Abstract:
An osmotic delivery system for controlled delivery of a beneficial agent includes an implant capsule having a beneficial agent reservoir, an osmotic agent which expands on contact with fluid imbibed through a permeable membrane retained by the implant capsule, a delivery port, and a valve for opening and closing the delivery port. When the osmotic agent expands, a pressure is exerted against a separating member positioned between the beneficial agent reservoir and the osmotic agent. The separating member moves within the capsule, thereby forcing the valve to move a distance such that the beneficial agent can exit the reservoir through the delivery port.

Description:
This application claims priority based on U.S. Provisional Patent Application Serial No. 60/171,305, filed Dec. 21, 1999, which is incorporated herein by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to osmotic delivery devices for delivering beneficial agents, and more particularly, to osmotic delivery devices having an osmotic engine and a valve to prevent expulsion of the beneficial agents. 
     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 method for controlled prolonged delivery of beneficial agents involves the use of osmotic delivery systems. These systems can be implanted within a body of a human or animal to release beneficial agents in a controlled manner over a preselected time or administration period. In general, osmotic delivery systems operate by imbibing liquid from the outside environment and releasing corresponding amounts of the beneficial agent. 
     A known osmotic delivery system, commonly referred to as an “osmotic pump,” generally includes some type of a capsule or enclosure having a semipermeable portion which selectively passes water into an interior of the capsule containing a water-attracting osmotic agent. In one known osmotic delivery system the walls of the capsule are substantially impermeable to items within and outside the capsule. A membrane plug is inserted into one end of the capsule and acts as the semipermeable portion allowing water to pass into the interior of the capsule. The difference in osmolarity between the water-attracting osmotic agent and the environment surrounding the capsule causes water to pass through the membrane plug into the capsule which in turn causes the beneficial agent within the capsule to be delivered through a delivery orifice. The water-attracting osmotic agent may be the beneficial agent delivered to the patient; however, in most cases a separate osmotic 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 and expands. As the osmotic agent expands, it causes the piston to move and the beneficial agent to be discharged through the delivery orifice at the same rate as the liquid, which is typically water, enters the osmotic agent by osmosis. Osmotic delivery systems may be designed to deliver a beneficial agent at a controlled constant rate, a varying rate, or in a pulsatile manner. 
     In the known osmotic delivery systems, an osmotic tablet is generally used as the osmotic agent and is placed inside the capsule adjacent the piston. A membrane plug is placed in an opening in the capsule through which the tablet and piston were inserted. Known membrane plugs are typically cylindrical members which seal the interior of the capsule from the exterior environment, permitting only certain liquid molecules from the environment of use to permeate through the membrane plug into the interior of the capsule. The rate that the liquid permeates through the membrane plug controls the rate at which the osmotic agent expands and drives the beneficial agent from the delivery system through the delivery orifice. The rate of delivery of the beneficial agent from the osmotic delivery system may be controlled by varying the size of the beneficial agent delivery orifice, the osmotic material, a size and shape of the membrane plug, or the permeability coefficient of the membrane plug. 
     It is desirable to seal the beneficial agent delivery orifice of the delivery system to prevent incursion of materials into the delivery system before sufficient osmotic pressure exists to insure a flow of the beneficial agent through the orifice. Protecting the beneficial agent from the external environment is particularly important when the beneficial agent is a protein formulation or other agent which breaks down when in contact with certain environmental compositions. 
     In order to prevent contamination or early release of the beneficial agent, some delivery systems are provided with a plug in the orifice which is discharged upon movement of the piston by the fluid pressure within the system. Typically, such osmotic delivery systems use mechanical plugs, bio-eroding, or dissolving plugs. 
     With mechanical plugs, such plugs are chemically stable materials discharged from the delivery system on movement of a piston contained within the system. Premature release of the beneficial agent may occur when the delivery system is jarred, thereby loosening the mechanical plug from the system. Further, mechanical plugs expelled from the delivery device may not be acceptable with the patient when left in the patient&#39;s body at the implant site. 
