Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-01-14
2002-03-05
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S472000, C424S422000, C424S423000, C424S424000, C424S427000, C424S435000, C424S436000, C424S437000, C514S772300, C514S781000, C514S784000, C514S785000, C514S786000
Reexamination Certificate
active
06352721
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to a delivery device for the controlled release of active agents to an environment of use. More particularly, the invention pertains to a device for the delivery of active agents over a prolonged and extended period of time. The controlled delivery device comprises an expandable-hydrophilic polymer-core located substantially in the center of the dosage form surrounded by a composition of the active agent(s) to be delivered. A novel dual function membrane permits delivery of the active agent(s) through a combination of diffusion and osmotic pumping mechanisms.
BACKGROUND OF THE INVENTION
Osmotic devices have demonstrated utility in delivering beneficial active agents, such as medicines, nutrients, food, pesticides, herbicides, germicides, algaecides, chemical reagents, and others, to an environment of use in a controlled manner over prolonged periods of time. Known devices include tablets, pills, and capsules.
Several advancements have been made in the art to improve the delivery of insoluble or slightly soluble products to an environment of use. The prior art has focused on the development of new membranes that deliver active agents by diffusion and/or osmotic pumping.
U.S. Pat. No. 4,235,236 to Theeuwes discloses an osmotic device that delivers drug by the combined mechanisms of diffusion and osmotic pumping. The device comprises a microporous wall surrounding a compartment containing an active agent and an expandable member. The expandable member consists of a semipermeable, flexible or expandable film surrounding a member selected from the group consisting of an osmotically effective solute, a gas generating couple and a swellable polymer. The external wall of the device is formed of a microporous material through which the active agent is delivered. This patent does not disclose the inclusion of a passageway in the external wall to provide delivery by osmotic pumping and diffusion. Even though the solution proposed by U.S. Pat. 4,235,236 allows the release of an active agent at a steady rate - the so called zero-order release-, it requires the manufacturing of an elastic film that separates the expandable member from the composition comprising the active agent. The adhesion process between said membrane and said composition comprising the active agent requires complicated processing steps that make the formulation very expensive.
U.S. Pat. No. 4,327,725 to Cortese and Theeuwes, discloses an osmotic device comprising a semipermeable wall surrounding two layers, one layer containing an active agent and the other an expandable hydrogel. A passageway in the wall communicates the active agent layer with the environment of use. The patent describes the use of cellulose acylate as the material comprising the semipermeable membrane.
U.S. Pat. Nos. 5,612,059 and 5,698,220 to Cardinal et al., disclose the use of asymmetric membranes in delivery devices. These membranes may be permeable, semipermeable, perforated or unperforated and can deliver an active substance by the combined mechanisms of diffusion and osmotic pumping. These patents also disclose the formation of asymmetric membranes with 398-10 (Eastman) cellulose acetate.
EP 636366 and EP 553392 disclose an active agent composition coated with an aqueous dispersion of plasticized acrylic polymer, which is subjected to a particular curing process. The controlled release formulation disclosed in these applications has a stable dissolution profile despite exposure to a variety of storage conditions.
U.S. Pat. 5,543,155 to Fekete et al. discloses a controlled delivery pharmaceutical composition core surrounded by a wall comprising an ammonium methacrylate copolymer which is permeable to low molecular weight (MW) molecules. This controlled delivery pharmaceutical composition contains an active pharmaceutical compound and hydroxypropyl methylcellulose (HPMC) as the hydrophilic polymer. Low MW osmagents are not incorporated into the composition. Tablets having a bi-layered core are prepared with a hydrophilic polymer layer comprising high molecular weight HPMC, which has a viscosity higher than 1000cP in a 2% aqueous solution.
U.S. Pat. 5,543,155 also discloses various combinations of Eudragit™ RL (easily permeable films) and Eudragit™ RS (not easily permeable films). The use of a permeable membrane alone, however, does not allow the inclusion of a low molecular weight osmotic agent in the pharmaceutical composition tablet core (for example, potassium chloride, sodium tartrate, sodium chloride, sodium sulfate, etc.). Thus, it limits the versatility of the device to the delivery of active agents that require a significant absorption of liquid to achieve an effective and constant delivery of solution or suspension of the active agent from the device. Osmotic devices having a bi-layered core, one layer containing the active agent and the other being a swellable placebo layer, surrounded by a semipermeable membrane possess significant disadvantages. The placebo layer consists mainly of a swellable polymer and/or a hydrogel that, while absorbing fluid from the environment of use, expands and exerts pressure over the layer that contains the active agent thereby releasing the active agent through a passageway in the wall. The prior art teaches that perforation of the semipermeable membrane needs to be carried out selectively on the side of the membrane that is adjacent to the layer comprising the active agent. In fact, if the membrane is perforated adjacent the placebo layer, the active agent will not be released. If two perforations are carried out, one adjacent the active-agent layer and the other adjacent the swellable polymer layer (“push” layer), both the active agent and the swellable polymer are released, resulting in loss of the “push” effect. The device would therefore act as a simple osmotic pump that would not allow the release of the entire charge of active agent in the dosage form. The precise selection of which portion of the membrane should be drilled requires the use of color or shape coding in order to distinguish the layers, as well as meticulous handling of the devices. The handling of the devices requires the use of sophisticated and expensive electronic equipment able to recognize the different layers of the tablet core.
U.S. Pat. 5,543,155 also discloses perforation of the membrane adjacent both layers of the core; however, a specific high molecular weight polymer (HPMC) is required to prevent the loss of the push layer leaving a significant number of available hydrophilic polymers unavailable for use in these devices.
While the prior art discloses a wide variety of osmotic devices, no single device has been found to be generally applicable and, in fact, most known devices are designed to operate within a relatively narrow range of conditions. For example, a first formulation of an osmotic device may be generally useful for delivering slightly to sparingly water soluble components to an environment of use, but that same formulation will require drastic changes in order to deliver a very water soluble component and vice versa. In addition, diffusion controlled devices are generally useful for delivering sparingly to very, but not slightly, water soluble components to an environment of use. Therefore, a need remains for a delivery device capable of delivering components having very different solubilities to an environment of use without requiring a dramatic reformulation of the device.
SUMMARY OF THE INVENTION
The present invention provides a controlled release device for active substances comprising an external dual delivery membrane having at least one preformed passageway and plural micropores, wherein the device releases the active agent through a combination of diffusion and osmotic pumping. The at least one passageway can be located anywhere in the dual delivery membrane.
The present invention also provides a controlled release device having an approximately centrally located core comprising a hydrophilic expandable polymer and, optionally, an osmagent, wherein the co
Innovar L.L.C.
Matos Rick
Osmotica Corp.
Spear James M.
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