WO2021102700A1 - Dispositif d'enregistrement de dose - Google Patents

Dispositif d'enregistrement de dose Download PDF

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Publication number
WO2021102700A1
WO2021102700A1 PCT/CN2019/121043 CN2019121043W WO2021102700A1 WO 2021102700 A1 WO2021102700 A1 WO 2021102700A1 CN 2019121043 W CN2019121043 W CN 2019121043W WO 2021102700 A1 WO2021102700 A1 WO 2021102700A1
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WO
WIPO (PCT)
Prior art keywords
unit
dose
recording device
inner housing
injection
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PCT/CN2019/121043
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English (en)
Inventor
Chunfeng SHAO
Yangfei DAI
Zhihua Zheng
Original Assignee
Sanofi
Sanofi (China) Investment Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi, Sanofi (China) Investment Co., Ltd. filed Critical Sanofi
Priority to PCT/CN2019/121043 priority Critical patent/WO2021102700A1/fr
Priority to CN201980102484.1A priority patent/CN114761056A/zh
Publication of WO2021102700A1 publication Critical patent/WO2021102700A1/fr

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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
    • A61M5/178—Syringes
    • A61M5/24—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
    • A61M2205/581—Means for facilitating use, e.g. by people with impaired vision by audible feedback

Definitions

  • the present invention relates to a dose-recording device for an injection device, in particular a pen type drug delivery device, for tracking dosage units ejected by the injection device, wherein the injection device generates audible injection clicks for each dosage unit that is ejected.
  • Pen type drug delivery devices have application where regular injection by persons without formal medical training occurs. This may be increasingly common among patients having diabetes where self-treatment enables such patients to conduct effective management of their disease. In practice, such a drug delivery device allows a user to individually select and dispense a number of user variable doses of a medicament.
  • resettable devices i.e., reusable
  • non-resettable i.e., disposable
  • disposable pen delivery devices are supplied as self-contained devices.
  • Such self-contained devices do not have removable pre-filled cartridges. Rather, the pre-filled cartridges may not be removed and replaced from these devices without destroying the device itself. Consequently, such disposable devices need not have a resettable dose setting mechanism.
  • the present invention is applicable for both types of devices, i.e. for disposable devices as well as for reusable devices.
  • a cartridge section that includes a cartridge or is adapted to receive a cartridge
  • a needle assembly connected to a distal end of the cartridge section
  • a proximal pen housing part or dosing section connected to another, proximal end of the cartridge section.
  • the cartridge typically includes a reservoir that is filled with a medication (e.g., insulin) , a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end.
  • a crimped annular metal band is typically used to hold the rubber seal in place.
  • the cartridge housing may be typically made of plastic
  • cartridge reservoirs have historically been made of glass.
  • a detachable pen cap is provided for covering the cartridge section and the needle assembly.
  • the needle assembly is typically a replaceable double-ended needle assembly. Before an injection, a replaceable double-ended needle assembly is attached to one end of the cartridge assembly, a dose is set, and then the set dose is administered. Such removable needle assemblies may be threaded onto, or pushed (i.e., snapped) onto the pierceable seal end of the cartridge assembly.
  • the dosing section or dose setting mechanism is typically the portion of the pen device that is used to set (select) a dose.
  • a spindle or piston rod contained within the dose setting mechanism presses against the bung or stopper of the cartridge. This force causes the medication contained within the cartridge to be injected through an attached needle assembly. After an injection, as generally recommended by most drug delivery device and/or needle assembly manufacturers and suppliers, the needle assembly is removed and discarded.
  • a further differentiation of drug delivery device types refers to the drive mechanism: There are devices which are manually driven, e.g. by a user applying a force to an injection button, devices which are driven by a spring or the like and devices which combine these two concepts, i.e. spring assisted devices which still require a user to exert an injection force.
  • the spring-type devices involve springs which are preloaded and springs which are loaded by the user during dose selecting. Some stored-energy devices use a combination of spring preload and additional energy provided by the user, for example during dose setting.
  • pen type drug delivery devices are provided with a display providing a visual feedback to a user regarding the actually set dose size.
  • the display of such devices typically involves a number sleeve with a series of numbers corresponding to dose sizes being provided on the outer surface of the number sleeve such that only the actually set dose is visible through an opening or window in the housing.
  • An injection device is disclosed, for example, in WO 2004/078239 A1.
  • the dose to be injected can be increased by predetermined increments only during dose setting, wherein each increment corresponds to a predetermined amount of medicament.
  • the predetermined increments are also called dosage units. Accordingly, each dose that can be set corresponds to one or more dosage units.
  • injection devices are adapted to provide an audible feedback during injection (dose dispense) .
  • dose dispense For each dosage unit that is ejected (dispensed) , an audible injection click is produced by the injection device. This allows the user to hear whether the injection process is performed properly.
  • a dose-recording feature can be easily implemented in fully automatic injection devices.
  • fully automatic injection devices are complex, expensive and may be more prone to be damaged than simpler, manually operated injection devices.
  • CN 106527293 A discloses a circuit for automatically identifying and analysing dose injection.
  • the dose-recording devices comprises:
  • a sound transducer unit adapted to receive the injection clicks and to generate an analogue electric sound signal on the basis of the injection clicks
  • a first filter unit connected to the sound transducer unit, wherein the first filter unit is adapted to provide an analogue electric filtered signal on the basis of the sound signal and to decouple operating points of the sound transducer unit and an amplifier unit;
  • the amplifier unit connected to the first filter unit, wherein the amplifier unit is adapted to provide an analogue electric amplified signal on the basis of filtered signal;
  • an integrator unit connected to the amplifier unit, wherein the integrator unit is adapted to provide an analogue electric integration curve on the basis of the amplified signal by integrating at least a part of the amplified signal;
  • a comparator unit connected to the integrator unit, wherein the comparator unit is adapted to generate a square wave output on the basis of integration curve;
  • microcontroller unit connected to the comparator unit, wherein the microcontroller unit is adapted to determine the dosage units ejected on the basis of the square wave output.
  • the amplifier unit comprises or consists of an active first-order low pass filter.
  • an input of the amplifier unit can be directly connected to an output of the first filter unit. It is not necessary to implement a complex and expensive additional unit between the first filter unit and the amplifier unit, which is adapted to invert negative signal parts of the filtered signal. Therefore, the proposed dose-recording device exhibits reduced complexity. Accordingly, it can be manufactured more cost-efficiently.
  • the dose-recording device is particularly inexpensive and simple to manufacture if the amplifier consists of the active first-order low pass filter.
  • the amplifier unit does not only amplify the filtered signal but also acts as a low-pass filter
  • the dose-recording device according to the present invention is less prone to external noise. Therefore, the reliability and accuracy of the dose-recording device are improved.
  • the sound transducer unit preferably consists of or comprises a microphone with analogue output.
  • Such microphones are inexpensive, light, and reliable and consume only little electric power.
  • a cut-off frequency of the amplifier unit is in the range from 500 Hz to 10 KHz, more preferably from 1 kHz to 2 kHz, most preferably from 1, 3 kHz to 1, 7 kHz.
  • an amplification ratio of the amplifier unit is preferably in the range from 2 to 50, more preferably from 3 to 15, most preferably from 4 to 8.
  • the amplification ratio can be lower than in known devices.
  • the amplification ratio may apply for frequencies higher than the cut-off frequency of the amplifier unit.
  • the integrator unit is adapted to integrate upper half waves of the amplified signal to an analogue envelope curve. Alternatively, it may be adapted to integrate lower half waves.
  • the integrator unit can be of simple design but is sufficiently effective.
  • the integrator unit may comprise a diode. An anode of the diode may be connected to an input of the integrator unit (which also includes the case that the anode constitutes said input) and a cathode of the diode may be connected to an output of the integrator unit (which also includes the case that the cathode constitutes said output) .
