Formulation comprising amoxicillin and an organic acid

ES 2 202 004 T3

DESCRIPTION

Novel treatment procedure using a strong dosage regimen of amoxicillin and potassium clavulanate.

The present invention relates to a novel treatment method using amoxicillin and potassium clavulanate and to novel formulations, in particular, formulations in the form of tablets, for use in said procedures.

Amoxicillin and potassium clavulanate are, respectively, a known beta-lactam antibiotic and a known / -Maclamase inhibitor. Products comprising amoxicillin and potassium clavulanate are marketed by SmithKline Beecham under the trademark "Augmentin". These products are particularly effective for treating community-acquired infections, particularly upper respiratory infections in adults and otitis media in children.

Various formulations in the form of tablets of amoxicillin and potassium clavulanate, approved for commercialization, comprise different weights and ratios of amoxicillin and potassium clavulanate, such as, for example, tablets for oral administration comprising 250/125, 500/125, 500 / 62.5 and 875/125 mg amoxicillin / clavulanate acid (as potassium clavulanate). Said tablets comprise amoxicillin and clavulanate acid in the ratio 2: 1, 4: 1, 8: 1 and 7: 1, respectively. The 875/125 mg tablet was developed to provide a tablet formulation that can be administered in a bid (twice daily) dosing schedule. Likewise, in Italy and Spain it is marketed in tid dose regimens (three times a day). The 500 / 62.5 mg tablet was also developed to provide a formulation that can be administered in a twice daily dose regimen, two tablets taken every 12 hours, preferably in a single 1000/125 mg tablet. . A single dose of 1000/250 mg is also available in France, but in the form of a single-dose sachet, rather than a tablet. Typically, approved guidelines provide a single 125 mg dose of potassium clavulanate.

Likewise, WO 97/09042 (SmithKline Beecham) describes a tablet formulation comprising amoxicillin and clavulanate acid in a ratio ranging from 12: 1 to 20: 1, preferably 14: 1. Furthermore, it has been suggested that the preferred 1750/125 mg dose may be administered in the form of two tablets, of which the first comprises 875/125 mg of amoxicillin and clavulanate acid and the second 875 mg of amoxicillin. This relationship was found to be useful for the empirical treatment of bacterial infection potentially caused by drug-resistant Streptococcus pneumoniae (DRSP). This patent application also describes pediatric formulations comprising amoxicillin and clavulanate in a ratio of 14: 1, thus administering a dose of 90 mg / kg / day of amoxicillin. Data suggest that this dose can provide sufficient antibiotic concentrations to eradicate DRSP with MIC of amoxicillin + / clavulanate acid <4μg / ml (Bottenfield et al., Pediatr Infect Dis J, 1998, 17, 963-8).

WO 94/16696 (SmithKline Beecham) generally discloses that clavulanate acid can surprisingly enhance the efficacy of amoxicillin against microorganisms that have a resistance mechanism not mediated by - -lactamase.

The marketed tablet formulations of amoxicillin and potassium clavulanate are conventional in that they provide immediate release of the active ingredients once the tablet reaches the stomach. Likewise, it is interesting to develop formulations in which the release profile is modified to allow intervals between higher doses, for example, every 12 hours (twice a day, every 12 hours) instead of every 8 hours (three times a day, every 8h).

Thus, for example, WO 95/20946 (SmithKline Beccham) describes layered tablets comprising amoxicillin and optionally potassium clavulanate, formed by a first layer which is an immediate release layer and a second layer which is a layer of slow release. The broader ratio of amoxicillin to clavulanate acid is 30: 1 to 1: 1, with a preferred range of 8: 1 to 1: 1. Amoxicillin is suitable in the form of amoxicillin trihydrate. The provided examples of the bilayer tablets contain amoxicillin trihydrate in the immediate release layer and amoxicillin plus clavulanate in the slow release layer. Layered tablets are described more generically in WO 94/06416 (Jagotec AG). Also, bilayer tablets comprising clavulanate acid and amoxicillin are described in WO 98/05305 (Quadrant Holdings Ltd). Said tablets consist of a small layer comprising amoxicillin and a second layer comprising clavulanate and the excipient trehalose, to stabilize the clavulanate.

Furthermore, WO 95/28148 (SmithKline Beecham) describes tablet preparations of amoxicillin / clavulanate potassium consisting of a core containing amoxicillin and potassium clavulanate coated with a release retarding agent and surrounded by an outer coating layer of amoxicillin. and potassium clavulanate. The release retarding agent is an enteric coating, so there is an immediate release of the contents of the outer core, followed by a second phase of the core that is delayed until the core reaches the intestine. Furthermore, WO 96/04908 (SmithKline Beecham) describes amoxicillin / potassium clavulanate tablet formulations comprising amoxicillin and potassium clavulanate in a matrix, for immediate release, and granules in a delayed release form comprising amoxicillin and potassium clavulanate. .

ES 2 202 004 T3

These granules are covered by an enteric coating, so that the release is delayed until the granules reach the intestine. WO 96/04908 (SmithKline Beecham) describes sustained or delayed release formulations of amoxicillin / clavulanate potassium formed from granules consisting of a core comprising amoxicillin and clavulanate potassium, surrounded by a layer comprising amoxicillin. WO 94/27557 (SmithKline Beecham) describes controlled release formulations of amoxicillin and clavulanate acid prepared using a hydrophobic waxy material which is subsequently thermally infused.

Controlled release formulations, comprising amoxicillin, have been described by several groups of authors. Thus, Arancibia et al. ((Int J of Cli Pharm, Ther and Tox, 1987, 25, 97-100) describe the pharmacokinetic properties and bioavailability of a controlled release formulation comprising 500 mg amoxicillin. No further details of the formulation are provided. However, the formulation was designed to release 21% to 35% during the first 60 minutes, from 51% to 66% at 4 hours, from 70% to 80% at 6 hours, from 81% to 90% at 8 hours and more than 94% at 12 hours. However, they found little correlation, if any, between dissolution rate in vitro and pharmacokinetic behavior in the body. Hilton et al. (International Journal of Pharmaceutics, 1992, 86, 79-88) described an alternative controlled release tablet that has a hydrophilic polymeric matrix and a gas delivery system, to provide intragastric buoyancy, and thus enhance gastric retention time. This fact does not offer any advantage over a conventional formulation in capsule form with reduced bioavailability. In contrast, Hilton et al. (Journal of Pharmaceutical Sciences, 1993, 82, 737-743) described a 750 mg controlled release tablet incorporating the enteric polymer hydroxypropyl methylcellulose acetate succinate. However, this fact did not present any advantage over a conventional capsule. In particular, the bioavailability was reduced to 64.6% compared to a capsule of the same dose. More recently, Hoffman et al. (Journal of Controlled Release, 1998, 54, 29-37 and WO 98/22091) have described a tablet comprising 500 mg of amoxicillin in a matrix comprising hydroxypropylmethylcellulose, designed to release 50% of its constituents during the first three hours and complete the drug release process over eight hours. The time above MIC was found to be significantly long compared to the capsule formulation, although insufficient for a 12 hour interval between doses. In this context, the discussion focuses on a theoretical MIC of 0.2 μg / ml.

Part of the challenge in providing amoxicillin preparations in which drug release is effectively modified (and a compelling explanation for the lack of success of previous studies) lies in the relatively narrow window of drug absorption in the small intestine and the relatively short half-life of the drug. Also, the rapid elimination of amoxicillin (excretion half-life is 1.3 hours) makes it difficult to maintain serum levels since clearance from the body is very rapid.

In currently existing tablet formulations comprising amoxicillin and potassium clavulanate, amoxicillin is presented in the form of amoxicillin trihydrate, since use in this form provides tablets with greater storage stability than those in which amoxicillin is presented in amoxicillin sodium form (see GB 2,005,538, Beecham Group Ltd). However, amoxicillin sodium is used as the amoxicillin constituent in existing formulations of amoxicillin and clavulanate potassium adapted for intravenous administration. The form of amoxicillin sodium used is a dry spray form. Furthermore, EP0131147-A1 (Beecham Group plc) also describes a form of amoxicillin sodium called "crystalline amoxicillin sodium". Another process for preparing salts of amoxicillin, including amoxicillin sodium, is described in WO 99/62910 (SmithKline Beecham). Amoxicillin sodium is relatively water soluble compared to amoxicillin trihydrate.

Formulations comprising clavulanate acid and a pharmaceutically acceptable organic acid or a type of salt derived therefrom such as, for example, calcium citrate, have been described in WO 96/07408 (SmithKline Beecham). It has been postulated that the presence of calcium citrate in such formulations may contribute to the suppression of gastrointestinal intolerance associated with the oral administration of clavulanate-containing products.

Likewise, US Patent No. 5,051,262 (Elan Corp) describes the addition of an organic acid in a modified release formulation to provide a microenvironment in which the locally modified pH helps prevent degradation of the active ingredient. .

