HK1137371B - Optical determination of the position of the stopper in glass ampoules - Google Patents

Description

Optical determination of the position of a stopper in a glass cartridge

The present invention relates to a method for determining the position of the bung of a cartridge in a medical device by means of a light source and a light sensitive sensor surface.

Many drugs must be injected into the body. This is especially true for those drugs that are inactive or have very low activity when administered orally. These drugs include, in particular, proteins (e.g. insulin, growth hormones, interferons), carbohydrates (e.g. heparin), antibodies or most vaccines. For in vivo injection, syringes, medication pens or drug pumps are mainly used.

A conventional insulin injection device is an insulin syringe. Since the start of insulin therapy, insulin syringes have been used, but in recent years, especially in germany, insulin syringes have been gradually replaced due to the introduction of insulin pens. Nevertheless, syringes are currently irreplaceable, for example when an insulin pen is lost or damaged, and many diabetics use syringes in conjunction with insulin pens. The advantage is maintenance free and easy availability, especially on trips.

Insulin syringes differ in their identity and scale according to the insulin concentration U40 or U100 to be used. The insulin may be taken from a vial or a pre-filled cartridge for an insulin pen. This allows mixing of different types of insulin and reduces the number of injections necessary. Special care must be taken to avoid air bubbles when drawing insulin into the syringe. The directly visible insulin dose drawn in allows the user to easily check the amount of insulin injected. Nevertheless, for error-free administration with insulin syringes, skilled and regular use is necessary.

Another injection device that is currently very widely used throughout the world, especially in europe, is the insulin pen.

The medical device was marker-pen sized, developed in the mid 80's of the 20 th century, and was primarily used for more intensive insulin therapy. A significant innovation compared to insulin syringes is the use of replaceable medicament containers. This container, also called a carpule or cartridge, is filled with insulin when supplied by the manufacturer and inserted into an insulin pen prior to use. When the pen is operated, the injection needle pierces the sealing disk of the cartridge and completes a parenteral injection of the preselected dose to administer the insulin. During injection, the injection and release mechanism produces an injection stroke that advances a plunger (plunger) or stopper in the cartridge and causes a preselected dose to be delivered into the target tissue. The mechanism typically consists of a rigid plunger rod (plungerstem) having a length corresponding to the stroke of the cartridge stopper.

Insulin pens are classified into disposable insulin pens and reusable insulin pens. For disposable insulin pens, the cartridge and the metering mechanism form a unit that is pre-manufactured by the manufacturer and after the cartridge is emptied, the cartridge and the metering mechanism are disposed of together. The metering mechanism is no longer used. Reusable pens have increased demands on users compared to prefabricated pens. Therefore, when changing the cartridge, the plunger rod has to be retracted to the starting position. Depending on its mode, this is done by twisting or sliding the plunger rod and simultaneously actuating a specific function of the metering mechanism. Due to the everyday use and high mechanical stress, malfunctions such as plunger rod sticking may occasionally occur, so that the user has to perform this operation very carefully.

Reusable insulin pens can also be divided into manual pens and semi-automatic pens. In the case of a manual pen, the user applies a force with the finger to actuate the injection button and thereby determine the duration and progress of the injection. In contrast, with a semi-automatic insulin pen, the spring that stores the energy necessary for the injection is manually tightened prior to use. During the actual injection step, the user releases the spring. The injection speed is fixed by the force of the spring and therefore cannot be adjusted to the individual needs.

WO 2004009163 discloses an optical sensor for a medicament administration system, by means of which the displacement of the plunger rod can be determined based on transparent or reflective markers. The light source used is an array of LEDs and a linear or two-dimensional CCD element is applied as the imaging element.

EP 858349B 1 discloses a device with a light source and an optical detector for optical measurement and electronic recording of dose. The detector is arranged so that it detects the total amount of light reflected by the syringe and the amount of light reflected is related to the amount of liquid in the syringe.

WO 200156635 discloses a device for administering a medicament comprising a sensor element with which the operating state of the identification element and/or the container (e.g. the distance by which the plunger is pushed in) can be identified.

The invention relates to a method for determining the position of a component along a distance of movement (travel distance) in a medical device by means of a) a light source and b) a holder (holder) for movably holding the component along the distance of movement and c) a light-sensitive sensor surface, wherein a silhouette (silhouette) of the component is first generated at the sensor surface by irradiating the component with light from a), and then the relevant data of the silhouette on the sensor surface is converted into the position of the component relative to the distance of movement by means of a data processing unit.

The data processing unit consists of the following components: firstly hardware components, such as, in particular, a central arithmetic unit, one or more memories, output and control devices, and technical connections between these components; secondly, software components, such as, in particular, an operating system and programs for controlling and evaluating the execution of the position determination.

In one embodiment, the method relates to the determination of the position of the stopper of a cartridge (which is used for a medicament), in particular to the determination of the position of the stopper of an insulin cartridge. The movement of the bung of a cartridge (for a drug, e.g. insulin) in a medical device (e.g. insulin pen, insulin pump) corresponds to the release of the drug. Thus, the determination of the position of the bung in the cartridge is used to control and monitor the amount of released drug (e.g. insulin) when the medical device is operated.

