Patent Publication Number: US-6217906-B1

Title: Self adjustable exit port

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of application Ser. No. 09/045,944, filed Mar. 23, 1998, now U.S. Pat. No. 5,997,527, which claims the benefit of U.S. Provisional Application No. 60/035,607, filed Mar. 24, 1997, pursuant to 35 U.S.C. §119(e). 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates generally to an implantable delivery device, and more particularly to an exit port, such as a slit orifice for an implantable osmotic delivery device which has a variable size. 
     2. Description of the Related Art 
     Controlled delivery of beneficial agents such as drugs in the medical and veterinary fields has been accomplished by a variety of methods. One approach for delivering a beneficial agent involves the use of implantable diffusional systems. For example, subdermal implants for contraception are described by Philip D. Darney in  Current Opinion in Obstetrics and Gynecology,  1991, 3:470-476. Norplant® requires the placement of 6 levonorgestrel-filled silastic capsules under the skin. Protection from conception for up to 5 years is achieved. The implants operate by simple diffusion, that is, the active agent diffuses through the polymeric material at a rate that is controlled by the characteristics of the active agent formulation and the polymeric material. 
     Another method for controlled prolonged delivery of a beneficial agent involves the use of an implantable osmotic delivery system. Osmotic delivery systems are very reliable in delivering the beneficial agent over an extended period of time. The osmotic pressure generated by an osmotic pump also produces a delivery rate of the beneficial agent into the body which is relatively constant as compared with other types of delivery systems. 
     In general, osmotic delivery systems operate by imbibing fluid from the outside environment and releasing corresponding amounts of the beneficial agent. Osmotic delivery systems, commonly referred to as “osmotic pumps”, generally include some type of a capsule having walls which selectively pass water into an interior of the capsule which contains a water-attracting agent. The absorption of water by the water-attracting agent within the capsule reservoir creates an osmotic pressure within the capsule which causes the beneficial agent to be delivered from the capsule. The water-attracting agent may be the beneficial agent delivered to the patient, however, in most cases, a separate agent is used specifically for its ability to draw water into the capsule. 
     When a separate osmotic agent is used, the osmotic agent may be separated from the beneficial agent within the capsule by a movable dividing member or piston. The structure of the capsule is such that the capsule does not expand when the osmotic agent takes in water. As the osmotic agent expands, it causes the movable dividing member or piston to move, which in turn causes the beneficial agent to be discharged through an orifice at the same volumetric rate that water enters the osmotic agent by osmosis. 
     The orifice controls the interaction of the beneficial agent with the external fluid environment. The orifice serves the important function of isolating the beneficial agent from the external fluid environment, since any contamination of the beneficial agent by external fluids may adversely affect the utility of the beneficial agent. For example, the inward flux of materials of the external fluid environment due to diffusion or osmosis may contaminate the interior of the capsule, destabilizing, diluting, or otherwise altering the beneficial agent formulation. Another important function of the orifice is to control or limit diffusional flow of the beneficial agent through the orifice into the external fluid environment. 
     In known delivery devices, these functions have typically been performed by flow moderators. A flow moderator may consist of a tubular passage having a particular cross sectional area and length. The cross sectional area and length of the flow moderator is chosen such that the average linear velocity of the exiting beneficial agent is higher than that of the linear inward flux of materials in the external environment due to diffusion or osmosis, thereby attenuating or moderating back diffusion and its deleterious effects of contaminating the interior of the osmotic pump. 
     In addition, the dimensions of the flow moderator may be chosen such that the diffusive flux of the beneficial agent out of the orifice is small in comparison to the convective flux. FIG. 1 is a graph showing the relationship between the orifice dimensions and drug diffusion as a percentage of pumped or connective delivery for one set of pumping rates and drug diffusivity. FIG. 1 shows, for example, that the diffusive flux of the beneficial agent can be kept to less than 10% of the convective flow using an orifice having a diameter of 5 mils and a length of at least 0.6 cm, or an orifice having a diameter of 10 mils and a length of at least 2.4 cm. 
     One problem with flow moderators, however, is that the passage may become clogged or obstructed with particles suspended in the beneficial agent or in fluid from the external environment. Such clogging may be reduced or eliminated by increasing the diameter of the passage to 5 mil or more, for example. However, as shown in FIG. 1, this increase results in a greater rate of diffusion of the beneficial agent out of the osmotic pump. A corresponding increase also occurs in the back diffusion of the external fluid into the osmotic pump which may contaminate the beneficial agent and adversely affect the desired delivery rate of the beneficial agent. Tolerances during fabrication also frequently dictate that the orifice diameter be greater than about 5 mils. 
     Systems with a long straight flow moderator are also impractical for implantation applications because they increase the size of the implant significantly making the system difficult to implant. 
     Current flow modulators also cause separation of beneficial agents which contain suspensions of bioactive macromolecules (proteins, genes, etc.). When such suspensions pass along a restriction in current flow modulators, the suspension separates and the delivery concentration of bioactive macromolecules varies. 
     SUMMARY OF THE INVENTION 
     According to one embodiment of the invention, an exemplary delivery device, such as described in U.S. patent application Ser. No. 08/595,761, the entire disclosure of which is incorporated herein by reference, may be provided with the slit orifice of the present invention. The delivery device comprises a capsule containing a beneficial agent and an osmotic agent, a membrane which forms a portion of a wall of the capsule, the membrane allowing fluid from an external environment to pass into the capsule by osmosis to create an osmotic pressure in the capsule, means for applying the osmotic pressure to the beneficial agent, and a flexible member having therein a slit orifice which is in fluid communication with the capsule. 
     In the presence of flow, the beneficial agent pushes through the slit, opening up a channel for delivery of the beneficial agent. Because the slit orifice remains closed in the absence of flow, back diffusion of external fluids is eliminated when the slit is closed, which prevents contamination of the beneficial agent by external fluids. Forward diffusion of the beneficial agent out of the capsule is also prevented. 
     In addition, the slit orifice allows a flow path to open around an obstruction in the slit orifice. In the event that a suspended particle becomes lodged in the slit orifice, a new flow path is created around the obstacle, thereby preventing clogging. The slit orifice is also very compact and easily fits inside the delivery device, which is advantageous when the delivery device is implanted subcutaneously. 
     This combination uniquely addresses the complex issues presented in the extremely low flow, high osmolar drug delivery systems as found, for example, in U.S. patent application Ser. No. 08/595,761 which has been converted to Provisional Application No. 60,122,056. These issues drug diffusion out of the orifice, back diffusion of liquid from the environment of use into the orifice, and clogging of the orifice, especially if the orifice is small enough to eliminate drug diffusion and back diffusion. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The foregoing and other objects, features and advantages of the present invention will be more readily understood upon reading the following detailed description in conjunction with the drawings in which: 
