WO2009017472A1 - Systems and methods for delivery of peritoneal dialysis (pd) solutions - Google Patents
Systems and methods for delivery of peritoneal dialysis (pd) solutions Download PDFInfo
- Publication number
- WO2009017472A1 WO2009017472A1 PCT/US2007/016906 US2007016906W WO2009017472A1 WO 2009017472 A1 WO2009017472 A1 WO 2009017472A1 US 2007016906 W US2007016906 W US 2007016906W WO 2009017472 A1 WO2009017472 A1 WO 2009017472A1
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- WIPO (PCT)
- Prior art keywords
- compartment
- container system
- agent
- seal
- vessel
- Prior art date
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- 0 CC1C*CC1 Chemical compound CC1C*CC1 0.000 description 2
Classifications
-
- 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
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/162—Needle sets, i.e. connections by puncture between reservoir and tube ; Connections between reservoir and tube
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
-
- 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
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1654—Dialysates therefor
- A61M1/1656—Apparatus for preparing dialysates
- A61M1/1668—Details of containers
-
- 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
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
Definitions
- the invention relates to peritoneal dialysis (PD).
- PD peritoneal dialysis
- GDPs glucose degradation products
- PD Peritoneal dialysis
- a solution is introduced into the patient's abdomen, where it remains for up to several hours, removing blood toxins via osmotic transfer through that membrane.
- the solution is drained from the body along with the toxins.
- An active constituent of the PD solution is an osmotic agent, such as glucose, that creates an osmotic gradient across the peritoneal membrane, allowing exchange of toxins from the blood into the peritoneal cavity, as described above.
- Another constituent is an electrolyte composition, such as a mixture of sodium, calcium, potassium, chlorine, magnesium, and so forth, which restores and maintains electrolyte balance in the blood.
- a final typical constituent is a buffering agent, such as lactate and pyruvate, which ensures that the blood pH remains at a physiological norms during the procedure.
- a major problem with commercially available PD solutions is the presence of degradation products. These products, which typically arise during long-term storage or sterilization of the solutions, damage the peritoneal wall and can adversely affect proteins elsewhere in the patient's body.
- Another object of the invention is to provide such containers and methods as can be fabricated at low cost.
- Still another object of the invention is to provide such containers and methods as can be fabricated utilizing existing materials and fabrication techniques
- Still yet still another object of the invention is to provide such containers and methods as can be provided PD solutions of physiologically optimal concentrations and pH levels.
- the foregoing and other objects are attained by the invention which provides, in some aspects, a container system for medical solutions such as peritoneal dialysis (PD) solutions.
- the invention particularly features a system which includes a first compartment that contains a first medical solution, e.g., a PD osmotic agent, and a second compartment that contains a second medical solution, e.g., a PD buffer agent.
- the compartments maintain their respective contents separately from one another for purposes of transport, storage and/or sterilization.
- the compartments are fluidly couplable, so that their respective contents can be combined with one another, e.g., following sterilization of the agents and prior to their introduction into the patient's abdomen.
- the PD buffer agent is highly concentrated and/or highly alkaline.
- the buffer agent can be about 3-fold higher in concentration than the chemically "Normal" concentration for that agent, preferably 5-fold or higher, more preferably, 7-fold or higher, more preferably, 10-fold or higher, and still more preferably, 15-fold or higher.
- the buffer agent according to these aspects of the invention can likewise be about 3 -fold higher in concentration than conventional buffer agents, preferably 5-fold or higher, more preferably, 7-fold or higher, more preferably, 10-fold or higher, and still more preferably, 15-fold or higher.
- Suitable PD buffer agents for use in these aspects of the invention include, but are not limited to, lactate, acetate, and pyruvate.
- the PD buffer agent has a pH of about 8.0 to about 14.0, and, more preferably, a pH of about 9.0 to about 13 and, still more preferably, a pH of about 10.0 to about 12.0.
- the second compartment in which that PD buffer agent is stored has a small volumetric capacity relative to that of the first compartment.
- the volumetric amount of PD buffer agent is small compared to that of the PD osmotic agent.
- the second compartment is sized between 5ml — 50ml, and preferably about 7.5 - 37.5ml.
- the ratio of the volumetric capacity of the first to second compartments is in the range of about 20:1 to about 200:1, preferably about 50:1 to about 150:1, and preferably about 70:1 to about 140:1, preferably about 90:1 to about 120:1, and most preferably about 133:1.
- the PD osmotic agent is at physiological use concentrations, i.e., substantially at concentrations at which that agent will be introduced into the patient's abdomen.
- concentrations are between 1.5% - 4.25% and, more preferably, between 2.0% - 4.0% and, still more preferably, between 2.0% - 3.0%.
- the PD osmotic agent is at a physiologically low pH, i.e., a pH below that at which that agent will be introduced into the patient's abdomen.
- those pH levels are between 1.0 — 6.0 and, most preferably, between 1.0 - 3.0.
- the PD osmotic agent can be, by way of non-limiting example, a sugar selected from the group consisting of glucose, dextrose, icodextrin, and fructose.
- the first compartment can contain electrolytes, in addition to the osmotic agent.
- the first and second compartments are, according to one aspect of the invention, formed in vessels that are fabricated separately from one another.
- the first compartment can be formed in a 1 - 5 liter glass container (e.g., an infusion bottle) or flexible bag (e.g., an infusion bag) made, for example, of PVC, polyolefin, polypropylene, or other medical-grade material) of the type typically used to contain and/or administer peritoneal dialysis fluids.
- the second compartment can be formed in separate container, such as a tube or vial of flexible, moldable or malleable material such as PVC, all by way of non-limiting example.
- a PVC bag in which the first compartment is formed can have a port for receiving, by fusing, bonding, interference-fit, screw-fit, or otherwise, a tube in which the first compartment is formed.
- that port can be arranged to receive a needle-like extension, bayonet, or other adapter affixed to such a tube.
- both vessels can be adapted to receive opposing ends of a common piece of medical-grade tubing.
- a seal is provided in a fluid-transfer path between the first and second compartments to prevent contact between the PD osmotic agent and the PD buffer agent.
- the seal is temporary and can be broken, e.g., by a patient, health care provider or manufacturer, to permit the agents to mix following their sterilization and prior to their introduction into the patient's abdomen.
- the seal may be formed integrally with either of the vessels, e.g., as in the case of a frangible seal formed in the PD buffer-containing vial, or otherwise.
- Still further aspects of the invention provide a container system for PD solutions comprising a flexible bag (or glass jar, by way of example) containing a PD osmotic agent and having a standard clinical use capacity, e.g., in the range of 1-5 liters.
- the system also has a tube containing a PD buffer agent and having a capacity, e.g., in the range of 10 - 15mls and/or a pH in the range of 10.0 - 12.0.
- the bag and tube are directly or indirectly coupled via respective ports in each of them.
- a frangible member in the tube prevents mixing of the agents until broken, e.g., by a patient, health care provider or manufacturer, following sterilization of the agents and prior to their introduction into to the abdominal cavity.
- kits comprising PD osmotic agent-containing and buffering agent-containing vessels as described above.
- kits can also include tubing and other apparatus for coupling the vessels, as well as for introducing the PD solution produced thereby to a patient's abdomen.
- those kits can also include apparatus to facilitate sterilization of the contained osmotic and buffering agents.
- they can include apparatus to facilitate breaking of the above-described frangible (or other sealing) members, e.g., following sterilization of the agents and prior to their introduction into to the abdominal cavity.
- the method further contemplates placing the first and second compartments in fluid communication following the sterilization step and mixing their contents with one another, prior to introducing the mixed contents into a patient's ahdomen.
- Still further aspects of the invention provide methods as described above in which the second compartment (in which that PD buffer agent is stored) has a small volumetric capacity relative to that of the first compartment and/or likewise, where the volumetric amount of PD buffer agent is small compared to that of the osmotic agent.
- Still further aspects of the invention provide methods as described above that include breaking of a seal between the first and second compartments and, thereby, allowing their contents to mix following the sterilization stage.
- This can include, for example, bending and/or squeezing a semi-rigid tube that contains the buffer agent in order to break a frangible sealing member that separates that agent from the osmotic agent.
