MXPA99007517A - Pharmaceutical formulations comprising amoxocyllin and clavulanate - Google Patents

Abstract

Novel co-amoxiclav formulations are described, having reduced weight compared to existing formulations, as well as formulations comprising amoxycillin and potassium clavulanate in a ratio of 8:1 and formulations prepared from granulates of amoxycillin and granulates of amoxycillin and clavulanate.

Description

PHARMACEUTICAL FORMULATION COMPRISING AMOXICILLINE. AND CLAVULANATO The present invention relates to novel formulations comprising amoxicillin and clavulanate (co-amoxiclav), to process their preparation and their use in therapy. The co-amoxiclav product is marketed by SmithKine Beecham as Augmentin to treat bacterial infections. It comprises a combination of the bacterial agent of β-lactam amoxicillin (present as the trihydrate) and the β-lactamase inhibitor clavulanic acid (present as the potassium salt). Various formulations are provided such as, for example, tablets, capsules, powders (to reconstitute them in aqueous syrups) and sacks containing free-flowing granules, which contain different ratios of amoxicillin and clavulanic acid. Therefore, tablets and powders (for reconstitution in aqueous syrups) are available comprising amoxicillin and clavulanic acid in ratios of 2: 1, 4: 1, and 7: 1, while bags are available with the same ratios, 8: 1 (Augmentin, Smith KIine Beecham, France, 'poudre pour suspension buvable at 100 mg / ml nourisson', comprising 100 mg / ml amoxicillin and 12.5 mg / ml clavulanate). This leads to a complexity in the manufacturing process since each product with a different ratio was prepared separately, mixing the different amounts of amoxicillin and clavulanate at an early stage of the process.

In addition, the clavulanate has been mixed with a diluent, conventionally in a ratio of 1: 1, for safer storage and transport. Silica gel (for example the product Syloid AL-1) has been used for the formulations that are not in the form of tablets and microcrystalline cellulose (for example the Avicei product) for tablet formulations, adding them so that there is an additional complexity in the manufacturing process. Therefore, there continues to be a need for a more efficient device for the manufacturing process, in order to reduce complexity and improve the economy of the process. It has been found that this can be achieved by the use of a common intermediate granulate comprising a fixed ratio of amoxicillin and clavulanate, with the different ratios in the final formulation being achieved by adding appropriate amounts of amoxicillin at a later stage in the process. Formulations having granulates comprising amoxicillin and clavulanate are described in GB 2 005 538-A (Beecham Group), WO 95/28927 (SmithKine Beecham) and WO 95/25516 (SmithKine Beecham). However, there is a suggestion to combine amoxicillin and clavulanate granules with amoxicillin granules. As the absolute amount of the substance in the drug increases, the size of the tablets also increases, making the tablets less attractive to pass. The tablets also comprise excipients such as disintegrants, diluents, lubricants that are necessary to allow the tablet to be manufactured and improve the pharmacokinetic performance of the tablets once they are taken. Said excipients also increase the gross weight of a tablet. In addition, the conventional practice of formulating tablets comprising clavulanate potassium of a 1: 1 mixture of potassium clavulanate and a diluent, referred to above, further increases the weight and size of a tablet. Therefore, the currently available (coatable) tablets comprising 500/125 and 875/125 mg of amoxicillin plus clavulanate (expressed with the weight of the corresponding free acids) have weight of 1050 and 1482 mg respectively, of which the substances of drugs account for approximately 70% and 81% by weight, respectively. The prototype formulations described in previous patent applications suggest tablets of 500/125 mg weighing 872 mg (uncoated), (Example 1, GB 2 005 538-A), 950 mg (uncoated), 1050 mg (coated) ( Example 14 and 15, WO 92/19227) and 875/125 mg weighing 1350 mg (uncoated) and 1450 mg (coated) (Example 14 and 15, WO 92/19227). Therefore, there is a need to provide tablet formulations that have a smaller size for a given amount of a drug substance. A new dose regimen of co-amoxiclav of 100/125 mg twice daily (bd) has generated the need for appropriate tablet formulations. This unit dose has not been provided as a tablet formulation since only increasing the size of the existing 875/125 mg tablet was considered to be a tablet that could be unacceptably large for the patient to pass through. Accordingly, in a first aspect, a present view provides a pharmaceutical formulation comprising amoxicillin and clavulanate in a ratio of n: 1 wherein n is a number from 1 to 16 comprising: a first group of granulates comprising amoxicillin and clavulanate; in a ratio of m: 1 to 1: 1 where m in a number less than n; and a second group of granulates comprising amoxicillin and non-clavulanate, in a ratio between the first and second group of granulates to give a ratio between amoxicillin and clavulanates of n: 1. Preferably, n is 2, 4, 6, 7, 8 , or 14. Preferably, m is a number from 1 to 5, more preferably, 1, 2 or 4. Preferably, the first group of granulates comprises ampicillin and clavulanate in a ratio of 1: 1, 2: 1 or 4: 1. , preferably 2: 1. In a further aspect, the present invention provides a scale of pharmaceutical formulations comprising different ratios of amoxicillin and clavulanate from 2: 1 to 14: 1, for example selected from 2: 1. 4: 1, 6: 1, 7: 1, 8: 1 and 14: 1, which is prepared from a first group of granulates having a fixed ratio of amoxicillin and clavulanate, for example, 1: 1, preferably 2: 1 , and a second group of granulates comprising amoxicillin, combining different relative proportions of two groups of granulates. Therefore, for example, a scale comprising formulations having ratios of 4: 1, 7: 1 and 8: 1 can be prepared by combining the granulates comprising amoxicillin and clavulanate in the ratio of 2: 1 with different relative amounts of granulates which comprise amoxicillin, for example in the ratios of 3: 2, 3: 5, and 3: 6 respectively. The terms "amoxicillin" and "clavulanate" used herein and, unless otherwise specified, include free mother acids and derivatives of said salts thereof. The weights and relationships are expressed in terms of the weight of the mother compound amoxicillin or clavulanic acid, we use this terminology through this description unless it is established otherwise. Suitable amoxicillin derivatives are amoxicillin trihydrate, anhydrous amoxicillin, and alkali metal salts of amoxicillin such as sodium amoxycillin. Preferably, the equilibrium relative humidity (HRE) of the amoxicillin trihydrate used as a raw material for the production of granulates is carefully controlled by appropriate drying so as not to compromise another aspect of the formulation. Preferably, the HRE is less than 50%. more preferably less than 30% and even more preferably 10 to 20%.

