Title:  Expandable gastro-retentive therapeutic system with controlled active substance release in the gastro-intestinal tract

United States Patent:  6,290,989

Assignee:  LTS Lohmann Therapie-Systeme AG (DE)

Filed:  August 31, 1999

PCT NO:  PCT/EP98/00099

102(e) Date:  August 31, 1999

PCT PUB. Date:  July 23, 1998

Foreign Application Priority Data:  Jan 14, 1997[DE] (197 00 915)

The present invention describes a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, having a component expandable on contact with gastric juice, which is surrounded by a polymer covering which is permeable to gastric juice and active compounds. The device contains at least one active compound which is present in a multiparticulate preparation which releases the active compound into the gastric juice with a delay. Compared with conventional pharmaceutical forms with delayed pyloric passage, the release of active compound from a device according to the invention can be better controlled; likewise the device can be easily rolled or folded and can be introduced into capsules without problems.

Description of the Invention

The invention relates to a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, having a component expanding on contact with gastric juice, which is surrounded by a polymer covering which is permeable to gastric juice and active compounds. It relates in particular to a device which, by means of the reversible expansion of a component contained in it, undergoes extension on contact with gastric juice, which delays the pyloric passage and thereby leads to a prolonged gastric residence time. U.S. Pat. No. 4,207,890 describes a device for the controlled release of active compounds, which by means of its expansion undergoes local retention in the stomach and thereby has a prolonged residence time in the same. The device has (a) a polymer covering, which is present in collapsed form before administration. The polymer covering itself has no openings and consists of a material which is virtually unhydratable, but is permeable to body fluids and active compounds. The device moreover has (b) an element which controls the release of active compound. According to Claim 2, this element can be the polymer covering itself. As a further element (c), the device has an expanding component on contact with body fluids.

Significant problems of the administration form remain unsolved, however. In particular, the patent specification gives no concrete advice on the preparation of the active compound or the manner of its introduction into the device. In the description of the invention (top of column 5), it is proposed to seal the active compound into a small sachet which in turn can be inserted into a capsule before it is incorporated into the device.

Such a solution is affected by serious disadvantages. In view of the fact that the entire device must be dimensioned such that it can still be administered orally, it is virtually impossible to accommodate in it an expandable element and a capsule which contains a sachet with active compound. The industrial production, filling and sealing of such a small sachet of active compound and its introduction into a small capsule could also be associated with great difficulties.

EP 0 307 904 A1 furthermore discloses a very specific embodiment of a gastroretentive device with an expanding component (a) which contains the active compound and whose expansion takes place by means of evolution of CO₂. A polymer covering (b) of polyvinyl alcohol in sachet form and (c) an additional covering decomposing in gastric juice, e.g. a capsule, are furthermore provided.

This EP 307 904 also offers no practical solution to the introduction of the active compound. According to the exemplary embodiments, active compound powder is introduced manually into the polyvinyl alcohol covering. It is particularly disadvantageous that active compound and--the alkaline--CO₂ generator are combined to give one element, although it is known that many active compounds are incompatible with alkaline auxiliaries, which even include some of those described in the patent specification as preferred (e.g. ASA).

Both EP 307 904 A1 and U.S. Pat. No. 4,207,890 lack advice on how the release rate is to be controlled independently of the permeability of the polymer covering provided, which is particularly important if a rapidly permeating active compound is to be administered over a relatively long time.

It is therefore the object of the present invention to create a gastroretentive pharmaceutical form having the advantages of an expandable device according to U.S. Pat. No. 4,207,890, but which is an improvement in

the sense of the production technology, the active compound stability and the control of the active compound release rate independently of the properties of the integrity-preserving polymer covering.

This object is achieved in very general form by a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, having a component expandable on contact with gastric juice, which is surrounded by a polymer covering which is permeable to gastric juice and active compounds, and which contains at least one active compound in the form of a multiparticulate preparation which releases the active compound into the gastric juice with a delay. Particular features of the invention follow from the subclaims and from the description below.

A device according to the invention offers the possibility of controlling the release rate of the active compound or of the active compounds relatively independently of the permeability of the polymer covering by means of the nature and composition of the multiparticulate preparation. The polymer covering can thus be optimized with respect to other important properties such as strength, sealing ability, flexibility and permeability for gastric juice and must not be adjusted as a top priority to the control of the release rate. The same polymer covering, for example, can thus be used for various products with different active compounds or different multiparticulate preparations of active compounds. Equally, the combined administration of two active compounds with differing permeabilities is made possible by means of a single device in that a multiparticulate preparation of each active compound having an appropriate release profile is provided in the same device.

The possibility of controlling the release rate, which is largely independent of the polymer covering, is therefore particularly of importance, since the requirement must be made of the same covering or membrane that on contact with gastric juice it very rapidly absorbs water or makes possible the diffusing-in of water, which must lead within a short time to the activation of the expansion mechanism of the device. An absorption and diffusion of water which is as rapid as possible, however, is accompanied by particularly high hydrophilicity and, as a rule, by a rapid diffusion of dissolved substances--properties which possibly counteract control of the active compound release by the membrane over a period of hours. Conversely, polymer membranes which release dissolved active compounds only slowly cannot [lacuna] water sufficiently rapidly into the device, so that in the case of a device having such a membrane the danger exists that it passes through the pylorus before its expansion mechanism could be activated. A multiparticulate preparation with controlled release of active compound accordingly makes possible a particularly advantageous and varied possibility of constructing expanding gastroretentive systems.

The advantage of the better control of the release rate is combined in a device according to the invention with the advantage of the better introduction of active compound during preparation and the better handling ability of the device after the introduction of the active compound. In particular, the possibility of rolling, folding or compressing the device for the purpose of introduction into hard gelatine capsules is thus guaranteed. The spatial separation of active compound and expansion-promoting propellants in the device is also advantageous, since it lowers the danger of incompatibilities.

Within the meaning of this invention, the concept of the multiparticulate preparation which releases the active compound into the gastric juice with a delay includes all multiparticulate delayed-release forms known in pharmaceutical technology. In this case, these are preparation forms in which a large number of particles in each case define one dose unit of the active compound and in which the delayed-release mechanism is combined with the construction or the formulation of the individual particles. Preparations of this type can have, for example, the form of pellets, powders, granules, microcapsules, nanoparticles, etc. with particle sizes of below 3 mm in diameter; particle sizes of up to 2 mm in diameter are preferred. The delaying of the active compound release can be effected by covering the individual particles with a polymer film or with a fatty or waxy substance or by embedding the active compound in a suitable carrier material which does not disintegrate rapidly in gastric juice. Suitable carrier materials therefore as a rule contain auxiliaries which are lipophilic and poorly and/or slowly soluble.

Claim 1 of 15 Claims

What is claimed is:

1. Device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage comprising a component expandable on contact with gastric juice, a flexible polymer covering which is permeable to gastric juice and active compounds, wherein said polymer covering surrounds said expandable component and wherein said polymer covering contains at least one active compound present in a multiparticulate preparation consisting of individual particles containing said active compound, wherein said active compound is released into the gastric juice with a delay.

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