- a system according to the invention comprises a first compartment and a second compartment, e.g., for first and second PD constituents.
- a first seal prevents fluid transfer between the first compartment and the second compartment, and a second seal prevents fluid transfer between the second compartment and an outlet fluid pathway that leads, e.g., to the patient.
- Protective structure is provided to deter the patient, his/her health care provider, or others, from breaking the second seal prior to the first seal.
- that protective structure is a cover initially positioned in protective relation to the second seal where it inhibits the breaking of that seal.
- That cover can include an inner passageway and can be slidably disposed to move from the initial position to a second position, where it does not protect the second seal.
- the size and/or shape of the vessel that forms the second compartment restrains such movement — prior to emptying of the second compartment (at least partially) following breaking of the first seal.
- the second seal is disposed within the vessel that forms the second compartment.
- Fluid or other pressure from a PD constituent e.g., a fluid buffer agent, initially contained in that vessel inhibits bending, twisting or other manipulation of it sufficient to break the second seal.
- Yet still further aspects of the invention provide systems for delivery of PD solutions as described above that include a diffuser in a fluid pathway between the first and second compartments.
- a diffuser in a fluid pathway between the first and second compartments.
- Such a diffuser can, for example, facilitate homogeneous mixing of the first and second PD agents, even where they are of different viscosities and/or densities.
- the diffuser comprises multiple apertures disposed within the first compartment.
- Those apertures can have diameters, in one aspect of the invention, in the range 1.0 mm— 1.5 mm. They can, according to still further aspects of the invention, effect angular dispersion of the PD constituent from the second compartment, upon its expulsion into the first compartment.
- Still other aspects of the invention provide systems for delivery of PD solutions as described above in which the vessel forming the second compartment folds upon application of force and expels the PD constituent contained therein in connection therewith.
- a cover that is provided as the aforementioned protective structure comprises a slot or other opening that is sized to slide over at least a portion of the the second compartment, depending on a quantity of PD constituent therein.
- the aforementioned slot or other opening is arranged to slide over at least a portion of the vessel forming the second compartment only if that vessel is at least partially folded, in a manner of butterfly wings.
- the aforementioned slot or other opening is arranged to slide over at least the portion of the vessel forming the second compartment only after a quantity of the PD constituent originally contained therein has been expelled therefrom.
- the slot or other opening is arranged to slide over at least the portion of the vessel forming the second compartment only after at least 10% — 30% of a quantity of the PD constituent originally contained in that compartment has been expelled therefrom.
- the slot or other opening is arranged to slide over at least the portion of the vessel forming the second compartment only after at least 30% — 50% of a quantity of the PD constituent originally contained in that compartment has been expelled therefrom.
- the slot or other opening is arranged to slide over at least the portion of the vessel forming the second compartment only after at least 75% of a quantity of the PD constituent originally contained in that compartment has been expelled therefrom.
- Figure 1 depicts a system for containing a peritoneal dialysis solution according to one practice of the invention and includes a break-out portion depicting one of the vessels of that system in greater detail;
- Figure 2 depicts a sequence for sterilizing and administering a peritoneal dialysis solution according to the invention
- Figure 3 depicts a system for containing a peritoneal dialysis solution according to a further practice of the invention and includes a break-out portion depicting one of the vessels of that system in greater detail;
- Figures 4A - 4C depict utilization of the system of Figure 3 to mix agents of the peritoneal dialysis solution (e.g., following sterilization) and to transfer the mixed agents to the patient.
- Figure 5 is a schematic of a frangible seal.
- Figure 6 depicts a system for containing a peritoneal dialysis solution according to one practice of the invention that includes a protective member adapted to inhibit breaking of a second seal prior to breaking of a first seal.
- Figures 7A - 7E illustrate operation of the system of Figure 6.
- Figures 8A - 8B illustrate an embodiment of the invention incorporating an alternate configuration of the second container of Figure 6.
- Figure 9 illustrates an embodiment of the invention in which the fluid-filled second compartment defines the protective member.
- Figures 1OA - 1OD illustrate operation of the system of Figure 9.
- Figures 1 IA - 1 IF illustrate configuration and use of the embodiment of Figures 8A - 8B.
- Figures 12 A — 12E depict use of a container system according to the invention that includes a diffuser in a fluid pathway between the vessels.
- Figures 13A — 13E depict a procedure for use of the container system depicted in Figures 12A - 12E.
- Figures 14A — 14E are graphs of pH as a function of the outflow volume of the catheter of sample systems of the type shown in Figures 12A - 12E when used with normally expected operating procedures.
- FIG. 1 illustrates a container system for PD solutions according to one practice of the invention.
- the container system 10 has a first vessel 12 that contains, in compartment 12a, a PD osmotic agent solution 14.
- a second vessel 20 contains, in compartment 20a, PD buffer agent solution 22.
- the vessels 12, 20 and, more particularly, the compartments 12a, 20a are coupled for fluid exchange via port 18 formed in vessel 12, as shown.
- a temporary seal 24 is provided in the fluid-transfer path between the compartments, also as shown. This prevents contact between or mixing of the PD osmotic agent and the PD buffer agent, e.g., until after sterilization of the agents.
- a further temporary seal 26 is provided in a catheter 28 that leads, e.g., to the patient's peritoneal cavity (not shown), and prevents flow of PD solution, e.g., until after mixing of the sterilized agents.
- Illustrated first vessel 12 is a conventional medical-grade PVC hanging "transfusion" bag, as illustrated. In other embodiments it may be of other configurations and/or comprised of other materials, such as a glass container or other flexible or non- flexible containers (of PVC, polyolefm, polypropylene, or other medical-grade material) of the type typically used to contain and/or administer peritoneal dialysis agents.
- the compartment 12a is formed within the vessel 12 in the conventional manner and, in the illustrated embodiment, is of standard clinical use capacity (e.g., sized between 1 - 5 liters), though other sizes may be used as well.
- vessel 12 includes at least one port 18 providing a fluid-transfer path to compartment 12a.
- This port can be used to transfer agents to and from the vessel 12, e.g., during manufacture at the pharmaceutical plant, during mixing of the agents, and/or during administration of the mixed agents to the patient.
- Other embodiments may use a greater or fewer number of ports than those illustrated and, indeed, may use no ports at all (e.g., where needles or other methods are used to add and remove agents from the compartment 12a).
- Illustrated vessel 20 is a tube-like vessel (or miniature bulb or "mini-bulb") of PVC or other medical grade material suitable for containing at least a PD buffer agent.
- the illustrated vessel is semi-rigid and, therefore, suitable for squeezing or other manipulation by a patient, health care provider or manufacturer, e.g., to facilitate breaking of the seal 24, extrusion of the PD buffer agent out from compartment 20a and into compartment 12a, and/or mixing of the PD agents.
- the vessel may be of other configurations and may be fabricated from other materials (e.g., rubber, polyolef ⁇ n, polypropylene, and/or other medical grade materials).
- the vessel need not be semi-rigid: it may be rigid or flexible, depending on how the patient, health care provider or manufacturer are expected to use it for purposes of breaking of seal 24, expelling the PD buffer agent and/or mixing of the PD agents
- vessel 20 has a tube-like configuration, other embodiments may utilize vessels of different shapes.
- Vessel 20 can be formed by a blow molded or dipping-formed bubble in-line with the solution bag outlet. Other methods for forming the second vessel are possible also, such as formation during the tubing extrusion process (commonly called Bump tubing) or heat forming vessel 20 in pre-extruded tubing.
- Illustrated vessel 20 is adapted for direct or indirect coupling with vessel 12 so as to provide a fluid transfer path between compartments 12a, 20a.
- vessel 20 has a proximal end port 25 adapted for fusing, bonding, interference-fit, screw-fit or other coupling with vessel 12, hereby, by way of its port 18, as shown in the drawing.
- fluidic coupling between the compartments 12a, 20a may be attained in other ways, e.g., by needle- or bayonet-like adapters affixed to either vessel (or its respective port) for receipt by the other vessel.
- Vessel 20 is likewise adapted for direct or indirect fluid transfer to the patient's peritoneal cavity. In the illustrated embodiment, this is by way of a distal port 27 adapted for fusing, bonding, interference-fit, screw-fit or other coupling with catheter 28, as shown. That catheter may lead directly to the peritoneal cavity or indirectly, e.g., by way of filters, heaters and/or other medical apparatus.