In another embodiment, the method involves the determination of the position of a component, which is a component of an adjustment device, by means of which the amount of drug to be delivered can be preset. The assembly is a component of the adjustment device, which may consist of a projection with a geometric shape (circle, oval, square, rectangle, star, combined shape and others), which is fixedly connected to the adjustment device and moves together with the adjustment device during the adjustment process and by which the corresponding movement of the silhouette along the sensor surface is converted by the data processing unit into the amount of drug (e.g. insulin) to be delivered. The adjusting means is then a holder for movably holding the assembly along the displacement distance. In another embodiment, the method involves the determination of the position of a supply unit (feed unit) for removing the drug from the cartridge. The supply unit translates a preset amount of the drug to be delivered into a movement of the other component to deliver the drug. The supply unit is firstly connected directly or indirectly to the bung of the cartridge and secondly to a presentation mechanism and a release mechanism to release the medicament. The determination of the position of the feed unit in the method according to the invention can be carried out by means of an element (for example a geometrically shaped three-dimensional object or a plate) which is fixedly connected to the feed unit, wherein a corresponding silhouette is generated on the sensor surface. In this case, the supply device is a holder that movably holds the assembly along the movement distance.

In another embodiment, for carrying out the method, a data processing unit integrated in the medical device is used, i.e. the data processing unit is an integral part of the medical device. In another embodiment of the method, the data processing unit is independently operable. Such a separately operating data processing unit may be used, for example a PC equipped with a program adapted to run the method of the invention. The exchange of data and control signals between the medical device and the data processing unit must then take place via a suitable connection means, such as in particular a cable connection, a wireless connection, or via a data carrier.

In another embodiment of the method, an aperture (aperture) and/or a lens (for focusing or dispersion) is/are attached between the light source and the holder movably holding the component along the movement distance and/or between the holder movably holding the component along the movement distance and the light-sensitive sensor surface.

In a preferred embodiment of the method, the light source is a row of LEDs (row). In this case, the LED rows may emit diffuse light. The individual LEDs in the LED row may have a small aperture angle. In another embodiment, a converging lens, in particular a cylindrical lens, may be added between the row of LEDs and the component whose position is to be determined or a holder for movably holding the component along the displacement distance.

In another embodiment of the method, red light is generated by the light source. In another embodiment of the method, the laser light is generated by at least two juxtaposed light sources. The laser may in particular be red.

In another embodiment of the method, the sensor surface consists of a row of aligned sensor elements, such as a CCD line scan camera (camera). The alignment is performed, for example, along one direction or in a square or rectangular area. These sensor elements may have a wavelength-dependent sensitivity, which is particularly most sensitive to red light.

The invention also relates to a device for carrying out the method according to the invention in one or more of the embodiments described above, wherein the device comprises at least

a) A light source (e.g., a row of LEDs emitting normal or diffuse light; or individual LEDs with normal, large or small aperture angles; or a light source that produces white, blue or red light; light sources that generate, inter alia, white, blue or red laser light), and

b) a holder movably holding the assembly (e.g., the bung of a cartridge; or a component of a metering device of a medical device, in particular an insulin pen; or in particular a component of a supply unit of a medical device, in particular an insulin pen), and

c) a light-sensitive sensor surface (e.g., a sensor element arranged in a line along the length or in an area (e.g., a CCD line scan camera); or a sensor element having a wavelength dependent sensitivity; or highest sensitivity to white, blue or red light), and

d) a data processing unit (for example consisting of: an input unit to receive data, a central arithmetic unit, one or more memory elements, an output unit to deliver control signals, and connection elements of the respective components; and an operating program and a program for evaluating the sensor surface in connection with the occurrence of a silhouette and determining the position of the respective component and evaluating the time-dependent change of the silhouette along the sensor surface and determining the position and movement of the respective component).

The data processing unit may be an integral part of the medical device or may operate independently of the medical device. In this respect, the integrated data processing unit comprises an operating system and a program for carrying out the position determination according to the invention. If the data processing unit is operated independently of the medical device, the data and control signal exchange between the medical device and the data processing unit takes place via a suitable connection, for example a cable connection, a wireless connection or via a movement of the data carrier, among others. A data processing system particularly suitable for stand-alone operation is a PC in which an operating system and a program for implementing the position determination of the invention are installed.

The device of the invention in one or more embodiments as described above may be used to assemble a medical device suitable for administering drugs, such as inter alia insulin, heparin, growth hormone, interferon, vaccines, antibodies, into a human or animal body while avoiding gastrointestinal tract conditions.

The invention also relates to a medical device for injecting a medicament (e.g. insulin) into a human body, the medical device comprising inter alia:

a) a base element for mounting at least one technical component;

b) a technical assembly (e.g. a cartridge) in the form of a medicament container in which the upper port is liquid-tightly closed by a stopper functionally connected to a plunger rod on the one hand and the lower port is connected to a cannula on the other hand, and through which cannula the substance can be forced out of the reservoir by moving the stopper through the plunger rod;

c) a technical assembly in the form of a delivery mechanism comprising on the one hand a plunger rod directly or indirectly connected to the stopper and on the other hand a delivery unit which, upon actuation of the release, converts a metered amount of medicament, which has been preset by the metering means (e.g. by a fixed rotational angle), into a suitable movement of the plunger rod and stopper;

d) a technical component in the form of a metering device for presetting a metered amount of a medicament;

e) a technical component in the form of a display device (mechanical or LCD display device) for displaying the quantity of the substance to be injected which is preset by the metering unit and is to be administered by the medical apparatus;

f) a technical assembly in the form of a release mechanism for initiating and completing an injection, in this case, further comprising removing air bubbles from the cartridge prior to performing the injection,

it also includes the device of the present invention in one or more embodiments as described above.