  • the diode prevents that negative parts of the amplified signal compensate positive parts of the amplified signal during integration.
  • the diode may be Zener diode. Depending on whether the upper half waves or the lower half waves are integrated, the diode may be connected vice versa.
  • the dose-recording device comprises a second filter unit connected to the integrator unit, wherein the comparator unit is connected to the second filter unit, and wherein the second filter unit is adapted to decouple operating points of the integrator unit and the comparator unit. Due to the decoupling, the comparator unit works more reliable and more accurate.
  • the second filter unit consists of or comprises an analogue RC filter.
  • an RC filter is inexpensive, easy to produce but yet sufficient.
  • the second filter may consist of or comprise an RC band pass filter.
  • An input resistor of said filter may be constituted by antecedent circuit elements of a circuit of the dose recording device.
  • the dose-recording device is detachably mountable on the injection device, for example on the dosing section.
  • the dose-recording device may be configured to be detachably clamped on the dosing section. Consequently, the dose-recording device is re-usable. This is, in particular, beneficial if the user applies the dose-recording device for disposable injection devices.
  • the dose-recording device comprises a housing.
  • the housing may include an inner housing and an outer housing, wherein the inner housing is adapted to be mounted on a dosing section of the injection device, and wherein the outer housing is mountable on the inner housing for fixing the dose-recording device to the dosing section.
  • the dose-recording device can be fixed to the dosing section in two steps: In a first step, the dosing section is inserted into the inner housing. In a further step, the outer housing is mounted on the inner housing. By mounting the outer housing on the inner housing, the inner housing may become fixed with regard to the dosing section. In particular, the inner housing may be prevented from moving along a longitudinal direction with respect to the dosing section when the outer housing is mounted on the inner housing.
  • a proximal part of the outer housing is adapted to be slit over the inner housing and to be detachably fixed on the inner housing.
  • the proximal part may be a sleeve part and be adapted to cover the inner housing circumferentially when mounted thereon.
  • the sleeve part may cover the inner housing circumferentially over at least three quarter of a length of the inner housing in the longitudinal direction when the outer housing is mounted on the inner housing.
  • the inner housing can be inserted in the proximal part of the inner housing (for example, the sleeve part) .
  • the dose-recording device comprises a securing means for securing the outer housing to the inner housing.
  • the securing means may prevent that the outer housing is detached from the inner housing unintentionally.
  • the securing means are for detachably securing the outer housing to the inner housing.
  • the outer housing can be removed from the inner housing, for example in order to replace a battery of the dose-recording device and/or in order to remove the dose-recording device from the injection device.
  • an interior of the inner housing is configured for receiving the dosing section of the injection device.
  • the inner housing has a shape that basically corresponds to a hollow cylinder.
  • the interior of the inner housing has an at least substantially cylindrical shape.
  • it is adapted to receive the dosing section, which may be of an at least substantially cylindrical shape.
  • an inner diameter of the inner housing i.e. a diameter of the interior of the inner housing
  • the housing of the dose-recording device may comprise at least one cushion.
  • the cushion may contribute to tight fitting of the outer housing onto the inner housing.
  • the cushion may be squeezed between the outer housing and an outer surface of the dosing section if the outer housing is mounted on the inner housing.
  • the cushions may be of elastomeric material. This facilitates mounting and/or demounting of the outer housing on the inner housing.
  • the cushion may be mounted in a recess (for example a slit) of the inner housing.
  • the cushion may have a T-shaped cross-section, wherein a web section of the cushion is mounted in the corresponding slit of the housing.
  • an outer side of a flange section of the cushion may abut on an inner side of the outer housing when the latter is mounted on the inner housing.
  • At least two cushions according to any of the embodiments described are provided.
  • the dose-recording device comprises engagement means for ensuring a final rotational position of the outer housing with respect to the inner housing when the outer housing is mounted on the inner housing. Hence, the correct rotational alignment of both housing part is ensured during mounting.
  • the dose-recording device comprises a proximal abutment means for the outer housing.
  • the proximal abutment means is configured to prevent the outer housing from further proximal movement beyond a predetermined position in the longitudinal direction with respect to the inner housing if the outer housing is mounted on the inner housing.
  • the dose-recording device may comprise a means for securing a position of the outer housing with respect to the dosing section when the outer housing is mounted on the dosing section (and/or on the inner housing, which is mounted on the dosing section) .
  • said means for securing may secure a rotational, longitudinal, and/or axial position of the outer housing with respect to the dosing section.
  • a distance in the longitudinal direction between a distal end of the housing (including the inner housing and the outer housing) and the sound transducer unit is between 29 mm and 49 mm when the outer housing is mounted on the inner housing, most preferably between 35 mm and 49 mm, for example between 40 mm and 47 mm. Additionally or alternatively, a distance in the longitudinal direction between a proximal end of the housing and the sound transducer unit is between 2 mm and 30 mm when the outer housing is mounted on the inner housing, most preferably between 2 mm and 15 mm, for example between 2 mm and 6 mm.
  • the dose-recording device may be adapted to be mounted on a distal side of the dosing section.
  • the distal end of the housing (for example, a distal end of the inner housing) is distanced less than 10 mm from a distal end of the dosing section when the dose recording device is completely mounted on the dosing section, most preferably less than 5 mm, even more preferred less than 2 mm.
  • the correct position of the dose-recording device and of the sound transducer unit improve the reliability and accuracy of the dose-recording device, respectively.
  • the injection clicks are usually generated in the dosing section. In some particular injection devices, the injection clicks are generated in the middle or in a distal half of the dosing section. The above specifications help to ensure optimal recording and recognition of the injection clicks. In particular, all the indications regarding the position of the sound transducer unit may relate to the microphone as such.
  • the dose-recording device comprises the battery.
  • the battery may be a coin battery. Hence, the battery is light and small. This improves the handiness of the dose-recording device.
  • the first filter unit may consist of or comprise an RC high pass filter. More preferably, a cut-off frequency of the first filter unit is between 300 Hz and 3 kHz, most preferably between 1 kHz and 2 kHz, for example 1, 5 kHz. Hence, in addition to the decoupling function, the first filter also suppresses low frequencies. This helps to reduce influences of external noise in order to improve the accuracy.
  • the microcontroller unit comprises a microprocessor.
  • the microprocessor is adapted to recognize the injection clicks based on the square wave output.
  • an interrupt input of the microprocessor may receive the square wave output.
  • the microprocessor counts the interrupts and hence the injection clicks.
  • the microcontroller unit may comprise a memory means.
  • the memory means may be adapted to store data corresponding to the dosage units injected in one and/or more injection processes.
  • the memory means may be connected to the microprocessor.
  • the microcontroller may comprise a data communication means. More preferably, the data communication means is a wireless data communication means.
  • the data communication means is or comprises a Bluetooth Low Energy Link.
  • the data communication means may be connected to the microprocessor and/or to the data storage means. It may be adapted to transmit data regarding the dosage units, which have been injected (recorded data) . It may be adapted to transmit these data immediately when it is obtained and/or later (for example, on demand) .
  • the dose-recording device may be configured to transmit recorded data regarding several injection processes of the past at one time.
  • the recording data can be transferred to another device, for example a personal computer, a laptop, and/or a smartphone. This makes it easier for the user to display and/or to evaluate the recorded data.
  • the input of the amplifier unit is directly connected to an output of the sound transducer unit. This keeps the dose-recording device simple and inexpensive.
  • the dose-recording device preferably comprises an activation button for activating a record mode.
  • the dose-recording device In the record mode, the dose-recording device is ready to record injection processes.
