WO2008040478A1 - Medikamentendosiersystem mittels mikropumpe - Google Patents
Medikamentendosiersystem mittels mikropumpe Download PDFInfo
- Publication number
- WO2008040478A1 WO2008040478A1 PCT/EP2007/008362 EP2007008362W WO2008040478A1 WO 2008040478 A1 WO2008040478 A1 WO 2008040478A1 EP 2007008362 W EP2007008362 W EP 2007008362W WO 2008040478 A1 WO2008040478 A1 WO 2008040478A1
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- WO
- WIPO (PCT)
- Prior art keywords
- component
- injection
- insulin
- pumping
- medical device
- Prior art date
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Classifications
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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
- 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
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14212—Pumping with an aspiration and an expulsion action
-
- 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
- A61M5/142—Pressure infusion, e.g. using pumps
Definitions
- the invention relates to a device for injecting a substance into the human or animal body, wherein the drug to be injected is removed by generating a negative pressure from a reservoir.
- the classic injection device for insulin is the insulin syringe. This has been used since the beginning of insulin therapy, but has been gradually replaced in recent years, especially in Germany by the introduction of insulin pens. Nevertheless, today the syringes, z. In the case of loss or defect of an insulin pen, are irreplaceable and used by many diabetics in combination with insulin pens. Especially when traveling the freedom from maintenance and worldwide availability is advantageous.
- Insulin syringes differ in their name and scale according to the concentration of the insulin U40 or U100 to be used.
- the insulin can be taken both from vials and from the prefilled ampules for insulin pens. This allows mixing of different types of insulin and reduces the number of injections needed.
- care must be taken to ensure freedom from bubbles.
- the directly visible, drawn-up insulin dose allows the user easy control over the amount of insulin injected. Nevertheless, insulin syringes require skill and regular application for error-free application.
- insulin pen insulin pen
- This pen-sized medical device was developed in the mid-80s and is mainly used in intensified insulin therapy.
- a major innovation to insulin syringes is the use of a removable medicine container.
- This container also called a cartridge or ampoule, is supplied filled with insulin by the manufacturer and used in the insulin pen before use.
- a needle pierces the ampoule sealing disc and realizes the parenteral injection of the preselected dose when the insulin is applied.
- An injection and triggering mechanism generates an injection stroke during the injection which causes the advancement of a plunger in the ampule and causes delivery of the preselected dose to the target tissue.
- the mechanism usually consists of a rigid piston rod with the Ampullenstopfenhub corresponding length.
- Insulin pens are divided into disposable and reusable.
- the ampoule and the metering mechanism form a unit prefabricated by the manufacturer and are disposed of together after emptying the ampoule. Reuse of the metering mechanism is not provided.
- reusable pens place increased demands on the user. So when changing the ampoule, the piston rod must be reset to the start position. Depending on the model, this is done by turning or pushing the piston rod while simultaneously activating a special function in the dosing mechanism. This must be done very carefully by the user, as due to the daily use and the high mechanical loads sometimes malfunctions, such. B. jamming of the piston rod, can occur.
- Reusable insulin pens are further subdivided into manual and semi-automatic pens.
- manual pens the user operates the injection button with his finger and thus determines the duration and course of the injection.
- semi-automatic insulin pens on the other hand, a spring is manually clamped before use, which stores the necessary injection energy. During the actual injection process, the spring is unlocked by the user. The Injection speed is determined by the spring force and can not be adapted to personal needs.
- EP 1045146 discloses a medical metering pump in which a pump is mounted between a container for a liquid medicament to be administered and a discharge line.
- the system is for operating a continuous medical metering pump that is secured to the body of the patient during operation.
- a medical dosing pump is designed to continuously deliver a drug in soluble form over a longer period of time (for example, from about 10 minutes to several hours).
- a medical dosing pump is to be distinguished herein in particular from an injection device such as a syringe or a medication pen (medicament pen) such as an insulin pen (insulin pen).
- an injection device such as a syringe or a medication pen (medicament pen) such as an insulin pen (insulin pen).
- the delivery of a predetermined amount of medicament within a short period of time is, for example, less than 1 second, 1 to 30 seconds, 1 to 60 seconds to 1 to 2 minutes.
- the continuous delivery of medication by means of a medical dosing pump has the disadvantage that over the relatively long time of the supply medical problems at the supply point z. As may occur by rejection of the body, contamination of the material or injury through the cannula. Continuous drug delivery requires a different treatment regime for a disease than the discrete delivery of the drug. Insulin pumps are usually used in type 1 diabetics.
- WO 2006/003130 an injection device is described by means of a suction device, in which the suction pump is operated by mechanical spring force.
- the mechanical drive is in this case a control, monitoring and signal processing by means of electronic components and software not accessible. This results in a possible only in the mechanical context administration of a Drug.
- the use of a mechanical spring also leads to a jerky fast and thus painful injection result.
- the removal of the drug from a storage container is carried out by negative pressure.
- the negative pressure is generated by mechanical contra-movement of equipment parts.
- this device is subject to the limited scope of a purely mechanical system. In addition, people with limited range of motion or muscle power will not be able to use this system or will only be able to use it to a very limited extent.
- the device according to the invention is therefore much more flexible compared to the known prior art, the patient significantly facilitates the injection process, can be easily adapted to accommodate completely differently designed reservoir (including from different manufacturers), the control and monitoring by electronic Systems accessible, is suitable for data acquisition and data exchange and can be operated remotely.
- the invention thus relates to a device for injecting a substance into the human or animal body, comprising inter alia a) at least one storage container; and b) one or more derivatives from a reservoir of a); and c) a pump mechanism mounted between a reservoir of a) and a drain of b); and d) a component which is suitable for injection and which is equipped with a
- Derivative of b) is functionally connected; characterized in that the pump mechanism is driven by engine power.
- a device consists of one or more components and serves the
- a component consists of one or more than one component and serves to fulfill a technical or non-technical function.
- a function is technical when it involves a transfer of force, work, energy, material, data and / or signals, the maintenance of the structure and / or shape or storage of a substance or storage of information.
