Abstract:
An osmotic pump includes a capsule having at least one delivery port formed at a first end and a membrane plug retained in a second end of the capsule remote from the delivery port to provide a fluid-permeable barrier between an interior and an exterior of the capsule. The membrane plug has a columnar body and at least one slot formed in the columnar body to vent pressure from the interior to the exterior of the capsule when the columnar body extends a predetermined distance relative to the second end of the capsule, thereby preventing expulsion of the membrane plug from the second end.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of U.S. Provisional Application No. 60/517,220, filed Oct. 31, 2003. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    The invention relates generally to osmotic pumps for delivering beneficial agents. More specifically, the invention relates to an osmotic pump having a membrane plug for controlling the delivery rate of a beneficial agent. 
         [0003]    Osmotic pumps for delivering beneficial agents within the body of a patient are known in the art. For illustration purposes,  FIG. 1A  shows a cross-section of a prior-art osmotic pump  100  having an implantable capsule  102  with open ends  104 ,  106 . A diffusion moderator (also called flow modulator)  108  is disposed in the open end  106  of the capsule  102 . The diffusion moderator  108  has a delivery path  110  that terminates at a delivery port  112  and allows fluid from the interior of the capsule  102  to be transported to the exterior of the capsule  102 . A membrane plug  114  is inserted in the open end  104  of the capsule  102 . The membrane plug  114  is made of a semipermeable material and forms a fluid-permeable barrier between the exterior and the interior of the capsule  102 . A piston  116  is disposed in the capsule  102 . The piston  116  defines two chambers  118 ,  120  within the capsule  102 . The chamber  118  contains an osmotic agent  122 , and the chamber  120  contains a beneficial agent  124 . 
         [0004]    When the osmotic pump  100  is implanted in a patient, fluid from the body of the patient enters the chamber  118  through the membrane plug  114 , permeates the osmotic agent  122 , and causes the osmotic agent  122  to swell. The swollen osmotic agent  122  pushes the piston  116  in a direction away from the membrane plug  114 , reducing the volume of the chamber  120  and forcing an amount of the beneficial agent  124  out of the capsule  102  through the diffusion moderator  108  into the body of the patient. The rate at which the osmotic pump  100  delivers the beneficial agent  124  to the body depends on the rate at which fluid permeates the membrane plug  114 . 
         [0005]    Typically, the membrane plug  114  is made of a hydratable compound that must hydrate in order for the osmotic agent  122  to begin absorbing moisture. The time to hydrate the membrane plug  114  and the osmotic agent  122  delays the start of ejection of the beneficial agent  124  from the chamber  120 . During this startup phase, body fluid, usually water, can back-diffuse into the delivery port  112  of the diffusion moderator  108  and degrade the beneficial agent  124  or the vehicle carrying the beneficial agent  124 . Some vehicles when they combine with water can plug the delivery path  110 . 
         [0006]    If the delivery path  110  or port  112  becomes plugged, for example, due to a lengthy startup, or if the piston  116  becomes stuck inside the capsule  102 , there will be pressure buildup in the chamber  118 , which may be sufficient to expel the membrane plug  114  from the capsule  102 . 
         [0007]    Various methods have been proposed for avoiding expulsion of the membrane plug  114  from the capsule  102 . One method involves securing the membrane plug  114  to the capsule  102  using an adhesive. This method requires an additional operation to apply the adhesive to the membrane plug  114  and/or the capsule  102 , and the adhesive may affect the permeability of the membrane plug  114 . Another method for avoiding expulsion of the membrane plug  114  is to drill a hole in the end portion of the capsule  102  containing the membrane plug  114 .  FIG. 1B  shows a hole  126  drilled in the capsule  102 . As shown in  FIG. 1B , the hole  126  is initially covered by the membrane plug  114 , but as the membrane plug  114  is forced out of the capsule  102  due to pressure buildup in the chamber  118 , the hole  126  will eventually become exposed, allowing pressure to be vented from the chamber  118  to the exterior of the capsule  102 . In this manner, the membrane plug  114  is prevented from becoming separated from the capsule  102 . This method requires an additional operation in the fabrication of the capsule  102  and increases the overall cost of the osmotic pump. 
       BRIEF SUMMARY OF THE INVENTION 
       [0008]    In one aspect, the invention relates to an osmotic pump which comprises a capsule having at least one delivery port formed at a first end and a membrane plug retained in a second end of the capsule remote from the delivery port to provide a fluid-permeable barrier between an interior and an exterior of the capsule. The membrane plug has a columnar body and at least one slot formed in the columnar body to vent pressure from the interior to the exterior of the capsule when the columnar body extends a predetermined distance relative to the second end of the capsule, thereby preventing expulsion of the membrane plug from the second end. 
