US20080269726A1 - Osmotic pump with self-retaining, fast-start membrane plug - Google Patents
Osmotic pump with self-retaining, fast-start membrane plugInfo
- Publication number
- US20080269726A1 US20080269726A1 US12/217,266 US21726608A US2008269726A1 US 20080269726 A1 US20080269726 A1 US 20080269726A1 US 21726608 A US21726608 A US 21726608A US 2008269726 A1 US2008269726 A1 US 2008269726A1
- Authority
- US
- United States
- Prior art keywords
- capsule
- columnar body
- osmotic pump
- membrane plug
- diameter
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
Definitions
- 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.
- 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
- the chamber 120 contains a beneficial agent 124 .
- the osmotic pump 100 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 .
- 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 .
- body fluid usually water
- 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 .
- FIG. 1B shows a hole 126 drilled in the capsule 102 .
- 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.
- 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.
- the invention in another aspect, 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.
- 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.
- FIGS. 1A and 1B are cross-sections of prior-art osmotic pumps.
- FIG. 2A is an enlarged view of a membrane plug according to an embodiment of the invention.
- FIG. 2B is an enlarged view of a membrane plug according to another embodiment of the invention.
- FIG. 2C is a cross-section of a membrane plug according to another embodiment of the invention.
- FIG. 3 shows an osmotic pump incorporating an embodiment of the membrane plug of the present invention.
- 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.
- the columnar body 202 terminates in an enlarged end cap 204 .
- 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.
- the end cap 204 may be omitted, allowing the membrane plug 200 to be fully inserted into the capsule.
- One or more slots 206 are formed in the columnar body 202 .
- the slots 206 are longitudinal, extending from the base 208 of the columnar body 202 to a point 210 below the end cap 204 .
- 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.
- 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 .
- 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.
- 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 .
- 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 .
- 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.
- 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.
- 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.
- plasticized cellulosic materials such as hydroxyethylmethacrylate (HEMA), and elastomeric materials such as polyurethanes and polyamides, polyether-polyamind copolymers, thermoplastic copolyesters, and the like.
- HEMA hydroxyethylmethacrylate
- FIG. 3 shows the membrane plug 200 used in an osmotic pump 300 .
- 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.
- 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
- 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 .
- 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.
- 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 .
- 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.
- 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 .
- 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.
- 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.
- the material of the capsule 302 may alternatively be a bioerodible material which bioerodes in the environment after dispensing of the beneficial agent.
- preferred materials for the capsule 302 are those acceptable for human implantation.
- 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.
- 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.
- the metallic components to which the formulation is exposed must be formed of titanium or its alloys as described above.
- the osmotic agent 320 may be in tablet form as shown or may have other shape, texture, density, and consistency.
- 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.
- 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.
- 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.
- FIG. 2C shows another embodiment of the membrane plug 200 .
- at least one orifice 216 is formed in the columnar body 202 .
- 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.
- 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.
- the volume, V, of the membrane plug 200 can be expressed as follows:
- V ⁇ ( 1 + b ) 3 L ⁇ ( 1 + b ) ⁇ ( D ⁇ ( 1 + b ) 2 ) 2 ⁇ ⁇ ( 2 )
- d is less than 35% of the diameter of the columnar body.
- d is in a range from 0.8 to 33% of the diameter of the columnar body.
- 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.
- 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.
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
- This application claims the benefit of U.S. Provisional Application No. 60/517,220, filed Oct. 31, 2003.
- 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.