  • the dose-recording device may be inactive (switched-off) if it is not in the record mode. This saves power and extends the lifetime of the battery.
  • the dose-recording device comprises a visual indication means.
  • the visual indication means indicates that the dose-recording device is in the recording mode.
  • the visual indication means may consist of or comprise a LED, for example.
  • the user gets visual feedback that the dose-recording device is ready for injection.
  • the dose-recording device comprises acoustic indication means for indicating that the dose-recording device is in the recording mode.
  • the momentary switch may be coupled to the activation button.
  • the dose-recording device preferably comprises a circuit unit including at least the sound transducer unit, the first filter unit, the amplifier unit, the integration unit, the comparator unit, and the microcontroller unit.
  • the circuit unit may also comprise the second filter unit, a battery connector for electrically connecting the battery to the circuit unit, a momentary switch, the visual indication means, and/or the acoustic indication means.
  • the circuit unit may comprise a printed circuit board (PCB) .
  • the other parts of the circuit unit may be connected to PCB, fixed to the PCB and/or be (at least partly) constituted by the PCB.
  • the circuit unit is fixed to the inner housing.
  • the circuit unit may be fixed to a top side of the inner housing (seen in a height direction perpendicular to the longitudinal direction) .
  • the outer housing may cover the circuit unit when the outer housing is mounted on the inner housing.
  • the outer housing may comprise a protuberance for accommodating the circuit unit when the outer housing is mounted on the inner housing.
  • the protuberance may be located at a top side of the sleeve part of the outer housing.
  • the outer housing can comprise a visual indication means window or hole. Said visual indication means window or hole allows that the user can see the visual indication means from the outside of the outer housing.
  • the injection device typically comprises a cartridge containing a medicament.
  • medicament means a pharmaceutical formulation containing at least one pharmaceutically active compound,
  • the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
  • the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS) , angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
  • diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS) , angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
  • ACS acute coronary syndrome
  • the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
  • the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
  • GLP-1 glucagon-like peptide
  • exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
  • Insulin analogues are for example Gly (A21) , Arg (B31) , Arg (B32) human insulin; Lys (B3) , Glu (B29) human insulin; Lys (B28) , Pro (B29) human insulin; Asp (B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala (B26) human insulin; Des (B28-B30) human insulin; Des (B27) human insulin and Des (B30) human insulin.
  • Insulin derivates are for example B29-N-myristoyl-des (B30) human insulin; B29-N-palmitoyl-des (B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N- (N-palmitoyl-Y-glutamyl) -des (B30) human insulin; B29-N- (N-lithocholyl-Y-glutamyl) -des (B30) human insulin; B29-N- ( ⁇ -carboxyheptadecanoyl) -des (B30) human insulin and B29-N- ( ⁇ -
  • Exendin-4 for example means Exendin-4 (1-39) , a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
  • Exendin-4 derivatives are for example selected from the following list of compounds:
  • Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin) , Somatropine (Somatropin) , Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
  • Gonadotropine Follitropin, Lutropin, Choriongonadotropin, Menotropin
  • Somatropine Somatropin
  • Desmopressin Terlipressin
  • Gonadorelin Triptorelin
  • Leuprorelin Buserelin
  • Nafarelin Goserelin.
  • a polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof.
  • An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
  • Antibodies are globular plasma proteins ( ⁇ 150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins.
  • the basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit) ; secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
  • Ig immunoglobulin
  • the Ig monomer is a "Y" -shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two ⁇ sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
  • Ig heavy chain There are five types of mammalian Ig heavy chain denoted by ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ .
  • the type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
  • Distinct heavy chains differ in size and composition; ⁇ and ⁇ contain approximately 450 amino acids and ⁇ approximately 500 amino acids, while ⁇ and ⁇ have approximately 550 amino acids.
  • Each heavy chain has two regions, the constant region (CH) and the variable region (VH) .
  • the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes.
  • Heavy chains ⁇ , ⁇ and ⁇ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains ⁇ and ⁇ have a constant region composed of four immunoglobulin domains.
  • the variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone.
  • the variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
  • a light chain has two successive domains: one constant domain (CL) and one variable domain (VL) .
  • CL constant domain
  • VL variable domain
  • the approximate length of a light chain is 211 to 217 amino acids.
  • Each antibody contains two light chains that are always identical; only one type of light chain, ⁇ or ⁇ , is present per antibody in mammals.
  • variable (V) regions are responsible for binding to the antigen, i.e. for its antigen specificity.
  • VL variable light
  • VH variable heavy chain
  • CDRs Complementarity Determining Regions
  • an “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from.
  • Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab) .
  • the Fc contains carbohydrates, complement-binding, and FcR-binding sites.
  • F (ab') 2 is divalent for antigen binding.
  • the disulfide bond of F (ab') 2 may be cleaved in order to obtain Fab'.
  • the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv) .
  • Pharmaceutically acceptable salts are for example acid addition salts and basic salts.
  • Acid addition salts are e.g. HCl or HBr salts.
  • Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+ (R1) (R2) (R3) (R4) , wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group.
  • solvates are for example hydrates.
  • Fig. 1 is an exploded view of an embodiment of a dose-recording device according to the present invention from a first perspective;
  • Fig. 2 is a further exploded view of the dose-recording device of Fig. 1 from a second perspective;
  • Fig. 3 is a scaled top view (seen along a height direction) of the dose-recording device of Fig. 1, wherein an outer housing of the dose-recording device is mounted on an inner housing of the dose-recording device;
  • Fig. 4 is a scaled, cross-sectional side view (seen along a lateral direction) of the dose-recording device of Fig. 3;
  • Fig. 5 is a perspective view of an injection device after a first mounting step, in which the inner housing of the dose-recording device of Fig. 1 has been mounted on a dosing section of the injection device;
  • Fig. 6 is a scaled side view of the injection device and the inner housing of the dose-recording device in the state of Fig. 5;
  • Fig. 7 is a perspective view of the injection device after a third mounting step, wherein the outer housing of the dose-recording device of Fig. 1 has been slipped over the inner housing of the dose-recording device, and wherein the outer housing has been secured to the inner housing;
  • Fig. 8 is a scaled side view of the injection device with the dose-recording device in the state of Fig. 7;
  • Fig. 9 is a schematic block diagram showing the basic structure of a circuit unit of the dose-recording device of Fig. 1;
  • Fig. 10 is a diagram showing a part of the circuit unit of Fig. 9 in more detail.
  • Fig. 1 is an exploded view of an embodiment of a dose-recording device 1 according to the present invention.
  • the dose-recording device 1 comprises a housing, a circuit unit 6, a battery 7 connected to the circuit unit 6 for providing power to the circuit unit 6, and an activation button 8.
  • the dose-recording device 1 is adapted to be detachably fixed to an injection device 400 as it is shown in Fig. 7 and Fig. 8.
  • the injection device 400 is, for example, a non-resettable pen type drug delivery device for selecting and dispensing a number of user variable doses of a medicament.
  • the injection device 400 comprises a pen housing.
  • the pen housing extends along a longitudinal direction of the injection device 400. It includes a proximal pen housing part (dosing section 401) , a distal pen housing part (cartridge section) , and a pen cap 402.
  • the pen cap 402 is detachably mountable on the cartridge section of the pen housing. If the pen cap 402 is mounted on the cartridge section, the pen cap 402 completely covers the latter. Hence, the cartridge section cannot be seen in the figures but is hidden under the pen cap 402. In particular, the cartridge section holds a cartridge filled with the medicament.
  • An outer shape of the proximal pen housing dosing section 401 is at least substantially cylindrical.
  • the dosing section 401 extends along the longitudinal direction of the injection device 400.
  • a user can set a dose by rotating a dose setting knob 403.