Increasing resistance to the pathogenic organism, such as those found in respiratory tract infections, to anti-infective agents, such as amoxicillin / clavulanate potassium, in particular drug-resistant S. pneumoniae, are of concern. Increased resistance to penicillin in S. pneumoniae (due to modification of penicillin-binding proteins) has developed around the world and is affecting clinical outcomes (see, for example, Applebaum PC, Ped Inf Dis J, 1996, 15 (10), 932 -9). These S. Penicillin-resistant pneumoniae (PRSP) have also been called “DRSP”, since they frequently show decreased sensitivity, not only to penicillin but also to a wide spectrum of antimicrobial classes, including macrolides, azalides, beta-lactamase , sulfonamides and tetracyclines. Amoxicillin (with or without clavulanate), along with some of the newer quinolones, has remained among the most active oral agents against growing resistant S. pneumoniae isolates, based on both MIC levels and the pharmacokinetic properties of these compounds. However, resistance rates (and MICs) have continued to rise. The resistance of S. pneumoniae to penicillin can be evaluated, according to the criteria developed by the National Committee for Clinical Laboratory Standard (NCCLS), such as the following: susceptible strains have a MIC of <0.06 μg / ml,

ES 2 202 004 T3 intermediate resistance is defined as a MIC within the range 0.12 to 1.0 µg / ml, while penicillin resistance is defined as a MIC of> 2 µg / ml. Furthermore, it has been found that 10% of pneumococci currently have an amoxicillin MIC of 2 μg / ml.

Consequently, it is necessary to provide new amoxicillin / clavulanate formulations that combine the known safety profile and a broad spectrum of potentiated activity against DRSPs, including PRSPs, with higher MICs in the empirical treatment of respiratory infections in which S. pneumoniae , H. influenzae and M. catorrhalis are probable pathogens.

With respect to beta-lactams, including amoxicillin, it has been recognized that time above minimum inhibitory concentration (T> MIC) is the pharmacodynamic parameter most closely related to efficacy. For a series of beta-lactams, a bacteriological cure rate of 85% to 100% is achieved when serum concentrations exceed the MIC by approximately 40% of the interval between doses (Craig and Andes, PedInf Dis J, 1996, 15, 255 -259). For a 12 hour interval between doses, it is approximately 4.8 hours.

Another parameter that can be of considerable importance is the ratio of the maximum plasma concentration (Cmax) to the MIC value, as it may be related to the potential to select for resistance. A very low ratio can favor the development of resistant strains. Preferably, a plasma Cmax value higher than the MIC value is appropriate, for example at least two times, more preferably at least three times, especially preferably at least four times the MIC value.

In a clinical study using currently available Augmentin 875/125 mg tablets, it was found that, when the dose was administered at 12 hour intervals, the time above MIC was approximately 40% for a MIC. 2 μg / ml and only about 30% for a MIC of 4 μg / ml. The currently available Augmentin 875/125 mg tablet has a C value_max 11.6 ± 2.8 μg / ml (Reference Physicians Desk, Medical Economics Co, 52nd Edition, 1998, 2802)

Based on the subsequent considerations, there is a continuing need to provide new dosage guidelines for amoxicillin / clavulanate that provide optimal pharmacokinetic profiles for amoxicillin, without compromising the bioavailability of clavulanate, in order to maximize therapy, particularly against the most resistant bacteria and also minimize the development of resistance. It has now been discovered that this fact can be achieved using a higher dose of amoxicillin than previously contemplated.

Accordingly, the present invention provides a modified release pharmaceutical formulation comprising amoxicillin and potassium clavulanate in the ratio of 14: 1 to 20: 1, more preferably 14: 1 to 16: 1, in which all of the potassium clavulanate and a first part of the amoxicillin is formulated with pharmaceutically acceptable excipients that allow the immediate release of potassium clavulanate and the first part of amoxicillin, to form an immediate release phase and also comprising a second part of amoxicillin formulated with pharmaceutically acceptable excipients that allow the slow release of the second part of amoxicillin, to form a slow release phase and in which the amoxicillin ratio in the slow and immediate release phases it is 3: 1 to 1: 3.

In another aspect, the present invention provides a method for the use of amoxicillin and potassium clavulanate in the manufacture of a medicament, as described below in Claim 1 of the present invention, for the treatment of bacterial infections in humans at intervals between doses about 12 hours.

Preferably, the dose regimen provides a mean plasma amoxicillin concentration of 4 µg / ml for at least 4.4 hours, more preferably for at least 4.6 hours, more preferably for at least 4 hours. 8 hours, especially preferred about 6 hours minimum.

More preferably, the dose regimen provides a mean plasma amoxicillin concentration of 8 μg / ml for at least 4.4 hours, more preferably for at least 4.6 hours, especially preferred for at least 4 hours. ,8 hours.

Preferably, the dosage regimen provides a mean maximum plasma concentration (Cmax) of amoxicillin of at least 8 µg / ml, preferably at least 12 µg / ml, even more preferably at least 14 µg. / ml, especially preferably at least 16 µg / ml.

Preferably, the mean plasma concentration of amoxicillin and the mean maximum plasma concentration of amoxicillin are measured after oral administration, at the start of a light meal, of the formulation comprising amoxicillin.

Bacterial infections tailored to the present invention include infections caused by the microorganisms S. pneumoniae (including drug resistant S. pneumoniae (PRSP)) and / or the e-lactamase producing respiratory pathogens, most notably H. influenzae and M. . catarrhalis, such as respiratory tract infections, including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), and acute bacterial sinusitis (ABS), in which the highest cutoff points achievable at across the per4

EN 2 202 004 T3 enhanced pharmacokinetic properties may be especially advantageous compared to existing antibacterial agents. Most outpatient respiratory infections caused by S. peneumoniae and / or ^ -lactamase producing bacteria are empirically treated, so there is a continuing need to develop treatment methods, such as that of the present invention, that provide a spectrum of activity that covers all these pathogens. The duration of therapy will generally be 7 to 14 days, typically 7 days for indications such as acute exacerbations of chronic bronchitis and 10 days for acute bacterial sinusitis. Typically, the dosage guidelines are intended for use in adult patients rather than pediatric patients.

The term "amoxicillin" is generally used to refer to amoxicillin or an alkaline salt thereof, in particular amoxicillin trihydrate and amoxicillin sodium (crystallized), without distinction and unless otherwise indicated.

Amoxicillin and clavulanate (potassium) weights refer to equivalent weights to the corresponding free acids, unless otherwise indicated. Furthermore, it will be appreciated that in practice, the weights of amoxicillin and clavulanate incorporated into a formulation will further be adjusted in accordance with conventional practice to estimate the potency of amoxicillin and clavulanate.

In the context of the present invention, the term "immediate release" refers to the release of most of the active ingredients contained in a relatively short time, such as, for example, within 1 hour, preferably within 30 minutes, after ingestion. . Examples of such immediate release formulations include tablets for oral administration, dispersible tablets, chewable tablets, single-dose sachets, and capsules.

The term "modified release", as used in the present invention, refers to the release of a substance with pharmacological activity from a pharmaceutical formulation, such as a tablet for conventional oral administration or a capsule, which may include an immediate release phase. and a slow release phase. Modified release formulations are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 19^to edition, 1995, Mack Publishing Co, Pennsylvania, USA).

Preferably, the modified release formulations of the present invention are formulated in such a way that the release of amoxicillin occurs predominantly throughout the stomach and small intestine, thereby maximizing absorption through the absorption zone. of specific amoxicillin. Preferably, the release profile of amoxicillin is constituted by the participation of an immediate release component that is complemented and subsequently extended by the continued contribution of a slow release constituent. Preferably, the potassium clavulanate is released substantially immediately from the formulation when said formulation reaches the stomach and is absorbed there, thus minimizing the risk of disintegration from prolonged exposure to the stomach. Said formulations are preferably prepared in such a way that the release of amoxicillin and potassium clavulanate is carried out, preferably, within 3 hours after ingestion of the formulation.

Typically, one dose can provide 125 mg of potassium clavulanate, the amount approved in currently existing guidelines where a lesser amount of amoxicillin is administered.

Representative modified release doses include 1500/125, 1750/125, and 2000/125 mg of amoxicillin and potassium clavulanate, respectively. A preferred dosage is that containing 2000/125 mg of amoxicillin and potassium clavulanate.

The dosage in a modified release formulation may conveniently be provided in the form of several orally administered tablets or capsules, for example two, three or four, which may be the same or comprise only amoxicillin without potassium clavulanate. Thus, for example, a dose of 2000 mg of amoxicillin and 125 mg of clavulanate potassium can be provided in two tablets, each comprising 1000 / 62.5 mg of amoxicillin / clavulanate potassium, one tablet comprising 1000 mg of amoxicillin and a tablet containing 1000/125 mg amoxicillin / clavulanate potassium, two tablets each comprising 500 mg amoxicillin and one tablet comprising 1000/125 mg amoxicillin / potassium clavulanate or four tablets each comprising 500 / 32.25 mg amoxicillin / potassium clavulanate. Likewise, a dose of 1750 mg of amoxicillin and 125 mg of clavulanate potassium can be provided in two tablets, each comprising 875 / 62.5 mg of amoxicillin / clavulanate potassium or in a tablet comprising 875 mg of amoxicillin and one tablet containing comprises 875/125 mg amoxicillin / potassium clavulanate. A preferred tablet comprises 1000 / 62.5 mg amoxicillin / potassium clavulanate.

