Claims for Patent: 4,777,049

Summary for Patent: 4,777,049

Title:	Constant release system with pulsed release
Abstract:	An osmotic delivery system is disclosed for delivering a useful agent at a controlled and constant rate modulated by a pulsed delivery of the useful agent to an environment of use.
Inventor(s):	Magruder; Paul R. (Palo Alto, CA), Barclay; Brian (Menlo Park, CA), Wong; Patrick S. L. (Hayward, CA), Theeuwes; Felix (Los Altos, CA)
Assignee:	ALZA Corporation (Palo Alto, CA)
Application Number:	07/001,599
Patent Claims:	1. An osmotic system for the delivery of a beneficial agent to an environment of use, comprising: (a) a wall formed of a semipermeable composition permeable to the passage of an exterior fluid, and substantially impermeable to the passage of beneficial agent, the wall surrounding and forming: (b) a compartment containing a beneficial agent and a modulating agent which modulating agent is a means for providing a pulsed delivery of the beneficial agent; and, (c) a passageway through the wall communicating the exterior of the system with the interior of the system for delivering the beneficial agent to the environment of use. 2. The osmotic system for the delivery of a beneficial agent to an environment of use according to claim 1, wherein the modulating agent is present in an amount that falls below saturation in fluid that enters the osmotic system thereby producing a pulsed delivery of beneficial agent that is followed by a substantially zero order delivery of beneficial agent. 3. The osmotic system for the delivery of a beneficial agent to an environment of use according to claim 1, wherein the beneficial agent solubility is enhanced in fluid imbibed into the osmotic system and in the presence of the modulating agent thereby producing a pulsed delivery of beneficial agent that interrupts a susbstantially zero order delivery of beneficial agent. 4. The osmotic system for the delivery of a beneficial agent to an environment of use according to claim 1, wherein the modulating agent decreases in concentration in fluid that enters the osmotic system thereby producing a pulsed delivery of beneficial agent that follows a substantially zero order delivery of beneficial agent. 5. The osmotic system for the delivery of a beneficial agent to an environment of use according to claim 1, wherein when the osmotic system is in operation in the environment of use, fluid is imbibed through the wall into the osmotic system accompanied by a pulsed delivery of beneficial agent from the osmotic systems is a larger amount than the amount of beneficial agent delivered at substantially zero order. 6. The osmotic system for delivery of a beneficial agent to an environment of use according to claim 1, wherein the wall comprises a member selected from the group consisting of a cellulose ester, cellulose diester, cellulose triester, cellulose ether, and a cellulose ester-ether and the ratio of the amount of modulating agent to useful agent present in the osmotic system is given by the formula 0<R<(S.sub.o /S.sub.d) wherein R is the ratio, and S.sub.o is the mutual solubility of the modulating agent and S.sub.d is the mutual solubility of the useful agent. 7. The osmotic system for the delivery of a beneficial agent to an environment of use according to claim 1, wherein the modulating agent is a member selected from the group consisting of an inorganic acid, an organic acid, a base and a salt. 8. The osmotic device for the controlled delivery of a beneficial agent to an environment of use according to claim 1, wherein the beneficial agent is a drug. 9. The osmotic device for the controlled delivery of a beneficial agent to an environment of use according to claim 1, wherein the environment of use is an animal. 10. An osmotic device for the controlled delivery of salbutamol, the osmotic device comprising: (a) a wall formed of a nontoxic material permeable to the passage of an exterior fluid and substantially impermeable to the passage of salbutamol and a modulating agent, which wall surrounds and defines: (b) a compartment containing salbutamol and a modulating agent, said modulating agent present in an amount less than the amount needed for it to maintain saturation in fluid imbibed into the device, thereby letting the amount of salbutamol in solution increase in fluid imbibed into the device and give a pulsed release of salbutamol; and, (c) a passageway through the wall communicating with the exterior of the device for the controlled delivery of salbutamol from the osmotic device. 11. A process for delivering a useful agent at a zero order rate modulated by a pulsed rate, wherein said process comprises the steps of: (a) placing in an environment of use an osmotic delivery device, the device comprising: (1) a wall formed of a semipermeable polymeric composition permeable to the passage of an exterior fluid, and substantially impermeable to the passage of useful agent and modulating agent, which wall surrounds and forms; (2) a compartment containing a useful agent and a modulating agent, said modulating agent being a means for pulsing the delivery of useful agent from the osmotic device; and, (3) a passageway in the wall connecting the exterior of the osmotic device with the interior of the osmotic device; (b) imbibing fluid from the environment through the semipermeable wall into the osmotic device; and, (c) delivering the useful agent through the passageway to the environment of use at a substantially zero order rate modulated by a pulsed rate delivery of the useful agent. 12. The process for delivering the useful agent at a zero order rate modulated by a pulsed rate according to claim 11, wherein the modulating agent is present in the osmotic device in an amount such that as the modulating agent is delivered from the osmotic device the concentration of modulating agent falls below saturation in fluid imbibed into the osmotic device, whereby the solubility of the useful agent increases in the imbibed fluid and is delivered from the osmotic device in a pulsed amount to the environment of use. 13. An osmotic system for the delivery of a beneficial agent to an environment of use, comprising: (a) a wall formed of a semipermeable composition permeable to the passage of an exterior fluid, and substantially impermeable to the passage of beneficial agent, the wall surrounding and forming: (b) a compartment containing a beneficial agent and a modulating agent which modulating agent is a means for providing a pulsed delivery of the beneficial agent and is a therapeutically acceptable salt having a common ion with the beneficial agent; and, (c) a passageway through the wall connecting the exterior of the osmotic system with the interior of the system for delivering the beneficial agent to the environment of use. 14. A process for delivering a useful agent at a release rate pattern comprising a constant rate of release and a pulsed rate of release within the same release rate period from an osmotic delivery system, wherein said process comprises: (a) placing in an environment of use an osmotic delivery system, the system comprising: (1) a wall formed of a semipermeable polymeric composition permeable to an exterior fluid, and substantially impermeable to the passage of useful agent and modulating agent, which wall surrounds and forms; (2) a compartment containing a useful agent and a modulating agent, said modulating agent being a means for pulsing the delivery of the useful agent from the osmotic system which modulating agent is a pharmaceutically acceptable salt and has a common ion with the useful agent (3) a passageway in the wall connecting the exterior of the osmotic system with the interior of the osmotic system; (b) imbibing fluid from the environment through the semipermeable wall into the osmotic system; and, (c) delivering the useful agent through the passageway at the release rate pattern from the osmotic system.