A formulation for modified release comprising amoxycillin and potassium clavulanate

Beecham Pharmaceuticals (Pte) Limited

Modified release formulation comprising amoxicillin and potassium clavulanate

The present invention relates to a new method of treatment using amoxicillin and potassium clavulanate, and to new formulations, in particular tablet formulations, for use in these methods.

Amoxicillin and potassium clavulanate are each known separately as a β-lactam antibiotic and a β-lactam inhibitor. The products, which include amoxicillin and potassium clavulanate, are sold under the Augmentin SmithKline Beecham brand. Such products are particularly effective in treating infections acquired by a group infection, in particular upper respiratory tract infections in adults and middle ear infections in children.

Different tablet formulations of amoxicillin and potassium clavulanate are approved for sale and include many different weights and ratios of amoxicillin and potassium clavulanate, e.g. conventional swallow tablets consist of 250/125, 500/125, 500 / 62,5 and 875/125 mg amoxicillin / clavulanic acid (as potassium clavulanate). Such tablets comprise amoxicillin and clavulanic acid in ratios of 2: 1, 4: 1, 8: 1 and. 7: 1. The 875/125 mg tablet was developed to provide a tablet formulation that would be administered with a bid (twice daily) dosage regimen. It is also sold in Italy and Spain for tid (three times daily) dosing. A 500 / 62.5 mg tablet was developed to provide a tablet formulation that would be administered with a bid dosage regimen, with two such tablets taking every 12 hours over one 1000/125 mg tablet. A single dose of 1000/125 mg is also available in France, but more in the form of a single-dose pad than tablets. The approved regimens typically provide a single dose of 125 mg of potassium clavulanate.

In addition, WO 97/09042 (SmithKline Beecham) describes tablet formulations comprising amoxicillin and clavulanic acid in a ratio ranging from 12: 1 to 20: 1, preferably 14: 1. They further state that the preferred dosage of 1750/125 mg can be provided as two tablets, the first comprising 875/125 mg of amoxicillin and clavulanic acid and the second 875 mg of amoxicillin. The 14: 1 ratio is said to be useful for the empirical treatment of bacterial infection potentially caused by drug-resistant S pneumoniae (DRSP). This patent application also describes pediatric formulations comprising amoxicillin and clavulanate in a ratio of 14: 1 for the administration of amoxicillin doses of 90 mg / kg / day. The data indicate that such a dose may provide antibiotic concentrations sufficient to suppress DRSP with amoxicillin ± clavulanic acid MIC <4 pg / ml (Bottenfield et al. Pediatr Infect Dis J, 1998, 17, 963-8).

WO 94/16696 (SmithKline Beecham) describes generally that clavulanic acid may unexpectedly increase the efficacy of amoxicillin for microorganisms having a β-lactamase-mediated resistance mechanism.

The commercially available tablet formulations of amoxicillin and potassium clavulanate are conventional in that they provide immediate release of the active ingredients when the tablet enters the stomach. There has also been some interest in developing formulations with a modified release profile that would allow a longer interval between dosages, e.g. rather, every 12 hours (bid, q 12 h) than every 8 hours (tid, q8h).

So e.g. WO 95/20946 (SmithKline Beecham) describes layered tablets comprising amoxicillin and optionally potassium clavulanate having a first layer being an immediate-release layer and a second layer being a slow-release layer. The broadest ratio of amoxicillin to clavulanic acid is from 30: 1 to 1: 1, with a preferred range from 8: 1 to 1: 1. Advantageously, amoxicillin is in the form of amoxicillin trihydrate. Examples providing such two-layer tablets have amoxicillin trihydrate in the immediate-release layer and amoxicillin and clavulanate in the slow-release layer. Multilayer tablets are described more generally in WO 94/06416 (Jagotec AG). Further two-layer tablets comprising clavulanic acid and amoxicillin are described in WO 98/05305 (Quadrant Holdings Ltd). In these tablets, the first layer comprises amoxicillin and the second layer contains clavulanate and a trehalose excipient to stabilize the clavulanate component.

In addition, WO 95/28148 (SmithKline Beecham) discloses amoxicillin / potassium clavulanate tablet formulations having a core containing amoxicillin and potassium clavulanate coated with a release retaining agent and surrounded by an outer coating of amoxicillin and potassium clavulanate. The release retention agent is an enteric coating, such that the immediate release of contents is from the outer nucleus, followed by a second phase of release from the nucleus, which is delayed until the nucleus reaches the intestine. WO 96/04908 (SmithKline Beecham) further discloses amoxicillin / potassium clavulanate tablet formulations comprising amoxicillin and potassium clavulanate in the immediate release matrix and delayed release granules comprising amoxicillin and potassium clavulanate. Such granules are coated with an enteric coating such that the release is delayed until the granules reach the intestine. WO 96/04908 (SmithKline Beecham) discloses amoxicillin / potassium clavulanate formulations for delayed or sustained release formed from granules having a core comprising amoxicillin and potassium clavulanate surrounded by a layer comprising amoxicillin. WO 94/27557 (SmithKline Beecham) describes controlled release formulations of amoxicillin and clavulanic acid prepared using a hydrophobic waxy material which is then subjected to heat infusion.

Controlled release formulations comprising amoxicillin have already been described by many groups. Thus, Arancibia et al (Int J of Ciin 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 are provided for these formulations. The formulation is formulated to release 21 to 35% in the first 60 minutes, 51 to 66% at 4 hours, 70 to 80% at 6 hours, 81 to 90% at 8 hours and more than 94% at 12 hours . They found little connection, if any, between the rate of in vitro dissolution and the pharmacokinetic property in the body. Hilton et al (International Journal of Pharmaceutics, 1992, 86, 79-88) describe an alternative controlled release matrix tablet with a hydrophilic polymer and gas release system to provide intragastric buoyancy to increase gastric retention time. This does not show any advantage over the conventional capsule formulation with a bioavailability that is reduced. In contrast, Hilton et al (Journal of

Pharmaceutical Sciences, 1993, 82, 737-743) describe a 750 mg controlled release tablet comprising an enteric polymer hydroxypropylmethylcellulose acetate succinate. However, no advantages over the conventional capsule are shown. In detail, bioavailability is reduced by 64.6% compared to the same dose provided in the capsule. Recently, Hoffman et al (Journal of Controlled Release, 1998, 54, 29-37 and WO 98/22091) described a tablet comprising 500 mg of amoxicillin in a matrix comprising hydroxypropylmethylcellulose formulated to release 50% of its contents in the first three hours and the drug release process is complete after 8 hours. Time over MIC was found to be significantly extended compared to the capsule formulation, but not sufficient for a 12 μm dose interval. The treatment is in accordance with the theoretical MIC of 0.2 μβ / πύ.

Partial challenge in providing amoxicillin formulations in which drug release is effectively modified (and a simple explanation for failure in the studies mentioned above) is the relatively narrow window for small intestine absorption and the relatively short half-life. Moreover, the rapid elimination of amoxicillin (elimination half-life is 1.3 hours) makes it difficult to maintain serum levels because discharge from the body is very rapid.

In the present tablet formulations comprising amoxicillin and potassium clavulanate, amoxicillin is in the form of amoxicillin trihydrate because the use of such formulation provides tablets with greater storage stability than those in which amoxicillin is in the form of sodium amoxicillin (see GB 2 005 538, Beecham Group Ltd.). However, sodium amoxicillin is of course used as an amoxicillin component in current formulations of amoxicillin and potassium clavulanate adapted for IV administration. The amoxicillin sodium used is in the form obtained by spray drying. In addition, EP 0 131 147-A1 (Beecham Group pic) describes a further form of sodium amoxicillin, crystalline sodium amoxicillin. A further process for the preparation of amoxicillin salts, including sodium amoxicillin, is described in WO 99/62910 (SmithKline Beecham). Amoxicillin sodium is relatively soluble in water compared to amoxicillin trihydrate.

Formulations comprising clavulanic acid and a pharmaceutically acceptable organic acid or salt-like derivative thereof, e.g. calcium citrate are described in WO 96/07408 (SmithKline Beecham). In these formulations, the presence of calcium citrate is thought to help suppress gastrointestinal intolerance associated with oral dosing of clavulanate-containing products.

Further, U.S. Pat. 5 051 262 (Elan Corp) describes the incorporation of organic acid into a modified release formulation to provide a microenvironment in which a locally modified pH helps protect the active ingredient from degradation.