     FIG. 1 is a graph of drug diffusion as a function of the diameter and length of the orifice of a delivery device; 
     FIG. 2 illustrates a delivery device which includes a slit orifice according to an exemplary embodiment of the invention; 
     FIG. 3 illustrates a delivery device which includes a slit orifice and a catheter according to another embodiment of the invention; 
     FIG. 4 is a graph which shows the release rates of the delivery devices of FIGS. 2 and 3 as a function of time; 
     FIG. 5 illustrates a delivery device which includes a slit orifice and a conical recess according to another embodiment of the invention; 
     FIG. 6 is a graph which shows the release rate of the delivery device of FIG. 5 as a function of time; 
     FIG. 7 illustrates a delivery device which includes a slit orifice and a rigid inner cylindrical member according to another embodiment of the invention; 
     FIG. 8 illustrates a delivery device which includes a plurality of slit orifices according to another embodiment of the present invention; and 
     FIG. 9 is a graph illustrating a comparison of the release rates of two osmotic delivery devices having an orifice according to one embodiment of the present invention with the release rates of two osmotic delivery devices having a spiral flow moderator. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Definitions 
     The term “beneficial agent” includes any physiologically or pharmacologically active substance or substances optionally in combination with pharmaceutically acceptable carriers and optionally additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc. 
     The term “impermeable” refers to a material that is sufficiently impermeable to environmental fluids as well as ingredients contained within the dispensing device such that the migration of such materials into or out of the device through the impermeable material is so low as to have substantially no adverse impact on the function of the device. 
     The term “semipermeable” refers to a material that is permeable to external fluids but substantially impermeable to other ingredients contained within the dispensing device and the environment of use. 
     Water-attracting agents which are used to drive the osmotic flow of an osmotic delivery device are referred to herein as “osmotic agents.” 
     FIG. 2 illustrates an example of an osmotic delivery device  10  according to an exemplary embodiment of the present invention. The osmotic delivery device  10  generally includes a first chamber  20 , a piston  30 , and a second chamber or reservoir  40 , all of which may be enclosed within an elongated substantially cylindrical capsule  15 . The elongated capsule  15  is formed of a material such as titanium which is sufficiently rigid to withstand expansion of an osmotic agent without changing size or shape. The elongated capsule  15  is impermeable to fluids and gases in the environment and to the ingredients contained therein. 
     The first chamber  20  contains an osmotic agent  25  which attracts water and which may be in the form of a tablet. The osmotic agent  25  may be, for example, a non-volatile water soluble osmagent, an osmopolymer which swells upon contact with water, or a mixture of the two. The second chamber  40  contains a beneficial agent, such as a drug, to be delivered. The second chamber  40  is separated from the first chamber  20  by a movable piston  30 . The movable piston  30  is a substantially cylindrical member which is configured to fit within the capsule  15  in a sealed manner and to slide along a longitudinal axis within the capsule. The piston  30  preferably is formed of an impermeable resilient material which forms a seal with the walls of the capsule  15 . 
     The drug delivery device  10  at its inlet end  12  includes a membrane  60  which forms at least a portion of a wall of the first chamber  20 . The membrane  60  is formed of a semipermeable material which allows fluid to pass from an exterior fluid environment into the first chamber  20  by osmosis to cause the osmotic agent to swell. The membrane  60  may be in the form of a semipermeable plug which is inserted in an open end  12  of the capsule  15  as shown in FIG.  2 . The membrane  60  is impermeable to the materials within the first chamber  20  so that they do not flow out of the capsule  15  through the membrane  60 . 
     Materials from which the membrane  60  can be made are those that are semipermeable and that can conform to the shape of the capsule  15  upon wetting and adhere to the rigid surface of the capsule  15 . The membrane  60  expands as it hydrates so that a seal is generated between the surface of the membrane  60  and the capsule  15 . The materials from which the membrane  60  is made vary based on desired pumping rates and device configuration requirements and include, but are not limited to, plasticized cellulosic materials, enhanced polymethylmethacrylates such as hydroxyethylmethacrylate (HEMA) and elastomeric materials such as polyurethanes and polyamides, polyether-polyamide copolymers, thermoplastic copolyesters and the like. 
     In operation, when the delivery device  10  is situated in an aqueous environment, water is drawn through the membrane  60  by osmosis into the first chamber  20  containing the osmotic agent. The osmotic agent swells, creating an osmotic pressure in the first chamber  20  which is applied to the second chamber  40  via the piston  30 . The piston slides away from the membrane  60  forcing the beneficial agent in the second chamber  40  to be delivered through at least one orifice  50  in the second chamber. The osmotic pump provides a relatively constant rate of water intake which can be used to reliably deliver a desired quantity of the beneficial agent over time. 
     The orifice  50 , according to one embodiment of the invention, is formed in a plug  52  of an elastic or semi-elastic material such as silicone, rubber, santoprene, polyurethane, or an elastomeric thermoplastic polymer such as C-FLEX. The plug  52  is retained in an outlet end  14  of the capsule  15 . The orifice  50  comprises a slit  54  made through the elastic or semi-elastic plug  52  which may be fluidly connected to a flow moderator  56  disposed in the plug  52 . The slit  54  and flow moderator  56  fluidly connect the interior of the second chamber  40  to the external fluid environment. 
     As shown in FIG. 2, the plug  52  may have two sections. The first section  57  has an outer diameter which is small enough to allow the plug  52  to be inserted into the outlet end  14  of the capsule  15 . The flow moderator  56  is disposed in the first section  57 . The second section  53  contains at least a portion of the slit  54  and extends beyond the outlet end  14  of the capsule  15 . 
     The orifice  50  operates as a valve which opens under the pressure of the beneficial agent. The slit  54  of the orifice  50  may be under slight compression, for example from compressive forces which form a seal between the outside of the plug  52  and the inside of the reservoir  15 , so that in the absence of flow, the slit  54  forms a closed valve which prevents fluid flow in either direction. Alternatively, the materials used and plug dimensions may be selected so that the slit seals or closes without the need for external compression. The slit  54  is preferably formed in the second section  53  of the plug  52  which extends beyond the capsule  15  so that the walls of the capsule  15  do not exert a significant closing force on the slit  54 . 
     In the presence of flow, the beneficial agent pushes through the slit  54 , opening up a channel for delivery of the beneficial agent. In the absence of flow, the slit  54  remains closed. When the slit is closed, back diffusion of external fluids is eliminated, which prevents contamination of the beneficial agent in the second chamber  40  by external fluids. In addition, forward diffusion of the beneficial agent out of the capsule  15  is prevented. In continuous flow osmotic delivery systems, the slit  54  will generally remain open throughout delivery of the beneficial agent. However, pulsatile and bolus type delivery systems will generally cause the slit  54  to close during non-delivery periods. 