In one embodiment, this type of medical device is in particular in the form of or has the function of an insulin pen or a pen suitable for injecting other drugs, such as heparin, growth hormones, interferons, vaccines, antibodies, among others.

In another embodiment, a medical device of this type comprises at least one means for storing and/or processing data and/or signals, and at least one interface for transferring data and/or signals to and/or from an external technical unit configured for storing and/or processing data and/or signals.

Such means and interfaces may especially be provided on the cap of the medical device.

The external technical unit may consist of a PC in which a program for storing and/or processing data and/or signals is installed.

The medical device in one or more of the embodiments may be used for injecting insulin (regular potency, long-acting, short-acting) or GLP-1 or cloxan (Lovenox) or other substances.

The invention also relates to the manufacture of a medical device for injecting a drug into the human or animal body in one or more of the above embodiments, wherein

a) Providing a base element for mounting at least one technical component;

b) providing a container (e.g., a cartridge for a drug, particularly insulin, heparin, GLP-1, peptide hormones, growth hormones, clathrin, vaccines, antibodies, etc.);

c) providing a plunger rod;

d) providing a supply mechanism;

e) providing a metering device;

f) providing a display device;

g) providing a release mechanism;

h) providing possible electronic means (e.g. means for storing and/or processing data and/or signals to and/or from a technical unit, such as a PC, for storing and/or processing data and/or signals);

i) providing the technical means of the invention in one or more embodiments as described above;

j) assembling the individual components from a) to i) to obtain a functional unit.

The medical device of the invention may be used in particular for the prevention and/or treatment of diseases and/or dysfunctions of the body by means of drugs whose pharmacological activity is reduced or abolished in the gastrointestinal tract, for example for the treatment of diabetes with insulin.

The device consists of one or more components and is used for specific medical purposes, in particular for injecting substances into the human or animal body. A component is composed of one or more elements and is used to implement technical or non-technical functions. It is technical if the function involves the transfer of force, work, energy, material (substance), data, and/or signals, the maintenance of structure and/or form, or the storage of substances or information. It is non-technical if the function involves the input or output of information to or from a user of the device or involves the input or output of a substance to or from a user of the device.

A component may be, for example, a part of a technical device, which component provides part of the functionality relating to the overall functionality of the device.

The component is for example a reservoir. The reservoir may be a replaceable cartridge containing a substance, in particular a drug, such as insulin. The replaceable cartridge may be particularly suitable for use in an insulin pen or other device for injecting a medicament into a human or animal body. Another example of a technical component is a device or a pump for pumping. Further examples of technical components are, in particular, syringes, needles, plunger rods, metering devices, mechanical display devices, tubes, gaskets, batteries, motors, actuators (transmissions), electronic display devices, electronic memories or electronic controllers. The meaning of the object in connection with the technical installation is in particular the movement of liquid from one place to another. For example, one purpose is to move the liquid volume from the reservoir to the outflow conduit. The object may also be to inject a drug into the human or animal body.

One component may be technically connected to one or more other components to achieve one purpose together. A technical connection is, for example, a connection of components adapted to transmit force, work, energy, material (substance), data and/or signals. The components may be connected, for example, by mechanical couplings, fixed mechanical connections (gluing, screwing, riveting, via linkage, etc.), gears, latches, interlocks, wires, optical waveguides, wireless connections, electromagnetic fields, light beams, etc.

Injection is the introduction of a substance, in particular a liquid, into the human or animal body through a cannula together with a syringe or a device with comparable functionality, such as in particular a pen. In particular, subcutaneous, intramuscular, intravenous, intradermal and intraarticular injections are well known. Subcutaneous injections are performed under the skin and are relatively easy to achieve, are not very painful and can be performed by the patient himself. Intramuscular injection is into muscle. This is usually done by medical staff, since in this case there is a greater risk, for example painful periosteal damage. Intravenous injections were performed directly through the vein after venipuncture.

In intradermal injection, the drug is delivered directly beneath the dermis. In intra-articular injection, a fluid is injected into the joint. Injecting a substance into the human or animal body is to be distinguished from introducing the substance, in particular by means of a drug pump, infusion or other type of continuous supply that occurs over a certain time.

The cannula is essentially a hollow needle, which is typically made of metal (e.g., steel, stainless steel, gold, silver, platinum). The end of the cannula is typically sharpened by grinding at an angle. The cannula may be pointed and/or sharpened at one end and blunt at the other end, but it may also be pointed and/or sharpened at both ends. At one of the two ends of the cannula there is a conical attachment, usually made of e.g. plastic, by means of which the hollow needle is mounted, e.g. by pushing or screwing, onto a medical device, such as a syringe, a medication pen (in particular an insulin pen), a medication container or a medication pump. The cannula together with a functionally associated syringe, pen, pump or other medical device suitable for the purpose is used for removing liquid from or supplying liquid to the human or animal body.

The diameter (outer diameter) of the cannula is generally expressed in mm or gauge (gage) (No. 18 ═ 1.2 mm; No. 20 ═ 0.9 mm; No. 21 ═ 0.8 mm; No. 22 ═ 0.7 mm; No. 23 ═ 0.6 mm; No. 25 ═ 0.5 mm; No. 27 ═ 0.4 mm). Another parameter characterizing a casing is its length. Typical lengths of the cannula are 40mm, 30mm, 25mm, 8mm, 6mm and others.