It is important to increase the resistance of pathogenic organisms, such as. those found in respiratory tract infections against anti-infectious agents such as. amoxicillin / potassium clavulanate, especially 5 drug-resistant pneumoniae. Increased resistance of S pneumoniae to penicillin (due to modified penicillin binding proteins) has evolved worldwide and affects clinical outcomes (e.g., Applebaum PC, Ped Inf Dis J, 1996, 15 (10), 932-9). This penicillin-resistant S pneumoniae (PRSP) is also called DRSP because it often shows increased sensitivity not only to penicillin but also to a wider range of antimicrobial classes, including macrolides, azalides, beta-lactams, sulfonamides and tetracyclines. Amoxicillin (with or without clavulanate), along with some newer quinolones, has remained among the most active oral medicines against the growing resistant isolate of S pneumoniae, based on both MIC levels and the pharmacokinetic properties of these compounds. Response rates (and MICs), of course, are increasing steadily. Penicillin resistance in S pneumoniae can be determined according to criteria developed by the National Committee for Clinical Laboratory Standards (NCCLS) as follows: sensitive strains have a MIC <0.06 pg / ml, intermediate resistance is defined as an MIC in the range of 0, 12 to 1.0 pg / ml, while penicillin resistance is defined as MIC> 2 pg / ml.

It was further found that approximately 10% of pneumococci now have amoxicillin MIC of 2 μ8 / πύ.

Therefore, there is a need to provide novel formulations of amoxicillin / clavulanate that combine a known safety profile and a broad spectrum with improved activity against DRSP, including PRSP, with higher MICs in the empirical treatment of respiratory infections where 5pneumoniae, H influenzae and M catarrhalis are likely pathogens .

Β-lactams, including amoxicillin, are recognized to be time above the minimum inhibitory concentration (T> MIC), the pharmacodynamic parameter most closely associated with efficacy. For various β-lactams, a bacteriological cure rate of 85 to 100% is achieved when serum concentrations exceed the MIC by more than about 40% of the dosing interval (Craig and Andes, Ped Inf Dis J, 1996, 15, 255-259). For a 12-hour dosing interval, this is approximately 4.8 hours.

A further parameter that may be relevant is the ratio of the maximum plasma concentration (Cmax) to the MIC, as this may be related to the selection potential for resistance. Too low a ratio can stimulate the development of resistant strains. Preferably, the plasma Cmax value is well above the MIC value, e.g. at least 2 times, more preferably at least 3 times, most preferably at least 4 times the MIC.

In a clinical study using the current Augmentin 875/125 mg tablet, dosing at 12-hour intervals was found to have a time above MIC about 40% for MIC 2 pg / ml, but only about 30% for MIC 4 pg / ml. The current Augmentin 875/125 mg tablet has a Cmax value of 11.6 ± 2.8 pg / ml (Physicians Desk Reference, Medical Economics Co., 52nd Edition, 1998, 2802).

Because of these findings, there is an ongoing need to provide new dosage regimens for amoxicillin / clavulanate that would provide optimized pharmacokinetic profiles for amoxicillin, while compromising the bioavailability of clavulanate so that therapy is maximized, especially against more resistant bacteria, while (further) development of resistance is minimized. We have now found that this can be achieved by using higher doses of amoxicillin than previously determined.

Accordingly, from the first aspect, the present invention provides a method for treating bacterial infections in humans comprising the oral administration thereof to a therapeutically effective amount of amoxicillin and potassium clavulanate such that the amount of amoxicillin ranges from 1900 to 2600 mg, preferably from 1950 to 2600 mg 2550 mg, and the amount of potassium clavulanate is such that the amoxicillin to clavulanate weight ratio is from 2: 1 to 20: 1, preferably from 7: 1 to 20: 1, more preferably from 14: 1 to 20: 1, at intervals of about 12 hours.

Preferably, the dosage regimen provides an average plasma concentration of amoxicillin of 4 μg / ml for at least 4.4 h, preferably at least 4.6 h, more preferably at least 4.8 h, most preferably for about 6 h or longer.

More preferably, the dosage regimen provides an average plasma concentration of amoxicillin of 8 μg / ml for at least 4.4 h, preferably at least 4.6 h, most preferably at least 4.8 h.

Preferably, the dosage regimen provides an average maximum plasma concentration (Cmax) for amoxicillin of at least 8 pg / ml, preferably at least 12 μg / ml, more preferably at least 14 pg / ml, most preferably at least 16 pg / ml.

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

In a further aspect, the present invention provides a method for treating bacterial infections in humans comprising administering to them a therapeutically effective amount of amoxicillin and potassium clavulanate such that the amount of amoxicillin is in the range of 1400 to 1900 mg, preferably 1500 to 1900 mg, and the amount is potassium clavulanate is such that the amoxicillin to clavulanate weight ratio is from 2: 1 to 14: 1, preferably from 7: 1 to 14.1, more preferably from 12: 1 to 14: 1, at intervals of about 12 h, so that the dosage regimen provides an average plasma concentration of amoxicillin 4 pg / ml for at least 4.4 h, preferably at least 4.6 h, more preferably at least 4.8 h, most preferably for about 6 h or longer; more preferably, the mean plasma concentration of amoxicillin is 8 pg / ml for at least 4.4 h, more preferably for at least 4.6 h, most preferably for at least 4.8 h, and the mean maximum plasma concentration (Cmax) of amoxicillin is at least 8 pg / ml. ml, preferably at least 12 pg / ml, more preferably at least 14 pg / ml, most preferably at least 16 pg / ml.

Bacterial infections achievable by the present invention include infections caused by organisms S pneumoniae (including drug-resistant pneumoniae (DRSP), e.g., penicillin-resistant pneumoniae (PRSP)) and / or βlactamase-producing respiratory pathogens, the most famous H influenzae and M catarrhalis, such as respiratory tract infections, including group-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), and acute bacterial sinusitis (ABS), where higher bursting points are achievable via an improved pharmacokinetic profile compared to current antibacterial agents. Most respiratory infections in outpatients are caused by either S pneumoniae and / or β-lactamase-producing bacteria and treated empirically, so that there is a continuing need for a treatment method such as e.g. according to the present invention to provide a spectrum of activity covering all such pathogens. The duration of therapy is generally between 7 m and 14 days, typically 7 days for indications such as acute exacerbation of chronic bronchitis, but 10 days for acute bacterial sinusitis. Typically, dosage regimens are better adapted for elderly patients than for pediatric patients.

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

Unless otherwise indicated, the masses of amoxicillin and (potassium) clavulanate refer to the equivalent masses of the corresponding free acids. In addition, it should be borne in mind that in practice the masses of amoxicillin and clavulanate to be incorporated into the formulation are further adapted in accordance with conventional practice, taking into account the capacity of amoxicillin and clavulanate.

In the first embodiment, a dose of amoxicillin from 1900 to 2600 mg and an appropriate amount of potassium clavulanate from the immediate-release formulation may be administered. According to another aspect, the present invention provides a method for treating bacterial infections in humans comprising administering to them a therapeutically effective amount of amoxicillin and potassium clavulanate such that the amount of amoxicillin is in the range of 1900 to 2600, preferably 1950 to 2550 mg and the amount is potassium clavulanate such that the amoxicillin to clavulanate weight ratio is from 2: 1 to 20: 1, preferably from 7: 1 to 20: 1, more preferably from 14: 1 to 20: 1, at intervals of about 12 h, the dose being administered from the immediate release formulation.

As used herein, the term immediate release refers to the release of most active substance content in a relatively short time, e.g. within 1 hour, preferably within 30 minutes, after oral administration. Examples of such immediate release formulations include conventional swallow tablets, dispersible tablets, chewable tablets, single dose pads and capsules.

Representative doses include 2000/125, 2250/125 and 2500/125 mg of amoxicillin and potassium clavulanate. The preferred dose is 2000/125 mg amoxicillin and potassium a clavulanate.

The dosage of the immediate-release formulation can be provided as a single tablet, e.g. a dispersible tablet, a chewable tablet that may be effervescent and / or dispersible, a single dose capsule or a single dose pad comprising, e.g. 2000, 2250 or 2500 mg amoxicillin and 125 mg potassium clavulanate. Alternatively, the dose may consist of several smaller tablets or capsules, e.g. 2, 3 or 4, some of which may be the same and some of which may contain only amoxicillin and zero potassium clavulanate. Representatives of such smaller tablets include swallow tablets, dispersible tablets and chewable tablets which may be effervescent and / or dispersible. Thus, e.g. a dose of 2000 mg amoxicillin and 125 mg potassium clavulanate is provided by a combination of three tablets, each comprising 500 mg amoxicillin, and one tablet containing 500 mg amoxicillin and 125 mg potassium clavulanate. Alternatively, such a dose may be provided by two tablets each comprising 1000 / 62.5 mg amoxicillin / potassium clavulanate. In addition, a dose of 2250 mg amoxicillin and 125 mg potassium clavulanate can be provided by a combination of four tablets comprising 500 mg amoxicillin and one tablet containing 250 mg amoxicillin and 125 mg potassium clavulanate, or two tablets containing 875 mg amoxicillin and one tablet containing 500 mg amoxicillin and 125 mg potassium clavulanate. Further, a dose of 2500 mg amoxicillin and 125 mg potassium clavulanate can be provided by a combination of four tablets comprising 500 mg amoxicillin and one tablet comprising 500 mg amoxicillin and 125 mg potassium clavulanate. Tablets containing 500 mg and 875 mg amoxicillin and 250/125, 500/125 and 875/125 mg amoxicillin / potassium clavulanate are already commercially available.

