Resumen
1. A pharmaceutical formulation comprising amoxycillin and clavulanate in a ratio of n: 1 where n is a number from 1 to 16 which comprises: a first set of granulates comprising amoxycillin and clavulanate in a ratio from 1:1 or 2:1; and a second set of granulates comprising amoxycillin and no clavulanate; providing to give an overall ratio between amoxycillin and clavulanate of n: 1, wherein the formulation when in the form of a tablet comprises the first and the second sets of granulates in a mixture. 2. A formulation as claimed in claim 1 in which n is 2, 4, 6, 7, 8, 14 or 16. 3. A formulation as claimed in claims 1 or 2 in which amoxycillin is present as amoxycillin trihydrate. 4. A formulation as claimed in any one of claims 1 to 3 in which clavulanate is present as potassium clavulanate. 5. A formulation as claimed in any one of claims 1 to 4 in which the granulates comprises an intragranular disintegrant in an amount from 1,25 to 3,5% by the granulate weight. 6. A formulation as claimed in any one of claims 1 to 5 in which the first set of granulates further comprises intragranular disintegrant as a silica gel in an amount from 5 to 25% by the clavulanate weight. 7. A formulation as claimed in any one of claims 1 to 6 in which the first set of granulates consist essentially of amoxycillin, potassium clavulanate, silica gel and an intragranular disintegrant. 8. A formulation as claimed in any one of claims 1 to 6 in which the second set of granulates consist essentially of amoxycillin and an intragranular disintegrant. 9. A formulation as claimed in any one of claims 5 to 8 in which the intragranular disintegrant is cross-linked N-vinyl-2-pyrrolidone or sodium starch glycollate. 10. A formulation as claimed in any one of claims 1 to 9 in the form of a tablet. 11. A formulation as claimed in claim 10 further comprising an extragranular excipient which is low-substituted hydroxyproylcellulose. 12. A formulation as claimed in claim 10 or 11 in which the combined weight of all excipients is less than 20% of the uncoated core weight of the tablet. 13. A formulation as claimed in claim 10, which comprises: amoxycillin granulates which consist essentially of amoxycillin trihydrate present in about 97wt% and CLPVP present in about 3wt%; amoxycillin and potassium clavulanate granulates which comprise a 2:1 ratio of amoxycillin to clavulanate, silica gel present in about 10 wt% of potassium clavulanate and about 3wt% of CLPVP; and extragranular excipients selected from the group including silica gel; low-substituted hydroxypropylcellulose or CLPVP; colloidal silica and magnesium stearate. 14. A formualtion as claimed in claim 12 in which the tablet cores have the weights: 500/125mg - 800 to 850mg; and 875/125mg - 1250 to 1350mg. 15. A formulation as claimed in any one of claims 1 to 9 in the form of a sachet or a powder for reconstitution as an aqueous syrup. 16. A process for preparing a formulation according to any one of the preceding claims which comprises blending together a first set of granulates comprising amoxycillin and clavulanate with a second set of granulates comprising amoxycillin and no clavulanate in an appropriate ratio with other excipients and then, if necessary and desired, further processing the blend to obtain the final desired formulation. 17. A process as claimed in claim 16 which comprises the preliminary step of preparing the first and/or second set of granulates by roller compaction. 18. A granulate comprising amoxycillin and no clavulanate in a ratio 2:1, which includes intragranular disintegrant in an amount from 5 to 25% by the clavulanate weight. 19. A granulate as claimed in claim 18 in which intragranular disintegrant is silica gel. 20. A granulate as claimed in claim 18 or 19 which further comprises intragranular disintegrant in an amount from 1,25 to 3,5% by the granulate weight. 21. A granulate as claimed in any claims 18 to 20 in which the granulates consist essentially of amoxycillin, potassium clavulanate, silicagel and an intragranular disintegrant. 22. A granulate as claimed in any claims 18 to 20 in which the intragranular disintegrant is cross-linked N-vinyl-2-pyrrolidone or sodium starch glycollate.