Medical devices are in particular devices for injecting a substance into the human or animal body. In addition to a syringe, it may be a medication pen, such as an insulin pen, for the device for injection. The drug pen is adapted for various forms and purposes and is commercially available from different manufacturers (e.g. Optiklick, Optipen, Optiset).

Each insulin pen must meet various requirements relating to ease of operation so that it can be used safely and without malfunction. The basic requirement is to display the pre-selected dose and the amount remaining in the cartridge. Furthermore, the setting of the dose and the completion of the injection process should be made audible, tactile and visible. The safety requirement is particularly caused by the limited perception capabilities of elderly type 2 diabetic patients.

In addition to insulin pens using needles, needle-less injection systems are also used for insulin therapy. The present example of an injection system using a needle-less needle isInjex injection system for AG. For this injector, insulin is injected into the adipose layer of the skin through a microneedle (microneedle) using extremely high pressure. For this purpose, the elastic spring is manually tensioned before the injection, so that it stores the necessary injection energy. In this case, the substance to be injected is distributed evenly and conically in the adipose tissue.

A non-negligible advantage of this device is the needle-less injection of the drug, which in some patients lowers the psychological suppression threshold for insulin administration. In addition, needle-less injection avoids infection at the puncture site. The disadvantage compared to conventional insulin pens is shown to be the transfer of insulin into a specific cartridge, the greater mass of such devices compared to and the inclusion of other accessories for tightening the spring.

Insulin pumps, unlike insulin syringes, are fully automated infusion systems for continuous subcutaneous injection of insulin. The insulin pump is approximately cigarette pack sized and is permanently carried on the body. Short-acting insulin is injected into the skin tissue through a catheter and a needle located in the skin according to a program preset by the patient. The task of an insulin pump is to mimic the pancreas to continuously deliver insulin to lower blood glucose levels, but not to regulate blood glucose in a closed-loop control manner. These pumps are advantageous because they provide a continuous and regulated supply of insulin, particularly for people who are engaged in physical activity and who have a large variation in daily activities. Insulin pump therapy can be used to compensate for large variations in blood glucose, for example in diabetic patients with significant DAWN phenomenon, who can be controlled by conventional methods with only increased effort. One disadvantage is that severe metabolic disturbances may occur when the insulin supply is interrupted due to a lack of depot of insulin in the human body. Insulin pumps are commercially available in various technical configurations and as technology develops devices with syringe-like containers have emerged. Like a pen with a needle, insulin is present in a reservoir with a removable stopper. The movable stopper is moved by a motor driven plunger rod.

Since insulin is fully automated and continuously delivered, the pump is equipped with a number of safety systems to protect the user from malfunctions with serious consequences. However, this does not mean that the responsible and intended (anticipatory) use of the device is not necessary.

In accordance with further technological developments in the current injection devices and medical and microsystem technology, there is a clear trend towards fully automated miniaturized drug metering systems. Further developments may be directed to implantable and extracorporeal drug metering systems. The goal of implantable insulin pumps is to free a diabetic patient from daily injections of insulin without the need to wear an external device on the body.

Insulin pens focus on important ergonomic and safety properties in EN ISO standard 11608. This again includes the geometry/material properties of the insulin cartridge and the pen needle. Thus, the handling and operation of the pen is substantially consistent for the user and independent of the model.

The contents of EN ISO standard 11608, which are expressly incorporated into this disclosure by reference, relate to insulin pens, insulin cartridges and needles.

In the design of the pen, some significant differences were found among the pens of different manufacturers. The reason for this is for example that it is designed for different target groups (children, elderly). These differences are particularly limited in the injection and release mechanisms because of the requirements of EN ISO standard 11608. The dose selector and the dose display device are mainly ergonomically compliant and are generated from the general design conditions of the respective model.

An important functional element of insulin pens is the injection mechanism. Which determines the type and size of the pen and the design of the release mechanism and the dose selector. The mechanism converts the preset dose on the dose selector into an injection stroke of the bung in the cartridge using injection energy from the release mechanism. This energy is transmitted directly into the injection mechanism or through a motion-modifying actuator.

For injection mechanisms in the shape of a plunger rod, variations in form are technically feasible.

In insulin pens currently available on the market, solutions with rigid (e.g. threaded shaft, rack) or flexible (e.g. curved rack, curved compression spring) designs have been established. Other possible configurations such as telescopic plunger rods (e.g. screw mechanisms, belt and chain drives, hydraulic drives, shaft drives) are not employed in insulin pens currently commercially available.

The design solutions of the rigid and flexible types vary widely and depend on the type of pen, i.e. reusable pen or disposable pen. The plunger rod used is a threaded shaft or a rack or a combination of the two. In the dose selector, the angle of rotation corresponding to the dose is preset with the aid of a stopper (dead) device and is transmitted to the injection mechanism via a subsequent screw mechanism and gear and converted into an injection stroke.

Drug delivery is performed by the described injection stroke and the resulting stopper movement. The amount of liquid delivered depends on the injection stroke and the inner diameter of the cartridge. To avoid dosage errors, the bubbles must be completely removed according to the manufacturer and EN ISO standard 11608. Furthermore, after delivery of the liquid, it is necessary to wait long enough to ensure a steady state, i.e. a normal pressure of the liquid in the cartridge and a relaxation of the stopper.

