MXPA99008737A - Implantable delivery device with self adjustable exit port - Google Patents

Abstract

A delivery device having a first chamber containing an osmotic agent, a membrane forming a wall of the first chamber through which fluid is imbibed by osmosis, a second chamber containing a beneficial agent to be delivered, and a moveable piston separating the two chambers. In fluid communiation with the second chamber is an orifice which comprises a slit valve. In the presence of pressure, the beneficial agent pushes through the slit, opening up a channel for deliveryof the beneficial agent and creating flow. Because the slit remains closed in the absence of flow (or when the pressure is below the pressure required to open the slit), back diffusion of external fluids is eliminated when the slit is closed, which prevents contamination of the beneficial agent in the second chamber by external fluids. In addition, forward diffusion of the beneficial agent out of the capsule is prevented when the slit is closed. The slit valve opens only to the minimum dimension required to allow the flow generated by the osmostic pumping rate. The slit valve also allows a flow path to open around any obstruction in the slit valve to prevent clogging.

Description

IMPLANTABLE SUPPLY DEVICE WITH A SELF ADJUSTABLE OUTPUT PORT BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention generally relates to an implantable delivery device, and more particularly, to an outlet port, such as a slot orifice for an implantable osmotic delivery device, which has a variable size. 2. Description of Related Art The controlled delivery of beneficial agents such as drugs in the medical and veterinary fields has been accomplished through a variety of methods. One aspect of providing 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 silastic capsules filled with levonogestrel under the skin. In this way protection against conception is achieved for up to 5 years. The implants operate through 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 material polymeric Another method for the prolonged and controlled delivery of a beneficial agent involves the use of an implantable osmotic delivery system. Osmotic delivery systems are very reliable to supply the beneficial agent for an extended period. The osmotic pressure generated by an osmotic pump also produces a rate of delivery of the beneficial agent to the body, which is relatively constant as compared to other types of delivery systems. In general, osmotic delivery systems operate by imbibing the fluid from the external environment and releasing corresponding amounts of the beneficial agent. Osmotic delivery systems, commonly referred to as "osmotic pumps", generally include some type of capsule having walls that selectively pass water into a capsule containing a water-attracting agent. The absorption of water by the water attraction agent within the capsule reservoir creates an osmotic pressure inside the capsule, which causes the beneficial agent to be delivered from the capsule. The water attractant may be the beneficial agent delivered to the patient, however, in many 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 can be separated from the beneficial agent within the capsule through a mobile splitting member or piston. The structure of the capsule is such that the capsule does not expand when the osmotic agent remains in the water. As the osmotic agent expands, it causes the mobile splitting member or piston to move, which in turn causes the beneficial agent to be discharged through an orifice at the same volumetric rate at which the water enters. in the osmotic agent, through osmosis. The orifice controls the interaction of the beneficial agent with the external fluid environment. The trade serves the important function of isolating the beneficial agent from the external fluid environment, since any contamination of the beneficial agent by external fluids can adversely affect the utility of the beneficial agent. For example, the inward flow of materials from the external fluid environment due to diffusion or osmosis may contaminate the interior of the capsule, destabilize, dilute or otherwise alter the formulation of the beneficial agent. Another important function of the orifice is to control or limit the 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 are selected so that the average linear velocity of the beneficial agent that comes out is greater than the linear inward flow of the materials in the external environment due to diffusion or osmosis, attenuating or moderating the return diffusion and its dangerous effects of contaminating the interior of the osmotic pump. In addition, the dimensions of the flow moderator can be chosen so that the diffusive flow of the beneficial agent out of the orifice is small in comparison with the convective flow. Figure 1 is a graph showing the relationship between orifice dimensions and drug diffusion as a percentage of the pumped or connective supply for a set of pumping rates and drug diffusion capacity. Figure 1 shows, for example, that the diffusion flow of the beneficial agent can be maintained at less than 10% of the convective flow using an orifice with a diameter of 127 microns and a length of at least 0.6 cm, or an orifice with a diameter of a diameter of 254 microns and a length of at least 2.4 cm. However, a problem with flow moderators is that the passage may be blocked or obstructed with particles suspended in the beneficial agent or in the fluid of the external environment. This obstruction can be reduced or eliminated by increasing the diameter of the passage to 127 microns or more, for example. However, as shown in Figure 1, this increase results in a higher rate of diffusion of the beneficial agent out of the osmotic pump. There is also a corresponding increase in the return diffusion of the external fluid to the osmotic pump, which can contaminate the agent beneficially and adversely affect the desired delivery rate of the beneficial agent. Tolerances during manufacture also often dictate that the diameter of the orifice be greater than about 27 microns. Systems with a long straight flow moderator are also impractical for implantation applications, since they significantly increase the size of the implant, making the system difficult to implant. Current flow modulators cause the separation of beneficial agents, which contain suspensions of bioactive macromolecules (proteins, genes, etc.). When said suspensions pass along a restriction in current flow modulators, the suspension is separated and the concentration of bioactive supply or macromolecule varies.

COMPENDIUM OF THE INVENTION According to one embodiment of the invention, an illustrative delivery device, such as described in US Patent Application Serial No. 08 / 595,761, the description of which is hereby incorporated by reference in its entirety, may be provided. with the slot hole of the present invention. The delivery device comprises a capsule containing a beneficial agent and an osmotic agent, a membrane that forms a portion of a wall of the capsule, the membrane allowing the fluid of a external environment that passes to the capsule through osmosis to create an osmotic pressure in the capsule, means to apply the osmotic pressure to the beneficial agent, and a flexible member having therein a slot orifice, which is in communication with fluid with the capsule. In the presence of flow, the beneficial agent pushes through the groove, opening a channel to supply the beneficial agent. Since the slot hole remains closed in the absence of flow, the return diffusion of external fluids is eliminated when the slot is closed, which prevents contamination of the beneficial agent by external fluids. Advance diffusion of the beneficial agent out of the capsule is also avoided. In addition, the slot hole allows a flow path to open around an obstruction in the slot orifice. In the event that a suspended particle is loaded in the slot hole, a new flow path is created around the obstacle, thus preventing plugging. The slot hole is also very compact and easily fits within the delivery device, which is advantageous when the delivery device is implanted subcutaneously. This combination only addresses the complex emissions presented in the extremely slow-flow, high osmolar drug delivery systems, as found, for example, in the patent application of E. U. A. Series No. 08 / 595,761. These emissions include the diffusion of the drug out of the hole, the diffusion of liquid return from the environment of use to the orifice, and orifice plugging, especially if the orifice is small enough to eliminate drug diffusion and diffusion back.