- a function is not technical if the input or output of information to or from the user of the device or a substance is affected by or to the user of the device.
- a component may be part of a technical device that provides a partial function relative to the overall function of the device.
- a component is for example a reservoir.
- Reservoir may be a replaceable ampule containing a substance (especially a drug such as insulin).
- the replaceable ampoule may be particularly suitable for use in an insulin pen or other device for injecting a drug into the human or animal body.
- Another example of a technical component is a device for pumping or a pump.
- Further examples of technical components are, in particular, syringes, needles, piston rods, metering devices, mechanical displays, hoses, seals, batteries, motors, transmissions, electronic displays, electronic memories or electronic controls.
- a purpose in connection with the technical device is to be understood in particular the movement of liquid from one place to another.
- a purpose is defined, for example, by moving a volume of liquid from a reservoir to a drain.
- Purpose may also be the injection of a drug into the human or animal body.
- a component may be connected to one or more other components in a technical manner to jointly serve a purpose.
- a technical connection is, for example, a connection of components which is suitable for the transmission of force, work, energy, material (substance), data and / or signals. Can be connected to the components z.
- B. a mechanical coupling, a solid mechanical connection (gluing, screws, rivets, linkage or the like), a gear, a Latch, a barrier, a metallic wire, a light guide, a radio link, an electromagnetic field, a light beam or the like.
- a reservoir is characterized by an outer shape and an inner volume contained therein, in which a substance, in particular a liquid is enclosed.
- the volume is sealed fluid-tight to the outside.
- the external shape can be made by machining glass, metal (e.g., aluminum) or plastic. Access can be through a perforable membrane or a screw cap.
- a reservoir is, for example, an insulin cartridge for use in an insulin pen.
- Injection is the introduction of substances, in particular liquids, by means of a cannula together with a syringe or functionally comparable device, in particular a pen, into the human or animal body.
- a syringe or functionally comparable device in particular a pen
- subcutaneous, intramuscular, intravenous, intracutaneous and intraarticular injection are known.
- the subcutaneous injection takes place under the skin, it is relatively easy to carry out, little painful and can be made by the patient himself.
- the intramuscular injection takes place in the muscle. Since this involves greater risks, such as the painful injury of periosteum, this is usually done by medical staff.
- the intravenous injection takes place after venipuncture directly via a vein.
- a drug is placed directly under the dermis.
- intra-articular injection a fluid is injected into a joint.
- the injection of a substance into the human or animal body is to be distinguished, in particular, from the introduction of a substance by a medicament pump, an infusion or another type of continuous delivery over a certain period of time.
- a pump mechanism is a functional unit consisting of one or more technical components for moving fluids.
- the pump mechanism in the sense of the present invention may consist of at least one pumping component and at least one further component, which supplies the pumping component with drive energy, be composed or consist thereof.
- a pumping component is for example a hose pump, diaphragm pump, gear pump or a piezoelectrically operated pump.
- an electric motor can be understood as a further component which supplies the pumping component with drive energy.
- a pump mechanism in the context of this invention may comprise at least one pumping component and also interfaces to this pumping component, via which an external technical device for generating engine power connected to the pumping component or via which a technical device for generating motor power to the pumping component can be coupled.
- An interface in this case relates in particular to the mechanical connection of the drive shaft of a technical device for generating motor power with the pumping action generating device part of the pumping component, such as the drive of a pump via an electric motor.
- Such an interface also includes mechanical mounts as well as possibly required electrical contacts or contacts for transmitting information, data and / or signals.
- a device such as an electric motor is present externally if it is not part of the device from the one hand, but is made available later to be held together on specially attached to the technical device interfaces with the device in a functional manner.
- a technical device for generating engine power such as an electric motor is functionally connected to the pumping component such as a peristaltic pump when technical device and component can be distinguished as their own units, for example, by a spatial distance between the devices. This does not preclude the functional connection, which can be maintained for example via pipes, wires, remote couplings and the like.
- a technical device for generating engine power such as an electric motor is coupled to the pumping component, for example, a peristaltic pump when both devices after connection via the interfaces as represent uniform device, for example, only at the same time and as an assembled unit can only be moved together.
- connection of the technical device for generating the engine power (for example, an electric motor) is connected to the pumping component (for example, a
- Peristaltic pump functionally connected when the drive movement of the shaft of such a device is converted by suitable technical connection members of the pumping component in a pumping action of the pumping component.
- suitable technical connecting links for such a functional connection are for example fixed links or detachable couplings between the shaft of the driving technical device and the shaft of the pumping component.
- the pumping mechanism according to this invention can in a preferred embodiment of a pumping component, which is present together with a drive energy supplying component in fully integrated form, exist, such as in the form of a motor pump.
- the pumping component of an invention as described above may in preferred drive forms consist of a peristaltic pump, a diaphragm pump or a piezoelectrically operated pump.
- bellows pumps piston pumps, rotary piston pumps, gear pumps, rotary disk pumps, toothed belt pumps, eccentric screw pumps, screw pumps and others can also be used.
- a pumping member such as a pump is a machine by means of which the energy contained in a liquid is increased by performing mechanical work. Either the pressure of the fluid is increased or the fluid is given kinetic energy. This can be achieved in the presence of the appropriate technical equipment a directional change in location of the liquid.
- the provision of mechanical work is possible by machines designed for this purpose, such as electric motors.
- An electric motor can do electrical or chemical work with the help of magnetic fields in mechanical Convert work. Electric motors can be operated with direct current, three-phase or alternating current.
- the engine power for driving the pumping member is generated by an electric motor.
- engine power can also be, for example, by a
- Solar cell motor a gas engine, a steam-powered engine, a mechanical energy-powered engine, or the like can be provided.
- an energy source for operating the component which applies the engine power in particular of an electric motor, it is preferred to use a battery, a rechargeable battery and / or a solar cell, and / or domestic power (possibly via a transformer).
- a releasable and re-connectable clutch and / or a transmission for reduction, translation synchronization or for the transformation of a movement form is inserted.
- a gear should be understood a mechanical component by means of which a rotational movement can be transmitted or transformed.
- Forming means, for example, the transfer of a rotational movement in a horizontal or vertical reciprocation.