- the compartment 20a of the second vessel 20 has small volumetric capacity in comparison to that of the first vessel 12.
- the first compartment 12a of the illustrated embodiment is of a capacity sized between 1 - 5 liters
- the second compartment 20a is sized about 5 — 50ml, preferably about 7.5 - 37.5ml.
- the ratio of volumetric capacity of the first to second compartments is about 20:1 to about 200:1, preferably about 50:1 to about 150:1, and preferably, about 70:1 to about 140:1, and most preferably about 133:1.
- Seal 24 is adapted to prevent fluid transfer (or other contact) between the PD agents contained in compartments during manufacture, transport, storage and sterilization of system 10, yet, to permit such fluid transfer upon breaking of that seal 24 (e.g., by a patient, health care provider, or manufacturer) for purposes of mixing the agents following sterilization.
- the patient, health care provider, or manufacturer need not introduce a foreign object (such as a needle) to break the seal 24. Rather, this may be accomplished by squeezing, twisting or other manipulation of vessel 20 and/or port 18.
- the seal 24 is a frangible member disposed between the aforementioned proximal port of the vessel 20 and the port 18 and is affixed to (and/or formed integrally with) an interior fluid-transfer path of one or both of those ports.
- Seal 24 can be fabricated from nylon, plastic, or other medical-grade material, and can be constructed in the manner of conventional frangible seals known in the art and commercially available in the marketplace, e.g., from medical supply manufacturers Baxter, Gambro and Qosina.
- One preferred seal 24 is constructed in the manner of the frangible seal commercially available from Fresenius Medical Care, e.g., as a component of its PremiereTM Plus Double Bag system. That seal is depicted in Figure 5.
- illustrated seal 24 comprises an elongate member having a head portion 24a and a tail portion 24b, as shown.
- the latter comprises a main body 24c and flanges 24d which, together, clamp the distal end of port 18 and the proximal end of vessel 20 (as shown), thus, providing physical coupling between the vessels 12 and 20.
- the tail portion 24b has a central throughway which permits fluid coupling between compartments 12a, 20a, when frangible bond 24e is broken, as discussed below.
- the head portion 24a shown here of generally mushroom cap shape, is coupled to tail portion 24b by frangible bond 24e.
- Head portion 24a does not include a fluid throughway and, hence, prevents fluid from flowing between compartments 12a, 20a through tail portion 24b so long as bond 24e remains intact.
- That bond 24e which may be formed by ultrasonic welding, adhesives, interference fit, fusing, integral molding, or otherwise, breaks upon bending or other manipulation of the seal 24 (e.g., by patient, health care provider, or manufacturer), thereby permitting such flow.
- Figure 5 depicts an example of a type of seal which can be used in practice of the invention and that seals of other configurations (frangible or otherwise) which prevent undesired contact between the PD agents, yet, permit such contact to be established by the patient, health care provider, or manufacturer, may be used instead or in addition.
- seal 26 is adapted to prevent fluid transfer to the patient prior to both sterilization and mixing of the PD agents.
- the patient, health care provider, or manufacturer does not need to introduce a foreign object (such as a needle) to break seal 26 but, rather, may be accomplish this by squeezing, twisting or other manipulation of vessel 20, the distal port thereof and/or catheter 28.
- the seal 26 of the illustrated embodiment is a frangible member disposed between the aforementioned distal port of the vessel 20 and the catheter and affixed to (and/or formed integrally with) an interior fluid-transfer path of one or both of those.
- the seal 26, too can be fabricated from nylon, plastic, or other medical- grade material, and it can be formed in the configurations discussed above in connection with seal 24 (and shown, for example, in Figure 5).
- the focus and/or type of manipulation required to break seal 26 differs from that required to break seal 24. This prevents both seals 24, 26 from being unintentionally broken at the same time and, thus, helps insure that the sterilized fluids are mixed prior to their being transferred to the patient.
- the seals 24, 26 can be colored differently to alert and remind the user of the proper order in which they are to be broken. Those skilled in the art will appreciate, of course, that coloration can be used in connection with other elements of the system 10, as well.
- FIG. 6 additional structure can be provided to further insure that the seals 24, 26 are broken in the proper order and, therefore, to prevent fluid transfer to the catheter 28 (and any downstream equipment) prior to sterilization and mixing of the PD agents.
- That drawing depicts container system 50 of the same general configuration as container system 10 of Figure 1 (as indicated by like reference numerals), albeit including a protective member in the form of cover 52 that slides from an initial position, wherein it protects seal 26 from manipulation, to a second position, wherein it permits that seal to be broken.
- Figures 6 and 7A - 7C show cover 52 in the initial position.
- Figure 7D - 7E show the cover 52 in the second position.
- cover 52 is shown in its initial position, disposed in protective relation to seal 26.
- cover 52 is, more particularly,
- the cover 52 which can comprise nylon, plastic, or other material (medical-grade or otherwise), preferably, in a rigid or semi-rigid formulation, includes an annular or other internal passageway 54 in which seal 26, the distal port of vessel 20, and/or proximal portion of catheter 28 are initially disposed, as shown in the drawing.
- the internal passageway extends from a distal end 56 to a proximal end 58 and, in the illustrated embodiment, has an internal diameter that can, though need not, vary therebetween, e.g., as shown.
- An inner diameter of the passageway 54 e.g., at the proximal end 58, is sized and shaped to inhibit movement of cover 52 in a distal-to-proximal direction (e.g., "upward” in the drawing) prior to breaking of seal 24, e.g., when vessel 20 contains its post-manufacture complement of PD buffer agent solution 22 (and/or other liquids, gasses or solids).
- the inner diameter of that passageway at the proximal end 58 is smaller than an outer diameter of vessel 20 prior to breaking of seal 24 and any of (a) at least some reduction in that outer diameter (via expulsion of a post-manufacture complement of solution 22 and/or other liquids, gasses or solids) from vessel 20 — and, preferably, at least 10% - 30% and, still more preferably, at least 30% - 50% and, yet still more preferably, at least 50% — of such reduction, and/or (b) a decrease in resistance to such reduction.
- the passageway 54 can have a larger inner diameter at the distal end 56 than at the proximal end 58, as shown in the drawing. This can help prevent bending of catheter 28 (e.g., at the point it emerges from end 56) and possible premature breakage of seal 26 during transport, storage and initial use.
- Proximal-to-distal movement of cover 52 can also be constrained by a suitable stop — here, for example, a flange 57 at the proximal end of catheter 28 and/or distal end of vessel 20 sized larger than the inner diameter passageway 54 at its proximal end 58 but smaller than the inner diameter of that passageway at its distal end 56.
- a suitable stop here, for example, a flange 57 at the proximal end of catheter 28 and/or distal end of vessel 20 sized larger than the inner diameter passageway 54 at its proximal end 58 but smaller than the inner diameter of that passageway at its distal end 56.
- the flange permits distal-to-proximal movement of the cover 52, but inhibits its proximal-to-distal movement.
- the cover 52, as well as the seals 24, 26, are colored differently to alert and remind the user of the proper order in which they are to be broken.
- coloration can be used in connection with other elements of the system 10, as well.
- Figures 7A — 7E depict use of cover 52 — initially protecting, then, permitting manipulation (and breaking) of seal 26.
- compartment 20a contains its post-manufacture complement of buffer agent 22 (and/or other gasses, fluids, solids). Consistent with the discussion above, with the compartment 20 in this condition, the size differential between outer diameter of vessel 20 and inner diameter of passageway 54 inhibits distal-to-proximal (e.g., "upward") movement of cover 52.
- the cover 52 remains in its initial position while the user breaks seal 24 (e.g., by bending the proximal end of vessel 20 relative to port 18) and compresses vessel 20 in order to expel buffer agent 22 for mixing with osmotic agent 14.
- the user slides the cover in the distal-to-proximal direction over the vessel 20 and away from the seal 26, once the seal 24 has been broken and the outer diameter of vessel 20 has been reduced (or, at least, resistance to such reduction has been eliminated).
