Novel method of treatment

Abstract

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

What is claimed is:  
     
         1 . A method of treating a bacterial infection in a human in need thereof which method comprises administering to said human a dosage of a therapeutically effective amount of amoxycillin in the range of 1900 to 2600 mg, at a dosage regimen interval of about 12 h.  
     
     
         2 . The method according to  claim 1  in which the dosage regimen provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.4 h and a mean maximum plasma concentration (C max ) of amoxycillin of at least 12 μg/mL.  
     
     
         3 . The method according to  claim 1  in which the dosage regimen provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.8 h and a mean maximum plasma concentration (C max ) of amoxycillin of at least 16 μg/mL.  
     
     
         4 . The method according to  claim 1  in which the dosage regimen provides a mean plasma concentration of amoxycillin of 8 μg/mL for at least 4.4 h.  
     
     
         5 . The method according to  claim 1  in which the dosage is delivered from an immediate release formulation.  
     
     
         6 . The method according to  claim 5  in which the dosage is 2000, 2250 or 2500 mg of amoxycillin.  
     
     
         7 . The method according to  claim 6  in which the dosage is provided as a single tablet, or as a number of smaller tablets, may be the same or different.  
     
     
         8 . The method according to  claim 1  in which the dosage is delivered from a modified release formulation.  
     
     
         9 . The method according to  claim 8  in which the dosage is provided as a number of tablets, which may be the same or different.  
     
     
         10 . The method according to  claim 8  in which the dosage is 2000, 2250 or 2500 mg of amoxycillin.  
     
     
         11 . The method according to  claim 1  in which the infection is caused by the organisms  S pneumoniae  (including Drug Resistant and Penicillin Resistant  S pneumoniae ),  H influenzae , M catarrhalis  and/or  S pyogenes.    
     
     
         12 . A method of treating a bacterial infection in a human in need thereof which method comprises administering to said human a dosage of a therapeutically effective amount of amoxycillin in the range 1400 to 1900 mg, at dosage regimen interval of about 12 h, such that the dosage regimen provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.4 h, and a mean maximum plasma concentration (Cmax) of amoxycillin of at least 12 μg/mL.  
     
     
         13 . The method according to  claim 12  in which the dosage regimen provides a mean plasma concentration of amoxycillin of 4 μg/ml for at least 4.8 h and a mean maximum plasma concentration (Cmax) of amoxycillin of at least 16 μg/ml.  
     
     
         14 . The method according to  claim 12  in which the dosage is delivered from a modified release formulation.  
     
     
         15 . The method according to  claim 12  in which the dosage is 1500 or 1750 mg of amoxycillin.  
     
     
         16 . The method according to  claim 12  in which the infection is caused by the organisms  S pneumoniae  (including Drug Resistant and Penicillin Resistant  S pneumoniae ),  H influenzae, M catarrhalis  and/or  S pyogenes.    
     
     
         17 . An immediate release pharmaceutical formulation comprising from 950 to 1300 or 1900 to 2600 mg amoxycillin, in combination with pharmaceutically acceptable excipients or carriers.  
     
     
         18 . An immediate release pharmaceutical tablet formulation according to  claim 17  comprising 1000 mg±5% amoxycillin in combination with pharmaceutically acceptable excipients or carriers.  
     
     
         19 . An immediate release pharmaceutical formulation according to  claim 17  in the form of a single dose sachet comprising 2000, 2250 or 2500 mg±5% amoxycillin or the corresponding half quantities thereof, in combination with pharmaceutically acceptable excipients or carriers.  
     
     
         20 . An immediate release formulation according to  claim 17  in the form of a dispersible tablet or a chewable tablet effervescent dispersible or effervescent chewable tablet comprising 2000, 2250, or 2500 mg amoxycillin or the corresponding half quantities thereof, in combination with a chewable base and, if effervescent, an effervescent couple, and other pharmaceutically acceptable carrier or excipient.  
     