It should be noted that the immediate-release tablets, comprising 1000 / 62.5 mg, are new. Therefore, in a further aspect, the present invention provides an immediate release pharmaceutical tablet formulation comprising 1000 mg ± 5% amoxicillin and 62.5 mg ± 5% potassium clavulanate in a nominal ratio of approximately 16: 1 in combination with pharmaceutically acceptable excipients or carriers. Immediate-release tablets comprising 1000 / 62.5 mg can be readily prepared by adjusting the compositions previously described for 875/125 and 1000/125 mg tablets (e.g., WO 95/28927 and WO 98/35672, SmithKline Beecham).

It should also be noted that the immediate-release single-dose pads comprising 2000/125 mg, 2250/125 mg or 2500/125 mg, or their corresponding half quantities, are new. Therefore, in a further aspect, the present invention provides an immediate release pharmaceutical dosage formulation in the form of single dose pads comprising 2000, 2250 or 2500 mg ± 5% amoxicillin and 125 mg ± 5% potassium clavulanate in a nominal ratio of approximately 16: 1, 18: 1 or 20: 1, or their corresponding half amounts, in combination with pharmaceutically acceptable excipients or carriers. Such pads can be easily prepared by adjusting the compositions previously described for 875/125 and 1000/125 mg pads (e.g., WO 92/19277 and WO 98/35672, SmithKline Beecham).

It should further be noted that chewable immediate release tablets comprising 2000, 2250 or 2500/125 mg are new. Therefore, in a further aspect, the present invention provides an immediate release pharmaceutical formulation in the form of a chewable, optionally effervescent tablet comprising 2000, 2250 or 2500 mg amoxicillin and 125 mg ± 5% potassium clavulanate in a nominal ratio of approximately 16: 1, 18: 1, or 20: 1, or their corresponding half amounts, in combination with a chewable base, and, if effervescent, effervescent, and other pharmaceutically acceptable excipients or carriers. Such chewable tablets can be readily prepared by adjusting compositions previously described for chewable tablets comprising amoxicillin and potassium clavulanate (e.g., EP-A-0 396 335, Beecham Group and WO 98/35672, SmithKline Beecham).

In other embodiments, a dose of amoxicillin from 1900 to 2600 mg and an appropriate amount of potassium clavulanate from the modified release formulation may be administered. Therefore, in a further aspect, the present invention provides a method for treating bacterial infections in humans comprising administering to them a therapeutically effective amount of amoxicillin and potassium clavulanate such that the amount of amoxicillin is in the range of 1900 to 2600 mg, preferably 1950 to 2550 mg, and the potassium clavulanate is present in a proportional amount such that the weight ratio of amoxicillin to potassium clavulanate is from 2: 1 to 20: 1, preferably from 7: 1 to 20: 1, more preferably from 14: 1 to 20: 1, at approximately 12 h intervals at which the dose is administered from the modified release formulation.

In a third embodiment, an amoxicillin dose of 1400 to 1900 mg and an appropriate amount of clavulanate from the modified release formulation may be administered. Therefore, from a further aspect, the present invention provides a method for treating bacterial infections in humans comprising administering to them a therapeutically effective amount of amoxicillin and potassium clavulanate such that the amount of amoxicillin in the range from 1400 to 1900 mg, preferably from 1500 to 1900 mg, is potassium clavulanate however, it is present in a proportional amount so that the weight ratio of amoxicillin to clavulanate is from 2: 1 to 14: 1, preferably from 7: 1 to 14: 1, more preferably from 12: 1 to 14: 1, at approximately 12 h intervals at which the dose is administered from the modified release formulation.

As used herein, the term modified release refers to the release of a drug substance from a pharmaceutical formulation that is slower than that of an immediate release formulation, such as e.g. a conventional swallow tablet or capsule, and may include an immediate release phase and a slow release phase. Modified release formulations are well known in the art, e.g. Remington: The Science and Practice of Pharmacy, 19. ed., 1995, Cats Publishing Co., Pennsylvania, USA.

Preferably, the modified release formulations of the invention are formulated such that amoxicillin release is predominantly induced through the stomach and small intestine so that absorption through specific amoxicillin absorption sites in the small intestine is maximized. Preferably, the amoxicillin release profile consists of a distribution from the immediate-release component, which is then complemented and expanded by continuing the distribution from the slow-release component. Preferably, potassium clavulanate is released substantially immediately from the formulation when it reaches and is absorbed from the stomach, thereby minimizing the risk of degradation due to excessive exposure to the stomach. Such formulations are preferably formulated to release amoxicillin and potassium clavulanate predominantly within 3 hours of ingestion of the formulation.

The dose typically provides 125 mg of potassium clavulanate, an amount approved under current regimens where less amoxicillin has been administered.

Representative modified release doses include 1500/125, 1750/125 respectively. 2000/125 mg amoxicillin and potassium clavulanate. The preferred dose is 2000/125 mg amoxicillin and potassium clavulanate.

The modified release formulation dose can conveniently be provided as multiple swallow tablets or capsules, e.g. two, three or four, some of which may be the same and some of which may contain only amoxicillin and zero potassium clavulanate. Thus, e.g. a dose of 2000 mg amoxicillin and 125 mg potassium clavulanate is provided with two tablets each containing 1000 / 62.5 mg amoxicillin / potassium clavulanate, one tablet containing 1000 mg amoxicillin and one tablet containing 1000/125 mg amoxicillin / potassium clavulanate , two tablets each containing 500 mg amoxicillin and one tablet containing 1000/125 mg amoxicillin / potassium clavulanate, or four tablets each containing 500 / 32.25 mg amoxicillin / potassium clavulanate. In addition, a dose of 1750 mg amoxicillin and 125 mg potassium clavulanate can be provided with two tablets each containing 875 / 62.5 mg amoxicillin / potassium clavulanate, or one tablet containing 875 mg amoxicillin and one tablet containing 875/125 mg amoxicillin / potassium clavulanate. The preferred tablet comprises 1000 / 62.5 mg amoxicillin / potassium clavulanate.

The dose for the modified release formulation can also be provided as one tablet. Due to the amount of drug substance used, it is preferably different from the swallowing tablet, e.g. a dispersible tablet or a chewable tablet, which may also be effervescent and / or dispersible, or a dispersible tablet. A single unit dose can conveniently be provided as a single dose pad. It should be noted that the dose can also be provided as a number of smaller, non-swallowable tablets or pads, e.g. 2 x 1000 / 62.5 mg or 4 x 500 / 32.25 mg amoxicillin / potassium clavulanate.

Preferably, in the modified release formulation, all potassium clavulanate is provided in the immediate-release phase, whereas amoxicillin is in the immediate-release and slow-release phases.

Therefore, in a further aspect, the present invention provides a modified release pharmaceutical formulation comprising amoxicillin bi potassium clavulanate in a ratio of 2: 1 to 20: 1, preferably 7: 1 to 20: 1, more preferably 12: 1 to 20: 1 , most preferably 14: 1 to 16: 1, in which all potassium clavulanate and the first moiety of amoxicillin are formulated with pharmaceutically acceptable excipients that allow the immediate release of potassium clavulanate and the first moiety of amoxicillin, to form an immediate-release phase and further comprise a second moiety of amoxicillin formulated with pharmaceutically acceptable excipients allowing the slow release of a second moiety of amoxicillin to form a slow-release phase.

As used herein, the term slow release refers to the gradual but continuous or sustained release over a relatively extended period of active substance content (in this case amoxicillin) after oral administration, which begins when the formulation reaches the stomach and begins to disintegrate. begins to dissolve. The release continues for some time, but may continue until the formulation reaches the intestine and beyond. This can be compared to the term delayed release, in which the release of the active ingredient does not begin as soon as the formulation reaches the stomach but is delayed for a period of time, e.g. until the formulation reaches the gut when increasing pH is used to trigger the release of the active substance 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 are dissolved within 30 minutes, further at which 50 to 75%, preferably 55 to 65%, of the amoxicillin content are dissolved within 60 minutes, further at which 55 to 85%, preferably 60 *

up to 70% of the amoxicillin content is dissolved in 120 minutes, further at which 70 to 95%, preferably 75 to 85%, of the amoxicillin content is dissolved in 180 minutes, and further at which 70 to 100%, preferably 75 to 100%, of the content dissolve amoxicillin in 240 minutes. In comparison, a conventional amoxicillin immediate-release tablet dissolves essentially completely within 30 minutes. The dissolution profile can be measured by a standard dissolution test, e.g. dissolution test <711>, apparatus 2, specified in USP 23, 1995, at 37.0 ± 0.5 ° C, using deionized water (900 ml) and a blade speed of 75 rpm.

Preferably, the modified release formulation has a biphasic profile in vivo with respect to amoxicillin, i.e. an initial burst from the immediate release phase to provide an acceptable Cmax value, supplemented by a further distribution from the slow release phase to extend the T> MIC parameter to an acceptable value.