     When the osmotic pressure is high enough to open the slit  54  in the orifice  50 , the slit  54  provides a flow channel of variable dimensions. The plug  52  in which the slit  54  resides preferably comprises an elastic or semi-elastic material. The osmotic pressure is great enough to overcome the elasticity of the plug  52  and force open the slit  54 . However, because the plug  52  is elastic, the flow channel which is formed is preferably just large enough to allow passage of the beneficial agent therethrough. The flow channel through the slit  54  may assume a range of sizes based on the osmotic pumping rate and the viscosity of the beneficial agent, for example. 
     The slit  54  generally opens to the smallest required diameter or opening to allow for flow of beneficial agent through it. This is much smaller than could be achieved with a rigid channel due to machining and tolerance limitations and/or particulate clogging of such a small rigid channel. 
     As will be appreciated by those skilled in the art, the dimensions and composition of the plug  52  and the slit  54  can be adjusted so that the slit  54  forms an orifice of a desired size when used with a particular beneficial agent and osmotic pump. For example, as the length of the slit  54  increases, the size of the orifice created by the slit  54  can increase. Also, as the thickness of the plug  52  along a longitudinal direction of the capsule  15  increases, the plug  52  becomes more resistant to forming an orifice from the slit  54 . The composition of the plug  52  also affects the tendency of the slit  54  to open into an orifice. A more elastic material will more easily form an orifice, or may form a wider orifice, than a more rigid material. By varying these properties of the plug  52  and slit  54 , the orifice can be configured to open to a desired degree given the parameters of the delivery device, e.g., the viscosity of the beneficial agent, the flow rate of the osmotic pump, and the pressure of the osmotic pump. By varying the parameters listed above, one can achieve an orifice that “opens” at a predetermined internal pressure, e.g. 30 lbf/in 2 . 
     The ability to vary the size of the orifice  50  has the advantage that the cross sectional area of the orifice  50  can be made small under the operating conditions of the delivery device, which reduces diffusion of the beneficial agent out of the delivery device, as shown in FIG. 1, and reduces back diffusion of external fluids into the delivery device. Generally, the system is designed so that the slit  54  is forced open to the smallest possible degree to let the formulation seep through its opening. 
     In addition, the requirement in prior delivery devices of a fixed dimension orifice of sufficient size to permit passage of micro-aggregates is eliminated because the slit  54  allows a flow path to open around an obstruction in the orifice  50 . In the event that a suspended particle becomes lodged in the orifice  50 , a new flow path is created around the obstacle, thereby preventing clogging. In operation, the active flow channel may be significantly smaller than is required in a fixed diameter orifice channel to prevent clogging. 
     Another advantage of the orifice  50  shown in FIG. 2 is that the orifice is very compact and easily fits inside the delivery device  10 , as compared with a conventional flow moderator which may be from 2 to 7 cm long, for example. The small size of the orifice  50  is advantageous when the delivery device  10  is implanted subcutaneously. 
     The flow moderator  56  may comprise a tube formed of a rigid or semi-rigid material such as Teflon, HDPE, LDPE, or a metal, for example. The flow moderator  56  forms a semi-rigid opening and allows compressive pressure to be used to form a seal between the outside of the plug  52  and the inside of the reservoir  15  without compressing the slit  54  shut. Thus, as illustrated in FIG. 2, the slit  54  may be located in the uncompressed second section  53  of the plug  52  such that the slit is not subject to the compression forces which form the seal between the plug  52  and the capsule  15 . Likewise, the slit  54  may extend into the first section  57  such that the slit is subject to these compressive forces. 
     Hence, the flow moderator  56  functions to improve the seal between the plug  52  and the capsule  15 . As shown in FIG. 2, the plug  52  may have several sealing ridges  62  which each form a seal between the plug  52  and the capsule  15  to effectively isolate the beneficial agent in the second chamber  40  from the external fluid environment. Because the flow moderator  56  may be formed of a rigid material, it may exert an outward radial force on the plug  52 , which is preferably less rigid than the flow moderator  56 . This outward radial force increases the pressure exerted by the sealing ridges  62  against the inside of the capsule  15 , which improves the seal between the plug  52  and the capsule  15 . In addition, the outward radial force increases the resistance of the plug  52  to being pushed out of the capsule  15  by the osmotic pressure generated by the osmotic pump. In other embodiments of the present invention, the outward radial forces may also regulate the flow of the beneficial agent and prevent back diffusion of external fluids into the capsule  15 . 
     According to one exemplary embodiment of the present invention, the slit  54  illustrated in FIG. 2 is formed by inserting a hypodermic needle, pin, or blade through the first and second sections  57 ,  53  of the plug  52 . For example, a hypodermic needle having a predetermined diameter is inserted through the body of the orifice  20  along the center axis of the orifice (parallel with the longitudinal axis of the capsule  15 ). Thereafter, the needle is removed from the orifice  50 . After the slit  54  has been formed in the orifice  50 , the flow moderator  56  is inserted into the first section  57  of the plug  52 . Depending upon the material of the plug  52 , and the dimensions of the slit  54  and flow moderator  56 , it may be necessary to drill, carve, punch, or mold a cylindrical recess in the first section  57  to receive the flow moderator. In any case, the flow moderator  56  is preferably positioned within the first section  57 , and secured to the first section  57  via an interference fit, although adhesives, threads and other means may be used to secure the flow moderator to the first section of the plug  52 . An end of the flow moderator  56  may protrude from the first section  57 , may be located within the first section, or may be inserted in the first section such that it is flush with the first section. 
     The slit  54  may also be formed after the flow moderator  56  has been inserted into the first section  57  of the plug  52 . According to this method, the flow moderator  56  is first inserted into the first section  57  of the plug  52 . Thereafter, a needle or device for forming the slit  54  is inserted completely through the cylindrical channel of the tubular flow moderator  56  and through the second section  53  of the plug  52  to form the slit. 
     For example, an orifice  50 , such as that illustrated in FIG. 2, may be formed by first inserting a 1.5 mm long portion of a 21 gauge (diameter of approximately 0.8 mm) hypodermic needle into the first section  57  of a plug  52  of styrene ethylene butadiene styrene block copolymer (C-FLEX LS 55A, commercially available from CONSOLIDATED POLYMER TECHNOLOGIES). The 1.5 mm long portion of the 21 gauge hypodermic needle is preferably at least half the length of the final slit  54  to be formed. The following dimensions of the plug  52  and capsule  15  are also preferred for this example: (1) the C-FLEX plug  52  is approximately 3.85 mm long (measured on an axis parallel with the longitudinal axis of the capsule into which the orifice  50  is to be inserted), although only 3.13 mm of the plug is inserted into the capsule  15  after the orifice  50  has been fabricated; (2) the plug  52  includes four equally spaced sealing ridges  62 , each having an outer diameter of approximately 3.24 mm and each approximately 0.26 mm thick (measured on an axis parallel with the longitudinal axis of the capsule into which the orifice  50  is to be inserted); (3) the diameter of the cylindrical body of the plug  52  at the base of the sealing ridges  62  is approximately 2.98 mm; and (4) the inner diameter of the capsule  15  that receives the plug  52  is approximately 3.0 mm. 