- the cover 52 moved the user can more readily manipulate the distal end of vessel 20 and/or the proximal end of catheter 28 in order to break seal 26. See Figure 7E.
- cover 52 and/or vessel 20 can have shapes other than those shown in Figures 6 and 1, yet, operate in the manner discussed above in connection therewith.
- FIG. 8A — 8B shows in front- and side-views, respectively, a vessel 21 having the same function as element 20, above — albeit shaped with a central portion that is elongate in the transverse direction and that generally defines an oval shape, as shown.
- the vessel 21 of the illustrated embodiment is formed from halves (or other portions) of PVC, polyolefin or other medical-grade flexible or semi-rigid material that are glued, ultrasonically welded or otherwise fused along an edge 21 A in the conventional manner known in the art (although the vessel can be formed — from a single portion or multiple portions — in other ways).
- cover 53 of Figures 8A - 8B functions in the same manner as cover 52, above, albeit it includes a slot 53 A that skirts the edge 21 A when the cover 53 is slid in the distal-to-proximal direction over the vessel 21 and away from the seal 26 (once the seal 24 has been broken and the volume of vessel 21 has been reduced).
- Figures 1 IA- HF depict a configuration and use of vessel 21 to facilitate expulsion of the post-manufacture complement of solution 22 (and/or other liquids, gasses or solids) into vessel 12 (not shown in these drawings) for mixing with solution 14 prior to introduction of the resulting solution into the patient's abdomen.
- expulsion is graphically depicted in Figures 11C — 1 IF by the arrow labeled 22.
- vessel 21 of Figures HA - HF serves a same function as vessel 20, described earlier, and may be used (e.g., preferably, along with cover 53) in place of vessel 20 (or alternates therefore, e.g., vessel 42, discussed elsewhere herein) in systems according to the invention.
- the vessel 21 of Figures 1 IA - HF has a central portion that is elongate in the transverse direction and that generally defines an oval shape. And, as above, it is formed from halves (or other portions) of PVC, polyolef ⁇ n or other medical-grade flexible or semi-rigid material that are glued, ultrasonically welded or otherwise fused along an edge 21 A in the conventional manner known in the art (although the vessel can be formed — from a single portion or multiple portions — in other ways).
- the vessel 21 of Figures 11A — HF is formed to facilitate folding of its halves 21B, 21C when the vessel is squeezed, e.g., by the patient, health care provider or otherwise, following breakage of seal 24.
- steps HB showing breaking of the seal 24 (as indicated by force arrows F B )
- 11C — HE showing folding of the halves 2 IB, 21 C when squeezed (as indicated by force arrows Fs).
- Such folding can be facilitated, by way of non-limiting example, by pre-creasing vessel 21 in a central region 21D, by reducing a cross-section of the vessel 21 in that region 2 ID, or otherwise. Indeed, in the illustrated embodiment, such folding is facilitated, at least in part, by the proximal and distal ports of the vessel 21, the affixation of which in vicinity of region 2 ID provide an axis about which halves 21B, 21 C tend to naturally bend.
- cover 53 of Figures HA - HF functions in the same manner as cover 53 of Figures 8A - 8B.
- slot 53A of the cover of Figures 1 IA - 1 IF is positioned, sized and shaped to inhibit movement of the cover in a distal-to-proximal direction prior to breaking of seal 24 and expulsion from vessel 21 of a post-manufacture complement of PD buffer agent solution 22 (and/or other liquids, gasses or solids).
- the slot is positioned so that it (and, consequently, cover 53 itself) cannot be slid in the distal-to-proximal direction until both sides 21B, 21 C are aligned with the slot. Since only one such slot is provided in the illustrated embodiment — generally, aligned normal to the plane of the vessel 21 (as shown in the drawings) — this necessitates squeezing the sides 21B, 21C together (in the manner of butterfly wings) or otherwise folding the vessel 21 at least partially and, preferably, substantially.
- the slot 53A is sized and shaped to prevent such sliding until a cross- section of the region of sides 21B, 21C over which it (slot 53A) slides is reduced, i.e., via squeezing and expulsion of solution 22 (and/or other liquids, gasses or solids) from vessel 21 — preferably, by at least 10% — 30% volumetrically and, still more preferably, at least 30% - 50% volumetrically and, yet still more preferably, at least 75% volumetrically and, yet, still more preferably, substantially all of that solution.
- step HF shows repositioning of the cover 53 via a sliding force, as indicated by arrow FL.
- the cover 53 of the illustrated embodiment does not cover the entire vessel 21 when repositioned but, rather, only the central portion: the outer "wings" of sides 2 IB, 21C remain outside.
- other embodiments may vary in this regard.
- slot 53A has rails, flats or other structures that effect further squeezing of the halves 2 IB, 21C and consequent expulsion of solution 22 (and/or other liquids, gasses or solids) therefrom when that cover is slid in the distal-to- proximal direction over those halves.
- the internal passageway of the cover 53 of Figures HA - HF can be sized analogously to slot 53A, i.e., to inhibit movement of the cover in a distal-to-proximal direction prior to breaking of seal 24 and reduction in that an outer diameter of a central region of vessel 21 via squeezing and expulsion of a post-manufacture complement of solution 22 (and/or other liquids, gasses or solids) from vessel 21.
- the internal passageway of. the cover 53 of Figures 11A - HF can have a larger inner diameter at the distal end than at the proximal end, e.g., to help prevent bending of catheter 28 and possible premature breakage of seal 26.
- proximal-to-distal movement of that cover 53 can be constrained by a suitable stop and/or relative sizing of the inner diameter of the internal passageway of the cover.
- slot (or other opening) 53 A and inner passageway of cover 53 of Figures 1 IA- HF can be aligned, shaped and sized otherwise (and, indeed, that multiple slots could be provided on cover 53A) in accord with the teachings hereof.
- the seal 24, the vessel 21, and the cover 53 are colored differently to alert and remind the user of the proper order in which they are to be utilized.
- the seal 24 can be colored red; the cover 53 can be colored white; and, the seal 26 can be colored blue.
- This red-white-blue combination can be effective in reminding patients or health care providers in locales where those colors have memorable significance (e.g., in the United States or France) that the seal 24 (red) is to be broken, first; the cover 53 (white) is to be slid, next (after squeezing out the contents of vessel 21); and, that the seal 26 (blue) is to be broken, last.
- other color combinations or visual indica e.g., lettering, numbering or other symbology
- the vessel 21 of Figures 11A — HF is formed to facilitate folding of its halves 21B, 21C when the vessel is squeezed, e.g., by the patient, health care provider or otherwise, following breakage of seal 24.
- steps 1 IB showing breaking of the seal 24 (as indicated by force arrows F B )
- 11C — HE showing folding of the halves 2 IB, 21C when squeezed (as indicated by force arrows Fs)-
- FIGS 12A — 12E depict a container system 10 in which port 18 of vessel 12 includes a diffuser 18A for facilitating mixing of solution 22 (and/or other liquids, gasses or solids of vessel 21) with solution 14 (of vessel 12).
- the diffuser 18A is shown in use with a system 10 that includes a vessel 12 of the type shown in Figures 1, 3, 4, 6, 9, and a vessel 21 and cover 53 of the types disclosed in Figures HA - HF; however, it will be appreciated that it the diffuser 18A can be utilized in connection with the other vessels and/or configurations shown and/or discussed herein.
- the diffuser 18A of the illustrated embodiment comprises a cap — here, of a generally elongated shape, but of other shapes in other embodiments — having a proximal end that is disposed within compartment 12A and that includes multiple inlet/outlet apertures 18B.
- a distal end of the diffuser cap is coupled to and/or comprises tubing (or other structure) defining port 18, which, as noted above, provides for fluid coupling between the vessels 12 and 21.
- apertures 18B are shown on the proximal end of the illustrated diffuser 18A 3 though, other pluralities of apertures may be used in other embodiments, e.g., two apertures, four apertures, five apertures, and so forth. And, while apertures 18B are disposed in the illustrated embodiment at the tip of the proximal end of the diffuser 18 A, in other embodiments they may be disposed elsewhere on diffuser 18A in fluid communication with compartment 12A
- Illustrated apertures 18B are in fluid communication with an internal channel 18C that extends to the distal end of diffuser 18A and that supports fluid coupling between vessels 12, 21, as shown.