BRIEF DESCRIPTION OF THE DRAWINGS The above objects and others, aspects and advantages of the present invention will be more readily understood after reading the following detailed description together with the accompanying drawings, in which: Figure 1 is a graph of a drug diffusion as a function of the diameter and length of the orifice of a delivery device; Figure 2 illustrates a delivery device that includes a slot orifice according to an illustrative embodiment of the invention; Figure 3 illustrates a delivery device, which includes a slot orifice and a catheter according to another embodiment of the invention; Figure 4 is a graph showing the release rates of the delivery devices of Figures 2 and 3 as a function of time; Figure 5 illustrates a delivery device, which includes a slot hole and a conical depression according to another MODE OF THE INVENTION: Figure 6 is a graph showing the release rate of the delivery device of Figure 5 as a function of time; Figure 7 illustrates a delivery device including a slot orifice and a rigid internal cylindrical member according to another embodiment of the invention; Figure 8 illustrates a delivery device, which includes a plurality of slot holes according to another embodiment of the present invention; and Figure 9 is a graph illustrating a comparison of the release rates of two osmotic delivery devices having an orifice according to an embodiment of the present invention, with the release rates of the two osmotic delivery devices having a moderator of spiral flow.

DESCRIPTION OF THE PREFERRED MODALITIES Definitions The term "beneficial agent" includes any physiologically or pharmacologically active substances or substances, optionally in combination with pharmaceutically acceptable carriers and optionally additional ingredients such as anti oxidants, stabilizing agents, penetration enhancers, etc. The term "waterproof" refers to a material that is sufficiently impermeable to environmental fluids as well as ingredients contained within the assortment device, such that the migration of said materials into and out of the device through the impermeable material is so slow that substantially there is 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 assortment device and the environment of use. The water attraction agents that are used to activate the osmotic flow of an osmotic delivery device are referred to herein as "osmotic agents". Figure 2 illustrates an example of an osmotic delivery device 10 according to an illustrative 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 these can be enclosed within a substantially cylindrical capsule 15, elongate. The elongated capsule 15 is formed of a material such as titanium, which is sufficiently rigid to withstand the expansion of an osmotic agent without changing the size or shape. The elongate 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. He Osmotic agent 25 can be. for example, a non-volatile water-soluble osmagent, an osmopolymer which swells after contact with water, or a mixture of the two. The second chamber 40 contains a beneficial agent, such as a drug, which will be delivered. The second chamber 40 is separated from the first chamber 20 through 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 form and slide along the a longitudinal axis inside the capsule. The piston 30 is preferably formed of an impermeable elastic 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 one portion of the wall of the first chamber 20. The membrane 60 is formed of a semipermeable material, which allows the fluid to pass from an environment of exterior fluid into the first chamber 20 through osmosis to cause the osmotic agent to swell . The membrane 60 may be in the form of a semipermeable plug, which is inserted into an open end 12 of the capsule 15 as shown in Figure 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. The materials from which the membrane 60 can be made are those which are semipermeable and which can be conform to the configuration of the capsule 15 after 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 membrane 60 is made vary based on the desired pumping rates and device configuration requirements, and include but are not limited to, plasticized cellulosic materials. improved polymethyl methacrylates such as hydroxyethyl methacrylate (HEMA) and elastomeric materials such as polyurethanes and polyamides, polyether-polyamide copolymers, thermoplastic copolyesters, and the like. During operation, when the delivery device 10 is placed in the aqueous environment, the water is extracted through the membrane 60 through 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 through the piston 30. The piston slides off the membrane 60 forcing the beneficial agent into the second chamber 40 to be supplied through at least one hole 50 in the second chamber. The osmotic pump provides a relatively constant rate of water ingress, which can be used to reliably deliver a desired amount of the beneficial agent over time. The hole 50, according to one embodiment of the invention, it is formed in a plug 52 of an elastic or semi-elastic material such as silicone. rubber, sanded, polyurethane or an elastomeric thermoplastic polymer such as C-FLEX. The plug 52 is retained at an outlet end 14 of the capsule 15. The hole 50 comprises a slot 54 made through the elastic or semi-elastic plug 52, which can be fluidly connected to a flow moderator 56 disposed in the plug 52 The slot 54 and the flow moderator 56 are fluidly connected to the interior of the second chamber 40 to the external fluid environment. As shown in Figure 2, the plug 52 can 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 slot 54 and extends beyond the outlet end 14 of the capsule 15. The orifice 50 operates as a valve that opens under the pressure of the beneficial agent. The slot 54 of the hole 50 can be under light compression, for example, of compressive forces that form a seal between the external part of the plug 52 and the interior of the reservoir 15, so that in the absence of flow, the slot 54 forms a valve closed that prevents fluid flow in any direction. Alternatively, the materials used and the dimensions of the plug can be selected so that the slot seals or closes without the need for external compression. The slot 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 exert no significant closing force on the slot 54. In the presence of flow, the beneficial agent pushes through the slot 54, opening a channel for the delivery of the beneficial agent. In the absence of flow, the slot 54 remains closed. When the slot is closed, the return diffusion of external fluids is eliminated, which avoids contamination of the beneficial agent in the second chamber 40 by external fluids. In addition, the advance spread of the beneficial agent out of the capsule 15 is avoided. In continuous flow osmotic delivery systems, the slot 54 will generally remain open through the delivery of the beneficial agent. However, pulsatile or bolus type delivery systems will generally cause the slot 54 to close during periods when there is no supply. When the osmotic pressure is high enough to open the slot 54 in the hole 50, the slot 54 provides a flow channel of variable dimensions. The plug 52 in which the slot 54 resides, preferably comprises an elastic or semi-elastic material. The osmotic pressure is large enough to overcome the elasticity of the plug 52 and force to open the slot 54. However, since the plug 52 is elastic, the flow channel that is formed is preferably large enough to allow passage. of the beneficial agent through it. The flow channel to through the slot 54 can assume a scale of sizes based on the osmotic pumping rate and the viscosity