UA71609C2 - Dosage form with delayed release and method for treating bacterial infections - Google Patents

Abstract

Bacterial infections may be treated using a high dosage regimen of amoxycillin and potassium clavulanate. Preferably, the dosage is provided by a bilayer tablet.

Description

was reduced. Opposite, Niyup ei ai. (Choshtai oi Rnapptaseciisa! Zsiepsev5, 1993, 82, 737-743) described a 750 mg controlled-release tablet that includes an enteric-soluble polymer - hydroxypropyl methylcellulose acetate succinate. At the same time, however, no advantage over conventional capsules was shown. In particular, bioavailability was reduced to 64,695 compared to the same dose received in a capsule. Later Neutap ei aiYi. (Chotsgtpa! oi Sopigoei VRieazie, 1998, 54, 29-37 and

M/098/22091) described tablets containing 500 mg of amoxicillin in a matrix consisting of hydroxypropylmethylcellulose, designed to release 5095% of their content after the first three hours, and to complete the drug release process after eight hours. The time when BMD is exceeded was found to be significantly increased compared to the drug in capsules, but not enough for a 12-hour interval between doses. The discussion takes place in the context of the theoretical MIC equal to 0.2μg/ml.

Part of the problem with obtaining amoxicillin preparations in which drug release is effectively altered (and a ready explanation for the lack of success in the studies already mentioned) is the relatively narrow window for drug absorption in the small intestine and the relatively short half-life of the drug in the body. Moreover, the rapid elimination of amoxicillin (elimination half-life is 1.3 hours) makes it difficult to maintain serum levels because clearance from the body is very rapid.

In existing tablet preparations containing amoxicillin and clavulanate potassium, amoxicillin is present in the form of amoxicillin trihydrate, because the use of this form gives tablets with higher storage stability than tablets in which amoxicillin is present in the form of amoxicillin sodium salt (see . sav2go05538, Veespat. Stotsr CA). Amoxicillin sodium, however, is used as an amoxicillin component in existing amoxicillin dosage forms, and potassium clavulanate is used for IV administration. The amoxicillin sodium form is used in a spray-dried form. In addition, in the patent

ЕРО131147-А1 (Vespat (Sagoir ris) describes an additional form of amoxicillin sodium, the so-called "crystalline amoxicillin sodium". An additional process for obtaining amoxicillin salts, including amoxicillin sodium, is described in U/099/62910 (ZtiiKipe Veespat). Amoxicillin sodium relatively well soluble in water compared to amoxicillin trihydrate.

Dosage forms comprising clavulanic acid and a pharmaceutically acceptable organic acid or its salt derivative, for example, calcium citrate, are described in UUO96/07408 (ZtiiiKiipe Veespat).

In such drugs, it is stipulated that the presence of calcium citrate should suppress gastrointestinal intolerance associated with oral intake of clavulanate-containing products.

In addition, US Patent 5,051,262 (EIap Sogr) describes the incorporation of an organic acid into a modified release dosage form to provide a microenvironment in which locally modified pH helps protect the active ingredient from degradation.

The increasing resistance of those pathogens found in respiratory tract infections to anti-infectives such as amoxicillin/clavulanate potassium, in particular, drug-resistant 5.rpeshtopiae, is of concern. Increased resistance to penicillin in 5.rpeshtopiae (due to altered proteins binding to penicillin) is developing worldwide and affects the clinical outcome of the disease (see, for example, Arrierat R.S., Ed. Ip'. Oiv. U, 1996 , 15(10), 932-9). These penicillin-resistant 5.rpentopiae (PRB5r) are also called "ULRbr" because they often show reduced sensitivity not only to penicillin, but also to a wide range of antimicrobial drug groups, including macrolides, azalides, beta-lactams, sulfonamides, and tetracyclines. Amoxicillin (with or without clavulanate), together with some of the newer quinolones, remains among the most active oral drugs against secreted strains of 5.rpestopiae with increased resistance, judging by both the BMD levels and the pharmacokinetic properties of these compounds. The degree of resistance (and IPC), however, continues to increase. Penicillin resistance in 5.rpeshtopiaye can be evaluated according to the criteria developed by Mayiopa! Sotticee og Siipisa! And arogayugu 5iapadaagav (MOSI 5), in the following way: sensitive strains have an IPC of 0.0 bmkg/ml, moderate resistance is defined as an IPC in the range from 0.12 to 1.Omkg/ml, while resistance to penicillin is defined by an IPC of 2 2 μg/ml. In addition, it was found that for approximately 1095 pneumococci, the current MIC of amoxicillin is 2 μg/ml.

Therefore, there is a need to obtain new dosage forms of amoxicillin/clavulanate, which combine known safety characteristics and a wide spectrum with improved activity against LRP, including PROpR, with higher MICs in the empiric treatment of respiratory infections, in which the probable causative agents are 5.rpeshtopiae, N.ipPpepgaye and M.sayattpayiv.

As for (p-lactams, including amoxicillin, it is known that the time during which the concentration of the drug is above the minimum inhibitory concentration (its » MIC) is the pharmacodynamic parameter most closely related to effectiveness. For a number of (p-lactams, the degree of bacteriological treatment equal to 85 to 10095 is achieved when serum concentrations exceed the MIC for more than approximately 4095 of the interval between the administration of doses (Stayid apa Apaev, Ray. Ip?i. Oiv. U, 1996, 15, 255-259). Relatively 12 - hourly interval between administration of doses is approximately 4.8 hours.

An additional parameter that may be important is the ratio of the maximum plasma concentration (Smax) to the MIC value, as this may be related to the possibility of selection for resistance.

Too low a ratio can promote the development of resistant strains. Preferably, when the value of Sm in plasma is significantly higher than the MIC value, for example, at least two times, more preferably, at least three times, most preferably, at least four times, higher than the MIC value.

In a clinical trial using existing Augmentin 875/125mg tablets, it was found that when doses were administered 12 hours apart, the time to concentrations above the MIC was approximately 4095 relative

MIC 2mcg/ml, but only about 3095 - relative to MIC 4mcg/ml. Existing tablets of Augmentin 875/125mMg give an Amax value of 11,622.8mcg/ml (Rpusisiapz OezKk Neiegepse, Medisa! Esopotisv So, 52 Ediop, 1998, 2802).

From the foregoing discussion, it appears that there is a continuing need for new amoxicillin/clavulanate dosing regimens that provide optimized pharmacokinetics relative to amoxicillin while not reducing the bioavailability of clavulanate so that therapy is maximized.

especially in relation to more resistant bacteria, while the (further) development of resistance is minimized. It has now been found that this can be achieved using the previously discussed dosages of amoxicillin.

Accordingly, in the first aspect, the present invention provides a method of treating bacterial infections in humans, which includes oral administration by them of 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 from 1950 to 25500 mg, and the amount of potassium clavulanate such that the weight ratio of amoxicillin to clavulanate is from 271 to 201, preferably from 7:1 to 201, more preferably from 14:21 to 201, at intervals of approximately 12 hours.

Preferably, the dosing regimen provides an average amoxicillin plasma concentration of 4 mcg/mL for at least 4.4 hours, preferably for at least 4.6 hours, more preferably for at least 4.8 hours, most preferably for approximately 6 hours or more

It is more preferable that the dosage regime provides an average concentration of amoxicillin in plasma equal to Zmkg/ml for at least 4.4 hours, more preferably at least 4.6 hours, most preferably at least 4.8 hours.

Preferably, the dosage regime provides an average maximum concentration of amoxicillin in plasma (Smax) equal to at least Zmcg/ml, preferably at least 12mcg/ml, even more preferably at least 14mcg/ml, most preferably at least 16mcg/ml.

Preferably, the average concentration of amoxicillin in plasma and the average maximum concentration of amoxicillin in plasma are determined after oral administration of the drug containing amoxicillin at the beginning of a light meal.

In an additional aspect, the present invention provides a method of treating bacterial infections in humans, which includes administering to them a therapeutically effective amount of amoxicillin and potassium clavulanate, such that the amount of amoxicillin is in the range of from 1400 to 1900mg, preferably from 1500 to 1900mg, and the amount of potassium clavulanate is such that that the weight ratio of amoxicillin to clavulanate is from 26:11 to 1471, preferably from 7:1 to 14:1, more preferably from 12:1 to 1471, at intervals equal to about 12 hours, so that the dosage regimen provides an average concentration amoxicillin in plasma equal to 4 μg/ml for at least 4.4 hours, preferably at least 4.6 hours, more preferably at least 4.8 hours, most preferably at least 6 hours or more; more preferably, the dosing regimen provides a mean amoxicillin plasma concentration equal to dmkg/ml for at least 4.4 hours, more preferably at least 4.6 hours, most preferably at least 4.8 hours, and a mean peak concentration of amoxicillin in plasma (Smax) equal to at least Zmkg/ml, preferably, to a lesser extent, 12mkg/ml, even more preferably, at least 14mkg/ml, most preferably, at least 1bmkg/ml.