The modified formulation preferably provides a value for the area under the curve (AUC), which is essentially e.g. at least 80%, preferably at least 90%, more preferably about 100% similar to the corresponding dose of amoxicillin taken as a conventional (immediate release) formulation, over the same dosing period, maximizing the absorption of the amoxicillin component from the slow release component.

The pharmacokinetic profile for the dose of the invention can be easily determined from a single dose bioavailability study in human volunteers. Plasma concentrations of amoxicillin can be readily determined in blood samples taken from patients according to procedures well known and documented in the art.

Representative modified release formulations include a tablet, including swallow tablets, dispersible tablets, chewable tablets which may be effervescent and / or dispersible, and a capsule, granules or pad typical of the swallow tablet.

Representative modified release formulations having an immediate and slow release phase provide a single dose in the range of 700 to 1300 mg, preferably 950 to 1300 mg of amoxicillin, e.g. single doses of 1000, 875 and 750 / 62.5 mg amoxicillin / clavulanate. Alternatively, and where the physical size of the dosage form is not a problem, a single dose may provide a complete dose, e.g. A single-dose pad, chewable tablet or dispersible tablet may comprise from 1400 to 2600 mg, preferably from 1900 to 2600 mg, of amoxicillin, e.g. single doses of 2000, 1750 and 1500/125 mg amoxicillin / clavulanate. It should be noted that such 1000, 875 and 750 / 62.5 mg formulations are novel.

Therefore, from a further aspect, the present invention provides a pharmaceutical formulation having an immediate release and a slow release phase and comprising:

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

Preferably, the immediate and slow release ratio of amoxicillin is from 3: 1 to 1: 3, more preferably from 2: 1 to 2: 3, even more preferably from 3: 2 to 1: 1. Representative ratios include about 2: 1, 9: 7 or 1: 1. We have found it 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 invention, a proportion of amoxicillin can be provided which is released immediately, such as amoxicillin trihydrate or an alkaline salt thereof, e.g. potassium or sodium amoxicillin, preferably (crystallized) sodium amoxicillin or a mixture thereof, preferably as amoxicillin trihydrate; while the slow-release part of amoxicillin is provided as amoxicillin trihydrate or an alkaline salt thereof, e.g. potassium or (crystallized) sodium amoxicillin or a mixture thereof, preferably as (crystallized) sodium amoxicillin.

Preferably, the modified release tablet is a tablet. In a preferred modified-release tablet comprising 1000 mg amoxicillin and 62.5 mg potassium clavulanate, the immediate-release phase comprises about 563 mg ± 5% amoxicillin trihydrate and about 62.5 mg ± 5% potassium clavulanate and a slow-release phase of ca. 438 mg ± 5% amoxicillin, preferably as (crystallized) sodium amoxicillin.

In the representative modified release tablet of the invention, the immediate release phase comprises about 438 mg of amoxicillin, preferably amoxicillin trihydrate and about 62.5 mg of potassium clavulanate, and the slow release phase of about 438 mg of amoxicillin, preferably as (crystallized) sodium amoxicillin, preferably provides the full 875 / 62.5 mg (14: 1) tablet.

In a further representative tablet of the invention, the immediate release phase comprises about 500 mg of amoxicillin and about 62.5 mg of potassium clavulanate and the slow release phase of about 250 mg of amoxicillin, preferably as (crystallized) sodium amoxicillin, providing a total of 750/62, 5 mg (12: 1) tablet.

It should be noted that the use of a mixture of amoxicillin trihydrate and sodium amoxicillin is more generally applicable to other pharmaceutical formulations comprising amoxicillin and potassium clavulanate.

Therefore, in a further aspect, the present invention provides a pharmaceutical formulation comprising amoxicillin and potassium clavulanate in a ratio of 1: 1 to 30: 1, preferably 2: 1 to 20: 1, more preferably 12: 1 to 20: 1, more preferably from 14: 1 to 16: 1, wherein amoxicillin is provided as a mixture of amoxicillin trihydrate and sodium amoxicillin in a ratio of 3: 1 to 1: 3, more preferably from 2: 1 to 2: 3, more preferably from 3: 2 to 1: 1. Preferably, sodium amoxicillin is crystallized sodium amoxicillin. Representative types for formulations include tablets, including immediate-release and modified-release tablets, as described herein, as well as other commercial dosage forms, such as e.g. capsules, single dose pads and granules. Representative tablets include those comprising 1000, 875, 500 and 250 mg of amoxicillin and an appropriate weight of potassium clavulanate. Representative ratios include 4: 1, 7: 1, 8: 1, 14: 1 and 16: 1 (amoxicillin: clavulanate). Preferably, in the modified-release formulations of the invention, amoxicillin in the immediate-release phase consists essentially of amoxicillin trihydrate, and amoxicillin in the slow-release phase consists essentially of sodium amoxicillin.

For the tablet formulation, immediate and slow release phases can be provided in several different forms.

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

Therefore, in a further aspect, the present invention provides a layered tablet formulation comprising potassium clavulanate and amoxicillin in the immediate-release layer phase and amoxicillin in the slow-release layer. A layer tablet may have two layers, or two layers and one or more barrier layers, as well as a coating layer. As used herein, the term two-layer tablet means a tablet consisting of an immediate release layer and a slow release layer, optionally with a coating layer.

The immediate release layer may be e.g. one that immediately or rapidly disintegrates and has a similar composition to those known tablets that immediately or rapidly disintegrate. The layer may comprise in addition to the content of the active substance e.g. also excipients, including diluents, such as e.g. microcrystalline cellulose; disintegrants such as e.g. cross-linked polyvinylpyrrolidone (CLPVP), sodium starch glycolate; compression excipients, such as e.g. colloidal silica and microcrystalline cellulose; and lubricants such as e.g. magnesium stearate. Such immediate release layer may comprise about 60 to 85% (all percentages given here are based on mass percentages, unless otherwise stated), preferably 70 to 85% of the active substance content, about 10 to 30%, preferably 10 to 20% of fillers / compression excipients, and conventional amounts of disintegrants and lubricants, typically about 0.5 to 3%, etc.

An alternative type of immediate release layer may be a swellable layer having a composition comprising polymeric materials which swell immediately and extensively in contact with water or aqueous media to form a water permeable but relatively large swollen mass.

The active substance content can be immediately extracted from this mass.

The slow release layers have a composition comprising amoxicillin together with a release retention excipient that permits the slow release of amoxicillin. Suitable release retention excipients include pH sensitive polymers, e.g. polymers based on copolymers of methacrylic acid, such as e.g. Eudragit (trademark), polymers, e.g. Eudragit L (trademark), which can be used either alone or with plasticizers; release retention polymers having a high degree of swelling in contact with water or aqueous media such as e.g. stomach contents; polymeric substances that form a gel in contact with water and aqueous media; and polymeric substances having both swelling and gelling properties in contact with water or aqueous media.

High-swelling release polymers include inter alia cross-linked sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, high-molecular weight hydroxypropylmethylcellulose, carboxymethylamide, high-potassium methacrylate polymethyl acetate, polymethyl acrylate, polymethyl acrylate, polymethyl acrylate, polymethyl acrylate

Gel-capable release retention polymers include methylcellulose, carboxymethylcellulose, low molecular weight hydroxypropylmethylcellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols, non-crosslinked polyvinylpyrrolidone, xanthan gum, etc.

Release retention polymers having both swelling and gelling properties include medium viscosity hydroxypropyl methylcellulose and medium viscosity polyvinyl alcohols.

A preferred release retention polymer is xanthan gum, especially xanthan gum of fine mesh quality, preferably xanthan gum of pharmaceutical grade 200 mesh, e.g. product Xantural 75 (also known as Keltrol CR, Trademark, Monsanto, 800 N Lindbergh Blvd, St Luis, MO 63167, USA). Xanthan gum is a polysaccharide which, after hydration, forms a viscous gelled layer around the tablet through which the active ingredient must diffuse. The sessions showed that the smaller the particles, the slower the release rate. In addition, the rate of drug release depends on the xanthan gum used and can be adjusted to obtain the desired profile. Controlled release formulations comprising from 7.5 to 25% xanthan gum are described in EP 0 234 670-A (Boots Co pic). A preferred embodiment is a tablet comprising ibuprofen as a drug substance and 15-20% xanthan gum for administration once a day.

Examples of other polymers that may be used include Methocel K4M (brand), Methocel E5 (brand), Methocel E5O (brand), Methocel E4M (brand), Methocel K15M (brand) and Methocel K100M (brand) ). An example of a suitable polymer blend is a mixture of Methocel E5 and K4M, e.g. 1: 1 wt.

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

Such a slow-release layer may contain polymers that immediately swell in contact with water or aqueous media, forming a relatively large swollen mass that does not immediately excrete from the stomach into the intestine.

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

When using xanthan gum as a release retention polymer, the layer then contains from 60 to 80% of amoxicillin, from 1 to 25%, preferably from 2 to 15%, more preferably from 4 to 15% of xanthan gum, from 10 to 30%, preferably from 10 to 20% of fillers / compression excipients and conventional amounts of lubricants, all percentages by weight of layers. 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 by weight of the layer .