Reivindicaciones
1. A granulate comprising amoxycillin trihydrate and potassium clavulanate in a ratio of 1:1, 2:1 or 4:1, wherein this ratio refers to the weight of parent compound amoxycillin or clavulanic acid, and an intragranular diluent present in from 5 to 25% by weight of potassium clavulanate. 2. A granulate as claimed in claim 1 wherein the intragranular diluent is present from 5 to 15% by weight of potassium clavulanate. 3. A granulate as claimed in claim 1 or 2 wherein the intragranular diluent is silica gel. 4. A granulate as claimed in any of claims 1 to 3 which further comprises an intragranular disintegrant present in from 1.25 to 3.5% by weight of the granulate. 5. A granulate as claimed in claim 4 wherein the intragranular disintegrant is sodium starch glycollate or cross-linked N-vinyl-2-pyrrolidinone. 6. A granulate as claimed in any of claims 1 to 5 which further comprises an intragranular lubricant present in from 0 to 0.35% by weight of the granulate. 7. A granulate as claimed in claim 6 wherein the intragranular lubricant is magnesium stearate. 8. A granulate as claimed in any of claims 1 to 7 wherein the equilibrium relative humidity of the amoxycillin trihydrate is from 10 to 20%. 9. A pharmaceutical formulation comprising granulates as defined in any of claims 1 to 8 and granulates comprising amoxycillin trihydrate (and no clavulanate) such that the overall ratio of amoxycillin trihydrate to potassium clavulanate is in a ratio of n: 1 where n is a number from 2 to16 and the ratio refers to the weight of parent compound amoxycillin or clavulanic acid. 10. A formulation as claimed in claim 9 wherein the overall ratio of amoxycillin trihydrate to potassium clavulanate is selected from 2:1, 4:1, 6:1, 7:1, 8:1 or 14:1 and the ratio refers to the weight of parent compound amoxycillin or clavulanic acid. 11. A formulation as claimed in claims 9 or 10 further comprising an extra-granular dessicant present in an amount up to 5% by weight of the formulation. 12. A formulation as claimed in claim 11 wherein the extra-granular dessicant is silica gel. 13. A formulation as claimed in any of claims 9 to 12 comprising amoxycillin trihydrate and potassium clavulanate in a ratio of n:1, where n is a number from 2 to 16 and the ratio refers to the weight of parent compound amoxycillin or clavulanic acid, and which comprises granulates consisting essentially of amoxycillin trihydrate and potassium clavulanate, cross-linked N-vinyl-2-pyrrolidinone (as an intragranular disintegrant) present in about 3wt% of amoxycillin trihydrate and silica gel (as an intragranular diluent/dessicant) present in about 10wt% of potassium clavulanate. 14. A formulation as claimed in any of claims 9 to 13 provided for paediatric use which is reconstituted into an aqueous suspension prior to use. 15. A paediatric formulation as claimed in claim 14 which further comprises extragranular excipients selected from a dessicating agent, thickeners, preservatives, sweetening agents, lubricants, glidants, and flavouring agents. 16. A paediatric formulation as claimed in claim 15 wherein the thickener is selected from xanthan gum, carboxymethylcellulose sodium, silica gel or hydroxpropylmethyl cellulose. 17. A paediatric formulation as claimed in claims 15 or 16 wherein the flavouring agent is a fruit flavour. 18. A formulation as claimed in any of claims 9 to 13 provided as a sachet product and containing free-flowing granulates in a suitable unit dose, for reconstituting in water to form a syrup formulation immediately prior to use. 19. A sachet product as claimed in claim 18 which further comprises excipients selected from sweetening agents, thickeners, preservatives and buffers. 20. A formulation as claimed in any of claims 9 to 13 provided as a tablet, which further comprises an extra-granular disintegrant. 21. A tablet formulation as claimed in claim 20 wherein the extra-granular disintegrant is low-substituted hydroxypropylcellulose. 22. A tablet formulation as claimed in claims 20 or 21 which further comprises an extra-granular lubricant. 