Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1996-06-13
2000-11-28
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
424456, A61K 948, A61K 964
Patent
active
061532185
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to improved capsule formulations, in particular biphasic capsule formulations.
BACKGROUND OF THE INVENTION
WO-A-9206680 discloses biphasic release formulations for lipophilic drugs comprising a C.sub.12 -C.sub.24 fatty acid and a pharmaceutically active substance. A portion of the formulation is formulated for non-sustained release and is generally in liquid form and a portion is formulated for sustained release on non-parenteral administration and will generally be a solid.
The formulations are extremely effective for the administration of lipophilic pharmaceutically active substances greatly enhancing oral bioavailibility of propranolol. These results have been published (Barnwell et al, J. Controlled Release, 28, 306-309 (1994)), but it has been discovered that there are certain problems with the stability of the compositions even when stored at ambient temperature.
After capsules containing biphasic formulations such as those described in WO-A-9206680 have been stored for periods of greater than 3 months at ambient temperature, there is a decline in in vitro dissolution performance compared with initial values. The level of propranolol released from the formulation after 12 months' storage at ambient temperature was found to be reduced by 50% compared with initial values. In contrast, prolonged storage of capsules containing only the liquid rapid-release phase and capsules containing only the solid sustained release phase did not result in any change in dissolution profile. This unstable release profile is therefore a problem only with biphasic formulations and represents a serious drawback in the development of such formulations since, clearly, a pharmaceutical formulation which is not stable under ambient storage conditions is of limited use in practice.
On investigation, it appeared that the deterioration in the release profile had arisen because, unexpectedly, the two phases of the formulation had become mixed during the storage of the capsules and the mixing of the phases had caused the release characteristics of both parts of the formulation to deteriorate. Deterioration was characterised by a visible intermixing between the two phases and a decline in in vitro dissolution performance. The rate of intermixing between the liquid rapid and solid sustained-release phases of the formulation was accelerated at elevated storage temperatures, eg 37.degree. C., but much reduced at 4.degree. C.
SUMMARY OF THE INVENTION
Therefore, in a first aspect of the invention there is provided a pharmaceutical formulation comprising a capsule containing at least two fill compositions, characterised in that the compositions are prevented from mixing with one another.
DETAILED DESCRIPTION OF THE INVENTION
The capsule fill compositions may be compositions comprising C.sub.12 -C.sub.24 fatty acids such as those disclosed in WO-A-9206680. The invention is particularly useful when one of the fill compositions is a solid and one a liquid, especially when the solid component also comprises glycerides, for example the GELUCIRE.TM. mixture disclosed in Example 1 of WO-A-9206680. In that case, the fatty acids tend to dissolve the lower molecular weight lipids of the solid composition so that they gradually mix with the liquid composition. The progressive solubilisation of the lower molecular weight glycerides into the liquid composition slows down the rapid release characteristics of the liquid phase. It also leaves in the solid phase only the higher molecular weight glyceride components which do not easily erode to allow the release of the remaining fatty acid and the active material. An example of a modified capsule would be an adaptation of the potato starch Capill.RTM. capsules manufactured by Capsugel Limited. In this case, the starch capsule would be manufactured with a central partition and two open ends. This would allow two separate formulation components to be filled, each end of the capsule being sealed by the usual potato starch cap. Thus the sustained r
REFERENCES:
patent: 4894978 (1990-01-01), Schonmann et al.
patent: 5387421 (1995-02-01), Amidon et al.
Barnwell Stephen George
Burns Stephen John
Higginbottom Simon
Whelan Ian Peter
Page Thurman K.
Provalis UK Limited
Tran Susan
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