Patent Publication Number: US-10773027-B2

Title: Injection Device

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is the national stage entry of International Patent Application No. PCT/EP2016/056105, filed on Mar. 21, 2016, and claims priority to Application No. EP 15160254.7, filed in on Mar. 23, 2015, the disclosures of which are expressly incorporated herein in entirety by reference thereto. 
     TECHNICAL FIELD 
     The present disclosure relates in one aspect to an injection device, such like a pen-type injector operable for setting and dispensing of a dose of a medicament. In particular, the disclosure relates to a cartridge filled with a liquid medicament, which cartridge is of reduced diameter compared to standard sized cartridges conventionally used with pen-type injection devices. In another aspect the disclosure relates to a method of improving the dosing accuracy of an injection device. 
     BACKGROUND 
     Injection devices for setting and dispensing a single or multiple doses of a liquid medicament are as such well-known in the art. Generally, such devices have substantially a similar purpose as that of an ordinary syringe. 
     Injection devices, in particular pen-type injectors have to meet a number of user-specific requirements. For instance, with patient&#39;s suffering chronic diseases, such like diabetes, the patient may be physically infirm and may also have impaired vision. Suitable injection devices especially intended for home medication therefore need to be robust in construction and should be easy to use. Furthermore, manipulation and general handling of the device and its components should be intelligible and easy understandable. Moreover, a dose setting as well as a dose dispensing procedure must be easy to operate and has to be unambiguous. 
     Typically, such devices comprise a housing including a particular cartridge holder, adapted to receive a cartridge at least partially filled with the medicament to be dispensed. Such devices further comprise a drive mechanism, usually having a displaceable piston rod which is adapted to operably engage with a piston of the cartridge. By means of the drive mechanism and its piston rod, the piston of the cartridge is displaceable in a distal direction or dispensing direction and may therefore expel a predefined amount of the medicament via a piercing assembly, which is to be releasably coupled with a distal end section of the housing of the injection device. 
     The medicament to be dispensed by the injection device is provided and contained in a multi-dose cartridge. Such cartridges typically comprise a vitreous barrel sealed in distal direction by means of a pierceable seal and being further sealed in proximal direction by the piston. With reusable injection devices an empty cartridge is replaceable by a new one. In contrast to that, injection devices of disposable type are to be discarded when the medicament in the cartridge has been dispensed or used-up. 
     Existing and commercially distributed pen-injectors may be equipped with cartridges providing a predefined volume for a liquid medicament, e.g. 3 ml. The injection devices are typically configured to provide user-operated variable setting of a dose and subsequent dispensing or delivery thereof. Typically, a dose can be selected and dispensed in discreet steps of e.g. one or several International Units (IU). Most injection devices on the market are configured and designed for use of grown up patients. 
     In the field of pediatric treatment it is desirable to reduce the dose of medicaments and to administer non-integer amounts of IU to a patient. This requires smaller dose increments to be selectable. It is therefore desirable to set and to dispense doses having a size of less than one IU, e.g. of half units. Hence, it is desirable to provide dose setting with increments of half units or less in order to increase dosing accuracy and to allow for a finely segmented, precise setting and dispensing of doses of a particularly small size. 
     In order to meet these requirements existing injection devices require modifications. 
     SUMMARY 
     Certain aspects of the present disclosure provide a rather simple approach to enable setting and dispensing of doses of reduced size, in particular to provide setting and dispensing of half units or other non-integer units of a liquid medicament by making use of an existing drive mechanism of an injection device. The present disclosure relates to modifications to an existing injection device, which modifications are simple and cost efficient to realize. 
     In a first aspect an injection device for delivery of a liquid medicament is provided. The injection device, typically of pen-injector type comprises a housing to accommodate a cartridge and a drive mechanism. The cartridge also belonging to the injection device comprises a tubular-shaped barrel filled with a liquid medicament. The cartridge is sealed in a proximal direction by a piston that is displaceably arranged inside the barrel. At a distal end the cartridge is typically provided with a pierceable seal acting and serving as a septum. For delivery of the liquid medicament, in particular for injecting of a dose of the liquid medicament into biological tissue the distal seal of the cartridge is to be pierced and penetrated by a double-tipped injection needle in such a way, that a proximally directed tapered or tipped end of the injection needle is located in the interior volume of the cartridge. Then, by exerting a distally directed pressure onto the piston the piston is advanced in distal direction by a predetermined distance thereby expelling a predefined amount of the medicament through the injection needle. 
     The injection device further comprises a drive mechanism having a piston rod to advance in a distal direction. The piston rod is configured to abut against a proximally facing surface of the piston of the cartridge. The drive mechanism is typically configured to provide setting and dispensing of doses of variable size. The drive mechanism typically comprises a dose setting member and a dose dispensing member that provide individual and variable setting and dispensing of a dose by the end user or patient. However, the injection device is not limited to drive mechanisms providing variable and user settable dose dispensing but the disclosure may also relate to so called fixed dose injection devices that provide repeated delivery of a dose of the medicament of constant size. 
     The drive mechanism of the injection device is configured to advance the piston rod in distal direction by a distance z 1  in order to dispense a reference volume V 1  of the medicament when operably engaged with a reference cartridge having a reference diameter D 1 . 
     Hence, the drive mechanism may be configured for standard sized cartridges, e.g. having an effective filling volume of about 3 ml. Dose setting and dose dispensing as indicated to the user, e.g. by a dose indicating member or dose indicating sleeve of the drive mechanism, is configured and adapted in accordance with the dispensing rate of the medicament arising when the piston is displaced in axial direction by a predefined distance. Depending on the geometry, in particular depending on the size of the cross-section of the tubular-shaped barrel of the cartridge a displacement z 1  of the piston corresponds to the ejection of a volume V 1  that is given by a multiplication of the axial displacement z 1  with the transverse cross-sectional area of the piston of the cartridge. 
     In the present context the axial direction points along the longitudinal or main cylinder axis of the tubular-shaped barrel whereas the transverse direction points perpendicular to the longitudinal direction. Furthermore, the distal direction denotes the direction pointing towards an injection site of a patient whereas the proximal direction is directed towards the opposite end of the device. An injection needle is typically arranged at a distal end of the device whereas dose setting and/or dose dispensing members of the drive mechanism are typically located at the opposite proximal end of the injection device. 
     The cartridge actually arranged inside the housing of the injection device has a diameter D 2  that is smaller than the reference diameter D 1 . In this way a volume V 2  of the medicament being smaller than the reference volume V 1  can be dispensed when the piston rod advances in distal direction by the distance z 1 . Hence, one aspect of the disclosure is particularly dedicated to replace a standard sized cartridge by a cartridge with a reduced diameter or reduced cross-section. In this way, the ejected volume per axial displacement of the piston can be effectively reduced. 
     Consequently, a diameter reduced cartridge can be used with a totally unaltered drive mechanism in order to dispense particularly small sized doses of the medicament. In this way, dosing accuracy can be enhanced rather easily. When replacing a standard sized cartridge by a diameter reduced cartridge the step size of discrete dose sizes to be set and dispensed by the device can be effectively reduced. Hence, with a drive mechanism originally intended to set and to dispense dose sizes of integer numbers of international units (IU) can be used straight forward to set and to dispense doses of the medicament with sizes of non-integer IU, e.g. of half-units or other fractions of one unit. For instance it is possible to set and to dispense doses of e.g. 1.5 IU, 3.8 IU, 7.5 IU, and so on. 
     The diameter D 2  as well as the reference diameter D 1  refer to inner diameters of the tubular-shaped barrel of respective cartridges. With a tubular-shaped barrel with a circular transverse cross-section the volume V 1  is related to the distance z 1  and to the diameter D 1  by the following formula: 
               V   ⁢           ⁢   1     =         (       D   ⁢           ⁢   1     2     )     2     ⁢   π   *   z   ⁢           ⁢   1.           
The same relationship is valid for the diameter reduced cartridge with an inner diameter of D 2  smaller than D 1 .
 