23. A tablet formulation as claimed in claim 22 wherein the extra-granular lubricant is magnesium stearate. 24. A tablet formulation as claimed in any of claims 20 to 23 which comprises amoxycillin granulates which consist essentially of amoxycillin trihydrate present in about 97wt% and cross-linked N-vinyl-2-pyrrolidinone present in about 3wt%; amoxycillin and potassium clavulanate granulates which comprise a 2:1 ratio of amoxycillin trihydrate to potassium clavulanate wherein the ratio refers to the weight of parent compound amoxycillin or clavulanic acid; silica gel present in about 10wt% of potassium clavulanate and about 3wt% of cross-linked N-vinyl-2-pyrrolidinone; and extra-granular excipients including: silica gel (1.0 to 1.2% by weight of the tablet) ; low-substituted hydroxypropylcellulose (5 to 6% by weight of the tablet); colloidal silica (0.1 to 0.3% by weight of the tablet); and magnesium stearate (0.3 to 0.4% by weight of the tablet); or cross-linked N-vinyl-2-pyrrolidinone (5 to 8% by weight of the tablet); and magnesium stearate (0.3 to 0.4% by weight of the tablet). 25. A formulation as claimed in any of claims 9 to 13 provided as a chewable tablet, which further comprises an extra-granular excipient, present in from 10 to 30% based on the weight of the final tablet, used to form a chewable base. 26. A tablet formulation as claimed in claim 25 wherein the extra-granular excipient is selected from mannitol, sorbitol, dextrose, fructose, or lactose, alone or in combination. 27. A tablet formulation as claimed in claims 25 or 26 which further comprises a disintegrating agent present in from 5 to 30% based on the weight of the final tablet. 28. A tablet formulation as claimed in claim 27 wherein the disintegrating agent is selected from microfine cellulose, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycollate or cross-linked N-vinyl-2-pyrrolidinone. 29. A tablet formulation as claimed in claims 25 or 26 which further comprises an effervescent couple, present in from 5 to 30% based on the weight of the final tablet. 30. A tablet formulation as claimed in claim 29 wherein the effervescent couple comprises a solid acid selected from citric acid, monosodium citrate, sodium hydrogen citrate, tartaric acid, adipic acid, fumaric acid or malic acid, and an alkali or alkaline earth metal carbonate or bicarbonate selected from sodium (bi)carbonate, potassium (bi)carbonate, calcium (bi)carbonate or sodium glycine carbonate. 31. A tablet formulation as claimed in any of claims 20 to 30 which comprises amoxycillin trihydrate, potassium clavulanate and pharmaceutically acceptable excipients, wherein the amoxycillin trihydrate is present in an amount equivalent to 500mg of amoxycillin (free acid) and the potassium clavulanate is present in an amount equivalent to 62.5mg of clavulanic acid. 32. A sachet formulation for suspension according to claim 18 in which the weights and relative proportions of the components are: Amoxycillin trihydrate 100% of theory (equivalent to 3000mg Amoxycillin 100%) 3443.22 mg Potassium Clavulanate 100% of theory 446.79 mg (equivalent to 375mg Clavulanic acid 100%) cross-linked N-vinyl-2-pyrrolidinone (CLPVP) (intra-granular) 103.29 mg Silica gel (intra-granular) (Syloid AL) 44.68 mg Silica gel (extra-granular) (Syloid AL) 500.00 mg Xanthan gum 25.20 mg Carboxymethylcellulose sodium salt 250.00 mg Sodium benzoate 51.00 mg Hydrophobic colloidal silica 15.00 mg Aspartame 96.00 mg Magnesium stearate 10.00 mg Strawberry flavour 150.00 mg wherein the weights and relative proportions of the components may be varied about the figures listed but are within ± 10%. 33. A process for preparing a formulation according to any of claims 9 to 32 which comprises blending together a first set of granulates according to claims 1-8 comprising amoxycillin trihydrate and potassium clavulanate with a second set of granulates comprising amoxycillin trihydrate and no clavulanate in an appropriate ratio with other excipients and then, if necessary and desired, further processing the blend to obtain the final desired formulation.