When using other release retention polymers such as xanthan gum, the slow release layer may contain from about 30 to 70%, preferably from 40 to 60% amoxicillin, from 15 to 45% release polymer, from 0 to 30% fillers / compression aids, conventional lubricants, and 5 to 20% soluble excipients, all percentages by weight of the layer.

It has been surprisingly found that when amoxicillin is in the slow-release layer in the form of its soluble salt, such as e.g. sodium amoxicillin, then its release may be retained by the inclusion of organic acid.

Therefore, in a further aspect, the present invention provides the use of a pharmaceutically acceptable organic acid as a release-retaining excipient in a formulation comprising a pharmaceutically acceptable soluble amoxicillin salt, e.g. sodium or potassium amoxicillin, preferably sodium amoxicillin.

It should be borne in mind that the use of organic acid as a release-retaining excipient is more generally suitable beyond the specific formulations described herein.

Therefore, the present invention further provides a pharmaceutical formulation comprising a pharmaceutically acceptable soluble salt of amoxicillin, e.g. sodium amoxicillin in the slow-release phase, further comprising a release-holding excipient, which is a pharmaceutically acceptable organic acid present in a molar ratio of 100: 1 to 1:10, preferably 50: 1 to 1: 5, more preferably 20: 1 to 1: 2 (amoxicillin versus organic acid).

It is believed that a good contact between the organic acid and the amoxicillin salt in a pharmaceutical formulation, e.g. as a result of compressed granular formation or direct compression into a tablet, it results in some form of interaction that modifies the release of the amoxicillin component from the formulation.

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

As used herein, the term pharmaceutically acceptable organic acid refers to organic acids which have no pharmacological effect in themselves, but which have acceptable organoleptic properties, acceptable density, have no extreme pH and are preferably solid. Examples of these include monocarboxylic and polycarboxylic acids of 2 to 25, preferably 2 to 10, carbon atoms; monocyclic and polycyclic aryl acids, such as e.g. benzoic acid, as well as monohydric, divodic, etc. metal salts of polyvalent acids. A single pharmaceutically acceptable salt may be used or two or more of such acids may be combined. Preferably, the organic acid is C₍₂-io) alkyl or alkenyl-carboxylic acid with one, two or three carboxylic acid groups and optionally with one or more hydroxy substituents or an additional CO group in the carbon chain, e.g. malonic, succinic, fumama, maleic, adipic, lactic, levulin, sorbic or fruit acids, such as e.g. tartaric, malic, ascorbic or citric acid, or an acid salt thereof, more preferably citric acid, in particular anhydrous citric acid.

Organic acid can be used alone or in combination with a release retention polymer as described herein. The preferred combination comprises citric acid and a release-retaining polymer capable of gelation, in particular xanthan gum. In the presence of an organic acid, e.g. citron gum, a lower level of xanthan gum may be used than when it is contained alone, e.g. from 0.5 to 8%, preferably from 1 to 5%, typically about 2%, based on the weight of the slow release layer.

When organic acid is used as a release-retaining excipient, the slow-release layer contains from 60 to 80% soluble amoxicillin salts, from 10 to 30%, preferably from 10 to 20% fillers / compression excipients, and conventional amounts of lubricants, wherein all percentages by weight of the layer. In a preferred embodiment, the slow-release layer comprises from 60 to 70% soluble amoxicillin salt, from 10 to 20% microcrystalline cellulose and from 1 to 2.5% magnesium stearate, all percentages by weight of the layer.

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

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

The tablet formulations of the invention may also include one or more barrier layers, which may be positioned between the respective first and second layers and / or on one or more outer surfaces of the first and second layers, e.g. on the end faces of the layers are essentially cylindrical tablets. Such barrier layers may be e.g. composed of polymers that are either substantially or completely impermeable to water or aqueous media, or capable of only slow erosion in water or aqueous media or biological fluids and / or swell in contact with water or aqueous media. Suitably, the barrier layer should be such that it retains these properties at least until the content of the active substance is completely or substantially completely transferred to the surrounding medium.

Suitable barrier layer polymers include acrylates, methacrylates, acrylic acid copolymers, celluloses and their derivatives, such as e.g. ethylcellulose, cellulose acetate propionate, polyethylene and polyvinyl alcohols, etc. Barrier layers comprising polymers which swell in contact with water or aqueous media may swell to such an extent that the swollen layer forms a relatively large swollen mass, delaying its immediate release from the stomach into the intestine. The barrier layer itself may contain the active substance, e.g. the barrier layer can be a layer for slow or delayed release. The barrier layers may have a typical individual thickness of 2 mm to 10 pm.

Suitable barrier layer polymers that are relatively watertight include Methocel (Trademark), a range of polymers mentioned above, e.g. Methocel K100M, Methocel K15M, Methocel E5 and Methocel E50, used singly or in combination or optionally in combination with Ethocel (Trademark) polymer. Such polymers can conveniently be used in combination with plasticizers such as e.g. hydrogenated castor oil. The barrier layer may also include conventional binders, fillers, lubricants and compression aids, e.g. Polyvidon K30 (trademark), magnesium stearate and silica, e.g. Syloid 244 (trademark).

The tablet formulation of the invention may be completely or partially coated with a coating layer, which may be a protective layer to prevent moisture from entering or damaging the tablet. The coating layer itself may contain the active substance and may be e.g. an immediate-release layer that immediately decomposes in contact with water or aqueous media to release the content of the active substance, e.g., amoxicillin and potassium clavulanate. Preferred coatings include hydroxypropylmethylcellulose and polyethylene glycol, with titanium dioxide as a turbidity agent, e.g. as described in WO 95/28927 (SmithKline Beecham).

Like the content of the active substance, etc., the tablet of the invention may also include a pH modifier such as e.g. pH buffer, which may be contained either in the immediate or slow release layer or in the coating around all or part of the tablet. A suitable buffer is calcium hydrogen phosphate.

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

It has been found that a satisfactory pharmacokinetic profile can be obtained for a two-layer tablet of the invention without incorporating a barrier layer. Therefore, a two-layer tablet is preferred. This also reduces the complexity of the production process.

It should be noted that 1000, 875 and 750 / 62.5 mg layered tablets having an immediate release and a slow release layer are new. Therefore, in a further aspect, the present invention provides a pharmaceutical layered tablet formulation comprising an immediate release layer and a slow release layer comprising from 700 to 1250 mg amoxicillin and a relative amount of potassium clavulanate, preferably 1000, 875 or 750 mg ± 5% amoxicillin and 62 , 5 mg ± 5% potassium clavulanate in a nominal ratio of approximately 16: 1, 14: 1 or 12: 1, in combination with pharmaceutically acceptable excipients or carriers. Preferably, the layered tablet is a two-layer tablet.

Suitably, the tablet formulations of the invention may be formulated using known compression tableting techniques, e.g. using the well known multi-layer tablet press. Preferably, in the previous step, compaction or compression with the rollers is used to form granules. Subsequently, lubricants and compression aids (if used) are added to form a compression mixture for further compression.

Preferred two-layer tablets of the invention can be made by a process comprising, as an early stage, the formation of compressed, slow-release granules, comprising the steps of: grinding sodium amoxicillin, part of the diluent / compression aid such as e.g. microcrystalline cellulose (typically about 30%), parts of a lubricant (typically about 70%) and pharmaceutically acceptable organic acids, such as e.g. fruit acid, e.g. citric acid, and then mixing with a release retardant polymer such as xanthan gum, if any, and compression aids such as e.g. colloidal silica, compression of a mixture, e.g. in a roller compactor, or by compacting, and then grinding to form slow release granules. Preferably, such granules have a size in the range of 100 to 1000 μιη. For the incorporation of xanthan gum, the session has been shown to be unexpectedly favorable for workability.

Such compressed slow release granules can then be mixed with other excipients such as e.g. residual magnesium stearate and microcrystalline cellulose to form a slow release compression mixture.

In addition, amoxicillin trihydrate, potassium clavulanate (preferably as a 1: 1 mixture with microcrystalline cellulose), microcrystalline cellulose (part of the whole used) are ground and mixed with a lubricant such as e.g. magnesium stearate (preferably about 50% of the total) and then compressed, e.g. in a roller compactor or by compacting, and grinding to form compressed granules for immediate release. These compressed immediate release granules can then be mixed with other excipients such as e.g. residual magnesium stearate and microcrystalline cellulose (about 13%), compression aids such as e.g. colloidal silica and disintegrants such as e.g. sodium starch glycolate to form an immediate release compression mixture.

Instant-release and slow-release compression mixtures can then be compressed as separate layers in a two-layer tablet press to form two-layer tablets.

Such slow release granules are new. Therefore, in a further aspect, the present invention provides compressed granules comprising a soluble amoxicillin salt, e.g. sodium amoxicillin, diluent / compression aid and organic acid or release retention polymer or mixture thereof as defined previously. In a further aspect, the present invention also provides compressed granules comprising amoxicillin trihydrate, diluent / compression aid, and release retention polymer as defined previously.