- Translation, reduction and synchronization means a corresponding ratio of the speeds or torques of the drive to the output.
- the reservoir has a non-flexible outer wall.
- This wall may for example consist of glass, metal, in particular steel, aluminum, titanium, gold, silver, platinum, wood, plastic in particular a polycarbonate or Plexiglas, a composite material of one or more of the aforementioned substances or another material.
- a storage container in the sense of this invention is in particular a bottle, cartridge or ampoule in which a medicinal product is stored or can be stored.
- Such storage containers are available, for example, as insulin ampoules for use in insulin pens or insulin pumps from various manufacturers (eg Sanofi-Aventis, Novo Nordisk, EIi Lilly) in the pharmaceutical trade, in particular in pharmacies.
- the reservoir has a flexible outer wall. From such a reservoir with a flexible wall liquid can be removed, for example, by generating negative pressure and consequent compression of the reservoir under the influence of the external air pressure or the pressure in a pressure chamber.
- the reservoir consists of a commercial vessel, a cartridge and / or ampoule each containing or suitable for storage of a drug.
- a drug is preferably insulin.
- a component is preferably used which has a cavity. This component is aligned with one side to the reservoir and connected thereto and aligned with another side of the pump mechanism and connected thereto.
- the connection can be made by common joining techniques for workpieces such as gluing, welding, riveting, bolting, clamping, flanging and other technicians.
- the discharge can also be formed from a part of the reservoir by such a part a cavity is inserted and a fitting connection to the pump mechanism or a possible intermediate piece is made. The exact connection can be made by appropriate external version of the reservoir.
- the discharge can also be formed from a part of the pump mechanism by such a part a cavity is inserted and a fitting connection to the reservoir or a possibly required intermediate piece is made.
- the fitting connection can be made by appropriate external Shaping the pump mechanism done.
- a tubular structure or a hose made of metal, in particular steel, aluminum or plastic or another material can be used.
- the drain has an internal cavity suitable for discharging a liquid from the reservoir.
- the cavity is usually cylindrically shaped.
- the connection of the discharge to the reservoir, the pumping mechanism and possibly other components is carried out as far as possible fluid-tight.
- the derivative is functional if it allows the substance in particular a liquid can be removed from the reservoir.
- a component for injecting a substance as a component of the device according to the invention consists in a preferred embodiment in particular of a cannula.
- a cannula is essentially a hollow needle, usually made of metal (eg steel, stainless steel, gold, silver, platinum).
- the end of the cannula is often sharpened with a beveled cut.
- the cannula may be pointed and / or sharpened at one end and blunt at the other end, but may also be pointed and / or sharpened at both ends.
- the cannula carries at one of the two ends a mostly cone-shaped attachment made of plastic, for example, by attaching the hollow needle, for example, by plugging or screwing on a medical device such as a syringe, a notednpen particular an insulin pen, a drug container or a drug pump is possible ,
- a medical device such as a syringe, a notednpen particular an insulin pen, a drug container or a drug pump is possible
- the cannula serves to functionally interact with a syringe, a pen, a pump, or other suitable medical device to withdraw or deliver fluid from or into the human or animal body.
- Another Characteristic for the characterization of the cannula is its length. Typical lengths of cannulas are 40 mm, 30 mm, 25 mm, 8 mm, 6 mm and other lengths.
- the technical device comprises at least one electronic component for controlling, monitoring and / or controlling the pumping component and / or the component which supplies the pumping component with motor power.
- the technical device comprises a flow sensor for determining the amount of the substance which is removed from the storage container and / or the amount which is used for the injection.
- the invention further relates to the manufacture of a device as described above wherein a) a component for receiving a reservoir is provided; b) a reservoir is provided. (This reservoir may contain a medicament in liquid form, for example insulin, but the reservoir may also be in an empty form); c) providing a discharge from the reservoir; d) a pump mechanism is provided; e) a component for injecting a substance is provided; f) possibly a flow sensor is provided; g) possibly electronic components for storage and / or data processing and / or data transfer are provided; h) the individual components as described in a) to g) to a functional
- a technical device according to the invention is suitable, for example, as part of a device which is suitable for injecting a substance into the human or animal body, bypassing the gastrointestinal tract.
- drugs and in particular insulin can preferably be administered.
- the present invention further relates to a medical device for injecting a drug into the human or animal body comprising inter alia the following components a) to f) or consisting wholly or partly of the following components a) to f): a) a basic body for mounting from at least one other
- this medical device comprises at least one means for storing and / or processing data and / or signals.
- this medical device further comprises an interface for the transmission of data and / or signals to and / or from an external technical unit, which is designed accordingly for the storage and / or processing of data and / or signals.
- an external technical unit can for example consist of a PC together with software installed thereon for the storage and / or processing of data and / or signals transmitted by a medical device.
- such a medical device contains insulin, in particular a long-acting and / or a short-acting insulin, and can accordingly be used to inject an insulin, in particular a long-acting and / or a short-acting insulin.
- Such a medical device in another preferred embodiment contains GLP-1 and can be used according to the injection of GLP-1 become.
- Such a medical device in a further preferred embodiment contains Lovenox and can be used according to the injection of Lovenox.
- the medical device according to the invention contains a medicament such as in particular insulin, for example in long-acting or short-acting form, GLP-1 or Lovenox in a storage container.
- a medicament such as in particular insulin, for example in long-acting or short-acting form, GLP-1 or Lovenox in a storage container.
- the medicaments mentioned and all other medicaments which can be injected by means of the device according to the invention are in solution or as a function of the solubility behavior of the substance at different temperature or pressure ratios (for example
- the drug for injection by means of the medical device according to the invention can also be provided in a reservoir with two or more separate chambers, one chamber containing the drug in solid form and another chamber containing a liquid such as water with or without additives such as buffer , Ions, preservatives, stabilizers, acids, bases, alcohols, organic solvents, and the like.
- the drug in the soluble Form are transferred before it is then injected.