The drug reservoir (also referred to as a cartridge) affects the structural and functional structure of the medication pen. In this regard, partial functions may be distinguished, first a protection function for the drug, then a delivery function, and finally a coupling function with the drug pen injection system. The protective function is achieved by the cartridge as a whole, i.e. by the stopper, the glass body and the sealing disc. The drug delivery function is imparted by a bung which is displaced with the aid of an injection mechanism and causes a change in volume in the cartridge. Finally, the coupling function with the injection system is produced by sealing means (e.g. a sealing disc).

In automatic medication pens, such as automatic insulin pens, the injection energy is provided by a driver with a subsequent actuator. Furthermore, an energy supply and control unit is required.

In the injection mechanism of the present invention, the medicament (e.g. insulin) is not delivered by displacing the stopper with the injection mechanism, but by introducing the pump means. The pump device is inserted between the cartridge and the injection system and is provided with a suitable interface.

The pump device may be equipped with a flow sensor. The flow sensor is in direct contact with a drug, e.g. insulin, thereby placing additional requirements, such as reduced organism count, sterility, biocompatibility, among others.

When applying this functional principle, many variables (e.g. the liquid pressure in the drug reservoir) are changed compared to conventional injection drug pens (e.g. insulin pens), because when the drug is sucked out, a sub-atmospheric pressure is created.

Insulin cartridges are used as primary packages for medicaments and have to meet high standards. The criteria relate to accuracy of cartridge dimensions and compatibility with other components related to dosage accuracy. EN ISO standard 11608-3 addresses these requirements and describes the basic aspects and geometry/material construction without unnecessary limitations to cartridge shape. Also, it is necessary to ensure that the cartridge is impermeable to the drug.

The cartridge is composed of a number of sub-assemblies. The main component is a cylinder of medicinal glass that is highly neutral and chemically resistant to insulin. The surface quality of the cylinder is improved by a siliconizing treatment before filling. This surface treatment reduces the sliding and dislodging force of the stopper, increases dosage accuracy and reduces dissolution of glass components during long term storage. In this regard, the degree of silicidation is related to the level of plug friction, and the sensitivity of insulin to silicone sets the limit of silicidation.

The cartridge is sealed at both ends with a resilient sealing member, a stopper and a sealing disc. In this regard, the key point is that it exhibits mechanical impermeability under a variety of stress conditions and is microbiologically impermeable to all organisms over long-term testing. Another key point is the maximum blocking force allowed and the number of punctures of the sealing disk by the cannula.

The pen needle is a disposable sterile product for introducing insulin from the cartridge into the target tissue. Similar to cartridges, the requirements are also strict, since the actual functioning of an insulin pen can only be accomplished by the cooperation of these two components. The needle consists of a cannula that is ground at both ends and that is placed in the cartridge connection part. The optimal abrasion of the cannula makes it possible to insert it into the target tissue of the patient substantially painlessly and also causes only slight tissue damage during withdrawal. Also, the cartridge sealing disk is pierced without causing significant breakage. This is a mandatory requirement, since the impermeability of the cartridge must also be ensured when the needle is periodically replaced. The connection part of the cartridge ensures that it can be securely mounted on the insulin pen.

After two or more uses, the pen needle should be replaced after each injection for sterility reasons, even if it shows signs of wear that are hardly visible to the eye. In addition, crystallized insulin may clog the needle. Furthermore, if a temperature change occurs, air may enter the cartridge, also causing a dosage error. In this regard, a temperature change of only 15K would cause up to 15 μ l of air to enter the cartridge.

Microfluidics is a branch of microsystem technology and includes the design, preparation, use and study of microsystems that manipulate and process the amount of fluid across a channel of 1 μm to 1mm in diameter. Microfluidic systems are used in medical technology, biochemistry, chemical engineering and analysis, and microreaction technology. These microsystems may have dimensions in the millimeter and centimeter range, since for practical applications it is the amount of fluid that is important and not the size of the microfluidic system. Furthermore, due to the small fluid volume and generally small system size, this type of system appears to be significantly different from conventional fluid systems. Miniaturization is accompanied by changes in fluid flow behavior because of the surface-related effects and the preponderance of electrostatic and electrokinetic forces. Thus, new methods are needed for the design, preparation and characterization of microfluidic components such as micropumps and sensors. The constant energy density of the actuator causes its output to drop, making it mismatched with conventional components in the macro scale (macro sector). For this reason, external actuators are often used, which sometimes greatly increases the size of the overall system. In addition, the physical and chemical properties of the delivered particles and molecules also limit the miniaturization of microfluidic components.

Diabetes is a condition in which the body itself is unable to produce and properly use any or sufficient amounts of insulin. Insulin is required to transport glucose from the blood to the cells of the body. Blood glucose levels remained constant over a narrow range (60-100 mg% or 3.33-5.55 mmol/l). It can be achieved by the interaction of the two hormones insulin and glucagon.

Diabetes is diagnosed after blood withdrawal using suitable laboratory equipment. For a definitive diagnosis, it is necessary to detect elevated blood glucose levels at least two different time periods.