     In order to provide a diameter reduced cartridge it would be sufficient to increase the sidewall thickness of the cartridge while keeping the outer diameter substantially constant. Then, the cartridge according to the present disclosure with a reduced inner diameter could be directly fitted into the housing of the injection device almost without any further modifications to be made to the drive mechanism or to a cartridge holder of the housing of the injection device. It may be only necessary to modify the size of a pressure piece at the distal end of the piston rod so as to match with the reduced diameter or transverse cross-section of the piston, which is equally reduced in diameter. 
     In other embodiments the diameter reduction of the cartridge also implies a respective geometric modification of a cartridge holder, typically forming a distal end of the housing of the injection device and being particularly configured to accommodate and to house the cartridge therein. In embodiments, wherein also the outer diameter of the cartridge is smaller than the outer diameter of the reference cartridge it is only required that an inner diameter or an inside facing geometry of a size reduced cartridge holder matches with the size reduced outer circumference of the cartridge. The outside facing appearance and geometry of such a cartridge holder can remain unchanged compared to a standard cartridge holder configured to accommodate a reference cartridge. In this way further housing components, such like a protective cap to cover the cartridge holder and to releasably engage with the cartridge holder can be left completely unaltered. 
     According to a further embodiment a ratio R of the diameter D 2  and the reference diameter D 1 , namely 
             R   =       (       D   ⁢           ⁢   2       D   ⁢           ⁢   1       )     2           
is smaller than 1 but larger than 0.1. In this way dose size increments can be reduced up to a factor of 10 compared to dose increments obtainable with the present drive mechanism when operably engaged with the reference cartridge. So the ratio R just defines the size reduction of the reference volume V 1  to the volume V 2 . The dispensed volumes V 1  and V 2  differ by the ratio R. Hence,
 