Bacterial infections amenable to treatment according to the present invention include infections caused by P. rpestopiae microorganisms (including drug-resistant Z. rpestopiae (IRbr), for example, penicillin-resistant P. rpestopiae (PROr) ) and/or pathogens that produce beta-lactamase respiratory infections, most significantly, N. ipisheplaye M. saiagtaii5, such as respiratory tract infections, including household pneumonia (SAP-BP), exacerbation of chronic bronchitis (AEV-OCHB) and acute bacterial sinusitis (AB5-OBS), in which a more significant break in the course of the disease is achieved due to improved pharmacokinetic characteristics compared to existing antibacterial agents. Most respiratory infections in ambulatory patients are caused by either 5. rpestopiae and/or beta-lactamase-producing bacteria and are treated empirically, so there is a continuing need for a method of their treatment, such as that of the present invention, which provides a spectrum of action covering all such causative agents The duration of therapy will usually be between 7 and 14 days, usually 7 days for indications such as exacerbation of chronic bronchitis, but 10 days for acute bacterial sinusitis. Usually, dosage regimens are developed for adult patients rather than for pediatric patients.

The term "amoxicillin" is used generally to refer to amoxicillin or its alkali metal salts, in particular, amoxicillin trihydrate and (crystalline) amoxicillin sodium without distinction, and unless otherwise specified.

Unless otherwise stated, the weight of amoxicillin and (potassium) clavulanate means the equivalent weight of the respective free acids. In addition, it will be understood that in practice the weight of amoxicillin and clavulanate to be included in the dosage form will further be established according to generally accepted practice, taking into account the activity of amoxicillin and clavulanate.

In the first embodiment, the dosage of amoxicillin from 1900 to 2600 Ωg and the corresponding amount of potassium clavulanate can be given by an immediate-release dosage form. Accordingly, in an additional aspect, the present invention provides a method of treating bacterial infections in humans, which includes administering to them a therapeutically effective amount of amoxicillin and potassium clavulanate, such that the amount of amoxicillin is in the range from 1900 to 2600, preferably from 1950 to 255Omg, and the amount of potassium clavulanate such that the weight ratio of amoxicillin to clavulanate is from 2:1 to 201, preferably from 7:1 to 201, more preferably from 14:1 to 2071, at intervals equal to about 12 hours, and the dose is delivered from a dosage form with immediate release

As used herein, the term "immediate release" refers to the release of most of the active ingredient content in a relatively short period of time, such as within 1 hour, preferably within 30 minutes, after oral administration. Examples of such immediate-release dosage forms include conventional oral tablets, dispersible tablets, chewable tablets, single-dose sachets, and capsules.

Typical doses include 2000/125, 2250/125, and 250/125 mg of amoxicillin and clavulanate potassium, respectively.

The best dose is 2000/125 mg of amoxicillin and potassium clavulanate.

An immediate-release dosage form may be presented as a single tablet, e.g., a dispersible tablet, a chewable tablet that may also be effervescent and/or dispersible, a single-dose capsule, or a single-dose sachet containing , for example, 2000, 2250 or

2500 mg of amoxicillin and 125 mg of potassium clavulanate. Alternatively, the dosage can be made in the form of a number of smaller tablets or capsules, for example 2, 3 or 4, some of which may be the same and some of which may contain only amoxicillin and no potassium clavulanate. Examples of such smaller tablets include swallowable tablets, dispersible tablets and chewable tablets, which may also be effervescent or dispersible. So, for example, a dosage of 2000 mg of amoxicillin and 125 mg of potassium clavulanate can be represented by a combination of three tablets, each of which contains 500 mg of amoxicillin and one tablet containing 500 mg of amoxicillin and 125 mg of potassium clavulanate. Alternatively, this dosage can be presented as two tablets, each of which contains 1000/62.5 mg amoxicillin/clavulanate potassium. In addition, a dose of 2250 mg of amoxicillin and 125 mg of clavulanate potassium can be represented by a combination of four tablets containing 500 mg of amoxicillin and one tablet containing 250 mg of amoxicillin and 125 mg of clavulanate potassium, or two tablets containing 875 mg of amoxicillin and one tablet containing 500 mg amoxicillin and 125 mg of potassium clavulanate. In addition, the dosage of 2500 mg of amoxicillin and 125 mg of potassium clavulanate can be represented by a combination of four tablets containing 500 mg of amoxicillin and one tablet containing 500 mg of amoxicillin and 125 mg of potassium clavulanate. Tablets containing 500 and 875 mg of amoxicillin and 250/125, 500/125 and 875/125 mg of amoxicillin/clavulanate potassium are now available for purchase.

It will be understood that the immediate release tablets containing 1000/62.5mg are new. Accordingly, in an additional aspect, the present invention provides an immediate release tablet formulation containing 1000mgE5905 amoxicillin and 62/5mgE590 potassium clavulanate in a nominal ratio of approximately 16:11 in combination with pharmaceutically acceptable excipients or carriers. Immediate-release tablets containing 1000/62.5 mg can be easily obtained by adapting the compositions previously described for the 875/125 and 1000/125 mg tablets (see, for example, M/095/28927 and UUO98/35672, ZtiyKiipe Veespat).

It will also be understood that immediate-release single-dose sachets containing 2000/125mg, 2250/125mg, or 2500/125mg, or their corresponding half amounts, are new. Accordingly, in an additional aspect, the present invention provides an immediate release dosage form in a single dose sachet containing 2000, 2250 or 2500 mgE-595 amoxicillin and 125 mg-590 potassium clavulanate at a nominal ratio of approximately 16:1, 18:11 or 20:1, respectively, or their respective half amounts, in combination with pharmaceutically acceptable excipients or carriers. Such sachets can be easily produced by adapting the compositions previously described for the 875/125 and 1000/125mg sachets (see, for example, UUO92/19277 and M/O98/35672, 5tiyNKiIipe Veespat).

In addition, it will be understood that immediate release chewable tablets containing 2000, 2250 or 2500/125mg are new. Accordingly, in an additional aspect, the present invention provides an immediate release dosage form in the form of chewable, optionally effervescent, tablets containing 2000, 2250 or 2500 mg of amoxicillin and 12524595 potassium clavulanate at a nominal ratio of 16:1, 18:11 or 201, respectively, or their corresponding half amounts in combination with the base for chewable tablets, and, if they are effervescent, effervescent steam, and other pharmaceutically acceptable fillers and carriers. Such chewable tablets can be easily obtained by adapting the compositions previously described for chewable tablets containing amoxicillin and clavulanate potassium (see, for example, EP-A-0396335, Veespat Stor and UUO98/35672, ZtiyKiipe

Veespat).

In a second embodiment, a dosage of amoxicillin equal to 1900 to 2600 Ωmtg and an appropriate amount of potassium clavulanate can be delivered from a modified release dosage form. Accordingly, in an additional aspect, the present invention provides a method of treating bacterial infections in humans, which comprises 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 2600mg, preferably 1950 to 2550mg, and potassium clavulanate is present in a proportional amount such that the weight ratio of amoxicillin to potassium clavulanate is from 2:1 to 2011, preferably from 7:1 to 20:1, more preferably from 14:1 to 2071, at intervals of about 12 hours, wherein the dose is delivered from a modified release dosage form.

In a third embodiment, a dose of amoxicillin equal to 1400 to 1900 Ω and an appropriate amount of clavulanate can be delivered from a dosage form with a modified release. Accordingly, in an additional aspect, the present invention provides a method of treating bacterial infections in humans, which comprises 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 potassium clavulanate is present in a proportional amount so that the weight ratio of amoxicillin to clavulanate is from 2:1 to 1471, preferably from 7:1 to 14:1, more preferably from 12:1 to 14:1, at intervals equal to about 12 hours, at in which the dose is delivered from a modified-release dosage form.

As used herein, the term "modified release" refers to the release of a drug substance from a dosage form that occurs at a slower rate than from an immediate release dosage form, such as a conventional oral tablet or capsule, and may include an immediate release phase and a slow release Modified release dosage forms are well known to those skilled in the art, see, e.g., NKetipdiyuop, Te bsiepse apa Rgasiise oi Rnagtasu, Mipeieepii Edp, 1995, Musk Rybiizpipd So., Reppzuimapia, O5A.

Preferably, dosage forms with a modified release of this invention are made so that the release of amoxicillin is carried out mainly in the stomach and small intestine, so that absorption at the site of specific absorption of amoxicillin in the small intestine increases as much as possible. Preferably, the release pattern of amoxicillin consists of a release from the immediate-release component, which is then supplemented and prolonged by a sustained release from the slow-release component.

Preferably, clavulanate potassium is released from the dosage form virtually immediately when the dosage form reaches the stomach and is absorbed there, thereby minimizing the risk of destruction from prolonged stay in the stomach. Such dosage forms are preferably manufactured in such a way that the release of amoxicillin and potassium clavulanate occurs mainly within 3 hours after taking the dosage form.

Usually the dosage will be 125mg of potassium clavulanate, which is the accepted amount for existing regimens where a smaller amount of amoxicillin is administered.

Typical modified-release dosages include 1500/125, 1750/125, and 2000/125 mg of amoxicillin and clavulanate potassium, respectively. The best dosage is 2000/125 mg of amoxicillin and potassium clavulanate.

A dose in a modified-release dosage form may typically be presented as a number of swallowable tablets or capsules, for example, two, three or four, some of which may be the same, and some of which may contain only amoxicillin and no potassium clavulanate. So, for example, a dosage of 2000 mg of amoxicillin and 125 mg of potassium clavulanate can be represented by two tablets, each containing 1000/62.5 mg of amoxicillin/clavulanate potassium, one tablet containing 1000 mg of amoxicillin and one tablet containing 1000/125 mg of amoxicillin/clavulanate potassium, two tablets each containing 500mg amoxicillin and one tablet containing 1000/125mg amoxicillin/clavulanate potassium or four tablets each containing 500/32.25mg amoxicillin/clavulanate potassium. In addition, the dosage of 1750 mg amoxicillin and 125 mg clavulanate potassium can be presented as two tablets, each containing 875/62.5 mg amoxicillin/clavulanate potassium, or one tablet containing 875 mg amoxicillin and one tablet containing 875/125 mg amoxicillin/ potassium clavulanate. The best tablet contains 1000/62.5 mg amoxicillin/clavulanate potassium.

