Patent EA-004310-B1 (EA)
Title: Novel method of treatment
Inventor: CONLEY CREIGHTON P
IPC: A61K31/431
Filed: 2000-04-11
Abstract: 1. A modified release pharmaceutical formulation comprising amoxycillin and potassium clavulanate in a ratio from 14:1 to 20:1 and adapted to provide a dosage in the range 1400 to 2600 mg amoxycillin and a corresponding amount of potassium clavulanate in which all of the potassium clavulanate and a first part of amoxycillin are formulated with pharmaceutically acceptable excipients which allow for immediate release of the potassium clavulanate and the first part of amoxycillin, to form an immediate release phase, and further comprising a second part of amoxycillin formulated with pharmaceutically acceptable excipients which allow for slow release of the second part of amoxycillin, to form a slow release phase and in which the ratio of amoxycillin in the immediate and slow release phases is from 3:1 to 1:3. 2. A pharmaceutical formulation as claimed in claim 1 in which the ratio of amoxycillin and potassium clavulanate is 16:1. 3. A pharmaceutical formulation as claimed in claim 1 or 2, which has a biphasic profile with respect to amoxycillin. 4. A pharmaceutical formulation as claimed in any one of claims 1 to 3 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. 5. A pharmaceutical formulation as claimed in any one of claims 1 to 4 in which the ratio of amoxycillin in the immediate and slow release phases is from 3:1 to 2:3. 6. A pharmaceutical formulation as claimed in any one of claims 1 to 5 comprising a unit dosage in the range 700 to 1300 mg or 1400 to 2600 mg amoxycillin and a corresponding amount of potassium clavulanate. 7. A pharmaceutical formulation as claimed in any one of claims 1 to 6 in which the unit dosage: is 1000 or 875 mg +-5% amoxycillin and 62.5 mg +-5% potassium clavulanate; or 2000 or 1750 mg +-5% amoxycillin and 125 mg +-5% potassium clavulanate; in a nominal ratio of about 16:1 or 14:1, respectively, in combination with pharmaceutically acceptable excipients or carriers. 8. A pharmaceutical formulation as claimed in any one of claims 1 to 7 which is a tablet formulation. 9. A pharmaceutical formulation as claimed in claim 8 comprising 1000 mg +-5% amoxycillin and 62.5 mg +-5% potassium clavulanate, in a nominal ratio of about 16:1 in which the immediate release phase comprises about 563 mg +-5% amoxycillin and about 62.5 mg +-5% of potassium clavulanate and the slow release phase comprises about 438 mg +-5% of amoxycillin. 10. A pharmaceutical formulation as claimed in any one of claims 1 to 9 in which the amoxycillin of the slow release phase consists essentially of crystallized sodium amoxycillin. 11. A pharmaceutical formulation as claimed in any one of claims 1 to 10 which is a layered tablet and in which the immediate and slow release phases are provided as separate layers of the layered tablet. 12. A layered tablet as claimed in claim 11 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; and a polymeric material which have both swelling and gelling characteristics in contact with water or aqueous media, or a mixture thereof. 13. A layered tablet as claimed in claim 12, in which the release retarding gellable polymer is selected from methylcellulose, carboxymethylcellulose, low-molecular weight hydroxypropyl methylcellulose, low-molecular weight polyvinyl alcohols, polyoxyethylene glycols, and non-cross linked polyvinylpyrrolidone, or xanthan gum. 14. A layered tablet as claimed in claim 12 or 13 in which the release retarding excipient is xanthan gum. 15. A layered tablet as claimed in claim 14 in which the xanthan gum is present in from 1 to 25% by weight of the layer. 16. A layered tablet as claimed in any one of claims 11 to 15 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 conventional quantities of lubricants. 17. A layered tablet as claimed in claim 11 in which the slow release phase comprises sodium amoxycillin and in which the slow release layer 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). 18. A layered tablet as claimed in claim 17 in which the pharmaceutically acceptable acid is present in a molar ratio of about 50:1 to 1:5. 19. A layered tablet as claimed in claim 17 in which the pharmaceutically acceptable organic acid is present in a molar ratio of from 20:1 to 1:5. 20. A layered tablet as claimed in claim 17 in which the pharmaceutically acceptable organic acid is present in a molar ratio of from 20:1 to 1:2. 21. A layered tablet as claimed in any one of claims claim 17 to 20 in which the pharmaceutically acceptable acid is citric acid. 22. A layered tablet as claimed in claim 21 in which citric acid is present in a molar ratio of about 2:1 to 1:1.2. 23. A layered tablet as claimed in any one of claims 17 to 22 further comprising a release retarding gellable polymer. 24. A layered tablet as claimed in claim 23 in which the release retarding gellable polymer is xanthan gum. 25. A layered tablet as claimed in claim 24 in which xanthan gum is present in from 0.5 to 8% by weight of the slow release layer. 26. A pharmaceutical layered tablet formulation as claimed in any one of claims 17 to 25 comprising from 700 to 1250 mg amoxycillin and a pro rata amount of potassium clavulanate, in a nominal ratio of about 16:1 or 14:1, respectively, in combination with pharmaceutically acceptable excipients or carriers. 27. A layered tablet as claimed in claim 26 which comprises 1000 mg +-5% of amoxycillin and 62.5 mg +-5% of potassium clavulanate and which comprises in the slow release layer about 438 mg +-5% of crystallized sodium amoxycillin, about 78 mg +-10% of citric acid and optionally about 2% by weight of xanthan gum. 28. A modified release pharmaceutical formulation as claimed in claim 1 in which the immediate release phase is formed from immediate release granules comprising amoxycillin and potassium clavulanate or immediate release granules comprising amoxycillin and potassium clavulanate and further immediate release granules comprising amoxycillin and the slow release phase is formed from slow release granules comprising amoxycillin. 29. A modified release pharmaceutical formulation as claimed in claim 28 which is a single dose sachet, a capsule, a monolith tablet, a dispersible tablet, or a chewable tablet which may be effervescent and/or dispersible. 30. A modified release pharmaceutical formulation as claimed in any one of claims 1 to 29 comprising 1000mg +-5% amoxycillin and 62.5mg +-5% potassium clavulanic acid, in a nominal ratio of about 16:1, in combination with pharmaceutically acceptable excipients or carriers. 31. A formulation as claimed in any one of claims 1 to 30 having an AUC, Cmax and tMax substantially according to Figure 4 (formulation VI or VII). 32. The use of amoxycillin and potassium clavulanate in the manufacture of a medicament as defined in claim 1 for treating bacterial infections in humans at dosage intervals of about 12 h. 33. The use as claimed in claim 32 in which the administration provides a mean plasma concentration of amoxycillin of 4 ug/mL for at least 4.4 h and a mean maximum plasma concentration (CMax) of amoxycillin of at least 12 ug/mL. 34. The use as claimed claim 32 or 33 in which the administration provides a mean plasma concentration of amoxycillin of 4 ug/mL for at least 4.8 h and a mean maximum plasma concentration (CMax) of amoxycillin of at least 16 ug/mL. 35. The use as claimed in any one of claims 32 to 34 in which the infection is caused by the organisms Spneumoniae (including Drug Resistant and Penicillin Resistant Spneumoniae), H influenzae and/or M catarrhalis.