     Bio-eroding or dissolving plugs also present drug delivery problems since such plugs allow the drug delivery orifice to open regardless of whether or not the osmotic agent can exert sufficient hydraulic pressure to insure flow of the beneficial agent. 
     Because of the above-identified problems associated with current osmotic delivery systems, it is desirable to prevent contamination of the beneficial agent and to prevent beneficial agent leakage by providing a delivery orifice valve which is not expelled into the patient&#39;s body. 
     SUMMARY OF THE INVENTION 
     The present invention relates to osmotic delivery systems having an osmotic engine and a valve to prevent contamination and/or expulsion of the beneficial agents. 
     In accordance with one aspect of the present invention, a delivery system for controlled delivery of a beneficial agent includes an implantable capsule having a delivery orifice, a separating member dividing the capsule into a beneficial agent reservoir and a driving reservoir, an osmotic engine in the driving reservoir, and a valve member that can move from a closed position to an open position. In the closed position, the valve member prevents the expulsion of beneficial agent from the beneficial agent reservoir through the delivery orifice. The implantable capsule can include an attachable cap having a vent. In operation, the osmotic engine imbibes fluid thereby causing the engine to swell. This swelling causes the osmotic engine to exert a pressure on the separating member whereby such pressure moves the separating member, the beneficial agent reservoir, and the valve member a distance such that the valve member moves to an open position, allowing passage of beneficial agent through the delivery orifice at a desired delivery rate. 
     In accordance with another aspect of the present invention, a method of preventing contamination from entering the osmotic delivery device before activation includes the steps of providing a delivery device capsule enclosing a first chamber which contains a beneficial agent and a valve member. The first chamber has an opening communicating with the external environment. Before activation of the delivery device, the valve member occludes the opening. This occlusion prevents the beneficial agent from leaving the device, as well as prevents the incursion of contaminants into the device. 
     In accordance with an additional aspect of the present invention, a method of controlling an initial release of a beneficial agent from an osmotic delivery device includes the steps of providing a delivery device capsule which encloses a first chamber containing the beneficial agent, a valve member, and a second chamber containing an osmotic agent. The first chamber has a beneficial agent delivery orifice communicating with the external environment. The valve member is initially in a closed position and blocks beneficial agent from passing through the beneficial agent delivery orifice. Upon implantation, the osmotic agent imbibes surrounding fluid to form an osmotic solute which expands and exerts a pressure on the first chamber. The osmotic imbibition of surrounding fluid builds pressure within the osmotic engine until sufficient force is exerted to move the first chamber and valve member, the valve member moving from the closed position to an open position. With the valve in the opened position, beneficial agent contained in the first chamber can pass through the beneficial agent delivery orifice to the external environment. 
     The present invention provides the advantage of a more controllable beneficial agent delivery rate by preventing expulsion of beneficial agent from the drug reservoir by using a valve to occlude the drug delivery orifice. The valve does not allow beneficial agent to pass through the delivery orifice until sufficient hydraulic pressure exists to displace the beneficial agent from the drug reservoir. Moreover, the present invention retains the valve within delivery device, whereby removing the implant from the patient after delivering the medication allows retrieval of both the valve and the implant device. 
    
    
     BRIEF DESCRIPTION OF THE FIGURES 
     The invention will now be described in greater detail with reference to the preferred embodiments illustrated in the accompanying drawings, in which like elements bear like reference numerals, and wherein: 
     FIG. 1 is a side cross-sectional view of an osmotic delivery device according to the present invention; 
     FIG. 2 is a side cross-sectional view of the osmotic delivery device of FIG. 1 delivering a beneficial agent through an orifice; 
     FIG. 3 is a side cross-sectional view of an osmotic delivery system having an alternative embodiment of a cap with the cap in closed position; and 
     FIG. 4 is a side cross-sectional view of an osmotic delivery system having an alternative embodiment of a cap with the cap in opened position. 