Modified-release dosage forms may also be presented as a single tablet. Because of the amount of drug substance to be used, it should preferably be other than an ingestible tablet, such as a dispersible tablet or a chewable tablet, which may also be an effervescent and/or dispersible tablet. A single dose may also be conventionally presented as a single dose in a sachet. It will be understood that the dose may be presented as a number of smaller, non-swallow tablets or in sachets, for example, 2x1000/62.5mg or 4x500/32.25mg amoxicillin/clavulanate sodium.

Preferably, in the modified release dosage form, all of the potassium clavulanate is present in the immediate release phase, while the amoxicillin is present in both the immediate release phase and the sustained release phase.

Accordingly/in an additional aspect, the present invention provides a dosage form containing amoxicillin and potassium clavulanate in a ratio of from 2:1 to 20:1, preferably from 7:1 to 20:11, more preferably from 12:1 to 201, the most preferably, from 14:1 to 16:1, in which all of the potassium clavulanate and the first part of the amoxicillin are processed with pharmaceutically acceptable excipients that enable immediate release of the potassium clavulanate, forming an immediate release phase, and additionally retaining the second part of the amoxicillin processed from pharmaceutically acceptable excipients, which enable the slow release of the second part of amoxicillin, to obtain a phase with a slow release.

As used herein, the term "slow release" refers to the gradual but sustained and sustained release over a relatively long period of the active ingredient (in this case, amoxicillin) after oral administration, which begins when the dosage form reaches the stomach and begins to disintegrate/dissolve. . The release will continue for some period of time and may continue until the dosage form reaches the intestine and beyond. This term can be contrasted with the term "sustained release", in which the release of the active substance does not begin immediately after the dosage form reaches the stomach, but is delayed for some time, for example, until the dosage form reaches the intestine, when a pH-increasing agent is used to initiate the release of the active substance from the dosage form.

Preferably, the dosage form with a modified release has the character of dissolving ip migo, in which from 45 to 6595, preferably from 45 to 5595 of amoxicillin contained, dissolves within 30 minutes; in addition, in which from 50 to 7595, preferably from 55 to 6595, of amoxicillin contained is dissolved during the bohv; in addition, in which from 55 to 8595, preferably from 60 to 7090 of the contained amoxicillin dissolves within 120 minutes; in addition, in which from 70 to 9595, preferably from 75 to 8595 of the contained amoxicillin dissolves within 180 minutes; in addition, in which from 70 to 10095, preferably from 75 to 10095 of the contained amoxicillin dissolves within 240 minutes. By comparison, a regular immediate-release tablet literally dissolves completely within 30 minutes. The nature of dissolution can be quantified by a standard dissolution study, for example, "711" Dissolution Study, Apparatus 2, presented in the United States Pharmacopoeia (O5P) 23, 1995, at 37.0320.5"C using deionized water (900 mL) and speed paddle mixer equal to 75 rpm.

Preferably, the modified-release dosage form has a biphasic ip mimo profile relative to amoxicillin, i.e., initial release from the immediate-release phase to obtain an acceptable value

Smach supplemented with further replenishment from the slow-release phase to extend the Tg/MPC parameter (time to exceed the minimum adding concentration) to an acceptable value.

Preferably, the modified dosage form presents an "area under the curve" (AUC) value that is strictly speaking equal to, for example, at least 8095, preferably at least 9095, more preferably, about 10095 of the value corresponding to a dose of amoxicillin taken in the form of conventional (immediate-release) dosage form, for the same dosing period, thereby maximizing the absorption of the amoxicillin component from the slow-release component.

Pharmacokinetic characteristics in relation to the dosage of this invention can be easily determined from blood samples taken from patients according to methods known to specialists in this field and documented.

Typical modified-release dosage forms include tablets, including swallowable tablets, dispersible tablets, chewable tablets, which may also be effervescent and/or dispersible, and capsules, granules, or sachets, typically swallowable tablets.

Typical modified release dosage forms having immediate and slow release phases represent a dosage unit in the range of 700 to 1300 mg, preferably 950 to 1300 mg of amoxicillin, for example dosage units equal to 1000, 875 and 760/62.5 mg of amoxicillin/clavulanate. Alternatively, and where the physical size of the dosage form is not an issue, a dosage unit may represent a complete dose,

for example, a single dose sachet, chewable tablet or dispersible tablet may contain from 1400 to 2600 mg, preferably from 1900 to 2600 mg, of amoxicillin, for example dosage units of 2000, 1750 and 1500/125 mg of amoxicillin clavulanate. It will be clear that such 1000, 875 and 750/62.5 mg drugs are new.

Accordingly, in an additional aspect, the present invention provides a dosage form having an immediate release phase and a slow release phase, which contains: (a) a dosage unit in the range of from 700 to 1300 mg, preferably from 950 to 1300 mg of amoxicillin and an appropriate amount of potassium clavulanate in the nominal ratios of about 16:1, 14:11, or 1271, for example, dosage units equal to 1000, 875, or 750 mgE595 amoxicillin and 62.5 mg2595 potassium clavulanate, respectively, or (b) a dosage unit in the range of 1400 to 2600 mg, preferably from 1900 up to 2600 mg of amoxicillin and an appropriate amount of potassium clavulanate in a nominal ratio of approximately 16:1, 14:11, or 1271, for example, dosage units equal to 2000, 1750, or 1500 mg595 amoxicillin and 62.5 mg2595 potassium clavulanate, respectively, in combination with pharmaceutically acceptable excipients or carriers .

Preferably, the ratio of amoxicillin in the immediate and slow release phases is from 3:1 to 1:3, more preferably from 2:11 to 2:3, even more preferably from 3:22 to 1:11. Typical ratios include approximately 2:1, 9:7, or 1:1. It has been found beneficial to use an excess of amoxicillin in the immediate release phase to ensure an adequate Smax value.

In dosage forms with modified release according to the present invention, the immediate-release part of amoxicillin can be presented in the form of amoxicillin or a hydrate of its salt with an alkali metal, for example, a salt of amoxicillin and potassium or sodium, preferably, sodium salt of amoxicillin (crystalline), or a mixture thereof , preferably, amoxicillin trihydrates; and the slow-release part of amoxicillin is presented in the form of amoxicillin trihydrate or its salt with an alkali metal, for example, amoxicillin and sodium (crystalline) or potassium salts, or their mixture, preferably sodium salt of amoxicillin (crystalline).

Preferably, the immediate release dosage form is a tablet. In a preferred modified-release tablet containing 1000 mg of amoxicillin and 62.5 mg of clavulanate potassium, the immediate-release phase contains approximately 563 mgE595 of amoxicillin trihydrate and approximately 62.5 mg2595 of clavulanate potassium and the sustained-release phase contains approximately 438 mgE595 of amoxicillin, preferably the (crystalline) sodium salt amoxicillin.

In a typical modified-release tablet of the present invention, the immediate-release phase contains approximately 438 mg of amoxicillin, preferably amoxicillin trihydrate, and approximately 62.5 mg of potassium clavulanate, and the sustained-release phase contains approximately 438 mg of amoxicillin, preferably amoxicillin sodium (crystalline), giving in total, a tablet of 875/62.5 mg (14.1).

In another typical tablet of the present invention, the immediate-release phase contains about 500 mg of amoxicillin and about 62.5 mg of potassium clavulanate, and the slow-release phase about 250 mg of amoxicillin, preferably the (crystalline) sodium salt of amoxicillin, representing a total of 750/ 62.5 mg (121).

It will be understood that the use of a mixture of amoxicillin trihydrate and amoxicillin sodium salt is also applicable to other dosage forms containing amoxicillin and potassium clavulanate.

Accordingly, in an additional aspect, the present invention provides a dosage form containing amoxicillin and potassium clavulanate in a ratio of from 1:11 to 30:1, preferably from 21 to 2071, more preferably from 12:1 to 201, even more preferably from 14:1 to 161, in which amoxicillin is presented as a mixture of amoxicillin trihydrate and amoxicillin sodium salt in a ratio of 3:1 to 1:3, more preferably, from 2:71 to 2:3, even more preferably from 3:22 until 1:11. Preferably, the amoxicillin sodium salt is the crystalline sodium salt of amoxicillin. Examples of dosage form types include tablets, including immediate-release and modified-release tablets described herein, as well as other solid dosage forms such as capsules, single-dose sachets, and granules. Typical tablets include tablets containing 1000, 875, 500 and 250 mg of amoxicillin and an appropriate weight amount of potassium clavulanate. Typical ratios include 41, 71, 8:11, 141, and 16:1 (amoxicillin:clavulanate). Preferably, in the modified-release dosage forms of the present invention, the amoxicillin in the immediate-release phase consists strictly of amoxicillin trihydrate, and the amoxicillin in the slow-release phase consists strictly of the sodium salt of amoxicillin.

In relation to the tablet dosage form, the immediate and slow release phases can be presented in a number of different forms.

In a preferred aspect, the immediate and slow release phases are presented in the form of a separate multilayer in a layer tablet.