- the invention relates to the production of a medical device according to the invention wherein a) a base body is provided for mounting at least one further component; b) providing a component for removing air bubbles from the liquid intended for injection; c) providing a component for presetting the amount of liquid intended for injection; d) a component is provided in the form of a display; e) a component in the form of a triggering mechanism is provided; f) at least one technical device according to the invention is provided as described above; g) the individual components from a) to f) are assembled into a functional unit.
- the invention further relates to the use of a medical device according to the invention for the prophylaxis and / or treatment of a disease and / or malfunction of the body by means of a substance whose pharmacological activity in the gastrointestinal tract is weakened or lost.
- a substance is for example a protein, carbohydrate, a nucleic acid or a vaccine.
- examples of such substances are insulins, growth hormones, interferons, interleukins, cytokines, heparins, monoclonal antibodies, attenuated virus infections (eg influenza) and others.
- a medical device relates inter alia to the treatment of diabetes, the administration of insulin, GLP-1, an interferon, growth hormone, heparin, Lovenox or a vaccine.
- a medical device in the context of this invention is used for the therapy of the human or animal body, in particular by supplying a substance such as insulin into the human or animal body.
- the delivery of a substance can be done by injection, such as by a syringe or a medicament pen, in particular an insulin pen.
- the supply by an insulin pump is in contrast to the injection in a continuous manner and is to be distinguished in the sense of this invention from an injection.
- a medical device is in particular a device for injecting the substance into the human or animal body.
- such a device for injection may be a medicament pen such as an insulin pen.
- Medicament pens are available in different forms and for different purposes and are available from various manufacturers on the market (eg Optitician, Optipen, Optiset).
- a basic body of a medical device such as an insulin pen
- its outer shell which also significantly determines the shape.
- This shape may be, for example, oblong, similar to a pin, oval, round, square, rectangular, in the form of an egg timer, hinged or telescopically collapsible.
- the material of the outer shell may be made of one or more plastics, glass, metal, wood or ceramic.
- Each insulin pen must meet numerous ease-of-use requirements to ensure safe and error-free use.
- the basic requirement is to display the preselected dose or the remaining quantity in the ampoule.
- the dose setting and the completion of the injection process is audible, palpable and visible. This safety requirement arises mainly from the limited perception in older type 2 diabetes patients.
- needle-free injection systems are also used in insulin therapy.
- a current application example for needle-free injection systems is the injection system Injex from Rösch AG. In this injector, the insulin is shot with extremely high pressure through a microneedle into the fat layer of the skin. A manually tensioned before the injection
- Spring stores the necessary injection energy.
- the injectate is distributed homogeneously and conically in the fatty tissue.
- a not insignificant advantage of these devices is the needle-free injection of the drug, which reduces the psychological inhibition threshold of insulin application in some patients. Furthermore, needle-free injection precludes infection of the puncture site.
- the disadvantage over conventional insulin pens proves the transfer of insulin into special ampoules, the comparatively larger mass of the device and the carrying of other accessories for tensioning the spring.
- insulin pumps are fully automated infusion systems for continuous subcutaneous insulin injection. They are about the size of a pack of cigarettes and are permanently worn on the body. The short-acting insulin is injected into the skin tissue via a catheter and a needle in the skin following the program prescribed by the patient.
- the job of the insulin pump is to mimic the continuous insulin output of the pancreas to lower the blood sugar level, but without being able to realize a closed loop blood glucose control. Due to the continuous and adaptable supply of insulin, these pumps offer advantages especially for physically active people or those with highly variable daily routines. With the insulin pump therapy, strong fluctuations in blood sugar, z. B. in diabetics with pronounced DAWN phenomenon, be compensated, which are manageable with conventional methods only with increased effort.
- Insulin pumps are available in various technical versions, with devices with syringe-like containers have prevailed in the course of technical development. Similar to insulin pens with needles, the insulin is in a storage container with a movable stopper. This is moved by a motor-driven piston rod.
- Insulin pens are concentrated in the essential ergonomic and safety features in the standard EN ISO 11608. This also includes the geometric-material properties of the insulin ampules and needle pins. Thus, for the user, the handling and operation of a pen is largely uniform and independent of the model.
- Insulin ampoules and needles is hereby expressly referred to as part of this disclosure.
- the essential functional element of an insulin pen is the injection mechanism. It determines the design and size of the pen as well as the design of the trigger mechanism and the dose selector.
- the mechanism translates the dose preset at the dose selector with the injection energy from the triggering mechanism into an injection stroke of the stopper in the ampule. This energy is transmitted either directly to the injection mechanism or through motion-transforming gears.
- the injection mechanism in the form of the piston rod is technically feasible in many forms.
- the delivery of the drug is done by specifying an injection stroke and the resulting displacement of the plug.
- the amount of liquid dispensed depends on the injection stroke and the inner diameter of the ampoule.
- air bubbles must be completely removed in accordance with the manufacturer's specifications and the EN ISO 11608 standard.
- a sufficiently long waiting time has to be observed in order to achieve a steady state, ie. H. Normal pressure of the liquid and relaxation of the plug in the ampoule to ensure.
- the reservoir for the drug influences the structure and the functional structure of the drug pen.
- the protective function is realized by the ampoule as a whole, ie by plug, glass body and sealing washer.
- the delivery function for the drug is provided by the stopper, which is displaced by means of the injection mechanism and causes a volume change in the ampoule.
- the coupling function to the injection system is produced by means of a sealant (eg sealing disk).
- an automatic medication pen eg automatic insulin pen or insulin pen
- the injection energy is applied by a drive with a downstream gear.
- power supply and control device are necessary.
- the promotion of the medicament does not take place via the displacement of the plug by means of an injection mechanism but via the introduction of a pump device.
- the pumping device is inserted between ampoule and injection system and is provided with appropriate interfaces.
- the pumping device can be provided with a flow sensor. It is in direct contact with the drug z. As insulin, resulting in additional requirements such as reduced bacterial count, sterility, Biskompatibiltician u. a. can result.
- Insulin vials serve as primary packaging for the drug and must meet high standards. This concerns the dimensional accuracy of the ampoule with regard to the dosing accuracy and compatibility with other components.