of the beneficial agent, for example. The slot 54 generally opens to the smaller required diameter or opening to allow the flow of beneficial agent therethrough. This is much smaller than could be achieved with a rigid channel due to the limitations of coincidence and tolerance and / or to particle packing of said small rigid channel. As will be appreciated by those skilled in the art, the dimensions and composition of the plug 52 and the slot 54 can be adjusted so that the slot 54 forms a hole of a desired size when used with a particular beneficial agent and an osmotic pump. For example, as the length of the slot 54 increases, the size of the hole created by the slot 54 may increase. Also, as the thickness of the plug 52 along a longitudinal direction of the capsule 15 increases, the plug 52 becomes stronger to form a hole in the slot 54. The composition of the plug 52 also affects the tendency of the slot 54 to be opened towards a hole. A more elastic material will more easily form a hole, or it can form a wider hole than a more rigid material. By varying these properties of the plug 52 and the slot 54, the hole can be configured to open to a desired degree, giving the parameters of the delivery device, for example, the viscosity of the beneficial agent, the flow velocity of the osmotic pump, and the pressure of the osmotic pump. By varying the parameters listed above, a hole can be obtained that "opens" at a predetermined internal pressure, for example, 0.63 kg-m / cm2. The ability to vary the size of the hole 50 has the advantage that the cross-sectional area of the hole 50 can be made small under the operating conditions of the delivery device, which reduces the diffusion of the beneficial agent out of the delivery device, as shown in Figure 1, and reduces the return diffusion of external fluids to the delivery device. In general, the system is designed so that the slot 54 is forced to open to a degree as small as possible to allow the formulation to filter through its opening. In addition, the requirement in the prior art delivery devices for a fixed dimension orifice of sufficient size to allow the passage of microaggregates is eliminated, since the slot 54 allows a flow path to open around an obstruction in the orifice 50. In the event that a suspended particle is lodged in the hole 50, a new flow path is created around the obstacle, thus preventing plugging. In operation, the active flow channel may be significant smaller than that required in a fixed diameter orifice channel to prevent plugging. Another advantage of the hole 50 shown in Figure 2 is that the hole is very compact and easily fits within the delivery device 10, according to compared to a conventional flow moderator, which can have a length of 2 to 7 cm, for example. The small size of the hole 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 54 forms a semi-rigid opening and allows the compressive pressure to form a seal between the outside of the plug 52 and the inside of the reservoir 15 without compressing the slot 54. In this way, as illustrated in Figure 2, the slot 54 can be located in the second non-compressed section 53 of the plug 52, so that the slot is not subjected to compression forces, which form the seal between the plug 52 and the capsule 15., the slot 54 can extend towards the first section 57, so that the slot is subjected to these compressive forces. Therefore, the flow moderator 56 functions to improve the seal between the cap 52 and the capsule 15. As shown in Figure 2, the cap 52 may have several seal flanges 62, which each form a seal between the plug 52 and the capsule 15 for effectively isolating the beneficial agent in the second chamber 40 from the external fluid environment. Since the flow moderator 56 can be formed of a rigid material, it can exert an external radial force on the plug 52, which is preferably less rigid than the flow moderator 56. This radial force towards outside increases the pressure exerted by the seal flanges 62 against the inside of the capsule 15, which improves the seal between the cap 52 and the capsule 15. Furthermore, the radial force outwardly increases the resistance of the cap 52 which is pushed out of the capsule 15 by the osmotic pressure generated by the osmotic pump. In other embodiments of the present invention, outward radial forces can also regulate the flow of the beneficial agent and prevent back diffusion of external fluids into the capsule 15. In accordance with an illustrative embodiment of the present invention, the slot 54 illustrated in Figure 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 central axis of the hole (parallel to the longitudinal axis of the capsule 15). Then, the needle is removed from the hole 50. After the slot 54 has been formed in the hole 50, the flow moderator 56 is inserted into the first section 57 of the plug 52. Depending on the material of the plug 52, and the dimensions of the slot 54 and the flow moderator 56, it may be necessary to drill, excavate, inflate, or mold a cylindrical depression in the first section 57 to receive the flow moderator. In any case, the flow moderator 56 is preferably placed within the first section 57, and secured to the first section 57 through an interference fit, although adhesives, threads or other may be used. means for securing the flow moderator to the first section of the plug 52. One end of the flow moderator 56 may exit the first section 57, may be located within the first section, or may be inserted in the first section, so which is at the level of the first section. The slot 54 can 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. After , a needle or device for forming the slot 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 slot. For example, an orifice 50, such as that illustrated in Figure 2, can be formed by first inserting a portion with a length of 1.5 mm of a 21-gauge hypodermic needle (diameter of about 0.8 mm) 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 portion with a length of 1.5 mm of the 21-gauge hypodermic needle is preferably at least half the length of the final slot 54 that will be formed. The following dimensions of the cap 52 and capsule 15 are also preferred for this example: (1) the plug 52 of C-FLEX has a length of approximately 3.85 mm (measured on a parallel axis) with the longitudinal axis of the capsule where the hole 50 is to be inserted), although only 3.13 mm of the cap is inserted in the capsule 15 after the hole 50 has been manufactured; (2) the plug 52 includes four equally spaced seal flanges 62, each having an outer diameter of about 3.24 mm and each having a thickness of about 0.26 mm (measured on an axis parallel to the longitudinal axis of the capsule where the hole 50 is going to be inserted); (3) the diameter of the cylindrical body of the plug 52 at the base of the lips of the seal 62 is approximately 2.98 mm; and (4) the internal diameter of the capsule 15 receiving the plug 52 is approximately 3.00 mm. After the portion with a length of 1.5 mm of the 21-gauge hypodermic needle has been inserted into the first section 57 of the cap 52, a second hypodermic needle having a diameter smaller 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 cap 52. This step forms the groove 54, and also removes any plug material within the portion of the 21-gauge hypodermic needle to form the flow moderator 56. If the second hypodermic needle dimensioned to fit tightly through the 21-gauge flow moderator , 56, the resulting slot 54 will have a width of approximately 0.4 mm as measured perpendicular to the central axis of the hole 50. A hole 50 having the above dimensions is intended for be particularly useful for delivering high viscosity