    
    
     DETAILED DESCRIPTION 
     The present invention relates to an osmotic delivery system for controlled delivery of a beneficial agent. FIGS. 1-4 illustrate two examples of osmotic delivery devices  10  according to the present invention. 
     The osmotic drug delivery device  10 , as illustrated in FIG. 1, includes a movable valve  28 , a first chamber  22  containing a beneficial agent, a separating member  20 , and a second chamber  24  containing an osmotic engine or agent, all of which are enclosed within an elongated substantially cylindrical enclosure or capsule  12 . The capsule  12  has a first end  14  and an open end  16 . The first end  14  of the capsule  12  has one or more orifices or ports  18  for delivering a beneficial agent contained within a first chamber  22  of the osmotic delivery device  10  to an external environment. In most configurations, one delivery port  18  will suffice. However, two or more delivery ports  18  may be present without departing from the present invention. 
     The valve  28  occludes the delivery orifice  18  when the valve is in a closed position, preventing the beneficial agent in the first chamber  22  from leaving the delivery device  10  as well as preventing the incursion of foreign materials into the device. The dimensions of the valve  28  in terms of both diameter and length are selected such that the valve will not exit the delivery device  10  through the delivery orifice  18 . 
     The separating member  20  also separates the first chamber  22  containing the beneficial agent from the second chamber  24  containing the osmotic agent. The separating member  20  and valve  28  are substantially cylindrical members which are configured to fit within the capsule  12  and are slidably movable along a longitudinal direction within the capsule. The separating member and valve  20 ,  28  preferably are formed of a resilient material which is impermeable to the compositions within the capsule  12 , and at least a portion of the separating member  20  and the valve  28  forms a seal with the inner surface of said capsule  12 . 
     In addition, the movable separating member and valve  20 ,  28  may be flexible members such as pistons, partitions, pads, flat sheets, spheroids, or rigid metal alloys, and may be made of any number of inert materials. Furthermore, the osmotic device  10  may function without the piston  20 , having simply an interface between the osmotic agent and the beneficial agent. 
     A semipermeable membrane  30  couples with the capsule  12  at the open end  16  and encloses the second chamber  24  containing the osmotic agent. The osmotic agent may be, for example, a nonvolatile water soluble osmagent, an osmopolymer which swells on contact with water, or a mixture of the two. The elongated capsule  12  is formed of a material which is sufficiently rigid to withstand expansion of the osmotic agent contained within a second chamber  24  of the delivery device  10  without changing size or shape. The elongated capsule  12  is preferably substantially impermeable to fluids in the environment as well as to ingredients contained within the osmotic delivery device  10  such that the migration of such materials into or out of the device through the impermeable material of the capsule is so low as to have substantially no adverse impact on the function of the osmotic delivery device. 
     As shown in FIGS. 1 and 2, the osmotic delivery device  10  of one embodiment of the present invention includes a semipermeable membrane  30 , which is coupled with the open end  16  of the capsule  12 . In operation, after placing the osmotic agent within the second chamber  24  of the capsule, the semipermeable membrane  30  allows liquid to pass from an environment of use into the capsule  12  to cause the osmotic agent to swell. However, the material forming the semipermeable membrane  30  is largely impermeable to the materials within the capsule  12  and to other ingredients within the environment of use. 
     The swelling osmotic agent exerts a pressure on the separating member or piston  20  and forces said separating member to move a distance D in a direction of the arrow A. The separating member  20  applies a force to the beneficial agent in the first chamber  22 , the beneficial agent transfers the force to the valve  28 . Accordingly, this force causes the valve  28  to move a distance C from the close position to an open position. A clearance  34  between the valve  28  and the first end  14  decreases by the distance C. In the open position, the valve  28  allows the beneficial agent to pass through the delivery orifice  18  to the external environment of use. 