Said clavulanic acid derivatives are alkali metal salts of clavulanic acids such as potassium clavulanate. Preferably, the formulations of this invention comprise amoxicillin trihydrate and potassium clavulanate, are in combination having met the regulatory approval and are particularly advantageous. Granules suitable for use in the present invention have been previously described in WO 92/19277 (SmithKline Beecham) and GB 2005 538-A (Beecham Group). Such suitable granulates may comprise, in addition to amoxicillin, and, if present, clavulanate, excipients conventionally used in said granulates, such as, for example, an intra-granular disintegrant, intra-granular lubricant and intra-granular diluent. Suitable intra-granular disintegrants include starches, such as corn starch and rice starch, crospovidone (entangled N-vinyl-2-pyrrilidinone, CLPVP), sodium starch glycolate, croscarmellose sodium and formaldehyde-casein, or combinations thereof. the same. The intra-granulated disintegrants include sodium starch glycolate and CLPVP, in particular CLPVP, for example, the product marketed under the trade names Polyplasdone XL and Polysplasdone XL-10.

Preferably, the intra-granular disintegrant is present from 0.1 to 10%, preferably from 1.0 to 8.0%, more preferably from 1.25 to 3.5% by weight of the granulate.

Suitable intra-granular lubricants are those conventional to the art, such as long chain fatty acids, such as stearic acid or salts thereof, and in particular, salts of Group II metals, such as magnesium or calcium. A preferred lubricant is magnesium stearate. Preferably, a lubricant is used in such a low proportion, for example, from 0 to 1%, preferably from 0 to 0.5%, more preferably from 0 to 0.35%. Preferably, if the granulate is formed from ingredients that have been compacted using a roller compactor, it is possible not to use the lubricant at all. Preferably, when the granulate contains potassium clauvulanate, the granulates also include an intra-granular diluent such as silica gel (which can also act as an intra-granular desiccant), for example the product Syloid AL-1, or microcrystalline cellulose (which it can also act as a compression desiccant), for example, the Avicel product. Preferably, the intra-granular diluent, if present, is silica gel taking into account its superior desiccant powder. Conventionally, a diluent is included in a weight ratio of about 1: 1 with respect to the weight of the potassium clavulanate, the granulate being prepared from a mixture of 1: 1 potassium clavulanate and silica gel or microcrystalline cellulose. However, it has been found possible to reduce the relative amount of intragranular diluent, in particular silica gel, to a much lower level and thus avoid the use thereof. Accordingly, in a further aspect, the present invention provides a granulate containing amoxicillin and clavulanate as defined above and an intra-granular diluent present from 0 to 100%, preferably from 0 to 50%, more preferably from 5 to 25%, even more preferably from 5 to 15%, usually about 10% by weight of the potassium clavulanate. Preferably, the desiccant diluent is included in a proportion of about 0.5-5% by weight of amoxicillin plus clavulanate, more preferably 1 to 3%. Said granulates allow the preparation of final formulations, in particular tablets, which has a reduced overall weight and size. Normally, the ratio in a granulate of amoxicillin and potassium clavulanate, if present, is from 90 to 99.9% by weight, preferably from 92 to 99% by weight, for example from 95 to 99% by weight, such as 96.5% by weight. 98.75% of the weight of the granulate. When the granulate comprises a diluent, it can comprise up to 30% by weight of the granulate, preferably up to 25% by weight, more preferably up to 10% by weight, preferably up to 5% by weight. When the granulate contains a diluent, the granulate will contain a corresponding lower proportion of amoxicillin or amoxicillin plus clavulanate, for example, from 70 to 99.9% by weight of the granulate, preferably 85%, more preferably 90%, normally from 93 to 97% by weight. weight. The amoxicillin granules comprise from 95 to 99% by weight, preferably from 96 to 98% by weight, more preferably from 96.5 to 97.5% by weight of amoxicillin trihydrate and from 1 to 5% by weight, preferably from 2 to 4% by weight, more preferably from 2.5 to 3.5% of starch glycolate or CLPVP. The simplest granules consist of approximately 97% by weight of amoxicillin trihydrate and 3% of CLPVP. The preferred amoxicillin and clavulanate potassium granules comprise a ratio of 2: 1 amoxicillin to clavulanate; the silica gel is present from 5 to 15% by weight of potassium clavulanate, usually 10% by weight; and CLPVP and 0.5 to 5% by weight amoxicillin trihydrate, preferably 1 to 4% by weight, usually about 3%. Preferably, in the granulates amoxicillin and clavulanate particles, if present, have a size scale of 1μm to 300μm, especially from 10μm to 200μm. A normal size distribution of the amoxicillin / clavulanic acid particles is: > 200μ, 5% or less; 200-100μ, 5-15%, 100-50μ, 7.5-15%; < 50μ, 70% or more. The granulates according to the present invention may be present in a variety of finished formulations, including, for example, tablets, for example, foaming tablets, dispersible and chewable tablets, optionally effervescent tablets; in capsules; watery syrups and sacks. These can be prepared by combining the granulates with additional, extra-granular excipients conventionally used in said formulations and further processed into finished formulations.

The tablets in the present invention can include an extra-granular disintegrant, for example, corn starch and rice starch, CLPVP, sodium starch glycolate, croscarmellose sodium, microcrystalline or microfine cellulose, hydroxypropyl cellulose substituted in low proportion (ie cellulose partially substituted with 2 hydroxypropyl groups, e.g. less than 25% substituted, preferably 7-16% substituted), interlaced sodium carboxymethylcellulose, swellable ion exchange resins, formaldehyde-casein, or alginates. A preferred extra-granular disintegrant is substituted hydroxypropylcellulose in a low ratio, for example the product L-HPC LH-11. This also has useful binding properties, allowing the preparation of highly hardening tablets for a relatively lower proportion of ingredients. Other useful extra-granular disintegrants include CLPVP and sodium glycolate. The proportion of extra-granular disintegrate of total tablet weight can vary between wide limits, for example, of 0.1-25%. For example, low-substituted hydroxypropyl cellulose, CLPVP or sodium starch glycolate, preferably can be used in a proportion of 0.1-15.0% by weight, preferably 1.0-10.0% by weight, preferably 3.0-8.0% by weight by total weight of the tablet. If the cellulose or a combination containing cellulose is used eg. as described above containing about 80-90% by weight of cellulose, the extra-granular disintegrant can comprise 1-20% by weight. The dispersible tablets will tend to comprise a relatively higher proportion of extra-granular disintegrant, to assist the process of dissolution. The tablets of the present invention can also include an extra-granular lubricant, for example a long-chain fatty acid, such as stearic acid, or salts thereof, in particular, salts of Group II metals thereof, such as salt of magnesium calcium, preferably magnesium stearate. Preferably, the extra-granular lubricant is used from 0.1 to 2%, more preferably from 0.2 to 0.5%, typically from 0.3 to 0.4% by weight of the tablet. The formulations of the present invention may also include an extra-granular desiccant such as silica gel. This may be present in an amount of up to 5% of the formulation, preferably, up to 2% of a tablet formulation. The careful control of the relative humidity in equilibrium of the amoxicillin trihydrate used for the granulates allows the use of a relatively lower proportion of extra-granular desiccant. Tablets may also include other conventional excipients, typically present up to about 10% of the total weight of tablets, for example flavoring agents, for example flavorings such as menthol, mint, vanilla or fruit flavors, the flavoring agents are usually present up to about 0.5-5% by weight of the whole tablet and sweetener, v.gr; Aspartame, present up to about 15 mg per unit dose. The excipients may also include coloring agents, preservatives, suspending aids and fillers such as silicon dioxide, microcrystalline cellulose, dicalcium phosphate, lactose, sorbitol, calcium carbonate and magnesium carbonate. Said excipients are preferably mixed with the extra-granular disintegrant and lubricants (if present). The materials present in the tablets should have a low free moisture content and should preferably be dried beforehand. The tablets of the present invention may also contain an effervescent couple of known type, e.g., and an alkali metal carbonate or bicarbonate which generates carbon dioxide in contact with water to aid in the disintegration of the tablet, for example citrate. of monosodium (56.04% w / w) and sodium bicarbonate (43.96% w / w). Preferably, the pair is supplied as granules prepared from monosodium citrate powder anhydride and sodium bicarbonate powder and compacted together by roll compaction, according to the process described in WO 97/02014 (SmithKine Beecham Laboratoires Pharmaceutiques). The tablets may be coated with a film in a conventional manner, e.g., for cosmetic purposes, of pleasant taste or production. Suitable coatings include hydroxypropylcellulose, acrylate and / or methacrylate copolymers such as the products available under the trademark Eudragit, resins etc. Alternatively, the coating may be an enteric coating, e.g., which is insoluble in acidic gastric juices but dissolvable in alkaline dissolvable juices. Said coating allows the tablet to pass through the stomach into the duodenum from where it is absorbed. Suitable enteric coatings include cellulose acetate phthalate. Preferably, a film coating is applied by aqueous film coating techniques, thus avoiding the need for organic solvents. Polymers suitable for use in such techniques include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose (for example ethylcellulose in a latex composition supplied by FMC (trademark)), methylhydroxyethylcellulose, polyvinylpyrrolidone ("PVP", e.g., supplied under the name Povidone. (trademark), sodium carboxymethylcellulose and acrylate polymers (e.g., the known methacrylic acid esters supplied under the tradename "Eudragit" (trademark) A preferred polymer is hydroxypropylmethylcellulose ("HPMC") preferably in combination with a polyethylene glycol ("PEG"). The low molecular weight PEG (series of 200 to 600) are liquid at room temperature and are used as plasticizers.The PEG with high molecular weight (900 to 8000) are solid serous ambient temperature and are used in combination of low molecular weight PEG and other polymers such as HPMC to modify the properties of film a and help the tablet shine.

