A tablet system for prolonged floating in or on gastric fluid for releasing therein pharmaceutically active substances in an alternate succession of substance release and no-release periods is made up of a multilayered core placed in a cup-shaped envelope. The core is made up of release layers and no-release layers devoid of pharmaceutically active substance, superposed in alternate succession. The cup-shaped envelope covers bottom and side surfaces of the core while leaving exposed an upper surface of the core. The cup-shaped envelope provides for buoyancy by being formed of a compression-sintered mixture comprising hydrophobic material and inert powdered filler. The hydrophobic material is composed of fatty and/or waxy material capable of being sintered by compression and whose bulk density is lower than gastric fluid density. The powdered filler has a loose powder density that is lower than gastric fluid density.

Description of the Invention

SUMMARY OF THE INVENTION

Thus, it is an object of the present invention to make available a pharmaceutical tablet system capable of prolonged floating in or on gastric fluid under conditions that are safe for a patient to whom said pharmaceutical tablet system is being administered, for releasing in the patient's stomach one or more pharmaceutically active substances in the course of an alternate succession of periods of substance release and no-release, said alternate succession including at least two periods of substance release separated by one period of no-release i.e. of latency, and which pharmaceutical tablet system does not have the drawbacks of the floating systems of the prior art mentioned above and in particular, should remain floating in or on the gastric fluid in a patient's stomach until the totality of the active substance contained in the pharmaceutical tablet system has been released, irrespective of the fact that said active substance may actually consist of a mixture of active compounds.

To attain this object, according to the present invention there is provided a pharmaceutical tablet system capable of prolonged floating in or on gastric fluid for releasing therein one or more pharmaceutically active substances in the course of an alternate succession of periods of substance release and no-release, said alternate succession including at least two periods of substance release separated by one period of no-release, whereby:

the tablet system is made up of a multilayered core placed in a cup-shaped envelope;

the core is made up of release and no-release layers superposed in alternate succession to form a pile of layers that includes at least two release layers flanking an intermediate no-release layer, each release layer being composed of pharmaceutically acceptable excipient and/or carrier having admixed thereto at least one of said pharmaceutically active substances, each no-release layer being composed of pharmaceutically acceptable excipient and/or carrier devoid of said pharmaceutically active substance;

the cup-shaped envelope covers a bottom surface and side surfaces of the core placed therein while leaving exposed an upper surface of the core;

the cup-shaped envelope provides for buoyancy of the pharmaceutical tablet system with respect to gastric fluid by being formed of a compression-sintered mixture that comprises pharmaceutically acceptable hydrophobic material and pharmaceutically acceptable inert powdered filler;

the hydrophobic material is composed of fatty and/or waxy material capable of being sintered by compression and whose bulk density is lower than gastric fluid density; and

the powdered filler having a loose powder density that is lower than gastric fluid density.

Preferably, in a pharmaceutical tablet system according to the present invention the voids may be interstices between grains of the powdered filler, and more preferably, may be generally sealed off from each other by virtue of the hydrophobic material. Also preferably, the voids may be micropores included within the hydrophobic material. Also preferably, the mixture, which the cup-shaped envelope is made of, also includes at least one or more pharmaceutically active agent different from said substances contained in one or more release layers.

A process of producing the above-defined pharmaceutical tablet system involves the steps of coating the powdered filler with the hydrophobic material, preferably by spray-coating performed under vigorous stirring; granulating the resulting coated material; placing a layer of the resulting granulated material into a die; placing a core onto the layer of granulated material within the die; forcing the core into the layer of granulated material within the die, which forcing preferably involves a compression of the tablet system made up of the cup-shaped envelope having the core inserted therein to provide a snug fit between mutually facing bottom and side surfaces of the core and surface portions of the cup-shaped envelope; and removing the resulting tablet system from the die.

A process of producing a cup-shaped envelope of the above-defined pharmaceutical tablet system involves the steps of coating the powdered filler with the hydrophobic material, preferably by spray-coating performed under vigorous stirring; granulating the resulting coated material; placing a layer of the resulting granulated material into a die; forming a cup-shaped recess into the layer of granulated material by forcing a correspondingly shaped body into it within the die; and removing the resulting cup-shaped envelope from the die.

In the pharmaceutical tablet system of the present invention it is the cup-shaped envelope that provides for buoyancy with respect to gastric fluid. The system is constructed to float on gastric fluid at least until the core will have disappeared completely by dissolution or digestion in the gastric fluid and/or subsequent gastric discharge, which also means that all of the active substance will have been fully released. Accordingly, a pharmaceutical tablet system of the present invention will reliably bring about the desired "multipulse release" defined above, irrespective of the fact that the active substance may actually consist of a mixture of active compounds, and irrespective of the duration of the release or no-release i.e. latency periods.

A great advantage of the pharmaceutical tablet system of the present invention is that it allows a patient to take one single drug unit form to reliably produce a drug plasma level scheme equivalent to that which would result from the patient's taking in succession two or more standard-type fast-release drug unit forms at respective predefined time instants separated by respective predefined no-release i.e. latency or waiting periods.

It is particularly advantageous to produce the tablet system by means of the preferred process according to the present invention, which process reliably allows to obtain a snug fit between mutually facing bottom and side surfaces of the core and surface portions of the cup-hasped envelope, which snug fit in turn prevents the core from detaching too early from the cup-shaped envelope and hence, allows the tablet system to provide reliably the desired "multipulse release".