Alternatively, a dry thickening process may be used, e.g. briquetting.The active substance content, pH modifier, buffers, fillers and / or diluent, release retention agents, disintegrants and binders, when used, are typically mixed and then lubricants and compression aids are added. The whole mixture can then be compressed under high pressure in a tablet press. A wet granulation process can also be used, e.g. with isopropanol as solvent and Polyvidon K-30 (trademark) as a wet granulation auxiliary.

The barrier layer, if any, can typically be made using wet granulation techniques or dry granulation techniques such as roller compression. A barrier substance, e.g. Methocel (trademark) is typically suspended in a solvent such as e.g. ethanol containing granulating acid, such as e.g. Ethocel or Polyvidon K-30 (trademark), then blend, sift and pelletize. Typically, a first layer can be formed, and then a barrier layer, e.g. by pressing, spraying or dipping techniques, then a second layer can be formed, leaving the barrier layer as a sandwich between the first and second layers. In addition or alternatively, the first and second layers may be formed, and then a barrier layer may be formed, e.g. by compressing, spraying or dipping on one or more end faces of the tablet.

The process for the preparation of crystallized sodium amoxicillin is described in EP-A-0 131

147 (Beecham Group pic).

Potassium clavulanate is known to be very sensitive to water. Therefore, tablet formulations containing potassium clavulanate should be made in dry conditions, preferably at 30% relative humidity or less, and the formulation ingredients should be pre-dried where necessary. The tablet formulations of the invention should be stored in containers that are hermetically sealed prior to entry of atmospheric moisture.

The tablet cores can then be coated with a coating layer that can be applied from an aqueous or organic solvent system, preferably an aqueous solvent system, to provide thin-film coated tablets.

The present invention also provides a method of manufacturing a tablet formulation as described above, comprising the formation stages of said first and second layers and any barrier layers and coating layers (coating layers) that may be present.

In addition to the layer tablets described previously, other types can be used to provide an immediate release phase and a slow release phase using the excipients described previously to provide the phases in various forms. Thus, the slow release phase may form the core of the tablet, which is then surrounded by an outer coating forming an immediate release phase, optionally with an intermediate coating layer around the core and / or a final coating layer around the outer coating (WO 95/28148, SmithKline Beecham ). The slow-release phase can also be provided as granules dispersed in the matrix of amoxicillin and potassium clavulanate, the matrix forming an immediate-release phase (WO 96/04908, SmithKline Beecham).

In a further embodiment, a slow release monolithic tablet may be prepared from compressed slow release granules comprising amoxicillin, a diluent / compression aid such as e.g. microcrystalline cellulose, and a pharmaceutically acceptable organic acid such as fruit acid, e.g. citric acid (if amoxicillin is present as its soluble salt), or a release retention polymer such as xanthan gum or a mixture thereof, preferably a release retention polymer (as described previously); and from compressed immediate-release granules comprising amoxicillin and potassium clavulanate (as previously described), or compressed immediate-release granules comprising amoxicillin and potassium clavulanate, e.g. in a 2: 1 ratio, and further, from compressed immediate-release granules comprising amoxicillin (as described in WO 98/35672, SmithKline Beecham Laboratoires Pharmaceutiques), the granules being combined with specially granulated excipients to form tablets. Such granules can also be processed into other pharmaceutical formulations, e.g. into single-dose pads, capsules or chewable tablets comprising a single dose as previously described.

The chewable tablets of the invention typically comprise a chewable base formed from e.g. mannitol, sorbitol, dextrose, fructose or lactose alone or in combination. The chewable tablet may further comprise excipients, e.g. disintegrants, lubricants, sweeteners, colorants and flavorings. Such further excipients are together preferably contained from 3 to 10%, more preferably from 4 to 8%, more preferably from 4 to 7%, by weight of the tablet. The disintegrants may contain from 1 to 4%, preferably from 1 to 3%, more preferably from 1 to 2%, by weight of the tablet. Representative disintegrants include crospovidone, sodium starch glycolate, starches such as e.g. corn and rice Starch, croscarmellose sodium and cellulose products such as microcrystalline cellulose, microfine cellulose, low substituted hydroxypropylcellulose, either used individually or in a mixture. The preferred disintegrant is crospovidone. Lubricants may be present in an amount of 0.25 to 2.0%, preferably 0.5 to 1.2%, by weight of the tablet. Preferred lubricants include magnesium stearate. Preferably the sweetener is an artificial sweetener, such as e.g. saccharin or aspartame, preferably aspartame, which may be present in an amount of 0.5 to 1.5% by weight of the tablet. Preferably, the tablet of the invention is essentially sugar-free (sucrose). Preferred flavors include fruit flavors that may be natural or synthetic, e.g. peppermint, cherry and banana or mixtures thereof.

The single-dose pads of the invention include excipients typically included in the formulation of the pads, e.g. sweetener, e.g. aspartame, flavorings, e.g. fruit flavors, optionally suspending an agent such as e.g. xanthan gum as well as silica gel to act as a dryer.

The capsules of the present invention comprise in addition to the drug substance excipients typically included in the capsules, e.g. starch, lactose, microcrystalline cellulose, magnesium stearate. It should be borne in mind that due to the hygroscopic nature of clavulanate, substances such as e.g. gelatin to avoid capsule formation. Preferably, capsules are prepared from materials such as HPMC or gelatin / PEG combination.

In a further embodiment, the slow release phase can be provided as a separate component, e.g. as a separate tablet so that a single dosage is provided as a combination of a conventional component in which amoxicillin and potassium clavulanate are released immediately, optionally with a conventional amoxicillin formulation such as e.g. tablet, and further formulations, e.g. a tablet containing amoxicillin (and zero potassium clavulanate) from which amoxicillin is released slowly. The weight of potassium clavulanate and the combined weight of amoxicillin in the conventional and slow release formulations provide the complete single dose. Thus, e.g. a dose of 2000/125 mg is provided by a combination of a 500/125 mg amoxicillin / potassium clavulanate tablet and a 500 mg amoxicillin tablet in combination with a slow-release tablet comprising 1000 mg amoxicillin. Further, a dose of 1750/125 mg can be provided with the current 875/125 mg tablet (as described in WO 95/28927, SmithKline Beecham) in combination with a slow-release tablet comprising 875 mg amoxicillin. In addition, a dose of 1500/125 mg can be provided with a 500/125 mg tablet and a 500 mg amoxicillin tablet in combination with a slow-release tablet comprising 500 mg amoxicillin. Therefore, in a further aspect, the present invention provides a kit comprising a conventional (immediate-release) tablet comprising amoxicillin and potassium clavulanate, optionally a conventional (immediate-release) tablet comprising amoxicillin and a slow-release tablet comprising amoxicillin (and zero potassium clavulanate).

In a further aspect, the present invention provides a pharmaceutical formulation, preferably a tablet comprising amoxicillin (as the only active ingredient) formulated with a release-retaining excipient that results in the slow release of amoxicillin from the formulation solely:

tablets containing 750 mg amoxicillin or less, in which amoxicillin is essentially contained as amoxicillin trihydrate; or tablets comprising from 400 to 500 mg of amoxicillin in which amoxicillin is contained as a mixture comprising at least 70% of amoxicillin trihydrate and up to 30% of sodium amoxicillin, in combination with hydroxypropyl methylcellulose as a release-retaining excipient.

Such formulations may comprise from 100 to 1250 mg of amoxicillin, which may be amoxicillin trihydrate or (crystallized) sodium amoxicillin or a mixture thereof, e.g. 500, 875 or 1000 mg amoxicillin. Suitable slow release excipients are those described previously for slow release layers. The formulation may comprise from 1 to 25%, preferably from 2 to 15%, more preferably from 4 to 10% of xanthan gum or from 10 to 25%, preferably from 15 to 20% of hydroxypropylmethylcellulose, e.g. Methocel K100LV or Methocel K4M. Alternatively, such formulations may comprise citric acid, optionally with xanthan gum, as described previously.

Preferably, the unit dosage forms of the invention are packaged in containers that prevent atmospheric moisture from entering, e.g. in blisters, tightly closed bottles or dried bags, etc., which are conventional in the art. Preferred bottles also include a dryer to help preserve clavulanate. Preferably, the bottles include HDPE bottles. Preferred blisters include cold formed blisters, each blister may contain one tablet or two, where a single dose is two tablets, e.g. 2 x 1000 / 62.5 mg tablets to improve patient compliance.

The present invention is further described in the Examples with reference to the accompanying drawings, in which:

FIG. 1 shows the structure of the various types of layered tablets of the invention, in particular the structure of substantially cylindrical compressed tablets is shown in longitudinal section. In FIG.