The preferred polymer that can be applied by aqueous film coating techniques is one or more of hydroxypropylmethyl cellulose combined with one or more PEG. Polymers HPMC have the advantage of solubility in physiological fluids as well as water, do not interfere with tablet disintegration, can be dissolved or are available as a drug, formation of a flexible film, freedom of flavor or objectionable odor, heat stability with light, air, humidity, compatibility with stabilizers, dyes, opacifiers and gloss. Hydroxypropylmethylcellulose functions as a film former and polyethylene glycol functions as a plasticizer. The ratio of hydroxypropylmethylcellulose: polyethylene glycol in the film coating is preferably between 7.5: 1 to 5.5: 1. v.gr., around 6.5: 1 ± 10%. Preferably, the hydroxypropylmethylcellulose is applied in the form of a mixture of 6 cps and 15 cps of hydroxypropylmethylcellulose in a ratio of 2: 1 to 4: 1, e.g., about 3: 1 ± 10%. Preferably, the polyethylene glycol is applied in the form of a mixture of polyethylene glycol 4000 and 6000 in a ratio between about 1: 2 to 2: 1, e.g., about 1: 1. The film coating may also preferably include an opacifier, for example titanium dioxide (white). Preferably, the opacifier may be present in a ratio of about 1: 1 ± 10% with the hydroxypropylmethylcellulose in the film coating.

The film coating materials are preferably applied by an aqueous film coating process, since the application in this manner, forms a film of a nature that also appears to contribute to the improved bioavailability consistency. A suitable solids charge for the aqueous film coating is around 10-30% w / v, normally 10-20%. v.gr., 15% ± 2%. Preferably, the film coating is applied so as to deposit a weight of dry film materials corresponding to 0.5 to 5%, preferably 1 and 4%, more preferably 1.5 to 3.5% of the total weight of the coated tablet .

Preferably the proportion of amoxycillin and clavulanate in tablets of the present invention is 60-98% by weight of the total tablet (calculated with the weight of the particular form used, for example, the weight of amoxycillin trihydrate or clavulanate potassium). Preferably, the tablets according to the present invention are provided in convenient unit dosage forms, for example, nominally comprising 125 / 62.5, 250 / 62.5, 250/125, 500 / 62.5, 500/125, 875/125 and 1000 / 125 mg of amoxicillin / clavulanate. The tablets can be dispersed in water before ingestion, or alternatively they can be chewed or passed complete. The skilled person will readily appreciate that, in the tablets of this invention, the granulates may be in the ground state resulting from tablet compaction and consequently may lack discrete limits or may be subdivided or separated into smaller granules. In the invention, it is intended to include tablets having such structure containing crushed granulates. Preferably, the size of the granulates is in the range of 100μm to 2mm, preferably around 1mm ± 0.25mm, of maximum dimension. Preferably, the tablets are packaged in a container that inhibits the ingress of atmospheric moisture, e.g., packages of ampoules and sealed-seal bottles, etc., as is conventional in the art. Preferably, the bottles also include a desiccant material to preserve the clavulanate. By reducing the relative amount of excipients used, in particular, intra-granular diluent, as well as minimizing the amounts of extracellular excipients used in a tablet formulation, tablets of reduced weight can be prepared. This is helped by careful control of the moisture content of these different excipients, as well as amoxilin trihydrate, to ensure that a greater capacity of desiccant is not required. Accordingly, in a further aspect, the present invention provides a tablet formulation comprising a first group of granulates comprising amoxicillin and clavulanate with a second group of granulates comprising amoxicillin and non-clavulanate as defined below in which the combined weight of all the excipients is less than 20%, preferably less than 18%, more preferably less than 15%, usually 10 to 12% of the uncoated core weight of the tablet. It provides tablets that are easier to pass through the patient. In addition, these reduced weight tablets are less expensive in their production since fewer raw materials are used, less material has to be transported around a manufacturing plant and the capacity of the equipment is effectively increased, since less material is processed per tablet . Preferred reduced weight tablets comprise: amoxicillin granulates consisting essentially of amoxycillin trihydrate present at approximately 97% by weight and CLPVP present at approximately 3% by weight; granules of amoxicillin and potassium clavulanate comprising a ratio of 2: 1 amoxicillin to clavulanate, silica gel present in about 10% by weight of potassium clavulanate and about 3% by weight of CLPVP; and extragranular excipients which include: silica gel (preferably 0.5 to 2.0%, more preferably about 1.0 to 1.2%), hydroxypropylcellulose substituted in low proportion (preferably 3 to 8%, more preferably 5 to 6%), silica colloidal (preferably 0.1 to 0.5%, more preferably 0.1 to 0.3%) and magnesium stearate (preferably 0.2 to 0.5%, more preferably 0.3 to 0.4%); or CLPVP (preferably 3 to 10%, more preferably 5 to 8%), and magnesium stearate (preferably 0.2 to 0.5%, more preferably 0.3 to 0.4%). Preferred 500 / 62.5 mg tablets will have tablet core weights in the range of 700 to 800 mg, more preferably 720 to 780 mg. Preferred 500/125 mg tablets will have tablet core weights in the range of 800 to 950 mg, more preferably 800 to 900 mg, even more preferably 800 to 850 mg. Preferred 875/125 mg tablets will have tablet core weights in the range of 1250 to 1375 mg, more preferably 1250 to 1125 mg. Preferred 100/125 mg tablets will have tablet core weights in the range of 1400 to 1550 mg, more preferably 1425 to 1475 mg. The preferred 500/125 mg tablets will have a total weight (core plus coating) less than 900 mg, more preferably less than 850 mg. Especially preferred 500 / 62.5 mg tablets will have a total weight (core plus coating) less than 850 mg, still more preferably less than 800 mg. Especially preferred 875/125 mg tablets will have a total weight (core plus coating) of less than 1400 mg, still more preferably less than 1350 mg. Especially preferred 1000/125 mg tablets will have a total weight (core plus coating) of less than 1550 mg, preferably less than 1500 mg.

