Patent EA-001773-B1 (EA)
Title: Oral pharmaceutical medicament as modified release miltiple units composition
Inventor: SKINHOJ ANETTE
IPC: A61K9/54
Filed: 1997-03-07
Abstract: 1. An oral pharmaceutical modified release multiple-units composition for the administration of analgesically effective amount of an opioid to obtain both a relatively fast onset of the analgesic effect and the maintenance of an analgesically active plasma concentration over a long period of time, a unit dosage of the composition comprising at least two fractions of multiple-units as follows: a first fraction of modified release coated multiple-units that comprise a coating of a substantially water insoluble material for relatively fast release in vivo of an opioid to obtain a therapeutically active plasma concentration within a relatively short period of time, and  a second fraction of modified release coated multiple-units for delayed release in vivo of an opioid to maintain an analgesically active plasma concentration for a period of at least 12 hours,  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:  i) a relative fast in vitro release of the opioid from the first fraction of modified release multiple-units, as measured by a dissolution method III, given in the description, ii) a delayed in vitro release of the opioid from the second fraction of delayed release multiple-units relative to the in vitro release of the first fraction of the opioid, as measured by said dissolution method III, given in the description, wherein the fast release and the delayed 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% release of the opioid contained in the first fraction at the time when 10% of the opioid contained in the second fraction is released as measured by said dissolution method III, mentioned above.  2. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the first fraction of modified fast release multiple-units provides within 0.5 hours a release as defined by said dissolution method III, mentioned in Claim 1 of at least 30% of the opioid.  3. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the first fraction of modified fast release multiple-units provides within 1 hour a release as defined by said dissolution method III, mentioned in Claim 1 of at least 50% of the opioid. 4. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the second fraction of delayed release multiple-units provides within 1 hour a release as defined by said dissolution method III, mentioned in Claim 1 of at least 0%-30% of the opioid. 5. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the second fraction of delayed release multiple-units provides within 3 hours a release as defined by said dissolution method III, mentioned in Claim 1 of at least 10%-70% of the opioid. 6. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the second fraction of delayed release multiple-units provides within 6 hours a release as defined by said dissolution method III, mentioned in Claim 1 of at least 35%-95% of the opioid. 7. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the second fraction of delayed release multiple-units provides within 9 hours a release as defined by said dissolution method III, mentioned in Claim 1 of at least 50%-100% of the opioid. 8. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the first and second fractions being adapted so that the first fraction is substantially released when the release from the second fraction is initiated corresponding to at least 50% release of the first fraction and 5% in the second fraction is released as measured by said dissolution method III, mentioned in Claim 1. 9. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the first and second fractions being adapted so that the first fraction is substantially released when the release from the second fraction is initiated corresponding to at least 70% release of the first fraction and 10% in the second fraction is released as measured by said dissolution method III, mentioned in Claim 1. 10. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the pharmaceutical composition provides within 1 hour a release of the opioid in the first and second fractions in the range of 5%-50% as defined by said dissolution method V, mentioned in description. 11. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the pharmaceutical composition provides within 3 hours a release in the range of 20%-80% as defined by said dissolution method V, mentioned in description. 12. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the pharmaceutical composition provides within 6 hours a release in the range of 40%-98% as defined by said dissolution method V, mentioned in description. 13. A pharmaceutical composition according to Claim 1, wherein the in vitro dissolution characteristics of the pharmaceutical composition provides within 9 hours a release in the range of 50%-100% as defined by said dissolution method V, mentioned in description. 14. A pharmaceutical composition according to Claim 1, wherein the ratio between the first and second fraction of multiple-units in the composition is in the range of 1:20-1:2 calculated on the weight of the fractions. 15. A pharmaceutical composition according to Claim 1, wherein the multiple-units are coated cross-sectionally substantially homogeneous pellets. 16. A pharmaceutical composition according to Claim 1, wherein the individual units of the first fraction are of substantially the same size and weight as the individual units of the second fraction. 17. A pharmaceutical composition according to Claim 1, wherein the first fraction results in a peak plasma concentration of opioid which is substantially the same as the peak plasma concentration resulting from the second fraction. 18. A pharmaceutical composition according to Claim 1, when administered provides the first fraction results in a peak plasma concentration of opioid which is higher than the peak plasma concentration resulting from the second fraction. 19. A pharmaceutical composition according to Claim 1, when administered provides the first fraction results in a peak plasma concentration of opioid which is lower than the peak plasma concentration resulting from the second fraction. 20. A pharmaceutical composition according to Claim 1, wherein the first fraction results in a therapeutically active plasma concentration of opioid until the delayed release of an opioid from the second fraction of delayed release multiple-units contributes to the maintenance of a therapeutically active plasma concentration of opioid. 21. A pharmaceutical composition according to Claim 1, wherein coating of each fraction comprises substantially the same coating components. 22. A pharmaceutical composition according to Claim 21, wherein the amount of coating of the first fraction calculated on the dry weight of the coating is present in a range corresponding to about 10% to about 80% calculated on the dry weight of the amount of coating of the second fraction. 23. A pharmaceutical composition according to Claim 1, wherein the coatings of the fractions are substantially water-insoluble, but water-diffusible and substantially pH-independent. 24. A pharmaceutical composition according to Claim 1, wherein a unit dosage of the composition comprises about 10 mg of the opioid. 25. A pharmaceutical composition according to Claim 1, wherein a unit dosage of the composition comprises about 20 mg of the opioid. 26. A pharmaceutical composition according to Claim 1, wherein a unit dosage of the composition comprises about 30 mg of the opioid. 27. A pharmaceutical composition according to Claim 1, wherein a unit dosage of the composition comprises about 50 mg of the opioid. 28. A pharmaceutical composition according to Claim 1, wherein a unit dosage of the composition comprises about 60 mg of the opioid. 29. A pharmaceutical composition according to Claim 1, wherein a unit dosage of the composition comprises about 100 mg of the opioid. 30. A pharmaceutical composition according to Claim 1, comprising a unit dosage for the administration of the analgesically effective amount of the opioid twice daily. 31. A pharmaceutical composition according to Claim 1 comprising a unit dosage for the administration of the analgesically effective amount of the opioid once daily. 32. A pharmaceutical composition according to Claim 1, wherein the unit dosage of the composition is in the form of a capsule. 33. A pharmaceutical composition according to Claim 1, wherein the opioid is morphine or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition according to Claim 1, wherein the opioid is morphine sulphate. 35. A pharmaceutical composition according to Claim 1, wherein the opioid is tramadol or a pharmaceutically acceptable salt thereof. 36. A process for the preparation of a unit dosage of an oral pharmaceutical modified release multiple-units composition according to any of Claims 1-30, the process comprising incorporating into the unit dosage at least two fractions of coated multiple-units as follows:  a first fraction of fast release coated multiple-units for relatively fast release in vivo of an opioid to obtain a therapeutically active plasma concentration within a relatively short period of time, and a second fraction of delayed release coated multipl