The dose in a modified release formulation can also be administered as a single tablet. Due to the amounts of the drug substance used, other dosage forms than the tablet for oral administration are preferred, such as, for example, a dispersible tablet or a chewable tablet which may also be an effervescent and / or dispersible or dispersible tablet. Also, a single dose may conveniently be administered in the form of a single dose sachet. It can be appreciated that the doses can also be administered in the form of tablets or small sachets such as, for example, 2x1000 / 62.5 mg or 4x500 / 32.25 mg amoxicillin / potassium clavulanate.

ES 2 202 004 T3

The term "slow release", as used in the present invention, refers to the gradual but continuous or sustained release of the active ingredient (in this case amoxicillin) over a relatively long period after oral ingestion, which is carried out when the formulation reaches the stomach and begins to disintegrate / dissolve. The release will continue for a period of time and may continue until the formulation reaches the intestine and even afterwards. This concept is opposed to the term "delayed release", in which the release of the active material does not begin immediately once the formulation reaches the stomach but is delayed for a period of time, for example, until the formulation reaches the intestine. , when the increased pH is used to cause the release of the active material from the formulation.

Preferably, the modified release formulation has an in vitro dissolution profile in which 45% to 65%, preferably 45% to 55% of the amoxicillin content dissolves within 30 minutes; furthermore wherein 50% to 75%, preferably 55% to 65% of the amoxicillin content dissolves within 60 minutes; further, wherein 55% to 85%, preferably 60% to 70% of the amoxicillin content dissolves within 120 minutes; furthermore, in which 70% to 95%, preferably 75% to 85% of the amoxicillin content dissolves in 180 minutes and furthermore, in which 70% to 100%, preferably 75% to 100% of the Amoxicillin content dissolves in 240 minutes. In comparison, a conventional amoxicillin immediate release tablet dissolves essentially completely within 30 minutes. The dissolution profile can be evaluated by a standard dissolution test such as, for example, Dissolution Test <711>, Apparatus 2, described in USP 23.1995, at 37 ° C ± 0.5 ° C, using deionized water (9θ0 ml ) and a paddle rotation at a speed of 75 rpm

Preferably, the modified release formulation exhibits an in vivo biphasic profile relative to amoxicillin, that is, it exhibits an immediate release phase burst to provide an acceptable Cmax value, supplemented with a subsequent slow release phase involvement, whereby the parameter T> CIM is extended until an acceptable value is achieved.

Preferably, the modified formulation provides an "area under the curve" (AUC) value substantially similar to, for example, at least 80%, preferably at least 90%, more preferably about 100%, of the value of the corresponding dose of amoxicillin taken as a conventional (immediate release) formulation, during the same dosing period, thus it maximizes the absorption of the amoxicillin component from the slow release component.

The pharmacokinetic profile of a dosage of the present invention can be readily determined from a study of the bioavailability of a single dose in human volunteers. Amoxicillin plasma concentrations can subsequently be readily determined in blood samples taken from patients according to procedures known and documented in the art.

Representative modified release formulations include a tablet, including orally administered tablets, dispersible tablets, chewable tablets that may be effervescent and / or dispersible, and a capsule, granules or a sachet, typically one tablet to be administered orally.

Representative modified release formulations, having a slow release phase and an immediate release phase, provide a dose of amoxicillin per unit in the range of 700 to 1300 mg, preferably 950 to 1300 mg, for example, dose per unit of 1000 , 875 and 750 / 62.5 mg amoxicillin / clavulanate. Alternatively and provided that the physical dimensions of the dosage form are not problematic, the unit dose can provide the total dose, for example a single dose sachet, a chewable tablet or a dispersible tablet can comprise 1400 to 2600 mg of amoxicillin , preferably 1900 to 2600 mg, for example 2000, 1750 and 1500/125 mg unit doses amoxicillin / clavulanate. It can be appreciated that these 1000, 875 and 750 / 62.5 mg formulations are novel.

Accordingly, in another aspect, the present invention provides a pharmaceutical formulation having an immediate release phase and a slow release phase and comprises:

(a) a unit dose in the range 700 to 1300 mg, preferably 950 to 1300 mg, of amoxicillin and a corresponding amount of potassium clavulanate, in a nominal ratio of about 16: 1, 14: 1, or 12: 1 , for example, unit doses of 1000, 875 and 750 mg ± 5% amoxicillin and 62.5 mg ± 5% potassium clavulanate, respectively, or (b) a unit dose in the range of 1400 to 2600 mg, preferably of 1900 to 2600 mg, amoxicillin and a corresponding amount of potassium clavulanate, in a nominal ratio of approximately 16: 1, 14: 1 or 12: 1, for example, unit doses of 2000, 1750 or 1500 mg ± 5% amoxicillin and 62.5 mg ± 5% potassium clavulanate, respectively, in combination with pharmaceutically acceptable excipients or carriers.

Preferably, the ratio of amoxicillin in the immediate or slow release phases is 2: 1 to 2: 3, more preferably 3: 2 to 1: 1. Representative ratios include about 2: 1, 9: 7, or 1: 1. It has been found

ES 2 202 004 T3 that it is useful to use an excess of amoxicillin in the immediate release phase to ensure an adequate Cmax value.

In the modified release formulations of the present invention, the immediately released portion of amoxicillin can be provided in the form of amoxicillin trihydrate or an alkaline salt thereof such as, for example, sodium or potassium amoxicillin, preferably sodium amoxicillin (crystallized ) or a mixture thereof, preferably amoxicillin trihydrate; while the slowly released portion of amoxicillin is provided in the form of amoxicillin trihydrate or an alkaline salt thereof such as, for example, potassium or sodium amoxicillin (crystallized) or a mixture thereof, preferably sodium amoxicillin (crystallized ).

Preferably, the modified release formulation is a tablet. In a preferred modified release tablet, comprising 1000 mg of amoxicillin and 62.5 mg of clavulanate potassium, the immediate release phase comprises approximately 563 mg ± 5% amoxicillin trihydrate and approximately 62.5 mg ± 5% potassium clavulanate, while the slow release phase comprises approximately 438 mg ± 5% amoxicillin, preferably in the form of sodium amoxicillin (crystallized).

In a representative modified release tablet of the present invention, the immediate release phase comprises approximately 438 mg of amoxicillin, preferably amoxicillin trihydrate, and approximately 62.5 mg of potassium clavulanate, while the slow release phase comprises approximately 438 mg amoxicillin, preferably amoxicillin sodium (crystallized) providing a tablet of 875 / 62.5 mg (14: 1) in total.

In another representative tablet of the present invention, the immediate release phase comprises approximately 500 mg of amoxicillin and approximately 62.5 mg of potassium clavulanate, while the slow release phase comprises approximately 250 mg of amoxicillin, preferably amoxicillin. sodium (crystallized), providing a 750 / 62.5 mg (12: 1) tablet in total.

In a tablet formulation, the slow and immediate release phases can be administered in several different formats.

In a preferred aspect, the slow and immediate release phases are provided as separate layers of a layered tablet.

Accordingly, in another aspect, the present invention provides a layered tablet formulation comprising potassium clavulanate and amoxicillin in an immediate release layer and amoxicillin in a slow release layer. The layered tablet may have two layers or two layers plus one or more barrier layers, as well as a coating layer. As used in the present invention, the term "bilayer" tablet refers to a tablet consisting of an immediate release layer and a slow release layer, and optionally a coating layer.

An immediate release layer can be, for example, a layer that disintegrates immediately or rapidly and has a composition similar to that of known tablets that disintegrate immediately or rapidly. For example, the layer may comprise, in addition to the active ingredient, excipients including diluents, such as microcrystalline cellulose, disintegrants, such as cross-linked polyvinylpyrrolidone (CLPVP) and sodium starch glycolate, compression media, such as silicon dioxide. colloidal and microcrystalline cellulose, and lubricants such as magnesium stearate. This immediate release layer can comprise approximately 60% to 85% (all the percentages of the present invention expressed in percentage by weight, unless otherwise indicated), preferably 70% to 85% of the active principle, approximately 10 30% to 30%, preferably 10% to 20% packing / filling aids, and conventional amounts of disintegrants and lubricants, typically about 0.5% to 3%, etc.

An alternative type of immediate release layer may be a swell layer containing a composition incorporating polymeric materials that swell immediately and widely on contact with water or an aqueous medium, to form a water-permeable, yet relatively large swollen mass. . The active material content can be leached from this mass.

The slow release layers contain a composition comprising amoxicillin in combination with a release retarding excipient that allows a slow release of amoxicillin. Suitable release retarding excipients include pH sensitive polymers such as polymers based on methacrylate acid copolymers, such as Eudragit (trade mark) polymers such as Eudragit L (trade mark) which can be used alone. or combined with a plasticizer; release-retarding polymers having a high swelling capacity in contact with water or aqueous medium, such as the contents of the stomach; polymeric materials that form a gel in contact with water or an aqueous medium; and polymeric materials that have both swelling and gelling properties in contact with water or any aqueous medium.

