt of clavulanic acid as special components, characterized in that the amoxicillin trihydrate is present in the form of an agglomerate and the mixture has a average grain size of 100-800 μm, preferably 200-600 μm, with the following grain size distribution: < 100 μm: 1% to 50%, preferably 10-50% 100 μm to 500 μm: 20% to 90%, preferably 30-70% 500 μm to 1000 μm: 20% to 70%, preferably 10-50% > 1000 μm: max. 15%, preferably of max.10% > 2000 μm: max. 0.1%, and having a global density of 0.3 g / ml-0.8 g / ml, preferably 0.4 g / ml-0.6 g / ml and a resting angle of < 40 °, preferably from < 35 °.