  • An injection button 404 is located at a proximal end of the injection device 400. After the dose has been set, the user can inject said dose by pressing an injection button 404 towards a distal direction of the injection device 400, wherein the distal direction of the injection device 400 is opposite to the proximal direction of the injection device 400.
  • an inner mechanism of the injection device 400 exhibits audible injection clicks.
  • Each injection click indicates that a certain amount (dosage unit) of the medicament has been ejected by the injection device 400.
  • the total number of injection clicks generated during a complete injection process provides audible feedback on how much medicament has been ejected in this process.
  • the dose-recording device 1 is adapted to be detachably fixed to the dosing section 401 of a housing of the injection device.
  • the dosing section 401 has a diameter of 15,5 mm, for example.
  • the dose-recording device 1 is preferably configured to be detachably fixed on an at least substantially cylindrical object having a diameter of 15, 5 mm.
  • the housing of the dose-recording device 1 comprises an inner housing 2, an outer housing 3, six cushions 4 and two screws 5.
  • the inner housing 2 has a shape that basically corresponds to a hollow cylinder.
  • the inner housing 2 extends along a central longitudinal axis A of the dose-recording device 1.
  • the central longitudinal axis A is parallel to a longitudinal direction X of the dose-recording device 1.
  • the inner housing 2 circumferentially encircles an interior thereof.
  • the interior of the inner housing 2 is a passage that extends along the longitudinal direction X throughout the inner housing 2. This interior is an empty space of an at least substantially cylindrical shape. It is configured for receiving a distal part of the dosing section 401.
  • a length of the inner housing in the longitudinal direction X is preferably in the range from 20 mm to 50 mm, more preferably from 30 mm to 40 mm.
  • the inner housing 2 has a length of 36, 5 mm.
  • a central longitudinal axis of the dosing section 401 and the longitudinal axis A of the dose-recording device 1 coincide when the dose-recording device 1 is mounted on the dosing section 401.
  • Regarding the longitudinal direction X of the dose-recording device 1 it may be further distinguished between a distal direction and a proximal direction.
  • the longitudinal direction of the injection device 400 wherein the two distal directions coincide if the dose-recording device 1 is mounted on the injection device 400.
  • corresponding directions of the dose-recording device 1 and of the injection device 400 may be used synonymously.
  • an inner diameter of the inner housing 2 is 16, 5 mm (without considered webs 310, which will be described below) .
  • the dosing section 401 can be inserted in the interior of the inner housing 2.
  • an outer diameter of the inner housing 2 is 17 mm.
  • the inner housing 2 comprises a flange 201.
  • the flange 201 extends radially outwards from an outer side of the inner housing 2.
  • the flange 201 constitutes a proximal abutment means for the outer housing 3, wherein said proximal abutment means is configured to prevent the outer housing 3 from further proximal movement beyond a predetermined position in the longitudinal direction L.
  • the inner housing 2 comprises six slits 202 for receiving the cushions 4. Each slit 202 is configured for holding one of the cushions 4, respectively. Two slits 202 are located opposite to each other in a lateral direction Y, respectively. The lateral direction Y is perpendicular to the longitudinal direction X. In other words, three pairs of slits 202 are provided in the inner housing 2, wherein each pair consist of two slits 202. Adjacent pairs of slits 202 are offset in the longitudinal direction X by 12 mm.
  • three of the slits 202 are located at one lateral side of the of the inner housing 2 in the lateral direction Y, wherein three other slits 202 are located at an opposite, other lateral side of the inner housing 2 in the lateral direction Y.
  • Each of the slits 202 extends along a certain part of a circumference of the inner housing 2 along a circumferential direction, respectively.
  • the certain part is less than half of the circumference.
  • the certain part may be more than one twelfth of said circumference.
  • the certain part may be a quarter of the circumference.
  • a cross-section of the slit 202 perpendicular to the circumferential direction is T-shaped.
  • a radially outward part of the slit 202 is wider along the longitudinal direction X than a radially inward part of the slit 202.
  • All cushions 4 are of the same shape.
  • one cushion 4 is mounted.
  • the cushion 4 extends along the circumferential direction.
  • a cross-section of the cushion 4 perpendicular to the circumferential direction is at least substantially T-shaped.
  • the shape of the cushion 4 is similar to a bent T-beam, which extends along the circumferential direction.
  • the cross-sectional T-shape of the cushion 4 is adapted to the T- shape of the corresponding slit 202.
  • a flange section 4-1 of the cushion 4 is wider in the longitudinal direction X of the dose-recording device 1 than a web section 4-2 of the cushion 4.
  • the web section 4-2 extends radially inwards from the flange section 4-1, in more detail from the middle of the web section 4-2 in the longitudinal direction X.
  • the web section 4-2 of the cushion 4 is inserted into the narrower, radially inward part of the corresponding slit 202.
  • the flange section 4-1 is inserted into the wider, radially outward part of the slit 202.
  • the cushion 4 is mounted in the corresponding slit 202.
  • the two inner circumferential surfaces of the flange section 4-1 abut on bottom surfaces 203 of the wider, radially outward part of the slit 202.
  • the cushion 4 abuts on the inner housing 2 in a radial direction perpendicular to the longitudinal axis A.
  • an inner side 309 of the housing 3 abuts on the outer circumferential surfaces 4-3 of the flange sections 4-1 of the cushions 4.
  • webs 310 are provided at the inner side 309.
  • the webs 310 extend along the longitudinal direction X and radially protrude inwardly at the inner side 309. Due to the webs 310, the engagement of the outer housing 3 with the inner housing 2 (in particular with the outer circumferential surfaces 4-3 of the cushions 4) is defined more precisely.
  • the flange sections 4-1 of the cushions 4 protrudes from an outer circumferential surface of the inner housing 2 in the radial direction. Hence, an effective diameter of the inner housing 2 in the radial direction is slightly increased by the cushions 4.
  • the cushions 4 can be made of an elastomeric material. Hence, the outer housing 3 fits snugly onto the inner housing 2 with the cushions 4.
  • the circuit unit 6 is fixed to an outer top side of the inner housing 2.
  • the circuit unit 6 In the lateral direction Y, the circuit unit 6 is located in the middle with regard to the two lateral sides with the slits 202.
  • the circuit unit 6 In a height direction Z, the circuit unit 6 is located at the top of the inner housing 2.
  • the height direction Z is perpendicular to the longitudinal direction X and perpendicular to the lateral direction Y.
  • the circuit unit 6 comprises a printed circuit board 90 (PCB 90) and the electric components mounted thereto.
  • PCB 90 printed circuit board 90
  • An electric circuit of the circuit board 6 is schematically shown in Fig. 9 and is explained in more detail with regard to Fig. 10 below.
  • the dose-recording device 1 comprises fixation means for fixing the circuit unit 6 to the inner housing 2, preferably in a detachable manner.
  • the fixation means comprise two inner threads 206 at the top side of the inner housing 2.
  • the fixation means further comprise two corresponding through holes 91 provided in the PCB 90 and two screws 208.
  • the PCB 90 is fixed to the inner housing 2 by inserting the screws 208 in the through holes 91 and fixing the screws 208 to the inner threads 206.
  • the battery 7 is mounted at the top side of the inner housing 2.
  • the battery 7 is detachably fixed by a battery mounting means for detachably holding the battery 7.
  • the battery 7 is electrically connected to the circuit unit 6 by a battery connector 92 and provides electrical power to the latter.
  • the battery 7 is a 3.0 V coin battery.
  • the battery 7 is located at the top side distally to the circuit unit 6. It is located at a distal end part of the inner housing 2.
  • the dose-recording device 1 further comprises a securing means for securing the outer housing 3 to the inner housing 2.
  • the securing means comprises the screws 5, inner threads 207 for the screws 5, and through holes 308 for the screws 5.
