CONTROLLED POROSITY OSMOTIC PUMP
BACKGROUND OF THE INVENTION
Diltiazem hydrochloride is a calcium ion influx inhib- 5 itor which is commercially utilized in the treatment of angina pectoris due to coronary artery spasm and chronic stable angina.
Controlled delivery devices for therapeutically active agents are well known in the art. Generally, these 10 devices may be characterized as either diffusion controlled delivery systems or osmotic dispensing devices. U.S. Pat. No. 3,538,214 discloses a diffusion controlled device in which a tablet core containing an active ingredient is surrounded by a water insoluble coating which 15 contains film modifying agent soluble in the external fluids in the gastrointestinal tract. An example of an osmotic device is described in U.S. Pat. Nos. 3,845,770 and 3,916,899 which is a core composition of an active agent and an osmotically effective solute which is en- 20 closed by an insoluble semipermeable wall having a release means. Numerous modifications to these types of delivery devices have been described in the art in an effort to improve their release characteristics.
The use of pore formers in substantially water imper- 25 meable polymers, such as polyvinyl chloride, is disclosed in J. Pharm. Sci. 72, 772-775 and U.S. Pat. No. 4,244,941. The devices release the core contents by simple diffusion through the pores in the coating.
U.S. Pat. No. 3,957,523 discloses a device which has 30 pH sensitive pore formers in the wall.
U.S. Pat. No. 4,256,108; 4,160,452; 4,200,098 and 4,285,987 disclose devices with pore formers in only one of at least two wall layers. These devices contain a drilled hole for the release of the core contents.. 35
Co-pending U.S. Pat. applications Attorney Docket Number IX112IB and IX112IC disclose systems which comprise an inner core compartment of osmotically active composition surrounded by an enclosing controlled porosity wall material that is substantially per- 40 meable to both solute and external fluid. These systems are osmotic dispensing devices for a broad range of therapeutically active agents. However, the delivery of a highly soluble agent from these devices at a constant rate is difficult to achieve. 45
U.S. Pat. No. 4,326,525 addresses the problem of delivering an active agent from an osmotic device by incorporating into the core a buffer which enters into a proton-transfer or neutralization reaction with the agent thereby producing an aqueous soluble agent salt within 50 the device.
BRIEF DESCRIPTION OF THE INVENTION
This invention concerns an osmotically activated system for dispensing diltiazem L-malate, as the phar- 55 macologically active agent, to biological receptor sites over a prolonged period of time. The system comprises an inner core compartment of osmotically active composition surrounded by an enclosing wall material. The core comprises diltiazem L-malate and sodium bitar- 60 trate, which exhibit unique solubility characteristics in an external fluid, and an osmotic pressure gradient across the wall against the external fluid. The wall constitutes a layer of controlled porosity that is substantially permeable to both the external fluid and the aque- 65 ous solution of the core composition. Diltiazem Lmalate and sodium bitartrate are released from the system in a nearly pH independent manner by external
of the active agent in the dissolved core composition and remains constant when excess solid core mass is present. In the present invention the volume flux contribution, (dV/dt)C, to the total rate is expected to be greater than the diffusive contribution, (dM/dt)o, and forms the basis for the osmotic pump action of the device.
The present invention include osmotic systems that are readily manufactureable to deliver a pre-determined dose of agent at a programmed rate from compositions of matter in the varied geometries and sizes of tablets, and such related dosage forms as familiar to those skilled in the art for oral, buccal, vaginal, rectal, nasal, ocular, parenteral and related routes of administration. The invention also provides osmotic systems that deliver agent on an equivalent mass per unit surface area basis.
A BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an embodiment of the osmotic pump.
FIG. 2 is the release profile (statistical average of several pumps) of the pumps produced in Example 1.
FIG. 3 is the release profile (statistical average of several pumps) of the pumps produced in Example 2.
FIGS. 4A through 4D are the release profiles (statistical average of several pumps) of the pumps produced in Example 3 formulations 3A through 3D, respectively.
DETAILED DESCRIPTION OF THE
The instant invention is directed to an osmotic pump, for the controlled release of diltiazem L-malate to an environment of use, said pump comprising:
(A) a core which comprises a therapeutically effective amount of diltiazem L-malate and an effective buffering amount of sodium bitartrate surrounded by
(B) a rate controlling water insoluble wall, having a fluid permeability of 6.96X10-18 to 6.96X 10-14cm3 sec/g and a reflection coefficient of less than 0.5, prepared from:
(i) a polymer permeable to water but impermeable to solute and
(ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), of at least one pH insensitive pore forming additive dispersed throughout said wall.
The osmotically active core composition mass (3) of FIG. I, is typically in the form of a solid conventional tablet. The core is completely encased by the controlled porosity wall (2). The core is comprised of a mixture of diltiazem L-malate and sodium bitartrate, as well as other inert pharmaceutically acceptable carriers, which