- 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-artosmotic pump 100 having animplantable capsule 102 withopen ends open end 106 of thecapsule 102. Thediffusion moderator 108 has adelivery path 110 that terminates at adelivery port 112 and allows fluid from the interior of thecapsule 102 to be transported to the exterior of thecapsule 102. Amembrane plug 114 is inserted in theopen end 104 of thecapsule 102. Themembrane plug 114 is made of a semipermeable material and forms a fluid-permeable barrier between the exterior and the interior of thecapsule 102. Apiston 116 is disposed in thecapsule 102. Thepiston 116 defines twochambers capsule 102. Thechamber 118 contains anosmotic agent 122, and thechamber 120 contains abeneficial agent 124. - When the
osmotic pump 100 is implanted in a patient, fluid from the body of the patient enters thechamber 118 through themembrane plug 114, permeates theosmotic agent 122, and causes theosmotic agent 122 to swell. The swollenosmotic agent 122 pushes thepiston 116 in a direction away from themembrane plug 114, reducing the volume of thechamber 120 and forcing an amount of thebeneficial agent 124 out of thecapsule 102 through thediffusion moderator 108 into the body of the patient. The rate at which theosmotic pump 100 delivers thebeneficial agent 124 to the body depends on the rate at which fluid permeates themembrane plug 114. - Typically, the
membrane plug 114 is made of a hydratable compound that must hydrate in order for theosmotic agent 122 to begin absorbing moisture. The time to hydrate themembrane plug 114 and theosmotic agent 122 delays the start of ejection of thebeneficial agent 124 from thechamber 120. During this startup phase, body fluid, usually water, can back-diffuse into thedelivery port 112 of thediffusion moderator 108 and degrade thebeneficial agent 124 or the vehicle carrying thebeneficial agent 124. Some vehicles when they combine with water can plug thedelivery path 110. - If the
delivery path 110 orport 112 becomes plugged, for example, due to a lengthy startup, or if thepiston 116 becomes stuck inside thecapsule 102, there will be pressure buildup in thechamber 118, which may be sufficient to expel themembrane plug 114 from thecapsule 102. - Various methods have been proposed for avoiding expulsion of the
membrane plug 114 from thecapsule 102. One method involves securing themembrane plug 114 to thecapsule 102 using an adhesive. This method requires an additional operation to apply the adhesive to themembrane plug 114 and/or thecapsule 102, and the adhesive may affect the permeability of themembrane plug 114. Another method for avoiding expulsion of themembrane plug 114 is to drill a hole in the end portion of thecapsule 102 containing themembrane plug 114.FIG. 1B shows ahole 126 drilled in thecapsule 102. As shown inFIG. 1B , thehole 126 is initially covered by themembrane plug 114, but as themembrane plug 114 is forced out of thecapsule 102 due to pressure buildup in thechamber 118, thehole 126 will eventually become exposed, allowing pressure to be vented from thechamber 118 to the exterior of thecapsule 102. In this manner, themembrane plug 114 is prevented from becoming separated from thecapsule 102. This method requires an additional operation in the fabrication of thecapsule 102 and increases the overall cost of the osmotic pump. - 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.
- 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.
- 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.
- Other features and advantages of the invention will be apparent from the following description and the appended claims.
-
FIGS. 1A and 1B are cross-sections of prior-art osmotic pumps. -
FIG. 2A is an enlarged view of a membrane plug according to an embodiment of the invention. -
FIG. 2B is an enlarged view of a membrane plug according to another embodiment of the invention. -
FIG. 2C is a cross-section of a membrane plug according to another embodiment of the invention. -
FIG. 3 shows an osmotic pump incorporating an embodiment of the membrane plug of the present invention. - 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.
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FIG. 2A shows amembrane plug 200 according to an embodiment of the invention. Themembrane 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. Themembrane plug 200 has acolumnar body 202. The outer diameter of thecolumnar body 202 is selected such that thecolumnar body 202 can fit into the capsule. In one embodiment, thecolumnar body 202 terminates in an enlargedend cap 204. When themembrane plug 200 is inserted in the capsule, theend cap 204 acts as a stop member engaging an end of the capsule and achieving a repeatable position of themembrane plug 200 inside the capsule. In an alternative embodiment, theend cap 204 may be omitted, allowing themembrane plug 200 to be fully inserted into the capsule. - One or