     
         21 . A modified release pharmaceutical formulation comprising an immediate release phase and a slow release phase; the immediate release phase comprising a first part of amoxycillin formulated with pharmaceutically acceptable excipients which allows for immediate release of the first part of amoxycillin, to form an immediate release phase, and the slow release phase comprising a second part of amoxycillin formulated with a release modifying pharmaceutically acceptable excipient, to form a slow release phase.  
     
     
         22 . The modified release formulation according to  claim 21  which has a biphasic profile with respect to amoxycillin.  
     
     
         23 . The modified release formulation according to  claim 21  which has an AUC value which is at least 80% of that of the corresponding dosage of amoxycillin taken as a conventional (immediate release) tablet(s), over the same dosage period.  
     
     
         24 . The pharmaceutical formulation according to  claim 21  in which the ratio of amoxycillin in the immediate and slow release phases is from 3:1 to 1:3.  
     
     
         25 . The pharmaceutical formulation according to  claim 21  comprising a unit dosage in the range 700 to 1300 mg amoxycillin or 1400 to 2600 mg.  
     
     
         26 . The pharmaceutical formulation according to  claim 25  in which the unit dosage is: 1000, 875 or 750 mg +5% amoxycillin; or 2000, 1750 or 1500 mg±5% amoxycillin, in combination with pharmaceutically acceptable excipients or carriers.  
     
     
         27 . The pharmaceutical formulation according to  claim 26  which is a tablet formulation.  
     
     
         28 . The pharmaceutical tablet according to  claim 27  comprising 1000 mg±5% amoxycillin in which the immediate release phase comprises about 563 mg ±5% amoxycillin and the slow release phase comprises about 438 mg±5% of amoxycillin.  
     
     
         29 . The pharmaceutical formulation according to  claim 21  in which the amoxycillin of the slow release phase consists essentially of crystallised sodium amoxycillin.  
     
     
         30 . The pharmaceutical formulation according to  claim 21  which is a layered tablet comprising an immediate release layer comprising amoxycillin and a slow release layer comprising amoxycillin and a release retarding excipient which tablet: 
 (a) is a bilayered tablet;  
 (b) comprises at least three layers, including an immediate release and a slow release layer, and comprising at least 275 mg of amoxycillin in the immediate release layer phase;  
 (c) comprises at least three layers, including an immediate release and a slow release layer, and in which the release retarding excipient in the slow release layer comprises xanthan gum and/or a pharmaceutically acceptable organic acid, or  
 (d) comprises at least three layers, including an immediate release and a slow release layer, and in which the amoxycillin is provided as a mixture of amoxycillin trihydatre and sodium amoxycillin, in a ratio of 3:1 to 1:3.  
 
     
     
         31 . The layered tablet according to  claim 30  in which the slow release layer comprises a release retarding excipient which is selected from a pH sensitive polymers; a release-retarding polymer which has a high degree of swelling in contact with water or aqueous media; a polymeric material which forms a gel on contact with water or aqueous media; a polymeric material which has both swelling and gelling characteristics in contact with water or aqueous media; a hydrocolloid; carbohydrate-based substances, proteinaceous substances, or a mixture thereof.  
     
     
         32 . The layered tablet according to  claim 31  in which the release retarding gellable polymer is selected from methylcellulose, carboxymethylcellulose, low-molecular weight hydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols, polyoxyethyleneglycols, and non-cross linked polyvinylpyrrolidone, or xanthan gum.  
     
     
         33 . The layered tablet according to  claim 31  in which the release retarding excipient is xanthan gum.  
     
     
         34 . The layered tablet according to  claim 33  in which the xanthan gum is present in from 1 to 25% by weight of the layer.  
     
     
         35 . The layered tablet according to  claim 30  in which the slow release layer comprises from 70 to 80% of amoxycillin, from 1 to 25% of xanthan gum, from 10 to 20% of fillers/compression aids, and a conventional quantity of a lubricant.  
     
     
         36 . The layered tablet according to  claim 30  in which the slow release phase comprises sodium amoxycillin and in which the slow release layer comprises a pharmaceutically acceptable organic acid present in a molar ratio of from 100: 1 to 1:10 (amoxycillin salt to organic acid).  
     