     After the 1.5 mm long portion of the 21 gauge hypodermic needle has been inserted into the first section  57  of the plug  52 , a second hypodermic needle having a smaller diameter than the portion of the 21 gauge hypodermic needle is inserted into the portion of the 21 gauge hypodermic needle and completely through the first and second sections  57 ,  53  of the plug  52 . This step forms the slit  54 , and also removes any plug material inside the portion of the 21 gauge hypodermic needle to form the flow moderator  56 . If the second hypodermic needle is sized to tightly fit through the 21 gauge flow moderator  56 , the resulting slit  54  will be approximately 0.4 mm wide as measured perpendicular to the center axis of the orifice  50 . An orifice  50  having the above dimensions is intended to be particularly useful for delivering high viscosity formulations of beneficial agents, such as 3% sodium carboxymethyl cellulose in water. 
     FIG. 9 is a graph of the release rate of beneficial agent over time and compares two osmotic delivery systems having a spiral flow moderator with two osmotic delivery systems or devices  10  having an orifice  50  according to embodiments of the present invention, such as that illustrated in FIG.  2 . The osmotic delivery devices  10  tested in FIG. 9 included the capsule  15  and orifice  50  dimensioned and described above having the C-FLEX LS 55A plug  52  with the 0.4 mm slit  54  and the 21 gauge flow moderator  56 . 
     As illustrated in FIG. 9, the two osmotic delivery systems having a spiral flow moderator and the two osmotic delivery systems  10  having the orifice  50  according to embodiments of the present invention were tested. The respective systems were configured to deliver a beneficial agent, in this case water with blue dye, over a one month and one year time period. 
     The osmotic delivery system  10  according to the present invention that was configured to deliver the beneficial agent over a one year time period delivered approximately 0.4 uL/day of the beneficial agent. Comparatively, the osmotic delivery system incorporating the spiral flow modulator and configured to deliver the beneficial agent over a one year time period also delivered approximately 0.4 uL/day of the beneficial agent. Thus, FIG. 9 illustrates that the osmotic delivery system  10  incorporating the orifice  50  and configured to deliver the beneficial agent over a one year time period performed as well as the osmotic delivery system incorporating the spiral flow modulator. 
     The osmotic delivery system  10  according to the present invention that was configured to deliver the beneficial agent over a one month time period delivered roughly 1.3 uL/day of the beneficial agent. Comparatively, the osmotic delivery system incorporating the spiral flow modulator and configured to deliver the beneficial agent over a one month time period also delivered roughly 1.3 uL/day of the beneficial agent. Thus, FIG. 9 illustrates that the osmotic delivery system  10  incorporating the orifice  50  and configured to deliver the beneficial agent over a one month time period performed as well as the osmotic delivery system incorporating the spiral flow modulator. In sum, the results depicted in FIG. 9 illustrate that the tested orifices  50  were as effective as the spiral flow moderators in delivering a beneficial agent at different release rates. 
     FIG. 3 illustrates another embodiment of the invention in which a catheter  156  is provided in fluid communication between the slit  154  and the capsule  115 . As shown in FIG. 3, the delivery device  110  includes a membrane  160  which may be in the form of a diffusion plug, a first chamber  120  which contains an osmotic agent  125 , a second chamber  140  which contains a beneficial agent, and a moveable piston  130  which separates the first chamber  120  from the second chamber  140 . The osmotic pump, including the first and second chambers, piston, and membrane, functions in the same manner as the pump of FIG.  2 . 
     As shown in FIG. 3, the delivery device  110  includes a plug  142  having a catheter  156  fixed therein. The plug  142  fits in the outlet end  114  of the capsule  115  and may include a plurality of ridges  162  to seal the plug  142  to the capsule  115 . The plug  142  may have a first portion  147  which fits inside the walls of the capsule  115  and a second portion  143  which extends beyond the outlet end  114  of the capsule  115 . The plug  142  may be formed of an elastic or semi-elastic material such as silicone, rubber, santoprene, polyurethane, etc. 
     The catheter  156  is disposed in the plug  142  and is in fluid communication with the beneficial agent in the second chamber  140 . The catheter  156  is preferably formed of a rigid or semi-rigid material such as Teflon, HDPE, LDPE, or a metal so that it exerts a radially outward force on the plug  142  to increase the pressure of the ridges  162  on the inside wall of the capsule  115 . The increased pressure improves the seal between the plug  142  and the capsule  115  and increases the resistance of the plug  142  to being forced out of the capsule  115  by the osmotic pressure generated by the osmotic pump. 
     The catheter  156  is also in fluid communication with a slit  154  formed in a flexible member  152 . The flexible member  152  preferably comprises an elastic or semi-elastic material such as silicone, rubber, santoprene, polyurethane, etc. The flexible member  152  may have two sections, a first section  157  in which the end of the catheter  156  is disposed, and a second section  153  in which the slit  154  is located. The slit  154  functions in much the same manner as the slit  54  of FIG.  2 . However, the slit  154  is not subject to compressive forces created by the seal between the plug  142  and the capsule  115 . 
     The slit  154  is designed such that in the absence of flow, the slit  154  forms a closed valve which prevents fluid flow in either direction. In the presence of flow, the beneficial agent pushes through the slit  154 , opening up a channel for delivery of the beneficial agent. The dimensions and composition of the flexible member  152  and slit  154  can be chosen so that the slit  154  forms an orifice of a desired size under the operating parameters of the delivery device, e.g., the viscosity of the beneficial agent, the flow rate of the osmotic pump, and the pressure of the osmotic pump. 
     Because the flexible member  152  is elastic, the flow channel which is formed is preferably just large enough to allow passage of the beneficial agent therethrough. The variability of the size of the orifice has the advantage that the cross sectional area of the orifice is small (e.g., significantly smaller than a flow moderator of fixed diameter), which reduces diffusion of the beneficial agent out of the delivery device, as shown in FIG. 1, and reduces diffusion of external fluids into the delivery device. The slit  154  also allows a flow path to open around an obstruction in the slit  154 . 
     The catheter  156  may have dimensions such that it performs as a flow moderator, if desired, to further reduce diffusion of the beneficial agent out the slit  154  and back diffusion of external fluids into the second chamber  140 . 
     The catheter  156  is also useful when the desired point of delivery of the beneficial agent is difficult to access. For example, it may be advantageous therapeutically to deliver the beneficial agent at a location which cannot accommodate or tolerate the capsule  115 . In this situation, the capsule  115  may be implanted in a more acceptable location while the catheter  156  transports the beneficial agent to the slit  154  at the delivery site. This embodiment may also be utilized to make the capsule  115  more accessible to a treating physician rather than being implanted at a location which requires an invasive procedure. For example, the capsule  115  may be implanted close to the surface of the skin while the catheter  156  delivers the beneficial agent to a more remote location. 
     The improved performance of the exemplary delivery devices of FIGS. 2 and 3 is shown in FIG.  4 . FIG. 4 is a graph of the release rate in microliters per day over time of the delivery devices of FIGS. 2 and 3. FIG. 4 also shows the release rate of a delivery device having a tubular flow moderator orifice in the shape of a spiral. The data used in FIG. 4 were obtained by placing each delivery device in a release rate bath. The delivery devices were filled with a 1% solution of blue dye in deionized water. At fixed points in time, the concentration of blue dye in the release rate bath was measured. The experiment was conducted five times, and the error bars shown in FIG. 4 represent the standard deviation of the measurements. 
     The procedure and materials used in obtaining the data shown in FIG. 4 are as follows: 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Granulation Tablet Compression: 
                   