Accordingly, in an additional aspect, the present invention provides a dosage form in the form of a multilayer tablet containing clavulanate potassium and amoxicillin in an immediate-release phase layer and amoxicillin in a slow-release phase layer. A multilayer tablet may have two layers or two layers plus one or more barrier layers, as well as a coating layer. As used herein, the term "bilayer" tablet refers to a tablet consisting of an immediate release layer and a slow release layer, optionally with a coating layer.

The immediate-release layer can be, for example, a layer that disintegrates immediately or rapidly and has a composition similar to the composition of known tablets that disintegrate immediately (immediately) or rapidly. For example, the layer may contain, in addition to the content of the active substance, fillers, including diluents, such as microcrystalline cellulose; disintegrants, such as structured polyvinylpyrrolidone (SPVP), sodium starch glycolate; auxiliary substances for pressing, such as colloidal silicon dioxide and microcrystalline cellulose; substances that improve gliding, such as magnesium stearate. Such an immediate release layer may contain from about 60 to 8595 (all percentages presented herein are by weight unless otherwise stated), preferably from 70 to 8595 of active ingredient, from about 1095 to 3095, preferably from 10 to 2095 of excipients/ pressing aids, and usual amounts of disintegrants and slip-promoting agents, usually from about 0.5 to 395, etc.

An alternative type of immediate release layer may be a swellable layer having a composition comprising polymeric materials that swell immediately and extensively upon contact with water or an aqueous medium to form a water-permeable but relatively large swollen mass. The active substance contained can be leached (salted out) from this mass.

Sustained-release layers have a formulation containing amoxicillin together with a release-retarding excipient that allows for slow release of the amoxicillin. Suitable release-retarding excipients include pH-sensitive polymers, such as polymers based on methacrylic acid copolymers, such as Eudrajit (Etsyagadi Trade Mark) polymers, such as Eudrazit G (Enadgaoi Trade Mark), which may be used alone, or with plasticizer; sustained release polymers that have a high degree of swelling upon contact with water or an aqueous medium such as gastric contents; polymer substances that form a gel when in contact with water or an aqueous environment; polymeric substances that have the properties of both swelling and gelling when in contact with water or an aqueous environment.

Retardant polymers that have 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 cellulose, carboxymethyl amide, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinyl pyrrolidone, high molecular weight polyvinyl alcohols, etc. .

Gelling polymers that slow release include methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methyl cellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols, non-crosslinked polyvinylpyrrolidone, xanthan gum, etc.

Sustained-release polymers that have both swelling and gelling properties include medium viscosity hydroxypropyl methylcellulose and medium viscosity polyvinyl alcohols.

A preferred release retarding polymer is xanthan gum, particularly fine mesh grade xanthan gum, preferably pharmaceutical grade, 200 mesh xanthan gum, such as the product Xantural 75 (Hapshgai) (also known as Keltrol SA (Keiig! SV), commercial brand, Mopsapiu, 800 M I iparego Vima., 5. I otsiv,

MO 63167, BOTH) . Xanthan gum is a polysaccharide that, when hydrated, will form a viscous gel layer around the tablet, through which the active substance must diffuse. It was shown that the smaller the particle size, the slower the release rate. In addition, the rate of release of the medicinal substance depends on the amount of xanthan gum used and can be adjusted to obtain the desired characteristics.

Controlled-release preparations containing from 7.5 to 2595 xanthan gum are described in EP 0234670-

A (Vooiv So ris) . A preferred embodiment is a tablet containing ibuprofen as the active ingredient and 15-2095 xanthan gum taken once daily.

Examples of other polymers that may be used include Methocel (Meipposei) KAM (trademark), Methocel E5 (trademark), Methocel E50 (trademark), Methocel E4M (trademark), Methocel

КИ5М (trademark) and metochel KTOOM (trademark). An example of a suitable mixture of polymers is a mixture of Metocel E5 and KAM, for example 1:1, weight:weight.

Other known sustained release polymers that may be incorporated include hydrocolloids such as natural or synthetic resins, cellulose derivatives other than those listed, carbohydrate-based substances such as gum acacia, tragacanth, locust bean gum, guar gum, agar, pectin, carrageenan, soluble and insoluble alginates, carboxypolymethylene, casein, zein, etc., and protein substances such as gelatin.

Such a slow-release layer may contain polymers that immediately swell upon contact with water or an aqueous medium so that they form a relatively large swollen mass that does not immediately pass from the stomach to the intestines.

The slow-release layer may also include diluents such as lactose: compression aids such as microcrystalline cellulose; and slip-enhancing agents such as magnesium stearate. The slow-release layer may, in addition, contain disintegrants such as cross-linked polyvinylpyrrolidone (CVP) and sodium starch glycolate; binders such as povidone (polyvinylpyrrolidone); dehydrating substances (desiccants), such as silicon dioxide; and soluble fillers such as mannitol or other soluble sugars.

Usually the slow release layer contains from about 60 to 8095 by weight of amoxicillin; 10 to 2,095 by weight of diluent/pressing aid and 1 to 2,595 by weight of slip-enhancing agent.

When xanthan gum is used as the retarding polymer, the layer contains from 60 to 8095 of amoxicillin, from 1 to 2595, preferably from 2 to 1595, more preferably from 4 to 1595 of xanthan gum, from 10 to 3095, preferably from 10 up to 2095 fillers/pressing aids and the usual amounts of slip-enhancing substances, all 9095 being by weight of the layer as a whole. In a preferred embodiment, the slow release layer contains 70 to 8095 amoxicillin, 4 to 10905 xanthan gum, 10 to 2090 microcrystalline cellulose, and 1 to 2.595 magnesium stearate, all by weight of the layer.

When other sustained-release polymers than xanthan gum are used, the sustained-release layer may contain from about 30 to 70,905, preferably from 40 to 6,095 of amoxicillin, from 15 to 4,595 of a sustained-release polymer, from 0 to 3,095 of excipients/excipients for pressing substances, the usual amounts of slip-enhancing substances, and from 5 to 2095 soluble fillers, all 96 presented by weight per layer.

Also, it was unexpectedly found that when the amoxicillin in the slow-release layer is in its salt form, such as the sodium salt of amoxicillin, its release can be slowed down by the inclusion of an organic acid.

Accordingly, in an additional aspect, the present invention provides the use of a pharmaceutically acceptable organic acid as a retarding excipient in a dosage form containing a pharmaceutically acceptable soluble salt of amoxicillin, for example, a sodium or potassium salt of amoxicillin, preferably a sodium salt of amoxicillin.

It will be understood that the use of an organic acid as a release retarding excipient is also applicable in addition to the specific dosage forms described hereinbefore.

Accordingly, the present invention further provides a pharmaceutical preparation comprising a pharmaceutically acceptable soluble salt of amoxicillin, e.g. amoxicillin sodium, in a sustained release phase further comprising a retarding excipient which is a pharmaceutically acceptable organic acid present in a molar ratio of from 100:1 to 1:10, preferably from 50:1 to 1:5, more preferably from 20:1 to 1:2 (amoxicillin to organic acid).

Close contact between the organic acid and the amoxicillin salt in the pharmaceutical preparation, for example as a result of the formation of compressed granules or direct compression into tablets, is believed to cause some form of interaction that modifies the release of the amoxicillin component from the preparation.

Soluble pharmaceutically acceptable salts of amoxicillin include salts of alkali metals such as sodium and potassium; alkaline earth metals such as magnesium and calcium and acid salts such as amoxicillin hydrochloride.

Preferably, the salt is a sodium salt of amoxicillin, more preferably, a crystalline sodium salt of amoxicillin.

As used herein, the term "pharmaceutically acceptable organic acid" refers to organic acids that have no per se pharmacological activity, organoleptic properties, have an acceptable density, do not create pH extremes, and are preferably solid. examples thereof include salts of monocarboxylic acids and polycarboxylic acids having from 2 to 25, preferably from 2 to 10, carbon atoms; monocyclic and polycyclic aryl acids, such as benzoic acid; as well as monosubstituted and disubstituted, etc. metal salts of polyvalent acids. A single pharmaceutically acceptable organic acid or two or more such acids in combination may be used. It is mainly an organic acid

An alkyl or alkenyl carboxylic acid having one, two or three carboxylic acid groups/ and optionally with one or more hydroxyl substituents or an additional CO group in the carbon chain, e.g. malonic acid, succinic acid, fumaric acid , maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid or a fruit acid such as tartaric acid, malonic acid, ascorbic acid or citric acid, or an acid salt thereof, more preferably citric acid, in particular anhydrous citric acid.

The organic acid may be used alone or in combination with a release retarding polymer described hereinbefore. The best combination consists of citric acid and a polymer that slows down the release of the gelling polymer, in particular, xanthan gum. In the presence of an organic acid, for example citric acid, xanthan gum can be used at a lower level than when it is included alone, for example from 0.5 to 895, preferably from 1 to 595, usually about 295 by weight of the layer of slow release

When an organic acid is used as the retarding agent, the slow release layer contains from 60 to 8095 of amoxicillin soluble salt, from 10 to 3095, preferably from 10 to 2095 of excipients/compression aids and conventional amounts of improvers sliding, all to presented by weight from weight layering. In a preferred embodiment, the slow release layer contains from 60 to 7095 soluble salts of amoxicillin, from 10 to 2095 of microcrystalline cellulose and from 1 to 2.595 of magnesium stearate, all 95 presented by weight of the weight of the layer.