         [0009]    In another aspect, the invention relates to a membrane plug for use with an osmotic pump having a delivery capsule. The membrane plug comprises a columnar body made of a semipermeable material and having an outer surface for engagement with an inner surface of the capsule. The columnar body is provided with at least one slot, which extends from a base of the columnar body to a non-basal point on the outer surface of the columnar body so that pressure can be selectively vented from an interior to an exterior of the capsule. 
         [0010]    In yet another aspect, the invention relates to a membrane plug for use with an osmotic pump having a delivery capsule which comprises a columnar body made of a semipermeable material. The columnar body has an outer surface for engagement with an inner surface of the capsule and is provided with an orifice that allows fluid flow into the capsule until the orifice becomes occluded due to swelling of the semipermeable material. 
         [0011]    Other features and advantages of the invention will be apparent from the following description and the appended claims. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIGS. 1A and 1B  are cross-sections of prior-art osmotic pumps. 
           [0013]      FIG. 2A  is an enlarged view of a membrane plug according to an embodiment of the invention. 
           [0014]      FIG. 2B  is an enlarged view of a membrane plug according to another embodiment of the invention. 
           [0015]      FIG. 2C  is a cross-section of a membrane plug according to another embodiment of the invention. 
           [0016]      FIG. 3  shows an osmotic pump incorporating an embodiment of the membrane plug of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0017]    The invention will now be described in detail with reference to a few preferred embodiments, as illustrated in accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that the invention may be practiced without some or all of these specific details. In other instances, well-known features and/or process steps have not been described in detail in order to not unnecessarily obscure the invention. The features and advantages of the invention may be better understood with reference to the drawings and discussions that follow. 
         [0018]      FIG. 2A  shows a membrane plug  200  according to an embodiment of the invention. The membrane plug  200  can be inserted into an open end of an osmotic pump capsule (not shown) to control the rate at which fluid enters the capsule. The membrane plug  200  has a columnar body  202 . The outer diameter of the columnar body  202  is selected such that the columnar body  202  can fit into the capsule. In one embodiment, the columnar body  202  terminates in an enlarged end cap  204 . When the membrane plug  200  is inserted in the capsule, the end cap  204  acts as a stop member engaging an end of the capsule and achieving a repeatable position of the membrane plug  200  inside the capsule. In an alternative embodiment, the end cap  204  may be omitted, allowing the membrane plug  200  to be fully inserted into the capsule. 
         [0019]    One or more slots  206  are formed in the columnar body  202 . In one embodiment, the slots  206  are longitudinal, extending from the base  208  of the columnar body  202  to a point  210  below the end cap  204 . In alternative embodiments, the slot(s) formed in the columnar body  202  may have other shapes. For example, a helical slot extending from the base  208  of the columnar body  202  to a point below the end cap  204  could be formed. Measured from the base  208  of the columnar body  202 , the extent or height (l o ) of the slot(s)  206  may be in a range from about 10 to 90% of the length (L) of the columnar body  202 , preferably in a range from about 20 to 80% of the length of the columnar body  202 , more preferably in a range from about 30 to 60% of the length of the columnar body  202 . In general, the extent or height (l o ) of the slot(s)  206  should be selected such that there is adequate (uninterrupted) sealing surface at the top portion  212  of the columnar body  202 . The depth and width of the slot(s)  206  can be variable. In general, the depth and width should be selected such that the structural integrity of the membrane plug  200  is not compromised in use. The depth and width of the slot(s)  206  should be sufficiently large to be reproducibly formed in the columnar body  202  and to prevent occlusion of the slot due to swelling of the membrane material when hydrated. The depth of the slot(s)  206  can be in a range from approximately 1 to 99% of the diameter of the columnar body  202 , preferably in a range from approximately 10 to 90% of the diameter of the columnar body  202 . The width of the slot(s)  206  can be in a range from approximately 1 to 99% of the diameter of the columnar body  202 , preferably in a range from approximately 10 to 90% of the diameter of the columnar body  202 . 