  • the inner threads 207 are arranged at a bottom side of the inner housing 2. The bottom side is opposite to the top side along the height direction Z.
  • the outer housing 3 comprises the two through holes 308 for inserting the screws 5. When it is fitted onto the inner housing 2, the outer housing 3 can be secured to the inner housing 2 by means of the screws 5.
  • a notch 204 is provided at a distal side of the inner housing 2, in more detail at the bottom side of the latter.
  • the notch 204 extends from a distal end of the inner housing 2 towards the proximal direction. It has a shape that substantially corresponds to a symmetric trapezoid.
  • the outer housing 3 also extends longitudinally along the longitudinal direction X. It circumferentially surrounds the inner housing 2 when it is mounted on the latter (see, for example, Fig. 4) . It has a length in the longitudinal direction L of (at least approximately) 52 mm. In more general, the length of the outer housing 3 is preferably larger than the length of the inner housing 2, more preferably by 5 mm to 20 mm, more preferably by 12 to 18 mm. Thus, outer housing 3 can cover at least most of the inner housing 2 and additionally directly abut on the dosing section 401 at the same time.
  • the outer housing 3 encircles an interior thereof.
  • the interior of the outer housing 3 is a passage that extends along the longitudinal direction X throughout the outer housing 3.
  • a distal end part of the outer housing 3 is constituted by a collar 301 of a substantially cylindrical shape. However, an outer circumferential surface of the collar 301 is slightly tapered towards the distal direction in the present embodiment.
  • an inward flange 302 is provided at the distal end of the outer housing 3.
  • the inward flange 302 is located at the distal end of the collar 301.
  • the inward flange 302 extends radially inward from the distal end of the collar 301.
  • the inward flange 302 constitutes a means for securing the position of the outer housing 3 with respect to the proximal pen housing part 301 when the outer housing 3 is mounted on the latter.
  • An interior of the collar 301 is adapted to receive a distal end part of the dosing section 401.
  • the collar 301 is adapted to cover said distal end part directly.
  • the inner housing 2 is not inserted into the interior of the collar 301 when the outer housing 3 is mounted on the latter.
  • the collar 301 does not encompass any part of the inner housing 2.
  • a proximal part of the outer housing 3 is adapted to be slit over the inner housing 2 and then to be detachably fixed on the inner housing 2.
  • This proximal part may be referred to as sleeve part 303.
  • the inner housing 2 can be inserted in the sleeve part.
  • a shoulder part 304 is located between the collar 301 and the sleeve part 303.
  • a proximal end surface of the sleeve part 303 is adapted to abut on the flange 201 of the inner housing 2. Furthermore, at the bottom of the outer housing 3, a protrusion 307 is provided. The protrusion 307 protrudes radially inward from the inner side 309 of the outer housing 3. A shape of the protrusion 307 corresponds at least substantially to a shape of a proximal notch tip 205 of the notch 204. The protrusion 307 engages with the notch 204 of the inner housing 2 when the outer housing 3 is slipped over the inner housing 2 as described below.
  • the housing (including both the inner housing 2 and the outer housing 3) encircles an interior thereof.
  • the interior of the housing is a passage that extends along the longitudinal direction X throughout the housing. This interior is an empty space of an at least substantially cylindrical shape. It is configured for receiving the distal part of the dosing section 401.
  • a distal part of the interior of the housing corresponds to the interior of the collar 301.
  • a proximal part of the interior of the housing corresponds to the interior of the inner housing 2.
  • a protuberance 305 is formed at a top side of the sleeve part 303 in the height direction Z.
  • the protuberance 305 is configured for accommodating and covering the circuit unit 6 and the battery 7.
  • the activation button 8 is mounted in the protuberance 305.
  • the activation button 8 is located at the top side of the outer housing 3.
  • the activation button 8 is coupled to a momentary switch 93 of the circuit unit 6 when the outer housing 3 is mounted on the inner housing 2.
  • a LED window 306 is provided at the top side of the outer housing 3.
  • the LED window is located proximally from the activation button 8.
  • the LED window 306 may be a simple hole or may be covered by a window.
  • the LED window 306 allows that the user can see when a LED 94 of the circuit unit 6 is on, even when the outer housing 3 is mounted on the inner housing 2 and covers the circuit unit 6.
  • the dose-recording device 1 can be easily fixed to the injection device 400 as follows, in more detail on the distal part of the dosing section 401.
  • the outer housing 3 is not mounted on the inner housing 2.
  • the pen cap 402 of the injection device 400 is detached.
  • the distal part of the dosing section 401 is inserted into the interior of the inner housing 2.
  • the cushions 4 can sidestep laterally. This means, that the cushions 4 can easily be moved in the lateral direction a bit away from the interior of the inner housing 2.
  • the inner housing 2 can be slipped over the distal end of the dosing section 401 easily.
  • Fig. 5 shows a perspective view of a state, in which the inner housing 2 has been mounted on the dosing section 401, hence after the first mounting step has been finished.
  • the pen cap 402 has been re-attached to the injection device 400. However, this is not necessary. In fact, it may be necessary to detach the pen cap 402 for a second mounting step (or to keep it detached after the first mounting step) .
  • the outer housing 3 is slipper over the inner housing 2. Due to the protrusion 307 and the notch 204, the outer housing 3 can be slipped over the inner housing 2 only with an allowed degree of initial rotational misalignment. This allowed degree is determined by the width of the notch 204 in the circumferential direction at the distal end of inner housing 2, and by the width of the protrusion 307 in the circumferential direction.
  • the outer housing 3 is moved further in the proximal direction relative to the inner housing 2. In other words, the outer housing 3 is slipped further over the inner housing 2.
  • the outer housing 3 has reached its predetermined position (i.e. its final position) , further proximal movement thereof is prevented.
  • the proximal end of the outer housing 3 abuts the flange 201.
  • the protrusion 307 abuts the proximal notch tip 205 of the notch 204.
  • the notch 204 has a shape that substantially corresponds to a symmetric trapezoid.
  • the notch 204 is tapered toward the proximal direction.
  • the lateral, tapered sides of the notch 204 guide the protrusion 307 towards its pre-determined final rotational position in the second mounting step.
  • the protrusion 307 and the notch 204 constitute engagement means for automatically ensuring the final rotational position of the outer housing 3 with respect to the inner housing 2.
  • these engagement means secure the outer housing 3 from being moved proximally and/or being rotated with respect to the inner housing 2.
  • the outer housing 3 fits snugly onto the inner housing 2 with the cushions 4.
  • the cushions 4 are now squeezed between the inner side 309 of the outer housing 3 (with the webs 310) and an outer circumferential surface of the dosing section 401.
  • the cushions 4 cannot sidestep any longer in order to allow relative longitudinal movement between the inner housing 2 and the dosing section 401.
  • the inner housing 2 is secured against movement along the longitudinal direction L with respect to the dosing section 401.
  • the outer housing 3 is additionally secured against relative movement in the distal direction with respect to the inner housing 2 by fastening the screws 5. Hence, the outer housing 3 is also secured against relative movement in the distal direction with respect to the dosing section 401.
  • the proximal end of the inner housing 2 in the longitudinal direction X constitutes a proximal end of the dose-recording device 1 in the longitudinal direction. Furthermore, the distal end of the outer housing 3 in the longitudinal direction X constitutes a distal end of the dose-recording device 1. Apart from the proximal end of the inner housing 2 with the flange 201, the inner housing 2 is completely inserted into the outer housing 3 in this state.
  • the dose-recording device 1 can be easily dismounted from the injection device 400. Again, the pen cap 402 may be removed for that purpose.
  • the outer housing 3 is pulled off from the inner housing 2. Therefore, the outer housing 3 is moved in the distal direction with respect to the inner housing 2. In other words, the outer housing 3 is slit away from the inner housing 2 towards the distal direction.