In a typical example, the multi-layered tablet contains, in the slow-release layer, amoxicillin sodium crystalline salt and citric acid in a molar ratio of about 50:1 to 1:2, preferably 201 to 1:2, more preferably 2:1 to 1:1 ,2, even more preferably, about 1:1. In a preferred embodiment, the slow release layer contains about 438 mg/590 mg of amoxicillin sodium crystalline, about 78 mg of amoxicillin salt, about 73 mg-1095 of citric acid, and about 2905 by weight of xanthan gum.

In a preferred multi-layered tablet containing 1000 mg of amoxicillin and 62.5 mg of potassium clavulanate, the immediate-release layer contains approximately 563 mgE595 of amoxicillin, preferably amoxicillin trihydrate, and approximately 62.5 mg25790 of potassium clavulanate, and the sustained-release layer contains approximately 4382595 of amoxicillin, preferably crystalline sodium amoxicillin salt, approximately 78mgE1095 of citric acid and approximately 290 by weight of xanthan gum.

Tablet dosage forms of the present invention may also 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 or second layers, for example, the end surfaces of the layers of cylindrical pills Such barrier layers may be formed, for example, from polymers that are substantially or completely impermeable to water or aqueous media, or that degrade slowly in water or aqueous media or biological fluids, and/or that swell upon contact with water or aqueous media . Accordingly, the barrier layer should be such that it retains these properties, at least until the complete or mostly complete transfer of the content of the active substance into the environment.

Suitable polymers for the barrier layer include acrylates, methacrylates, copolymers of acrylic acid, celluloses and their derivatives, such as ethyl celluloses, cellulose acetate propionate, polyethylenes and polyvinyl alcohols, etc. Barrier layers containing polymers that swell upon contact with water or aqueous media may swell to such an extent that the swollen layer forms a relatively large swollen mass, the size of which delays its immediate evacuation from the stomach to the intestine. The barrier layer itself may contain a portion of the active substance, for example, the barrier layer may be a slow or sustained release layer. Barrier layers can usually have an individual thickness from 2 mm to 10 microns.

Suitable polymers for barrier layers that are relatively impermeable to water include the Metosel (MeshShosey trade mark) series of polymers noted above, for example, Metosel KI0OM, Metosel K15M, Metosel E5 and Metosel E50, used alone or in combination, or, optionally, in combination with Etosel polymer (EShosei, trade mark). Such polymers can, accordingly, be used in combination with a plasticizer such as hydrogenated castor oil. The barrier layer may also include conventional binders, fillers that improve the sliding of the substance and auxiliaries for pressing, etc., such as polyvidone KZO (Royumidop, trade mark), magnesium stearate, silicon dioxide, for example, Siloid 244 (5uioia , trademark).

The tablet dosage form of the present invention may be completely or partially covered with a coating layer, which may be a protective layer to prevent moisture penetration or damage to the tablet. The coating layer (sheath) itself may contain a portion of the active substance and may, for example, be an immediate-release layer that immediately breaks down upon contact with water or an aqueous environment, releasing the active substance contained in it, for example, amoxicillin or potassium clavulanate. Preferred covering materials include hydroxypropylmethylcellulose and polyethylene glycol with titanium dioxide as a light-proofing agent, for example, as described in UUO95/28927 (5thijKiipe Veespat).

As well as a portion of the active substance, the tablet of the present invention may, inter alia, also include a pH-altering substance, such as a pH buffer, which may be contained in the immediate or slow release layer, or in the shell of all or part of the tablet. A suitable buffer is calcium hydrogen phosphate.

In a tablet without a barrier layer, the immediate release layer contains from 50 to 6095 and the slow release layer contains from 40 to 50905 of the total weight of the tablet. When a barrier layer is present, the immediate release layer usually contains from 40 to 5095 and the slow release layer contains from 35 to 4595 and the barrier layer contains from 5 to 2095 of the total weight of the tablet.

It was found that satisfactory pharmacokinetic properties can be obtained in a two-layer tablet of this invention, without the need to include a barrier layer. Accordingly, two-layer tablets are better. It also reduces the complexity of the manufacturing process.

It will be understood that the 1000, 875 and 750/62.5mg multi-layer tablets having an immediate release layer and a slow release layer are new. Accordingly, in an additional aspect, the present invention provides a pharmaceutical preparation in the form of a multilayer tablet consisting of an immediate-release layer and a slow-release layer and containing from 700 to 1250 mg of amoxicillin and a proportional amount of potassium clavulanate, preferably 1000, 875 or 750 mg of amoxicillin and 62, 5mgE590 potassium clavulanate in a nominal ratio of approximately 16:1, 1421 or 12:1, respectively, in combination with pharmaceutically acceptable excipients or carriers. Preferably, the multilayer tablet is a two-layer tablet.

Accordingly, the tablet dosage forms of this invention can be produced by known methods of tableting by pressing, for example, using a known press for multilayer tableting.

Predominantly, at the previous stage, impact or rolling compaction is used to form granules.

Gliding agents and press aids (if used) are then added to form the mixture for subsequent pressing.

The preferred bilayer tablets of the present invention may be manufactured by a process which includes, in the initial step, forming slow-release compressed granules, which includes the steps of grinding amoxicillin sodium, part diluent/compression aid such as microcrystalline cellulose (typically about 3095), part a glidant (usually about 70905) and a pharmaceutically acceptable organic acid such as a fruit acid such as citric acid, and then mixing with a release retarding polymer such as xanthan gum, if present, and a compression aid , such as colloidal silicon dioxide, pressing the mixture, for example on a rolling press or by impact, and then grinding to form slow-release granules.

Preferably, such granules have a size in the range from 100 to 1000 microns. The inclusion of xanthan gum also appears to have an unexpected beneficial effect on downstream processing.

Such compacted slow-release granules can then be mixed with other excipients such as the remaining magnesium stearate and microcrystalline cellulose to form a slow-release compression mix.

In addition, amoxicillin trihydrate, potassium clavulanate (preferably as a 1:1 mixture with microcrystalline cellulose), microcrystalline cellulose is ground and mixed with a slip-enhancing agent such as magnesium stearate (preferably about 50905 of the total amount) and then pressed, e.g. , on a rolling press or with the help of an impact mechanism, and crushed to form compacted granules with immediate release. These compacted immediate-release granules can then be mixed with other excipients such as the remaining magnesium stearate and microcrystalline cellulose (ca. 1395), a compression aid such as colloidal silica, and a disintegrant such as sodium starch glycolate to form immediate release blends for pressing.

The compression mixtures for the immediate and slow release layers can then be compressed as individual layers in a bilayer tablet press.

These immediate release pellets are new. Accordingly, in an additional aspect, the present invention provides compacted granules comprising a soluble salt of amoxicillin, such as amoxicillin sodium, a diluent/compression aid, and an organic acid or polymer that slows release, or a mixture thereof, as previously described herein. In yet another additional aspect, the present invention also provides compacted granules comprising amoxicillin trihydrate, a diluent/compression aid, and a release retarding polymer as previously described herein.

Alternatively, a dry compaction process such as briquetting can be used. Typically, the active ingredient, pH modifiers, buffers, fillers and/or diluents, release retarders, disintegrants and binders, when used, are mixed, then slip improvers and compression aids are added. The final mixture can be pressed in a tablet press under high pressure. A wet granulation process can also be used,

for example, with isopropanol as a solvent and polyvidone K-30 (Roiumidop, trade mark) as a wet granulation aid.

The barrier layer, if present, can usually be produced using a wet granulation method or a dry granulation method, such as roll pressing. Typically, a barrier material such as Methosel (Meipose!, a trademark) is suspended in a solvent such as ethanol containing an acid for granulation, such as Etocel or Polyvidon K-30 (EShosei, Royumidop, trademarks), followed by mixing, sieving and granulation. Typically, a first layer can be formed, then a barrier layer applied thereto, for example by pressing, spraying or dipping techniques, then a second layer can be formed so that the barrier layer is sandwiched between the first and second layers. In addition, or alternatively, the first and second layers can be formed, and then a barrier layer can be formed, for example, by pressing, spraying or dipping on one or more of the end surfaces of the tablet.

The method of obtaining the crystalline sodium salt of amoxicillin is described in EP-A-0131147 (Vespat Stor ris).

Potassium clavulanate is known to be extremely sensitive to water. Therefore, tablet preparations containing clavulanate potassium should be prepared under dry conditions, preferably at 3095 relative humidity or less, and the ingredients of the preparation should be pre-dried when appropriate. Tablet preparations of this invention should be stored in containers that are hermetically sealed against the penetration 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 produce film-coated tablets.

The present invention also represents a method of producing a tablet preparation, as described above, which includes the stages of forming the specified first and second layers and any barrier layers and layers) of the coating that may be present.

In addition to the technology of multilayer tablets described above, it is possible to use tablets of other types to obtain an immediate-release phase and a slow-release phase using the fillers described above, but obtaining phases of other types. Thus, the slow-release phase may form the core of the tablet, which is then surrounded by an immediate-release shell-forming phase, optionally with an intermediate coating layer around the core and/or a final coating layer around the outer shell (see, UUO95/28148, ZtiiiKiipe Veespat ). The slow-release phase can also be presented as granules dispersed in a matrix of amoxicillin and potassium clavulanate, and the matrix will form an immediate-release phase (see, MUO96/04908, ZtiiiKiipe Veespat).