Release-retarding polymers having a high degree of swelling include, but are not limited to, cross-linked sodium carboxymethyl cellulose, cross-linked hydroxypropyl cellulose, high molecular weight hydroxypropyl methyl cellulose7

ES 2 202 004 T3 lar, carboxymethylamide, potassium methacrylate vinylbenzene copolymer, polymethylmethacrylate, cross-linked polyvinylpyrrolidone, high molecular weight polyvinyl alcohols, etc.

Release-retarding gelling polymers include methylcellulose, carboxymethylcellulose, low molecular weight hydroxypropylmethylcellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols, non-cross-linked polyvinylpyrrolidone, xanthan gum, etc.

Release-retarding polymers, which simultaneously possess swelling and gelling properties, include medium viscosity hydroxypropylmethylcellulose and medium viscosity polyvinyl alcohols.

A preferred release retarding polymer is xanthan gum, in particular a fine mesh class of dexanthan gum, preferably a 200 mesh of pharmaceutical grade xanthan gum, such as, for example, the product Xantural 75 (also known as Keltrol CR, Registered Trademark, Monsanto, 800 N Lindbergh Blvd., St Louis, MO 63167, USA). Xanthan gum is a polysaccharide that, when hydrated, forms a viscous gel layer around the tablet through which the active principle diffuses. It has been shown that the smaller the size, the slower the release rate. Furthermore, the release rate of the drug depends on the amount of xanthan gum used, which can be adjusted to provide the desired profile. Controlled release formulations comprising 7.5% to 25% xanthan gum are described in EP 0234670-A (Boots Co plc). The preferred embodiment is a single dose tablet comprising ibuprofen as a drug substance and between 15% and 20% xanthan gum.

Other polymers that can be used include, for example, Methocel K4M (Trademark), Methocel E5 (Trademark), Methocel E4M (Trademark), Methocel K15 (Trademark), and Methocel K100M (Trademark). An example of a suitable polymer blend is a blend of Methocel E5 and K4M in a weight ratio of, for example, 1: 1.

Other known release-retarding polymers that can be incorporated include hydrocolloids, such as natural or synthetic gums, cellulose derivatives other than those mentioned above, carbohydrate-based substances, such as acacia, gum tragacanth, gum seed carob, guar gum, agar, pectin, carrageenan, soluble and insoluble alginates, carboxypolymethylene, casein, zein and the like, and protein substances such as gelatin.

Such a slow release layer can contain polymers that swell rapidly on contact with water or an aqueous medium, such that they form a relatively large swollen mass that is not immediately released from the stomach into the intestine.

The slow release layer can also include diluents such as lactose, compaction aids, such as microcrystalline cellulose, and lubricants such as magnesium stearate. The slow release layer may further comprise disintegrants, such as cross-linked polyvinylpyrrilodone (CLPVP) and sodium starch glycolate, binders such as povidone (polyvinylpyrrolidone), desiccants, such as silicon dioxide; and soluble excipients such as mannitol or other soluble sugars. Typically, the slow release layer comprises about 60% to 80% by weight of amoxicillin; 10% to 20% by weight of compaction aid / solvent and 1% to 2.5% by weight of lubricant.

When xanthan gum is used as a release retarding polymer, the layer contains 60% to 80% amoxicillin, 1% to 25%, preferably 2% to 15%, more preferably 4% to 15% of xanthan gum, 10% to 30%, preferably 10% to 20% compaction / filling aid, and conventional amounts of lubricants, all percentages expressed by weight of the layer. In a preferred embodiment, the slow release layer comprises 70% to 80% amoxicillin, 4% to 10% xanthan gum, 10% to 20% microcrystalline cellulose, and 1% to 2%. 5% magnesium stearate, all percentages (%) expressed by weight of the layer.

When using other release retarding polymers than xanthan gum, the slow release layer may contain about 30% to 70%, preferably 40% to 60% amoxicillin, 15% to 45% amoxicillin. release retardant polymer, 0% to 30% compaction / filling aid, conventional amounts of lubricants and 5% to 20% of soluble excipients, all percentages (%) expressed by weight of the layer.

Also, it has been surprisingly discovered that when amoxicillin appears in the form of a soluble salt thereof, such as amoxicillin sodium, in the slow release layer, the release thereof may subsequently be delayed by the introduction of a organic acid.

Accordingly, the present invention further provides a pharmaceutical formulation, as described in the present invention, comprising a soluble pharmaceutically acceptable salt of amoxicillin, such as amoxicillin sodium, in a slow release phase comprising , in addition, a release-retarding excipient, which is a pharmaceutically acceptable organic acid, present in a molar ratio of 100: 1 to 1:10, preferably 50: 1 to 1:50, more preferably 20: 1 to 1: 2 (amoxicillin / organic acid).

ES 2 202 004 T3

It is considered that the close contact between the organic acid and the amoxicillin salt in the pharmaceutical formulation, for example, as a consequence of the formation of compacted granules or direct compression into a tablet, causes some form of interaction that modifies the release of the component. in amoxicillin from the formulation.

Soluble pharmaceutically acceptable salts of amoxicillin include alkali metal salts, such as sodium and potassium, alkaline earth metal salts, such as magnesium and calcium, and acid salts, such as amoxicillin hydrochloride. Preferably the salt is amoxicillin sodium, more preferably crystalline amoxicillin sodium.

As used in the present invention, the term "pharmaceutically acceptable organic acid" refers to organic acids that have no pharmacological effect per se, that have acceptable organoleptic properties, that have an acceptable density, do not have extreme pH, and are preferably solid. Examples of these include monocarboxylic acids and polycarboxylic acids having 2 to 25, preferably 2 to 10, carbon atoms, monocyclic and polycyclic aryl acids such as benzoic acid, as well as salts of metals monohydrogen, dihydrogen, etc. of plurivalent acids. A single pharmaceutically acceptable organic acid can be used, or two or more of these can be used in combination. Preferably, the organic acid is a C (2-10) alkyl or alkenyl carboxylic acid having one, two or three carboxylic acid groups and optionally one or more hydroxy substituents or an additional CO group in the carbon chain as for example malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid or fruit acid such as tartaric acid, malic acid, ascorbic acid or citric acid, or an acidic salt thereof, more preferably citric acid, in particular anhydrous citric acid.

The organic acid can be used alone or in combination with a release retarding polymer, as previously described in the present invention. A preferred combination comprises citric acid and a release retarding gelling polymer, in particular xanthan gum. In the presence of an organic acid such as citric acid, xanthan gum can be used at a lower level than when it is included by itself, such as 0.5% to 8%, preferably 1%. % to 5%, typically about 2%, by weight of the slow release layer.

When an organic acid is used as a release retarding excipient, the slow release layer contains 60% to 80% of a soluble salt of amoxicillin, 10% to 30%, preferably 10% to 20% of compaction / fillings, and conventional amounts of lubricants, all percentages (%) expressed by weight of the layer. In a preferred embodiment, the slow release layer comprises 60% to 70% soluble salt of amoxicillin, 10% to 20% microcrystalline cellulose and 1% to 2.5% magnesium stearate, all the percentages (%) expressed by weight of the layer.

In a representative example, a layered tablet comprises in the slow release layer crystallized amoxicillin sodium and citric acid, in a molar ratio of from about 50: 1 to 1: 2, preferably from 20: 1 to 1: 2, more preferably from 2: 1 to 1: 1.2, and even more preferably 1: 1. In a preferred embodiment, the slow release layer comprises about 438 mg ± 5% of crystallized amoxicillin sodium, about 78 mg ± 10% of citric acid and about 2% by weight of xanthan gum.

In a preferred layered tablet comprising 1000 mg of amoxicillin and 62.5 mg of potassium clavulanate, the immediate release layer comprises about 563 mg ± 5% amoxicillin, preferably amoxicillin trihydrate, and about 62.5 mg ± 5% potassium clavulanate and the slow release layer approximately 438 mg ± 5% amoxicillin, preferably crystallized sodium amoxicillin, about 78 mg ± 10% citric acid and about 2% xanthan gum by weight.

The tablet formulations of the invention may further include one or more barrier layers, which may be located between the corresponding first and second layers, and / or on one or more of the outer surfaces of the first and second layers. , for example, the end faces of the layers of a substantially cylindrical tablet. Said barrier layers can, for example, be composed of polymers that are substantially or completely impervious to water or aqueous media or that slowly erode in water, in aqueous media or in biological liquids and / or that swell on contact with water or aqueous media. The barrier layer must be adequately capable of preserving these properties until, at least, completely, substantially or totally, the transfer of the active principle to the medium.