The skilled person will readily appreciate that the aforementioned tablets can also be produced by a more conventional approach, using a single group of granules comprising amoxicillin and clavulanate in the final ratio of, for example, 4: 1, 7: 1 or 8: 1, instead of the two groups of granules described above, using intra- and extra-granular excipients in the same proportions. The present invention covers all said tablets. As described above, a unit dose of 1000/125 mg in a tablet formulation can be provided as a single tablet, preferably of reduced weight. The preferred reduced weight 1000/125 mg tablets comprise amoxicillin and clavulanate present from 83 to 95%, preferably from 85 to 93%, more preferably from 87 to 91% by weight of the core tablet and the pharmaceutically acceptable excipients present from 5 to 17%, preferably 7 to 15%, more preferably, 9 to 13% by weight of the core weight of the tablet (excluding any coating). The skilled person, however, will readily appreciate that the two is can also be provided using two 500 / 62.5 mg tablets (ratio amox./cJav = 8: 1). Such tablets will be intrinsically smaller since they contain less of their drug substance so that tablets are also based on more conventional formulations, for example, existing 500/125 mg formulations where there is no need to reduce the weight and size of the tablet. Accordingly, in a further aspect, the present invention provides a tablet comprising approximately 500 mg of amoxicillin and approximately 62.5 mg of potassium clavulanate and pharmaceutically acceptable excipients. The experts will further appreciate that a dose of 1000/125 mg can also be provided by the combination of a 500/125 mg amoxicillin / clavulanate tablet and a 500 mg amoxicillin tablet, for example, using said existing tablets or adapting one or the other to distinguish them more easily, for example, by shape or color. Compliance of the patient with said strategy of two tablets, can be improved by providing the tablets in a presentation of packaging of ampoules, each vial containing two tablets. The present invention covers all of these approaches. A unit dose of 1000/125 mg can also be provided as a chewable, optionally effervescent tablet, so the problem of having to pass a large complete tablet is overcome by being chewed by the patient, and breaking it into smaller pieces before being passed. . Accordingly, in a further aspect, the present invention provides a chewable, optionally effervescent tablet comprising 1000/125 mg of amoxicillin and clavulanate. The chewable tablets can be prepared by combining granulates as described above, with extragranular excipients conventionally to form a chewable base, for example, mannitol, sorbitol, dextrose, fructose or lactose, alone or in combination, preferably present from 10 to 30% based on the weight of the final tablet, more preferably 15 to 25%. The tablets may also contain conventional lubricants such as magnesium stearate, sweetening agents such as aspartame or sodium saccharin and flavoring and coloring agents. A disintegrating agent can also be incorporated as an extragranular excipient, to give the patient the option to disperse the tablet in a small amount of water before administering it. Suitable disintegrating agents include cellulose based products such as microfine cellulose, microcrystalline cellulose or hydroxypropyl cellulose, as well as sodium starch glycolate and CLPVP. The disintegrant is preferably present from 5 to 30%, more preferably from 5 to 15%, based on the weight of the final tablet. Preferably, the chewable tablet is also provided with an effervescent couple. Formulations of effervescent chewable tablets comprising 250/125 or 250/62.5 mg of amoxicillin / clavulanate have previously been described in EP 0 396 335 A1 (Beecham Group foot). Suitable effervescent couples are well known in the art and usually comprise a solid acid and an alkali metal carbonate or bicarbonate which causes the carbon dioxide to come into contact with water, for example citric acid, monosodium citrate or citrate sodium acid and sodium bicarbonate. Other pharmaceutically acceptable acid carbonate / alkali metal or alkaline earth metal mixtures can also be used, for example, tartaric, adipic, fumaric or malic acids and sodium, potassium or calcium bicarbonates or sodium glycine carbonate. Preferably, the two components are employed in a chemical molecular equivalent base in the range of 4: 3 to 1: 3, more preferably approximately 2: 3 (acid component: basic). Preferred pairs comprise citric acid / sodium bicarbonate and monosodium / sodium bicarbonate citrate, in particular monosodium citrate (56.04% w / w) and sodium bicarbonate (43.95% w / w). Preferably, this was provided as granules prepared from monosodium citrate powder anhydride and sodium bicarbonate powder and compacted together by roll compaction, according to the process described in WO 97/02014 (SmithKine Beecham Laboratories Pharmaceutiques). Suitable grades of the monosodium citrate anhydride powder comprises particles which substantially (ie, approximately more than 90%) are within the range of 0 to 500 microns, preferably 355 microns, more preferably 0 to 250 microns. Suitable grades are available from Roche (monosodium citrate anhydride powder, max 5% w / w with size of gano >; 0.250 mm), Boheringer Ingelheim (monosodium citrate 'wasserfrei Art-Nr 661 511', minimum of 90% w / w with grain size <0.150 mm), Jungburtzlauer (maximum of 5% w / w with grain size > 0.3555 mm) and Haarmann% Reimer Corp. (maximum of 1% with grain size> 0.500 mm). Suitable grades of sodium bicarbonate comprise particles which substantially (ie, approximately more than 90%) are within the range of 0 to 500 microns, preferably 270 microns, more preferably 0 to 130 microns. Suitable grades of sodium bicarbonate powder are available from Solvay, for example grades 0 to 13 (particle size, by sieving method> 0.15 mm max; 15g / kg) and extra fine (particle size by the method sieving 0.125 mm max, 20 g / kg). Preferably, 5 to 30% of the final weight of the tablet is present, more preferably 5 to 15%, usually about 10%. The granules described above can also be used to prepare other pharmaceutical formulations, in addition to the tablets. For example, they can be supplied as a bag product containing a free-flowing granular formulation in a suitable unit dose, for reconstitution in water in order to form a syrup formulation immediately before use, for example, for administration to Small children. Said free-flowing granular formulation may comprise additional excipients such as sweetening, thickening, preservative agents such as sodium benzoate and buffer solutions such as sodium citrate. Preferred sacs comprise amoxicillin granules consisting essentially of amoxycillin trihydrate present in about 97% by weight and CLPVP present in about 3% by weight, amoxicillin granules and potassium clavulanate comprising a ratio of 2: 1 amoxicillin to clavulanate, silica gel present in about 10% by weight of potassium clavulanate and extragranular excipients including silica gel (preferably 5 to 20%, more preferably about 10 to 15%) and flavor (preferably 2 to 10%) , more preferably from 3 to 8%). Said bags may preferably be provided as "sugar-free" formulations, comprising, as an artificial sweetening agent tai such as aspartame, instead of sugar. Preferably, said formulations preferably comprise from 1 to 10%, more preferably from about 1 to 5% aspartame. Said bag formulations have a reduced weight compared to existing bag formulations comprising corresponding weights of amoxicillin and clavulanate and therefore can be supplied in smaller bags, saving packing costs. Suitable additional formulations include encapsulated formulations which may optionally include extragranular lubricant, which if present, is preferably in an amount less than 0.5% by weight of the granulates, being contained within a pharmaceutical capsule. The pharmaceutical capsule can be a completely conventional capsule, capable of dissolving in the stomach to release its contents, for example, made of gelatin. The bag and the encapsulated formulations described above preferably contain unit doses of amoxicillin, for example, sacks nominally comprising 125 / 31.25, 250 / 31.25, 250 / 62.5, 500/125, 500 / 62.5, 875/125 or 1000/125 mg of amoxicillin / clavulanate. Other suitable formulations include formulations for pediatric use that is constituted in aqueous suspensions before use. Said formulations may comprise additional extragranular excipients, such as, for example, a drying agent, for example, silica gel or dry maltodextrin, thickeners such as xanthan gum, sodium carboxymethylcellulose, silica gel and hydroxypropylmethyl cellulose, preservatives such as benzoate. sodium, sweetening agents such as aspartame, potassium accesulfamate and sodium saccharin, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide and flavoring agents such as fruit flavors. It is found that said formulations have a lower volume so that they can be provided in a smaller container. The formulations are provided comprising an appropriate amount of amoxicillin and clavulanate to be reconstituted in an aqueous solution, eg, 100/125 mg / ml in 30 ml, 100/125 mg / ml in 60 ml, 125/31.25 mg / 5 ml. from 60 to 80 ml and 250 / 62.5 mg / 5 ml in 60 to 80 ml.