In a further embodiment, a modified-release monolithic tablet may be prepared from compacted slow-release granules containing amoxicillin, a diluent, compression aids such as microcrystalline cellulose, and a pharmaceutically acceptable organic acid such as a fruit acid such as citric acid ( if amoxicillin is present in the form of a soluble salt thereof), or a polymer that slows the release, such as xanthan gum, or a mixture thereof, preferably a polymer that slows the release (which is described above); and immediate-release compacted granules containing amoxicillin and potassium clavulanate (as described above) or immediate-release compacted granules containing amoxicillin and potassium clavulanate, for example, in a 2:1 ratio, and in addition immediate-release compacted granules, containing amoxicillin (which are described in UUO98/35672, ZtiyKipe Veespat Iarogayoigev5

RPaptaseshiidnev), and the granules are combined with extragranular fillers to form tablets. Such granules may also be processed into other dosage forms, such as single-dose sachets, capsules, or chewable tablets containing a unit dose as described above.

Chewable tablets according to the present invention usually contain a base for chewable tablets formed from, for example, mannitol, sorbitol, dextrose, fructose or lactose, or separately in a mixture. The chewable tablet may also additionally contain auxiliary substances, for example, disintegrants that improve the sliding of the substance, sweeteners that color and improve the taste and smell of the substance. Such additional excipients together will preferably comprise from 3 to 1095, more preferably from 4 to 895, even more preferably from 4 to 795 by weight of the weight of the tablet. Disintegrants can be present in an amount from 1 to 495, preferably from 1 to 3905, more preferably from 1 to 295 by weight of the tablet. Typical disintegrants include crospovidone, sodium starch glycolate, starches such as corn starch and rice starch, croscarmellose sodium, and cellulose products such as microcrystalline cellulose, microfine cellulose, low-substituted hydroxypropyl cellulose, either alone or in admixture. Preferably, the disintegrant is crospovidone.

The slip-enhancing substance can be present in an amount from 0.25 to 295, preferably from 0.5 to 1.290 by weight of the weight of the tablet. The best slip-enhancing agents include magnesium stearate. Preferably, the sweetener is an artificial sweetener such as sodium saccharin or aspartame, preferably aspartame, which may be present in an amount of from 0.5 to 1.595 by weight of the weight of the tablet. Preferably, the tablet of this invention does not actually contain sugar (sucrose). The best taste and smell improving substances include fruit flavoring and flavoring additives, which can be natural or synthetic, for example, having the taste and smell of peppermint, cherry and banana, or their mixtures.

Single-dose sachets according to the present invention contain, in addition to the medicinal substance, auxiliary substances, which are usually included in the preparation in the sachet, such as a sweetener, for example, aspartame, substances that improve taste and smell, for example, fruit flavors and aromas, optionally, a suspending agent such as xanthan gum, as well as silica gel acting as a desiccant.

Capsules according to the present invention contain, in addition to the medicinal substance, auxiliary substances that are usually included in capsules, for example, starch, lactose, microcrystalline cellulose, magnesium stearate.

It will be understood that due to the hygroscopic nature of clavulanate, the use of materials such as gelatin to form capsules should be avoided. Preferably, capsules are made from materials such as HPMC or a gelatin/PEG combination.

In an additional embodiment, the slow-release phase may be presented as a separate component, for example, as a separate tablet, so that the dosage unit is presented as a combination of a conventional component in which amoxicillin and clavulanate potassium are released immediately, optionally with a conventional amoxicillin formulation. such as a tablet, and an additional drug, such as a tablet containing amoxicillin (and clavulanate potassium), from which amoxicillin is released slowly. The weight of potassium clavulanate and the combined weight of amoxicillin in the regular and slow-release formulations will create a total dosage unit. So, for example, a dose of 2000/125 mg can be represented by a combination of an existing tablet of 500/125 mg of amoxicillin/clavulanate potassium and a tablet of 500 mg of amoxicillin in combination with a slow-release tablet containing 1000 mg of amoxicillin. In addition, the 1750/125 mg dose can be represented by the existing 875/125 mg tablet (which is described in U/O95/28927, ZtiijKiipe Veespat) in combination with a slow-release tablet containing 875 mg of amoxicillin. In addition, the 1500/125 mg dose may be represented by an existing 500/125 mg tablet and an existing 500 mg amoxicillin tablet in combination with a slow-release tablet containing 500 mg amoxicillin. Accordingly, in an additional aspect, the present invention provides a kit consisting of a regular (immediate-release) tablet containing amoxicillin and clavulanate potassium, optionally with a regular (immediate-release) tablet containing amoxicillin and a slow-release tablet release containing amoxicillin (and clavulanate potassium).

In an additional aspect, the present invention provides a pharmaceutical preparation, preferably a tablet containing amoxicillin (as the sole active ingredient), manufactured with a sustained-release excipient that provides a slow release of amoxicillin from the dosage form, and in addition to: tablets containing 750 mg or less amoxicillin, in which amoxicillin is present mainly as amoxicillin trihydrate; or tablets containing from 400 to 500 mg of amoxicillin, in which the amoxicillin is present in a mixture containing at least 7095 of amoxicillin trihydrate and up to 3095 of amoxicillin sodium salt in combination with hydroxypropyl methylcellulose as an excipient that slows the release.

Such preparations can contain from 100 to 1250 mg of amoxicillin, which can be amoxicillin trihydrate or (crystalline) sodium salt of amoxicillin or their mixture, for example, 500, 750 or 1000 mg of amoxicillin.

Suitable slow release fillers are those described above for slow release layers. The dosage form may contain from 1 to 2595, preferably from 2 to 1595, more preferably)/ from 4 to 1095 of xanthan gum or from 10 to 25, preferably from 15 to 2095 of hydroxypropyl methylcellulose, for example, methocel KI00I M or methocel KAM. Alternatively, such preparations contain citric acid, optionally with xanthan gum, as described above.

Preferably, the unit dosage forms of this invention are packaged in containers that prevent the penetration of atmospheric moisture, for example, in blister packs, tightly closed vials or desiccatable packet packs, etc., which are common in this field of technology. Preferably, the vials include HDPE (High Density Polyethylene) vials. Preferred blister packs include cold-formed blister packs, wherein each blister may contain one tablet or two tablets where one dose is contained in two tablets, eg 2x1000/62.5mg tablets to improve patient acceptability.

Next, the invention will be described by way of an example with reference to the accompanying drawings, from which:

Fig. 1 represents the structure of various types of layered tablets of this invention, in particular, the structure of cylindrical compressed tablets is shown in a longitudinal section. In figure 1A: the tablet consists of a first layer (1) and a second layer (2) without a barrier layer or a covering layer. In Fig.18: the tablet consists of a first layer (1), a second layer (2) and a barrier layer (3) placed between the first and second layers (1) and (2). In Fig.1C: the tablet consists of a first layer (1) and a second layer (2) and a barrier layer (3) located on the end surface of the second layer (2). In Fig. 10: the tablet consists of a first layer (1), a second layer (2), a barrier layer (3), placed between the first and second layers (1) and (2), and a covering layer (4), which partially covers the tablet. The dashed line shows the possibility of a shell layer (4A) covering the entire tablet. In Fig. 1E: the tablet consists of the first layer (1), the second layer (2) and the third layer (3), intermediate between the first and second layers (1) and (2). All three of these layers (1), (2) and (3) contain an active substance.

All publications and references, including but not limited to patents and patent applications cited herein, are incorporated herein by reference in their entirety as if each individual publication or source were specifically and individually indicated to be incorporated by reference as on presented in full.

Any patent application to which priority is claimed from this application is also incorporated herein by reference in its entirety, in the same manner as set forth above for publications and references.

Example 1

Tablet with modified release 1000/62.5 mg

Ingredient mg/pill by weight

Layer with immediate release

Amoxicillin trihydrate is 40.88

Potassium clavulanate 76.2 and 4.76

Microcrystalline 136.4 8.52 cellulose

Sodium starch glycolate 18.0 112

Colloidal silicon dioxide 6.3 0.39

Magnesium stearate 9.0 0.56

Total (layer with immediate release 900.0 56.23)

Slow release layer

Crystalline sodium salt of amoxicillin 480.87" 30.05

Microcrystalline cellulose 115.2 7.08

Xanthan gum 14.0 0.87

Anhydrous citric acid 78.0 4.87

Colloidal silicon dioxide 1.50 0.08

Magnesium stearate 14.0 0.87

Total (layer with slow 43.74 release) 700.0

Film coating

Opadry Uu5-1-7700 - composition:

Hydroxypropylmethylcellulose 11.6 2910 bsp

Hydroxypropylmethylcellulose 3.9 2910 15sp

Titanium dioxide 15.1

Polyethylene glycol 3350 2.3

Polyethylene glycol 8000 2.3

Total tablet weight in the shell 16352 "Equivalent to 562.5 mg of amoxicillin, based on analysis equal to 86905 "Equivalent to 62.5 mg of clavulanic acid, based on analysis equal to 82.09 "Equivalent to 437 5 mg of amoxicillin, based on analysis equal to 91.090

Example 2

Modified-release tablet 1000/62.5 mg

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

Ingredient mg/tablet 95 weight.

