CN1225246C - Therapeutic method - 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

The pharmaceutical formulation that contains the improvement release of amoxicillin

The present invention relates to use the novel method of treatment of amoxicillin and be used for the new formulation of such Therapeutic Method, especially tablet.

The amoxicillin is to use well-known beta-Lactam antibiotic for many years.Be subjected to the beta-lactamase inhibition that drug-resistant microorganism produces although suspect the amoxicillin, the amoxicillin still is widely used in the treatment common bacteria and infects because of has a broad antifungal spectrum.Specifically, treatment pathogenic microorganism in amoxicillin almost has only throat pain-acute bacterial tonsillitis and/or the pharyngitis of pyogenesis hammer (Streptococcus pyogenes) effective especially.

Be commercially available various Wymoxs, for example contain 250 or the capsule of 500mg amoxicillin, contain 500 or the tablet of 875mg amoxicillin, contain 125 or the chewable tablet of 250mg amoxicillin and be used for being formulated as again the dry powder formulations of oral administration mixed suspension.Other preparation types comprise dispersible tablet that the 500mg amoxicillin is provided, contain 125,250 or the chewing effervescent tablet and contain 750 or the single dose wafer (single dosesachet) of 3000mg amoxicillin of 500mg amoxicillin.Standard adult dosage is 250mg, and every day three times (tid), more severe infections increases to 500mg, every day three times.In addition, 875mg, twice of every day (bid), as 500mg, every day three times alternative dosage regimen.The 1000mg chewable tablet (ACPharma, referring to the 2472nd phase of SCRIP, on JIUYUE 15th, 1999, the 11st page) that announcement is recently being developed.Recommend 3g in appropriate circumstances, every day, twice high dose was used for the treatment of the serious or recurrent pyogenic infection of respiratory tract.For brachytherapy, simple property urinary tract infection: 3g was administered twice at interval in 10-12 hour; Dental abscess: 3g was administered twice at interval in 8 hours; Gonorrhea: single-dose 3g.In addition, the 1g amoxicillin, every day twice is as the part of the conjoint therapy of eradicating peptic ulcer disease helicobacter pylori (Helicobacter pylori).In addition, the tablet of various amoxicillin and potassium clavulanate provides amoxicillin and p-lactamase restrainer potassium clavulanate simultaneously, described tablet comprises the amoxicillin and the potassium clavulanate of various Different Weight and ratio, and for example the routine sheet of swallowing contains 250/125,500/125,500/62.5 and 875/125mg amoxicillin/clavulanic acid (potassium clavulanate form).Amoxicillin that this class tablet contains and clavulanic acid ratio were respectively 2: 1,4: 1,8: 1 and 7: 1.Also developed the 875/125mg tablet, can be to provide with the tablet of the scheme administration of twice administration every day.In Italy and Spain, also has the amoxicillin of commercially available every day of three administrations.Also develop the 500/62.5mg tablet, provide and to take 2 in per 12 hours with the tablet of the scheme administration of twice administration every day, preferably given 1 tablet of 1000/125mg tablet.Also can obtain the 1000/125mg of single dose in France, but be the wafer rather than the tablet of single dose.Usually the potassium clavulanate single dose of design approval is 125mg.

In addition, WO 97/09042 (SmithKline Beecham) has introduced that to comprise proportion be 12: 1 to 20: 1, preferred 14: 1 amoxicillin and the tablet of clavulanic acid.And the preferred dose that proposes 1750/125mg can provide by two kinds of tablets, and first kind of tablet comprises 875/125mg amoxicillin and clavulanic acid, and second kind of tablet is the 875mg amoxicillin.It is believed that, 14: 1 ratios can be used for empirical treatment may by drug resistance streptococcus pneumoniae (Spneumoniae) (DRSP) cause bacterial infection.The amoxicillin that comprises 14: 1 ratios and the pediatric formulation of clavulanate have also been introduced in this patent application, and its amoxicillin dosage is 90mg/kg/ days.The Notes of Key Data, this dosage can obtain to be enough to the amoxicillin+/-clavulanic acid MIC≤4 μ g/ml eliminate DRSP antibiotic concentration (Bottenfield etc., Pediatr Infect Dis J, 1998,17,963-8).

Commercially available amoxicillin tablet is a conventional tablet at present, because they discharge described active component immediately after tablet arrives stomach.In addition, what also cause certain concern is that exploitation improves release type and makes the longer preparation in interval between each agent administration, be administered once in for example per 12 hours (bid, q12h) rather than be administered once in per 8 hours (tid, q8h).

Therefore, for example WO 94/06416 (Jagotec AG) has introduced at the gentle slow releasing layer of immediate release layer and has contained the equally distributed amoxicillin of 500mg multilayer tablet.In addition, it is immediate release layer and the second layer is the multilayer tablet of containing of slow releasing layer of about 500mg amoxicillin that WO95/20946 (SmithKline Beecham) has introduced ground floor especially, two-layer amoxicillin ratio is about 1: 2.6, has the intermediate barrier layer between two-layer.WO 98/05305 (QuadrantHoldings Ltd) has also introduced the double-layer tablet that contains clavulanic acid and amoxicillin.In this tablet, ground floor contains the amoxicillin, and the second layer contains the excipient trehalose of clavulanate and stabilization rod hydrochlorate composition.

In addition, WO 95/28148 (SmithKline Beecham) has introduced especially and has comprised the amoxicillin and the optional tablet that contains clavulanate, and it has with the amoxicillin core that postpones the releasing agent coating, and medicine nuclear is outer to be amoxicillin and potassium clavulanate outer shell.Described delay releasing agent is an enteric coating, make to discharge the outer medicine of nuclear immediately, then second mutually the medicine nuclear pharmaceuticals when being delayed to medicine nuclear and arriving intestinal discharge.In addition, WO 96/04908 (SmithKline Beecham) has introduced especially and contained amoxicillin tablet that discharges immediately and the delay release type granule that contains the amoxicillin in skeleton.This granule is an enteric coated granule, so its hangover to granule is when arriving intestinal.WO 96/04908 (SmithKline Beecham) has introduced delay release or the lasting Wymox that discharges that granule constitutes especially, and described granule has the medicine nuclear that contains the amoxicillin, is the amoxicillin layer outside the medicine nuclear.

In addition, WO 94/27557 (SmithKline Beecham) has introduced the amoxicillin that utilizes the hydrophobic wax material preparation of carrying out the hot dipping stain after the preparation and the controlled release preparation of clavulanic acid.

Several research groups have also been reported the controlled release preparation that contains the amoxicillin.Therefore, and Arancibia etc. (Int J of Clin Pharm, Ther and Tox, 1987,25,97-100) introduced the pharmacokinetic properties and the bioavailability of the controlled release preparation that contains the 500mg amoxicillin.But do not provide being described in further detail about said preparation.But, design described preparation and discharged 21-35% at initial 60 minutes, discharged 51-66%, discharged 70-80%, discharged 81-90%, discharged more than 94% in 12 hours in 8 hours in 6 hours in 4 hours.Yet if there is dependency, the dependency of dissolution in vitro speed and intravital pharmacokinetic properties is also very small.(International Journal of Pharmaceutics, 1992,86 such as Hilton, 79-88) introduced another kind of controlled release tablet, this controlled release tablet possess hydrophilic property polymeric matrix and gas delivery system to be provided at the buoyancy of gastric, prolong the time of staying at gastric.Confirm this controlled release tablet and be not better than conventional capsule because of its bioavailability reduction.On the contrary, and Hilton etc. (Journal ofPharmaceutical Sciences, 1993,82,737-743) introduced the 750mg controlled release tablet of mixing enteric polymer acetic acid succinic acid hydroxypropyl emthylcellulose ester.Yet this controlled release tablet does not demonstrate any advantage that is better than conventional capsule.Specifically, compare with the capsule of same dose, its declined bioavailability of oral administration is 64.6%.Recently, (Journal ofControlled Release such as Hoffman, 1998,54,29-37 and WO 94/22091) introduced the tablet that in containing the substrate of hydroxypropyl emthylcellulose, contains the 500mg amoxicillin, this tablet design discharges its 50% content in initial 3 hours, finished drug release process in 8 hours.Compare with capsule, find the time significant prolongation that MIC is above, but its time is not enough to administration in 12 hours at interval.The condition of described argumentation is that theoretical MIC is 0.2 μ g/ml.

The part challenge (and ready-made explanation that described research is failed to succeed) that obtains the Wymox that drug release effectively improves is that medicine is narrower at the absorption window of small intestinal and half-life medicine is shorter.And the quick elimination of amoxicillin (draining the half-life is 1.3 hours) makes it be difficult to keep serum levels, because the removing of body is very fast.

In containing the existing tablet of amoxicillin, the amoxicillin is a Utimox, because the storage-stable of tablet that uses this form amoxicillin is than Amoxicillin Sodium stability of formulation higher (referring to GB 2005538, Beecham Group Ltd).Yet Amoxicillin Sodium is as the amoxicillin component in the existing preparation of amoxicillin that is applicable to the IV administration and potassium clavulanate.The form of used Amoxicillin Sodium is a spray-dried forms.In addition, EP 0 131 147-A1 (Beecham Group plc) have introduced other form Amoxicillin Sodiums of so-called " crystallization Amoxicillin Sodium ".WO 99/62910 (SmithKline Beecham) has introduced the additive method for preparing the amoxicillin crystal salt that comprises Amoxicillin Sodium.Compare with Utimox, Amoxicillin Sodium is more soluble in water.

WO 96/07408 (SmithKline Beecham) has introduced the preparation that comprises clavulanic acid and pharmaceutically acceptable organic acid or their salt derivative such as calcium citrate.In this preparation, prerequisite is that having of calcium citrate helps suppress orally give and contain the gastrointestinal side effect that the clavulanate goods are followed.