formulations of beneficial agents, sas 3% sodium carboxymethylcellulose in water. Figure 9 is a graph of the release rate of the beneficial agent over time and compares two osmotic delivery systems having a spiral flow moderator with two osmotic delivery systems or devices 10 having a hole 50 according to the modes of of the present invention, as illustrated in Figure 2. The osmotic delivery devices 10 tested in Figure 1 include the capsule 15 and port 50 sized and described above having a plug 52 of C-FLEX LS 55A with slot 54 of 0.4 mm and the flow attendant 56 of caliber 21. As illustrated in Figure 9, the two osmotic delivery systems having a spiral flow moderator and the two osmotic delivery systems 10 having the hole 50 in accordance with the modalities of the present invention were tested. The respective systems were configured to supply a beneficial agent in this case water with blue dye, one for a month and one for a year. The osmotic delivery system 10 according to the present invention that was configured for delivery of the beneficial agent over a period of one year supplied approximately 0.4 μL / day of the beneficial agent. Comparatively, the osmotic delivery system incorporating the spiral flow modulator and configured to deliver the beneficial agent over a period of one year also supplied approximately 0.4 μL / day of the beneficial agent. In this way, Figure 9 illustrates that the osmotic delivery system 10 incorporating the orifice 50 and configured to deliver the beneficial agent over a period of one year also worked 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 period of one month provided only 1.3 μL / day of the beneficial agent. Comparatively, the osmotic delivery system incorporating the spiral flow modulator and configured to deliver the beneficial agent over a period of one month also provided poorly 1.3 μL / day of the beneficial agent. In this way, Figure 9 illustrates that the osmotic delivery system 10 incorporating the orifice 50 and configured to deliver the beneficial agent over a period of one month also worked as the osmotic delivery system incorporating the spiral flow modulator. In summary, the results illustrated in Figure 9 illustrate that the holes tested were as effective as the spiral flow modulators in delivering a beneficial agent at different release rates. Figure 3 illustrates another embodiment of the invention wherein a catheter 156 is provided in fluid communication between the slot 154 and the capsule 115. As shown in Figure 3, the 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 containing a beneficial agent and a mobile 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 Figure 2. As shown in Figure 3, the device delivery 110 includes a plug 142 having a catheter 156 fixed thereto. The cap 142 is fixed to the outlet end 114 of the capsule 115 and may include a plurality of ridges 162 to seal the cap 142 to the capsule 115. In the cap 142 it may have a first portion 147, which is fixed within the capsules. walls of the capsule 115 and a second portion 143, which extends beyond the exit end 114 of the capsule 115. The stopper 142 may be formed of an elastic or semi-elastic material sas 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 as to exert a force radially outwardly on the cap 142 to increase the pressure of the ridges 162 on the inner wall of the capsule 115. The increased pressure improves the seal between the cap 142 and the capsule 115 and increases the resistance of the cap. stopper 142 which will be 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 groove 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 where the end of the catheter 156 is disposed, and a second section 153 where the slot 154 is located. The groove 154 functions in the same manner as the groove 54 in Figure 2. However, the groove 154 is not subjected to compressive forces created by the seal between the plug 142 and the capsule 115. The groove 154 is designed so that in the absence of flow, the groove 154 forms a closed valve which prevents fluid flow in any direction. In the presence of flow, the beneficial agent pushes through the slot 154, opening a channel for the delivery of the beneficial agent. The dimensions and composition of the flexible member 152 and the groove 154 can be selected so that the groove 154 forms an orifice of a desired size under the operating parameters of the delivery device, for example, the viscosity of the beneficial agent, the flow rate of the osmotic pump, and the pressure of the osmotic pump. Since the flexible member 152 is elastic, the flow channel that is formed is preferably large enough to allow the passage of the beneficial agent therethrough. The Orifice size variability has the advantage that the orifice cross-sectional area is small (e.g., significantly smaller than a fixed-diameter flow moderator), which reduces diffusion of the beneficial agent out of the delivery device, as shows in Figure 1, and reduces the diffusion of external fluids to the delivery device. Slot 154 also allows a flow path to be opened around an obstruction in slot 154. Catheter 156 may have dimensions so that it works as a flow moderator, if desired, to further reduce diffusion of the beneficial agent out of the slot 154 and the return diffusion of external fluids to 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 therapeutically advantageous to deliver the beneficial agent to a site that can not adapt or tolerate the capsule 115. In this situation, the capsule 115 can be implanted in a more acceptable site, while the catheter 156 transports the beneficial agent to slot 154 at the supply site. This modality can also be used to make the capsule 115 more accessible to a treating physician, rather than being implanted in a site that requires an invasive procedure. For example, the capsule 115 may be implanted close to the surface of the skin, while the catheter 156 supplies the beneficial agent in a further location. far away The improved performance of the illustrative delivery devices of Figures 2 and 3 is shown in Figure 4. Figure 4 is a graph of the release rate in microliters per day during the time of the delivery devices of Figures 2 and 3. 3. Figure 4 also shows a release rate of a delivery device having a tubular flow moderator hole in the shape of a spiral. The data used in Figure 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 of time, the concentration of the blue dye in the bath of release rate was measured. The experiment was conducted five times, and the error bars shown in Figure 4 represent the standard deviation of the measurements. The procedure and materials used to obtain the data shown in Figure 4 are as follows: Tablet Compression by Granulation: COUPLED: 0.297 cm flat face GRANULATION: 80.0% NaCl, 5.0% NaCMC 7H4F, 14.25% Povidone, 0.75% Stearate of Magnesium WEIGHT OF THE TABLET: 0.0841 g HEIGHT OF THE TABLET: 0.627 cm COMPRESSION: 227 kg PROCEDURE: 1. Lubricate the large flanged piston with medical fluid 100cs CODE 80036 CONTROL 258887. 2. Original capsule (membrane end). 3. Insert large flanged piston into a Hoechst Celanese capsule using the inserted piston. 4. Push the piston up and down using a bar. 5. Insert the osmotic motor tablet into the membrane end capsule and push the motor tablet down. 6. Insert half of the membrane plug. 7. Add two drops of glue on each side of the membrane plug. 8. Compress the entire downward trajectory of the membrane plug and rub the glue residue with a paper towel. 9. Add the beneficial agent in the capsule almost all the way to the top. 10. Insert hole. 11. Insert hole in half and add two drops of glue on each side of the hole plug (all holes were glued, except systems 26-30).