- two of the three apertures 18B extend from the channel 18C at an angle ⁇ , while one of the apertures is in line with the channel 18C, all as shown.
- diffuser 18A of the illustrated embodiment causes solution 22 that is expelled into vessel 12 to disperse with an angular dispersion of 2 ⁇ into solution 14, though the diffuser of other embodiments may effect other angular dispersions.
- the angle ⁇ of the illustrated embodiment is in the range 20° — 70° (with a resulting angular dispersion 2 ⁇ in the range 40° - 140°) and, more preferably 30° — 60° (with a resulting angular dispersion 2 ⁇ in the range 60° — 120°) and, still more preferably, about 25° (with a resulting angular dispersion 2 ⁇ of about 50°), as shown.
- other angular ranges may be used depending on the location of the proximal tip of diffuser 18A within compartment 12 A, the size of that compartment, the characteristics of the fluids being mixed, and so forth.
- the apertures are disposed symmetrically about an axis in the illustrated embodiment, other embodiments may forego such symmetry.
- Diffuser 18A may comprises nylon, plastic, or other medical-grade material (and, preferably, such medical materials as do not fuse to PVC during heat sterilization).
- diffuser 18A is fabricated from polycarbonate and is the same material as used in frangible members (e.g., 62, 64) discussed elsewhere herein.
- diffuseT 18A is fabricated from polyvinylchloride (PVC) and is the same material as used for the catheter 28 and other ports and/or tubing that comprise system 10.
- the apertures 18C of the illustrated embodiment are preferably 1.0 to 1.5mm in diameter, though other embodiments may use apertures of different and/or varying sizes, e.g., depending on the characteristics of the fluids being mixed and other factors indicated above, all by way of example.
- Diffuser 18A facilitates mixing of solution 22 (and/or other liquids, gasses or solids in vessel 21) with solution 14 when the patient or health care provider squeezes vessel 21 in the manner shown in Figures 11C — HF.
- This is graphically depicted in steps 12B — 12D showing expulsion of fluid 22 (as indicated by arrows 22) when container 21 is squeezed (as indicated by force arrows Fs) and cover 53 is slid (as indicated by force arrow F L ).
- Diffuser 18A further facilitates mixing of those solutions, following breakage of seal 26, when the combined PD solution is expelled into the catheter 28 (and any downstream equipment) for introduction to a patient.
- This is graphically depicted in step 12E showing expulsion (e.g., under the force of gravity and/or manipulation of vessel 12) of the combined solutions 14, 22 from the vessels 12 and 21, and exit via the catheter 28 (all as indicated by the unlabelled arrows).
- vessel 21 may be used (e.g., along with cover 53 or alternates therefor) in place of vessel 20 (or alternates therefor, e.g., vessel 42) discussed below and elsewhere herein.
- Advantages of the configurations shown in Figures 1 IA — 1 IF and 12A — 12E include that they permit the solutions 14 and 22 to be more readily combined following expulsion of solution 22 into vessel 12, e.g., necessitating limited manipulation by the patient or health care provider in order to assure an acceptable mix of PD solution that lacks pH extremes and is an appropriate range for introduction to the patient.
- the diffuser 18A facilitates mixing PD solutions of different densities and/or viscosities — and, particularly, by way of non-limiting example, a PD buffer solution 22 that has density and/or viscosity greater than that of the PD osmotic agent 14 — to be mixed quickly and homogeneously, with minimal effort.
- An advantage of the vessel 21 of Figures HA is that squeezable folding of its sides 21B, 21C (as detailed above) increases infusion pressure of solution 22 for better mixing in vessel 12. It also better increases chances for complete infusion of solution 22.
- FIG. 13A— 13F a procedure for use of system 10 as shown in Figures 12A - 12E is shown in Figures 13A— 13F.
- the system of Figures 13A— 13F additionally includes a drain bag 23, which can be supplied with the system 10 for use in draining spent PD solution from the patient.
- the patient or health care provider next breaks the seal 24 (which, as noted above, can be differentially colored red or otherwise in some embodiments) and, then, folds the vessel 21 in half, squeezing firmly until the solution 22 originally contained in the vessel 21 is expelled into solution 14 of vessel 12.
- seal 24 which, as noted above, can be differentially colored red or otherwise in some embodiments
- the patient or health care provider next presses on vessel 12 in order to push solution back into vessel 21.
- the steps shown in Figures 13B and 13C are carried out three times to facilitate thoroughly "washing" solution 22 from vessel 21.
- the patient or health care provider next inverts the system 10 (and, significantly, vessel 12) to facilitate still more thorough mixing of the solutions 22, 44.
- the step shown in Figure 13D is carried out three times to facilitate thorough mixing of the solutions 14, 22.
- the patient or health care provider next folds vessel 21 in half and slides the cover 53 (which, as noted above, can be differentially colored white or otherwise in some embodiments) up over the central portion of the vessel 21 until the seal 26 (which, as noted above, can be differentially colored blue or otherwise in some embodiments) is exposed where the tubing comprising catheter 28 is attached.
- cover 53 which, as noted above, can be differentially colored white or otherwise in some embodiments
- the patient or health care provider next grips the cover 53 (which is now repositioned over at least a portion of vessel 21) and grips the seal 26 with the other hand and bends to break the seal 26, thereby, opening a fluid pathway for outflow of the combined solutions 14, 22 (e.g., under gravity feed as effected by hanging system 10 and, significantly, vessel 12 vertically) via catheter 28 to the patient.
- the cover 53 which is now repositioned over at least a portion of vessel 21
- the seal 26 with the other hand and bends to break the seal 26, thereby, opening a fluid pathway for outflow of the combined solutions 14, 22 (e.g., under gravity feed as effected by hanging system 10 and, significantly, vessel 12 vertically) via catheter 28 to the patient.
- Figures 14A - 14F are graphs depicting pH as a function of time of the outflow of catheter 28 for such alternate procedures for sample system(s) of the type shown in Figures 12A— 12E when used with normally expected operating procedures (e.g., by way of non-limiting example, where vessel 21 is squeezed with at least a nominal squeezing force sufficient to achieve a fluid pressure of about 8 psi).
- the initial solution 14 in vessel 12 comprised dextrose, calcium chloride, magnesium chloride, and sodium chloride at pH 2.6 -3.2
- the initial solution 22 in vessel 21 comprised sodium lactate and sodium bicarbonate at pH 9.2 - 9.4.
- the steps shown in Figures 13B and 13C were carried out two times with only nominal squeezing forces exerted on the vessel 21; inverting step shown in Figure 13D was not carried out.
- the sample system(s) were as describe in the preceding example.
- FIG. 9 an alternate arrangement of the structures shown in Figure 1 can further insure that the seals are broken in an order that prevents fluid transfer to the catheter 28 (and any downstream equipment) prior to mixing of the PD agents.
- That drawing depicts container system 60 of the same general configuration as container system 10 of Figure 1 (as indicated by like reference numerals), albeit with the second seal (element 26 of Figure 1, element 62 of Figure 9) disposed within vessel 20 (e.g., rather than between the distal port of that vessel 20 and the catheter 28) so as to inhibit its manipulation and breaking until seal 24 is broken and fluid (or other) pressure within the vessel is reduced.
- seal 62 is a frangible member that can be fabricated from nylon, plastic, or other medical-grade material, and that can be formed in the configurations discussed above in connection with seal 24 (and shown, for example, in Figure 5). Moreover, like seal 26, seal 62 can be disposed between the distal port of the vessel 20 and the catheter 28 and affixed to (and/or formed integrally with) an interior fluid- transfer path of one or both of those.
- seal 62 is disposed so as to inhibit it from being manipulated (and, more significantly, broken) when vessel 20 contains its post-manufacture complement of PD buffer agent solution 22 (and/or other liquids, gasses or solids).