  • a third dismounting step the inner housing 2 is pulled off from the dosing section 401.
  • the inner housing 2 is moved in the distal direction with respect to the dosing section 401.
  • the dose-recording device 1 may be re-mounted on another injection device, for example. This is of particular advantage if non-resettable pens are use as the injection device 400.
  • the outer housing 3 can be dismounted from the inner housing 2 (first and second dismounting step) . This allows the user to replace the battery 7, especially without dismounting the inner housing 2 from the injection device 400. Thereafter, the outer housing 3 can be re-mounted as noted above.
  • the outer housing 3 can be mounted to and dismounted from the inner housing 2 if the inner housing 2 is not attached to the injection device 400 in the same manner.
  • the dose-recording device 1 is adapted to monitor the injection processes of the medicament by the injection device 400.
  • the dose-recording device 1 is adapted to receive and recognize the injection clicks of the injection device 400 when the dose-recording device 1 is mounted on the injection device 400.
  • the dose-recording device 1 counts the injection clicks of each injection process. Thus, it tracks quantitatively how much of the medicament is ejected by the injection device 400 in each injection process.
  • Fig. 9 is a schematic block diagram showing the basic structure of a circuit unit 6 of the dose-recording device 1.
  • the circuit unit 6 comprises a sound transducer unit 10, a first filter unit 20, an amplifier unit 30, an integrator unit 40, a second filter unit 50, a comparator unit 60 and a microcontroller unit 80 (MCU 80) .
  • MCU 80 microcontroller unit 80
  • the circuit unit 6 comprises the battery connector 92 for electrically connecting the battery 7 to the circuit unit 6, the momentary switch 93, and the LED 94.
  • circuit unit 6 all elements of the circuit unit 6 are fixed to or are part of the one single PCB 90.
  • circuit unit 6 will be explained in more detail now with regard to Fig. 9 and Fig. 10.
  • the sound transducer unit 10 consists of a microphone 11.
  • the microphone 11 comprises six pins 11-1, 11-2, 11-3, 11-4, 11-5, 11-6. Three ground pins 11-2, 11-3, 11-4 of the microphone 11 are connected to ground.
  • a power-supply pin 11-5 is provided with a supply voltage Vdd. In this embodiment, the power supply is the battery 7.
  • An output pin 11-6 of the microphone 11 constitutes an output of the sound transducer unit 10.
  • the microphone 11 is adapted to receive the audible injection clicks of the injection device 400. It is a micro-mechanical systems (MEMS) microphone with analogue output.
  • the microphone 11 provides an analogue electric sound signal (microphone signal) at the output pin 11-6 when the dose-recording device 1 is in the recording mode.
  • the microphone 11 receives an injection click.
  • the microphone signal is changed by each injection click. For example, each click may create a "wave packet" in the microphone signal.
  • the microphone 11 converts the audible injection clicks in analogue electric signal features of the microphone signal.
  • the analogue microphone signal is biased.
  • the microphone 11 may be an omnidirectional microphone.
  • the microphone 11 has a sensitivity between -39 dB and -37 dB, an output impedance of 400 ⁇ , and a rated current of 200 ⁇ A. Due to its small rated current, the microphone 11 only needs little electric power. Hence, the operating lifetime of the battery 7 is large.
  • a S/N ratio of the microphone 11 may be at least approximately 66 dB (A-weighted) . These values are valid under the following conditions: 94 dB SPL at 1 kHz with the supply voltage Vdd being 2, 2 V.
  • the microphone 11 is fixed at a proximal end part of the PCB 90.
  • a distance in the longitudinal direction X between the proximal end of the inner housing 2 and the microphone 11 is preferably between 2 mm and 30 mm, more preferably between 2 mm and 6 mm, for example approximately 3, 5 mm.
  • the proximal end of the inner housing 2 constitutes the distal end of the dose-recording device 1 when the outer housing 3 is mounted, the same applies with regard to the proximal end of the dose-recording device 1.
  • a distance in the longitudinal direction X between the distal end of the inner housing 2 and the microphone 11 is between 11 mm and 34 mm, for example approximately 29 mm. If the outer housing 3 is mounted on the inner housing 3, a distance in the longitudinal direction X between the distal end of the outer housing 3 and the microphone 11 is preferably between 29 mm and 49 mm, for example approximately between 40 mm and 47 mm.
  • An adequate position of the microphone 11 improves the reliability of correctly recording and recognizing the injection clicks.
  • the first filter unit 20 is directly connected to the output of the sound transducer unit 10.
  • the first filter unit 20 is adapted to receive the microphone signal. It is adapted to provide an analogue electric filtered signal based on the microphone signal.
  • the first filter unit 20 is an analogue high pass filter.
  • a cut-off frequency of the first filter unit 20 is between 1 kHz and 2 kHz, for example 1, 5 kHz.
  • the first filter unit 20 is a RC high pass filter and comprises a capacitor 21 and a resistor 22.
  • the capacitor 21 is directly connected to a signal output of the first filter unit 20.
  • the resistor 22 is connected to the capacitor 21 in parallel to the signal output.
  • the other side of the resistor 22 is connected to a reference connection of the first filter unit 20. Said reference connection is connected to a reference voltage line 70.
  • the first filter unit 20 consists only of the capacitor 21 and the resistor 22, it is particularly inexpensive and easy to manufacture but, nevertheless, sufficiently functional.
  • the first filter unit 20 cuts off lower frequencies of the microphone signal for generating the filtered signal.
  • the first filter unit 20 blocks DC voltage components of the microphone signal.
  • the first filter unit 20 decouples the operating points of the sound transducer unit 10 and the amplifier unit 30.
  • the operating point of an operational amplifier 31 of the amplifier unit 30 is decoupled from an operating point of the microphone 11 (i.e. the operating point of the sound transducer unit 10) .
  • An amplifier input of the amplifier unit 30 is directly connected to a signal output of the first filter unit 20.
  • the amplifier unit 30 amplifies the filtered signal.
  • the amplifier unit 30 generates an analogue amplified signal based on the filtered signal.
  • the amplifier unit 30 does not only amplify the filtered signal but also filters the filtered signal further.
  • the amplifier unit 30 is an active first-order low-pass filter.
  • a cut-off frequency of the amplifier is 1, 5 kHz in the present embodiment.
  • the amplifier unit 30 comprises or consists of the operational amplifier 31, a first resistor 32, a second resistor 33, and a capacitor 34.
  • a non-inverting input of the operational amplifier 31 is directly connected to the amplifier input of the amplifier unit 30.
  • the non-inverting input is directly connected to the capacitor 21 of the first filter unit 20.
  • the non-inverting input is connected to the capacitor 21 in parallel with the resistor 22.
  • An output of the operational amplifier 31 is directly connected to an amplifier output of the amplifier unit 30.
  • the second resistor 33 is connected to the output of the operational amplifier 31 in parallel with the amplifier output of the amplifier unit 30.
  • the second resistor 33 is connected to an inverting input of the operational amplifier 31.
  • the output of the operational amplifier 31 is connected to the inverting input via the second resistor 33.
  • the capacitor 34 connects the output of the operational amplifier 31 with its inverting input.
  • the first resistor 32 is connected to the inverting input in parallel with the second resistor 33 and the capacitor 34. Another side of the resistor 32 is connected to a reference connection of the amplifier unit 30, wherein said reference connection is connected to the reference voltage line 70. Consequently, the output of the operational amplifier 31 is connected to the reference voltage line 70 via the second resistor 33 and the capacitor 34 (in parallel) in series with the first resistor 32.
  • a ratio of the resistances of the second resistor 33 and the first resistor 32 influences an amplification ratio.