more slots 206 are formed in thecolumnar body 202. In one embodiment, theslots 206 are longitudinal, extending from thebase 208 of thecolumnar body 202 to apoint 210 below theend cap 204. In alternative embodiments, the slot(s) formed in thecolumnar body 202 may have other shapes. For example, a helical slot extending from thebase 208 of thecolumnar body 202 to a point below theend cap 204 could be formed. Measured from thebase 208 of thecolumnar body 202, the extent or height (lo) of the slot(s) 206 may be in a range from about 10 to 90% of the length (L) of thecolumnar body 202, preferably in a range from about 20 to 80% of the length of thecolumnar body 202, more preferably in a range from about 30 to 60% of the length of thecolumnar body 202. In general, the extent or height (lo) of the slot(s) 206 should be selected such that there is adequate (uninterrupted) sealing surface at thetop portion 212 of thecolumnar 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 themembrane 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 thecolumnar 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 thecolumnar body 202, preferably in a range from approximately 10 to 90% of the diameter of thecolumnar body 202. The width of the slot(s) 206 can be in a range from approximately 1 to 99% of the diameter of thecolumnar body 202, preferably in a range from approximately 10 to 90% of the diameter of thecolumnar body 202. - Protrusions, such as ribs, ridges, threads, or the like, may be formed on the
columnar body 202 to enhance sealing between thecolumnar 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 showscircumferential ribs 214 formed on thecolumnar body 202 with theslots 206 cutting through theribs 214. Preferably, the length of the slot(s) 206 is such that there arecontinuous ribs 214 in thetop portion 212 of thecolumnar body 202 to ensure proper sealing between thetop portion 212 and the inner surface of the osmotic pump capsule. - 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 themembrane 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. -
FIG. 3 shows themembrane plug 200 used in anosmotic pump 300. It should be noted that the internal structure of theosmotic 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. - The
osmotic pump 300 includes an elongatedcylindrical capsule 302, which may be sized such that it can be implanted within a body. Thecapsule 302 hasopen ends membrane plug 200 is inserted in theopen end 304, and a diffusion moderator (or flow modulator) 308 is inserted in theopen end 306. Thediffusion moderator 308 includes adelivery path 310 which terminates in adelivery port 312. Although not shown, thediffusion 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, thediffusion moderator 308 could be omitted, and theopen end 306 could be replaced with a closed end having a delivery port. The diffusion moderator 308 (or delivery port) allows fluid from within thecapsule 302 to be delivered to the exterior of thecapsule 302, while themembrane plug 200 allows fluid from the exterior of thecapsule 302 to enter the interior of thecapsule 302. - Two
chambers capsule 302. Thechambers piston 318, which is configured to fit within thecapsule 302 in a sealing manner and to move longitudinally within thecapsule 302. Thepiston 318 may be made of an impermeable resilient material. As an example, thepiston 318 may include annular ring shape protrusion(s) 319 that form a seal with the inner surface of thecapsule 302. Anosmotic agent 320 is disposed in thechamber 314 adjacent themembrane plug 200, and abeneficial agent 322 to be delivered to a body is disposed in thechamber 316 adjacent thediffusion moderator 308. Thepiston 318 isolates thebeneficial agent 322 from the environmental liquids that are permitted to enter thecapsule 302 through themembrane plug 200 such that in use, at steady-state flow, thebeneficial agent 322 is expelled through thedelivery port 312 at a rate corresponding to the rate at which liquid from the environment of use flows into theosmotic agent 320 through themembrane plug 200. - In operation, fluid enters the
chamber 314 through themembrane plug 200 and permeates theosmotic agent 320. The wettedosmotic agent 320 swells and pushes thepiston 318 in a direction away from themembrane plug 200, reducing the volume of thechamber 316 and forcing an amount of thebeneficial agent 322 out through thediffusion moderator 308. If thediffusion moderator 308 becomes plugged or thepiston 318 becomes stuck, pressure will build up in thechamber 314. This pressure buildup will force themembrane plug 200 in a direction away from thepiston 318. Themembrane plug 200 will slide out of thecapsule 302 until the slot(s) 206 are exposed. As soon as theslots 206 are exposed, pressure from thechamber 314 will escape to the exterior of thecapsule 302, thereby preventing further movement of themembrane plug 200 out of thecapsule 302. Themembrane plug 200 may return to its original position after the pressure buildup in thechamber 314 has been vented. - In general, materials suitable for constructing the
capsule 302 must be sufficiently rigid to withstand expansion of theosmotic agent 320 without changing its size or shape. Further, the materials should ensure that thecapsule 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. Thecapsule 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 thecapsule 302 may alternatively be a bioerodible material which bioerodes in the environment after dispensing of the beneficial agent. Generally, preferred materials for thecapsule 302 are those acceptable for human implantation. - 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 thecapsule 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. - 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 thecapsule 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. - The
