Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-04-26
2004-08-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S456000, C424S457000, C424S458000, C424S466000, C424S489000, C424S490000, C424S492000
Reexamination Certificate
active
06776999
ABSTRACT:
This application is a 371 of PCT/EP99/08043 filed Oct. 23, 1999.
The present invention describes a device for delaying the pyloric passage of orally assimilable pharmaceutical forms having a component which is expandable on contact with gastric juice and a polymer coat which is permeable to liquids but gas-tight. The device can contain an active compound which is mainly released into the gastric juice in a controlled manner by the incorporated pharmaceutical form. Compared with conventional pharmaceutical forms having a delayed pyloric passage, the release of active compound is less dependent on the nature and composition of the polymer coat and is mainly determined by the incorporated form. The device according to the invention can be easily rolled or folded and can be filled into capsules.
U.S. Pat. No. 4,207,890 describes a device for the controlled release of active compounds, which due to its expansion undergoes local retention in the stomach and thereby has a prolonged residence time in the stomach. The device has (a) a polymer coat which is present in collapsed form before administration. The polymer coat itself has no openings and consists of a material which is virtually unhydratable, but is permeable to body fluids. The device additionally has (b) an element which controls the release of active compound. According to claim
2
, this element can be the polymer coat itself. As a further element (c), the device has a component which is expandable in contact with body fluids.
The driving principle of the retentive action is osmosis, the element (c) being an osmotically active substance which drives water through the polymer coat (a) and thereby causes the formation of a solution in the device. The device will thus contain an aqueous solution in the expanded state and on account of the concentration conditions will make possible a diffusion of active compound from the device, but will correspond approximately to the chyme in its apparent density. The device will thus float or sink in the chyme. The retentive principle is exclusively the size of the device. A possible deflation mechanism is not described, thus removal of the device from the stomach and disposal after active compound administration is not elucidated.
A modification of the principle of retention is shown in EP 0 307 904 A1 and U.S. Pat. No. 4,996,058. Expandable components indicated are substances which, under admission of acid, form gaseous components such as carbon dioxide or nitrogen which inflate the polymer coat (a) and thus form a device which can be floated on the chyme. The principle of retention (see U.S. Pat. No. 4,996,058 column 3, lines 6 to 7) is floating on the chyme and thus the device is protected from emptying of the stomach through the pylorus. These devices have crucial disadvantages. In both cases, the control of the release of active compound essentially takes place through the polymer coat. At the same time, the inflation kinetics of the device are essentially limited by the polymer coat, as water and hydronium ions must diffuse through the polymer coat, but on the other hand active compound molecules must diffuse out in the opposite direction. The diffusion constant in the polymer coat is a crucial parameter. In the case of damage to the relatively thin and thus sensitive polymer coat by mechanical or chemical action, there is the danger of a sudden release of the active compound in the sense of dose-dumping. The extent of the expanding amount of gas produced depends, inter alia, strongly on the acidity of the environment and thus, however, on the composition of the chyme and the secretion of gastric acid. In the case of a strongly acidic environment and thus high gas production, the mechanical stress on the devices must not reach the bursting limit, on the other hand, in the case of a less acidic environment, an adequate production of gas must be achieved. This dilemma leads to highly variable states of the devices as a result of circadian variations in the gastric acidity.
The invention is therefore based on the object of making available a gastroretentive system which avoids these disadvantages of the systems known in the prior art.
According to the invention, these problems are solved by a gastroretentive device which contains the following elements:
(a) a polymer coat of microporous membrane or partially microporous membrane or a combination of both with another nonporous film-like polymer. The production of the pores can be carried out according to the invention by any desired process, e.g. by stretching of films, by use of multiphase systems and evaporation of a part of the system, by controlled polymerization, e.g. in the form of ionomers, by mechanical processes such as needling, by thermal processes such as lasers, or by irradiation with ionizing radiation and subsequent etching etc. Materials which can be used according to the invention for the microporous membrane are: polyurethanes, polypropylene, polyvinyl alcohol, polyvinyl acetate, polyacrylic acid and derivatives, polymethylmethacrylic acid and derivatives, polycarbonates, polyvinylidene difluoride, polytetrafluoroethylene and any other desired polymers which can be provided with pores of suitable size. According to the invention, the size of these pores is between 0.1 and 20 &mgr;m, preferably between 0.3 and 10 &mgr;m and particularly preferably between 0.5 and 1 &mgr;m. If appropriate, in order to make the pores better wettable, the membranes according to the invention can be impregnated with wetting agents or other hydrophilic components.
(b) an expandable component which produces a gas such as, for example, carbon dioxide or nitrogen on contact with gastric juice, in particular under the action of acid. Examples of these used according to the invention are, for example, carbonates and hydrogencarbonates of the alkali metals and alkaline earth metals, the ammonium cations or sodium azide or mixtures thereof. These expandable components can be optionally modified for the modification of the gas production kinetics, e.g. by coating with or embedding in lipophilic components such as waxes or fats or suitable coatings such as polymethacrylates or polymethylmethacrylates and derivatives or similar substances known to the person skilled in the art. According to the invention, the expandable component can also be foam-forming, e.g. as a result of the incorporation into polyvinyl alcohol, or in the form of a semisolid, ointment-like preparation, in order to control the deflation kinetics.
(c) a component containing the active compound such as, for example, multiparticulate preparations, tablets, capsules or semisolid, ointment-like preparations, or foams. Possible active compounds are fundamentally all substances having a physiological action, in particular pharmaceuticals for human or veterinary medicine, preferably those which are absorbed by the gastric mucosa or act on the surface of the gastric mucosa. Such pharmaceutical active compounds are known to the person skilled in the art. The components (b) and (c) can also be present in a joint preparation.
The device can be filled into a container made of physiologically acceptable material, for example into a hard gelatin capsule, in order to facilitate administration and handling.
The inflated form of the device is preferably that of an inflated triangle in order to have a planar structure of maximum bulk. Due to the planarity, in the state floating on the chyme, two preferred positions are stable which both allow passage of the chyme past the gastroretentive device such that the chyme cannot force the inflated form through the pylorus. Among the planar forms, the form of a triangle is a good compromise of bulkiness and stiffness of the structure in the inflated state and is therefore proposed for the retentive device. In the stomach, the bulky structure wedges between the stomach walls and allows the chyme to escape through the pylorus. The wedging in the lumen only has to withstand the flow resistance in the chyme. The more spherical the device, the more likely a bulb
Bennett Rachel M.
Frommer & Lawrence & Haug LLP
LTS Lohmann Therapie-Systeme AG
Page Thurman K.
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