- this is achieved by extending the seal 62 within the vessel 20, e.g., in the manner shown in Figure 9, so as to inhibit squeezing, twisting or other manipulation of vessel 20, catheter 28 or otherwise from breaking seal 62 prior to breaking of seal 24 and (i) expulsion of at least some of its post-manufacturing complement of PD buffering agent 22 (and/or other liquids, gasses or solids) — and, preferably, expulsion of at least 10% — 30% and, still more preferably, at least 30% — 50% and, yet still more preferably, at least 50% — of such agent (and/or other liquids, gasses or solids) and/or (ii) reduction of the turgidity or other pressure effected within the vessel 20 by that agent
- the seals 24, 62 are colored differently to alert and remind the user of the proper order in which they are to be broken. Those skilled in the art will appreciate, of course, that coloration can be used in connection with other elements of the system 10, as well.
- FIG. 10A - 1OD depict utilization of PD system 60, including seal 62, in a manner according to the invention.
- seals 24, 26 are unbroken and compartment 20a contains its post-manufacture complement of buffer agent 22 (and/or other gasses, fluids, solids).
- vessel 20 is under sufficient fluid (or other) pressure to inhibit squeezing, twisting or other manipulation of it sufficient to break seal 62.
- seal 62 remains intact while the user breaks seal 24 (e.g., by bending the proximal end of vessel 20 relative to port 18) and compresses vessel 20 in order to expel buffer agent 22 for mixing with osmotic agent 14.
- the user bends or otherwise manipulates vessel 20 in order to break seal 62, once the seal 24 has been broken and the pressure within vessel 20 has been reduced. Once that seal 62 is broken, the mixed PD constituents can pass to catheter 28 (and/or other downstream equipment).
- the first compartment houses a PD osmotic agent at physiological use concentrations, i.e., substantially at concentrations at which that agent will be introduced into the patient's abdomen.
- concentrations for example of dextrose is about 1.5% - 4.25%, more preferably, about 2.0% - 4.0% and, still more preferably, about 2.0% - 3.0%.
- the PD osmotic agent is also at a physiologically low pH, i.e., a pH below that at which that agent will be introduced into the patient's abdomen, preferably, the pH is about 1.0 - 6.0 and, most preferably, about 1.0 - 3.0.
- Suitable PD osmotic agents include, but are not limited to, sugars such as glucose (e.g., dextrose), poly(glucose) (i.e., a polymer made from repeating glucose residues, e.g., icodextrin, made from repeating dextrose units), fructose, dextrans, polyanions, and the like.
- Other PD osmotic agents may be non-sugar osmotic agent that function as an equivalent could be a viable substitute, such as small amino acids.
- the PD osmotic agent is dextrose.
- the concentration of dextrose is about 1.5% - 4.25%, more preferably, about 2.0% - 4.0% and, still more preferably, about 2.0% - 3.0%.
- mEq/L refers to the concentration of a particular PD solution component (solute) present in proportion to the amount of water present. More specifically, mEq/L refers to the number of milli-equivalents of solute per liter of water. Milli-equivalents per liter are calculated by multiplying the moles per liter of solute by the number of charged species (groups) per molecule of solute, which is then multiplied by a factor of 1,000. As an example, when 10 grams of citric acid are added to a liter of water, the citric acid is present at a concentration of 10 g/L.
- Anhydrous citric acid has a molecular weight of 192.12 g/mol; therefore, the number of moles per liter of citric acid, and consequently citrate anion (since there is one mole of citrate anion per mole of citric acid), is 10 g/L divided by 192.12 g/mol, which is 0.05 mol/L.
- Citrate anion has three negatively charged species in the form of carboxylate groups. Accordingly, the citrate concentration of 0.05 mol/L is multiplied by three and then by 1,000, in order to provide a concentration of citrate in terms of mEq/L, which in the present example is 156 mEq/L of citrate anion.
- the same method of calculation can be used to determine the mEq/L of other agents such as lactate and dextrose.
- lactate for example, 4.48 grams of sodium lactate (molecular weight of 112.1 gram/mol) per liter of water provides 40 mEq/L of sodium cations and 40 mEq/L of lactate anions.
- dextrose 42.5 grams of dextrose (molecular weight of 180.2 gram/mol) per liter of water provides 235.8 mEq/L of dextrose.
- the PD osmotic agent can contain electrolytes, in addition to the osmotic agent. Suitable electrolytes may include, for example, sodium, potassium, calcium and magnesium.
- electrolytes may include, for example, sodium, potassium, calcium and magnesium.
- the preferred concentration range for sodium is from about 100 to about 132 mEq/L.
- the preferred concentration range for potassium is less than about 3.50 mEq/L.
- the preferred concentration range for calcium is less than about 2.50 mEq/L.
- the preferred concentration range for magnesium is less than about 1.50 mEq/L.
- the solution in the second container can be a concentrated agent and, specifically, in the illustrated embodiment (for example), a concentrated PD buffer solution.
- concentration refers to an agent that is stronger than the chemically "Normal” concentration for that particular agent.
- the te ⁇ ns "Normal” and “Normal concentration” are used herein in the conventional sense of the chemical arts to refer to solutions having a concentration of 1 gram equivalent per liter of a solute.
- the Normal concentration of an ionic buffer agent is effectively equal to the molar concentration divided by the valence (the number of free or missing electrons) of the ion.
- a standard amount of a buffer agent is 60% (w/w)
- 6OmIs of that buffer agent would be added to one liter of water in order to obtain Normal concentration for that agent.
- concentration e.g., as in some embodiments of the invention
- only 6mls of the buffer is needed in one liter of solution.
- the concentrated agent and, more specifically, the concentrated buffer utilized in systems and methods according to the invention can be of any concentration that is stronger than the chemically Normal concentration.
- the concentrated buffer can be about 3-fold higher than Normal, 5-fold, 7-fold, 10-fold, 15-fold, and up to at least 50-fold higher than the Normal buffer.
- conventional, commercially available PD solutions such as Deflex, by way of non-limiting example, are of chemically "Normal" concentration.
- the concentrated PD buffer agents utilized in embodiments of the present invention are of manifold increases in concentration relative to the commercial norm. The advantage of using concentrated buffers is that they can be stored and sterilized in small volume containers.
- a sufficient quantity of buffer to produce a Normal concentration of a buffer upon mixing can be stored in a reduced volume.
- a Normal amount of lactate buffer is typically 60% (w/w), i.e., 7.46 grams of sodium lactate buffer to one liter of solution.
- the lactate buffer can be contained in the vessel 20 such that 7.46 grams of sodium lactate is contained in a vessel with a volumetric capacity of about ISmIs.
- the advantage of the invention is that the buffers can be contained and sterilized in small volume containers.
- buffers include, but are not limited to, lactates, acetates, pyruvates, citrates, and the like.
- the lactate source may be any of lactic acid, sodium lactate, potassium lactate, calcium lactate, magnesium lactate, and the like.
- the acetate source may be any of acetic acid, sodium acetate, potassium acetate, calcium acetate, calcium acetate, magnesium acetate, and the like. Any or all of these chemicals are commercially available, in USP-grade if desired, from many chemical supply houses including, for example, Aldrich Chemical Co., Milwaukee Wis.
- a preferred example of a PD buffer solution is a concentrated lactate buffer solution comprising lactate at a concentration of 20 miliequivalent per liter (mEq/1) to about 60 mEq/1, preferably a concentration of about 30 mEq/1 to about 50 mEq/1, and most preferably, a concentration of 40 mEq/1.
- the lactate buffer solution may further comprise a bicarbonate at a concentration of about 5 mEq/1 to about 10 mEq/1.
- a preferred buffer comprises 30 - 35 mEq/L of sodium lactate and 10 — 5.0 mEq/L of sodium bicarbonate.
- the pH range of the PD osmotic agent solution is about 1.0 — 6.0 and, most preferably, between 1.0 — 3.0.
- the pH range of the PD buffer agent solution is about 8.0 to about 14.0, and, more preferably, a pH of about 9.0 to about 12 and, still more preferably, a pH of about 9.0 to about 10.0.
- the different PD components can be dissolved in water that is essentially pyrogen- ftee and that at least meets the purity requirements established by United States Pharmacopia (USP)-grade for PD solutions.
- USP United States Pharmacopia
- a Normal PD solution typically comprises dextrose, sodium chloride, magnesium chloride and calcium chloride, sodium lactate, sodium hydroxide or hydrochloric acid added to adjust pH levels.