osmotic agent 320 may be in tablet form as shown or may have other shape, texture, density, and consistency. For example, theosmotic agent 320 may be in powder or granular form. Theosmotic 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. - 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. - 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. Abeneficial agent 322 can be used alone or mixed with other beneficial agents. Thebeneficial agent 322 may optionally include pharmaceutically acceptable carriers and/or additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc. -
FIG. 2C shows another embodiment of themembrane plug 200. In this embodiment, at least oneorifice 216 is formed in thecolumnar body 202. When themembrane plug 200 is inserted at an end of an osmotic pump, such as osmotic pump (300 inFIG. 3 ), theorifice 216 allows fluid to pass through themembrane plug 200 to the osmotic agent (320 inFIG. 3 ) and permeate the osmotic agent (320 inFIG. 3 ) before themembrane plug 200 is fully hydrated. This has the effect of accelerating the startup phase of the osmotic pump. The size of theorifice 216 is such that fluid can flow through thecolumnar body 202. The size of theorifice 216 is also such that upon adequate hydration/swelling of thecolumnar body 202 theorifice 216 becomes occluded, allowing the osmotic function of the system to be fully activated. - The diameter of the
orifice 216 depends on the outside diameter of thecolumnar body 202 of themembrane plug 200, the inside diameter of the capsule (302 inFIG. 3 ), and the percentage of fluid themembrane plug 200 material will absorb. The diameter of theorifice 216 may be selected based on the assumption that themembrane plug 200 material will expand the same percentage in all directions until it meets a constraint such as the capsule. - The volume, V, of the
membrane plug 200 can be expressed as follows: -
V=πL(D/2)2 (1) - where L is the length of the
membrane plug 200 and D is the diameter of thecolumnar body 202. Multiplying both sides of equation (1) by (1+b)3 gives: -
- 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 themembrane plug 200 due to fluid absorption, then: -
(1+b)3=1+c (3) - If the outside diameter of the
membrane plug 200 is the same as the inside diameter of the capsule (302 inFIG. 3 ), then the area of theorifice 216 attime 0 before the plug expands (Ao,t=0) must be less than the difference between the cross-sectional area of the plug attime 0 before the plug expands (Ap,t=0) and the cross-sectional area of the plug at time 1 after the plug expands (Ap,t=1). That is, -
A o,t=0 <A p,t=1 −A p,t=0 (4) -
where -
A o,t=0=(d/2)2π (5) - where d is the diameter of the orifice before the plug expands (t=0) and
-
A p,t=0=(D/2)2π (6) -
and -
A p,t=1 =[D(1+b)/2]2π (7) - The following expression is obtained by combining equation (3) with equation (7):
-
A p=t=1=(D/2)2(1+c)2/3π (8) - From equations (6) and (8), the difference between the cross-sectional area of the plug at
time 0 and time 1 becomes: -
A p,t=1 −A p,t=0=(D/2)2[(1+c)2/3−1]π (9) - The following expression is obtained by substituting equations (5) and (9) into equation (4) and solving for d:
-
d<√{square root over ((D)2[(1+c)2/3−1])}{square root over ((D)2[(1+c)2/3−1])} (10) - 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<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.
- 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.
- 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.
Claims (22)
1. An osmotic pump, comprising:
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;
wherein 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.
2. The osmotic pump of claim 1 , wherein the slot extends from a base of the columnar body and terminates at a non-basal point in the columnar body.
3. The osmotic pump of claim 2 , wherein the non-basal point is in a range from 10 to 90% of a length of the columnar body.
4. The osmotic pump of claim 2 , wherein the non-basal point is in a range from 20 to 80% of a length of the columnar body.
5. The osmotic pump of claim 2 , wherein the non-basal point is in a range from 30 to 60% of a length of the columnar body.
6. The osmotic pump of claim 1 , wherein the columnar body terminates in an enlarged end cap, the end cap having a surface for engagement with the second end of the capsule so as to establish a repeatable position of the columnar body in the capsule.
7. The osmotic pump of claim 1 , wherein a plurality of protrusions are provided on the surface of the columnar body for engaging an inner surface of the capsule.
8. The osmotic pump of claim 1 , wherein the membrane plug is made of a semipermeable material.
9. The osmotic pump of claim 1 , further comprising a first and a second chamber defined in the capsule for containing an osmotic agent and a beneficial agent, respectively.