Slow release layer

Crystalline sodium salt of amoxicillin 480.87 30.05 microcrystalline cellulose 127.2 7.95

Xanthan gum 14.0 0.87

Anhydrous citric acid 78.0 4.87

Colloidal silicon dioxide 1.50 0.09

Magnesium stearate 14.0 0.87

Total (slow release layer) 700.0 43.74

Total weight of coated tablet 16352 "Equivalent to 437.5mg of amoxicillin, based on analysis equal to 91.095 Manufacture of modified release tablets Modified release tablets were prepared from immediate and slow release mixtures in a batch process on a 900 and 700 kg scale, respectively. For the immediate-release formulation, the containers were loaded with dry microcrystalline cellulose (1), amoxicillin trihydrate (2) and (5) in a 1:1 ratio), potassium clavulanate/microcrystalline cellulose (121), and magnesium stearate (approximately 5095 of the total quantity) (4) . The contents of the containers (1) and (2) were passed through a sieve, ground in the "Riiiitiya" at 1500 rpm and mixed with the contents of the container (3). The contents of the container (4) were then sieved and ground, and mixed with the original mixture, and then mixed with the contents of the container (5), which had passed the previous stage of sieving and grinding. This mixture was then subjected to rolling compression using a SpPiivopayi operating at a pressure of 1000 psi? 200 psi? (6894.721378.9kPa) and the product was ground and sieved through a 14 and 80 mesh vibrating screen to obtain immediate release granules. The remaining excipients (colloidal silicon dioxide, magnesium stearate, dry microcrystalline cellulose and dry sodium starch glycolate) were then sieved and ground and combined with the immediate release granule portion in a mixer, mixed and then combined with the granules that remained, and stirred to form a mixture with HO.

For the slow-release formulation, containers were loaded with dry microcrystalline cellulose (ca. 70905) and anhydrous citric acid (1), amoxicillin sodium (2) and (4) (in a 1:1 ratio), and magnesium stearate (ca. 70905), colloidal silicon oxide and xanthan gum (3). The contents of containers (1) and (2) were sifted and ground in RBiitia), and then mixed with the contents of container (3), mixed then with the contents of container (4), which had been ground and sieved in the previous stage. This mixture was subjected to roll pressing on a SpNiizopaya?!, operating at a pressure of 600 psi? 100 psi? (4136.8-4689.5 kPa), crushed and sieved to obtain slow-release granules. The remaining excipients (magnesium stearate, dry microcrystalline cellulose) were sieved and combined with a portion of slow-release granules, mixed, and then the remaining slow-release granules were added and mixed to obtain a mixture with MO.

The mixtures of HO and MO were then compressed as individual layers in a bilayer tablet press equipped with punches measuring 0.0406 in. (1.033 mm) by 0.8730 in. (22.17 mm) and having a modified capsule form For the first layer (with immediate release), no preliminary pressing was done, and the main compression was less than 10kN. For the second layer, preliminary compression was done at less than 2OkN and the main pressing at less than bOkN. The tablets obtained in this way had a total weight of 1600mg and 48mgH, a hardness in the range from 8 to 18 5SI and a brittleness of less than 0.595. | at the end of the core, the tablets were coated with an aqueous film coating in a 60-inch (152.4 cm) coating bowl operating at a 300 kg portion load. The bowl was supplied with 4 nozzles and rotated at a speed of 3 to 5 rpm. The inlet air was dehumidified at a temperature in the range of 56-60"C, while the humidity of the outlet air was in the range from 4 to 1295, and the temperature was in the range from 43 to 5070. The spray rate was from 80 to 120 ml/min/sprayer.

Example C

Sustained-release tablets (875mg) (a) Amoxicillin sodium tablet mg/tablet Fo

Crystalline sodium salt of amoxicillin 91907 961.54 73.96

Dry microcrystalline cellulose 273.46 21.04

Magnesium stearate 13.0 1.00

Xanthan gum 200 mesh" 52.0 4.00

Total 1300 100 (r) Amoxicillin sodium salt tablet with citric acid mg/tablet 90

Crystalline sodium salt of amoxicillin 919057 961.54 66/31

Dry microcrystalline cellulose 288.96 19.92

Magnesium stearate 14.50 1.00

Citric acid 156 10.75

Xanthan gum 200 mesh" 29.0 2.00

Total 1450 100 (s) Amoxicillin trihydrate tablet mg/tablet 905 amoxicillin trihydrate 86" 10174 8.26

Dry microcrystalline cellulose 217.6 16.74

Magnesium stearate 13.0 1.00

Xanthan gum 200 mesh" 52.0 4.00

A total of 1300 100 "proved by the activity of the amoxicillin component and the corresponding 875 mg of amoxicillin, "Xantural 75

Example 4

Modified-release tablet 875/62.5 mg

Slow release layer

This layer can be formulated using half the amount presented above for the slow release layer containing approximately 438 mg of amoxicillin.

Layer with immediate release - 1

Amoxicillin tripdrate 507mMg (free acid equivalent of amoxicillin) (438)

Potassium clavulanate 71.8 (clavulanic acid equivalent) (62.5)

Microcrystalline cellulose (Amise! pH 102) 125

Sodium starch glycolate (Echrioigar) 26

Magnesium stearate 6.5

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

Layer with immediate release - 2

Amoxicillin trihydrate 507 mg (free acid equivalent of amoxicillin) (438)

Potassium clavulanate 71.8 (clavulanic acid equivalent) (62.5)

Microcrystalline cellulose (Amicei

RN 102) 135

Sodium starch glycolate (Echrioigar) 34

Talc 67

Magnesium stearate 25

Silicon dioxide (5uioia) 17

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

Barrier layers

Barrier layers and methods of their production are described in UUO95/20946 (5tiiipKiipe Veespat)

Production of tablets

Mix active ingredients, fillers and diluents (microcrystalline cellulose), substances that regulate the release (if they are present), disintegrants (crospovidone, sodium starch glycolate), etc.

Substances that improve gliding and colloidal silicon dioxide (buissium 244) are added and mixing is continued for another minute. The entire mixture is pressed on a tablet press or rolling press (briquetting stage) followed by size reduction (Arekh, BiigtiiY, Egeum) and passing through a vibrating screen or particle size separator (Kasop, bmeso). If the fluidity properties are unsatisfactory, the briquetting stage is repeated. Prepare separate compressed mixtures for layers with immediate and slow release and barrier, if it is present.

In some cases, when the bulk density is quite low, a compaction stage (pre-tablet and screening as in the briquetting method) may be necessary to reach the nominal weight of a particular layer. The mixtures are then compressed in the form of separate layers on a press for layered tablets to obtain two-layered tablets. The tablets may then be coated with a white opaque coating, such as the product Ora-agu, Oravrgau (Soiogsop).

Example 5

Methods of research on decay

The release of amoxicillin and clavulanate from tablets into a static environment was quantified according to "711" Disintegration Study, Apparatus 2 presented in OBR 23, 1995 (US Pharmacopoeia 23,1995).

Experiment conditions: temperature: 37,050,570 medium: deionized water, 900 ml blade stirrer speed: 75 rpm

Method

Media aliquots were taken for testing at 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min, with each aliquot replaced simultaneously with an equal volume of media to maintain a constant volume . The amount of medicinal substance was determined using UV spectrophotometry at 272 nm. The resulting disintegration profile for tablets from examples 1 and 2 is shown in Fig.2.

Pharmacokinetic evaluation of drugs ip mimo

The bioavailability of doses of the present invention was evaluated in two human volunteer studies, as study A and study B. These studies were open-label, randomized cross-over studies in healthy volunteers. Each dose was administered with approximately 200 ml of water at the beginning of a light breakfast and after an overnight break between meals. Blood samples were collected in tubes containing EDTA at a given time before dose administration and 0.5, 1, 1, 5, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after receiving the dose to determine levels of amoxicillin and clavulanate in plasma. The samples were cooled in an ice bath until further processing. Plasma was separated by centrifugation in a refrigerated centrifuge at 4°C and transferred into appropriately labeled polypropylene sample containers and stored frozen at approximately -70°C until examination.

Samples were tested for amoxicillin using a method based on protein precipitation with acetonitrile.

Amoxicillin was extracted from human plasma (5 µl) by protein precipitation using an acetonitrile-retaining internal standard and quantified by LC/MS/MS. Specifically, human plasma (500 μl) was pipetted into a 1.5 ml Eppendorf tube followed by the addition of acetonitrile containing an internal standard (GZSe|-amoxicillin, 200 μl). The test tube was closed with a lid, mixed by rotation and shaken for 15 minutes. After centrifugation of the sample (approximately at 11,000 x d for 15 minutes), the supernatant was transferred into a silanized 1.1-ml conical vial of the automatic sample feeding device, containing 200 μl of 5 mM ammonium acetate solution. An aliquot sample of the extract was introduced into the system for HPLC/MS/MS analysis. The mass spectrometer operated according to the method with positive ionization using the Tigo Iopbrgau interaction device. To identify components, amoxicillin and

GZSev|-amoxicillin, multiple tracking of reactions was used (tiiirie heasiyop topiuhypo, MAM).

The MAM technique includes (1) mass selection of the characteristic ions of the required medicinal substance or internal standard in the first quadrupole mass analyzer, (2) fragmentation of the selected ion in the collision chamber of the device, (3) detection of the fragment ion that is characteristic of the investigated compound. Quantification is performed by comparing the area of the chromatographic peak of the medicinal substance with the area of the internal standard. Linear dependences were observed for the ratios of the peaks of the analytical sample/internal standard in relation to the analytical concentrations in the range from 0O.05μg/ml (lower limit of quantification: НПК-ХИ С) to 1Ωkg/ml (upper limit of quantification: ВИПК-ШИ С) .

