Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-04-25
2001-09-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S469000, C424S484000, C424S486000, C424S488000
Reexamination Certificate
active
06294201
ABSTRACT:
This invention relates to an orally administered osmotic drug release system that consists of a shell and a core containing a pharmaceutically active substance, as well as a process for its production. The invention relates further to an osmotic drug release system for use as a drug in human beings and animals, as well as the use of the osmotic drug release system in the production of a drug for the treatment and/or prevention of illnesses in human beings and animals.
In principle, osmotic drug release systems are known in the state of the art. Osmotic pressure is generally used as the energy source for delivering the active ingredient of a drug to the surrounding medium at a controlled rate. Consequently, these types of systems are referred to as osmotic pumps. A comprehensive overview of osmotic drug release systems can be found in Journal of Controlled Release 35 (1995), 1-21, where a basic distinction is drawn between multiple-chamber systems and single-chamber systems. In its most basic form, the single-chamber system consists of a conventional tablet comprising a shell made of a semi-permeable membrane with an outlet, as well as a core containing the active ingredient in solid form. Following oral administration, water passes into the core through the semi-permeable membrane and dissolves the active ingredient, which is then released through the outlet (U.S. Pat. No. 3,845,770). However, this principle is only suitable for use with highly water-soluble active ingredients, as these are the only active ingredients capable of generating sufficiently high osmotic pressure. Consequently, so-called double-chamber systems (“push-pull” systems) were developed specifically for poorly soluble active ingredients (U.S. Pat. No. 4,111,202; European patent application no. 52 917). However, the production of such two-chamber systems is highly complex in technical terms. Consequently, the single-chamber system possesses a fundamental advantage over multiple-chamber systems. To utilize the advantages of the single-chamber system for poorly soluble drugs while achieving sufficient osmotic pressure in the interior of the tablet, single-chamber systems were proposed in which a core consists of the active ingredient and certain polymeric swelling agents which, upon the addition of water, expand through the outer semi-permeable membrane and are released together with the active ingredient, which is partially suspended in the swelling agent. The selection of certain polymeric swelling agents is of decisive importance in this system, as certain swelling agents, as has been described in EP-A-0 277 092, such as polyvinyl pyrrolidone, polyethylene oxide or polymethylacrylate produce so much expansion pressure that the semi-permeable shell membrane bursts open completely after a short time and the active ingredient is released within a short period of time instead of being released in a delayed or controlled manner, as desired. Thus, to solve this problem, EP-A-0 277 092 provides for a specific selection of hydrophilic polymeric swelling agents, namely a mixture of a vinyl pyrrolidone - vinyl acetate copolymer and an ethylene oxide homopolymer.
WO 96/40080 claims generic protection for osmotic single-chamber systems comprising a core made of a pharmaceutical active ingredient, a water-soluble osmotic agent and a water-expandable polymer. However, as has already been specified in EP-A-0 277 092, not all polymeric hydrophilic swelling agents are suited for use in these single-chamber systems, and a careful selection must be made to ensure that the active substance is released from the single-chamber system in a controlled manner, as desired. In the concrete forms of execution of WO 96/40080, polyethylene oxide and cellulose, or derivatives thereof, are among the materials used as water-expandable polymers.
An osmotic drug release system with controlled, i.e., generally delayed release, that consists of a single-chamber system should, in principle, allow for maximum release of the active ingredient without the outlet being torn open during release and resulting in uncontrolled release of the active ingredient. However, a common problem among singlehamber systems is that a substantial portion of the active ingredient remains in the tablet, as insufficient osmotic pressure is generated in the interior of the tablet to fully release the active ingredient. Thus, a disadvantage of the systems described above is that they do not fully release the active substance from the shell membrane and through the outlet, so that relatively large component of the active substance is not absorbed and is excreted unused. However, the use of a water-expandable polymer that generates substantial osmotic pressure may result in the tablet being torn open or even bursting, thus preventing delayed, controlled release from being achieved.
Another problem commonly found in osmotic drug release systems known in the art is that the uncoated tablet cores lack sufficient mechanical stability, which makes them difficult to coat.
In principle, an osmotic drug release system should be easily manufactured, consist of reasonably priced and pharmacologically tolerable materials, and allow for the release of the active ingredient in an advantageous manner.
Surprisingly, it was found that the use of a combination of two specific hydrophilic water-expandable polymers as core components, at specific weight proportions, is particularly suited for achieving the aforementioned desired attributes of an osmotic single-chamber drug release system that contains a pharmaceutically active substance, preferably a dihydropyridine as its active ingredient. The inventors of this invention found that a combination of the heteropolysaccharide xanthan and a vinyl pyrrolidone—vinyl acetate copolymer as water-expandable polymers in specific weight concentrations allows for the virtually complete release of the active substance from the shell without resulting in the outlet being torn open and the active ingredient being released in an uncontrolled manner.
Without relying on theoretical constraints, it is assumed that the highly favorable release properties of the combination between xanthan and the vinyl pyrrolidone—vinyl acetate copolymer are due, in particular, to the fact that it forms structurally viscous solutions, the viscosity of which decreases during flow in response to increasing transverse strain. Apparently, this allows for especially uniform release of the active substance from the outlet without the membrane being torn open, so that the active substance is released uniformly and almost completely over a relatively long period of time.
When used as a water-expandable polymer, xanthan also possesses the advantage of being easier to handle than the polyethylene oxides used in EP-A-0 277 092 and WO 96/40080, as it does not induce the so-called TOMS effect (reduction in frictional resistance). Another advantage associated with the use of xanthan in comparison with the use of polyethylene oxide as a water-expandable polymer consists in the fact that polyethylene oxides are generally only wet-granulated with organic solvents (as, for example, in EP-A-0 277 092), so that explosion protection measures must be taken during production; alternatively, tablets must be produced in a dry state (WO 96/40080), which results in the known disadvantages of dry tablet-making, such as poor flow properties of the mixture of core components, dust development and a low degree of hardness of the tablet core.
This invention overcomes the problems of the state of the art described above by presenting an osmotic drug release system that consists of:
a shell consisting of a material that is water-permeable but impermeable to the components of the core, with at least one opening, and
a core, containing
15 to 35% in weight of a pharmaceutically active substance
20 to 50% in weight of xanthan
10 to 30% in weight of a vinyl pyrrolidone—vinyl acetate copolymer in which, if necessary, the balance of the 100% in weight is made up by at least one component selected from a group cons
Bosche Patrick
Brendel Erich
Chantraine Ernst
Eisele Michael
Kanikanti Ranga-Rao
Bayer Aktiengesellschaft
Chiu Jerrie L.
Page Thurman K.
Tran S.
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