               
               
                 TOWLING: 
                 0.117″ flat face 
               
               
                 GRANULATION: 
                 80.0% NaCl, 5.0% NaCMC 7H4F, 
               
               
                   
                 14.25% Povidone, 0.75% 
               
               
                   
                 Magnesium Stearate. 
               
               
                 TABLET WEIGHT: 
                 0.0841 g. 
               
               
                 TABLET HEIGHT: 
                 0.247 in. 
               
               
                 COMPRESSION: 
                 500 lb. 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                   
                 Tablet Height 
               
               
                 Tablet No. 
                 Tablet Weight (g) 
                 (in) 
               
               
                   
               
               
                 1 
                 0.0955 
                 0.309 
               
               
                 2 
                 0.0877 
                 0.284 
               
               
                 3 
                 0.0848 
                 0.273 
               
               
                 4 
                 0.0914 
                 0.294 
               
               
                 5 
                 0.0825 
                 0.265 
               
               
                 Average 
                 0.0884 
                 0.385 
               
               
                   
               
            
           
           
               
            
               
                 PROCEDURE: 
               
            
           
           
               
               
            
               
                 1. 
                 Lubricate large flanched piston with medical fluid 100cs CODE 
               
               
                   
                 80036 CONTROL 258887 
               
               
                 2. 
                 Prime capsule (membrane end). 
               
               
                 3. 
                 Insert large flanched piston into Hoechst Celanese capsule using 
               
               
                   
                 the piston inserted. 
               
               
                 4. 
                 Push piston up &amp; down using a rod. 
               
               
                 5. 
                 Insert osmotic engine tablet into capsule from the membrane 
               
               
                   
                 end and push engine tablet down. 
               
               
                 6. 
                 Insert half way the membrane plug. 
               
               
                 7. 
                 Add two drops of glue in each side of membrane plug. 
               
               
                 8. 
                 Press all the way down membrane plug and wipe glue residue 
               
               
                   
                 with a paper towel. 
               
               
                 9. 
                 Add beneficial agent into capsule almost all the way to the top. 
               
               
                 10. 
                 Insert orifice. 
               
               
                 11. 
                 Insert orifice half way and add two drops of glue in each side of 
               
               
                   
                 orifice plug (all orifices were glued except systems 26-30). 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                 COMPONENTS: 
                   
               
               
                   
                 Formulation #1: 
                 1% blue dye in deionized water 
               
               
                   
                 Membrane: 
                 Fast “K” 100% hytrel 8171 
               
               
                   
                 Engine Tablet: 
                 80.0% NaCl, 5.0% NaCMC 7H4F, 14.25% 
               
               
                   
                   
                 Povidone, 0.75% Magnesium Stearate. 
               
               
                   
                 Piston: 
                 Large santoprene flanched 
               
               
                   
                 Orifice: 
                 1-5 screw spiral 
               
               
                   
                 Orifice: 
                 11-15 external flow moderator (Figure 3) 
               
               
                   
                 Orifice: 
                 21-25 internal 1 mm duckbill (Figure 2) 
               
               
                   
                   
               
            
           
         
       