- the standard EN ISO 11608-3 takes up these requirements and describes the basic ones
- the ampoules consist of several subcomponents. The most important is the cylinder made of pharmaceutical glass with a high neutrality and chemical
- the surface quality of the cylinder is improved by siliconization.
- This surface treatment reduces the sliding and breakaway forces of the plug, increases the dosing accuracy and reduces the detachment of glass components with a long storage time.
- the degree of siliconization correlates with the height of the frictional forces of the plug, with a limit being set by the sensitivity of the insulin to the silicone.
- the ampoule is sealed on both sides by elastomeric closing parts, the stopper and the sealing disc.
- Decisive here are the proven mechanical tightness in different pressure situations as well as the microbiological tightness against germs in long-term tests. Also important are the maximum acceptable plug forces and the number of punctures of the sealing disc with a cannula.
- Penny tubes are sterile disposable products used to deliver insulin from the ampule to the target tissue. As well as ampoules, they are subject to stringent requirements because the actual functionality of the insulin pen is only achieved through the interaction of the two components.
- the needle consists of a cannula ground on both sides, which is enclosed in a vial attachment piece. Optimized cannulae sutures enable the patient to pierce the target tissue largely painlessly and cause only minimal tissue damage when retreating. Likewise, the ampoule disc is pierced without severe fragmentation. This is a mandatory prerequisite, since even with regular replacement of the needle, the tightness of the ampoule must be guaranteed.
- the ampoule attachment ensures a secure fit on the insulin pen.
- Microfluidics is a branch of microsystems technology and includes the design, manufacture, application, and study of microsystems that manipulate and treat fluid quantities in channel cross-sections from 1 ⁇ m to 1 mm in size.
- Microfluidic systems are used in medical technology, biochemistry, chemical engineering and analytics as well as micro-reaction technology. These microsystems can have dimensions in the millimeter and centimeter range, since for practical application, the amount of fluid and not the size of the microfluidic system is important. In addition, such systems have significant differences from conventional fluidic systems due to low fluid volumes and often small system sizes.
- microfluidic components e.g. As micropumps and sensors
- their power output drops so that they are not comparable with that of conventional components in the macro range.
- external actuators are often used, which sometimes significantly increase the dimensions of the overall system.
- physics and chemistry of the particles and molecules to be transported limit the miniaturization of microfluidic components.
- Micropumps have the task of dosing smallest amounts of liquid with simultaneously low production costs and small external dimensions.
- the miniaturization of the pump makes use of physical effects that are only concomitant in the macroscopic technique. As a result, can be divide the pumps into two groups, those with adapted macroscopic and novel microscopic action.
- micro displacement pumps consist essentially of three units, a pump chamber, an actuator for moving the fluid and a valve unit for controlling the flow direction.
- the pumping process is divided into two phases. In the suction phase, the actuator increases the chamber volume, creates a negative pressure, and the fluid is sucked through the inlet. In the displacement phase, the actuator moves in the opposite direction and reduces the volume of the pump chamber. The fluid is pumped out of the pump through the outlet.
- the valve unit produces a directed liquid flow throughout the process.
- the actuator principle and the structure of the valve unit are determined by the required pump parameters, i. H. Pump performance, the manufacturing process, the fluid properties, the power supply and the permitted size significantly determined. Both functional units are coordinated and influence the operating characteristics of the pump.
- micropumps Important parameters for comparison and selection of the micropumps are the maximum achievable values of delivery pressure and delivery rate.
- Microfluidic sensors are essentially divided into two groups. Flow sensors are used to record the volume or quantity of substance per unit of time, which passes the considered pipe cross-section. With the help of an integration device, the total volume can be determined, which is especially important for dosing tasks.
- Chemical sensors on the other hand, detect the presence or concentration of various substances, molecules or ions in the fluid, e.g. B. sensors for determining the pH.
- B. sensors for determining the pH.
- Flow sensors can be realized with the aid of various physical laws that can already be used in macroscopic applications or only through miniaturization. Depending on the method of measurement, flow rates ranging from a few nanolitems to a few milliliters per minute can be measured.
- a temperature signal is fed with a heating element in the liquid stream and detected by a temperature sensor again.
- the flow velocity can be calculated on the basis of the measured signal runtime and the distance covered.
- Diabetes mellitus is a condition in which the body itself can produce no or insufficient amounts of insulin or use it adequately. Insulin is needed to transport sugar from the blood into the body's cells. The blood sugar level is constantly kept constant within narrow limits (60-100 mg% or 3.33-5.55 mmol / l). This is done through the interaction of the two hormones insulin and glucagon.
- Diabetes mellitus takes place after blood collection by means of appropriate laboratory equipment. An elevated blood sugar level must be detected at least twice at different times to confirm the diagnosis. Diabetes mellitus is when the glucose value measured in the blood plasma exceeds the stated value in at least one of the following cases: a) Fasting blood sugar - 7.0 mmol / l or 126 mg / dl b) Blood sugar two hours after administration of 75 mg Glucose (oral glucose tolerance test) - 11, 1 mmol / l or 200 mg / dl c) Blood sugar 11, 1 mmol / l or 200 mg / dl combined with severe thirst (polydipsia), frequent urination (polyuria) or weight loss ,
- diabetes Left untreated, diabetes leads to elevated blood sugar levels, which can lead to various symptoms and sequelae, such as polyneuropathy.
- Microangiopathy, macroangiopathy, retinopathy, nephropathy and others The lower the non-enzymatic glycation of the erythrocytes (HbA1c value), the lower the risk of late diabetic damage
- Diabetic coma is a life-threatening acute complication of diabetes.
- the blood sugar value can reach over 1000 mg / dl along with a strong hyperacidity of the blood (metabolic acidosis).
- Diabetic coma can be triggered by infections, ingestion of excess carbohydrates, alcohol abuse or incorrect dosage of insulin.
- Type 1 diabetes In type 1 diabetes, there is an absolute insulin deficiency right from the beginning, which can only be treated with insulin.
- Type 2 diabetes is characterized by decreased insulin sensitivity and relative insulin deficiency. Type 2 diabetes can usually be treated first with dietary measures and tablets. Often, insulin substitution becomes necessary during the course of the disease.