Moreover, the lightweight material used in the pharmaceutical tablet system of the present invention is advantageously well adapted to be compressed in currently used rotary or reciprocating presses without giving rise to any sticking or feeding problems. This finding is quite surprising in view of the difficulties (e.g. unreliable and irregular filling of press moulds, sticking to the moulding plug, impaired compression) that are encountered when fats and oils are used to obtain a low apparent density as taught in the prior art e.g. of JP-A-1-016715 quoted above.

Also, inherent to producing the pharmaceutical tablet system of the present invention according to the above said process, the lightweight material may advantageously be imparted such appropriate hardness and friability properties that will allow an easy handling of intermediate and final products during any subsequent operations such as film coating, packaging etc.

In the process of producing the pharmaceutical tablet system of the invention, the combined provision of using of a hydrophobic material composed of fatty and/or waxy material capable of being sintered by compression, using a powdered filler having a loose powder density that is lower than gastric fluid density and compressing the cup-shaped envelope having the core inserted therein is advantageous in that it results in a snug fit between the core and the cup-shaped envelope. This snug fit seals off the core from the gastric fluid except for the outer face of the core and thus, precludes any poor contact and attachment between the core and the cup-hasped envelope. As no gastric fluid is allowed to infiltrate along the interface between the core and the cup-shaped envelope, the risk of early dissolution or degradation of any other portions of the core than the vicinity if its outer surface is avoided. Such early dissolution would make the no-release or latency period unreliable and/or cause early release of active substance from lower layers of the core, which in turn would lead e.g. to a sustained release instead of a multipulse release of active substance from the pharmaceutical tablet system.

It is a further advantage of the pharmaceutical tablet system of the invention that the hydrophobic material composed of fatty and/or waxy material is sintered by compression, not by melting. Both the degree of sintering and the degree of penetration of the hydrophobic material into the powdered filler can be varied by means of the sintering pressure used, which allows to vary the final properties of the cup-shaped envelope, including the latter's final porosity and thus, the overall porosity of the system.

It is a still further advantage of the pharmaceutical tablet system of the invention that its mechanisms that provide for release and no-release and for buoyancy are independent from each other. This is because no hydrocolloids are used to provide for buoyancy with respect to gastric fluid, the tablet system experiences no change of volume, its buoyancy is not obtained by any gelling of hydrocolloids, and the active substance may be released by other mechanisms that diffusion through a gelled body, which latter mechanism usually leads to a sustained release. All the more, hydrocolloids have a gelling speed that, in a patient's gastric fluid, depends on physiological circumstances such as on the patient's stress, the fluid quantity available in the stomach, the instant filling state of the stomach etc., and in the pharmaceutical tablet system of the invention this is avoided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be explained in closer detail with reference to an exemplary structure of a pharmaceutical tablet system, which structure is of the kind generally known from EP-A-788790. This exemplary structure is constructed cylindrical, and an axial section thereof is illustrated schematically in FIG. 1 (see Original Patent).

Generally, the tablet structure illustrated in FIG. 1 comprises a core partially enclosed within an envelope made of lightweight material that provides for buoyancy of the pharmaceutical tablet system with respect to gastric fluid e.g. in a patient's stomach. The core is made up of of three planar layers that are superposed sandwich-like in a generally cylindrical stack having a latency layer 2 located intermediate between active layers 1 and 3. Also, the core is snugly enclosed within a cup-shaped envelope 4 that is generally shaped as a blin-dend hollow cylinder having an axial cylindrical cavity in which the core i.e. the stack of layers 1, 2 and 3 is snugly accommodated in such manner that an outer face of the outer layer 1 of the stack remains uncovered and unprotected by the envelope 4.

The active layers 1 and 3 each are designed to provide release of one or more pharmaceutically active substances and thus, they each contain active substance that is, in the present description and by way of example, diltiazem HCl. The latency layer 2 is designed devoid of active substance so as to provide a period of no-release i.e. of latency.
 

Claim 1 of 12 Claims

1. A pharmaceutical tablet system capable of prolonged floating in or on gastric fluid for releasing therein one or more pharmaceutically active substances in the course of an alternate succession of periods of substance release and no-release, said alternate succession having at least two periods of substance release separated by one period of no-release, whereby the tablet system is made up of a multilayered core placed in a cup-shaped envelope, the core is made up of release and no-release layers superposed in alternate succession to form a pile of layers that has at least two release layers flanking an intermediate no-release layer, each release layer being composed of pharmaceutically acceptable excipient and/or carrier having admixed thereto at least one of said pharmaceutically active substances, each no-release layer being composed of pharmaceutically acceptable excipient and/or carrier devoid of said pharmaceutically active substance, the cup-shaped envelope covers a bottom surface and side surfaces of the core placed therein while leaving exposed an upper surface of the core, characterized in that the cup-shaped envelope provides for buoyancy of the pharmaceutical tablet system with respect to gastric fluid by being formed of a compression-sintered mixture with voids, the mixture being comprised by buoyancy-providing materials in the form of a pharmaceutically acceptable hydrophobic material and a pharmaceutically acceptable inert powdered filler, the hydrophobic material being composed of fatty and/or waxy material capable of being sintered by compression and whose bulk density is lower than gastric fluid density, and the powdered filler having a loose powder density that is lower than gastric fluid density, the powdered filler consisting of magnesium aluminometasilicate; and the buoyancy-providing materials of the cup-shaped envelope being incorporated in the finished pharmaceutical tablet system in the range of 69 to 72 percent by weight.
 

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