     
     As shown in FIG. 4, the release rate of the delivery devices of FIGS. 2 and 3 having the slit orifices is significantly more constant than the release rate of the delivery device having a spiral shaped flow moderator. This characteristic is of course very important when the delivery device is used to supply drugs to humans over an extended period of time. The slit orifice may be used to alter the start-up beneficial agent delivery profile by changing the pressure at which the orifice opens and/or decreasing the initial diffusive burst from the flow modulator. 
     In assembling the delivery device of the present invention, the beneficial agent may also be added with the capsule after the orifice has been inserted into the capsule. In such an assembly, a needle is inserted through the orifice and into the capsule such that beneficial agent is delivered into the capsule via the needle. This technique is advantageous because the slit orifice allows air to escape the capsule as the beneficial agent fills the capsule. Thus, after the delivery device is inserted into the environment of use, the osmotic agent need not compress any air bubbles in the beneficial agent which would ordinarily delay start-up of beneficial agent delivery. 
     FIG. 5 illustrates another embodiment of the invention which includes a mechanism for varying the pressure required to open the orifice. As shown in FIG.  5 , the orifice  250  is located at the outlet end  214  of a capsule  215 . The delivery device  210  also includes a membrane  260 , a first chamber  220  containing an osmotic agent, a second chamber  240  containing a beneficial agent, and a moveable piston  230  separating the first chamber  220  from the second chamber  240 . The membrane  260 , osmotic agent, piston  230 , and second chamber  240  form an osmotic pump which functions as described above with respect to FIGS. 2 and 3. 
     The orifice  250 , according to an exemplary embodiment, comprises three sections. A first portion  257  is located between the slit  254  and the second chamber  240  and is in fluid communication with both. A second portion  253  contains the slit  254 . A third portion  259  occupies the annular space between the first and second portions and the inner wall of the capsule  215 . 
     The slit  254  is housed in the second portion  253 . The second portion is generally cylindrical in shape and preferably is formed of an elastic or semi-elastic material such as silicone, rubber, santoprene, polyurethane, etc. The elasticity of the second portion  253  allows the slit  254  to open under pressure from the beneficial agent. 
     Upstream of the slit  254  and second portion  253  is the first portion  257 . The first portion  257  is also generally cylindrical in shape and has an inner recess  252 . The outer radius of the first portion  257  may be greater than the outer radius of the second portion  253  so that a shoulder  251  is formed to secure the first and second portions in the delivery device  210 . The first and second portions may be integrally formed as a single piece of material. 
     According to a preferred embodiment, the inner recess  252  of the first portion  257  has at least one wall  258  which is at an acute angle to the direction of flow  255  of the beneficial agent. Preferably, the inner recess  252  is in the shape of a cone so that its entire wall  258  is at an acute angle with respect to the direction of flow  255  of the beneficial agent. As the beneficial agent is forced into the inner recess  252 , the beneficial agent exerts a force on the wall  258  of the inner recess  252  which has a radial component. The radial force operates to open the slit  254  in the second portion  253  of the orifice. Because the first and second portions are formed of an elastic or semi-elastic material, the force of the beneficial agent opens the slit  254  just wide enough to deliver the beneficial agent with very little if any forward diffusion of the beneficial agent or backward diffusion of external fluids into the second chamber  240 . 
     The shape and composition of the first and second portions  257  and  253  and of the slit  254  may be adapted to accommodate beneficial agents of different viscosities or to adjust the pressure required to open the slit  254 . For example, a beneficial agent with a relatively low viscosity will more easily flow through a smaller opening of the slit  254  than a beneficial agent with a higher viscosity. To equalize this discrepancy, the angle between the wall  258  and the direction of flow  255  can be adjusted for the viscous beneficial agent so that the slit is more easily opened. The angle between the wall  258  and the direction of flow  255  can also be adjusted to vary the pressure at which the slit will open and close for a beneficial agent of a given viscosity. In addition the dimensions and composition of the second portion  253  can be adjusted so that the slit  254  forms an orifice of a desired size under the operating parameters of the delivery device, e.g., the viscosity of the beneficial agent, the flow rate of the osmotic pump, and the pressure of the osmotic pump. 
     The third portion  259  occupies the annular space between the first and second portions and the inner wall of the capsule  215 . The third portion  259  may have grooves  272  which mate with corresponding ridges  274  projecting from the inner wall of the capsule  215 . The grooves  272  and ridges  274  may be circular or they may be in the form of screw threads such that the third portion  259  may be screwed into the outlet end of the capsule  215 . The ridges and grooves are provided to secure the third portion  259  in the end of the capsule  215  in spite of the osmotic pressure generated by the osmotic pump. 
     The third portion  259  also includes an inwardly extending flange  276  which contacts the shoulder  251  formed between the first and second portions  257  and  253 . The flange  276  contacts the shoulder  251  to retain the first and second portions in the capsule  215 . The flange  276  may also function to apply a slight radial inward pressure on the second portion  253  so that the slit  254  remains closed in the absence of flow. 
     The orifice  250  provides the advantage that the flow channel may be significantly smaller than is required in a fixed diameter orifice, since the flow channel opens just large enough to deliver the beneficial agent. In addition, in the event that a suspended particle becomes lodged in the orifice  250 , a new flow path is created around the obstacle. The orifice  250  is also very compact, as illustrated in FIG.  5 . 
     The improved performance of the exemplary delivery device of FIG. 5 is shown in FIG.  6 . FIG. 6 is a graph of the release rate in microliters per day over time of the delivery device of FIG.  5 . FIG. 6 also shows the release rate of a delivery device having a flow moderator orifice in the shape of a spiral. The data used in FIG. 6 were obtained by placing each delivery device in a release rate bath. The delivery devices were filled with a 1% solution of blue dye in deionized water. At fixed points in time, measurements were taken of the concentration of blue dye in the release rate bath. 
     As shown in FIG. 6, the release rate of the delivery devices of FIG. 5 having the slit orifice is significantly more constant than the release rate of the delivery device having a spiral shaped flow moderator. 
     FIG. 7 illustrates another embodiment of an orifice which includes an inner recess  352  and an inner cylindrical member  359 . As shown in FIG. 7, the orifice  350  is located at the outlet end  314  of the capsule  315 . The delivery device  310  also includes a membrane  360 , a first chamber  320  containing an osmotic agent, a second chamber  340  containing a beneficial agent, and a moveable piston  330  separating the first chamber  320  from the second chamber  340 . The membrane  360 , osmotic agent, piston  330 , and second chamber  340  form an osmotic pump which functions as described above with respect to FIGS. 2 and 3. 
     The orifice  350 , according to an exemplary embodiment, comprises three components. A first portion  357  is located between the slit  354  and the second chamber  340  and is in fluid communication with both. A second portion  353  contains the slit  354 . A third portion  359  resides in the annular space between the first and second portions and the inner wall of the capsule  315 . 