  • the amplification ratio is preferably between 2 and 30, more preferably between 3 and 10. For example, the amplification ratio may be 6.
  • both the reference connection of the first filter unit 20 and the reference connection of the amplifier unit 30 are connected in parallel to the reference voltage line 70.
  • the amplifying unit 30 consists only of the elements noted, it is particularly inexpensive and easy to manufacture but, nevertheless, sufficiently functional.
  • the operational amplifier 31 is of the rail-to-rail input and output type. In addition, it is a micro power, low voltage amplifier. It may have a minimum supply voltage of less than 3.0 V, for example 1.8 V. Preferably, the operational amplifier 31 exhibits low noise of less than 5 ⁇ V PP , for example 3,5 ⁇ V PP (from 0, 1 Hz to 10 Hz) . A quiescent current of the operational amplifier 31 may be less than 10 ⁇ A, more preferably less than 3 ⁇ A, for example 2,5 ⁇ A. This enhances the lifespan of the battery 7. Preferably, an offset voltage of the operational amplifier 31 is less than 0, 9 mV. Preferably, a gain-bandwidth product of the operation amplifier 31 is at least 100 kHz, more preferably at least 110 kHz, for example 120 kHz.
  • the operational amplifier 31 requires little voltage, exhibits low power consumption and a suitable GBWP. The latter ensures that a target frequency can be amplified by a multiple.
  • the integrator unit 40 comprises or consists of a diode, a resistor 42, and a capacitor 43.
  • the diode is a Zener diode 41.
  • the resistor 42 and the capacitor 43 are connected to a cathode of the Zener diode 41 in parallel.
  • the other sides of the resistor 42 and the capacitor 43 are grounded, respectively.
  • an output of the integrator unit 40 is connected to the cathode of the Zener diode 41 (i.e. in parallel with the resistor 42 and the capacitor 43) .
  • An anode of the Zener diode 41 is connected to an input of the integrator unit 40.
  • the input of the integrator unit 40 is connected to the amplifier output. In other words, the anode of the Zener diode 41 is directly connected to the output of the operational amplifier 31.
  • the integrator unit 40 consists only of the elements noted, it is particularly inexpensive and easy to manufacture but is, nevertheless, sufficiently functional.
  • the integrator unit 40 is adapted to receive the amplified signal from the amplifying unit 30. Furthermore, the integrator unit 40 is adapted to integrate at least a part of the amplified signal to an integration curve.
  • the integration curve still is an analogue electric signal.
  • the amplifying unit is adapted to integrate upper half waves of the amplified signal to an analogue envelope curve.
  • the envelope curve constitutes the integration curve.
  • the envelope curve is provided at the output of the integrator unit 40.
  • the amplification ratio of the amplifier unit 30 can be considerably smaller. As noted above, due to the integrator unit 40, the amplification ratio is 6 in this embodiment, for example. With the integrator unit 40, the efficiency of the circuit unit 6 is enhanced.
  • the amplifying unit 30 being an active low-pass filter and the proposed integrator unit 40.
  • the second filter unit 50 is directly connected to the output of the integrator unit 40.
  • the second filter unit 50 is adapted to receive the envelope curve provided by the integrator unit 40. Furthermore, it is adapted to provide a filtered envelope based on the envelope curve.
  • the filtered envelope is still an analogue electric signal.
  • the second filter unit 50 is an analogue RC filter. It comprises or consists of a first capacitor 51, a resistor 52, and a second capacitor 53. One side of the first capacitor 51 is directly connected to the input of the second filter unit 50. Hence, the first capacitor 51 is directly connected to the cathode of the Zener diode 41. An output of the second filter unit 50, the resistor 52, and the second capacitor 53 are connected to the other side of the first capacitor 51 in parallel to each other. The other sides of the resistor 52 and the second capacitor 53 are grounded, respectively.
  • the second filter unit 50 consists of the first capacitor 51, the resistor 52 and the second capacitor 53, it is particularly inexpensive and easy to manufacture but is, nevertheless, sufficiently functional.
  • the second filter unit 50 decouples the operating points of the integrator unit 40 and the comparator unit 60. According to another aspect, the second filter unit 50 may further exhibit a band pass functionality.
  • the comparator unit 60 is indirectly connected to the integrator means 40.
  • the comparator unit 60 is adapted to generate a square wave output on the basis of the integration curve.
  • an input of the comparator unit 60 is directly connected to an output of the second filter unit 50.
  • the comparator unit 60 is connected to the integrator unit 40 via the second filter unit 50.
  • the comparator unit 60 is adapted to receive the filtered envelope provided by the second filter unit 50.
  • the comparator unit 60 is adapted to generate a square wave output on the basis of the filtered envelope. In other words, the comparator unit 60 converts the filtered envelope into the square wave output.
  • the comparator unit digitizes the filtered envelope.
  • the comparator unit 60 comprises a comparator 61, a first resistor 62, a second resistor 63, and a capacitor 64.
  • the comparator 61 comprises a push-pull output stage and rail-to-rail-inputs (RRIO type) . It is configured for single-supply operation. Hence, the circuit unit 6 can be kept of simple structure.
  • the comparator 61 has six pins 61-1, 61-2, 61-3, 61-4, 61-5, and 61-6.
  • a non-inverting input pin 61-1 (+IN) is directly connected to the input of comparator unit 60. In fact, the non-inverting input pin 61-1 may constitute the input of the comparator unit 60.
  • a negative voltage supply pin 61-2 (-V s ) is grounded.
  • a positive voltage supply pin 61-6 (+V S ) is provided with supply voltage.
  • An output pin 61-3 is directly connected to an output of the comparator unit 60. In fact, the output pin 61-3 may constitute the output of the comparator unit 60.
  • the second resistor 63 and the capacitor 64 of the comparator unit 60 are connected to an inverting input pin 61-4 (-IN) of the comparator 61 in parallel.
  • the other sides of the second resistor 63 and the capacitor 64 are grounded, respectively.
  • the first resistor 62 and the reference voltage line 70 are connected to a reference voltage pin 61-5 (V REF ) of the comparator 60 in parallel.
  • the other side of the first resistor 62 is connected in parallel to the inverting input pin 61-4, the second resistor 63, and the capacitor 64. Accordingly, the reference voltage pin 61-5 is connected to ground via the first resistor 62 and the second resistor 63 in series. In addition, the reference voltage pin 61-5 is connected to ground via the first resistor 62 and the capacitor 64 in series.
  • the comparator 61 is a micro-power comparator with integrated voltage reference.
  • a reference voltage provided by the comparator 61 may be 1, 2 V, for example.
  • the reference voltage is provided at the reference voltage pin 61-5.
  • the reference voltage is divided by the first resistor 62 and the second resistor 63.
  • the part of the reference voltage that drops across the second resistor 63 is applied to the inverting input pin 61-4.
  • a voltage threshold for the filtered envelope is determined. If a voltage of the filtered envelope is below said voltage threshold, the comparator 61 outputs the ground potential (no voltage) at the output pin 61-3. It has been noted above that the negative voltage supply pin 61-2 is grounded. If the voltage of the filtered envelope is equal or larger than the voltage threshold, the comparator 61 outputs the supply voltage at the output pin 61-3. By this, the comparator 61 converts the filtered envelope into the square wave output.
  • a sensitivity of the drug delivery device 1 for recognizing injection click can be adjusted.
  • the reference voltage line 70 is connected to the reference voltage pin 61-5, the first filter unit 20, and the amplifier unit 30, the reference voltage is consistent in the circuit unit 6.
  • a drift of the reference voltage provided by the comparator 61 may be less than 60 ⁇ V/°C, for example 42 ⁇ V/°C. This is of importance as the user may use the injection device 400 and the dose-recording device 1 both in cold and hot climate conditions.