- Type 2 diabetes has become a widespread disease mainly in industrialized countries. The main cause is overeating, physical inactivity and overweight. Type 2 diabetes can be characterized by exercise training and diabetic measures, in particular Targeting weight loss, counteract effectively. In addition, in the case of type 2 diabetes oral antidiabetics such. As acarbose, biguanides, sulfonylurea, glitazone and others are used. Therapy using insulin becomes necessary if, by means of the above-mentioned measures, the blood sugar level can no longer be maintained with sufficient sustainability in or near the normal range.
- the fast-acting insulins include human insulin as well as various fast and short-acting insulin analogues such as glulisine (trade name: Apidra), lispro (trade name: Humalog) and aspart (trade name: Novo Rapid).
- glulisine trade name: Apidra
- lispro trade name: Humalog
- aspart trade name: Novo Rapid
- NPH insulin human insulin delayed by neutral protamine hawthorn
- zinc insulins various insulin analogs such as glargine (trade name: Lantus) and detemir (trade name: Levemir).
- Mixed insulins consist of a fast-acting insulin and a
- Delay insulin in different mixing ratios Usual are mixtures of 10/90%, 25/75%, 30/70%, 50/50%. Insulin therapy must always be accompanied by regular measurements of blood sugar levels.
- In conventional insulin therapy a certain amount of mixed insulin is injected at fixed times. Intensified conventional insulin therapy is mainly used in the treatment of type 1 diabetics. Here is a Basic care is provided via a delay insulin (based) and given in addition to meals a fast acting insulin (bolus).
- the continuous subcutaneous insulin infusion by means of a pump is mainly for type 1 diabetics in question.
- the insulin is not injected but passed by a small pump in the body.
- the pump is permanently on the body.
- the insulin is delivered via a catheter with cannula.
- the insulin pump will usually deliver fast acting insulin at small even intervals over a longer period of time.
- GLP1 Glucagon-like-Reptide 1
- GIP glucose-dependent insulinotropic peptide
- Incretins are formed as hormones in the intestine and regulate, among other things, the blood sugar level by stimulating the insulin secretion in the pancreas.
- the amount of intestinal hormones formed depends on the amount of carbohydrates ingested orally.
- the level of GLP1 increases much more after oral glucose intake than after intravenous glucose.
- Investigations have shown that intravenous infusion and subcutaneous injection of GLP1 in type 2 diabetics in many cases leads to a complete normalization of blood sugar levels.
- the problem is that GLP1 is inhibited within a very short time by dipeptidyl peptidase IV (DPP-IV).
- DPP-IV dipeptidyl peptidase IV
- Subcutaneous injection of GLP1 can only maintain effective plasma concentrations for approximately 1-2 hours.
- One solution to the long-term effects of GLP1 may be found in the development of longer-acting GLP analogues or the inhibition of DPP-IV by drugs.
- Growth hormones are substances that stimulate growth in humans, animals and plants.
- the somatotropin human
- the bovine somatotropin (bovine) and auxin and gibberellic acid (plant) are known.
- Somatotropin (STH) is also known as Human Growth Hormone (HGH), Growth Hormone (GH) or Growth Hormone (WH).
- HGH Human Growth Hormone
- GH Growth Hormone
- WH Growth Hormone
- STH is a peptide hormone with 191 amino acids. Formation occurs in the anterior pituitary with regulation of the somatotropin releasing factor (SRF; GHRH; GRF) from the hypothalamus. STH is essential for normal length growth. With reduced production or reduced response of the cells to STH, dwarfism occurs. Overproduction leads to gigantism or acromegaly.
- Interferons are formed as tissue hormones from human or animal leukocytes, fibroblasts or T lymphocytes.
- An interferon is a protein or glycoprotein with an immunostimulatory (eg anti-viral) or anti-hormonal action.
- the interferons are divided into alpha interferons, beta interferons and gamma interferons.
- Interferons are available from several manufacturers for indications such as viral diseases (eg SARS), cancer, multiple sclerosis, hepatitis B / C, hepatitis C.
- a vaccine is a biologically or genetically engineered composition containing, inter alia, individual proteins and / or RNA or DNA fragments and / or killed or attenuated pathogens (eg influenza, SARS, Pockervirus, measles pathogens, mumps, Rubella, polio, pathogens of whooping cough).
- pathogens eg influenza, SARS, Pockervirus, measles pathogens, mumps, Rubella, polio, pathogens of whooping cough.
- Live vaccines eg cowpox
- attenuated live vaccines with attenuated viruses or bacteria eg M M R vaccine, yellow fever
- Heparins are therapeutically used substances to inhibit blood clotting. Heparins consist of alternating sequences of D-glucosamine and D-glucuronic acid or L-iduronic acid. Chain lengths consisting of 5 units may already be anticoagulant.
- the polysaccharide chains usually have a molecular weight between 4,000 and 40,000. In addition to unfractionated heparins, low molecular weight fractionated heparins with a molecular weight of about 5,000 are also used. Heparins are not absorbed from the gastrointestinal tract, but must be administered parenterally. Heparins act by binding to antitrhombin III and thus accelerate inactivation of activated coagulation factors.
- Lovenox also known as Clexane
- Clexane is a commercially available pharmaceutical preparation containing the pharmacologically active substance enoxaprin sodium.
- the active ingredient is one of the low molecular weight heparins with a linear dose-response relationship and a consistently high bioavailability.
- the indications of Lovenox are the primary prophylaxis of deep vein thrombosis, the treatment of deep venous thrombosis with and without pulmonary embolism, the treatment of unstable angina pectoris and the so-called non-Q-wave heart attack as well as thrombosis prophylaxis and anticoagulation during hemodialysis. example
- the central component of the pen thereby forms the pumping device, which sucks the insulin out of the ampoule and injected through the needle into the target tissue. This device comes in direct contact with the liquid.
- Insulin dosage should be done with the help of a sensor.
- the use of the ampoules and the Pennadeln is given, so that the Operating characteristics of the pumping device to be adapted to these components.
- Important parameters for dimensioning are the producible intake or counterpressure at a constant delivery rate.