     The osmotic agent in conjunction with the separating member  20  drive the beneficial agent from the first chamber  22  and insures a flow of beneficial agent out of the delivery orifice  18 . The valve  28  is retained within the delivery device  10  at the closed first end  14  of the capsule  12  and, as described above, the valve  28  has dimensions such that it will not leave the delivery device  10  through the delivery orifice  18 . In a preferred embodiment, the capsule  12  has a vent  32  at the first end  14 , allowing fluid to escape from the clearance  34  between the valve  28  and the capsule  12  when the valve  28  moves toward the first end  14 . 
     Depending on the application, the clearance  34  between the valve  28  and the capsule  12  may be filled with a bio-compatible liquid or gas. The configuration of the osmotic delivery system and the material of the semipermeable membrane  30  control the delivery rate of a beneficial agent from the osmotic delivery system. 
     In assembling the osmotic delivery device  10  according to the embodiment of the present invention shown in FIGS. 1 and 2, the capsule  12  is prepared by forming at least one vent  32  at the first end  14  of the capsule. The vent  32  may be formed by mechanical drilling, laser drilling, molding, or any other known method. The delivery port  18  is an orifice formed by conventional techniques which are known in the art. Included among these methods are mechanical drilling, laser drilling, and molding. The dimensions of the delivery port  18  in terms of both diameter and length will vary with the type of beneficial agent, the rate at which the beneficial agent is to be delivered, and the environment into which it is to be delivered. The considerations involved in determining the optimum dimensions of the delivery port  18  for any particular capsule  12  or beneficial agent and the selection of the appropriate dimensions will be readily apparent to those skilled in the art. 
     Once the capsule  12  of FIGS. 1 and 2 has been prepared with the vent  32  and at least one delivery port  18 , having a number, shape, and size to achieve a desired delivery rate of the beneficial agent, the valve  28  is inserted into the capsule  12  through the open end  16 . 
     According to one embodiment of the present invention, the beneficial agent contained in the first chamber  22  of the capsule  12  is a flowable composition such as a liquid, suspension, or slurry, and is typically poured into the first chamber  22  of the capsule after the valve  28  has been inserted. The separating member  20  is inserted into the capsule  12  through the open end  16  and is positioned adjacent the beneficial agent. 
     Once the osmotic agent pellet(s) or tablet(s) have been formed, they are placed inside the pre-formed capsule in the second chamber  24  adjacent the separating member  20 . Then the semipermeable membrane  30 , according to one embodiment of the present invention, is placed into or over the open end  16  of the capsule  12  to close off and seal the open end of the osmotic delivery system. 
     An alternative embodiment of the invention illustrated in FIGS. 3-4 includes a cap  36  having a hollow interior and a substantially constant thickness cylindrical side wall  42  and an end wall  44 . The cap  36  forms the first end  50  of the capsule  12 . In a preferred embodiment, the cap  36  affixes to the body of the capsule  12  by a snap fitting mechanism  38 , such as a barbed stake. The cap  36  preferably has a vent  48  in the end wall  44  which after assembly allows the valve  28  to move in a direction towards the end wall  14 . In a different embodiment, the cap  36  can be pivotally rotated about a hinge in a direction of the arrow B, as depicted in FIG.  4 . 
     The first chamber  22  of the osmotic delivery device  40  has at least one opening  46  which communicates with the environment of use. As shown in FIG. 3, the opening  46  is formed in the body of the capsule  12  and is positioned adjacent the contacting surfaces of the cap. Alternatively, the opening  46  can be formed in the cap  36  and positioned adjacent the contacting surfaces of the body of the capsule  12 . The semipermeable membrane  30  couples with the capsule  12  at the opened second end  52 . 
     In assembling the osmotic delivery device  10  according to the embodiment of the present invention shown in FIGS. 3 and 4, the cap  36  is prepared by forming at least one vent  48  at the end wall  44 . The vent  48  may be formed by mechanical drilling, laser drilling, molding, or any other known method. 