In addition, United States Patent (USP) the 5 051 No. 262 (Elan Corp) has been introduced in improving delivery formulations and has been mixed organic acid, helps to protect active component to avoid the microenvironment of degrading with the pH that minor betterment is provided.

Troubling is that the pathogenic former Drug resistance to anti-infectives such as amoxicillin that pathogenic organisms for example sees respiratory tract infection constantly increases, especially the drug resistance streptococcus pneumoniae.Streptococcus pneumoniae is taken place in the global range increases (because modifying penicillin-binding protein) to the resistance of penicillin, and influence clinical effectiveness (referring to for example Applebaum P C, Ped InfDis J, 1996,15 (10), 932-9).These penicillin resistance streptococcus pneumoniae (PRSP) are also referred to as " DRSP ", because they not only reduce the sensitivity of penicillin usually, and the sensitivity of various antimicrobial class medicines reduced, comprise Macrolide, azalides, beta-lactam, sulfonamides and Tetracyclines.According to the MIC level and the pharmacokinetic properties of these chemical compounds, the quinolones that amoxicillin and part are new still is the most effective oral drugs of ever-increasing streptococcus pneumoniae resistance separated strain.Yet resistance rate (and MIC) continuous increasing.Standard according to national clinical experiment standard committee (NCCLS) formulation, can evaluate the penicillin resistance of streptococcus pneumoniae, described standard is as follows: the MIC of susceptible strain≤0.06 μ g/ml, the moderate resistance is defined as MIC 0.12-1.0 μ g/ml, and penicillin resistance is defined as MIC 〉=2 μ g/ml.In addition, find that at present about 10% pneumococcal amoxicillin MIC is 2 μ g/ml.

Therefore, novel Wymox need be provided, this preparation comprehensively has known security feature and has a broad antifungal spectrum and higher to increased activity, the MIC of the DRSP that comprises PRSP, and it may be the former respiratory tract infection of possible causing a disease for cause a disease former respiratory tract infection and streptococcus pyogenes that this new formulation is used for empirical treatment streptococcus pneumoniae, hemophilus influenza (Hinfluenzae) and M catarrhalis.

About comprising the beta-lactam of amoxicillin, it is believed that (T＞MIC) was and renderd a service the closest pharmacodynamic parameter the above time of minimal inhibitory concentration.For various beta-lactams, when serum-concentration surpasses the about dosing interval more than 40% of MIC bacteriology's cure rate reach 85%-100% (Craig and Andes, Ped Inf Dis J, 1996,15,255-259).If be 12 hours dosing intervals, it then is about 4.8 hours.

May other important parameters be maximal plasma concentration (C _Max) with the ratio of MIC value because this ratio may be relevant with the potentiality of selection resistance.This ratio is too low to be had and helps produce resistant strain.Preferred plasma C _MaxValue substantially exceeds the MIC value, for example is at least 2 times of MIC value, more preferably at least 3 times, most preferably at least 4 times.

In clinical research, confirm that the average pharmacokinetic parameter in amoxicillin is: AUC with Amoxil 875mg tablet (SmithKline Beecham) _0-∞=35.4 ± 8.1 μ g.hr/mL; C _Max=13.8 ± 4.1 μ g.hr/mL (Physicians Desk Reference, MedicalEconomics Co, 52 editions, 1998,2802).For MIC 2 μ g/ml, the above time of MIC is 12 hours dosing intervals of about 40%, is for MIC 4 μ g/ml about 30% dosing interval (SmithKline Beecham data).

Based on above consideration, still need the amoxicillin dosage regimen that provides new, optimize the pharmacokinetic profile of amoxicillin, make the therapeutic effect maximization, especially to the maximum effect of more tolerant bacteria, resistance (further) generation is minimized.Find at present to adopt just can reach this purpose than the amoxicillin of designing the higher dosage of dosage in the past.

Therefore, first aspect the invention provides the method for the treatment of people's bacterial infection, and this method comprises the amoxicillin to the treatment effective dose of described patient's orally give 1900-2600mg, preferred 1950-2550mg scope, about 12 hours of dosing interval.

Preferably described dosage regimen makes 4 μ g/mL amoxicillin mean plasma concentrations continue at least 4.4 hours, preferably at least 4.6 hours, more preferably at least 4.8 hours, most preferably from about 6 hours or longer.

More preferably described dosage regimen makes 8 μ g/mL amoxicillin mean plasma concentrations continue at least 4.4 hours, more preferably at least 4.6 hours, most preferably at least 4.8 hours.

Preferably described dosage regimen makes the average maximal plasma concentration in amoxicillin (Cmax) be at least 8 μ g/mL, preferably at least 12 μ g/mL even more preferably at least 14 μ g/mL, at least 16 μ g/mL most preferably.

Preferably in beginning during informal dinner, measure the mean plasma concentration of amoxicillin and the average maximal plasma concentration of amoxicillin behind the oral preparation that contains the amoxicillin.

Advance on the one hand, the invention provides the method for treatment people bacterial infection, this method comprises the treatment effective dose amoxicillin that described patient is given 1400-1900mg, preferred 1500-1900mg scope, about 12 hours of dosing interval makes described dosage regimen that amoxicillin mean plasma concentration 4 μ g/mL at least 4.4 hours, preferably at least 4.6 hours, more preferably at least 4.8 hours, most preferably from about 6 hours or longer are provided; More preferably described dosage regimen provides amoxicillin mean plasma concentration 8 μ g/mL at least 4.4 hours, more preferably at least 4.6 hours, most preferably at least 4.8 hours and described dosage regimen provide the amoxicillin average maximal plasma concentration (C _Max) be at least 8 μ g/mL, preferably at least 12 μ g/mL, more preferably at least 14 μ g/mL, at least 16 μ g/mL most preferably.

Be applicable to that bacterial infection of the present invention comprises that biological streptococcus pneumoniae (comprises drug resistance streptococcus pneumoniae (DRSP), penicillin resistance streptococcus pneumoniae (PRSP) for example) and/or the respiratory tract microbial infection of causing a disease, the most noticeable is hemophilus influenza and M catarrhalis, for example respiratory tract infection, comprise community acquired pneumonia (community acquiredpneumoniae) (CAP), acute episode of chronic bronchitis (AECB) and acute bacterial sinusitis (ABS), in this case by improving the high breakpoint (thehigher break points) that pharmacokinetic profile is realized, comparing with existing antibacterials, is useful especially.Be applicable to that other bacterial infections of the present invention comprise the infection that streptococcus pyogenes causes, for example acute bacterial tonsillitis and/or pharyngitis.Treatment is generally 7-14 days the course of treatment, for most of indications common courses of treatment be 7 days, but the acute bacterial sinusitis is 10 days.

Term " amoxicillin " generally is used for being equal to and refers to amoxicillin or its basic salt, especially Utimox and (crystallization) Amoxicillin Sodium, except as otherwise noted.

Except as otherwise noted, otherwise the weight of amoxicillin is meant the suitable weight of corresponding free acid.In addition, it is pointed out that the amoxicillin weight of in fact mixing in the preparation need consider the effectiveness of amoxicillin, further adjust according to conventional practice.

In first embodiment, available immediate release formulation gives 1900-2600mg amoxicillin dosage.Therefore, again on the one hand, the invention provides the method for treatment people bacterial infection, this method comprises the treatment effective dose amoxicillin that gives in described patient 1900-2600mg, the preferred 1950-2550mg scope, about 12 hours of dosing interval wherein gives described dosage with immediate release formulation.

Term used herein " immediately discharge " for example is meant in the short period of oral back in 1 hour, the major part of release of active agent content in preferred 30 minutes.The example of this immediate release formulation comprises routine swallow sheet, chewable tablet, dispersible tablet, single dose wafer and capsule.

Typical doses comprises 2000,2250 and the 2500mg amoxicillin.Preferred dose is the 2000mg amoxicillin.

Can provide immediate release formulation dosage with a slice medicine or a medicine, for example a slice dispersible tablet, a tablet chewable tablets (also can for a slice effervescent chewable tablet and/disperse chewable tablet), a single agent capsules agent or a single dose wafer, described tablet for example comprises 2000,2250 or the 2500mg amoxicillin.On the other hand, described dosage can be made up of many more low dose of tablets or capsule, and for example by 2,3 or 4 or form, they can be same dose or various dose.Typical this low dose of tablet comprises the sheet of swallowing, dispersible tablet and chewable tablet (also can and/or disperse chewable tablet for the effervescent chewable tablet).Therefore, for example 2000mg amoxicillin dosage can be united with 4 every tablet tablet that contains the 500mg amoxicillin or 2 every tablet tablet that contains the 1000mg amoxicillin and provided.In addition, 2250mg amoxicillin dosage can contain the tablet of 875mg amoxicillin and 1 every tablet tablet that contains the 500mg amoxicillin with 4 every tablet tablet that contains the 500mg amoxicillin and 1 every tablet tablet that contains the 250mg amoxicillin or 2 every and unites and provide.In addition, the dosage of 2500mg amoxicillin can be united with 5 every tablet tablet that contains the 500mg amoxicillin provides.The tablet that contains 500mg and 875mg amoxicillin is existing marketed tablet.

It is pointed out that release tablet immediately, the especially chewable tablet or the dispersible tablet that contain 1000mg are novel.Therefore, more on the one hand, the invention provides contain nominal than about 16: 1 1000mg ± 5% amoxicillin and pharmaceutically acceptable excipient or carrier the tablet of release medicinal immediately.Can make the release tablet immediately that contains 1000mg at an easy rate by changing 875/125mg and the 1000/125mg tablet composition (referring to for example WO 95/28927 and WO 98/35672, SmithKline Beecham) introduced previously.