1Α comprises a first layer tablet (1) and a second layer (2) without any barrier or coating layer. In FIG. IB comprises a tablet of the first layer (1), the second layer (2) and a barrier layer (3) inserted between the first layer (1) and the second layer (2). FIG. 1C shows a tablet comprising a first layer (1), a second layer (2) and a barrier layer (3) mounted on the end face of the second layer (2). In FIG. 2 showing a tablet comprising a first layer (1), a second layer (2), a barrier layer (3) inserted between the first layer (1) and the second layer (2), and a coating layer (4) partially covering tablet. The dashed line shows the possibility of a coating layer (4A) covering the entire tablet. FIG. IE shows a tablet comprising a first layer (1), a second layer (2) and a third layer (3) in between the first layer (1) and the second layer (2). All three of these layers (1), (2) and (3) include the active substance content.

All publications and references, including, but not limited to, patents and patent applications cited in this specification, are hereby incorporated by reference in their entirety, as if for each individual publication or reference were specifically and individually stated to be incorporated herein by reference, as is fully explained. Any patent application for which this application claims priority is also incorporated herein by reference in its entirety in the manner described above for publications and references.

Example 1 - 1000 / 62.5 mg modified release tablet

<td>Ingredient</td><td>mg / tablet</td><td>wt./mas.%</td>

<td colspan="3">Instant release layer</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 silica</td><td> 6,3</td><td> 0,39</td>

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

<td>total (instant release layer)</td><td> 900,0</td><td> 56,23</td>

Slow release layer

<td>crystallized sodium amoxicillin</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 silica</td><td> 1,50</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>Thin film coating</td><td></td><td></td>

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

<td>hydroxypropyl methylcellulose 2910 6cp</td><td> 11,6</td><td></td>

<td>hydroxypropyl methylcellulose 2910 15cp</td><td> 3,9</td><td></td>

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

<td>polyethylene glycol 3350</td><td> 2,3</td><td></td>

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

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

equivalent to 562.5 mg amoxicillin, based on test 86.0% # equivalent to 62.5 mg clavulanic acid, based on test 82.0% ** equivalent to 437.5 mg amoxicillin, based on test 91.0%.

Example 2 - 1000 / 62.5 mg modified release tablet

The immediate release layer and the thin film coating are the same as those of the Example 1 tablet

<td>Ingredient</td><td>mg / tablet</td><td>wt./mass</td>

<td colspan="3">Slow release layer</td>

<td>crystallized sodium amoxicillin</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></td><td> 34</td><td></td>

<td>colloidal silica</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>The total weight of the coated tablet</td><td> 1635,2</td><td></td>

** equivalent to 437.5 mg amoxicillin, based on 91.0% test.

Preparing tablets for modified release

Modified release tablets are prepared from immediate and slow release blends in a batch process in the range of 900 resp. 700 kg. For immediate release mixture, dry microcrystalline cellulose (1), amoxicillin trihydrate (2) and (5) (1: 1 ratio), potassium clavulanate / dried microcrystalline cellulose mixture (1: 1) and magnesium stearate (approximately 50) are placed in containers for immediate release. % of total) (4). The contents of containers (1) and (2) are passed through the openings, ground in a Fitzmill mill operating at 1500 rpm and mixed with the contents of the container (3). The contents of the container (4) are then sieved and milled and mixed with the initial mixture, and then mixed with the contents of the container (5), which have been subjected to previous sieving and grinding stage. This mixture is then subjected to compression by cylinders, using a Chilsonator that operates at a pressure of 6.7x10.⁶ Pa ± l, 34xl0⁶ Well, we grind and sift the product with a 14 and 80 mesh vibrator to provide immediate release granules. The remaining excipients (colloidal silicon dioxide, magnesium stearate, dried microcrystalline cellulose and dried sodium starch glycolate) are then sieved, milled and combined with a portion of immediate release granules in a mixer and mixed, and then combined with the remaining granules to form and mix.

For the slow release mixture, dry microcrystalline cellulose (about 70%) and anhydrous citric acid (1), sodium amoxicillin (2) and (4) (1: 1 ratio) and magnesium stearate (about 70%), colloidal, are placed in the containers. silica and xanthan gum (3). The contents of containers (1) and (2) are then sieved and milled in a Fitzmill mill, then mixed with the contents of the container (3) and then the contents of the container (4), which have been ground and sieved in the previous step. This mixture is subjected to compression with cylinders on a Chilsonator operating at a pressure of 4.0 χ 10⁶ Pa ± 0.7 x 10⁶ Well, grind and sift to provide slow-release granules. The remaining excipients (magnesium stearate, dried microcrystalline cellulose) are screened and combined with a portion of the slow-release granules, mixed and then added to the remaining slow-release granules and mixed to provide an SR mixture.

The IR and SR mixtures are then compressed as separate layers in a two-layer tablet press equipped with tools measuring 0.1 cm x 2.2 cm and having a modified capsule shape. For the first (immediate release) layer, there is no overpressure, and the main compression is less than 10 kN. For the second layer, the overpressure is less than 20 kN and the main compression is less than 60 kN. The tablets thus produced have a total weight of 1600 mg ± 48 mg, a hardness in the range of 8 to 18 SCU and a brittleness of less than 0.5%.

Finally, the tablet cores are coated with an aqueous thin film coating in a pan (152.4 cm) for coating, which operates at 300 kg sub-batch. Equip the pan with 4 spray guns and rotate it from 3 to 5 rpm. Humidity is removed from the inlet air at a temperature in the range of 56 to 60 ° C, while the outlet air has a humidity in the range of 4 to 12% and a temperature in the range of 43 to 50 ° C. The spray rate is 80 to 120 ml / min / spray gun.

<td>Example 3 - Slow-release tablet</td><td>(875 mg)</td><td></td>

<td>(a) Amoxicillin sodium tablet</td><td></td><td></td>

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

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

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

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

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

a total of 1300 100 (b) citric acid sodium amoxicillin tablet

<td>crystallized sodium amoxicillin 91% *</td><td>mg / tablet 961,54</td><td> % 66,31</td>

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

<td>total</td><td> 1450</td><td> 100</td>

(c) Amoxicillin trihydrate tablet

<td>$ amoxicillin trihydrate 86%</td><td>mg / tablet 1017,4</td><td> % 78,26</td>

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

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

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

<td>total</td><td> 1300</td><td> 100</td>

adjusted for the capacity of the amoxicillin component and corresponds to 875 mg amoxicillin ** xantural 75

Example 4 - 875 / 62.5 mg modified-release tablet

Slow release layer

This can be formed using the half amounts given above for a slow-release layer comprising about 438 mg of amoxicillin.

Instant-release layer - 1 amoxicillin trihydrate (eq. For amoxicillin free acid)

507 mg (438) potassium clavulanate (eq. for clavulanic acid) microcrystalline cellulose (Avicel PH102) sodium starch glycolate (Explotab) magnesium stearate

71,8 (62,5)

125

6,5

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

Instant-release layer - 2 Amoxicillin trihydrate (eq. For amoxicillin free acid) potassium clavulanate (eq. For clavulanic acid) microcrystalline cellulose (Avicel PH102) sodium starch glycolate (Explotab) talc magnesium stearate

507 mg (438) 71.8 (62.5)

135

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

Partition layers

Barrier layers and processes for preparing them are described in WO 95/20946 (SmithKline Beecham).

Preparation of tablets

Mix active ingredients, fillers and thinners (microcrystalline cellulose), release control agents (if any) and disintegrants (crospovidone, sodium starch glycolate), etc. Lubricants (talc, Mg stearate) and colloidal silica (Syloid 244) were added and stirring was continued for another minute. The whole mixture is compacted on a tablet press or compressed with rollers (briquetting rate), then reduced in size (Apex, Fitzmill, Frewitt) and passed through an oscillate sieve or particle size classifier (Kason, Sweco). If the flowability is unsatisfactory, repeat the briquetting step. Separate compressed mixtures should be prepared for immediate and slow release layers and, if any, bulkhead.

In some cases where the bulk density is rather low, a compaction rate (pre-tabletting and sieving, as in the briquetting method) is required in order to obtain a nominal mass of the special layer.

The mixtures are then compressed as separate layers on a layer-pressed tablet to form a two-layer tablet. The tablets can then be coated with a white matte coating, e.g. product of Opadry, Opaspray (Colorcon).

Example 5 - Dissolution test methods

The release of amoxicillin and clavulanate from tablets in static media was measured using the dissolution test &lt;711&gt;, apparatus 2, cited in USP 23, 1995.

Test Specifications:

temperature: 37.0 ± 0.5 ° C medium: deionized water, 900 ml speed: 75 rpm.

The method

Aliquots of the media were removed for testing after 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min., Replacing each aliquot simultaneously with the same volume of medium to maintain a constant volume. The amount of drug substance was determined by UV spectrometry at 272 nm. The resulting dissolution profiles of the tablets of Examples 1 and 2 are shown in FIG. 2.

Pharmacokinetic evaluation of in vivo formulations

The bioavailability of doses of the present invention is assessed by studies in two human volunteers, Study A and Study B. These are open-label, random, cross-sectional studies in healthy volunteers. Each dose is given with approximately 200 ml of water at the beginning of a light breakfast and after an overnight fast. Blood samples were collected in tubes containing EDTA at nominal pre-dose times and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after initiation of dosing for the plasma test amoxicillin and clavulanate levels. The samples were cooled in an ice bath, where they were allowed to wait for further treatment. Plasma was separated by cooled centrifugation at 4 ° C and transferred to appropriately labeled polypropylene sample containers and stored frozen at approximately -70 ° C for testing.