COMPONENTS: Formulation # 1: 1% blue dye in deionized water Membrane: 100% hytrel 8171 rapid "K" Motor Tablet 80.0% NaCl, 5.0% NaCMC 7H4F, 14.25% Povidone, 0.75% Magnesium Stearate Piston: Large flanged Santoprene Orifice: Screw spiral 1-5 Hole: External flow moderator 11-15 (Figure 3) Hole: Platypus type 1 mm inner mouth 21-25 (Figure 2) As shown in Figure 4, the release rate of the delivery devices of Figures 2 and 3 having the slot holes is significantly more constant than the release rate of the delivery device having a shaped flow moderator. of spiral. This feature, of course, is very important when the delivery device is used to deliver drugs to humans for an extended period. The slot orifice can be used to alter the start of the beneficial agent delivery profile by changing the pressure at which the orifice is opened and / or reducing the pressure. burst of initial diffusion from the flow modulator. To assemble the delivery device of the present invention, the beneficial agent can also be added with the capsule after the hole has been inserted into the capsule. In said assembly, a needle is inserted through the hole and makes the capsule, so that the beneficial agent is delivered into the capsule through the needle. This technique is advantageous since the slot orifice allows air to escape from the capsule as the beneficial agent fills the capsule. In this way, after the delivery device is inserted into the environment of use, the osmotic agent does not need to compress any air bubbles in the beneficial agent, which could ordinarily delay the start of delivery of the beneficial agent. Figure 5 illustrates another embodiment of the invention, which includes a mechanism to vary the pressure required to open the orifice. As shown in Figure 5, the hole 250 is located at the outlet end 214 and 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 movable piston 230 separating the first chamber 220 from the second chamber 240. The membrane 260, the osmotic agent, the piston 230 and the second chamber 240 form an osmotic pump, which functions as described above with respect to to Figures 2 and 3. The hole 250, according to an illustrative embodiment, It comprises three sections. A first portion 257 is located between the slot 254 and the second chamber 240 and is in fluid communication with both. A second portion 253 contains the slot 254. A third portion 259 occupies the annular space between the first and second portions and the inner wall of the capsule 215. The slot 254 is housed in the second portion 253. The second portion generally has a shape cylindrical and preferably is formed of an elastic or semi-elastic material such as silicon, rubber, santoprene, polyurethane, etc. The elasticity of the second portion 254 allows the slot 254 to open under pressure by the beneficial agent. Upstream of the slot 254 and the second portion 253 is the first portion 257. The first portion 257 also has a generally cylindrical shape and has an internal depression 252. The outer radius of the first portion 257 may be larger than the outer radius of the first portion 257. 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 with a single piece of material. According to a preferred embodiment, the internal depression 252 of the first portion 257 has at least one wall 258, which is at an acute angle to the flow direction 155 of the beneficial agent. Preferably, the internal depression 252 is in the shape of a cone, so that its entire wall 258 is at an angle acute with respect to the flow direction 257 of the beneficial agent. As the beneficial agent is forced into the internal depression 252, the beneficial agent exerts a force on the wall 258 of the internal depression 252, which has a radial component. The radial force operates to open the slot 254 in the second portion 253 of the hole. Since the first and second portions are formed of an elastic or semi-elastic material, the force of the beneficial agent opens the groove 254 just to become wide enough to deliver the beneficial agent with very little if any advance diffusion of the beneficial agent or recoil diffusion of the external fluids into the second chamber 240. The shape and composition of the first and second portions 257 and 253 and of the slot 254 can be adapted to accommodate beneficial agents of different viscosities or to adjust the pressure required to open slot 254. For example, a beneficial agent with a relatively low viscosity will flow more easily through a smaller opening in slot 254 than a beneficial agent with a higher viscosity. To equalize this discrepancy, the angle between the wall 258 and the flow direction 255 can be adjusted for the viscous beneficial agent, so that the groove opens much more easily. The angle between the wall 258 and the flow direction 255 can also be adjusted to vary the pressure at which the slot 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 from slot 254 forms a hole of a desired size under the operating parameters of the delivery device, for example, 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 slots 272, which coincide with corresponding ridges 274 projecting from the inner wall of the capsule 215. slots 272 and flanges 274 may be circular or may be in the form of screw threads so that third portion 259 may be screwed to the outlet end of capsule 215. The ridges and slots are provided to secure the third portion 259 at the end of the capsule 215 despite the osmotic pressure generated by the osmotic pump. The third portion 259 also includes a flange 276 extending inward, which makes contact with 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 also functions to apply a slightly radial inward pressure in the second portion 253, so that the slot 254 remains closed in the absence of flow. The orifice 250 provides the advantage that the flow channel can be significantly smaller than that required in a fixed diameter hole, since the flow channel opens just big enough to supply the beneficial agent. In addition, in the event that a suspended particle is housed in the hole 250, a new path of flow around the obstacle is created. The hole 250 is also very compact, as illustrated in Figure 5. The improved operation of the illustrative delivery device of Figure 5 is shown in Figure 6. Figure 6 is a graph of the release rate in microliters per day during the time of the delivery device of Figure 5. Figure 6 also shows the release rate of a delivery device having a flow moderator orifice in the form of a spiral. The data used in Figure 6 was obtained by replacing 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 of time, measurements of the blue dye concentration in the release rate bath were taken. As shown in Figure 6, the release rate of the delivery devices of Figure 5 having the slot hole is significantly more constant than the release rate of the delivery device having a flow moderator in spiral form. Figure 7 illustrates another embodiment of an orifice that includes an internal depression 352 and an internal cylindrical member 359. As shown in Figure 7, the hole 350 is located at the exit 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 movable piston 330 separating the first chamber 320 from the second chamber 340. The membrane 360, the osmotic agent, the piston 330 and the second chamber 340 form an osmotic pump , which functions as described above with respect to Figures 2 and 3. The orifice 350, according to an illustrative embodiment, comprises three components. A first portion 357 is located between the slot 354 and the second chamber 340 and is in fluid communication with both. A second portion 353 contains the slot 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 slot 354 is housed in the second portion 353. The second portion generally has a Cylindrical shape and preferably is formed of an elastic or semi-elastic material such as silicone, rubber, sanded, polyurethane or an elastomeric thermoplastic polymer such as C-FLEX. The electricity of the second portion 353 allows the slot 354 to open under the pressure of the beneficial agent. Upstream of slot 354 and second portion 353 is first portion 357. First portion 357 generally also it has a cylindrical shape and has an internal depression 352. The external radius of the first portion 357 may be larger than the external radius of the second portion 353, so that a shoulder 351 is formed to secure the first and second portions in the device of supply 310. The first and second portions can be integrally formed as an individual piece of material. According to a preferred embodiment, the internal depression 352 of the first portion 357 has at least one wall 358, which is at an acute angle to the flow direction 355 of the beneficial agent. Preferably, the internal depression 352 is in the shape of a cone, so that its entire wall 358 is at an acute angle with respect to the flow direction 355 of the beneficial agent. As the beneficial agent is forced into the internal depression 352, the beneficial agent exerts a force on the wall 358 in the internal depression 352, which has a radial component. The radial force operates to open the slot 354 in the second portion 353 of the hole. Since the first and second portions are formed of an elastic or semi-elastic material, the strength of the beneficial agent opens the groove 354 wide enough to deliver the beneficial agent with little if there is diffusion of advancement of the beneficial agent or back diffusion of the external fluids towards the second chamber 340. The shape of the internal depression 352 (for example, the angle of the wall 358) must be adapted to accommodate the beneficial agents or different viscosities or to In addition, the dimensions and compositions of the second portion 353 can be chosen so that the slot 354 forms an orifice of a desired size under the operating parameters of the delivery device, for example, the viscosity of the beneficial agent, the flow velocity 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 from a rigid material such as titanium. The third portion may generally be in the form of an internal 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 sufficiently small that the third portion 359 can be compressed at 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 at the outlet end 314 of the capsule 315 in the presence of the osmotic pressure generated by the osmotic pump. When appropriately 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 makes contact with 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 over the entire path inward toward the second portion 353. , so that there is a gap 390 between the second portion containing the slot 354 and the flange 376. The recess 390 is provided so that the flange 376 exerts no force on the slot 354. The hole 350 provides the advantages that the Flow channel that opens under pressure of the beneficial agent, can be significantly smaller than that required in a fixed diameter orifice, since the flow channel opens large enough to supply the beneficial agent. In addition, in the event that a suspended particle is housed in the hole 350, a new flow path is created around the obstacle. The third rigid portion 359 is also very effective in maintaining the hole 350 in the capsule against the osmotic pressure. The hole is also very compact, which is advantageous for subcutaneous implantation. Figure 8 illustrates another embodiment of a hole 450, which includes a plurality of slot holes 454. As shown in Figure 8, the hole 450 is located at the outlet end of the capsule 415. The delivery device 400 it also includes a membrane 460, a first chamber 420 containing an osmotic agent, a second chamber 440 containing a beneficial agent and a hollow movable piston 30 separating the first chamber 420 from the second chamber 440. The membrane 460, the osmotic agent, the piston 430 and the second chamber 440 form an osmotic pump, which functions as described above with respect to FIGS. and 3. The hole 450, according to an illustrative embodiment, includes a plurality of slot holes similar to those described above with reference to Figures 2, 5 and 7. As shown in Figure 8, an internal cylindrical member 459 it is positioned at the end of the capsule 415 opposite the membrane 460. In this embodiment, a flexible member 456, which contains the plurality of slot holes 454 and internal depressions 452, has been pre-positioned on the internal cylindrical member 459. Similar to the embodiment illustrated in Figure 5, the internal cylindrical member 459 can be made of a material that helps maintain the seal between the capsule 415 and the hole 450. For example, the member cylindrical ro 459 may be made of a less elastic material than flexible member 456, which contains the plurality of grooves 454. In another embodiment of the present invention not illustrated, internal cylindrical member 459 is not included, and flexible member 456 is adapted and configured to form a seal with the capsule 515. As illustrated in Figure 8, the hole 450 includes a plurality of slot holes 454 and internal depressions 452, which are particularly useful for delivering beneficial agents having suspensions of bioactive macromolecules such as proteins and genes. Known supply ports can cause such suspension formation to separate as the formulation moves into a small chamber such as a helical hole before being released into the environment of use. The embodiment of the present invention incorporating a plurality of slot holes 454, allows said suspension formulations to travel relatively unrestrictedly, minimizing the amount of separation before it leaves the delivery device 400. In this regard, the plurality of slot holes 454 in combination with the plurality of internal depressions 452 allows an almost constant front of beneficial agent, such as suspensions containing bioactive macromolecules, to be released from the delivery device 400, which also minimizes the return diffusion of external fluids to the delivery device. further, the embodiment of the present invention illustrated in Figure 8 also provides many of the advantages described above with reference to Figures 1-7. In the event that one or some of the slot holes 454 are obstructed with macromolecules or particles, the unimpeded slot holes of the delivery device 400 will continue to release the beneficial agent. In this way, the plurality of slots 454 and depressions 452 act as a security, ensuring that the supply of beneficial agent continues.