         [0020]    Protrusions, such as ribs, ridges, threads, or the like, may be formed on the columnar body  202  to enhance sealing between the columnar body  202  and the osmotic pump capsule (not shown), as taught by Chen et al. in U.S. Pat. No. 6,113,938.  FIG. 2B  shows circumferential ribs  214  formed on the columnar body  202  with the slots  206  cutting through the ribs  214 . Preferably, the length of the slot(s)  206  is such that there are continuous ribs  214  in the top portion  212  of the columnar body  202  to ensure proper sealing between the top portion  212  and the inner surface of the osmotic pump capsule. 
         [0021]    The membrane plug  200  is made of a semipermeable material that allows fluid, usually water, to pass into the interior of an osmotic pump capsule while preventing compositions within the capsule from passing out of the capsule. Semipermeable materials suitable for use in the invention are well known in the art. Semipermeable materials for the membrane plug  200  are those that can conform to the shape of the capsule upon wetting and that can adhere to the inner surface of the capsule. Typically, these materials are polymeric materials, which can be selected based on the pumping rates and system configuration requirements, and include, but are not limited to, plasticized cellulosic materials, enhanced PMMAs such as hydroxyethylmethacrylate (HEMA), and elastomeric materials such as polyurethanes and polyamides, polyether-polyamind copolymers, thermoplastic copolyesters, and the like. 
         [0022]      FIG. 3  shows the membrane plug  200  used in an osmotic pump  300 . It should be noted that the internal structure of the osmotic pump  300  is presented for illustration purposes only and is not to be construed as limiting the present invention. The present invention is generally applicable to all osmotic pumps having any number of shapes, and to all such pumps administered in implantable osmotic delivery techniques. 
         [0023]    The osmotic pump  300  includes an elongated cylindrical capsule  302 , which may be sized such that it can be implanted within a body. The capsule  302  has open ends  304 ,  306 . The membrane plug  200  is inserted in the open end  304 , and a diffusion moderator (or flow modulator)  308  is inserted in the open end  306 . The diffusion moderator  308  includes a delivery path  310  which terminates in a delivery port  312 . Although not shown, the diffusion moderator  308  may also include a vent hole and optionally a fill hole, as taught by Peterson et al. in U.S. Pat. No. 6,524,305. In an alternative embodiment, the diffusion moderator  308  could be omitted, and the open end  306  could be replaced with a closed end having a delivery port. The diffusion moderator  308  (or delivery port) allows fluid from within the capsule  302  to be delivered to the exterior of the capsule  302 , while the membrane plug  200  allows fluid from the exterior of the capsule  302  to enter the interior of the capsule  302 . 
         [0024]    Two chambers  314 ,  316  are defined inside the capsule  302 . The chambers  314 ,  316  are separated by a piston  318 , which is configured to fit within the capsule  302  in a sealing manner and to move longitudinally within the capsule  302 . The piston  318  may be made of an impermeable resilient material. As an example, the piston  318  may include annular ring shape protrusion(s)  319  that form a seal with the inner surface of the capsule  302 . An osmotic agent  320  is disposed in the chamber  314  adjacent the membrane plug  200 , and a beneficial agent  322  to be delivered to a body is disposed in the chamber  316  adjacent the diffusion moderator  308 . The piston  318  isolates the beneficial agent  322  from the environmental liquids that are permitted to enter the capsule  302  through the membrane plug  200  such that in use, at steady-state flow, the beneficial agent  322  is expelled through the delivery port  312  at a rate corresponding to the rate at which liquid from the environment of use flows into the osmotic agent  320  through the membrane plug  200 . 
         [0025]    In operation, fluid enters the chamber  314  through the membrane plug  200  and permeates the osmotic agent  320 . The wetted osmotic agent  320  swells and pushes the piston  318  in a direction away from the membrane plug  200 , reducing the volume of the chamber  316  and forcing an amount of the beneficial agent  322  out through the diffusion moderator  308 . If the diffusion moderator  308  becomes plugged or the piston  318  becomes stuck, pressure will build up in the chamber  314 . This pressure buildup will force the membrane plug  200  in a direction away from the piston  318 . The membrane plug  200  will slide out of the capsule  302  until the slot(s)  206  are exposed. As soon as the slots  206  are exposed, pressure from the chamber  314  will escape to the exterior of the capsule  302 , thereby preventing further movement of the membrane plug  200  out of the capsule  302 . The membrane plug  200  may return to its original position after the pressure buildup in the chamber  314  has been vented. 