- the resulting pH of Normal PD solutions is about pH 5.0- 6.0, which is less than optimum for blood, which has a pH of about 7.35 and 7.45.
- the Normal PD solutions often also contain GDPs.
- the seven commonly identified and published GDPs are acetaldehyde (AcA), 3-deoxglucosone (3-DG), 5- hydroxymethylfuraldehyde (5-HMF) 5 glyoxal (GIx), methglyoxal (M-GIx), formaldehyde (FoA), and furaldehyde (FurA).
- the systems and methods of the present invention provide PD solutions with reduced GDPs, as well as with more physiologically optimal concentrations and pH's.
- the PD osmotic agent solution and PD buffer agent are sterilized separately, thus, reducing the formation of degradation products that would otherwise result from the reaction of those agents at sterilization (or other high temperatures).
- the pH of the separate solutions is adjusted, moreover, in the illustrated embodiment, to further minimize GDP production during sterilization.
- the pH range of the PD osmotic agent solution is about 1.0 — 6.0 and, more preferably, between 1.0 — 3.0, while the pH range of the PD buffer agent solution is about 8.0 to about 14.0, and, more preferably, a pH of about 9.0 to about 12 and, still more preferably, a pH of about 9.0 to about 10.0.
- the buffer agent can be added to the osmotic agent solution, producing a mixed PD solution with a pH in the physiologically optimal range of about 5.0 to about 8.0 and, more preferably, about 6.0 to about 7.0, and, most preferably, about pH 7.2.
- systems and methods as described herein can provide PD solutions with an overall reduction in GDPs in the range of about 50% to about 80% compared with Normal PD solutions.
- vessels 12 and 20 are manufactured, shipped and stored with seals 24 and 26 intact.
- Those containers may be pre-assembled, e.g., so that they are available for use by a patient, health care provider or manufacturer in the configuration shown in Figure 1 (not including attachment of catheter 28), or they may be manufactured, shipped and stored as kits, e.g., with the vessels 12 and 20 filled with their respective PD agents, but in unassembled form.
- the seal 24 may also be broken after sterilization at the time of manufacture.
- step 30 of Figure 2 is a flow chart depicting a sequence for sterilizing and administering a PD solution according to the invention.
- This sterilization which can be performed by the manufacturer and/or the health care provider, is achieved by steam-sterilization or other such conventional methods known in the art. Sterilization times and temperatures/pressures are in accord with those appropriate for the separated agents contained in vessels 12, 20, not reduced times and temperatures/pressures which might otherwise be necessary to prevent GDP build-up in sterilization of the combined components.
- step 32 following sterilization, seal 24 is broken (e.g., by squeezing and/or twisting of vessel 20 and/or port 18) to permit mixing of the PD buffer agent with the PD osmotic agent.
- the agents can be mixed by shaking, kneading or other action on the vessels 12, 20. See step 34.
- the solution is ready for administration - pending, for example, warming or other steps necessary for patient comfort or well being.
- seal 26 is broken, e.g., by squeezing or twisting of the distal port of vessel 20 and/or its interface with catheter 28. See step 36.
- step 36 can further include the step of moving the protective member to allow access to, and breaking of, seal 26. Once seal 26 is broken, the PD solution can exit from the port into the catheter (and any downstream equipment) and, finally, to a patient. See step 38.
- Figure 3 depicts system 40 according to a further embodiment of the invention generally constructed and utilized (as indicated by like reference numerals) as system 10, described above. Differences in construction and utilization are discussed in the text that follows and are evident in the drawings.
- Vessel 42 of system 40 comprises compartment 42a for, by way of example, PD buffer agent solution 22, as generally described above.
- Compartment 42a and vessel 42 are collapsible - i.e., they are configured such that force applied thereto, e.g., by a patient, health care provider or other, causes the volume of compartment 42a to at least temporarily decrease so as to expel fluid contained therein.
- vessel 42 has fan-fold walls, or bellows, along an axis aligned with a direction of fluid expulsion — here, along the fluid transfer path between vessel 42 and vessel 12.
- Other embodiments may utilize walls of other construction to facilitate collapse along the same or other axes. Regardless, those walls are preferably sufficiently durable to prevent leakage, e.g., so that after fluid expulsion, the compartment 42a can form part of a fluid transfer path between the compartment 12a and the patient's peritoneal cavity.
- Illustrated vessel 42 may be fabricated from PVC, polyolefin, polypropylene, rubber and/or other medical grade materials suitable for forming a collapsible container as described herein. As with vessel 20 ( Figure 1), above, vessel 42 can be formed, e.g., by blow molding, dip-forming, or otherwise.
- seal 24 is adapted to prevent fluid transfer (or other contact) between the PD agents contained in the compartments during manufacture, transport, storage and sterilization of system 40, yet, to permit such fluid transfer upon squeezing, twisting or other manipulation of vessel 42 and/or port 18 by a patient, health care provider, or manufacturer, e.g., following sterilization.
- seal 44 of system 40 is adapted to prevent fluid transfer to the catheter 28 (and any downstream equipment) prior to sterilization and mixing of the PD agents.
- seal 44 (which, too, is disposed at the distal port of the vessel 42) is broken by a further member 46 that is disposed in compartment 42a and that pierces, cuts or otherwise breaks seal 44 when the vessel 42 and compartment 42a have been compressed sufficiently to insure expulsion of the fluid 22 into compartment 12a.
- Seal 44 can be formed of PVC, polyolefin, polypropylene, rubber and/or other medical grade materials suitable for preventing fluid transfer, e.g., during manufacture, shipping, storage, sterilization, but susceptible to being broken, e.g., by member 46 as described here, following sterilization and mixing of the agents 14, 22.
- member 46 is depicted as a bayonet, though in other embodiments it may be of another shape. It can be constructed of the same materials utilized, e.g., for element 24. Member 46 can be formed near the proximal port of vessel 42 (e.g., opposite seal 24) and affixed to (and/or formed integrally with) an interior fluid-transfer path between the vessels, as shown, though in other embodiments it may be disposed elsewhere, e.g., preferably so that it breaks member 44 upon sufficient compression of vessel 42 and compartment 42a. To this end, in the illustration, member 46 is of such length that its tip (for piercing seal 44) is disposed approximately 40% from the proximal end of compartment 42a.
- the member may be of other lengths, depending upon the compressibility of compartment 42a and on the desired degree of expulsion of fluid 22 from compartment 42a to compartment 12a prior to piercing of seal 44.
- the container system 40 permits the PD osmotic agent solution and PD buffer agent to be sterilized separately, thus, reducing the formation of degradation products that would otherwise result from the reaction of the osmotic agent with the buffer agent at high temperature.
- the vessels 12 and 42 are manufactured, shipped and stored with seals 24 and 44 intact.
- Those containers may be pre-assemble, e.g., so that they are available for use by a patient or health care provider in the configuration shown in Figure 3 (not including attachment of catheter 28), or they may be manufactured, shipped and stored as kits, e.g., with the vessels 12 and 42 filled with their respective PD agents, but in unassembled form.
- the seal 24 may also be broken after sterilization at the time of manufacture.
- the vessels 12, 42 are sterilized before the seal 24 is broken and, therefore, before their respective contents have had a chance to mix. Such sterilization may be accomplished as described above, e.g., in connection with step 30 of Figure 2.
- seal 24 e.g., by squeezing and/or twisting of vessel 42 and/or port 18; see, Figure 4A. He or she then compresses (or collapses) vessel 42 to expel agent 22 from compartment 42a into compartment 12a, thereby, facilitating its mixing with agent 14; see, Figure 4B.
- systems and methods according to the invention are applicable to a range of peritoneal dialysis applications and other medical applications in which at least one agent (or combination of agents) requires separate sterilization prior to combination with another agent (or combination thereof).
- agents are sometimes combined prior to sterilization or, if combined after sterilization, for example, by injecting one of them into a medication port of a container that holds the other agent.
- the former increases risk of degradation of the agents.
- the latter increases the risk to health care personnel and/or the patient.
- Systems and methods of the invention avoid these risks and other shortcomings of the prior art by allowing the agent(s) to be sterilized separately and, then, combined, e.g., without the use of needles or other mechanisms that are expensive, unwieldy, and/or place the agent(s), health care personnel and/or patients at risk.