The materials that can be used for the capsule must be strong enough to ensure that the capsule will not drip, crack, break or distort under stresses that could be subjected during implantation or under conditions due to pressures generated during the operation. The capsule may be formed of natural or synthetic, biocompatible and chemically inert 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 can alternatively be of a bioerodible material, which is bioerosed in the environment after the assortment of the beneficial agent. In general, the preferred materials for the capsule are those acceptable for implants in humans. In general, typical building materials available 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, tetrafluoroethylene copolymer and hexafluoropropylene; polyimide, polysulfone; polycarbonate; polyethylene; Polypropylene; polyvinyl chloride-acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene, and the like. Useful metallic materials for the capsule include stainless steel, titanium, platinum, tantalum, gold and its alloys, as well as ferrous alloys with gold plate. Ferrous alloys with platinum plate, chrome-cobalt alloys and stainless steel coated with titanium nitride. In general, materials suitable for use in the piston are elastomeric materials including the non-reactive polymers listed above, as well as general eiastomers, 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 direct the flow of the beneficial agent. The osmotic agent may be an osmagent, an osmopolymer, or a mixture of the two. The species that fall within the osmoagent category, that is, the non-volatile species that is soluble in water and create the osmotic gradient that drives the osmotic flow 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. The species that fall within the category of osmopolymer are hydrophilic polymers that swell when making contact with the water, and these vary widely as well. The osmopolymers may be of plant or animal origin, or synthetic, and examples of osmopolymers are well known in the art. Examples include: poly (hydro-alkyl methacrylate) with a molecular weight of 30,000 to 5,000,000, polyvinylpyrrolidone with a molecular weight of 10,000 to 360,000, anionic and cationic hydrogels, polyelectrolyte complexes, polyvinyl alcohol having a low residual acetate content, optionally entangled with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of 200 to 30,000, a mixture of methyl cellulose, crosslinked agar and carboxymethylcellulose, a mixture of hydroxypropylmethylcellulose and sodium carboxymethylcellulose, polymers of N-vinyl-lactams, 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, polyolefin gels, carboxylic acid carboxy copolymers having molecular weights of 250,000 to 4,000,000, polyacrylamides Cynamer, interlaced maleic indene-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, cotton graft copolymers, and acrylate polymer polysaccharides of Aqua-Keeps. The delivery capsules according to the present invention for the delivery of beneficial agents, can be formulated through a variety of techniques, many of which are known in the field. In one embodiment of this invention, the beneficial agents contained in the second chamber are f luous compositions such as liquids, suspensions or slurries, and are emptied into the capsule after the osmotic agent and the piston have been inserted. Alternatively, in said flowable compositions they can be injected with a needle through a slot in the plug, which allows filling without bubbles of air. Still other alternatives may include any wide variety of techniques known in the art to form capsules used in the pharmaceutical industry.