         [0026]    In general, materials suitable for constructing the capsule  302  must be sufficiently rigid to withstand expansion of the osmotic agent  320  without changing its size or shape. Further, the materials should ensure that the capsule  302  will not leak, crack, break, or distort under stress to which it could be subjected during implantation or under stresses due to the pressures generated during operation. The capsule  302  may be formed of chemically inert biocompatible, natural or synthetic materials which are known in the art. The capsule material is preferably a non-bioerodible material which remains in the patient after use, such as titanium. However, the material of the capsule  302  may alternatively be a bioerodible material which bioerodes in the environment after dispensing of the beneficial agent. Generally, preferred materials for the capsule  302  are those acceptable for human implantation. 
         [0027]    In general, typical materials of construction suitable for the capsule  302  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 polytetraflouroethylene, polychlorotrifluoroethylene, copolymer tetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and the like. Metallic materials useful for the capsule  302  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. 
         [0028]    A capsule  302  made from the titanium or a titanium alloy having greater than 60%, often greater than 85% titanium, is particularly preferred for the most size-critical applications, for high payload capability and for long duration applications, and for those applications where the formulation is sensitive to body chemistry at the implantation site or where the body is sensitive to the formulation. In certain embodiments, and for applications other than the fluid-imbibing devices specifically described, where unstable beneficial agent formulations are in the capsule  302 , particularly protein and/or peptide formulations, the metallic components to which the formulation is exposed must be formed of titanium or its alloys as described above. 
         [0029]    The osmotic agent  320  may be in tablet form as shown or may have other shape, texture, density, and consistency. For example, the osmotic agent  320  may be in powder or granular form. The osmotic agent  320  may be, for example, a nonvolatile water soluble osmagent, an osmopolymer which swells on contact with water, or a mixture of the two. 
         [0030]    In general, the present invention applies to the administration of beneficial agents, which include any physiologically or pharmacologically active substance. The beneficial agent  322  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. Drug agents which may be delivered by the present invention include drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, ocular drugs and synthetic analogs of these species. An exemplary list of drugs that may be delivered using the osmotic pump is disclosed in U.S. Pat. No. 6,270,787. The list is incorporated herein by reference. 
         [0031]    The beneficial agent  322  can be present in a wide variety of chemical and physical forms, such as solids, liquids and slurries. On the molecular level, the various forms may include uncharged molecules, molecular complexes, and pharmaceutically acceptable acid addition and base addition salts such as hydrochlorides, hydrobromides, sulfate, laurylate, oleate, and salicylate. For acidic compounds, salts of metals, amines or organic cations may be used. Derivatives such as esters, ethers and amides can also be used. A beneficial agent  322  can be used alone or mixed with other beneficial agents. The beneficial agent  322  may optionally include pharmaceutically acceptable carriers and/or additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc. 
         [0032]      FIG. 2C  shows another embodiment of the membrane plug  200 . In this embodiment, at least one orifice  216  is formed in the columnar body  202 . When the membrane plug  200  is inserted at an end of an osmotic pump, such as osmotic pump ( 300  in  FIG. 3 ), the orifice  216  allows fluid to pass through the membrane plug  200  to the osmotic agent ( 320  in  FIG. 3 ) and permeate the osmotic agent ( 320  in  FIG. 3 ) before the membrane plug  200  is fully hydrated. This has the effect of accelerating the startup phase of the osmotic pump. The size of the orifice  216  is such that fluid can flow through the columnar body  202 . The size of the orifice  216  is also such that upon adequate hydration/swelling of the columnar body  202  the orifice  216  becomes occluded, allowing the osmotic function of the system to be fully activated. 
         [0033]    The diameter of the orifice  216  depends on the outside diameter of the columnar body  202  of the membrane plug  200 , the inside diameter of the capsule ( 302  in  FIG. 3 ), and the percentage of fluid the membrane plug  200  material will absorb. The diameter of the orifice  216  may be selected based on the assumption that the membrane plug  200  material will expand the same percentage in all directions until it meets a constraint such as the capsule. 
         [0034]    The volume, V, of the membrane plug  200  can be expressed as follows: 
         [0000]        V=πL ( D/ 2) 2   (1) 
         [0000]    where L is the length of the membrane plug  200  and D is the diameter of the columnar body  202 . Multiplying both sides of equation (1) by (1+b) 3  gives: 
         [0000]    
       