- Another advantage of systems and methods of the invention is that depending on the requirements of the agent that will be added to the medical solution, the second vessel can be coated with materials that maintain the shelf life and/or stability of the agent or additive.
- additives that can be administered with this invention are amino acids, proteins, heparin, and vitamins.
- Table 1 shows sample preparations with the PD solutions constituents at different pH values.
- the sample labeled "Buffer” has concentrated lactate buffer solution added to it.
- Table 2 shows the results of HPLC analysis of the samples to examine the various degradation products.
- the seven degradation products that were analyzed are as follows: acetaldehyde (AcA), 3-deoxglucosone (3-DG), 5-hydroxymethylfuraldehyde (5-HMF), glyoxal (Gix), methglyoxal (M-Gix), formaldehyde (FoA), and furaldehyde (FurA).
- the data from Table 2 shows that GDPs formation around pH 3.0 is the lowest among the solutions prepared and the Normal/commercial products.
- Sodium lactate as a buffer agent in PD solutions results in acetaldehyde (AcA) formation (See column entitled "pH" in Table 2).
- the PD solutions are produced with reduced GDPs by using a buffer solution with a bicarbonate (e.g., sodium bicarbonate).
- the first vessel 12 contains a PD osmotic agent solution with dextrose, sodium chloride, magnesium chloride, calcium chloride, and hydrochloric acid to adjust the pH to 3.0.
- the vessel 20 is filled with a concentrated PD lactate buffer solution with lactate only, adjusted to a pH of about 10.0 to about 12.0.
- Sodium hydroxide can be used to adjust the pH of the lactate buffer.
- a suitable concentration of lactate buffer is 40 mEq/1 lactate buffer.
- the second vessel 20 is filled with a concentrated PD lactate buffer solution comprising a bicarbonate buffer, adjusted to a pH of about 8.0 to about 9.0. Suitable concentrations are, 37 mEq/1 lactate buffer with 3 mEq/1 bicarbonate buffer.
- Table 4 shows the results of an average of 3 samples.
- the concentrated PD lactate buffer was mixed with PVC bag contents containing the PD osmotic agent solution post sterilization. After combining the PD lactate buffer with the PD osmotic agent buffer, the resulting PD solution was examined and had a significantly reduced amount of AcA compared with the existing commercially available PD solutions referred to as "Deflex" and "Balance.” Also, by maintaining the pH of the PD osmotic solution at 3.0 and then by adding concentrated PD lactate buffer at a pH of 10.0 to 12.0, the final pH of the resulting PD solution was at a more physiologically optimal pH of 7.2 (Table 4).
- the concentrated PD lactate buffer may also contain bicarbonate.
- the PD lactate-bicarbonate buffer was added to the PD osmotic agent solution, the resulting PD solution also had significantly reduced GDPs, and a near neutral pH of about 7.4.
- first and second PD agent-containing compartments are merely examples of the invention and that other embodiments, incorporating changes thereto, fall within the scope of the invention.
- first and second PD agent-containing compartments are shown as formed in separate vessels (e.g., bag 12 and tube 20), in other embodiments those compartments may be formed in a single vessel (e.g., a dual compartment bag).
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Abstract
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ605451A NZ605451A (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
EP07836291.0A EP2173401B1 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
AU2007357133A AU2007357133B2 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
CA2692271A CA2692271C (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
KR1020107001426A KR101697946B1 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
CN2007801000416A CN101808678B (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
PCT/US2007/016906 WO2009017472A1 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
NZ574925A NZ574925A (en) | 2007-07-27 | 2007-07-27 | Container system for peritoneal dialysis solutions having a first a compartment containing with PD osmotic agent and a second compartment with a PD buffer agent |
EP16186695.9A EP3124061B1 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/US2007/016906 WO2009017472A1 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
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WO2009017472A1 true WO2009017472A1 (en) | 2009-02-05 |
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PCT/US2007/016906 WO2009017472A1 (en) | 2007-07-27 | 2007-07-27 | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
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EP (2) | EP3124061B1 (en) |
KR (1) | KR101697946B1 (en) |
CN (1) | CN101808678B (en) |
AU (1) | AU2007357133B2 (en) |
CA (1) | CA2692271C (en) |
NZ (2) | NZ574925A (en) |
WO (1) | WO2009017472A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7837666B2 (en) | 2005-01-28 | 2010-11-23 | Fresenius Medical Care North America | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
US9585810B2 (en) | 2010-10-14 | 2017-03-07 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions with integrated inter-chamber diffuser |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3172146B1 (en) | 2014-07-22 | 2019-06-05 | Entegris, Inc. | Molded fluoropolymer breakseal with compliant material |
CN113164708A (en) | 2018-09-26 | 2021-07-23 | 纳科斯达格医药股份有限公司 | Configurable fluid passage sealing device and method |
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2007
- 2007-07-27 EP EP16186695.9A patent/EP3124061B1/en active Active
- 2007-07-27 CA CA2692271A patent/CA2692271C/en active Active
- 2007-07-27 EP EP07836291.0A patent/EP2173401B1/en active Active
- 2007-07-27 NZ NZ574925A patent/NZ574925A/en unknown
- 2007-07-27 AU AU2007357133A patent/AU2007357133B2/en active Active
- 2007-07-27 CN CN2007801000416A patent/CN101808678B/en active Active
- 2007-07-27 WO PCT/US2007/016906 patent/WO2009017472A1/en active Application Filing
- 2007-07-27 NZ NZ605451A patent/NZ605451A/en unknown
- 2007-07-27 KR KR1020107001426A patent/KR101697946B1/en active IP Right Grant
Patent Citations (4)
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US6277815B1 (en) | 1997-10-31 | 2001-08-21 | Fresenius Medical Care Deutschland Gmbh | Solution for peritoneal dialysis |
US20030159953A1 (en) * | 2000-05-25 | 2003-08-28 | Torbjorn Linden | Carbohydrate medical solution and sulphite stabilisator in a multiple compartment container and use thereof |
US20070106205A1 (en) * | 2002-02-11 | 2007-05-10 | Baxter International Inc. | Dialysis connector and cap having an integral disinfectant |
WO2006083653A2 (en) | 2005-01-28 | 2006-08-10 | Fresenius Medical Care Holdings, Inc | Systems and methods for delivery of peritoneal dialysis (pd) solutions |
Cited By (9)
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US7837666B2 (en) | 2005-01-28 | 2010-11-23 | Fresenius Medical Care North America | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
US7935070B2 (en) | 2005-01-28 | 2011-05-03 | Fresenius Medical Care North America | Systems and methods for dextrose containing peritoneal dialysis (PD) solutions with neutral pH and reduced glucose degradation product |
US7985212B2 (en) | 2005-01-28 | 2011-07-26 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
US8052631B2 (en) | 2005-01-28 | 2011-11-08 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
US8328784B2 (en) | 2005-01-28 | 2012-12-11 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
US9180069B2 (en) | 2005-01-28 | 2015-11-10 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
US9585810B2 (en) | 2010-10-14 | 2017-03-07 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions with integrated inter-chamber diffuser |
US10842714B2 (en) | 2010-10-14 | 2020-11-24 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions with integrated inter chamber diffuser |
US11779519B2 (en) | 2010-10-14 | 2023-10-10 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions with integrated inter-chamber diffuser |
Also Published As
Publication number | Publication date |
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CA2692271A1 (en) | 2009-02-05 |
NZ574925A (en) | 2013-02-22 |
NZ605451A (en) | 2014-08-29 |
KR20100049552A (en) | 2010-05-12 |
CA2692271C (en) | 2015-04-28 |
CN101808678A (en) | 2010-08-18 |
EP3124061B1 (en) | 2018-06-20 |
EP2173401A4 (en) | 2012-03-21 |
EP3124061A1 (en) | 2017-02-01 |
EP2173401A1 (en) | 2010-04-14 |
AU2007357133B2 (en) | 2014-08-14 |
EP2173401B1 (en) | 2016-09-21 |
AU2007357133A2 (en) | 2010-02-18 |
KR101697946B1 (en) | 2017-01-19 |
AU2007357133A1 (en) | 2009-02-05 |
CN101808678B (en) | 2013-05-08 |
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