The animals to which the drugs can be administered using the systems of this invention include humans and other animals. The invention is of particular interest for application to humans and domestic animals, sports and farm animals, particularly mammals. For the administration of the beneficial agents to animals, the devices of the present invention can be implanted subcutaneously or intraperitoneally, or anywhere else in a biological environment where the fluids of the aqueous body 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 can be used in intravenous systems (attached to an IV pump or bag or to an IV bottle, for example) to provide beneficial agents to animals, mainly humans. They can also be used in blood oxygenators, kidney dialysis and electrophoresis, for example. In addition, the devices of the present invention can be used in the biotechnological area, such as to deliver nutrients or growth-regulating components to cell cultures. The present invention is applied to the administration of beneficial agents in general, including any physiologically or pharmacologically active substance. The beneficial agent can be any of the agents that are known to be delivered to the body of a human or animal such as drug agents, drugs, vitamins, nutrients, or the like. The beneficial agent can also be an agent that is supplied to other types of aqueous environments such as swimming pools, tanks, reservoirs, and the like. Included among the types of agents that meet this description are biocides, sterilization agents, nutrients, vitamins, food supplements, sex sterilizers, fertility inhibitors and fertility promoters. Drug agents that can be delivered through the present invention include drugs, which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroefector binding sites, endocrine and hormone systems, the immune system, the reproductive system, the skeletal system, autacoid systems, the food and excretory systems, the histamine system and the central nervous system. Suitable agents can be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins. polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, eye drugs and synthetic analogs of these species. Examples of drugs that can be delivered through the devices according to this invention include, but are not limited to, proclorpercin edilisate, ferrous sulfate, aminicaphoic acid, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride. , bensamphetamine hydrochloride, isoproterenol sulfate, fenmetrazine hydrochloride, bentanecol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexetyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline chitoste, cephalexin hydrochloride, diphenidol , medicine hydrochloride, prochlorperazine maleate, phenoxybenzamine, tiethylperidine maleate, anisindone, diphenadione-erythrityl tetranitrate, digoxin, isofluorophonate, acetazolamide, methazolamide, bendroflumetide, chloropromaide, tolasamide, chlormadinone acetate, fenalglycodol, aiopurinol, aluminum aspirin, methotrexate , acetyl sulfisoxazole, arithromycin, hydrocortisone, hydrocortisterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinole, methyl testosterone, 17-S-estradiol, ethinylestradius, ethinylestradi-3-methyl ether, prednisolone, 17-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel , norethindrone, norethisterone, noretiederone, progesterone, norgesterone, norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranol, timolol, atenol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa , dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, buprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinon, capropril, mandol, quanbenzo, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen , tolmetin, alclofenac, mefemanic, flufenamic, difuinal, nimodipyrine, nitrendipine, nisoldipine, nicardipine, faith lodipine, lidoflacin, tiapamil, gallopamil, amlodpine, myoflacin, lisinolpril, enalapril, enalaprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, etimidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptyline, and imipramine. Other examples are proteins and peptides including, but not limited to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle stimulating hormone, gonadotropin chorionic gonadotropin releasing hormone, bovine somatotropin, somatotropin porcine, oxytoxin, vasopressin, GRF, prolactin, somatostatin, lyserin, pancreozimine, 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 prostaglandins, fertility promoters, growth factors, coagulation factors, human pancreatic hormone release system, analogues and derivatives of these compounds and pharmaceutically acceptable salts of their compounds or their analogues or derivatives. The beneficial agent may be present in this invention in a wide variety of chemical and physical forms, such as solids, liquids and slurries. At a 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, laurilate, oleate and salicylate. For acidic compounds, salts of metals, amines or organic cations can also 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 can take different forms. For example, the piston can be replaced with a flexible member such as a diaphragm, division, pad, flat sheet, spheroid, rigid metal alloy, and can be made from any number of inert materials. In addition, the osmotic device can function without the piston, simply by having an abutting surface between the osmotic agent / fluid additive and the beneficial agent. The embodiments illustrated and described above are intended to be illustrative in all respects, rather than as a restriction of the present invention. In this way, the present invention is capable of many variations in the detailed implementation that can be derived from the description herein contained by one skilled in the art. All of these variations and modifications are considered within the scope and spirit of the present invention as defined in the following claims.

