Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-10-30
2001-11-27
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S488000
Reexamination Certificate
active
06322813
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a compact member having extended release of an active compound. In particular it relates to a tablet based on multiple-units made of porous cellulose matrices (PCMs), and having the property of at the same time being easily handled without being damaged, and having an adequate rate of disintegration. The release rate of the active compound is controllable.
BACKGROUND OF THE INVENTION AND PRIOR ART
Simple incorporation of drugs into PCMs (without coating) may retard the drug release but usually not to an extent sufficient for extended release purposes, and has therefore not been commercially feasible.
Extended release of an active compound, e.g. a drug, is possible to achieve by providing drug-loaded porous beads with a coating, such as a release-controlling, water permeable film or membrane. This technique has been extensively used heretofore in the art. In the process of forming such films or membranes organic solvents are often needed, which from both economic and environmental point of view is undesirable.
Multiple-unit (MU) preparations containing a plurality of pellets have been used as carriers of drugs previously. The use of MU drug preparations is considered to promote good absorption properties since they are dispersed over a large area in the gastrointestinal (GI) tract. Furthermore, they are considered to have a lower transit rate especially in the colon compared to matrix tablets. In addition, MU preparations are preferable to single unit preparations, since they may be divided into smaller portions all having the same release and absorption properties which will give greater flexibility in selection of the dose size. Also, MU preparations will facilitate administration of the drug to patients having problems to swallow and will considerably reduce the risk of dose dumping.
Extended release multiple-units (MUs), based on porous matrices of the type mentioned above, as carriers of drugs have commonly been filled in hard gelatine capsules. However, there is an increasing interest in the compaction of extended release multiple-units into disintegrating tablets. The reason for this is the advantages of tablets over the above mentioned capsules, such as more rational production, higher dose accuracy and lower risk of tampering. Unfortunately the release rate is often affected by compaction. The release rate may increase due to crushing, formation of cracks in the release-controlling coating etc., or decrease due to complete or partial failure of tablets to disintegrate. Tablets made of coated multiple-units with intact or nearly intact release rate by the use of relatively large amounts of excipients have been reported. The function of the added excipients may be to protect the film by absorbing energy during compaction or to act as disintegrants.
PCMs may e.g. be prepared by a wet or a dry method as disclosed in International Patent Applications WO-A-91/18590 and WO-A-94/23703, respectively, both assigned to Pharmacia & Upjohn AB of Sweden. The preparation of PCMs does not form part of the invention, and will not be specifically discussed herein. Instead, the said patent applications are incorporated by reference. PCMs are normally small spherical particles, so-called pellets, with a diameter in the range of from about 0.5 up to about 1.5 mm, suitably with a diameter of about 1 mm.
Other methods for making pellets of cellulose, optionally incorporating one or more additional substances, e.g. lipids, could be extrusion/spheronization, “layering”, melt-pelletization and spray-cooling.
Extrusion/spheronization is performed by pressing a moistured powder mass through a metal sheet wherein a plurality of holes has been made. The mass thereby forms spaghetti-like threads. These threads are transferred to a horizontally rotating plate, where they are broken to pieces and formed to spheres which subsequently are allowed to dry.
In “layering”, powder and liquid are added to small seeds (commonly sugar), having been rotated in a so-called pan or the like. Layer by layer, larger spheres are built.
In melt-pelletization, spheres can be formed in a Teflon®-coated mixer when part of the powder melts.
In spray-cooling a melt is commninuted into small droplets that solidify and form small spheres.
The above methods are part of the prior art and the skilled man will be able to manufacture beads according to any of said routes by virtue of his ordinary skill.
Porous cellulose matrices (PCMs) have been shown to be potential multiple-unit (MU) drug carriers (Davidson et al., “Porous cellulose matrices—a novel excipient for the formulation of solid dosage forms”, Int. J. Pharm. 100 (1993) 49-54).
A possible method to modify the drug release rate from non-compacted PCMs is by incorporating release-modifying substances together with the drug into the pores of the cellulose matrix, as disclosed in WO-A-91/18590.
If thermoplastic materials could be used as release modifiers, the incorporation could be done by making use of such materials in a molten state. It might then be possible that the process be carried out without excessive energy input or organic solvents. Especially if the drug could be incorporated by suspending it in or otherwise mix it with the melted release modifier, this process could be very cost effective.
Non-compacted PCMs have been shown to extend the release of paracetamol incorporated together with lipids in the matrix pores. This type of spherical extended release pellets could be produced very cost effectively with low energy consumption and without any organic solvents. Another possible advantage of this type of system is that drug release from matrix pellets of this type may be less sensitive to compression than pellets coated with a thin membrane. It also seems reasonable that the disintegrating effect of cellulose could be advantageous when trying to compact PCMs into disintegrating multiple-unit tablets.
As mentioned above, MUs are commonly delivered in doses contained in hard gelatine capsules. It would be desirable to be able to manufacture tablets by compression of MUs, because manufacture would thereby become more cost effective, tablets would be more easily divided in subdoses etc. However, MUs are difficult to make into tablets by compression since
1) tablets made from MUs do not easily disintegrate upon oral administration, and
2) the MUs are easily crushed or damaged during the compaction process, having as a consequence that the release rate is substantially increased.
In order to avoid the above problems the prior art teaches addition of substantial amounts of various additives, located between the particles. Such measures adds to the complexity and cost of the manufacturing process, apart from introducing unnecessary chemicals into the medicaments.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide compact members (tablets) having extended release of an active compound, said compact members having the properties of
1) being easy to handle without said members being damaged; and
2) rapidly disintegrating in-vivo (in the gastrointestinal tract) e.g. when administered orally.
In addition, the above object should be achieved without having to incorporate large amounts of additives in the compact members.
This object is achieved in one aspect of the invention with a compact member comprising a plurality of PCMs, and providing extended release of an active compound contained therein.
The advantage of the compact member of the present invention is thus the combination of
1) it being easy to handle in industrial processes, such as packaging etc., by virtue of its low friability, and
2) disintegration times suitable for its intended purpose.
The compact member suitably contains talc. The release rate may be controlled by varying the talc content Thereby, the release rate of the active compound can be practically equal to the release rate of free PCMs.
Especially it is suited for use in its preferred embodiment as a tablet containing a drug.
In another aspect of the inve
Green Torkel
Nystrom Christer
Dinsmore & Shohl LLP
Kulkosky Peter F.
Pharmacia AB
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