It is pointed out that also the single dose wafer that discharges immediately that contains 2000mg, 2250mg or 2500mg amoxicillin or their corresponding half amount is novel.Therefore, more on the one hand, the invention provides the preparation of release medicinal immediately of the single dose wafer form that contains 2000mg, 2250mg or 2500mg ± 5% amoxicillin or their corresponding half amount and pharmaceutically acceptable excipient or carrier.Can make such wafer at an easy rate by changing 875/125mg and the 1000/125mg amoxicillin/potassium clavulanate wafer compositions (referring to for example WO 92/19277 and WO 98/35672, SmithKline Beecham) introduced previously.

It is pointed out that also the chewable tablet that discharges immediately that contains 2000mg, 2250mg or 2500/125mg is novel.Therefore, again on the one hand, the invention provides the preparation of release medicinal immediately of chewable tablet form, it can be the effervescent chewable tablet and/or disperses chewable tablet, said preparation contains 2000mg, 2250mg or 2500mg amoxicillin or they correspondingly partly measures and chews base, if be effervescent formulation, it is right then also to comprise effervescent, and other pharmaceutically acceptable excipient or carriers.Can make such chewable tablet at an easy rate by changing the chewable tablet compositions of introducing previously that contains the amoxicillin (referring to for example EP-A-0 396 335, Beecham Group and WO 98/35672, SmithKline Beecham).

In second embodiment, available improved delivery formulations gives 1900-2600mg amoxicillin dosage.Therefore, again on the one hand, the invention provides the method for treatment people bacterial infection, this method comprises and gives described patient 1400-2600mg, preferred 1900-2600mg, the more preferably treatment effective dose amoxicillin in the 1950-2550mg scope, about 12 hours of dosing interval wherein gives described dosage with improved delivery formulations.

Term used herein " improve discharge " is meant with swallow sheet or capsule of immediate release formulation such as routine and compares, and pharmaceutical formulation is discharging drug substance than low rate, and its release can comprise that discharging gentle mutually slow release immediately puts phase.It is well-known in the art improving delivery formulations, referring to for example Remington:The Science and Practice of Pharmacy, the 19th edition, 1995, Mack Publishing Co, Pennsylvania, USA.

Preferably prepare the present invention and improve delivery formulations and make the release of amoxicillin mainly realize, so that reach maximum by the absorption of the specific amoxicillin of small intestinal absorption site by the harmonization of the stomach small intestinal.Preferably the amoxicillin release profile is made of the slow release component release that immediate-release component release and continuation subsequently replenish continuity.Preferably preparing this preparation made the release of amoxicillin mainly occur in to take behind the described preparation in 3 hours.

The typical case improve to discharge dosage and comprises 1500,1750 and the 2000mg amoxicillin.Preferred dose is the 2000mg amoxicillin.

Described improvement delivery formulations dosage can provide easily with multi-disc (grain) swallow sheet or capsule, for example 2,3 or 4 or, they can be same dose or various dose.Therefore, for example 2000mg amoxicillin dosage can contain 1000mg or 4 every tablet tablet that contains the 500mg amoxicillin provides with 2 every tablet tablet that contains the 1000mg amoxicillin, 2 every tablet tablet that contains the 500mg amoxicillin and 1.In addition, 1750mg amoxicillin dosage can provide with 2 every tablet tablet that contains the 875mg amoxicillin.Preferred tablet contains the 1000mg amoxicillin.

Also can provide the dosage that improves delivery formulations with a slice medicine.Because the content of employed drug substance, this tablet should be the non-sheet of swallowing, and for example is dispersible tablet or chewable tablet (also can and/or disperse chewable tablet for the effervescent chewable tablet) or dispersible tablet.Can also 1 single dose wafer provide a unit dose easily.It is pointed out that described dosage also can with some low doses non-swallow sheet or wafer for example 2 * 1000 or 4 * 500mg amoxicillin provide.

Preferably put with the gentle mutually slow release of release immediately the amoxicillin is provided mutually with the improvement delivery formulations.

Therefore, again on the one hand, the invention provides and improve the pharmaceutical formulation that discharges, it comprises amoxicillin and pharmaceutically acceptable excipient, wherein prepare the first amoxicillin, discharge phase immediately to form with the pharmaceutically acceptable excipient that can discharge the first amoxicillin immediately; With the pharmaceutically acceptable excipient preparation second portion amoxicillin that can slowly discharge the second portion amoxicillin, to form slow release phase; Thereby described discharge immediately with slow release mutually in the amoxicillin ratio be 3: 1 to 2: 3, and said preparation provides the amoxicillin of 1900-2600mg dosage.

Term used herein " slowly discharge " be meant oral back in the time that prolongs relatively gradually but continue release of active agent composition (under situation of the present invention, being the amoxicillin), and when described preparation arrives gastric and begin disintegrate/dissolving, just begin release.Described release certain time and sustainable when described preparation arrives small intestinal even after arriving small intestinal.What these were different with term " delay discharges " is, the active substance that postpones to discharge discharges and begins immediately after not described preparation arrives stomach, discharge but postpone certain hour,, utilize the pH that raises to come the initiating activity material to discharge from described preparation for example up to when described preparation arrives small intestinal.

The dissolution in vitro that preferably improves delivery formulations is distributed as: the 45-65% of amoxicillin content, preferred 45-55% dissolved in 30 minutes; Further the 50-75% of amoxicillin content, preferred 55%-65% dissolved in 60 minutes; And then the 55-85% of amoxicillin content, preferred 60-70% dissolved in 120 minutes; Again and the 70-95% of amoxicillin content, preferred 75-85% dissolved in 180 minutes; The 70-100% of a step amoxicillin content, preferred 75-100% dissolved in 240 minutes again.Comparatively speaking, routine discharges the dissolving fully in 30 minutes basically of amoxicillin tablet immediately.Can use deionized water (900mL) and oar rotating speed 75rpm in 37.0 ± 0.5 ℃ with standard dissolving algoscopy, for example USP 23,1995 provide＜711〉solubility test, device 2, measure dissolution profiles.

With regard to the amoxicillin, preferably improve delivery formulations and have two-phase distribution in the body, that is to say that discharging the phase initial burst immediately provides acceptable C _MaxValue, that continues prolongs T＞MIC parameter to acceptable value for slowly discharging further to discharge mutually.

Preferably improve preparation substantially similar " area under curve (AUC) " value of taking the corresponding dosage amoxicillin of routine (discharging immediately) preparation in the same dose administration cycle is provided, for example be at least 80%, preferably at least 90%, more preferably from about 100%, make thus by slow release component absorption amoxicillin component to reach maximum.

According to the pharmacokinetic profile that can determine dosage of the present invention at the bioavailability study of the single dose of human volunteer at an easy rate.Then can be well-known according to this area and the method record of this area document measure amoxicillin plasma concentration from the blood sample that the patient obtains at an easy rate.

The typical delivery formulations that improves comprises tablet (comprising the sheet of swallowing, dispersible tablet, chewable tablet (also can and/or disperse chewable tablet for the effervescent chewable tablet)) and capsule, granule or wafer, is generally the sheet of swallowing.

Have immediately and to discharge typical case that gentle mutually slow release puts phase and improve delivery formulations 700-1300mg, preferred 950-1300mg, the more preferably unit dose amoxicillin in the 850-1250mg scope are provided, for example 1000,875 and the amoxicillin of 750mg unit dose.On the other hand, when the physics size of described dosage form does not have problems, unit dose can provide all dosage, and for example single dose wafer or dispersible tablet can comprise 1400-2600mg, preferred 1900-2600mg amoxicillin, and for example 2000,1750 and the amoxicillin of 1500mg unit dose.It is pointed out that such 1000,875 and 750mg preparation are new.

Therefore, more on the one hand, the invention provides to have and discharge gentle mutually slow release immediately and put the pharmaceutical formulation of phase, it comprises:

(a) the unit dose amoxicillin in 700-1300mg, the preferred 950-1300mg scope, for example 1000,875 or the amoxicillin of 750mg ± 5% unit dose, or

(b) 1400-2600mg, preferred 1700-2600mg, the more preferably unit dose amoxicillin in the 1900-2600mg scope, for example 2000,1750 or the amoxicillin of 1500mg ± 5% unit dose,

And pharmaceutically acceptable excipient or carrier.

Preferably discharging the gentle slow release in phase amoxicillin immediately, to put the ratio of phase amoxicillin be 3: 1 to 1: 3, more preferably 2: 1 to 2: 3 even more preferably 3: 2 to 1: 1.Typical proportions comprises about 2: 1,9: 7 or 1: 1.Discovery discharges immediately uses excessive amoxicillin can effectively guarantee enough C mutually _MaxValue.

In improvement delivery formulations of the present invention, immediately the amoxicillin part of Shi Fanging can Utimox or its basic salt provide, for example amoxicillin potassium or Amoxicillin Sodium, preferred (crystallization) Amoxicillin Sodium or their mixture are preferably Utimox; And the amoxicillin part that slowly discharges provides with Utimox or its basic salt, for example amoxicillin potassium or (crystallization) Amoxicillin Sodium or its mixture, preferably (crystallization) Amoxicillin Sodium.

Preferred described improvement delivery formulations is a tablet.In a kind of advantageous embodiment release tablet that comprises the 1000mg amoxicillin, discharge immediately and comprise about 563mg ± 5% Utimox mutually and slow release comprises about 438mg ± 5% amoxicillin mutually, is preferably (crystallization) Amoxicillin Sodium.

Improve in the release tablet a kind of the present invention typical case, discharge immediately comprise about 438mg amoxicillin, preferred fine hair shape Utimox mutually and slowly release comprise about 438mg amoxicillin, preferred (crystallization) Amoxicillin Sodium mutually, it is the tablet of 875mg (14: 1) that total amount is provided.

In another typical tablet of the present invention, discharge immediately comprise about 500mg amoxicillin mutually and slowly release comprise about 250mg amoxicillin, preferred (crystallization) Amoxicillin Sodium mutually, it is the tablet of 750mg (12: 1) that total amount is provided.