  • the reference voltage may be stable up to 6 nF capacitive load, for example up to 10 nF capacitive load.
  • the comparator 61 is configured to source up at least up to 2 mA of output current, for example up to 2 mA.
  • the power supply current is less than 5 ⁇ A, for example 2,2 ⁇ A.
  • the comparator 61 exhibits low power consumption and low costs.
  • the MCU 80 is connected to the output pin 61-3 of the comparator 61.
  • the MCU 80 comprises a microprocessor 81, a memory means 82, and a data communication means 83.
  • the output pin 61-3 is connected to an interrupt input of the microprocessor 81.
  • the microprocessor 81 is an ARM Cortex processor, for example a 16 MHz, 32-bit ARM Cortex-M0 processor.
  • the microprocessor 81 is adapted to calculate the dosage units injected in an injection process.
  • the sound transducer unit 10, the first filter unit 20, the amplifier unit 30, the integrator unit 40, the second filter unit 50, and the comparator unit 60 are configured such that each injection click recorded is converted into a square pulse of the square wave output. Vice versa, each square pulse represents the injection of one dosage unit. As each square pulse leads to an interrupt sequence at the microprocessor 81, the latter counts the interrupt sequences and hence the square pulses in order to monitor the dosage units injected.
  • the memory means 82 is adapted to store data corresponding to one or more injection processes.
  • the memory means 82 may comprise or consist of a flash memory.
  • the data communication means 83 is a Bluetooth Low Energy link.
  • the Bluetooth Low Energy link may comprise a 2, 4 GHz CMOS transceiver.
  • data regarding injection processes can be transferred wirelessly to another device. These data may comprise, for example, how many injection processes have been recorded, the time of the individual injection processes, how many dosage units have been injected in an individual injection process, and/or how many dosage units have been injected altogether in several injection processes.
  • the user has to press the activation button 8.
  • the activation button 8 activates the momentary switch 93 of the circuit unit 6.
  • the dose-recording device 1 is in the recording mode.
  • the dose-recording device 1 is activated and ready for receiving and processing the audible injection clicks from the injection device 400.
  • the dose-recording device 1 exhibits user-friendly one-button-operation.
  • the user can press the activation button 8 with its index finger and/or its middle finger while holding the injection device 400 with the same hand.
  • the user can press the injection button 404 with its thumb of the same hand.
  • the dose-recording device 1 is configured for one-hand operation together with the injection button 404. This user-friendly operation is possible due to the proposed location of the dose-recording device 1 on the dosing section and due to the position of the activation button 8.
  • the LED window 306 is located at the top side and proximally from the activation button 8, the user can see it between its thumb and index finger of the same hand during operation.
  • the dose-recording device 1 When the activation button 8 is not pressed, the dose-recording device 1 is not in the recording mode. This reduces the risk that the dose-recording device 1 incorrectly detects the injection of dosage units due to noise.
  • the LED 94 When the dose-recording device 1 is in the recording mode, the LED 94 is on. This provides visual feedback for the user that the recording mode is active and that the dose-recording device 1 is ready to monitor the injection process. When the dose-recording device 1 is not in the recording mode, the LED 94 is off.
  • the sound transducer unit 10, the first filter unit 20, the amplifier unit 30, the integrator unit 40, the second filter unit 50, and the comparator unit 60 consist only of analogue electric components, respectively.
  • the analogue circuit elements are readily available, inexpensive, and reliable. As a result, the dose-recording device 1 can be manufactured very cost-efficiently.
  • the amplifier unit 30 are only activated in the recording mode, the circuit unit 6 exhibits very little power consumption.
  • the comparator unit 60 and/or the microprocessor unit 80 may be only activated if the dose-recording device is in the recording mode. Accordingly, the operating lifetime of the battery 7 is large. For example, a standby time of 380 days is obtained if two injection processes per day are recorded and if the dose-recording device 1 wirelessly synchronized with another device four times per day.
  • the dose-recording device 1 allows recording the dosage units, which are ejected by the injection device 400 in one or more injection processes, in a simple manner. It is easy to handle by the user. The injected dosage units are reliably detected and stored. The corresponding data can be wirelessly transmitted to other devices. Thus, the dose-recording device 1 helps a user to document the injected dosage units. Finally, the proposed dose-recording device 1 is simple to manufacture, inexpensive, and re-usable.
  • MCU microcontroller unit
  • PCB printed circuit board

Abstract

L'invention concerne un dispositif d'enregistrement de dose (1) pour un dispositif d'injection (400) pour suivre des unités de dosage éjectées par le dispositif d'injection (400), le dispositif d'injection (400) générant des clics d'injection audibles pour chaque unité de dosage qui est éjectée. Le dispositif comprend une unité de transducteur sonore (10), qui est conçue pour générer un signal sonore électrique analogique sur la base des clics d'injection, et une première unité de filtre (20) conçue pour fournir un signal filtré électrique analogique sur la base du signal sonore et pour découpler des points de fonctionnement de l'unité de transducteur sonore (10) et une unité d'amplificateur (30). L'unité d'amplificateur (30) est conçue pour fournir un signal amplifié électrique analogique sur la base d'un signal filtré. Un bloc intégrateur (40) est conçu pour fournir une courbe d'intégration sur la base du signal amplifié par intégration d'au moins une partie du signal amplifié. Une unité de comparaison (60) est connectée à l'unité d'intégrateur (40) et est conçue pour générer une sortie d'onde carrée sur la base de la courbe d'intégration. Enfin, une unité de microcontrôleur (80) est conçue pour déterminer les unités de dosage éjectées sur la base de la sortie d'onde carrée. L'invention vise à réduire la complexité du dispositif d'enregistrement de doses (1), réduire ses coûts de fabrication et augmenter la fiabilité et la précision du dispositif d'enregistrement de dose (1), l'unité d'amplificateur (30) comprend ou est constituée d'un filtre passe-bas de premier ordre actif.
PCT/CN2019/121043 2019-11-26 2019-11-26 Dispositif d'enregistrement de dose WO2021102700A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2019/121043 WO2021102700A1 (fr) 2019-11-26 2019-11-26 Dispositif d'enregistrement de dose
CN201980102484.1A CN114761056A (zh) 2019-11-26 2019-11-26 剂量记录装置

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/121043 WO2021102700A1 (fr) 2019-11-26 2019-11-26 Dispositif d'enregistrement de dose

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078239A1 (fr) * 2003-03-03 2004-09-16 Dca Design International Ltd. Mecanisme d'entrainement pour dispositifs de distribution de medicaments
US20070180915A1 (en) * 2005-12-20 2007-08-09 Jack Goldberg Method and system for noise dosimeter
CN106527293A (zh) * 2016-12-24 2017-03-22 北京糖护科技有限公司 一种自动识别分析胰岛素笔注射声音的电路
US20170312455A1 (en) * 2016-04-29 2017-11-02 Verily Life Sciences Llc Air shot detection
US20180280624A1 (en) * 2014-11-05 2018-10-04 Insuline Medical Ltd. Drug tracking device

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078239A1 (fr) * 2003-03-03 2004-09-16 Dca Design International Ltd. Mecanisme d'entrainement pour dispositifs de distribution de medicaments
US20070180915A1 (en) * 2005-12-20 2007-08-09 Jack Goldberg Method and system for noise dosimeter
US20180280624A1 (en) * 2014-11-05 2018-10-04 Insuline Medical Ltd. Drug tracking device
US20170312455A1 (en) * 2016-04-29 2017-11-02 Verily Life Sciences Llc Air shot detection
CN106527293A (zh) * 2016-12-24 2017-03-22 北京糖护科技有限公司 一种自动识别分析胰岛素笔注射声音的电路

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