     The capsule  12  is prepared having an opened first end  50  and an opened second end  52 . The delivery port  46  is an orifice positioned at the edge of the cap  36  adjacent the capsule  12 , or the delivery port  46  is positioned at the edge of the capsule  12  adjacent the cap  36 . The delivery port  18  is formed by conventional techniques which are known in the art. Included among these methods are laser drilling, mechanical drilling, grooving the edge of the capsule or cap, and molding. 
     The separating member  20  is inserted into the capsule  12  through the first or second end  50 ,  52 . Once the osmotic agent pellet(s) or tablet(s) have been formed, they are placed inside the capsule  12  in the second chamber  24 , adjacent the separating member  20 . The semipermeable membrane  30  is placed into or over the second end  52  to close off and seal that end. 
     Beneficial agent is added into the first chamber  22  of the capsule  12  through the first end  50 , and the valve  28  is inserted adjacent the beneficial agent in a closed position. As discussed, the valve  28  in a closed position prevents the beneficial agent from leaving the delivery device  10  and prevents incursion of foreign materials into the device. Then the cap  36  is placed at the first end  50  of the capsule to close off and seal that open end of the osmotic delivery system  10 . The cap  36  may be secured to the capsule  12  by press fitting, snap fitting, threading, adhesive, welding, staking, or the like. 
     In general, materials suitable for use in the movable separating member  20  and the valve  28  are elastomeric materials including non-reactive polymers, as well as elastomers in general, such as polyurethanes and polyamides, chlorinated rubbers, styrene-butadiene rubbers, and chloroprene rubbers. The polymers include acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer, and the like; halogenated polymers such as polytetraflouroethylene, polychlorotrifluoroethylene, copolymer tetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and the like. 
     Semipermeable compositions suitable for the semipermeable membrane  30  are well known in the art, examples of which are disclosed in U.S. Pat. No. 4,874,388, the entire disclosure of which is incorporated herein by reference. Such possible semipermeable materials from which the membrane  30  can be made include, but are not limited to, for example, Hytrel polyester elastomers (DuPont), cellulose esters, cellulose ethers, and cellulose ester-ethers, water flux enhanced ethylene-vinyl acetate copolymers, semipermeable membranes made by blending a rigid polymer with water-soluble low molecular weight compounds, and other semipermeable materials well known in the art. The above cellulosic polymers have a degree of substitution, D.S., on the anhydroglucose unit, from greater than 0 up to 3 inclusive. By “degree of substitution” or “D.S.” is meant the average number of hydroxyl groups originally present on the anhydroglucose unit comprising the cellulose polymer that are replaced by a substituting group. Representative materials include, but are not limited to, one selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and tricellulose alkanylates, mono-, di-, and tricellulose aroylates, and the like. Exemplary cellulosic polymers include cellulose acetate having a D.S. up to 1 and an acetyl content up to 21%; cellulose acetate having a D.S. of 1 to 2 and an acetyl content of 21% to 35%; cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35% to 44.8%, and the like. More specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 and a propionyl content of 39.2% to 45% and a hydroxyl content of 2.8% to 5.4%; cellulose acetate butyrate having a D.S. of 1.8 and an acetyl content of 13% to 15% and a butyryl content of 34% to 39%; cellulose acetate butyrate having an acetyl content of 2% to 29%, a butyryl content of 17% to 53%, and a hydroxyl content of 0.5% to 4.7%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 4% average weight percent, and a butyryl content of 51%; cellulose triacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentate; coesters of cellulose such as cellulose acetate butyrate and cellulose, cellulose acetate propionate, and the like. 
     Other materials for the membrane  30  are polyurethane, polyetherblockamide (PEBAX, commercially available from ELF ATOCHEM, Inc.), and injection-moldable thermoplastic polymers with some hydrophilicity such as ethylene vinyl alcohol (EVA). In general, the membrane  30  is made from semipermeable materials having a water uptake ranging from 1% to 80% but preferably less than 50%. The composition of the semipermeable membrane  30  is permeable to the passage of external liquids such as water and biological liquids, and it is substantially impermeable to the passage of beneficial agents, osmopolymers, osmagents, and the like. 