- the core of the study is the suction pressure required to deliver the insulin caused by the friction between the glass cylinder and the plug. If possible, proposals for the optimization of the pumping process in the pen to be developed should also be submitted. Subsequently, the pressure drop when pumping the insulin should be determined on representative Pennadeln. Based on these test results, an active principle for the pumping device must be selected and then proof of suitability during a functional test. In addition to the pumping capacity, criteria include interchangeability, compliance with medical requirements and miniaturization. The investigations of a sensor principle to record the insulin current form the conclusion of the chapter.
- Ampoules and the injection needle form an adapted functional unit for the delivery of insulin.
- a force balance between the piston rod force and the sum of the resulting forces from the stopper friction and the fluid pressure arises when the stopper is advanced.
- the plug position and feed rate are determined at all times, neglecting plug compressibility, by the piston rod position.
- an overpressure which pumps the liquid through the Pennadel.
- the state variables in the system change.
- the negative pressure also referred to as relative pressure
- the maximum acting plug force is limited to about 7.3 N by this pressure difference.
- the stopper velocity depends exclusively on the stopper friction and the suction pressure. In the area of starting friction, this can be low even at high intake pressure.
- the delivery rate is dependent on the stopper velocity and varies accordingly.
- the air dissolved in the liquid can outgas due to the negative pressure.
- Existing air bubbles experience an increase in volume depending on the fluid pressure. A very high intake pressure could lead to cavitation when the vapor pressure is reached. This is absolutely to be avoided.
- both the liquid pressure and the stopper position are to be measured. They should give information about the suitability of the ampoules for this active principle. Likewise, statements must be made regarding the necessary intake capacity of the pumping device or for optimizing the intake process. Of particular importance are the aspects of elastomeric plug friction in the area of starting and sliding friction. The investigations should be carried out on a sufficiently large number or with ampoules of different batches to obtain meaningful results.
- the measuring station consists of the four main components, syringe pump, pressure sensor, optical sensor and measuring computer with the software LabView ( Figure 6.1).
- the syringe pump of the company TSE GmbH, Model 540060 is a hose and a Injection needle connected to the ampoule and can be programmed and controlled by the computer. It is designed for suction and pressure operation and generates delivery rates in a defined range.
- a pressure sensor from the company Active Sensor, Model AUS + 1.0 bar pierces the sealing disk of the ampoule.
- the sensor is equipped with a hose and injection needle.
- the fluid pressure in relation to the air pressure in the ampoule can be measured since there is no fluid flow in the hose and the capillary pressure in the injection needle is negligible.
- a line sensor from TAOS Inc., ModelTSLR1410R is used to determine the stopper position. This is arranged parallel to the ampoule and has a resolution of 400 dpi. When illuminated with parallel light and shielding the ampoule from the ambient light, this detects the shadow of the plug.
- a data acquisition program calculates the stopper position with an accuracy of up to 50 ⁇ m from the shadow image using special algorithms and interpolation. The measured value as well as the fluid pressure are stored for further processing.
- the experiment is carried out according to a specified pattern.
- the syringe pump Before starting the actual measurements, the syringe pump must be programmed with the desired pumping sequence. The sequence may be composed of withdrawing one or more doses with intermediate pauses or different delivery rates. Then the measuring station is to be equipped with a new ampoule. Then the hoses filled with water and the syringe pump are examined for air bubbles and if necessary removed. In general, care must be taken to keep dead volumes in the system as low as possible. Finally, make the fluidic connections to the ampoule. Then the measurement can be started. At the same time, the measuring computer activates the syringe pump and starts reading the sensor signals. The measuring program converts the signals and saves them time-dependently in a file. for a better understanding or representation of the fluid pressure is always relative to the air pressure with negative
- the absolute fluid pressure of, for example, 60 kPa in the ampoule thus corresponds to a positive relative pressure to the normal air pressure of about 39 kPa.
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- Health & Medical Sciences (AREA)
- Vascular Medicine (AREA)
- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0718233-3A BRPI0718233A2 (pt) | 2006-10-07 | 2007-09-26 | Sistema para dosagem de droga operado por microbomba |
CA2665274A CA2665274C (en) | 2006-10-07 | 2007-09-26 | Micropump-operated drug dosing system |
EP07818446A EP2076298A1 (de) | 2006-10-07 | 2007-09-26 | Medikamentendosiersystem mittels mikropumpe |
JP2009530777A JP2010505474A (ja) | 2006-10-07 | 2007-09-26 | マイクロポンプ作動の薬剤投与システム |
AU2007304461A AU2007304461A1 (en) | 2006-10-07 | 2007-09-26 | Micropump-operated drug dosing system |
MX2009003494A MX2009003494A (es) | 2006-10-07 | 2007-09-26 | Sistema dosificador de medicamento accionado por una microbomba. |
US12/415,222 US20090292245A1 (en) | 2006-10-07 | 2009-03-31 | Micropump-operated drug dosing system |
