Patent EA-002806-B1 (EA)
Title: Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (nsaid)
Inventor: SKINHOJ ANNETTE
IPC: A61K31/557
Filed: 1998-09-10
Abstract: 1. An oral pharmaceutical modified release composition in unit dosage form for administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance (an NSAID substance), a unit dosage form comprising at least two NSAID-containing fractions, i) a first NSAID-containing fraction of multiple-units for quick release of the NSAID substance, and ii) a second NSAID-containing fraction of multiple-units for extended release of the NSAID substance, the first fraction which - when subjected to dissolution method II as defined herein employing 0.07 N HCl as dissolution medium - releases at least 50% w/w of the NSAID substance present in the fraction within the first 20 min of the test, the second fraction being in the form of coated delayed release multiple units for extended release of the NSAID substance. 2. A composition according to Claim 1, wherein the first fraction - when subjected to dissolution method II as defined herein employing 0.07 N HCl as dissolution medium releases at least 55% w/w of the total NSAID substance present in the first fraction within the first 20 min of the test. 3. A composition according to Claim 1 or 2, wherein the quick release and the extended release being adapted so that the first fraction is substantially released in vitro when the release in vitro from the second fraction is initiated corresponding to at least 50% w/w release of the NSAID substance contained in the first fraction at the time when at the most 15% w/w of the NSAID substance contained in the second fraction is released as measured by the dissolution method III defined herein. 4. A composition according to any one of the preceding Claims, wherein the NSAID substance contained in the first fraction has a pKa value between from about 3.0 to about 5.5 and the first fraction is in the form of uncoated units. 5. A composition according to any one of the preceding Claims, wherein the NSAID substance has a solubility in 0.1 N hydrochloric acid at room temperature of at the most about 0.5% w/v. 6. A composition according to any one of Claims 1-3, wherein the NSAID substance contained in the first fraction has a pKa value of at least 5.0. 7. A composition according to Claim 6, wherein the first fraction is present in the form of coated units. 8. A composition according to any one of Claims 1-3 or 6-7, wherein the NSAID substance has a solubility in 0.1 N hydrochloric acid at room temperature of at least about 0.1% w/v. 9. A composition comprising modified release composition multiple-units in unit dosage form for administration of a therapeutically and/or prophylactically effective amount of an NSAID substance to obtain both a relatively fast onset of the therapeutic effect and the maintenance of therapeutically active plasma concentration for a relatively long period of time, a unit dosage of the composition comprising at least two fractions as follows: a first fraction of quick release multiple-units for relatively quick release in vivo of an NSAID substance to obtain a therapeutically and/or prophylactically active plasma concentration within a relatively short period of time, and a second fraction of coated modified release multiple-units for extended release in vivo of an NSAID substance to maintain a therapeutically and/or prophylactically active plasma concentration in order to enable dosing once or twice daily, the formulation of the first and the second fractions, with respect to release therefrom and with respect to the ratio between the first and the second fraction in the unit dosage, being adapted so as to obtain: a relative quick in vitro release of the NSAID substance from the first fraction of quick release multiple-units, as measured by the dissolution method II as defined herein, an extended in vitro release of the NSAID substance from the second fraction of extended release multiple-units relative to the in vitro release of the first fraction of the NSAID substance, as measured by e.g. the dissolution method III as defined herein, the quick release and the extended in vitro release being adapted so that the first fraction is substantially released when the release from the second fraction is initiated corresponding to at least 50% w/w release of the NSAID substance contained in the first fraction at the time when at least about 15% w/w of the NSAID substance contained in the second fraction is released as measured by the dissolution method III defined herein. 10. A composition according to any one of the preceding Claims, wherein the NSAID substance is selected from the group consisting of lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, piroxicam (betacyclodextrin), naproxen, ketoprofen, tenoxicam, aceclofenac, indometacin, nabumetone, acemetacin, morniflumate, meloxicam, flurbiprofen, tiaprofenic acid, proglumetacin, mefenamic acid, fenbufen, etodolac, tolfenamic acid, sulindac, phenylbutazone, fenoprofen, tolmetin, acetylsalicylic acid, dexibuprofen, and pharmaceutically acceptable salts, complexes and/or prodrugs thereof and mixtures thereof. 11. A composition according to any one of the preceding Claims, wherein the NSAID substance in the first fraction is the same as or different from the NSAID substance contained in the second fraction. 12. A composition according to any one of the preceding Claims, wherein the NSAID substance in the first fraction is lornoxicam. 13. A composition according to any one of the preceding Claims, wherein the NSAID substance in the second fraction is lornoxicam. 14. A composition according to any one of the preceding Claims comprising a further active drug substance, which is included in at least one of the first and second fraction. 15. A composition according to Claim 14, wherein the further active drug substance is an antidepressant, an opioid, a prostaglandine analog (e.g. misoprostol), a glucocorticosteroid, a cytostaticum (e.g. methotrexate), a H2 receptor antagonist (e.g. cimetidine, ranitidine), a proton pump inhibitor (e.g. pantoprazole, omeprazole, lansoprazole) and/or an antacidum. 16. A composition according to Claim 14, wherein the further active drug substance is paracetamol, penicillamine, sulfasalazine and/or auranorfin. 17.A composition according to any one of the preceding Claims, wherein the quick release multiple-units of the first fraction have a mean particle size of at the most about 250 μm. 18. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the first fraction of quick release multiple-units provides within 1 hour a release as defined by the dissolution method II defined herein of at least 50% w/w of the NSAID substance. 19. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the second fraction of extended release multiple-units provides within 1 hour a release as defined by the dissolution method III defined herein in the range of 0%-30% w/w of the NSAID substance. 20. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the second fraction of extended release multiple-units provides within 3 hours a release as defined by the dissolution method III defined herein in the range of about 10%-70% w/w of the NSAID substance. 21. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the second fraction of extended release multiple-units provides within 6 hours a release as defined by the dissolution method III defined herein in the range of about 35%-95% w/w of the NSAID substance. 22. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the second fraction of modified release multiple-units provides within 9 hours a release as defined by the dissolution method III defined herein in the range of about 50%-100% w/w of the NSAID substance. 23. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the first and second fractions are adapted so that NSAID substance of the first fraction is substantially released when the release of NSAID substance from the second fraction is initiated corresponding to at least 50% w/w of the first fraction NSAID substance at the time at the most about 15% w/w of the second fraction NSAID substance is released as measured by the dissolution method III defined herein. 24. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the first and second fractions are adapted so that the first fraction NSAID substance is substantially released when the release from the second fraction NSAID substance is initiated corresponding to at least 70% w/w release of the first fraction NSAID substance at the time at the most about 20% w/w of the second fraction NSAID substance is released as measured by the dissolution method III as defined herein. 25. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the composition provides within 1 hour a release of the NSAID substance from the composition in the range of about 5-50% w/w as, for example, is defined by the dissolution method III as defined herein. 26. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the composition provides within 3 hours a NSAID substance release as defined by the dissolution method III as defined herein in the range of about 20-80% w/w. 27. A composition according to any one of the preceding Claims, wherein the in vitro dissolution characteristics of the composition provides within 6 hours a NSAID substance release as defined by the dissolution method III defined herein in the range of about 40-98% w/w. 28. A composition according to any one of the preceding Claims, wherein th