It is pointed out that the mixture of using Utimox and Amoxicillin Sodium generally is more suitable for the pharmaceutical formulation that other comprise the amoxicillin.

Therefore, again on the one hand, the invention provides the pharmaceutical formulation that comprises the amoxicillin, wherein the mixture with Utimox and A Moxi sodium provides the amoxicillin, wherein the ratio of Utimox and Amoxicillin Sodium is 3: 1 to 1: 3, more preferably 7: 3 to 1: 3, even more preferably 2: 1 to 2: 3, most preferably 3: 2 to 1: 1.Preferred described preparation comprises the above amoxicillin of 500mg, more preferably 600mg amoxicillin at least, most preferably 700mg amoxicillin at least.Preferred Amoxicillin Sodium is the crystallization Amoxicillin Sodium.The exemplary formulations type comprises tablet (comprise the release tablet immediately that this paper introduces and improve release tablet) and other solid dosage formss, for example capsule, single dose wafer and granule.Typical tablet comprises and comprises 1000,875,500 and the tablet of 250mg amoxicillin.In improvement delivery formulations of the present invention, the amoxicillin that preferably discharges phase immediately mainly is made of Utimox and the amoxicillin that slowly discharges phase mainly is made of Amoxicillin Sodium.

For tablet, the gentle mutually slow release of release is immediately put mutually can several multi-form providing.

One preferred aspect, discharging the independent stratum that gentle mutually slow release puts with multilayer tablet immediately provides.

Therefore, on the one hand, the invention provides multilayer tablet again, it comprises the immediate release layer that contains the amoxicillin and contains the amoxicillin and the slow releasing layer of delay release excipient, this multilayer tablet:

(a) be double-layer tablet;

(b) comprise at least three layers, comprise the immediate release layer slow releasing layer that eases up, and comprise 275mg amoxicillin at least mutually at immediate release layer;

(c) comprise at least three layers, comprise the immediate release layer slow releasing layer that eases up, and slowly the delay release excipient in the releasing layer comprises xanthan gum and/or pharmaceutically acceptable organic acid; Or

(d) comprise at least three layers, comprise the immediate release layer slow releasing layer that eases up, and described amoxicillin provides with the Utimox and the Amoxicillin Sodium mixture of 3: 1 to 1: 3 ratios.

Term used herein " bilayer " sheet is meant the tablet of being made up of the gentle slow releasing layer of immediate release layer, has coatings and choose wantonly.

Immediate release layer can be for example immediately or fast disintegrate and contain the releasing layer of the component of immediately similar or quickly disintegrated known tablet.For example except the active substance composition, immediate release layer can contain excipient, comprises diluent such as microcrystalline Cellulose; Disintegrating agent such as crospolyvinylpyrrolidone (CLPVP) and Explotab; Compression aid such as silica sol and microcrystalline Cellulose; And lubricant such as magnesium stearate.This immediate release layer can comprise about 60-85%, and (all percentage rate that this paper provides are weight percent, preferred 70-85% active substance composition except as otherwise noted),, about 10-30%, preferred 10-20% filler/compression aid, and convention amount disintegrating agent and lubricant, about 0.5-3% etc. usually.

The substituted type immediate release layer can be for containing the expanding layer of the component of mixing polymeric material, and fully expanding immediately when described polymer contacts with water or aqueous medium forms water permeable but bigger dilatant.The active substance composition can leach from this dilatant immediately.

Slowly releasing layer contains the component that comprises the amoxicillin and postpone release excipient, and described delay release excipient can slowly discharge the amoxicillin.Suitable delay release excipient comprises the pH sensitive polymer, for example based on the polymer such as Eudragit (trade mark) polymer of methacrylic acid copolymer, for example can use separately or unites the Eudragit L (trade mark) of use with plasticizer; The delay release polymers of high level expansion when contact water or aqueous medium such as gastric content; Contact water or aqueous medium form the polymeric material of gel; And have when contact water or aqueous medium and expand and the polymeric material of gelling characteristics.

The delay release polymers of high level expansion is particularly including cross-linking sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, high molecular weight hydroxypropyl methyl cellulose, carboxymethyl amide, methacrylic acid potassium divinyl benzene copolymer, polymethyl methacrylate, crospolyvinylpyrrolidone, high molecular weight polyvinyl alcohol etc.

Postpone the release gels polymer and comprise methylcellulose, carboxymethyl cellulose, low-molecular-weight hydroxypropyl emthylcellulose, low molecular weight polyethylene alcohol, polyoxyethylene enediol, non-crosslinked polyvinylpyrrolidone, xanthan gum etc.

The delay release polymers that has expansion and gelling characteristics simultaneously comprises medium-viscosity hydroxypropyl emthylcellulose and medium-viscosity polyvinyl alcohol.

Preferred delay release polymers is xanthan gum, especially detailed catalogue level xanthan gum, preferred pharmaceutical grade 200 icteric sclera virgin rubbers, and for example product Xantural 75 (is also referred to as Keltrol CR, trade mark, Monsanto, 800N Lindbergh Blvd, St Louis, MO 63167, USA).Xanthan gum is a kind of polysaccharide, and it can form the viscogel layer in hydration around the tablet, and described active substance discharges by this gel layer disperse.Confirmed that granularity is more little, rate of release is slow more.In addition, the drug substance rate of release depends on used xanthan gum amount, can regulate the release profile that the drug release rate acquisition needs.EP 0 234 670-A (Boots Co plc) have introduced the controlled release preparation that comprises the 7.5-25% xanthan gum.Embodiment preferred is the tablet that comprises ibuprofen pharmaceutical material and 15-20% xanthan gum, and this tablet is taken once every day.

Spendable other examples of polymer comprise Methocel K4M (trade mark), MethocelE5 (trade mark), Methocel E5O (trade mark), Methocel E4M (trade mark), MethocelK15M (trade mark) and Methocel K100M (trade mark).An example of suitable polymers mixture is for example 1: 1 (w: Methocel E5 w) and K4M mixture.

Other known delay release polymers that can mix comprise hydrocolloid such as natural or paragutta, above cellulose derivative, glycosyl material such as acacin, tragacanth, tracasol, guar gum, agar, pectin, angle dish glue, solubility and insoluble alginate, carboxypolymethylene, casein, zein beyond listed etc., and protein substance such as gelatin.

Described slow releasing layer can contain contact water or the expansible immediately polymer of aqueous medium, so that they form bigger dilatant, and makes it not enter small intestinal from stomach immediately.

Slowly releasing layer also can comprise diluent such as lactose; Compression aid such as microcrystalline Cellulose; And lubricant such as magnesium stearate.Slowly releasing layer can also contain disintegrating agent such as crospolyvinylpyrrolidone (CLPVP) and Explotab; Adhesive such as polyvinylpyrrolidone; Desiccant such as silicon dioxide; And soluble excipient such as mannitol or other soluble sugars.Usually slowly releasing layer comprises about 60-80% (weight) amoxicillin, 10-20% (weight) diluent/compression aid and 1-2.5% (weight) lubricant.

When xanthan gum is used as the delay release polymers, slowly releasing layer contains the 60-80% amoxicillin, 1-25%, preferred 2-15%, more preferably 4-15% xanthan gum, 10-30%, preferred 10-20% filler/compression aid and convention amount lubricant, all % are the weight percent of slow releasing layer.In a preferred embodiment, slowly releasing layer comprises 70-80% amoxicillin, 4-10% xanthan gum, 10-20% microcrystalline Cellulose and 1-2.5% magnesium stearate, and all % are the weight percent of slow releasing layer.

When the delay release polymers beyond the use xanthan gum, slowly releasing layer can contain the 30-70% that has an appointment, preferred 40-60% amoxicillin, 15-45% postpones release polymers, 0-30% filler/compression aid, convention amount lubricant and 5-20% soluble excipient, all % are the weight percent of slow releasing layer.

In addition, be surprisingly found out that when the amoxicillin in the slow releasing layer was its soluble-salt such as Amoxicillin Sodium, then its release can postpone because comprising a kind of organic acid.

Therefore, again on the one hand, the invention provides the purposes of delay release excipient of pharmaceutically acceptable organic acid as the preparation that comprises pharmaceutically acceptable amoxicillin soluble salt, described amoxicillin soluble salt is Amoxicillin Sodium or amoxicillin potassium, preferred Amoxicillin Sodium for example.

It is pointed out that except that the concrete preparation that this paper introduces previously it is more suitable in general to use organic acid do delay release excipient.

Therefore, the present invention also is provided at slow release and contains for example pharmaceutical formulation of Amoxicillin Sodium of pharmaceutically acceptable solubility salts of amoxycillin mutually, described slow release also is included as pharmaceutically acceptable organic acid mutually and postpones release excipient, and its mol ratio content (amoxicillin and organic acid mol ratio) is 100: 1 to 1: 10, preferred 50: 1 to 1: 5, more preferably 20: 1 to 1: 2.

It is believed that organic acid in the pharmaceutical formulation and the close of salts of amoxycillin contact, for example, cause certain interaction and improve described preparation and discharge the amoxicillin component because compression is granulated or direct compression.

Pharmaceutically acceptable solubility salts of amoxycillin comprises alkali metal salt such as sodium salt and potassium salt; Alkali salt such as magnesium salt and calcium salt, and acid salt example hydrochloric acid amoxicillin.Preferred described salt is Amoxicillin Sodium, more preferably crystallization Amoxicillin Sodium.