     Materials which may be used for the capsule  12  and the cap  36  must be sufficiently strong to ensure that the capsule will not leak, crack, break, or distort under stresses to which it is subjected during implantation or under stresses due to the pressures generated during operation. The capsule  12  may be formed of chemically inert and biocompatible, natural or synthetic materials which are known in the art. The capsule material is preferably a nonbioerodible material which remains in the patient after use, such as titanium or a titanium alloy, and is largely impermeable to materials within and outside the capsule. However, the material of the capsule  12  may alternatively be a bioerodible material which bioerodes in the environment after dispensing of the beneficial agent. Generally, preferred materials for the capsule  12  are those acceptable for animal and human implants. 
     In general, typical materials of construction suitable for the capsule  12  according to the present invention include non-reactive polymers or biocompatible metals or alloys. Metallic materials useful for the capsule  12  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. 
     The capsule  12  may be formed from any of the wall-forming materials disclosed above by the use of a mold, with the materials applied either over the mold or inside the mold, depending on the mold configuration. Any of the wide variety of techniques known in the pharmaceutical industry may be used to form the capsule  12 . 
     The osmotic agent is a liquid-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(hydroxyalkyl 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 hydroxypropl methycellulose and sodium carboxymethylcellulose, polymers of N-vinyllactams, polyoxyethylene-polyoxypropylene gels, polyoxybutylene-polyethylene block copolymer gels, carob gum, polyacrylic gels, polyester gels, polyuria 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. 
     The osmotic agent may be a solid osmotic tablet or a fluid osmotic agent. The osmotic tablet may be formed in many different conceivable shapes, textures, densities, and consistencies and still be within the confines of the present invention. The osmotic agent may be manufactured by a variety of techniques, many of which are known in the art. In one such technique, the osmotically active agent is prepared as solid or semi-solid formulation and pressed into pellets or tablets whose dimensions correspond to slightly less than the internal dimensions of the respective chambers which they will occupy in the capsule interior. Depending on the nature of the materials used, the agent and other solid ingredients which may be included may be processed prior to the formation of the pellets by such procedures as ballmilling, calendaring, stirring, or rollmilling to achieve a fine particle size and hence fairly uniform mixtures of each. 
     The present invention applies to the administration of beneficial agents in general, which include any physiologically or pharmacologically active substance. 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-inflanunatory 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, coagultion factors, human pancreas hormone releasing factor, analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or their analogs or derivatives. 
     On the molecular level, the various forms of the beneficial agent may include uncharged molecules, molecular complexes, and pharmaceutically acceptable acid addition and base addition salts such as hydrochlorides, hydrobromides, acetate, 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. A beneficial agent can be used alone or mixed with other agents. The beneficial agent may optionally include pharmaceutically acceptable carriers and/or additional ingredients such as antioxidants, stabilizing agents, permeation enhances, and the like. 
     Animals to whom beneficial agents 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 wherein aqueous body fluids are available to activate the osmotic agent. Devices of the invention may also be administered to the rumen of ruminant animals, in which embodiment the devices may further comprise a density element for maintaining the device in the rumen for extended periods of time of up to 120 days or longer. Density elements are well known in the art of drug delivery devices. 
     The delivery devices of this invention are also useful in environments outside of physiological or aqueous environments. For example, the delivery 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 an animal, primarily to humans. They may also be utilized in blood oxygenators, kidney dialysis and electrophoresis, for example. Additionally, delivery devices of the present invention may be used in the biotechnology area, such as to deliver nutrients or growth regulating compounds to cell cultures. In such instances, activating mechanisms such as mechanical mechanisms are particularly useful. 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 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. 
     While the invention has been described in detail with reference to preferred embodiments thereof, it will be apparent to one skilled in the art that various changes can be made, and equivalents employed without departing from the invention.