     The slit  354  is housed in the second portion  353 . The second portion is generally cylindrical in shape and preferably is formed of an elastic or semi-elastic material such as silicone, rubber, santoprene, polyurethane or an elastomeric thermoplastic polymer such as C-FLEX. The elasticity of the second portion  353  allows the slit  354  to open under pressure from the beneficial agent. 
     Upstream of the slit  354  and second portion  353  is the first portion  357 . The first portion  357  is also generally cylindrical in shape and has an inner recess  352 . The outer radius of the first portion  357  may be greater than the outer radius of the second portion  353  so that a shoulder  351  is formed to secure the first and second portions in the delivery device  310 . The first and second portions may be integrally formed as a single piece of material. 
     According to a preferred embodiment, the inner recess  352  of the first portion  357  has at least one wall  358  which is at an acute angle to the direction of flow  355  of the beneficial agent. Preferably, the inner recess  352  is in the shape of a cone so that its entire wall  358  is at an acute angle with respect to the direction of flow  355  of the beneficial agent. As the beneficial agent is forced into the inner recess  352 , the beneficial agent exerts a force on the wall  358  of the inner recess  352  which has a radial component. The radial force operates to open the slit  354  in the second portion  353  of the orifice. Because the first and second portions are formed of an elastic or semi-elastic material, the force of the beneficial agent opens the slit  354  just wide enough to deliver the beneficial agent with little if any forward diffusion of the beneficial agent or backward diffusion of external fluids into the second chamber  340 . The shape of the inner recess  352  (e.g., the angle of the wall  358 ) may be adapted to accommodate beneficial agents of different viscosities or to adjust the pressure required to open the slit  354 . In addition, the dimensions and composition of the second portion  353  can be chosen so that the slit  354  forms an orifice of a desired size under the operating parameters of the delivery device, e.g., the viscosity of the beneficial agent, the flow rate of the osmotic pump, and the pressure of the osmotic pump. 
     The third portion  359  resides in the annular space between the first and second portions and the inner wall of the capsule  315 . The third portion  359  is preferably formed of a rigid material such as titanium. The third portion may be generally in the form of an inner cylindrical member or “cup” with a hole  380  in its bottom. The third portion  359  is preferably formed to have an outer diameter which is small enough that the third portion  359  may be pressed into the outlet end  314  of the capsule  315 . The outer diameter of the third portion  359  is preferably large enough, however, that the third portion  359  is frictionally retained in the outlet end  314  of the capsule  315  in the presence of the osmotic pressure generated by the osmotic pump. When properly dimensioned, the frictional force between the third portion  359  and the capsule  315  is sufficient to permanently retain the third portion  359  in the capsule  315 . 
     The third portion  359  also includes an inwardly extending flange  376  which contacts the shoulder  351  formed between the first and second portions  357  and  353 . The flange  376  contacts the shoulder  351  to retain the first and second portions in the capsule  315 . The flange  376  preferably does not extend all the way inward to the second portion  353  so that a gap  390  exists between the second portion containing the slit  354  and the flange  376 . The gap  390  is provided so that the flange  376  does not exert any pressure on the slit  354 . 
     The orifice  350  provides the advantages that the flow channel which opens under pressure from the beneficial agent may be significantly smaller than is required in a fixed diameter orifice, since the flow channel opens just large enough to deliver the beneficial agent. In addition, in the event that a suspended particle becomes lodged in the orifice  350 , a new flow path is created around the obstacle. The rigid third portion  359  is also very effective in maintaining the orifice  350  in the capsule against the osmotic pressure. The orifice is also very compact, which is advantageous for subcutaneous implantation. 
     FIG. 8 illustrates another embodiment of an orifice  450  which includes a plurality of slit orifices  454 . As shown in FIG. 8, the orifice  450  is located at the outlet end of the capsule  415 . The delivery device  400  also includes a membrane  460 , a first chamber  420  containing an osmotic agent, a second chamber  440  containing a beneficial agent, and a movable piston  430  separating the first chamber  420  from the second chamber  440 . The membrane  460 , osmotic agent, piston  430 , and second chamber  440  form an osmotic pump which functions as described above with respect to FIGS. 2 and 3. 
     The orifice  450 , according to an exemplary embodiment, includes a plurality of slit orifices similar to those described above in reference to FIGS. 2,  5 , and  7 . As shown in FIG. 8, an inner cylindrical member  459  is positioned in the end of the capsule  415  opposite the membrane  460 . In this embodiment, a flexible member  456 , which contains the plurality of slit orifices  454  and inner recesses  452 , has been prepositioned in the inner cylindrical member  459 . Similar to the embodiment depicted in FIG. 5, the inner cylindrical member  459  may be made of a material which helps maintain the seal between the capsule  415  and the orifice  450 . For example, the inner cylindrical member  459  may be made of less resilient material than the flexible member  456  which contains the plurality of slits  454 . In another embodiment of the present invention not depicted, the inner cylindrical member  459  is not included, and the flexible member  456  is adapted and configured to form a seal with the capsule  415 . 
     As illustrated in FIG. 8, the orifice  450  includes a plurality of slit orifices  454  and inner recesses  452 , which are particularly useful for delivering beneficial agents having suspensions of bioactive macromolecules such as proteins and genes. Known delivery orifices may cause such suspension formation to separate as the formulation is moved into a small chamber such as a helical orifice prior to being released into the environment of use. The embodiment of the present invention which incorporates a plurality of slit orifices  454  allows such suspension formulations to travel relatively unrestricted, minimizing the amount of separation before it exits the delivery device  400 . In this regard, the plurality of slit orifices  454  in combination with the plurality of inner recesses  452  allows for a nearly constant front of beneficial agent, such as suspensions containing bioactive macromolecules, to be released from the delivery device  400 , while also minimizing back diffusion of external fluids into the delivery device. Furthermore, the embodiment of the present invention illustrated in FIG. 8 also provides the many advantages described above in reference to FIGS. 1-7. 
     In the event that one or some of the slit orifices  454  becomes clogged with macromolecules or particles, the other non-clogged slit orifices of the delivery device  400  will continue to release the beneficial agent. Thus, the plurality of slits  454  and recesses  452  acts as a safety, ensuring that beneficial agent delivery continues. 
     Materials which may be used for the capsule should be sufficiently strong to ensure that the capsule will not leak, crack, break, or distort under stresses to which they would be subjected during implantation or under stresses due to the pressures generated during operation. The capsule may be formed of chemically inert and biocompatible, natural or synthetic materials which are known in the art. The material of the capsule is preferably a non-bioerodible material which remains in the patient after use, such as titanium. However, the material of the capsule may alternatively be of bioerodible material which bioerodes in the environment after dispensing of the beneficial agent. Generally, preferred materials for the capsule are those acceptable for human implants. 