     
         37 . The layered tablet according to  claim 36  in which the pharmaceutically acceptable acid is citric acid present in a molar ratio of about 50:1 to 1:2.  
     
     
         38 . The layered tablet according to  claim 37  further comprising a release retarding gellable polymer.  
     
     
         39 . The layered tablet according to  claim 38  in which the release retarding gellable polymer is xanthan gum.  
     
     
         40 . The layered tablet according to  claim 39  in which xanthan gum is present in from 0.5 to 8% by weight of the slow release layer.  
     
     
         41 . The layered tablet according to  claim 36  which comprises 1000 mg±5% of amoxycillin and which comprises in the slow release layer about 438 mg±5% of crystallised sodium amoxycillin, about 78 mg±10% of citric acid and about 2% by weight of xanthan gum  
     
     
         42 . The pharmaceutical formulation according to  claim 21  in which the immediate release phase is formed from immediate release granules comprising amoxycillin and the slow release phase is formed from slow release granules comprising amoxycillin.  
     
     
         43 . The pharmaceutical formulation according to  claim 42  which is a single dose sachet, a capsule, a monolith tablet, a dispersible tablet, a chewable tablet, effervescent chewable tablet, or an effervescent dispersible tablet.  
     
     
         44 . A pharmaceutical formulation comprising 1000 mg±5% amoxycillin, in combination with pharmaceutically acceptable excipients or carriers.  
     
     
         45 . The pharmaceutical formulation according to  claim 44  in which the amoxycillin is present as a mixture of amoxycillin trihydrate and sodium amoxycillin in a ratio of 3:1 to 1:3.  
     
     
         46 . A pharmaceutical formulation comprising amoxycillin in which amoxycillin is provided as a mixture of amoxycillin trihydrate and sodium amoxycillin in a ratio of from 3:1 to 1:3.  
     
     
         47 . The pharmaceutical formulation according to  claim 46  in which the ratio of amoxycillin trihydrate and sodium amoxycillin is from 3:2 to 2:3.  
     
     
         48 . A pharmaceutical formulation comprising a pharmaceutically acceptable soluble salt of amoxycillin in a slow release phase which further comprises a release retarding excipient which is a pharmaceutically acceptable organic acid present in a molar ratio of from 100:1 to 1: 10 (amoxycillin salt to organic acid).  
     
     
         49 . The pharmaceutical formulation according to  claim 48  in which the molar ratio, is 50:1 to 1:5.  
     
     
         50 . The pharmaceutical formulation according to  claim 48  in which the organic acid is citric acid.  
     
     
         51 . The pharmaceutical formulation according to  claim 48  in which the soluble salt of amoxycillin is, sodium amoxycillin.  
     
     
         52 . A kit comprising an immediate release formulation comprising amoxycillin, and a slow release formulation comprising amoxycillin (and no potassium clavulanate).  
     
     
         53 . Compacted granules for use in a pharmaceutical formulation comprising amoxycillin, a diluent/compression aid, and an organic acid (if amoxycillin is present as a soluble salt thereof) or a release retarding polymer or a mixture thereof.  
     
     
         54 . Compacted granules for use in a pharmaceutical formulation comprising sodium amoxycillin, microcrystalline cellulose, and an organic acid or a release retarding polymer or a mixture thereof.  
     
     
         55 . The process for preparing compacted granules according to  claim 54  which process comprises the steps of blending together sodium amoxycillin, microcrystalline cellulose, and organic acid or release retarding polymer or mixture thereof, compacting the blend and then milling.  
     
     
         56 . The pharmaceutical formulation according to  claim 42  comprising slow release compacted granules comprising amoxycillin, a diluent/compression aid, and an organic acid (if amoxycillin is present as a soluble salt thereof) or a release retarding polymer or a mixture thereof, , and further immediate release compacted granules comprising amoxycillin.  
     
     
         57 . The formulation according to  claim 21  having an AUC, C max , and t max  substantially according to FIG. 4 (formulation VI or VII).  
     
     
         58 . A formulation which is bioequiivalent to the formulation of  claim 57.