The skilled person will readily appreciate that the aforementioned bag, encapsulated and pediatric formulations can also be produced by a more conventional approach, using a unique set of granules comprising amoxicillin and clavulanate in the final ratio of, for example, 4: 1, 7: 1 or 8: 1, instead of two groups of granules described above, using intra and extragranular excipients in the same proportions. The present invention covers all said formulations. In a further aspect, the present invention provides pharmaceutical formulations comprising amoxycillin and ciavulanate in a ratio of n: 1, as defined above, preferably 2: 1, 4: 1, 7: 1 and 8: 1, and comprising granulates consisting essentially of amoxicillin and clavulanate, CLPVP (as an intragranular disintegrant) present from 0.5 to 5% by weight, amoxicillin trihydrate, preferably 1 to 4% by weight, usually about 3%, and silica gel (as a intragranular diluent / desiccant) present from 5 to 15% by weight of potassium clavulanate, usually about 10% by weight. In a further aspect, the present invention provides a process for preparing the formulations of the present invention defined above, which process comprises mixing together a first group of granulates comprising amoxicillin and clavulanate with a group of granulates comprising amoxicillin and non-clavulanate in an appropriate ratio and then further processing it to obtain the desired final formulation, for example, by compressing it into tablets, filling in bags, bottles or capsules. It will be readily appreciated that a scale of different formulations with different ratios of amoxicillin to clavulanate can be easily prepared using common intermediate granules comprising a given ratio of amoxicillin and clavulanate, for example 2: 1, and then adding it in different relative amounts of granulates comprising amoxicillin alone, to provide different final relationships. It will be further appreciated that the use of granules comprising silica gel and silica gel as an extra-granular excipient, rather than microfine cellulose allows the development of a scale of various types of formulations with smaller different types of excipient, reducing as well as the complexity of the manufacturing process. Preferably, the amoxicillin and clavulanate, if present, (drug substance) is ground and sieved to achieve the desired particle size scale. Preferably, the intra-granular disintegrant is also milled and sieved to a suitable particle size, for example, in the case of CLPVP, approximately 30μ, but the particle size does not appear to be critical. The drug substance prepared and the intra-granular excipients are mixed in a dry state and compacted under pressure. This can be done by conventional dry compaction means, for example, pressing, rolling, deformation, extrusion, etc., and a suitable pressure for the compaction process is 30-200kN, for example 70-100, preferably, 80-90 kN for amoxicillin granulates and 50 -80, preferably, 60-70 kN for amoxicillin / clavulanate granules. The granulated formulations described above are particularly suitable for roll compaction formation. The use of roller compaction to prepare granules comprising amoxicillin clavulanate potassium was described in WO 92/19227 and WO 95/28927 (both SmithKine Beecham). Potassium clavulanate is known to be highly sensitive to moisture so that it is preferred that the preparation of the formulations of the invention is carried out under low humidity conditions, for example less than 30% RH, more preferably less than 20% of RH, ideally of 7-10% of RH.

For further processing into tablets, it may be necessary to grind and sieve the granulates so that they achieve an adequate fraction of the granulate size. Tablet compression can be carried out in a conventional manner, for example, in a conventional tabletting machine. As an optional additional step, the tablets may be coated as described above. The formulations of this invention can be provided for the treatment of bacterial infections, generally, for example, one or more upper respiratory tract infections, lower respiratory tract infections, genito-urinary tract infections and skin and soft tissue infections, among other. Accordingly, in a further aspect, the present invention provides the use of a first group of granulates comprising amoxicillin and clavulanate with a second group of granulates comprising amoxicillin and non-clavulanate in the manufacture of a medicament for treating bacterial infections.