     In general, typical materials of construction suitable for the capsule according to the present invention include non-reactive polymers or biocompatible metals or alloys. The polymers include acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer, and the like; halogenated polymers such as polytetrafluoroethylene, polychlorotrifluoroethylene, copolymer of tetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and the like. Metallic materials useful for the capsule include stainless steel, titanium, platinum, tantalum, gold, and their alloys, as well as gold-plated ferrous alloys, platinum-plated ferrous alloys, cobalt-chromium alloys and titanium nitride coated stainless steel. 
     In general, materials suitable for use in the piston are elastomeric materials including the non-reactive polymers listed above, as well as elastomers in general, such as polyurethanes and polyamides, chlorinated rubbers, styrene-butadiene rubbers, and chloroprene rubbers. 
     The osmotic tablet is an osmotic agent which is a fluid-attracting agent used to drive the flow of the beneficial agent. The osmotic agent may be an osmagent, an osmopolymer, or a mixture of the two. Species which fall within the category of osmagent, i.e., the non-volatile species which are soluble in water and create the osmotic gradient driving the osmotic inflow of water, vary widely. Examples are well known in the art and include magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various monosaccharides, oligosaccharides and polysaccharides such as sucrose, glucose, lactose, fructose, and dextran, as well as mixtures of any of these various species. 
     Species which fall within the category of osmopolymer are hydrophilic polymers that swell upon contact with water, and these vary widely as well. Osmopolymers may be of plant or animal origin, or synthetic, and examples of osmopolymers are well known in the art. Examples include: poly(hydroxy-allyl methacrylates) with molecular weight of 30,000 to 5,000,000, poly(vinylpyrrolidone) with molecular weight of 10,000 to 360,000, anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) having low acetate residual, optionally cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of 200 to 30,000, a mixture of methyl cellulose, cross-linked agar and carboxymethylcellulose, a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose, polymers of N-vinyllactams, polyoxyethylene-polyoxypropylene gels, polyoxybutylene-polyethylene block copolymer gels, carob gum, polyacrylic gels, polyester gels, polyurea gels, polyether gels, polyamide gels, polypeptide gels, polyamino acid gels, polycellulosic gels, carbopol acidic carboxy polymers having molecular weights of 250,000 to 4,000,000, Cyanamer polyacrylamides, cross-linked indene-maleic anhydride polymers, Good-Rite polyacrylic acids having molecular weights of 80,000 to 200,000, Polyox polyethylene oxide polymers having molecular weights of 100,000 to 5,000,000, starch graft copolymers, and Aqua-Keeps acrylate polymer polysaccharides. 
     Delivery capsules in accordance with the present invention for the delivery of beneficial agents, may be manufactured by a variety of techniques, many of which are known in the art. 
     In one such embodiment of this invention, the beneficial agents contained in the second chamber are flowable compositions such as liquids, suspension, or slurries, and are poured into the capsule after the osmotic agent and the piston have been inserted. Alternatively, such flowable compositions may be injected with a needle through a slit in the plug, which allows for filling without air bubbles. Still further alternatives may include any of the wide variety of techniques known in the art for forming capsules used in the pharmaceutical industry. 
     Animals to whom drugs may be administered using systems of this invention include humans and other animals. The invention is of particular interest for application to humans and household, sport, and farm animals, particularly mammals. For the administration of beneficial agents to animals, the devices of the present invention may be implanted subcutaneously or intraperitoneally or at any other location in a biological environment where aqueous body fluids are available to activate the osmotic engine. 
     The devices of this invention are also useful in environments outside of physiological or aqueous environments. For example, the devices may be used in intravenous systems (attached to an IV pump or bag or to an IV bottle, for example) for delivering beneficial agents to animals, primarily to humans. They may also be utilized in blood oxygenators, kidney dialysis and electrophoresis, for example. Additionally, devices of the present invention may be used in the biotechnology area, such as to deliver nutrients or growth regulating compounds to cell cultures. 
     The present invention applies to the administration of beneficial agents in general, which include any physiologically or pharmacologically active substance. The beneficial agent may be any of the agents which are known to be delivered to the body of a human or an animal such as drug agents, medicaments, vitamins, nutrients, or the like. The beneficial agent may also be an agent which is delivered to other types of aqueous environments such as pools, tanks, reservoirs, and the like. Included among the types of agents which meet this description are biocides, sterilization agents, nutrients, vitamins, food supplements, sex sterilants, fertility inhibitors and fertility promoters. 
     Drug agents which may be delivered by the present invention include drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, ocular drugs and synthetic analogs of these species. 
     Examples of drugs which may be delivered by devices according to this invention include, but are not limited to prochlorperzine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzamphetamine hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperzine maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chloropromaide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone, capropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptyline, and imipramine. Further examples are proteins and peptides which include, but are not limited to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin, GRF, prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH, LHRH agonists and antagonists, leuprolide, interferons, interleukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as the prostaglandins, fertility promoters, growth factors, coagulation factors, human pancreas hormone releasing factor, analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or their analogs or derivatives. 
     The beneficial agent can be present in this invention in a wide variety of chemical and physical forms, such as solids, liquids and slurries. On the molecular level, the various forms may include uncharged molecules, molecular complexes, and pharmaceutically acceptable acid addition and base addition salts such as hydrochlorides, hydrobromides, sulfate, laurylate, oleate, and salicylate. For acidic compounds, salts of metals, amines or organic cations may be used. Derivatives such as esters, ethers and amides can also be used. An active agent can be used alone or mixed with other active agents. 
     According to other embodiments of the present invention, the delivery device may take different forms. For example, the piston may be replaced with a flexible member such as a diaphragm, partition, pad, flat sheet, spheroid, or rigid metal alloy, and may be made of any number of inert materials. Furthermore, the osmotic device may function without the piston, having simply an interface between the osmotic agent/fluid additive and the beneficial agent. 
     The above-described exemplary embodiments are intended to be illustrative in all respects, rather than restrictive, of the present invention. Thus the present invention is capable of many variations in detailed implementation that can be derived from the description contained herein by a person skilled in the art. All such variations and modifications are considered to be within the scope and spirit of the present invention as defined by the following claims.