Claims (18)

1. - A delivery device comprising: a capsule having an opening, said capsule containing a beneficial agent and an osmotic agent; at least a portion of the capsule being permeable to the fluid from an external environment to allow the fluid to pass into the capsule through osmosis to create an osmotic pressure in the capsule; means for applying osmotic pressure to the beneficial agent; and a flexible plug at least partially located in the opening of the capsule, at least a portion of the flexible plug located in the opening being in a compression state through the application of a compression force, said flexible plug having in the same at least one slot hole, which is in fluid communication with the capsule, the slot hole closing when a beneficial agent pressure is less than a predetermined pressure, said slot orifice having a portion not subjected to the compression force.

2. The supply device according to claim 1, wherein the capsule applies said compression force to the portion of the flexible cap to produce the compression state.

3. The supply device according to claim 1, wherein the flexible plug includes a portion internal, which extends outside said opening, the outer portion having at least a portion of the slot hole.

4. The supply device according to claim 1, characterized in that it further comprises a tubular member at least partially located in the capsule, the tubular member applying a compressive force to the flexible plug portion to produce said compression state.

5. The supply device according to claim 1, wherein the slot orifice is located outside said capsule.

6. The supply device according to claim 1, wherein the slot hole is located inside the capsule.

7. The supply device according to claim 1, wherein the flexible plug includes an opening that receives a tube, the tube forcing the plug outwardly in a radial direction.

8. The delivery device according to claim 1, wherein the portion of the capsule that is permeable to the fluid includes a membrane.

9. The supply device according to claim 1, wherein said portion of the flexible plug at least partially located in the opening includes a depression, the depression having a wall that is at an acute angle with respect to the direction of flow of the beneficial agent, so that the flow of the beneficial agent exerts a radial force outwardly on the flexible member.

10. The supply device according to claim 9, wherein the wall of the depression is in the form of a cone with the slot hole intersecting the apex of the cone.

11. The supply device according to claim 1, wherein the flexible plug includes a plurality of slot holes.

12. A delivery device comprising: a capsule containing a beneficial agent and an osmotic agent; a portion of the capsule being permeable to the fluid from an external environment to allow the fluid to pass into the capsule through osmosis to create an osmotic pressure in the capsule; means for applying osmotic pressure to the beneficial agent; and a flexible member located at least partially in the capsule and having therein at least one slot hole, said slot hole being located at least partially external to the capsule.

13. A supply device comprising: a chamber containing a beneficial agent that will be supplied; a flexible member having therein a slot hole, which is in fluid communication with an interior of the chamber, the flexible member comprising: a first portion upstream of the slot orifice, the first portion having a cone-shaped depression; and a second portion wherein the slot hole is located; and means for applying a pressure to the beneficial agent to force the beneficial agent through the depression and the slot orifice.

14. The delivery device according to claim 13, wherein the capsule has a cylindrical wall, the delivery device further comprising: an internal cylindrical member, which is fixed within the cylindrical wall of the capsule, the member internal cylindrical comprising a flange extending radially outward to maintain the flexible member in the internal cylindrical member.

15. The supply device according to claim 14, wherein the internal cylindrical member comprises a metal.

16. The supply device according to claim 13, further comprising a flange extending inwardly from an outer wall of the capsule, the flange defining a central opening, the central opening having a first transverse area, which is less than a transverse area of the first portion of the flexible member and which is greater than a transverse area of the second portion of the flexible member.

17. - A method for forming a delivery device comprising the steps of: filling a chamber of the delivery device with a beneficial agent having a known viscosity; providing an exit passage through which the beneficial agent is to be delivered, the exit passage comprising a first portion having a wall that is at an angle to a flow direction of the beneficial agent, the exit passage also comprises an orifice of groove running downstream of the first portion; and selecting the angle of the wall with respect to the flow direction of the beneficial agent based on the viscosity of the beneficial agent.

18. The method according to claim 16, characterized in that it further comprises the step of forming the first portion of the outlet passage in the shape of a cone with the slot hole intersecting a vertex of the cone.