Diabetes is a term used when the glucose level measured in plasma exceeds a specified value in at least one of the indicated cases:

a) fasting blood glucose is-7.0 mmol/l or 126mg/dl

b) Blood glucose two hours after administration of 75mg glucose (oral glucose tolerance test) -11.1mmol/l or 200mg/dl

c) Blood glucose 11.1mmol/l or 200mg/dl with severe thirst (polydipsia), frequent urination (polyuria) or weight loss.

Untreated diabetes results in elevated blood glucose levels, which can lead to a number of symptoms and end-stage consequences such as polyneuropathy, microangiopathy, macroangiopathy, retinopathy, nephropathy, and the like. When the non-enzymatic glycation of erythrocytes (HbA1c levels) is low, there is less risk of diabetes leading to late-stage damage.

Diabetic coma is a life-threatening acute diabetic complication. In such cases, blood glucose levels may exceed 1000mg/dl with excessive blood acidity (metabolic acidosis). Diabetic coma can be particularly triggered by infection, ingestion of too much carbohydrate, alcohol abuse, or incorrect insulin dosage.

Type 1 diabetes is different from type 2 diabetes. In type 1 diabetes, there is an absolute insulin deficiency from the outset and treatment can only be achieved by administration of insulin.

Type 2 diabetes is characterized by decreased insulin sensitivity and relative insulin deficiency. In the early days, type 2 diabetes can be treated with dietary measures and tablets. During the course of the disorder, it often becomes necessary to replace it with insulin.

Type 2 diabetes has become a very common disease, especially in industrialized countries. The main reasons for this are believed to be overeating, lack of exercise and obesity. Exercise training and diabetes measures, especially those aimed at reducing body weight, can be effective in alleviating type 2 diabetes. In type 2 diabetes, oral hypoglycemic agents such as acarbose, biguanides, sulfonylureas, glitazone and the like may also be used. When the measures no longer last long enough to maintain blood glucose levels at or near the normal range, treatment with insulin is necessary.

Various insulin substances are available for insulin therapy. These substances are usually distinguished by the time of action or by chemical structure. Insulin analogues have different amino acids at individual positions compared to human insulin. And thus its properties may change.

Fast-acting insulins include human insulin and various rapid and short-acting insulin analogs such as gelucin insulin (trade name: Apidra), lispro human insulin (lispro) (trade name: Youline) and insulin aspart (trade name: Noherui)

Slow-acting or long-acting insulins are NPH insulin (human insulin prolonged by neutral protamine zinc insulin), zinc insulin and various insulin analogs such as insulin glargine (trade name: leflus) and insulin detemir (trade name: Levemir).

In insulin therapy, mixed insulin and recently inhaled insulin may also be used.

The mixed insulin consists of fast acting insulin and long acting insulin in different mixing ratio. Typically 10/90%, 25/75%, 30/70%, 50/50% of the mixture. Insulin therapy must always be accompanied by regular measurements of blood glucose levels.

In conventional insulin therapy, a defined amount of mixed insulin is injected at a fixed time. More intensive conventional insulin therapy is mainly used to treat type 1 diabetes. In this case, long-acting insulin (basal) is used to ensure basal delivery, and rapid-acting insulin (bolus) is given at mealtimes.

Continuous subcutaneous infusion of insulin with a pump is primarily indicated for type 1 diabetes. Insulin is not injected but is delivered to the body by a small pump. The pump is present on the body for a long time. Insulin is delivered through a catheter having a cannula. Insulin pumps typically deliver fast acting insulin at equally short intervals over a long period of time.

In addition to glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1(GLP1) is one of the most important members of the incretin class. Incretins are produced in the intestine in the form of hormones and regulate blood glucose levels, in particular by stimulating insulin release in the pancreas.

The amount of gut hormone produced depends on the amount of carbohydrates taken orally. The increase in GLP1 levels after oral glucose ingestion was much higher than the increase after intravenous glucose administration. It has been shown by studies that intravenous infusion and subcutaneous injection of GLP1 can completely normalize blood glucose levels in many cases in type 2 diabetic patients. The problem is that GLP1 is inhibited by dipeptidyl peptidase IV (DPP-IV) in a very short time. Subcutaneous injection of GLP1 maintained effective plasma concentrations for only about 1-2 hours. Solutions to obtain a sustained effect of GLP1 may be found in the development of long acting GLP analogs or in the inhibition of DPP-IV with drugs.

Growth hormones are substances that stimulate the growth of humans, animals and plants. Known examples are somatotropin (human), bovine growth hormone (bovine) and auxin and gibberellic acid (plant).

Somatotropin (STH) is also known as Human Growth Hormone (HGH) and Growth Hormone (GH). STH is a peptide hormone with 191 amino acids. It is produced in the anterior pituitary under the control of somatotropin-releasing factor (SRF; GHRH; GRF) from the hypothalamus. STH is absolutely necessary for normal linear growth. Reduced production or reduced cellular response to STH results in short stature. Its overproduction can lead to gigantism or acromegaly (acromegalie).

Short stature due to growth hormone deficiency has been treated for years by administering STH. STH was made possible in 1985 by genetic manipulation, which was originally obtained from cadaveric pituitary glands.

Interferons are produced as tissue hormones by human or animal leukocytes, fibroblasts or T lymphocytes. Interferons are proteins or glycoproteins that have immunostimulatory (e.g., antiviral) or antihormonal effects. Interferons are divided into alpha-interferons, beta-interferons and gamma-interferons. Interferons are available from many manufacturers for indications such as viral diseases (e.g. SARS), cancer, multiple sclerosis, hepatitis b/c, hepatitis c.