Suitable polymers for the barrier layer include acrylates, methacrylates, acrylic acid copolymers, celluloses, and derivatives thereof, such as ethyl celluloses, cellulose acetate propionate, polyethylenes, and polyvinyl alcohols, etc. Barrier layers comprising polymers that swell on contact with water or aqueous media can swell to such a degree that the swollen layer forms a relatively large swollen mass, the size of which delays its immediate release from the stomach to the intestine. The barrier layer can contain an active ingredient, for example, the barrier layer can be a slow or delayed release layer. Barrier layers can typically have a single thickness of 2mm to 10 microns.

Suitable polymers for barrier layers that are relatively impermeable to water include the Methocel (trademark) series of polymers, mentioned above as, for example, Methocel K100M, Methocel K15M, Methocel E5 and Methocel E50, used alone or in combination or optionally , combined with a polymer

ES 2 202 004 T3

Ethocel (registered trademark). These polymers can suitably be used in combination with a plasticizer such as hydrogenated castor oil. The barrier layer may also include conventional binders, fillers, lubricants, compression acids, etc., such as Polyvidon K30 (trade mark), magnesium stearate, and silicon dioxide, such as Syloid 244 (trade mark). .

The tablet formulation of the invention may be completely or partially covered by a coating layer, which may be a protective layer that prevents moisture and injury to the tablet. The coating layer can contain an active ingredient and can, for example, be an immediate release layer, which immediately disintegrates on contact with water or an aqueous medium to release the active ingredient, for example amoxicillin or potassium clavulanate . Preferred coating materials comprise hydroxypropylmethylcellulose and polyethylene glycol, with titanium dioxide as an opacifying agent, for example, as described in WO 95/28927 (SmithKline Beecham).

Likewise, the tablet of the invention can include, in addition to the active principle, etc., a pH modifying agent, such as a pH buffer, which can form part of both the immediate and intermediate release layers, or in a coating around the whole. or a part of the tablet. A suitable buffer is calcium hydrogen phosphate.

In a tablet without a barrier layer, the immediate release layer comprises 50% to 60% and the slow release layer comprises 40% to 50% of the total weight of the tablet. When a barrier layer is present, the immediate release layer typically comprises 40% to 50%, the slow release layer comprises 35% to 45%, and the barrier layer comprises 5% to 20% of the total weight of the tablet.

It has been discovered that a satisfactory pharmacokinetic profile can be obtained from a bilayer tablet of the present invention, without the need to include a barrier layer. Accordingly, a two-layer tablet is preferred. Also, this fact reduces the complexity of the manufacturing process.

It will be appreciated that 1000,875 / 62.5 mg layered tablets containing an immediate release layer and a slow release layer are novel. Accordingly, in another aspect, the present invention provides a layered pharmaceutical tablet formulation, consisting of an immediate release layer and a slow release layer, comprising 700 to 1250 mg of amoxicilia and a proportional amount of potassium clavulanate preferably 1000 or 875 mg ± 5% of amoxicillin and 62.5 mg ± 5% of clavulanate potassium, in a normal ratio of approximately 16: 1 or 14: 1, respectively, in combination with pharmaceutically acceptable excipients or carriers. Preferably, the layered tablet is a bilayer tablet.

The tablet formulation of the invention can suitably be made by conventional tablet production techniques, such as using a press or layer compaction machine. Preferably, in a pre-manufacturing stage, granules are produced by pre-compression or roller compaction. Lubricants and compaction aids (if used) are then added to form a compression mixture for subsequent compaction.

The preferred two-layer tablets of the present invention can be made by a process that comprises, as a first phase, the formation of compacted slow-release granules, which in turn comprises the step of mixing amoxicillin sodium, a portion of the adjuvant compaction / solvent such as microcrystalline cellulose (typically about 30%), a portion of lubricant (typically, about 70%) and a pharmaceutically acceptable organic acid, such as a fruit acid such as citric acid; and subsequently mixing with a release-retarding polymer, such as xanthan gum, if present, and a compaction aid, such as colloidal silicon dioxide, compacting the mixture, for example, by means of a roller compactor or by means of pre-compression, then mixing to form slow release granules. Preferably, said granules have a size ranging from 100 to 1000 microns. Also, the incorporation of xanthan gum can be unexpectedly beneficial in the process.

Such slow release granules can subsequently be mixed with other excipients, such as the remaining magnesium stearate and microcrystalline cellulose, to form a slow release compression blend.

Likewise, amoxicillin trihydrate, potassium clavulanate (preferably in a 1: 1 mixture with microcrystalline cellulose), microcrystalline cellulose (a portion of the total used), is mixed and bound with a lubricant, such as magnesium stearate ( preferably about 50% of the total), and subsequently compacted, for example, by a roller compactor or by pre-compression to form the immediate release compacted granules. These immediate release compacted granules can then be bound with other excipients, such as the remaining magnesium stearate and crystalline cellulose (approximately 13%), a compaction aid, such as colloidal silicon, and a disintegrant, such as such as sodium starch glycolate, to form an immediate release compression mix.

Immediate or slow release compression blends can then be compressed as separate layers in a double layer compaction press to form two layer tablets.

ES 2 202 004 T3

Alternatively, a dry densification process can be used, for example briquetting. Typically, the active ingredient is mixed together with the pH modifiers, buffers, fillers and / or solvents, release retarding agents, disintegrants and binders, when used, and subsequently lubricants and compaction aids are added. . The entire mix can subsequently be compressed under high pressure in the press or compaction machine. A dry granulation process can also be used with, for example, isopropanol as a solvent and Polyvidon K-30 (trade mark) as a wet granulation aid.

A barrier layer, if one exists, can typically be made by a wet granulation technique or by dry granulation techniques, such as roller compaction. Typically, barrier materials, for example Methocel (trade mark) are suspended in a solvent such as ethanol containing a granulating acid such as Ethocel or Polyvidon K-30 (trade mark), followed by mixing , sieving and granulation. Typically, a first layer can be formed, then a barrier layer is deposited thereon, for example by compression, spraying or dipping techniques, then the second layer can be formed, so that the barrier layer is between the first and the second layer. Also, or alternatively, the first and second layers can be formed and a barrier layer can subsequently be formed, for example, by compression, spraying or dipping, of one or more of the end faces of the tablet.

A process for the preparation of crystallized amoxicillin sodium is described in EP-A-0131147 (Beecham Group plc).

Potassium clavulanate is known to be extremely sensitive to water. Therefore, tablet formulations containing potassium clavulanate should be made under dry conditions, preferably at a relative humidity of 30% or less, and the components of the formulation should be pre-dried in appropriate places. The tablet formulations of the invention should be stored in packages isolated from atmospheric moisture.

The tablet cores can then be covered with a coating layer which can be applied in the form of an organic or aqueous solvent system, preferably an aqueous solvent system, to provide tablets with a coating film.

The invention also provides a process for the manufacture of a formulation in tablet form, as described above, comprising the steps of forming said first and second layers and any barrier layer and coating layer (s) that may be present.

In another variant, a monolithic modified release tablet can be prepared from compacted slow release granules comprising amoxicillin, a dilution / compression adjuvant such as microcrystalline cellulose, a pharmaceutically acceptable organic acid, such as a fruit acid, for example citric acid (if amoxicillin is present as a soluble salt thereof), or a release-retarding polymer, such as xanthan gum or a mixture thereof, preferably a release retarding polymer (as described in the present invention); and immediate release compacted granules, comprising amoxicillin and potassium clavulanate (as described in the present invention above) or immediate release compacted granules comprising amoxicillin and potassium clavulanate, for example, in a ratio of 2: 1, and others immediate release compacted granules comprising amoxicillin (as described in WO 98/35672, SmithKline Beecham Laboratoires Pharmaceutiques), combined with extra-granular excipients to form tablets. Said granules can also be processed into other pharmaceutical preparations such as, for example, single dose sachets, capsules or chewable tablets comprising a unit dose as described above in the present invention.

Chewable tablets according to the present invention typically comprise a chewable base formed from, for example, mannitol, sorbitol, dextrose, fructose or lactose alone or in combination. A chewable tablet may further comprise excipients such as disintegrants, lubricants, sweetening, coloring and flavoring agents. The set of these excipients will preferably comprise from 3% to 10%, more preferably from 4% to 8%, even more preferably from 4% to 7% by weight of the tablet. The disintegrants can represent 1% to 4%, preferably 1% to 3%, more preferably 1% to 2% by weight of the tablet. Representative disintegrators include crospovidone, sodium starch glycolate, starch such as cornstarch and rice starch, croscarmellose sodium, and cellulose products, such as microcrystalline cellulose, microfine cellulose, lower substituted hydroxypropyl cellulose, used alone or in combination. Preferably, the disintegrant is crospovidone. The lubricants can represent 0.25% to 2.0%, preferably 0.5% to 1.2% by weight of the tablet. Preferred lubricants include magnesium stearate. Preferably, the sweetening agent is an artificial sweetening agent, such as sodium saccharin or aspartame, preferably aspartame, which can represent 0.5% to 1.5% by weight of the tablet. Preferably, a tablet of the present invention is substantially free of sugar (sucrose). Preferably, the flavoring agents include fruit flavors that can be natural or synthetic, for example, peppermint, cherry and banana or a mixture thereof.