Samples were tested for clavulanate using a method based on acetonitrile protein precipitation. Clavulanate was extracted from human plasma using a liquid/liquid method using an internal standard and quantified by LC/MS/MS. Specifically, human plasma (50 μL) was pipetted into a 1.5 mL Eppendorf tube followed by the addition of 0.2 mM ammonium acetate (200 μL) before the addition of acetonitrile containing the internal standard (b-aminopenicillanic acid, 40 μL). The test tube was closed with a lid, mixed by rotation and shaken for 20 minutes. After centrifugation of the sample (approximately at 14,500 x d for 15 minutes), the supernatant was transferred to a clean Eppendorf tube and dichloromethane was added. After further mixing and centrifugation (at approximately 14,500 x d for 10 minutes), the supernatant (no more than 150 μl) was transferred to a 1.1 ml conical vial of the autosampler and left uncovered for 20 minutes to allow any trace amounts of dichloromethane to evaporate. . An aliquot sample of the extract was introduced into the system for HPLC/MS/MS analysis. The mass spectrometer operated according to the method with positive ionization using the Tigro Jupbrgau interaction device. To identify the components, clavulanate and 6-aminopenicillanic acid, multiple tracking of reactions was used

MAM). The MAM technique includes (1) mass selection of the characteristic ions of the required medicinal substance or internal standard in the first quadrupole mass analyzer, (2) fragmentation of the selected ion in the collision chamber of the device, (3) detection of the fragment ion that is characteristic of the investigated compound.

Quantification is performed by comparing the area of the chromatographic peaks of the medicinal substance with the area for the internal standard. Linear dependences were observed for the ratios of the peaks of the analytical sample/internal standard in relation to the analytical concentrations in the range from 0O.05μg/ml (lower limit of quantification: NPKA-GI O)) to 10μg/ml (upper limit of quantification: VPK-SHI OS) .

Samples for quality control (QC-OS) were examined for each batch of samples in comparison with separately prepared standards for calibration. The results with QC samples were used to evaluate the performance of the study on different days.

Plasma concentration-time data for each subject at each regimen were analyzed using split-free methods using a split-free pharmacokinetic analysis program,

MuipMopeiip Rgoitezziopa! Megwiop 1.5. All calculations were based on actual sampling dates.

Pharmacokinetic parameters determined included the maximum observed plasma concentrations (Cmax) and the time to reach the maximum plasma concentration (Tmax). by the method of least squares with a visual review of the data to determine the appropriate number of points for the calculation 17. The half-life of the pretended final elimination (T 1/2) is calculated as

IP(2)/17.

The area under the curve of dependence of plasma concentration on time from the zero moment to the last determined concentration in plasma (PPK(0-)-АШС(0-)| was determined using the trapezoidal formula for each decremental trapezoid (Spoioi MU.G., U. RnagtasokKipei. Viorpagtt., 1978, 6, 539-547|. The area under the plasma concentration-time curve extrapolated to infinity (PPK(O-os)| was calculated as the sum of PPK(0O-) and C(O/Lya, where C() is the concentration predicted by Iod-linear regression analysis at the time of the last determination.

When exceeding the minimum inhibitory concentration in plasma (T » MPC) was calculated manually by graphical interpolation, where the minimum inhibitory concentration in plasma is defined as 4μg/ml for amoxicillin.

Plots of the average concentration versus time for amoxicillin and clavulanate were obtained for each given sampling period for each drug. In cases where the post-dose value was indeterminate, a value of 75 110) (0.05O0μg/ml) was set to calculate the mean value. When the calculated mean value was less than 100 or based on values greater than 5090

MO), the value of MO) was set for this term of sample selection.

Gaudet-transformed Smax and untransformed T » MIC for each of the drugs were analyzed using analysis of covariance (AMSOMA), establishing a single term for the drug and selecting data on the compared drug as a covariate. 9590 confidence intervals for the mean values for each drug were established using the residual variance from the model. For Smakh, the estimates of the confidence interval in the Id scale were subjected to inverse transformation to obtain 9595 confidence intervals of the geometric mean. These results were presented graphically.

Assumptions underlying the analyzes were assessed by viewing residual plots. Homogeneity of variance was assessed by plotting studentized residuals against predicted values from the model, while normality was assessed using normal probability plots. Special attention was paid to any significantly different values observed in the comparator drug.

Research by A

In the first study, three drugs with modified release were compared in doses: 1750/125 mg (drugs I to II) and the fourth drug with modified release in a dose of 1500/125 mg (drug IM) with a drug with immediate release in a dose of 1750/125 mg (drug U ) such as: (a) amoxicillin/clavulanate potassium 1750/125mg dose, formulated as a combination of one modified-release tablet containing 875/125mg amoxicillin trihydrate/clavulanate and 495 xanthan gum and one immediate-release tablet containing 875mg amoxicillin trihydrate (drug I); (b) amoxicillin/clavulanate potassium 1750/125mg dose, manufactured as a combination of one modified-release tablet containing 875/125mg amoxicillin/clavulanate sodium crystalline salt and 490 xanthan gum and one immediate-release tablet containing 875mg amoxicillin trihydrate ( drug II); (c) amoxicillin/clavulanate potassium 1750/125mg dose, manufactured as a combination of one modified-release tablet containing 875/125mg amoxicillin/clavulanate sodium crystalline salt and 290 xanthan gum and one immediate-release tablet containing 875mg amoxicillin trihydrate ( drug II); (4) amoxicillin/clavulanate potassium 1500/125mg dose, manufactured as a combination of one modified-release tablet containing 500/125mg amoxicillin/clavulanate sodium crystalline salt and 490 xanthan gum, and two immediate-release tablets containing 500mg amoxicillin trihydrate ( amoxil, ZtiyKiipe Veespat (IM drug); and (e) amoxicillin/clavulanate potassium 1750/125mg dose, formulated as a single immediate-release tablet combination containing 875/125mg amoxicillin/clavulanate trihydrate (augmentin,

Veespat) and one immediate-release tablet containing 875 mg of amoxicillin trihydrate (Amoxil,

ZtiyKiipe Veespat) (preparation M). 181 11111lalvya, | 7777 Used) 71147830 11111118 1171111 BGN/vby, | 7777 44000017 57467 61111118 11711113, 11157905 | 775493 4 nyny t o EE ACT MONO POT SAME NNYA POLON I and MON () standard deviation tI arithmetic mean value 2T » BMD is the time (hour) in which the concentration of amoxicillin is above 4mcg/ml

ZArea under the curve (from 0 to 12 hours, μg-time/ml).

The pharmacokinetic profile is presented in Figure 3.

Research by V

In the second study, two different 2000/125 mg modified-release formulations (MI and MI formulations) were compared with an immediate-release 2000/125 mg formulation (MI formulation), such as: (a) amoxicillin/clavulanate potassium 2000 dose /125 mg, made in the form of two two-layer tablets according to example 1 (preparation MI); (b) a dose of amoxicillin/clavulanate potassium 2000/125 mg, made in the form of two two-layer tablets according to example 2 (MII drug); (c) a dose of amoxicillin/clavulanate potassium 2000/125mg, made in the form of a combination of three tablets, and one tablet contains 500mg of amoxicillin and 125mg of clavulanate potassium (augmentin, ZtiyKiipe

Veespat (MIP drug).

Results mm 177 1 li 11111 6bo011171717711111111481171 11174980 7 M'11117 178 1 1746 | 2 sh5B sh|40 | 7 0) the standard deviation and the arithmetic mean value of 2T»MPK is the time (hour) in which the concentration of amoxicillin is higher than 4 μg/ml

ZT»MPC is the time (hour) in which the concentration of amoxicillin is higher than μg/ml with Area under the curve (from 0 to 12 hours, μg-time/ml)

Comparison of PPK values for preparations MI and MI! (bilayer tablets) with the value for the MIII drug (immediate-release tablets) shows that the absorption of the amoxicillin component was not impaired when formed from part of its slow-release layer. This means that there is no special non-absorbable amoxicillin, which can otherwise cause problems further down in the gastrointestinal tract, for example, due to lack of absorption and disruption of bacterial symbiosis.

It was also found that there was less intersubject variability in amoxicillin plasma concentrations for the MI drug than for the MII drug. These drugs were identical except that the drug

MI also contains xanthan gum (2905) in a slow-release layer.

The pharmacokinetic profile for amoxicillin plasma concentration is shown in Figure 4 (in which A represents drug MI, B represents drug MII, O represents drug MI).

The pharmacokinetic profile for the clavulanate component was essentially the same for both bilayer and immediate-release tablets, showing that its bioavailability was not impaired when incorporated into the immediate-release bilayer tablet.

This invention also applies to drugs that are bioequivalent to tablets of drugs MI Her MI! in terms of both the rate and degree of absorption, for example as defined by 5 Rosa apa Ogcid Aatipivigaynop (Guidelines for the Quality Control of Foods, Medicines and Cosmetics) and discussed in the so-called Yellow-Hot Book (Ogapde Vook) (Arrgomea Ogyd Rhodysiv my TNegareshiys EdyimaIepse

Emaichainopv, 05 Oeri oi Neay apa Nytap Begmisev, 191" edp, 1999).

Data for reference

Existing Augmentin 875/125mg tablets have an Smax value of 11,622.8mcg/ml (RPuzisiape YuOevzk

Veiegepse, Medes! Esopotisz So, 52 Еаиоп, 1998, 2802). The time for concentrations to exceed the MIC was approximately 4095 of the 12-hour dosing interval for an MIC of 2 mcg/ml and approximately 3095 for a MIC of 4 mcg/ml (data from 5tyNKiipe Veespat). - WHERE are they? 1

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