Vaccines are compositions produced biologically or by genetic manipulation and comprise, inter alia, various proteins and/or RNA or DNA fragments and/or killed pathogens or attenuated pathogens (e.g. influenza, SARS, poxvirus, measles pathogens, mumps, rubella, polio, pertussis pathogens).

Known types are live vaccines (e.g. vaccinia), live attenuated vaccines containing attenuated viruses or bacteria (e.g. MMR vaccine, yellow fever, polio) and killed vaccines containing inactivated or killed viruses or bacteria or components thereof (e.g. influenza, cholera, bubonic plague, hepatitis a).

Heparins are substances that are used therapeutically to inhibit blood coagulation. Heparins consist in each case of alternating sequences of D-glucosamine and D-glucuronic acid or L-iduronic acid. A chain length consisting of 5 units is sufficient for anticoagulation.

The polysaccharide chains mostly have a molecular weight of 4000 to 40000. In addition to unfractionated heparin, low molecular weight fractionated heparin having a molecular weight of about 5000 is used. Heparins are not absorbed from the gastrointestinal tract but must be administered parenterally. Heparins act by binding to antithrombin III and thereby accelerating the inactivation of activated coagulation factors

Clexel (also known as clexane) is a commercially available pharmaceutical preparation containing the pharmacologically active ingredient enoxaparin sodium. The active ingredient is one of the low molecular weight heparins that has a linear dose-response relationship and consistently has high bioavailability.

Indications for mosaic range from primary prevention of deep vein thrombosis, treatment of deep vein thrombosis with or without pulmonary embolism, treatment of unstable angina and so-called non-Q-wave myocardial infarction, and thrombosis prevention and anticoagulation during hemodialysis.

Examples

A measurement device was constructed for transilluminating the cartridge, receiving the silhouette, transmitting the measurement to a PC and then performing image analysis.

The measuring device consists of a light source, a slit, a cartridge with a fixture and a line scan sensor.

In each case, the light source optionally includes a row of LEDs emitting diffuse light, a row of LEDs consisting of LEDs having a small aperture angle, or a point source with a converging lens. The line-scan sensor used is a CCD line-scan camera without lens and with wavelength-dependent sensitivity (maximum in the red light wave range).

To reduce stray radiation, slits are placed in the front and rear of the cartridge.

The cartridge is transilluminated in a plane at an intermediate position. The silhouette consists of partial and complete shadows of the plug. After the intensity measurements of the individual sensor elements have been digitized and transmitted to the PC, the position of the plug is determined by determining the pixels below a certain brightness (threshold comparison) with appropriate software.

The identification system is particularly suitable for measuring in an injection pen for metering and determining the dose.

The measuring device consists of three main components: a light source, a line scan sensor with a slit, and evaluation electronics (fig. 1). Light emitting diodes having an aperture angle of about 6 ° arranged in a line are used as the light source. In this way, by means of a suitable arrangement, a uniform irradiation of the cartridge can be achieved, which is necessary for the edge determination. A slit is present between the light source and the cartridge to improve the accuracy of the contrast and measurement results. It is necessary to compensate for the brightness fluctuations at the sensor due to the difference in light refraction (when the cartridge is full and empty) and to avoid scattered light via total reflection on the glass cylinder.

The line scan sensor has 1280 pixels in total, with a pixel distance of 63.5 μm, which can completely detect the silhouette of the cartridge. The light-sensitive pixels of the sensor convert incident light into electrical signals whose values depend on the intensity of the light and on the integration time. The sensor electronics transmit the sensor values to the evaluation electronics interface on an 8-bit scale. Dark areas, for example in the complete shadow behind the stopper, have in this case values close to zero. When operating in ambient light, after about 2ms, the sensor is overloaded and it is no longer feasible to evaluate a silhouette. Thus, in the laboratory mode case, the sensor system is placed in a light-tight chamber, thereby shielding it. The sensor data was evaluated by a measurement computer and LabView software. An edge determination algorithm is used to process the sensor data and calculate the stopper position from the adapted program. The clock interval for calculating the plug position is about 20ms due to the computing power of the measuring computer, the data transmission between the sensor and the PC and the intensity of the silhouette. The metering process and delivery device are controlled by software by converting the stopper position to a volume amount. A characteristic silhouette with typical optical results relating to the plug position is shown in figure 1. The different brightness distributions between the filled and empty glass cylinders described previously are evident. Furthermore, disturbances at the top and tail of the cartridge (due to the geometry of the cartridge) are easily discernable. This entails that the edge determination must be treated differently and the cartridge divided into a plurality of regions. In this connection, the most accurate measurement is achieved in the middle region of the cartridge, since there is a homogeneous glass structure.