Term used herein " pharmaceutically acceptable organic acid " is meant itself not to be had pharmacological action and has can accept sense quality, can accept density, pH is moderate and is preferably solid organic acid.The example comprises monocarboxylic acid and has the polybasic carboxylic acid of 2-25, preferred 2-10 carbon atom; Monocyclic aryl acid and polyaromatic acid are as benzoic acid; And slaine such as polyacid hydrogen, dihydro.Can use a kind of pharmaceutically acceptable organic acid, perhaps can unite the described organic acid that uses more than 2 kinds or 2 kinds.Preferred described organic acid is to have optional C with one or more hydroxyl substituents or extra CO base in 1,2 or 3 carboxylic acid group and the carbochain _(2-10)Alkyl carboxylic acid or C _(2-10)Alkenyl-carboxylic, for example malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulic acid, sorbic acid or fruit acid such as tartaric acid, malic acid, ascorbic acid or citric acid, perhaps their acid salt, more preferably citric acid, especially anhydrous citric acid.

But using organic acid singly perhaps can be united use with the delay release polymers that this paper introduces previously.But preferred compositions comprises citric acid and postpones to discharge gel polymer, especially xanthan gum.When containing organic acid such as citric acid, the xanthan gum use amount can be lower than the content when only containing xanthan gum, for example the 0.5-8% (weight) of slow releasing layer, preferred 1-5% (weight), common about 2% (weight).

When organic acid was used as the delay release excipient, slowly releasing layer comprised 60-80% solubility salts of amoxycillin, 10-30%, preferred 10-20% filler/compression aid and convention amount lubricant, and all % are the weight percent of slow releasing layer.In a preferred embodiment, slowly releasing layer comprises 60-70% solubility salts of amoxycillin, 10-20% microcrystalline Cellulose and 1-2.5% magnesium stearate, and all % are the weight percent of slow releasing layer.

In a representative instance, multilayer tablet comprises crystallization Amoxicillin Sodium and citric acid, their mol ratio about 50: 1 to 1: 2, preferred 20: 1 to 1: 2, more preferably 2: 1 to 1: 1.2 even more preferably from about 1: 1 at slow releasing layer.In a preferred embodiment, slowly releasing layer comprises about 438mg ± 5% crystallization Amoxicillin Sodium, about 78mg ± 10% citric acid and about 2% (weight) xanthan gum.

In a kind of preferred multilayer tablet that comprises the 1000mg amoxicillin, immediate release layer comprises about 563mg ± 5% amoxicillin, preferred Utimox, and slowly releasing layer comprises about 438mg ± 5% solubility salts of amoxycillin, preferred crystallization Amoxicillin Sodium, about 78mg ± 10% citric acid and about 2% (weight) xanthan gum.

Tablet of the present invention can also comprise one or more barrier layers, and barrier layer can be between the corresponding ground floor and the second layer, and/or one or more outer surfaces of the ground floor and the second layer, for example end face of each layer of substantial cylindrical tablet (end face).Such barrier layer can be made of for example polymer, and basic or the complete waterproof or aqueous medium of described polymer expands in the time of perhaps can and/or contacting water or aqueous medium by water or aqueous medium or the slow etch of biological fluid.Suitable barrier layer is should be at least complete or complete substantially at described active matter quality possesses these characteristics before transferring to surrounding medium.

The suitable polymers of barrier layer comprises acrylate, methacrylate, acrylic acid copolymer, cellulose and derivant thereof (for example ethyl cellulose, cellulose acetate propionate ester), polyethylene and polyvinyl alcohol etc.The inflatable degree to the big dilatant of expanding layer formation of the barrier layer of expansible polymer when comprising contact water or aqueous medium, the size of described dilatant can not enter the small intestinal described preparation immediately from stomach.Barrier layer itself can comprise the active substance composition, and for example barrier layer can be slow releasing layer or postpone releasing layer.Usually each barrier layer thickness can be 2mm to 10 μ m.

Fluid-tight relatively barrier layer suitable polymers comprises above-mentioned Methocel (trade mark) series polymer, for example Methocel K100M, Methocel K15M, Methocel E5 and Methocel E50, they can use or unite use separately, and perhaps optional and Ethocel (trade mark) combination with polymers is used.This polymer can suitably be united use with plasticizer such as castor oil hydrogenated.Barrier layer also can comprise conventional binding agent, filler, lubricant and compression aid etc., for example Polyvidon K30 (trade mark), magnesium stearate and silicon dioxide, for example Syloid 244 (trade mark).

Tablet of the present invention can coat coatings wholly or in part, and coatings can be a protective layer, prevents that dampness from immersing tablet or preventing that tablet from damaging.Coatings itself can comprise the active substance composition, and can for example be immediate release layer, and disintegrate immediately discharges its active substance composition, for example amoxicillin and potassium clavulanate when contact water or aqueous medium.Preferred coating substance comprises hydroxypropyl emthylcellulose and Polyethylene Glycol and as the titanium dioxide of opacifier, for example sees that WO95/28927 (SmithKline Beecham) introduces.

Tablet of the present invention also can contain the pH regulator agent except containing active substance becomes to grade, pH buffer agent for example, and the pH regulator agent can be included in immediate release layer or slowly in the releasing layer, or is included in the coatings of whole tablet periphery or tablet part periphery.Suitable reducing is a calcium hydrogen phosphate.

In not having the tablet of barrier layer, immediate release layer accounts for the 50-60% of whole tablet weight, and slow releasing layer accounts for the 40-50% of whole tablet weight.When having barrier layer, immediate release layer accounts for the 40-50% of whole tablet weight usually, and slowly releasing layer accounts for the 35-45% of whole tablet weight, and barrier layer accounts for the 5-20% of whole tablet weight.

Find to obtain satisfied pharmacokinetic profile, and do not need to comprise barrier layer with double-layer tablet of the present invention.Therefore, preferred double-layer tablet.This also can reduce the complexity of production technology.

It is pointed out that 1000,875 and 750mg multilayer tablet with the gentle slow releasing layer of immediate release layer are new.Therefore, more on the one hand, the invention provides the medicinal multilayer tablet that comprises the gentle slow releasing layer of immediate release layer, this tablet comprises 700-1250mg amoxicillin, preferred 1000,875 or 750mg ± 5% amoxicillin and pharmaceutically acceptable excipient or carrier.Preferred described multilayer tablet is a bilayer tablet.

Can suitably use known pressed-disc technique, for example known multilayer tablet pressed-disc technique prepares tablet of the present invention.In initial step, the preferred use hit piece (slugging) compaction or the granulation of roll compaction method.Adding lubricant and compression aid (if you are using) then forms for the compressed mixture that presses film-making subsequently.

Can use a kind of method and prepare preferred double-layer tablet of the present invention, described method is included in the initial stage, preparation slowly discharges presses granule, its preparation process comprises: make Amoxicillin Sodium and diluent/compression aid such as microcrystalline Cellulose, a part of lubricant (40-60%, common about 50%) and pharmaceutically acceptable organic acid such as fruit acid (for example citric acid) or postpone release polymers such as xanthan gum or its mixture to mix; For example press mixture, perhaps by pre-tabletting (slugging) with the roll compaction device; Pulverize afterwards and form slow release particles.Preferred described particulate magnitude range is 100-1000 μ m.Add xanthan gum and as if also processing characteristics is had unexpected benefit.

Can make this slow release press granule then and mix slowly release compressed mixture of formation with other excipient such as magnesium stearate.

In addition, Utimox, microcrystalline Cellulose, disintegrating agent such as Explotab and lubricant such as magnesium stearate are mixed, for example compress, pulverize then to form to discharge immediately and press granule with the roll compaction device or by pre-tabletting.This discharges immediately and presses granule and can mix to form with other excipient such as magnesium stearate and silica sol and discharge compressed mixture immediately then.

Available then double-layer tablet tablet machine makes and discharges the gentle slow release of compressed mixture immediately and put compressed mixture and be suppressed into independent stratum and make double-layer tablet.

Slow release granules like this is new.Therefore, more on the one hand, the invention provides the granule that presses that comprises amoxicillin soluble salt such as Amoxicillin Sodium, diluent/compression aid and previously defined organic acid or postpone release polymers or their mixture.Another aspect, the present invention also provides the granule that presses that comprises Utimox, diluent/compression aid and previously defined delay release polymers.

On the other hand, can use the dry type compaction process, for example briquetting technology.Mix when active substance composition, pH regulator agent, buffer agent, filler and/or diluent, delay releasing agent, disintegrating agent and binding agent use usually, add lubricant and compression aid then.The mixture of available then tablet machine high pressure compacting all the components.Also can use wet granulation technology, for example make solvent with isopropyl alcohol and Polyvidon K-30 (trade mark) as the wet granulation auxiliary agent.

If there is barrier layer, common available wet granulation technique of barrier layer or dry granulation technology such as roll compaction make.Usually make the barrier material for example Methocel (trade mark) be suspended in the solvent such as ethanol that contains granulation auxiliary agent such as Ethocel or Polyvidon K-30 (trade mark), then mix, sieve and granulate.Usually can make ground floor earlier, by compression, spraying or dipping technique barrier layer is deposited on the ground floor then, can prepare the second layer after again, barrier layer is between the ground floor and the second layer.Perhaps, can prepare the ground floor and the second layer earlier, the one or more end faces at described tablet for example prepare barrier layer by compression, spraying or dipping then.

Can make coatings on the sheet nuclear coating then, obtain thin membrane coated tablet, described coatings can be with aqueous solvent system or organic solvent system, preferred aqueous solvent system coating.

The present invention also provides the method for producing aforesaid tablet, and this method may further comprise the steps: prepare the described ground floor and the second layer, and any barrier layer and the coatings that may need.

Except the foregoing multilayer tablet preparation method of this paper, the tablet of other types also can be used for utilizing the excipient of introducing previously to obtain to discharge immediately gentle mutually slow release and put phase, but the release phase form difference that obtains.Therefore, slowly discharge phase and can constitute sheet nuclear, it is outer for constituting the outer shell that discharges phase immediately, chooses the outermost layer coatings (referring to WO 95/28148, SmithKline Beecham) that has outside sheet is examined outside middle coatings and/or the outer shell wantonly.Slowly discharging mutually also can provide with granule, and Dispersion of Particles is in the substrate of amoxicillin, and substrate formation in amoxicillin discharges phase (referring to WO 96/04908, SmithKline Beecham) immediately.