IL197974A IL197974A (en) | 2006-10-07 | 2009-04-05 | A packet dispensing system of a micro-pump drug |
NO20091767A NO20091767L (no) | 2006-10-07 | 2009-05-05 | Mikropumpe-operert medisindoseringssystem |
IL242028A IL242028A0 (en) | 2006-10-07 | 2015-10-12 | A system for dispensing doses of medicine operated by means of a micro-pump |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102006047538A DE102006047538A1 (de) | 2006-10-07 | 2006-10-07 | Medikamentendosiersystem mittels Mikropumpe |
DE102006047538.0 | 2006-10-07 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/415,222 Continuation US20090292245A1 (en) | 2006-10-07 | 2009-03-31 | Micropump-operated drug dosing system |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008040478A1 true WO2008040478A1 (de) | 2008-04-10 |
Family
ID=38924819
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2007/008362 WO2008040478A1 (de) | 2006-10-07 | 2007-09-26 | Medikamentendosiersystem mittels mikropumpe |
Country Status (15)
Country | Link |
---|---|
US (1) | US20090292245A1 (de) |
EP (1) | EP2076298A1 (de) |
JP (1) | JP2010505474A (de) |
KR (1) | KR20090059146A (de) |
CN (1) | CN101522236A (de) |
AR (1) | AR063135A1 (de) |
AU (1) | AU2007304461A1 (de) |
BR (1) | BRPI0718233A2 (de) |
CA (1) | CA2665274C (de) |
DE (1) | DE102006047538A1 (de) |
IL (2) | IL197974A (de) |
MX (1) | MX2009003494A (de) |
NO (1) | NO20091767L (de) |
TW (1) | TW200833386A (de) |
WO (1) | WO2008040478A1 (de) |
Cited By (4)
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US8496621B2 (en) | 2006-10-07 | 2013-07-30 | Sanofi-Aventis Deutschland Gmbh | Peristaltic micropump with exchangeable pump head |
US10603428B2 (en) | 2013-05-30 | 2020-03-31 | Actelion Pharmaceuticals Ltd. | Device for dispensing a fluid to a patient |
US11185629B2 (en) | 2016-06-08 | 2021-11-30 | Shl Medical Ag | Dosing apparatus and injection device |
US11253652B2 (en) | 2016-11-28 | 2022-02-22 | Shl Medical Ag | Device for dispensing a substance |
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US20080172026A1 (en) | 2006-10-17 | 2008-07-17 | Blomquist Michael L | Insulin pump having a suspension bolus |
US8986253B2 (en) | 2008-01-25 | 2015-03-24 | Tandem Diabetes Care, Inc. | Two chamber pumps and related methods |
US8408421B2 (en) | 2008-09-16 | 2013-04-02 | Tandem Diabetes Care, Inc. | Flow regulating stopcocks and related methods |
EP2334234A4 (de) | 2008-09-19 | 2013-03-20 | Tandem Diabetes Care Inc | Vorrichtung zur messung der konzentration eines gelösten stoffs und entsprechende verfahren |
US8608699B2 (en) | 2009-03-31 | 2013-12-17 | Tandem Diabetes Care, Inc. | Systems and methods to address air, leaks and occlusions in an insulin pump system |
US9211377B2 (en) | 2009-07-30 | 2015-12-15 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
KR101086869B1 (ko) * | 2009-10-20 | 2011-11-24 | 주식회사 이담테크 | 자동 분유혼합장치 |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
US9603995B2 (en) | 2013-03-15 | 2017-03-28 | Tandem Diabetes Care. Inc. | Device and method for setting therapeutic parameters for an infusion device |
JO3749B1 (ar) * | 2015-08-27 | 2021-01-31 | Lilly Co Eli | تركيبات إنسولين سريعة المفعول |
AU2017345743B2 (en) | 2016-10-21 | 2023-02-16 | Franklin Electric Co., Inc. | Motor drive system and method |
KR102049001B1 (ko) * | 2017-11-27 | 2019-11-26 | 재단법인 대구경북첨단의료산업진흥재단 | 약물 주입 장치 |
US11174852B2 (en) | 2018-07-20 | 2021-11-16 | Becton, Dickinson And Company | Reciprocating pump |
KR102365840B1 (ko) | 2019-11-27 | 2022-02-22 | 고려대학교 산학협력단 | 초흡수성 폴리머를 이용한 하이브리드 동력 기반의 시린지리스 펌프 |
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2006
- 2006-10-07 DE DE102006047538A patent/DE102006047538A1/de not_active Withdrawn
-
2007
- 2007-09-26 WO PCT/EP2007/008362 patent/WO2008040478A1/de active Application Filing
- 2007-09-26 MX MX2009003494A patent/MX2009003494A/es unknown
- 2007-09-26 EP EP07818446A patent/EP2076298A1/de not_active Withdrawn
- 2007-09-26 JP JP2009530777A patent/JP2010505474A/ja active Pending
- 2007-09-26 AU AU2007304461A patent/AU2007304461A1/en not_active Abandoned
- 2007-09-26 CA CA2665274A patent/CA2665274C/en not_active Expired - Fee Related
- 2007-09-26 KR KR1020097006997A patent/KR20090059146A/ko not_active Application Discontinuation
- 2007-09-26 BR BRPI0718233-3A patent/BRPI0718233A2/pt not_active IP Right Cessation
- 2007-09-26 CN CNA2007800374258A patent/CN101522236A/zh active Pending
- 2007-10-04 TW TW096137187A patent/TW200833386A/zh unknown
- 2007-10-04 AR ARP070104406A patent/AR063135A1/es not_active Application Discontinuation
-
2009
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- 2009-04-05 IL IL197974A patent/IL197974A/en not_active IP Right Cessation
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2015
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US8496621B2 (en) | 2006-10-07 | 2013-07-30 | Sanofi-Aventis Deutschland Gmbh | Peristaltic micropump with exchangeable pump head |
US10603428B2 (en) | 2013-05-30 | 2020-03-31 | Actelion Pharmaceuticals Ltd. | Device for dispensing a fluid to a patient |
US11185629B2 (en) | 2016-06-08 | 2021-11-30 | Shl Medical Ag | Dosing apparatus and injection device |
US11253652B2 (en) | 2016-11-28 | 2022-02-22 | Shl Medical Ag | Device for dispensing a substance |
Also Published As
Publication number | Publication date |
---|---|
JP2010505474A (ja) | 2010-02-25 |
AR063135A1 (es) | 2008-12-30 |
EP2076298A1 (de) | 2009-07-08 |
IL197974A0 (en) | 2009-12-24 |
MX2009003494A (es) | 2009-04-14 |
CA2665274C (en) | 2015-11-10 |
CA2665274A1 (en) | 2008-04-10 |
CN101522236A (zh) | 2009-09-02 |
US20090292245A1 (en) | 2009-11-26 |
BRPI0718233A2 (pt) | 2013-11-12 |
DE102006047538A1 (de) | 2008-04-10 |
IL197974A (en) | 2015-10-29 |
AU2007304461A1 (en) | 2008-04-10 |
TW200833386A (en) | 2008-08-16 |
IL242028A0 (en) | 2015-11-30 |
KR20090059146A (ko) | 2009-06-10 |
NO20091767L (no) | 2009-07-01 |
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