The single dose sachets, according to the present invention comprise, in addition to the substance of pharmacological activity, those excipients that are typically included in a formulation in the form of a sachet, such as

ES 2 202 004 T3 sweeteners, for example aspartame, flavorings, for example fruit flavorings, optionally a suspending agent, such as xanthan gum, as well as silicon gel, which acts as a desiccant.

The capsules, according to the present invention, comprise, in addition to the drug, those excipients that are typically included in a capsule, such as, for example, starch, lactose, microcrystalline cellulose, magnesium stearate. It will be appreciated that due to the hygroscopic nature of clavulanate, the use of components such as gelatin should be avoided in the manufacture of capsules. Preferably, the capsules are prepared from a component such as HPMC or a gelatin / PEG combination.

Preferably, the unit dosage forms of the present invention are packaged in containers that prevent atmospheric moisture, for example, in blisters, sealed bottles or dried bag packages, etc., which are conventional in the art. Preferably, the bottles also include a desiccant component to preserve the clavulanate. Preferred bottles include HDPE bottles. Preferred blisters include HDPE bottles. Preferred blisters include cold rolled blisters, where each blister may contain one or two tablets, where the unit dose is two tablets, for example 2 x 1000 / 62.5 mg tablets, to improve acceptability by part. of the patient.

The invention will now be described, by way of example, only with reference to the accompanying drawings, in which:

Fig. 1 shows the structure of various types of layered tablets of the present invention, in particular, the structure of substantially cylindrical tablets is shown in longitudinal section. In Fig 1, the tablet comprises a first layer (1) and a second layer (2), without any barrier layer or coating layer. In Fig. 1B, the tablet comprises a first layer (1), a second layer (2) and a barrier layer (3) located between the first and second layers, (1) and (2). In Fig. 1C, the tablet comprises a first layer (1), a second layer (2) and a barrier layer (3) located on the end face of the second layer (2). In Fig. 1D, the tablet comprises a first layer (1), a second layer (2), a barrier layer (3) located between the first and second layers (1) and (2), and a coating layer (4) that partially covers the tablet. In Fig. 1E, the tablet comprises a first layer (1), a second layer (2), and a third layer (3) intermediate between the first layer (1) and (2). These three layers (1), (2) and (3) contain the active principle.

(Table goes to next page)

ES 2 202 004 T3

Example 1

1000 / 62.5 mg modified release tablet

<td>Component</td><td>mg / tablet</td><td>% p / p</td>

<td>Immediate Release Layer</td><td></td><td></td>

<td>Amoxicillin Trihydrate</td><td> 654,1*</td><td> 40,88</td>

<td>Potassium clavulanate</td><td> 76,2#</td><td> 4,76</td>

<td>Microcrystalline cellulose</td><td> 136,4</td><td> 8,52</td>

<td>Sodium starch glycolate</td><td> 18,0</td><td> 1,12</td>

<td>Colloidal silicon dioxide</td><td> 6,3</td><td> 0,39</td>

<td>Magnesium stearate</td><td> 9,0</td><td> 0,56</td>

<td>Total (immediate release layer)</td><td> 900,0</td><td> 56,23</td>

<td>Slow release layer</td><td></td><td></td>

<td>Crystallized Amoxicillin Sodium</td><td> 480,8**</td><td> 30,05</td>

<td>Microcrystalline cellulose</td><td> 113,2</td><td> 7,08</td>

<td>Xanthan gum</td><td> 14,0</td><td> 0,87</td>

<td>Anhydrous citric acid</td><td> 78,0</td><td> 4,87</td>

<td>Colloidal silicon dioxide</td><td> 1,5</td><td> 0,08</td>

<td>Magnesium stearate</td><td> 14,0</td><td> 0,87</td>

<td>Total (slow release layer)</td><td> 700,0</td><td> 43,74</td>

<td>Film cover</td><td></td><td></td>

<td>Opadry YS-1-7700-Composition:</td><td></td><td></td>

<td>Hydroxypropylmethylcellulose 2910 6cp</td><td> 11,6</td><td></td>

<td>Hydroxypropylmethylcellulose 2910 15cp</td><td> 3,9</td><td></td>

<td>Titanium dioxide</td><td> 15,1</td><td></td>

<td>Polyethylene glycol 3355</td><td> 2,3</td><td></td>

<td>Polyethylene glycol 8000</td><td> 2,3</td><td></td>

<td>Total weight of the coated tablet</td><td> 1635,2</td><td></td>

* Equivalent to 562.5 mg amoxicillin based on 86.0% yield # Equivalent to 62.5 mg clavulanate acid based on 82.0% yield ** Equivalent to 437.5 mg amoxicillin based on 91.0% yield

ES 2 202 004 T3

Example 2

1000 / 62.5 mg modified release tablet

The immediate release layer and the film coat are the same as the tablet of Example 1.

<td>Compound</td><td>mg / tablet</td><td>% p / p</td>

<td>Slow release layer</td><td></td><td></td>

<td>Crystallized Amoxicillin Sodium</td><td> 480,8**</td><td> 30,05</td>

<td>Microcrystalline cellulose</td><td> 127,2</td><td> 7,95</td>

<td>Anhydrous citric acid</td><td> 78,0</td><td> 4,87</td>

<td>Colloidal silicon dioxide</td><td> 1,5</td><td> 0,09</td>

<td>Magnesium stearate</td><td> 14,0</td><td> 0,87</td>

<td>Total (Slow Release Layer)</td><td> 700,0</td><td> 43,74</td>

<td>Total weight of the coated tablet</td><td> 1635,2</td><td></td>

** Equivalent to 437.5 mg amoxicillin based on 91.0% yield

Preparation of modified-release tablets

The modified release tablets were prepared from mixtures of immediate and slow release, in a batch process on a scale of 900 and 700kg respectively. For the immediate release mixture, the containers were filled with dry microcrystalline cellulose (1), amoxicillin trihydrate (2) and (5) (in a 1: 1 ratio), a potassium clavulanate / dry microcrystalline cellulose mixture (1: 1) and magnesium stearate (approximately 50% of the total) (4). The contents of containers (1) and (2) were passed through a mesh or sieve, mixed in a "Fitzmill" operating at 1500 rpm and bound with the contents of container (3). The contents of the container (4) were subsequently screened, mixed and bound with the initial mix, and finally bound with the contents of the container (5) subjected to a preliminary sieving and mixing stage. This mix is ​​then subjected to roller compaction using a Chilsonator roller compactor operating at a pressure of 1000 psi ± 200 psi. The mixed and screened product passes through a 14 and 80 mesh vibrating screen to provide immediate release granules. The remaining excipients (colloidal silicon dioxide, magnesium stearate, dry microcrystalline cellulose and sodium starch glycolate) were subsequently screened, mixed and bound with a portion of immediate release granules in a mixing machine, mixed and subsequently combined with the granules. remnants, and mixed to form the immediate release mixture.

For the slow release mix, the containers were filled with dry microcrystalline cellulose (approximately 70%) and anhydrous citric acid (1), amoxicillin sodium (2) and (4) (in a ratio of 1: 1), and stearate magnesium (approximately 70%), colloidal silicon dioxide and xanthan gum (3). The contents of containers (1) and (2) were sieved and mixed in a Fitzmill, and subsequently bound with the contents of the bound container (3) and then with the contents of container (4), which had been mixed and sieved in the preliminary stage. This mixture is subjected to roller compaction in a Chilsonator, operating at a pressure of 600 psi ± 100 psi, mixed and sieved, to provide slow release granules. The remaining excipients (magnesium stearate, dry crystalline cellulose) were screened and combined with a portion of the slow release granules, ligated and subsequently the remaining slow release granules were added and ligated to provide a slow release mixture.

The slow and immediate release mixtures were then compressed as separate layers in a two layer compacting machine or press equipped with punches measuring 1.01 by 22.17 mm and having a modified capsule shape. For the first layer (immediate release), there is no pre-compression and the main compression was less than 10KN. For the second layer, there was a precompression less than 20KN, and a main compression less than 60KN. The subsequently produced tablets have a total weight of 1600 mg ± 48 mg, a hardness ranging from 8 to 18 SCU and a friability of less than 0.5%.

Finally, the core of the tablet was covered with an aqueous film coating in a 152.4 mm feed vat, operating on a 300 kg sublot. The tank was equipped with 4 spray guns rotating at a speed between 3 and 5 rpm. The inlet air was dehumidified at a temperature ranging from 56 ° C to 60 ° C, while the air humidity of output ranged from 4% to

ES 2 202 004 T3

12% and the temperature in the range of 43 ° C to 50 ° C. The spray rate was 80-120 ml / min / spray gun.