In a version again, granule is pressed in available slow release and preparation of granules monolithic (monolith) improvement release tablet is pressed in release immediately, the described granule that presses comprises amoxicillin, diluent/compression aid such as microcrystalline Cellulose and pharmaceutically acceptable organic acid such as fruit acid (for example citric acid) (if the amoxicillin that exists for its soluble-salt time) or postpones release polymers such as xanthan gum or its mixture, preferably postpones release polymers (as mentioned above); Described release is immediately pressed granule and is comprised amoxicillin (as mentioned above), and described granule and extra-granular excipient are mixed and made into tablet.Described granule also can be processed into other pharmaceutical formulations, for example comprises single dose wafer, capsule or the chewable tablet of aforesaid unit dose.

Chewable tablet of the present invention comprises usually by what for example mannitol, sorbitol, glucose, fructose or lactose formed alone or in combination chews base.Chewable tablet can also contain other excipient, for example disintegrating agent, lubricant, sweeting agent, coloring agent and flavoring agent.Preferred other such excipient account for the 3-10% of described tablet, more preferably 4-8% even more preferably 4-7% (weight) together.The content of disintegrating agent can be the 1-4% of described tablet, preferred 1-3%, more preferably 1-2% (weight).Typical case's disintegrating agent comprises polyvinylpyrrolidone, Explotab, starch such as corn starch and rice starch, cross-linking sodium carboxymethyl cellulose and cellulose products such as microcrystalline Cellulose, microfine cellulose, low-substituted hydroxypropyl cellulose, and these disintegrating agents can use or mix use separately.Disintegrating agent is preferably polyvinylpyrrolidone.The content of lubricant can be the 0.25-2.0% of described tablet, preferred 0.5-1.2% (weight).Preferred lubricant comprises magnesium stearate.Preferred sweeteners is an artificial sweetening agent, for example saccharin sodium or aspartame, and preferred aspartame, the content of sweeting agent is the 0.5-1.5% (weight) of described tablet.Preferred tablet of the present invention is substantially free of sugar (sucrose).Preferred flavorings comprises flavoring agent of fruit, and flavoring agent of fruit can be natural flavouring or synthetic flavoring agent, for example Herba Menthae, Fructus Pruni pseudocerasi and Fructus Musae or their mixture.

Except described drug substance, single dose wafer of the present invention also comprises the excipient that the wafer preparation comprises usually, for example sweeting agent such as aspartame, flavoring agent such as flavoring agent of fruit and as the silica gel of desiccant.

Except described drug substance, capsule of the present invention also comprises the excipient that capsule comprises usually, for example starch, lactose, microcrystalline Cellulose, magnesium stearate.Preferably use material preparation capsule such as HPMC or gelatin/PEG combination.

EP-A-0 131 147 (Beecham Group plc) has introduced the method for preparing the crystallization Amoxicillin Sodium.

In another embodiment, available independent component for example independently tablet slow release phase is provided, make other preparations that contain the amoxicillin that the gentle slow release of conventional component that discharges immediately with the amoxicillin puts the amoxicillin as tablet unite provide as described in unit dose.The amoxicillin total amount that the gentle slow release of conventional formulation is put in the preparation provides whole unit dose.Therefore, for example available 2 tablets of existing 500mg amoxicillin tablets and the 1 slow release tablet that comprises the 1000mg amoxicillin provides the dosage of 2000mg.In addition, available 1 tablet of existing 875mg tablet (SmithKlineBeecham) and the 1 slow release tablet that contains the 875mg amoxicillin provides the dosage of 1750mg.In addition, available 2 tablets of existing 500mg amoxicillin tablets and the 1 slow release tablet that contains the 500mg amoxicillin provides the dosage of 1500mg.Therefore, more on the one hand, the invention provides and comprise routine (discharging immediately) tablet that contains the amoxicillin and the kit of parts that comprises the slow release tablet of amoxicillin.

Again on the one hand, the invention provides the slow release medicinal preparation that comprises amoxicillin (for unique active component), be preferably tablet, described pharmaceutical formulation is with making described preparation slowly discharge the delay release excipient preparation of amoxicillin, and described pharmaceutical formulation does not comprise:

Comprise the tablet of 750mg or the following amoxicillin of 750mg, wherein the amoxicillin of Cun Zaiing is essentially Utimox; Or

Comprise the 400-500mg amoxicillin and as the tablet of the hydroxypropyl emthylcellulose that postpones release excipient, the amoxicillin of wherein containing is the mixture that comprises at least 70% Utimox and 30% following Amoxicillin Sodium.

Described preparation can comprise the 100-1250mg amoxicillin, and for example 500,875 or the 1000mg amoxicillin, wherein the amoxicillin can be Utimox or (crystallization) Amoxicillin Sodium or their mixture.The excipient that is used for slow releasing layer that the appropriate excipients that is used for slowly discharging is introduced previously for this paper.Described preparation can comprise 1-25%, preferred 2-15%, more preferably 4-10% xanthan gum, perhaps can comprise 10-25%, preferred 15-20% hydroxypropyl emthylcellulose, for example Methocel K100LV or Methocel K4M.On the other hand, as mentioned above, described preparation can comprise citric acid, the optional xanthan gum that comprises.

Preferably with the container package unit dosage forms of the present invention of avoiding air moisture to enter, described container for example is the conventional blister package in this area, air-tight bottle or dry capsule bag packing etc.Preferably medicine bottle also comprises dry matter, to preserve clavulanate.Preferred medicine bottle comprises the HDPE medicine bottle.Preferred blister package comprises the blister package of cold formation, and wherein each bubble-cap can be adorned 1, perhaps adorns 2, and this moment, unit dose was 2, and for example 2 * 1000/62.5mg tablet can improve patient's compliance like this.

It is pointed out that the application relates to the invention that drug substance wherein is made of the amoxicillin basically, does not relate to the invention that drug substance is amoxicillin and potassium clavulanate and do not extend.

Now just illustrate the present invention by embodiment, wherein with reference to accompanying drawing

Fig. 1 illustrates the structure of all kinds multilayer tablet of the present invention, specifically shows the structure of substantial cylindrical tabletting with longitudinal section.Among Figure 1A, tablet comprises the ground floor (1) and the second layer (2), and without any barrier layer or coatings.Among Figure 1B, tablet comprise ground floor (1), the second layer (2) and be positioned at ground floor (1) and the second layer (2) between barrier layer (3).Among Fig. 1 C, tablet comprises ground floor (1), the second layer (2) and the barrier layer (3) that is positioned at the second layer (2) end face.Among Fig. 1 D, the coatings (4) that tablet comprises ground floor (1), the second layer (2), is positioned at the barrier layer (3) between the ground floor (1) and the second layer (2) and partly coats tablet.Dotted line represents to coat the coatings (4A) of whole tablet.Among Fig. 1 E, tablet comprises ground floor (1), the second layer (2) and ground floor (1) and intermediary the 3rd layer (3) of the second layer (2).All these 3 layers (1), (2) and (3) all comprise the active substance composition.

All public publications and the list of references quoted in this description include but not limited to patent and patent application, and all integral body is attached to herein by reference, as specifically point out individually each publication or list of references by reference integral body be attached to herein.The application requires any patent application of priority also to be attached to herein by reference in the mode of above-mentioned publication and list of references.

Embodiment 1-1000mg improves release tablet

Composition title mg/ sheet %

t w/w

Immediate release layer

Utimox 654.1 ^*40.88

Microcrystalline Cellulose 216.6 13.28

Explotab 18.0 1.12

Silica sol 6.3 0.39

Magnesium stearate 9.0 0.56

Amount to (immediate release layer) 900.0 56.23

Slow releasing layer

Amoxicillin Sodium 480.8 ^*30.05

Microcrystalline Cellulose 113.2 7.08

Xanthan gum 14.0 0.87

Anhydrous citric acid 78.0 4.87

Silica sol 1.5 0.09

Magnesium stearate 14.0 0.87

Amount to (continuing releasing layer) 700.0 43.74

Film coating-Opadry YS-1-7700

Composition

Hydroxypropyl methylcellulose 2910 6cp 11.6

Hydroxypropyl methylcellulose 2910 15cp 3.9

Titanium dioxide 15.1

Polyethylene Glycol 3,350 2.3

Polyethylene Glycol 8,000 2.3

Coated tablet gross weight 1635.2

^*Quantitative analysis according to 86.0% is equivalent to the 562.5mg amoxicillin

^*Quantitative analysis according to 91.0% is equivalent to the 437.5mg amoxicillin

Embodiment 2-1000/62.5mg improves release tablet

Immediate release layer and film coating are with the tablet of embodiment 1.

Composition title mg/ sheet % (w/w)

Slow releasing layer

Amoxicillin Sodium 480.8 ^*30.05

Microcrystalline Cellulose 127.2 7.95

Anhydrous citric acid 78.0 4.87

Silica sol 1.5 0.09

Magnesium stearate 14.0 0.87

Amount to (slowly releasing layer) 700.0 43.74

Coated tablet gross weight 1635.2

^*Quantitative analysis according to 91.0% is equivalent to the 437.5mg amoxicillin

Improve the preparation of release tablet

Grind, sieve Utimox and microcrystalline Cellulose (be about total amount 90%) make it mix with magnesium stearate then.With Chilsonater roll-type pressing mixt, grind and form release particles immediately.Grind again, sieve rest of stearic acid magnesium and microcrystalline Cellulose, Explotab and silica sol add it to mix in described granule to form and discharge compressed mixture immediately.