10. The osmotic pump of claim 9 , further comprising a piston movably disposed between the first and second chambers.
11. The osmotic pump of claim 1 , wherein the delivery port is provided by a diffusion moderator retained in the first end of the capsule.
12. The osmotic pump of claim 1 , wherein an orifice is provided in the columnar body to allow fluid flow through the columnar body until the orifice becomes occluded due to swelling of the columnar body.
13. The osmotic pump of claim 12 , wherein a diameter of the orifice is less than 35% of a diameter of the columnar body.
14. The osmotic pump of claim 12 , wherein a diameter of the orifice is in a range from 0.8 to 33% of a diameter of the columnar body.
15. A membrane plug for use with an osmotic pump having a delivery capsule, comprising:
a columnar body made of a semipermeable material, the columnar body having an outer surface for engagement with an inner surface of the capsule and being provided with a slot, the slot extending 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.
16. The membrane plug of claim 15 , wherein the non-basal point is in a range from 10 to 90% of a length of the columnar body.
17-19. (canceled)
20. The membrane plug of claim 15 , wherein a plurality of protrusions are provided on the surface of the columnar body for engagement with the inner surface of the capsule.
21-23. (canceled)
24. A membrane plug for use with an osmotic pump having a delivery capsule, comprising:
a columnar body made of a semipermeable material, the columnar body having an outer surface for engagement with an inner surface of the capsule and being provided with an orifice that allows fluid flow into the capsule until the orifice becomes occluded due to swelling of the semipermeable material.
25. The membrane plug of claim 24 , wherein a diameter of the orifice is less than 35% of a diameter of the columnar body.
26. The membrane plug of claim 24 , wherein a diameter of the orifice is in a range from 0.8 to 33% of a diameter of the columnar body.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US12/217,266 US20080269726A1 (en) | 2003-10-31 | 2008-07-01 | Osmotic pump with self-retaining, fast-start membrane plug |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US51722003P | 2003-10-31 | 2003-10-31 | |
US10/969,753 US7407499B2 (en) | 2003-10-31 | 2004-10-20 | Osmotic pump with self-retaining, fast-start membrane plug |
US12/217,266 US20080269726A1 (en) | 2003-10-31 | 2008-07-01 | Osmotic pump with self-retaining, fast-start membrane plug |
Related Parent Applications (1)
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US10/969,753 Continuation US7407499B2 (en) | 2003-10-31 | 2004-10-20 | Osmotic pump with self-retaining, fast-start membrane plug |
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US20080269726A1 true US20080269726A1 (en) | 2008-10-30 |
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US12/217,266 Abandoned US20080269726A1 (en) | 2003-10-31 | 2008-07-01 | Osmotic pump with self-retaining, fast-start membrane plug |
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US10/969,753 Active 2025-05-08 US7407499B2 (en) | 2003-10-31 | 2004-10-20 | Osmotic pump with self-retaining, fast-start membrane plug |
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US (2) | US7407499B2 (en) |
EP (1) | EP1686968A2 (en) |
JP (1) | JP2007509703A (en) |
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CN (1) | CN1905861A (en) |
AR (1) | AR046312A1 (en) |
AU (1) | AU2004287402A1 (en) |
BR (1) | BRPI0416094A (en) |
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TW (1) | TW200526273A (en) |
WO (1) | WO2005044239A2 (en) |
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Also Published As
Publication number | Publication date |
---|---|
NO20062334L (en) | 2006-05-23 |
CN1905861A (en) | 2007-01-31 |
MXPA06002030A (en) | 2006-05-17 |
ZA200604431B (en) | 2007-09-26 |
KR20060112650A (en) | 2006-11-01 |
US20050095284A1 (en) | 2005-05-05 |
US7407499B2 (en) | 2008-08-05 |
WO2005044239A2 (en) | 2005-05-19 |
RU2006118808A (en) | 2007-12-10 |
AU2004287402A1 (en) | 2005-05-19 |
JP2007509703A (en) | 2007-04-19 |
BRPI0416094A (en) | 2007-01-02 |
CA2537811A1 (en) | 2005-05-19 |
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AR046312A1 (en) | 2005-11-30 |
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