Reference Example 3

Slow-release tablet (875 mg) (a) Amoxicillin sodium tablet

<td></td><td>mg / tablet</td><td> %</td>

<td>Amoxicillin sodium crystallized 91% *</td><td> 961,54</td><td> 73,96</td>

<td>Dry microcrystalline cellulose</td><td> 273,46</td><td> 21,04</td>

<td>Magnesium stearate</td><td> 13,0</td><td> 1,00</td>

<td>200 mesh xanthan gum **</td><td> 52,0</td><td> 4,00</td>

<td>Total</td><td> 1300</td><td> 100</td>

(b) Amoxicillin sodium tablet with citric acid

<td></td><td>mg / tablet</td><td> %</td>

<td>Amoxicillin sodium crystallized 91% *</td><td> 961,54</td><td> 66,31</td>

<td>Dry microcrystalline cellulose</td><td> 288,96</td><td> 19,92</td>

<td>Magnesium stearate</td><td> 14,50</td><td> 1,00</td>

<td>Citric acid</td><td> 156</td><td> 10,75</td>

<td>200 mesh xanthan gum **</td><td> 29,0</td><td> 2,00</td>

<td>Total</td><td> 1450</td><td> 100</td>

(c) Amoxicillin trihydrate tablet

<td></td><td>mg / tablet</td><td> %</td>

<td>Amoxicillin Trihydrate 86% *</td><td> 1017,4</td><td> 78,26</td>

<td>Dry microcrystalline cellulose</td><td> 217,6</td><td> 16,74</td>

<td>Magnesium stearate</td><td> 13,0</td><td> 1,00</td>

<td>200 mesh xanthan gum **</td><td> 52,0</td><td> 4,00</td>

<td>Total</td><td> 1300</td><td> 100</td>

* adjusted to the potency of amoxicillin and corresponding to 875 mg of amoxicillin ** Xantural 75

ES 2 202 004 T3

Example 4

875 / 62.5 mg modified-release tablet Slow-release tablet

This tablet can be formed using half the amounts mentioned above, for a slow release layer comprising approximately 438 mg of amoxicillin.

<td>Immediate Release Layer-1</td><td></td>

<td>Amoxicillin Trihydrate</td><td>507 mg</td>

<td>(equivalent to amoxicillin free acid)</td><td> (438)</td>

<td>Potassium clavulanate</td><td> 71,8</td>

<td>(equivalent to clavulanate acid)</td><td> (62,5)</td>

<td>Microcrystalline cellulose (Avicel PH102)</td><td> 125</td>

<td>Sodium starch glycolate (Explotab)</td><td> 26</td>

<td>Magnesium stearate</td><td> 6,5</td>

The immediate release layer typically comprises 438 / 62.5 mg amoxicillin / clavulanate

<td>Immediate Release Layer-2</td><td></td>

<td>Amoxicillin Trihydrate</td><td>507 mg</td>

<td>(equivalent to amoxicillin free acid)</td><td> (438)</td>

<td>Potassium clavulanate</td><td> 71,8</td>

<td>(equivalent to clavulanate acid)</td><td> (62,5)</td>

<td>Microcrystalline cellulose (Avicel PH102)</td><td> 135</td>

<td>Sodium starch glycolate (Explotab)</td><td> 34</td>

<td>talcum powder</td><td> 67</td>

<td>Magnesium stearate</td><td> 25</td>

<td>Silicon (Syloid)</td><td> 17</td>

The immediate release layer nominally comprises 438 / 62.5 mg amoxicillin / clavulanate.

Barrier layers

Barrier layers and procedures for their preparation are described in WO 95/20946 (SmithKline).

Tablet preparation

Active ingredients, fillers and solvents (microcrystalline cellulose), release control agents (if any), disintegrants (crospovidone, sodium starch glycolate), etc., are mixed. Lubricants (talc, magnesium stearate) and colloidal silicon dioxide (Syloid 244) are added and mixing continues for one minute. The entire mix is ​​subjected to pre-compression in a press or compaction machine or a compactor with rollers (briquetting stage), which is followed by a reduction in size (Apex, Fitzmill, Frewitt) and passage through an oscillating screen or a particle size classifier (Kason, Sweco). If the properties

ES 2 202 004 T3 slip are unsatisfactory, the briquetting step is repeated. Separate compressed blends are prepared for the immediate and slow release layers and the barrier layer, if any.

In those cases where the bulk density is relatively lower, a densification step (pre-compression and sieving as in the briquetting process) may be required to achieve the nominal weight of a given layer.

The blends are subsequently compressed as separate layers in a layer compression press to form two-layer tablets. The tablets can then be covered with an opaque white coating such as, for example, the Opadry product, Opaspray (Colorcon).

Example 5

Procedures for dissolution testing

Release of amoxicillin and clavulanate from tablets to static media was measured using Dissolution Test &lt;711&gt;, Apparatus 2, described in USP 23, 1995.

<td>Assay Specifications</td><td></td>

<td>Temperature:</td><td>37.0 ± 0.5 ° C</td>

<td>Half:</td><td>Deionized water 900 ml</td>

<td>Paddle speed</td><td>75 rpm</td>

Process

Aliquots of medium were obtained from the assay at the following times: 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 minutes. Each aliquot was simultaneously replaced by an equal volume of medium to keep the volume constant. The amount of drug was determined by UV spectrometry, at 272 nM. The dissolution profile resulting from the tablets of Example 1 and 2 is shown in Fig. 2.

In vivo Pharmacokinetic Evaluation of Formulations

The bioavailability of the doses, according to the present invention, was evaluated in two studies with human volunteers: study A and study B. These studies, carried out in healthy volunteers, were open-label, randomized and with crossover groups. Each dose was administered with the help of approximately 200 ml of water, before a light breakfast and after an overnight fast. Blood samples were collected in tubes containing EDTA at nominal predose times and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after the start of dosing. dosing, to measure plasma levels of amoxicillin and clavulanate. The samples were frozen in ice water before being subjected to other processes. Plasma was separated by centrifugation refrigerated at 4 ° C and transferred to labeled polypropylene test containers, which were frozen at approximately -70 ° C until analyzed.

The samples were analyzed for amoxicillin using a procedure based on the precipitation of proteins with acetonitrile. Amoxicillin was extracted from human plasma (50μ0 by protein precipitation, using acetonitrile containing the internal standard, and quantified by LC / MS / MS. Specifically, human plasma (50μ0 was pipetted into an Eppendorf tube of 1.5 ml to which acetonitrile containing the internal standard ([¹³C₆] amoxicillin, 200 µ / l). The tube was sealed, mixed with a centrifuge, and shaken for approximately 15 minutes. After the sample was centrifuged (approximately 11,000 xg, for 15 minutes), the supernatant was transferred to a silanized 1.1 ml threaded Autosampler vial containing 200 µl of a 5 mM ammonium acetate solution. An aliquot of the extract was injected into the HPLC / MS / MS system for analysis. The mass spectrophotometer operated in cation mode, employing a Turbo IonSpray interface. Multiple Reaction Monitored (MRM) was used to detect the components, amoxicillin and [¹³C6] -amoxycillin. The MRM procedure involves (1) mass selection of an ion characteristic of the required drug or internal standard on the first quadrupole mass analyzer (2) fragmentation of the selected ion in instrument cell collision (3) detection of a characteristic fragmented ion of the compound of interest. Quantification is performed by comparing the chromatographic peak areas of the drug corresponding to the area of ​​the internal standard. Linear responses in the internal standard / assay peak area ratios were observed at the assayed concentrations that ranged from 0.05 μg / ml (low limit of quantification: LLQ) to 10 μg / ml (high limit of quantification). : UlQ).

Samples were analyzed for clavulanate using a procedure based on protein precipitation with acetonitrile. Clavulanate was extracted from human plasma by liquid / liquid using the internal standard and quantified by LC / MS / MS. Specifically, human plasma (50 μθ was pipetted into a 1.5 ml Eppendorf tube to which 200 μl of ammonium acetate (0.2 mM) was added before the addition of acetonitrile containing the internal standard (6-acid aminopenicillanic acid, 400μ / l). The tube was sealed, mixed with a centrifuge, and shaken for

ES 2 202 004 T3 approximately 20 minutes. After the sample was centrifuged (approximately 14,000 xg, for 15 minutes), the supernatant was transferred to a clean Eppendorf tube and dichloromethane was added. After mixing and centrifuging again (approximately 14,500 xg, for 10 minutes), the supernatant (no more than 150 ml) was transferred to a silanized 1.1 ml Autosampler vial, and remained unsealed for at least 20 minutes to allow any trace of dichloromethane to evaporate. An aliquot of the extract was injected into the HPLC / MS / MS system for analysis. The mass spectrophotometer operated in cation mode, employing a Turbo IonSpray interface. The multiple reaction monitored (MRM) was used to detect the components, clavulanate and 6-aminopenicillanic acid. The MRM procedure involves (1) the selection of the mass of an ion characteristic of the required drug or the internal standard in the first quadrupole mass analyzer (2) the fragmentation of the selected ion in the instrument cell collision (3) the detection of a characteristic fragmented ion of the compound of interest. Quantification is performed by comparing the chromatographic peak areas of the drug corresponding to the area of ​​the internal standard. The linear responses in the peak area ratios of the internal standard / assayed were observed for the assayed concentrations that varied between 0.05 μg / ml (low limit of quantification: LLQ) and 10 μg / ml (high limit of quantification : ULQ).