The invention will now be described, by way of example only. In this, the weights and% are the actual weights and% trihydrate of amoxicillin and potassium clavulanate, instead of the corresponding free acid equivalents. In the following examples, the use of amoxicillin trihydrate in which the Relative Balance Humidity is in the range of 10-20% is preferred, thus allowing the relative desiccant amount to be reduced to a minimum level. Example 1 - Amoxicillin granulate The amoxicillin trihydrate was ground and sieved using an aperture screen of 1.0 to 0.7 mm and mixed for 15 minutes in a mixer with dry interlaced poiivinylpyrrolidinone (CLPVP) having a molecular weight of about 1 million and a density of 1.22 mg / cm3 (Polyplasdone XL - Trade Mark), the mixture containing 3.4% of CLPVP by weight. The mixture was consolidated using a roller compactor at a controlled pressure of 50 kN. The compacted flakes were granulated in a mill, or granulated through a sieve adapted with a 1 mm mesh to obtain a fraction of adequate size. Example 2 - amoxicillin granulate Amoxicillin Trihydrate 97.087% CLPVP (Poliplasdone XL) 2,913 Amoxicillin trihydrate ground and crospovidone (moisture < 2%, sieved in a 1 mm sieve) where it was weighed separately and then introduced in a mixer (first amox.) To mix them, both operations being carried out in a controlled area (t ° = 20 +/- 1 ° C, RH <30%). The resulting mixture was discharged in double polyethylene bags in marked and stored containers for subsequent roll compaction. A Bepex roller compactor was fed with the mixture, maintaining a constant level in the feed hopper, the load cell fixed at 15 kN and the compactor at a roller force of 80-90 kN. The resulting flakes were calibrated in an oscillating granulator adapted with an aperture screen of 1 mm. Uncompacted material that passed through a 1 mm screen was recycled. The granules were weighed and recovered in double polyethylene bags and drums. Roll compaction and calibration was carried out in a controlled area (t ° = 20 +/- 1 ° C, RH <30%). Example 3. Amoxicillin Granulate The granulates were prepared using 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 an intragranular disintegrant. Example 4. Amoxicillin / Clavulanate Granulate The granulates comprising amoxicillin and clavulanate in a ratio of 2: 1 were prepared using a procedure identical to that of Example 1, comprising: Amoxicillin Trihydrate 46.3% Potassium Clavulanate 24.3 Silica Gel (Syloid AL -1) 24.3 CLPVP (Poliplasdone XL) (Dry) 1.38 Potassium clavulanate and silica gel were used as a 1: 1 mixture (based on the actual weight of potassium clavulanate). Example 5. Amoxicillin / Clavulanate Granules Granules comprising amoxicillin and clavulanate in a ratio of 2: 1 and a smaller proportion of silica gel than in Example 4, were prepared using a procedure identical to Example 1, comprising: Amoxicillin Trihydrate 63.3% Potassium Clavulanate 31.7 Silica Gel (Syloid AL-1) 3.1 CLPVP (Poliplasdone XL) (Dry) 1.9 Amoxicillin, crospovidone (moisture <2%) and silica gel (sieved in 1 mm) milled and finally a 1: 1 mixture of amoxicillin trihydrate / potassium clavuiate (screened in 1 mm), were introduced in succession into a mixer and mixed together in a controlled area (t ° = 20 +/- 1 ° C, RH < 30%). The mixture was then discharged in double polyethylene bags with desiccant in labeled containers to be stored prior to roll compaction. A Bepex roller compactor was fed with the maintenance of mixture maintaining a constant level in the feed hopper, with the load cell set at 15 kN; and the compactor at a roll resistance of 60-70 kN. The resulting flakes were calibrated in the oscillating granulator adapted with a sieve with 1 mm opening. The non-compacted material that is passed through a 1 mm sieve was recycled. The granules were weighed and recovered in double polyethylene bags and drums. Roll compaction and calibration was carried out in a controlled area (t ° = 20 +/- 1 ° C, RH <30%). Example 6. Reduced weight tablets A reduced weight tablet comprising 500 mg / 62.5 mg, 500 mg / 125 mg, 875 mg / 125 mg or 1 g / 125 mg of amoxicillipa / clavulanate was prepared by combining granulates comprising amoxicillin and potassium clavulanate ( Example 5) in a ratio of 2: 1 with granulates comprising amoxicillin (Example 2), to give an overall ratio of 8: 1, 4: 1, 7: 1 or 8: 1 respectively with extragranular excipients, in particular hydroxypropylcellulose with a low substitution ratio as the extragranular disintegrant, so that the overall composition was as follows: 500/125 875/125 1g / 125 mg Mg Mg Nucleus Mg mg g Amoxicillin Trihydrate 573.87 1004,272 1147.74 (100%, theoretically equivalent to 500, 875mg to 1g of Amox, 100%) Potassium clavulanate (100% 148.93 148.930 148.930 in theory, equivalent to 125mg of 100% clavulanic acid) Silica gel (intra-granular) 14.89 14.890 14,890 CLPVP (intra-granular) 17.21 30,130 34,430 Silica gel (extra-granular) 8.3 14,000 16,000 Substituted hydroxypropylcellulose 50.00 70,000 80,000 in a low proportion Colloidal silica 1.70 2.700 3.000 Magnesium stearate 3.00 4.600 5.300 Total weight (core) 817.9 1289.520 1450.29 Sheathing Hydroxypropylmethylcellulose 5cP 6.93 10.925 12.288 Hydroxypropylmethylcellulose 15cP 2.31 3.642 4.096 Polyethylene glycol 4000 1.369 2.158 2.427 Polyethylene glycol 6000 1.369 2.158 2.427 Titanium dioxide 9,022 14,225 15,997 Total Coating Weight 21 33.108 37.235 Total weight of coated tablet 838.9 1322,628 1487,525 500 / 62.5 500 / 62.5 500 / 62.5 mg mg Mg Core mg mg mg Amoxicillin Trihydrate (100%; 573.87 573.87 573.87 in theory equivalent to 500, 875mg to 1g Amox, 100%) Potassium clavulanate (100% in 74.46 74.46 74.46 theory, equivalent to 125mg of 100% ciavulanic acid) Silica gel ( intragranular) 7.45 7.45 7.45 CLPVP (intra-granular) 17.21 17.21 17.21 Silica gel (extra-granular) 7.4 15.3 17.2 Hydroxypropylcellulose substituted in 44.5 61.3 78.4 a low proportion Colloidal silica 1.50 1.50 1.50 Magnesium stearate 2.7 2.8 2.8 Total weight (core) 729.09 753.89 772.99 Coating (as before) 19 19 19 Total weight of coated tablet 748.09 772.89 792.99 1: Syloid AL-1 2: L-HPC LH-11 or equivalent; 3: Aerosil 200 or equivalent. The manufacture of tablets was carried out in a controlled area (t ° = 20 +/- 1 ° C RH <30%). A compression mixture was prepared by introducing amoxicillin granules, amoxicillin / clavulanate 2/1 granules, silica gel, L-HPC-LH-11 and colloidal silicon dioxide sieved in 0.5 mm into a mixer. These materials were mixed together. Magnesium stearate (sieved in 0.5 mm = was added later, followed by additional mixing) This mixture was then compressed using concave oval grains to give tablets of the desired weight.The uncoated tablets were shown every 5-15 min during the operation of compression and were revised for hardness, thickness, average weight, mass uniformity and friability.