Samples are tested for amoxicillin using a method based on protein staining with acetonitrile. Amoxicillin was extracted from human plasma (50 μπύ) by protein precipitation using acetonitrile containing the internal standard and quantified by LC / MS / MS. In more detail, the human plasma (50 μΐ) was pipetted into 1.5 ml Eppendorf tube and then acetonitrile containing the internal standard ([C₆] -amoxicillin, 200 μΐ). Close the tube, vortex stir and shake for about 15 minutes. After centrifugation of the sample (approximately 11000 g for 15 minutes), transfer the supernatant to a silanized 1.1 ml conical autosampling vial containing 200 μΐ 5 mM ammonium acetate solution. An aliquot of the extract was injected into the HPLC / MS / MS assay system. The mass spectrometer operates on the principle of positive ions using the Turbo IonSpray boundary plane. Multiple Reaction Control (MRM) is used to detect components, amoxicillin and [¹³C6] -amoxicillin. The MRM process involves (1) mass selection of the characteristic ion of the drug or internal standard required in the first quadrupole mass analyzer, (2) fragmentation of the selected ion in the instrument collision cell, (3) detection of the fragment ion characteristic of the compound of interest. The quantification is performed by comparing the surface of the chromatographic tip of the drug with the surface of the internal standard. Linear responses at the peak area ratio of the analyte / intem standard are observed for analyte concentrations in the range of 0.05 pg / ml (lower limit of quantitation; LLQ) to 10 pg / ml (upper limit of quantitative determination: ULQ).

Samples were tested for clavulanate using a protein-based acetonitrile staining method. The clavulanate was extracted from human plasma in a liquid / liquid manner using an internal standard and quantified by LC / MS / MS. In more detail, the human plasma (50 μΐ) was pipetted into 1.5 ml Eppendorf tube and then 0.2 mM ammonium acetate (200 μΐ) was added before the addition of acetonitrile containing the internal standard (6-aminopenicilic acid, 400 μΐ). Cover the tube, vortex stir and shake for about 20 minutes. After centrifugation of the sample (approximately 14500 g for 15 minutes), transfer the supernatant into a clean Eppendorf tube and add dichloromethane. After further stirring and centrifugation (approximately 14500 g for 10 minutes), the supernatant (not more than 150 μΐ) was transferred to a conical 1.1 ml autosampling vial and allowed to open 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 assay system. The mass spectrometer operates on the principle of positive ions using the Turbo IonSpray boundary plane. Multiple Reaction Control (MRM) is used to detect components, clavulanate and 6-aminopenicillanic acid. The MRM process involves (1) mass selection of the characteristic ion of the selected drug or internal standard in the first quadrupole mass analyzer, (2) fragmentation of the selected ion in the instrument collision cell, (3) detection of the fragment ion characteristic of the compound of interest. The quantification is performed by comparing the surface of the chromatographic tip of the drug with the surface of the internal standard. Linear responses at analyte / intemal peak area ratios are observed for analyte concentrations in the range of 0.05 pg / ml (lower limit of quantitation; LLQ) to 10 pg / ml (upper limit of quantitative determination: ULQ).

QC samples are tested for each batch of samples against separately prepared calibration standards. The results of the QC samples are used to determine the day-to-day performance of the test.

Plasma Concentration Data - Time for each subject in each regimen was analyzed by non-compartmental methods using the WinNonlin Professional Version 1.5 noncompartmental pharmacokinetic analysis program. All calculations are based on actual sampling times. The pharmacokinetic parameters identified include maximum detected plasma concentration (Cmax) and time to reach maximum plasma concentration (Tmax). The apparent terminal elimination rate constant (lz) is derived from the log-lineame disposition phase of the concentration-time curve using linear least squares regression with visual data control to determine the appropriate number of points to calculate lz. The apparent terminal elimination half-life (Tl / 2) is calculated as ln (2) / lz.

The area under the plasma concentration curve - time from time 0 to the last quantifiable plasma concentration [AUC (Ot)] is determined using a linear trapezoidal rule for each incremental trapezoid and a log trapezoidal rule for each incremental trapezoid [Chiou WL ., J. Pharmacokinet. Biopharm., 1978, 6, 539-547], The area under the plasma concentration curve - time extrapolated to infinity [AUC (O-inf)] is calculated as the sum of AUC (Ot) and C (t) / lz, where C (t) predicted concentration from log-lineame regression analysis at the last measurable time point.

The time above the minimum inhibitory plasma concentration (T&gt; MIC) is calculated manually by graphical interpolation, where the minimum inhibitory plasma concentration is defined as 4 pig / ml for amoxicillin.

Average concentration-time profiles for amoxicillin and clavulanate are derived from each nominal sampling time for each formulation. In cases where the post-dose value cannot be quantified, 1/2 LLQ (0.050 μg / ml) is determined to determine the average value. Where the calculated average value is less than LLQ or based on a value greater than 50% NQ, the NQ value is determined for that sampling time.

Log_e-transformed Cmax and untransformed T&gt; MIC for each formulation were analyzed using covariance analysis (ANCOVA), which adjusts a single expression for the formulation and fits the reference formulation data as covariates. 95% confidential intervals for averages are formulated for each formulation using residual variance from the model. For Cmax, we then transform back the confidential interval specified on the log scale to obtain 95% of the confidential intervals of the geometric mean. These results are shown graphically.

The assumptions underlying the analyzes are determined by controlling the residual graphs. The homogeneity of variance is determined by graphically representing the residuals studied compared to the predicted values ​​of the model, while normal is determined by using normal probabilistic graphical representations. Particular attention should be paid to any remote values ​​detected in the reference formulation.

Study A

The first study compares three modified-release doses of 1750/125 mg (Formulations I to III) and a fourth modified-release dose of 1500/125 mg (Formula IV) with an immediate release dose of 1750/125 mg (Formulation V), as follows:

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

(b) a dose of 1750/125 mg of amoxicillin / potassium clavulanate consisting of a combination of one modified-release tablet comprising 875/125 mg of crystallized sodium amoxicillin / clavulanate and 4% xanthan gum, and one immediate-release tablet comprising 875 mg amoxicillin trihydrate (formulation II);

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

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

Results

<td>Formulation</td><td>n</td><td>Cmax¹</td><td>T&gt; MIC¹²</td><td>AUC^1,3</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 the amoxicillin concentration of 4 pg / ml ³ curve area (0 to 12 h, pg.h / ml)

The pharmacokinetic profile is shown in Figure 3.

Study B

Another study investigates two different 2000/125 mg modified-release doses (formulations VI and VII) compared to the 2000/125 immediate-release mg dosage (formulation VIII), namely:

(a) a dose of 2000/125 mg of amoxicillin / potassium clavulanate consisting of two two-layer tablets in accordance with Example 1 (formulation VI);

(b) a dose of 2000/125 mg of amoxicillin / potassium clavulanate consisting of two two-layer tablets in accordance with Example 2 (formulation VII);

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

Results

<td>Formulation</td><td>n</td><td>- - Cmax</td><td>T&gt; MIC^1,2</td><td>T&gt; MIC^1,3</td><td>AUC¹’⁴</td>

<td>VI</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 the amoxicillin concentration of 4 pg / ml ³ T&gt; MIC is the time (h) above the amoxicillin concentration of 8 pg / ml ⁴ curve area (0 to 12 h, pg.h / ml)

Comparison of the AUC values ​​for Formulations VI and VII (two-layer tablets) with Formulation VIII (immediate-release tablets) shows that the absorption of the amoxicillin component was not compromised by formulating part of it in the slow-release layer. This means that there is no specific unabsorbed amoxicillin that could otherwise cause problems lower in the gastrointestinal tract, e.g. due to lack of absorption and destruction of symbiotic bacteria.

We also found that formulation VI had less intra-subject variability in amoxicillin plasma concentrations than formulation VII. These formulations are identical except that formulation VI also comprises xanthan gum (2%) in the slow release layer.

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

The pharmacokinetic profile for the clavulanate component is essentially the same for the two-layer and immediate-release tablets, indicating that its bioavailability is not compromised by incorporation into the immediate-release layer of the two-layer tablet.

The present invention also encompasses formulations that are bioequivalent to tablets of Formulas VI and VII in terms of both rate and extent of absorption, e.g. as defined by the US Food and Drug Administration and discussed in the Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations, US Dept. of Health and Human Services, 19th ed., 1999).

Reference data

The current Augmentin 875/125 mg tablet has a Cmax value of 11.6 ± 2.8 μg / ml (Physicians Desk Reference, Medical Economics Co., 52nd ed., 1998, 2802). The time above the MIC is about 40% of the 12 μm dosing interval for MIC 2 pg / ml and about 30% for MIC 4 pg / ml (SmithKline Beecham data).