Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-11-22
2003-09-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S450000, C424S453000, C424S456000, C424S463000, C424S490000
Reexamination Certificate
active
06613353
ABSTRACT:
The present invention relates to improved capsule formulations, in particular biphasic capsule formulations.
FIELD OF THE INVENTION
Background of the Invention
WO-A-9206680 discloses biphasic release formulations for lipophilic drugs comprising a C
12
-C
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° C., but much reduced at 4° 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
12
-C
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™ 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® 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 release of the active material from the solid component is retarded. These changes in drug release may be monitored using an in vitro dissolution method such as that described in Example 2 below.
However, there may be other reasons for wishing to separate the two fill compositions, for example they may contain different active compounds or different excipients which interact in an unfavourable manner and therefore the present invention is not limited to compositions such as those described in WO-A-9206680.
For example, with compositions such as those disclosed in GB Application No 9417524.7 there is the possibility of unfavourable interaction of the active ingredient, particularly if it is a protein, and the pH modifying agent (for instance, carbonate or bicarbonate). Thus, the present invention is particularly useful for such formulations.
The simplest method of preventing phase mixing is to formulate both of the fill compositions as solids but of course this will not be possible in all cases. Therefore, it is often desirable to provide some sort of physical barrier within the capsule to prevent mixing of the fill compositions.
However, there are problems with this approach. One problem is that the placing of a physical barrier between two compositions in a capsule often leads to the collapse of the capsule walls and any barrier which has this effect is of no use whatever.
Secondly, it is important to ensure that any material used as a physical barrier between fill compositions in a capsule does not interact with the fill compositions themselves. One solution which may overcome this problem is to provide a barrier of the same material as the capsule. This may be achieved by manufacturing capsules having two compartments and will be particularly effective for hard gelatin capsules and starch capsules.
In some cases, it will not be possible to manufacture the barrier from the same material as the capsule shell. There may be a variety of reasons for this, for example the difficulties in manufacturing a two-compartment capsule and the weakness in the capsule wall which a central barrier within the capsule may introduce. In addition, for soft gelatin capsules, the capsule walls may not be strong enough to support a central barrier in the capsule.
In such cases a barrier must be introduced into the capsule after manufacture and this will usually be done as the capsule is filled. This will retain the advantage of low manufacturing cost of the capsules whilst still separating the fill compositions and preventing them from mixing.
The choice of material for the barrier is important and several factors must be taken into account. For example, if hydrophobic fill compositions are used, it may be desirable to use a hydrophilic material as a barrier between the fill compositions. On the other hand, if the fill compositions are hydrophilic in nature, then a hydrophobic material will be more suitable.
It is also highly desirable that the material used as a barrier should have a melting point such that it is a solid at any likely storage temperature. Therefore, the melting point should, at the least, be higher than 25° C. (room temperature) but it is much preferred that the material should not begin to melt until it reaches about 37° C. (body temperature).
A barrier formed from such a material has the advantage of easy formation since the barrier material can simply be filled into the capsules in a molten state at a temperature above its melting point and then allowed to cool and form a solid barrier. The barrier material will be added to the capsule after the first fill composition has been put into the capsule but before the addition of the second fill composition so as to form an effective barrier between the two compositions.
If the capsule is required to contain more than two fill compositions then layers of the barrier material can be added to the capsule between additions of the different fill compositions.
In addition, the barrier material must, of course, be physiologically compatible since it is to be included in a ph
Barnwell Stephen George
Burns Stephen John
Higginbottom Simon
Whelan Ian Peter
Leydig , Voit & Mayer, Ltd.
Page Thurman K.
PII Drug Delivery, LLC
Tran S.
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