The uncoated tablet cores were then coated with film with a coating suspension (15% w / w in water) in a suitable coating machine, rotating the cores and spraying the film coating suspension until an amount had been applied. theoretical film coating (WO 95/28927, SmithKine Beecham). The film coated tablets were stored in appropriate sealed containers. For the 500/125 mg tablet, the tablet has a total weight of approximately 817.9 mg, including 63 mg of extragranular excipients plus a coating of approximately 21 mg. The amoxicillin trihydrate and the potassium clavulanate account for approximately 89.6% of the weight of the tablet core. This may be in contrast to the present 500/125 mg tablet having a core weight of 1050 mg of which the amoxicillin trihydrate and potassium clavulanate amount to approximately 69.3% and microcrystalline cellulose of approximately 27%. The amounts can be halved to give a tablet of 250 / 62.5 mg. In 875/125 mg tablets, amoxicillin trihydrate and potassium clavulanate account for approximately 89.43% of the core weight of the tablet. This may be in contrast to the current 875/125 mg tablet having a core weight of 1450 mg, of which amoxicillin trihydrate and potassium clavulanate amount to approximately 80% and microcrystalline cellulose of approximately 15.6% (WO 95). / 28927, SmithKIine Beecham). In tablets of 1g / 125 mg, amoxicillin trihydrate and potassium clavulanate account for approximately 89.41% of the weight of the tablet core. The amounts can be half, to give a 500 / 62.5 mg tablet. Example 7. Reduced weight tablets A reduced weight tablet comprising 500 mg / 125 mg, 875 mg / 125 mg or 1 g / 125 mg amoxicillin / clavulanate was prepared by combining granulates comprising amoxicillin and potassium clavulanate (Example 5) in a ratio of 2: 1 with granulates comprising amoxicillin (Example 1), to give an overall ratio of 4: 1, 7: 1 or 8: 1, repetitively with extragranular excipients, in particular CLPVP as the extragranular disintegrant, so that the composition global is as follows: 500/125 875/125 1g / 125 mg mg Mg Nucleus Mg mg Amoxicillin Trihydrate (86.4%, in 5 57788..77 1012.7 1157.4 theory equivalent to 500, 875mg to 1g Amox 100%) Potassium clavulanate (82.5 % in 151.5 151.5 151.5 theory, by KCA, equivalent to 125mg of clavulanic acid 100%) Silica gel (non-granular) 15.2 15.2 15.2 CLPVP (intra-granular) 17.4 30.4 34.7 CLPVP (extra-granular) 60 90 100 Magnesium stearate 3.00 4.50 5.0 Total Weight (core) 825.8 1304.3 1463.8 1 Syloid AL-1 A coating-based solvent for the cores of the above tablets is as follows: Dimethicone 200 0.04mg Ethylcellulose 3.21 Hydroxypropylmethylcellulose 12.8 Suspension of titanium dioxide 11.34 Diethyl phthalate 3.78 Total coating weight 37.17 Example 8. Sachets of 500mg / 125mg and 1g / 125mg The granulates were prepared using procedures identical to Examples 1 and 5. granulates were then mixed in the appropriate ratio with normal bag excipients to produce a bag formula comprising: 500/125 1g / 125mg Mg Amoxicillin Trihydrate (100% theoretically 573.87mg 1147.4 equivalent to 500mg to 1g Amox 100%) Potassium clavulanate (100% in theory, 148.93 148.93 equivalent to 125 mg of clavulanic acid 100%) CLPVP (intra-granular) 17.21 34.42 Silica gel (intra-granular) 14.89 14.89 Silica gel (extra-granular) 65.00 130.00 Aspartame 15.00 30.00 Peach flavor, lemon, strawberry 30.00 60.0 Total weight 864.90 1565.98 1 Syloid AL-1 Sachets comprising 500 / 62.5mg and 250.31.25mg can be prepared using pro rat amounts based on the 1g / 125mg formulation. Example 9. Sacks of 250 / 62.5, 500/125 and 875 / 125mg Granules were prepared using procedures identical to those of Examples 1 and 5. The granulates were then mixed in the appropriate ratio with normal suspension excipients to produce a formula of sack containing: 250 / 62.5 500/125 875/125 mg mg mg Amoxicillin Trihydrate (86.4%, in 289.35 573.87mg 1147.4 theory equivalent to 250, 500 and 875mg Amox 100%) Potassium Clavulanate (82.5% in 75.75 148.93 148.93 theory, equivalent to 62.5 and 125mg of 100% clavulanic acid) CLPVP (intra-granular) 8.7 17.4 30.4 Silica gel (intra-granular) 7.6 15.2 15.2 Silica gel (extra-granular) 167.5 335 335 Aspartame 6 12.00 12.00 Flavor to peach, lemon, strawberry 107 214 214 Microcrystalline cellulose 213.1 426.2 229.2 1 Syloid AL-1 Example 10. 100 mg / 12.5 mg / ml suspension - 30 ml. The granulates were prepared using procedures identical to Examples 1 to 5. The granulates were then mixed in the appropriate ratio with normal suspension excipients to produce a sack formula comprising: Amoxicillin Trihydrate (100%, theoretically 3443.22mg equivalent to 3000mg Amox 100%) Potassium clavulanate (100% in theory, 446.79 equivalent to 375mg of 100% clavulanic acid) CLPVP (intra-granular) 103.29 Silica gel ( Ntra-granular) 44.68 Silica gel (extra-granular) 500.00 Xanthan gum 25.2 Sodium salt Carboxymethylcellulose 250.00 Sodium benzoate 51.00 Hydrophobic colloidal silica 15.00 Aspartame 96.00 Magnesium stearate 10.00 Strawberry flavor 150.00 Total weight 5135.50mg 1 Syloid AL- 1 The formulation was made in 30 ml of aqueous solution immediately before the first use. The same formulation can also be constituted in an aqueous solution of 60 ml.

Example 11. Chewable effervescent tablet (1g / 125 mg) mg Amoxicillin Trihydrate (equivalent to 1147.74 1000.0 Amox.) Potassium clavulanate (equivalent to 125.0 148.93 clavulanic acid) CLPVP 34.43 Silica gel (non-granular) 14.89 Silica gel (extra-granular) 120.00 Monosodium Citrate 156.91 Sodium bicarbonate 123.09 Microcrystalline cellulose 280.00 Flavors 90.00 Aspartame 40.00 Magnesium Stearate 30.00 DC mannitol 614.01 Total Weight 2,800 1 Crospovidone 2 Syloid AL-1 3 Avicel PH1 12 Example 12. Tablet of conventional 500/125 mg Amoxicillin Trihydrate Core (equivalent to 500.0 578.87 Amox.) Potassium clavulanate (equivalent to 125.0 148.93 of clavulanic acid) Anhydrous colloidal silicon dioxide 10.50 Sodium starch glycolate 21.00 Magnesium stearate 7.27 Microcrystalline cellulose is 1050 Coating Methylhydroxypropylcellulose 11.88 Polyethylene glycol 4000 1.76 Polyethylene glycol 6000 1.76 Titanium dioxide 0.14 Dimeticona 27.14 Total 1077mg (Primojel / Explotab Example 13. 500/125 mg tablet Core Amoxicillin Trihydrate (equivalent to 500.0 581.4 Amox., Based on 86% potency) Potassium clavulanate (equivalent to 62.5 of 76.2 clavulanic acid, based on 82% potency) Dioxide of colloidal silicon 8.2 Sodium starch glycolate 16.4 Magnesium stearate 5.7 Weight 817.0 Coating As in Example 6 24.5 Total 841.5mg The source of amoxicillin, clavulanate (either as a 1: 1 mixture of clav: amox, or a 1: 1 mixture of clav., And microcrystalline cellulose), most of the microcrystalline cellulose, and a portion of the magnesium stearate They mixed together. This mixture was compacted by roller and milled to form granules. These granules were mixed with the glycolate of sodium starch, colloidal silicon dioxide, the remaining microcrystalline cellulose (about 38.55 of the total amount) and the magnesium stearate and the mixture is then compressed into tablet cores. In a final step, the cores were coated with an aqueous suspension of the coating. The relative weights and proportions of the components of the above examples 1 to 13 may vary with respect to the listed figures, but are preferably within + 10%, more preferably within + 2.5%. Surplus active ingredients may be used if necessary and justified. It will be appreciated that the above formulations can also be produced using a single group of granules comprising amoxycillin and clavulanate in the final ratio of 4: 1, 7: 1, or 8: 1 instead of two described groups, using intra- and extragranular excipients. in the same proportions. The present invention covers said formulations.