Grind crystallization Amoxicillin Sodium, microcrystalline Cellulose (be about total amount 70%) and anhydrous citric acid, it is mixed with xanthan gum (if suitable), magnesium stearate (be about total amount 70%) and silica sol.Use Chilsonater roll-type pressing mixt then, grind and form slow release particles.Rest of stearic acid magnesium and microcrystalline Cellulose are added the slow compressed mixture that discharges of mixing formation in the described granule.

With the double-layer tablet tablet machine two kinds of mixture are compressed into independent stratum afterwards, tablet machine is equipped with 0.0406 * 0.8730 inch and have the drift that improves capsule shape.Last in can holding 60 inches coating pan of the following tablet of 300kg, utilize 15% solid aqueous float to make sheet nuclear coat the aqueous coatings film.Coating pan is equipped with 4 ejecting guns, rotates with 3-5rpm.

The slow release tablet of embodiment 3-(875mg)

(a) amoxicillin sodium tablet

Mg/ sheet %

Crystallization Amoxicillin Sodium 91% ^*961.54 73.96

Dry microcrystalline Cellulose 273.46 21.04

Magnesium stearate 13.0 1.00

Xanthan gum 200 orders ^*52.0 4.00

Amount to 1,300 100

(b) contain the amoxicillin sodium tablet of citric acid

Mg/ sheet %

Crystallization Amoxicillin Sodium 91% ^*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 orders ^*29.0 2.00

Amount to 1,450 100

(c) Utimox tablet

Mg/ sheet %

Utimox 86% ^*1017.4 78.26

Dry microcrystalline Cellulose 217.6 16.74

Magnesium stearate 13.0 1.00

Xanthan gum 200 orders ^*52.0 4.00

Amount to 1,300 100

^*Regulate tiring and being equivalent to the 875mg amoxicillin of amoxicillin component,

^**Xantural 75

Embodiment 4-875mg improves release tablet

Slow releasing layer

For the slow releasing layer that contains about 438mg amoxicillin, can use above half this layer of amount preparation of giving output.

Immediate release layer-1

Utimox 507mg

(being equivalent to the amoxicillin free acid) (438)

Microcrystalline Cellulose (Avicel PH102) 196.8

Explotab (Explotab) 26

Magnesium stearate 6.5

Immediate release layer-2

Utimox 507mg

(being equivalent to the amoxicillin free acid) (438)

Microcrystalline Cellulose (Avicel PH102) 206

Explotab (Explotab) 34

Pulvis Talci 67

Magnesium stearate 25

Silicon dioxide (Syloid) 17

Barrier layer

WO 95/20946 (SmithKline Beecham) has introduced barrier layer and preparation method thereof.

The preparation of tablet

Mixed active composition, filler and diluent (microcrystalline Cellulose), controlled release agent (if containing), disintegrating agent (polyvinylpyrrolidone, Explotab) etc.Add lubricant (Pulvis Talci, magnesium stearate) and silica sol (Syloid 244), remix 1 minute.Make the pre-tabletting of complete mixture with tablet machine or roll compaction (briquetting step), grind then make its size reduce (Apex, Fitzmill, Frewitt), make again its pass through shaking screen or size sorting device (Kason, Sweco).If flow behavior is undesirable, then repeat the briquetting step.The independent compression mixture for preparing gentle slow releasing layer of immediate release layer and barrier layer (if present) respectively.

In some cases, when bulk density is too low, may need compacting step (prefabricated film in the briquetting method and sieve), so that obtain the concrete layer of nominal weight.

Make mixture be collapsed into independent stratum with the synusia tablet machine then, thereby obtain double-layer tablet.Available then White-opalescent coating such as product Opadry, Opaspray (Colorcon) coating tablet.

Embodiment 5-dissolution test method

With USP 23,1995 provide＜711〉solubility test, device 2 is measured tablets and is released into amoxicillin in the static medium.

Experimental condition:

Temperature: 37.0 ± 0.5 ℃

Medium: deionized water, 900mL

Oar speed 75rpm

Method

15, take out the equal portions medium after 30,45,60,90,120,150,180,240,300,360,420 and 480 minutes and measure, replace respectively taking out the equal portions medium with the equal-volume medium simultaneously, to keep constant volume.Measure the drug substance amount with ultraviolet spectroscopy in 272nm.The dissolution profiles of example 1 and example 2 tablets the results are shown in Figure 2.

The body giving drugs into nose of preparation is for the kinetics evaluation

In 2 human volunteer researchs, promptly study A and research B, estimate the bioavailability of the dosage form that comprises amoxicillin and potassium clavulanate.Do not predict, exist potassium clavulanate can influence the performance of amoxicillin component.

Described 2 researchs be the opening carried out in healthy premenopausal volunteers, at random, crossing research.Take each dose drug by means of about 200mL water behind beginning breakfast informal dinner and the overnight fasting.Before the administration that indicates and after the beginning administration 0.5,1,1.5,2,3,4,5,6,7,8,10 and 12 hour, blood sample is collected in the test tube that contains EDTA, to measure the blood plasma level of amoxicillin and clavulanate.The sample cooling is deposited in the ice bath standby.In 4 ℃ of frozen centrifugation separated plasmas, blood plasma to be transferred in the polypropylene specimen container of suitable labelling, freezing is standby in-70 ℃ of pacts.

With the acetonitrile utilization based on the amoxicillin in the method working sample of albumen precipitation.The target acetonitrile extracted the amoxicillin by albumen precipitation from human plasma (50 μ L) in application comprised, with the quantitative amoxicillin of LC/MS/MS.Specifically, draw human plasma (50 μ L) and add in the 1.5mLEppendorf pipe, add then contain interior mark ([ ¹³C ₆]-amoxicillin, 200 μ L) acetonitrile.The Eppendorf pipe is closed the lid, and vortex mixed was also vibrated about 15 minutes.Behind the centrifugal sample (about 11,000 * g, 15 minutes), supernatant is transferred in the 1.1mL taper Autosampler bottle of the silanization that 200 μ L 5mM Spirit of Mindererus. are housed.The equal portions extract is injected into the HPLC/MS/MS system and analyzes.Use Turbo IonSpray interface, with cation mode operation mass spectrograph.Utilize multiple-reaction monitoring (MRM) detected components amoxicillin and [ ¹³C ₆]-amoxicillin.The MRM method comprises that (1) carry out quality with first four-electrode quality analyzer to needs medicine or interior target characteristic ion and select, and (2) make selected ion fragmentation in the collision pond of instrument, (3) testing goal compound characteristic fragment ion.Chromatographic peak area and internal standard area by comparative drug are carried out quantitatively.In 0.05 μ g/mL (lower limit of quantitation; LLQ)-10 μ g/mL (upper limit of quantification; ULQ) analyte concentration observes the linear response of analyte/interior mark peak area ratio.

With every batch sample the calibration criterion of independent preparation is analyzed the QC sample.The result of QC sample is used for estimating the daily performance of described analysis.

Use non-chamber pharmacokinetic analysis program WinNonlin Professional Version1.5, the plasma concentration-time data of each object by non-each scheme of chamber methods analyst.All calculate to be as the criterion actual sample time.The pharmacokinetic parameter of measuring comprises observation maximal plasma concentration (C _Max) and reach time (Tmax) of maximal plasma concentration.Use that linear least square returns and the described data of naked-eye observation are determined the right quantity point of calculating lz, draw apparent end last elimination rate constant (lz) according to the log-linear processing section of concentration-time curve.Calculate apparent end eventually with ln (2)/lz and eliminate the half-life (Tl/2).

Utilize and respectively increase progressively trapezoid linear trapezoidal rule and the trapezoid logarithm trapezoidal rule that respectively successively decreases, determine area [AUC (0-t)] [Chiou WL., J.Phamacokinet.Biopharm., 1978 under the plasma concentration-time graph from 0 time to the last quantitatively plasma concentration time, 6,539-547].Summation with AUC (0-t) and C (t)/lz is calculated area [AUC (0-inf)] under the plasma concentration-time graph that is extrapolated to the infinite time, and C this moment (t) is the expection concentration that last minute point log-linear regression is analyzed.

(T＞MIC), minimum inhibition this moment plasma concentration is defined as 4 μ g/mL amoxicillin above the minimum time of suppressing plasma concentration with the artificial calculating of diagram interpolation.

Calculating each nominal of each preparation amoxicillin mean concentration of sample time-time distributes.After can not dosed administration, during value (postdose value), specify 1/2LLQ (0.050 μ g/mL) value to determine meansigma methods.When calculating mean value is lower than LLQ or based on greater than the 50%NQ value time, specifies the NQ value of this sample time.

Utilize the reference preparation data of the first phase (single term) and the common variable (co-variate) of match conduct of covariance analysis (ANCOVA) match preparation, analyze the log of each preparation _eThe C that transforms _MaxWith unconverted T＞MIC.Utilize the residual variance (residual variance) of described model to make up 95% credibility interval of each preparation mean.Make the C of the estimation of log scale then _Max95% credibility interval that obtains geometric mean is reversed in the credibility interval.These results show with figure.

Estimate the basis (assumption) of described analysis by detecting residual plot (residual plot).With of the desired value mapping of studentised residual error, estimate homogeneity of variance, and estimate normality with normal probability paper figure to described model.Pay special attention to any deviation value (outlyingvalue) that reference preparation observes.