FIG. 1: characteristic intensity distribution on a glass cartridge in case of parallel incident light

Due to the curvature and inhomogeneity of the glass, reflections occur at the shoulder and tail of the cartridge and hinder the threshold determination. The plug position is determined in three steps: compensating for clock interval deviations, edge determination and calculating plug position using the corrected optical results. In a first step, the intensity value error due to clock interval deviations is compensated by the computer. In normal operation, deviations of the clock interval and the integration time of at most 2ms occur due to the use of the measuring computer. As a result, even under the same illumination, different brightness values occur at the individual pixels, which can be compensated by measuring the actual integration time. The effect of pixel noise can additionally be reduced by averaging. In a second step, edges are determined by threshold validation. The brightness distribution in fig. 1 shows that the shaded areas of the plug and the bright directly illuminated areas are clearly separated. In this case, the first edge is obtained from the position of the pixel whose first luminance is lower than the previously fixed threshold. The second position is determined by the pixel position having a luminance value above the threshold. If the threshold is between two pixels, the position is determined by interpolation, while the resolution of the edge position can be increased. In a third step, the position of the plug is calculated from the edge of the plug. In this respect, it is necessary to distinguish between the positions of the plugs:

1) in region 1 at the starting position, the position of the plug is calculated from the position of the leading edge. The maximum measurement error corresponds to a single pixel distance, i.e. 64 μm.

2) In the cartridge area 2 the stopper position is provided by the position of the front and rear edges. The maximum measurement error in this region is about 32 μm, corresponding to half the pixel width.

3) In the cartridge area 3, the position of the rear edge of the stopper is used. This results in a measurement error of a single pixel width of about 64 μm. For error-free transfer of the plug position, the width of the plug can likewise be used.

The measured plug width is used to help avoid skipping plug locations when switching between regions.

Description of the drawings:

FIG. 1: sensor system for determining the position of a stopper (without electronic means for evaluation)

FIG. 2: characteristic intensity distribution on a glass cartridge in case of parallel incident light

Claims (29)

1. Method for determining the position of a bung of a cartridge along a distance of travel in a medical device, the method relying on

a) Light source and

b) a holder for movably holding the stopper along a moving distance, and

c) photosensitive sensor surface

This is achieved by first generating a silhouette of the stopper on the light-sensitive sensor surface by illuminating the stopper with light from a), and then converting the relevant data of the silhouette into the position of the stopper along the travel distance by means of a data processing unit.

2. A method as claimed in claim 1, wherein the cartridge is an insulin cartridge.

3. A method as claimed in claim 1, wherein the data processing unit is integrated in the medical device.

4. A method as claimed in claim 1, wherein a separate data processing unit is operated with the medical device.

5. A method as claimed in claim 1, wherein an aperture is added between a) and b) and/or between b) and c).

6. A method as claimed in claim 1, wherein the light source consists of a row of LEDs.

7. A method as claimed in claim 6, wherein the rows of LEDs emit diffuse light.

8. A method as claimed in claim 6, wherein the individual LEDs of the LED row have a small aperture angle.

9. A method as claimed in claim 6, wherein a converging lens is inserted between the row of LEDs and the plug.

10. A method as claimed in claim 9, wherein the converging lens is a cylindrical lens.

11. A method as claimed in claim 1, wherein the light source produces red light.

12. A method as claimed in claim 1, wherein the laser light is generated by at least two juxtaposed light sources.

13. A method as claimed in claim 12, wherein the light source generates a red laser.

14. A method as claimed in claim 1, wherein the light-sensitive sensor surface consists of a row of arranged sensor elements.

15. A method as claimed in claim 14, wherein the sensor element consists of a CCD line scan camera.

16. A method as claimed in claim 14, wherein the sensitivity of the sensor element to red light is highest.

17. A method as claimed in claim 15, wherein the sensitivity of the sensor element to red light is highest.

18. Apparatus for implementing a method as claimed in any one of claims 1 to 17, the apparatus comprising at least

a) A light source; and

b) a holder movably holding a cartridge containing a stopper along a moving distance; and

c) a photosensitive sensor surface; and

d) a data processing unit.

19. Use of a device as claimed in claim 18 for assembling a medical device adapted for administering a drug into a human or animal body while avoiding the gastrointestinal tract.

20. The use as claimed in claim 19 wherein the medicament is insulin.

21. Medical device for injecting a drug into the human or animal body, comprising

a) A base element for mounting at least one technical component;

b) a technical component in the form of a medicament container;

c) a technical component in the form of a feed mechanism;

d) a technical component in the form of a metering device;

e) a technical component in the form of a display device;

f) a technical assembly in the form of a release mechanism for initiating and completing an injection;

it also comprises at least one device as claimed in claim 18.

22. A medical device as claimed in claim 21, wherein the medical device is in the form of or functions as an insulin pen.

23. A medical device as claimed in claim 21, comprising at least one means of storing and/or processing data and/or signals, and at least one interface for transmitting data and/or signals to and/or from an external technical unit configured for storing and/or processing data and/or signals.

24. A medical device as claimed in claim 23, wherein the external technical unit consists of a PC equipped with a program for storing and/or processing data and/or signals.

25. A medical device as claimed in claim 21 for injecting insulin.

26. A medical device as claimed in claim 25, wherein the insulin is a long acting insulin and/or a short acting insulin.

27. A medical device as claimed in claim 21 for injecting GLP-1.

28. A medical device as claimed in claim 21 for injecting a mosaic.

29. A method of manufacturing a medical device as claimed in any one of claims 21 to 28 for injecting a medicament into the human or animal body, wherein

a) Providing a base unit for mounting at least one technical component according to claim 21;

b) providing a container;

c) providing a plunger rod;

d) providing a supply mechanism;

e) providing a metering device;

f) providing a display device;

g) providing a release mechanism;

h) providing an electronic component;

i) providing an apparatus as claimed in claim 18;

j) assembling the individual components from a) to i) to obtain a functional unit.