Claims (27)

1. CLAIMS 1. A pharmaceutical formulation comprising amoxicillin and clavulanate in a ratio of n: 1 wherein n is a number from 1 to 16 comprising: a first group of granulates comprising amoxicillin and clavulanate in a ratio of m: 1 to 1 : 1 where m is a minor number an; and a second group of granulates comprising amoxicillin and not clavulanate; in a ratio between the first and second groups of granulates to give a global ratio between amoxicillin and clavulanate of n: 1, and in which the formulation, when in the form of a tablet, comprises the first and second groups of granules in mixture .
2. 2. A formulation according to claim 1, wherein the first group of granulates comprises amoxicillin and clavulanate in a ratio of 1: 1 to 2: 1.
3. 3. A formulation according to claim 1 or 2, wherein n is 2, 4, 6, 7, 8 or 14.
4. 4. A formulation according to any of claims 1 to 3, wherein the amoxicillin it is present as amoxicillin trihydrate.
5. 5. A formulation according to any of claims 1 to 4, wherein the clavulanate is present as potassium clavulanate.
6. 6. A formulation according to any of claims 1 to 5, wherein the granulates comprise an intragranular disintegrant.
7. 7. A formulation according to any of claims 1 to 6, wherein the first group of granulates consists essentially of amoxicillin, potassium clavulanate, silica gel and an intragralunar disintegrant.
8. 8. A formulation according to any of claims 1 to 6, wherein the second group of granulates consists essentially of amoxicillin and an intragranular disintegrant.
9. 9. A formulation according to any of claims 6 to 8, wherein the intragranular disintegrant is starch glycolate of N-vinyl-2-pyrrolidone or sodium interlaced.
10. 10. A formulation according to any of claims 1 to 9, further comprising an extragranular excipient which is hydroxypropylcellulose substituted in a low ratio.
11. 11. A formulation according to any of the preceding claims in the form of a tablet, sachet, capsule or powder for reconstitution as an aqueous syrup.
12. 12. A tablet formulation comprising a first group of granulates comprising amoxicillin and clavulanate with a second group of granulates comprising amoxicillin and non-clavulanate as defined in claim 1, wherein the combined weight of all excipients is lower at 20% of the weight of the uncoated core of the tablet.
13. 13. A tablet formulation according to claim 12, comprising: amoxicillin granulates consisting essentially of amoxycillin trihydrate present in about 97% by weight and CLPVP present in about 3%; granules of amoxicillin and potassium clavulanate comprising a ratio of 2: 1 amoxicillin to clavulanate; silica gel present in about 10% by weight of potassium clavulanate and CLPV present in about 3% by weight; and extragranular excipients including silica gel; low-substituted hydroxypropylcellulose or CLPVP; colloidal silica and magnesium stearate.
14. 14. A tablet formulation according to claim 13, wherein the tablet cores have the weights: 500 / 62.5 - 700-800 mg; 500/125 mg - 800 to 950 mg: 875/125 mg - 1250 to 1350 mg; and 1000/125 mg - 1400 to 1550 mg.
15. 15. Amoxicillin / clavulanate tablets having a total tablet weight (core plus coating): 500 / 62.5 mg - less than 850 mg; 500/125 mg - less than 900 mg; and 1000/125 mg - less than 1550 mg.
16. 16. A 1000/125 mg tablet comprising amoxicillin and clavulanate present from 83 to 95% and pharmaceutically acceptable excipients present from 5 to 17% by weight of the core weight of the tablet (excluding any coating).
17. 17. A tablet comprising approximately 500 mg of amoxicillin and approximately 62.5 mg of potassium clavulanate and pharmaceutically acceptable excipients.
18. 18. A package of tablet ampoules comprising in each vial two tablets of those defined in claim 17.
19. 19. The use of two tablets defined in claim 17, to provide a unit dose of 1000 mg of amoxicillin and 125 mg of potassium clavulanate.
20. 20. A tablet formulation that is a chewable, optionally effervescent tablet, and which comprises approximately 1000 mg of amoxicillin and approximately 125 mg of clavuanate.
21. 21. A chewable effervescent tablet according to claim 20, wherein the effervescent couple is monosodium citrate and sodium bicarbonate, preferably provided as granulates.
22. 22. A process for preparing a formulation according to any of the preceding claims comprising mixing a first group of granulates comprising amoxicillin and clavulanate with a second group of granulates comprising amoxicillin and non-clavulanate in an appropriate ratio with other excipients and then, if it is necessary and desired to further process the mixture to obtain the desired final formulation.
23. 23. A process according to claim 22, comprising the preliminary step of preparing the first and / or second group of granulates by roller compaction.
24. 24. The use of a first group of granulates comprising amoxicillin and clavulanate in the ratio of 2: 1 to a second group of granulates comprising amoxicillin and non-clavulanate, in the manufacture of a pharmaceutical formulation comprising amoxicillin and clavulanate in a ratio greater than 2: 1.
25. 25. The use of a first group of granulates comprising amoxicillin and clavulanate with a second group of granulates comprising amoxicillin and non-clavulanate, in the manufacture of a medicament for treating bacterial infections.
26. 26. A granulate as defined in any one of the preceding claims comprising amoxicillin and clavulanate plus an intragranular diluent present in a ratio of 1: 1 to 1:20 by weight of clavulanate.
27. 27. A scale of pharmaceutical formulations comprising different ratios of amoxicillin and clavulanate from 2: 1 to 14: 1, for example, selected from 2: 1, 4: 1, 6: 1, 7: 1, 8: 1 and 14 : 1 which was prepared from a first group of granulates having a fixed ratio of amoxicillin and clavulanate, for example, 1: 1 or 2: 1, preferably 2: 1. and a second group of granulates comprising amoxicillin, combining different proportions of the two groups of granulates.