Research A

First research has been compared 3 kinds of 1750/125mg dosage and improved delivery formulations (preparation I-III) and the 4th kind of 1500/125mg dosage improvement delivery formulations (preparation IV) and 1750/125mg dosage immediate release formulation (preparation V), and is specific as follows:

(a) amoxicillin/potassium clavulanate of 1750/125mg dosage is united by 1 improvement release tablet that contains 875/125mg Utimox/clavulanate and 4% xanthan gum and 1 release tablet immediately that contains the 875mg Utimox and is constituted (preparation I);

(b) amoxicillin/potassium clavulanate of 1750/125mg dosage is united by 1 improvement release tablet that contains 875/125mg crystallization Amoxicillin Sodium/clavulanate and 4% xanthan gum and 1 release tablet immediately that contains the 875mg Utimox and is constituted (Formulation II);

(c) amoxicillin/potassium clavulanate of 1750/125mg dosage is united formation (Formulation III) by 1 improvement release tablet and 1 release tablet immediately that contains the 875mg Utimox that contains 875/125mg crystallization Amoxicillin Sodium/clavulanate, citric acid (156mg) and 2% xanthan gum;

(d) amoxicillin/potassium clavulanate of 1500/125mg dosage is united formation (preparation IV) by 1 improvement release tablet and 2 release tablet immediately that contain the 500mg Utimox (Amoxyl, SmithKline Beecham) that contain 500/125mg crystallization Amoxicillin Sodium/potassium clavulanate; And

(e) amoxicillin/potassium clavulanate of 1750/125mg dosage is by 1 (Augmentin of release tablet immediately that contains 875/125mg Utimox/clavulanate, SmithKline Beecham) and 1 release tablet immediately (Amoxyl, SmithKline Beecham) that contains the 875mg Utimox unite formation (preparation V).

The result

Preparation	n	C max 1	T＞MIC 1，2	AUC 1，3
					I	8	12.75(4.96)	4.5(1.8)	47.83
II	8	18.56(4.72)	4.4(1.0)	57.46
					III	8	13.03(2.34)	5.73(2.54)	54.93
IV	8	17.33(4.66)	4.8(0.9)	56.71
					V	40	20.21(6.09)	4.2(0.9)	56.33

0 standard deviation

¹Arithmetic mean of instantaneous value

²T＞MIC is for surpassing the time (h) of 4 μ g/ml amoxicillin concentration

³Area under curve (0-12 hour, μ g.h/mL)

Pharmacokinetic profile is seen Fig. 3.

Research B

Different delivery formulations (preparation VI and VII) and the a kind of 2000/125mg immediate release formulation (preparation VIII) of improving of 2 kinds of 2000/125mg have been studied in second research, and are specific as follows:

(a) amoxicillin/potassium clavulanate of 2000/125mg dosage constitutes (preparation VI) by the double-layer tablet of 2 embodiment 1;

(b) amoxicillin/potassium clavulanate of 2000/125mg dosage constitutes (preparation VII) by the double-layer tablet of 2 embodiment 2;

(c) amoxicillin/potassium clavulanate of 2000/125mg dosage is by 3 every tablet (Amoxyl that contains the 500mg amoxicillin, SmithKline Beecham) and 1 tablet of tablet (Augmentin, SmithKline Beecham) that comprises 500mg amoxicillin and 125mg potassium clavulanate unite formation (preparation VIII).

The result

Preparation	n	C max 1	T＞MIC 1，2	T＞MIC 1，3	AUC 1.4
						VI	7	17.41(1.93)	6.0(1.3)	4.8(1.2)	74.9
VII	8	17.46(6.02)	5.9(1.3)	4.0(1.3)	71.5
						VIII	12	23.75(5.73)	4.9(1.1)	3.5(1.0)	69.2

() standard deviation

¹Arithmetic mean of instantaneous value

²T＞MIC is for surpassing the time (h) of 4 μ g/ml amoxicillin concentration

³T＞MIC is for surpassing the time (h) of 8 μ g/ml amoxicillin concentration

⁴Area under curve (0-12 hour, μ g.h/mL)

Comparative formulations VI and VII (double-layer tablet) confirm that with the AUC value of VIII (release tablet immediately) absorption of amoxicillin component is not influenced because of its part is formulated in slow releasing layer.This means does not have possibility because the other problems that produces at the bathygastria intestinal, and for example do not absorb and destroy fungal component, and the extra not absorption amoxicillin that causes.

In addition, the variability of amoxicillin plasma concentration between the experimental subject individuality of discovery preparation VI is little than Formulation II.These two kinds of preparations are identical, and different is that preparation VI is also slowly comprising xanthan gum (2%) in the releasing layer.

The pharmacokinetic profile of amoxicillin plasma concentration is seen Fig. 4 (wherein A is preparation VI, and B is preparation VII, and D is preparation VIII).

For example the invention still further relates to and (ratify the treatment equivalence evaluation of medicine according to the regulation and the argumentation in so-called " Orang Book " of FDA (Food and Drug Adminstration), the U.S. human health service portion, the 19th edition, 1999), aspect absorption rate and degree of absorption with preparation VI tablet and the bioequivalent preparation of preparation VII tablet.

Reference data

The C of existing Augmentin 875/125mg tablet _MaxValue is 11.6 ± 2.8 μ g/ml (Physicians Desk Reference, Medical Economics Co, the 52nd edition, 1998,2802).During MIC 2 μ g/ml, the time that is higher than MIC is 12 hours dosing intervals of about 40%, and during MIC 4 μ g/ml, the time that is higher than MIC is 12 hours dosing intervals (SmithKline Beecham data) of about 30%.

Claims (16)

1. pharmaceutical formulation that improves release, it comprises amoxicillin and pharmaceutically acceptable excipient, wherein with the pharmaceutically acceptable excipient preparation first amoxicillin that discharges the first amoxicillin immediately, discharges phase immediately to form; With the pharmaceutically acceptable excipient preparation second portion amoxicillin of slow release second portion amoxicillin, to form slow release phase; Thereby described discharge immediately with slow release mutually in the amoxicillin ratio be 3: 1 to 2: 3, and said preparation provides the amoxicillin of 1900-2600mg dosage.

2. the claimed pharmaceutical formulation of claim 1, it comprises the unit dose amoxicillin in 950-1300mg or the 1900-2600mg scope.

3. claim 1 or 2 claimed pharmaceutical formulations, wherein said unit dose is 1000mg ± 5% amoxicillin.

4. claim 1 or 2 claimed pharmaceutical formulations, it is a tablet.

5. claim 1 or 2 claimed pharmaceutical formulations, it comprises 1000mg ± 5% amoxicillin, and wherein said release immediately comprises 563mg ± 5% amoxicillin and described slow release comprises 438mg ± 5% amoxicillin mutually mutually.

6. claim 1 or 2 claimed pharmaceutical formulations, the amoxicillin of wherein said slow release phase is made up of the crystallization Amoxicillin Sodium basically.

7. claim 1 or 2 claimed pharmaceutical formulations, it is a multilayer tablet, comprises the immediate release layer that contains the amoxicillin and contains the amoxicillin and postpone the slow releasing layer of release excipient, described tablet:

(a) be double-layer tablet;

(b) comprise at least three layers, comprise the immediate release layer slow releasing layer that eases up, and comprise 275mg amoxicillin at least mutually at immediate release layer;

(c) comprise at least three layers, comprise the immediate release layer slow releasing layer that eases up, and the delay release excipient in the wherein said slow releasing layer comprises xanthan gum and/or pharmaceutically acceptable organic acid; Or

(d) comprise at least three layers, comprise the immediate release layer slow releasing layer that eases up, and wherein said amoxicillin provides with the Utimox of 3: 1 to 1: 3 ratios and the mixture of Amoxicillin Sodium.

8. the claimed pharmaceutical formulation of claim 7, it is a multilayer tablet, and wherein said slow releasing layer comprises the delay release excipient, and described delay release excipient is selected from the pH sensitive polymer; The delay release polymers of high level expansion when contact water or aqueous medium; Contact water or aqueous medium form the polymeric material of gel; Contact water or aqueous medium have the polymeric material of expansion and gelling characteristics; Hydrocolloid; Glycosyl material, protein material or their mixture.

9. the claimed pharmaceutical formulation of claim 8; it is a multilayer tablet, and the polymer that wherein said contact water or aqueous medium form gel is selected from methylcellulose, carboxymethyl cellulose, low-molecular-weight hydroxypropyl emthylcellulose, low molecular weight polyethylene alcohol, polyoxyethylene enediol and non-crosslinked polyvinylpyrrolidone or xanthan gum.

10. the claimed pharmaceutical formulation of claim 8, it is a multilayer tablet, wherein said delay release excipient is an xanthan gum.

11. the pharmaceutical formulation that claim 10 is claimed, it is a multilayer tablet, and the content of wherein said xanthan gum is the 1-25 weight % of this layer.

12. the pharmaceutical formulation that claim 7 is claimed; it is a multilayer tablet; wherein said slow releasing layer comprises 70-80% amoxicillin, 1-25% xanthan gum, 10-20% filler and/or compression aid and convention amount lubricant, and prerequisite is that the total amount sum of all components in the described slow releasing layer is 100%.

13. the pharmaceutical formulation that claim 7 is claimed; it is a multilayer tablet; wherein said slow releasing layer comprises Amoxicillin Sodium, and wherein said slow releasing layer to comprise with salts of amoxycillin and organic acid mol ratio be the pharmaceutically acceptable organic acid that existed in 100: 1 to 1: 10.

14. the pharmaceutical formulation that claim 13 is claimed, it is a multilayer tablet, and wherein said pharmaceutically acceptable organic acid is to be the citric acid of existence in 50: 1 to 1: 2 with salts of amoxycillin and organic acid mol ratio.

15. the pharmaceutical formulation that claim 13 is claimed, it is a multilayer tablet, and it also comprises and postpones the release gels polymer, the xanthan gum that this delay release gels polymer exists for the 0.5-8 weight % with described slow releasing layer.

16. the pharmaceutical formulation that claim 13 is claimed, it is a multilayer tablet, and it comprises 1000mg ± 5% amoxicillin, and it comprises 438mg ± 5% crystallization Amoxicillin Sodium, 78mg ± 10% citric acid and 2 weight % xanthan gum in described slow releasing layer.

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