         
           
             
               
                 
                   
                     
                       V 
                        
                       
                         ( 
                         
                           1 
                           + 
                           b 
                         
                         ) 
                       
                     
                     3 
                   
                   = 
                   
                     
                       L 
                        
                       
                         ( 
                         
                           1 
                           + 
                           b 
                         
                         ) 
                       
                     
                      
                     
                       
                         ( 
                         
                           
                             D 
                              
                             
                               ( 
                               
                                 1 
                                 + 
                                 b 
                               
                               ) 
                             
                           
                           2 
                         
                         ) 
                       
                       2 
                     
                      
                     π 
                   
                 
               
               
                 
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                   2 
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         [0000]    where b is the change in the linear dimension of the membrane plug  200  due to fluid absorption. Let c be the change in volume of the membrane plug  200  due to fluid absorption, then: 
         [0000]      (1 +b ) 3 =1 +c   (3) 
         [0035]    If the outside diameter of the membrane plug  200  is the same as the inside diameter of the capsule ( 302  in  FIG. 3 ), then the area of the orifice  216  at time 0 before the plug expands (A o,t=0 ) must be less than the difference between the cross-sectional area of the plug at time 0 before the plug expands (A p,t=0 ) and the cross-sectional area of the plug at time 1 after the plug expands (A p,t=1 ). That is, 
         [0000]        A   o,t=0   &lt;A   p,t=1   −A   p,t=0   (4) 
         [0000]      where 
         [0000]        A   o,t=0 =( d/ 2) 2 π  (5) 
         [0000]    where d is the diameter of the orifice before the plug expands (t=0) and 
         [0000]        A   p,t=0 =( D/ 2) 2 π  (6) 
         [0000]      and 
         [0000]        A   p,t=1   =[D (1 +b )/2] 2 π  (7) 
         [0000]    The following expression is obtained by combining equation (3) with equation (7): 
         [0000]        A   p=t=1 =( D/ 2) 2 (1 +c ) 2/3 π  (8) 
         [0000]    From equations (6) and (8), the difference between the cross-sectional area of the plug at time 0 and time 1 becomes: 
         [0000]        A   p,t=1   −A   p,t=0 =( D/ 2) 2 [(1 +c ) 2/3 −1]π  (9) 
         [0036]    The following expression is obtained by substituting equations (5) and (9) into equation (4) and solving for d: 
         [0000]        d &lt;√{square root over (( D ) 2 [(1 +c ) 2/3 −1])}{square root over (( D ) 2 [(1 +c ) 2/3 −1])}  (10) 
         [0037]    Thus, for a membrane plug that expands 18% (c=18%) with a columnar diameter of 3 mm (D=3 mm) in a capsule with a diameter of 3 mm, d&lt;1.02 mm. For this example, d is less than 35% of the diameter of the columnar body. Preferably, d is in a range from 0.8 to 33% of the diameter of the columnar body. 
         [0038]    The invention typically provides the following advantages. The membrane plug of the invention has a built-in mechanism that prevents its expulsion from an osmotic pump capsule once inserted in the capsule. As a result, additional operations to glue the membrane plug to the capsule or drill holes in the capsule are avoided. Further, any compromise in the operation of the membrane plug due to gluing of the membrane plug to the capsule is avoided. The mechanism for preventing expulsion of the membrane plug from the capsule, i.e., the vent slot(s), can be formed in the membrane plug at the time that the membrane plug is fabricated. For example, if the membrane plug is formed by molding, the mold design would already account for the slot(s) in the membrane plug. Because this solution does not require an additional operation, it should not significantly increase the cost of the osmotic pump. The membrane plug can include an orifice that allows the osmotic agent to start hydrating even before the membrane plug is fully hydrated. This has the effect of accelerating the startup phase of the osmotic pump. 
         [0039]    While the invention has been described with respect to a limited number of embodiments, those skilled in the art, having benefit of this disclosure, will appreciate that other embodiments can be devised which do not depart from the scope of the invention as disclosed herein. Accordingly, the scope of the invention should be limited only by the attached claims.