The QC samples were analyzed in each lot against the calibration standards prepared separately. The results of the QC samples were used to evaluate the daily performance of the assay.

The results of plasma concentration versus time, for each case in each regimen, were analyzed by non-compartmental techniques using the WinNoulin Professional Version 1.5 non-compartmental pharmacokinetic analysis program. All calculations were based on actual sampling times. The pharmacokinetic parameters determined included the maximum observed plasma concentration (Cmax) and the time required to reach the maximum plasma concentration (Tmax). The apparent terminal elimination rate constant (Iz) was derived from the logarithmic and linear disposition phase of the concentration-time curve, using the least squares method of linear regression with visual recording of the data to determine the appropriate number. of points to calculate the Iz. The apparent terminal elimination half-life (T ½) was calculated as ln (2) / Iz.

The area under the plasma concentration-time curve, from time zero to the last quantifiable plasma concentration [AUC (0-t)], was determined using the trapezoid rule for each incremental trapezoid and the logarithmic trapezoid rule for each decreasing trapezoid [ Chiou WL., J. Pharmacokinet. Biopharm., 1978, 6, 539547]. The area under the plasma concentration-time curve extrapolated to infinity [AUC (0-inf)] was calculated as the sum of AUC (0-t)] and C (t) / Iz, where C (t) was the concentration predicted from the analysis of the logarithmic and linear regression in the last time that can be measured.

The time to minimum inhibitory plasma concentration (T&gt; MIC) was calculated manually by graphical interpolation, where the minimum inhibitory plasma concentrations were defined as 4 μg / ml for amoxicillin.

The mean concentration-time profiles for amoxicillin and clavulanate were obtained from the nominal sampling times of each formulation. In those cases in which a post-dose value was not quantified, a value of * / 2 the LLQ (0.05 μg / ml) was assigned to determine the mean value. In those cases in which the calculated mean value was lower than the LLQ or higher than 50% of the NQ values, a NQ value was assigned to each sampling time.

The loge transformed Cmax and the non-transformed T&gt; MIC were analyzed for each formulation using Analysis of Covariance (ANCOVA), fitting a single term per formulation and fitting the reference formulation data as a covariate. The 95% confidence intervals for the means of each formulation were constructed using the residual variance of the model. For Cmax, the confidence intervals estimated on a logarithmic scale were subsequently transformed again to obtain the 95% confidence intervals of the geometric mean. These results were represented graphically.

The underlying hypotheses of the analyzes were evaluated by observing the residual plots. Homogeneity of variance was assessed by plotting studentized residuals against predicted model values, while normality was assessed using a normal probability plot. Particular attention should be paid to any peripheral values ​​observed with the reference formulation.

I study

The first study compares three modified release doses of 1750/125 mg (formulations I-III) and four modified release doses of 1500/125 mg that are not part of the present invention (formulation IV) versus an immediate release dosage 1750/125 mg (Formulation V), as shown below:

(a) a dose of 1750/125 mg of amoxicillin / clavulanate potassium, made from the combination of a modified-release tablet comprising 875/125 mg of amoxicillin trihydrate / clavulanate and xanthan gum 4% and a tablet immediate release comprising 875 mg of amoxicillin trihydrate (formulation I);

ES 2 202 004 T3 (b) a dose of 1750/125 mg of amoxicillin / clavulanate potassium, made from a combination of a modified release tablet comprising 875/125 mg of crystallized amoxicillin sodium / clavulanate and xanthan gum al 4% and an immediate release tablet comprising 875 mg of amoxicillin trihydrate (formulation II);

(c) a dose of 1750/125 mg of amoxicillin / clavulanate potassium, made from a combination of a modified-release tablet comprising 875/125 mg of crystallized amoxicillin sodium / clavulanate, citric acid (156 mg) and gum 2% xanthan and an immediate release tablet comprising 875 mg of amoxicillin trihydrate (formulation III);

(d) a dose of 1500/125 mg of amoxicillin / clavulanate potassium (made from one modified-release tablet comprising 500/125 mg of crystallized amoxicillin sodium / clavulanate potassium and two immediate-release tablets comprising 500 mg of amoxicillin trihydrate ( Amoxyl, SmithKline Beecham) (formulation IV); and (e) a 1750/125 mg dose of amoxicillin / clavulanate potassium, made from a combination of an immediate-release tablet comprising 875/125 mg of amoxicillin trihydrate / clavulanate (Augmentin, SmithKline Beecham) and one tablet. immediate release containing 875 mg of amoxicillin trihydrate (Amoxyl, SmithKline Beecham) (formulation V).

Results

<td>Formulation</td><td>n</td><td>C ¹max</td><td>T&gt; CIM</td><td>AUC¹,³</td>

<td>I</td><td> 8</td><td> 12,75(4,96)</td><td> 4,5(1,8)</td><td> 47,83</td>

<td>II</td><td> 8</td><td> 18,56(4,72)</td><td> 4,4(1,0)</td><td> 57,46</td>

<td>III</td><td> 8</td><td> 13,03(2,34)</td><td> 5,73(2,54)</td><td> 54,93</td>

<td>IV</td><td> 8</td><td> 17,33(4,66)</td><td> 4,8(0,9)</td><td> 56,71</td>

<td>V</td><td> 40</td><td> 20,21(6,09)</td><td> 4,2(0,9)</td><td> 56,33</td>

( ) standard deviation ¹ arithmetic mean value ² T&gt; MIC is the time (h) above an amoxicillin concentration of 4 μg / ml ³ Area under the curve (0 to 12 h, μg.h / ml)

The pharmacokinetic profile is shown in Figure 3.

Study B

The second study investigated two different 2000/125 mg modified release doses (formulations VI and VII) versus a 2000/125 mg immediate release dose (formulation VIII), as shown below:

(a) a dose of 2000/125 mg of amoxicillin / potassium clavulanate, made from two two-layer tablets according to Example 1 (formulation VI);

(b) a dose of 2000/125 mg of amoxicillin / potassium clavulanate, made from two two-layer tablets according to Example 2 (formulation VII);

(c) a 2000/125 mg dose of amoxicillin / potassium clavulanate, made from the combination of three tablets, each containing 500 mg of amoxicillin (Amoxyl, SmithKline Beecham), and one tablet comprising 500 mg amoxicillin and 125 mg potassium clavulanate (Augmentin, SmithKline Beecham) (formulation VIII).

ES 2 202 004 T3

Results

<td>Formulation</td><td>N</td><td>C ¹max</td><td>T&gt; CIM¹·²</td><td>T&gt; CIM¹·³</td><td>AUC¹·⁴</td>

<td>SAW</td><td> 7</td><td> 17,41(1,93)</td><td> 6,0(1,3)</td><td> 4,8(1,2)</td><td> 74,9</td>

<td>VII</td><td> 8</td><td> 17,46(6,02)</td><td> 5,9(1,3)</td><td> 4,0(1,3)</td><td> 71,5</td>

<td>VIII</td><td> 12</td><td> 23,75(5,73)</td><td> 4,9(1,1)</td><td> 3,5(1,0)</td><td> 69,2</td>

( ) standard deviation ¹ arithmetic mean value ² T&gt; MIC is the time (h) above an amoxicillin concentration of 4 μg / ml ³ T&gt; MIC is the time (h) greater than an amoxicillin concentration of 8 μg / ml ⁴ area under the curve (0 to 12 h, μg.h / ml)

Comparison of the AUC values ​​of formulations VI and VII (two-layer tablets) versus formulation VIII (immediate-release tablets) shows that the absorption of amoxicillin is not affected when partially formulated in a slow-release layer. This means that there are no unabsorbed traces of amoxicillin that could otherwise cause problems in the lower gastrointestinal tract, for example resulting from lack of absorption and the destruction of symbiotic bacteria.

Likewise, it was found that formulation VI depends to a lesser extent on the variability of plasma amoxicillin concentrations than formulation VII. These formulations were the same, except for formulation VI which also comprised xanthan gum (2%) in the slow release layer.

The pharmacokinetic profile of plasma amoxicillin concentration is shown in Figure 4 (where A is formulation VI, B is formulation VII, D is formulation VIII).

The pharmacokinetic profile of clavulanate was substantially the same in the bilayer tablets and in the immediate release tablets, showing that its bioavailability was not affected by its incorporation into the immediate release layer of the bilayer tablet.

Furthermore, the present invention is extensible to formulations bioequivalent to tablets of formulations VI and VII, in terms of both speed and extent of absorption, for example, as defined by the Food and Drug Administration. ) from the USA and is discussed in the so-called “Orange Book” (Approved Drug Products with Therapeuic Equivalence Evaluations, US Dep. of Health and Human Services, 19^to Ed., 1999).

Reference Data

The currently available Augmentin 875/125 mg tablet has a value of C_max 11.6 ± 2.8 μg / ml (Reference Physicians Desk, Medical Economics Co, 52nd edition, 1998, 2802). The time above MIC was approximately 40% in the 12 hour interval between doses with a MIC of 2 µg / ml and approximately 30% with a MIC of 4 µg / ml (SmithKline Beecham data).