     
       
         
           
             
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     In this way the reduction of the ejected volume and hence the minimum dose increment or the size of discrete dose steps can be easily modified and determined on the basis of the relation of the diameter D 2  in comparison to the reference diameter D 1 . 
     Generally, the diameters D 1  or D 2  are substantially constant over almost the entire axial elongation of the tubular-shaped barrel of the respective cartridge. Only near a distal end the barrel may comprise a radially narrowing neck portion adjacent to the distal seal. When referring to the diameters D 1  and D 2  reference is made to the nominal inner diameter of the proximal end or of an axial middle section of the barrel of the cartridge. 
     Reducing the diameter of the cartridge and hence of its barrel is also beneficial in that the piston providing a proximal seal for the barrel is also provided with a correspondingly reduced transverse diameter or cross-section. This has the further effect, that a contact surface between the piston and an inside facing portion of the sidewall of the barrel is reduced compared to the reference cartridge. In this way, frictional forces arising from the sealing engagement of the piston and the barrel of the cartridge can be effectively reduced, thereby decreasing mechanical friction for displacing the piston inside the barrel. In effect, static friction as well as dynamic friction between the piston and the barrel can be reduced thereby also decreasing a driving force to be provided by the piston rod in order to expel the medicament from the cartridge. 
     According to another embodiment the ratio R=n/m, with n and m being integer numbers. When the ratio R is a rational number a further modification of the drive mechanism, especially in terms of indicating the size of a dose actually set can be simplified. 
     According to another embodiment the ratio R substantially equals one of the following ratios: 1/2, 1/3, 1/4, 1/5, 1/6, 2/3, 2/5, 3/4, 3/5, 4/5 or 5/6. By making use of a ratio R of 1/2 the volume V 2  dispensed by a displacement of the piston rod of z 1  is just divided by a factor 2 compared to the Volume V 1  otherwise dispensed with the reference cartridge. With a ratio R=1/3 the volume V 1  is just divided by 3. For the purpose of indicating the size of a dose actually set making use of such rational numbers is of particular benefit. When replacing the reference cartridge by a cartridge with a ratio R=1/2 the size of the dose increments can be divided by a factor 2. If the drive mechanism is originally intended to provide setting of a dose with a step size of 1 IU implementation and use of a diameter reduced cartridge exhibiting a ratio R=1/2 the dosing step size can be reduced to 0.5 IU. 
     According to another embodiment the drive mechanism comprises a dose indicating member with a dose indicating scale to appear in a window of the housing for indicating a size of a dose actually set, wherein the dose indicating scale is re-sized by the ratio R compared to a reference dose indicating scale that applies or which is applicable with the dose indicating member when the drive mechanism is operably engaged with the reference cartridge. Here the ratio R does not necessarily comprise a rational number but may comprise any positive number between 0.1 and 1. 
     When replacing the reference cartridge by a diameter reduced cartridge according to the present disclosure it is also of particular benefit also to replace the dose indicating member or at least to replace a dose indicating scale provided thereon. The dose indicating member and almost all further components of the drive mechanism may be manufactured as injection molded plastic components. For replacing a dose indicating scale it may be only necessary to modify the outer appearance of the dose indicating member. It may be sufficient to replace a printed scale on the outer circumference of the dose indicating member. The dose indicating scale may be printed or adhesively attached to the outer circumference of the dose indicating member, e.g. by means of a printed label. 
     Therefore, replacing the reference dose indicating scale by the dose indicating scale matching to the cartridge actually in use may just require to exchange a printed outer surface of the dose indicating member or to make use of a label provided with the re-sized dose indicating scale, which label is to be adhered to the outer circumference of the dose indicating member. The dose indicating member itself, hence its geometry and its functional implementation in the drive mechanism can remain completely unaltered. 
     In a further embodiment the dose indicating member comprises a sleeve rotatably supported in the housing. Typically, the dose indicating member is rotatably supported in a body of the housing. The dose indicating member is typically rotatable with regard to a longitudinal axis extending through the symmetry axis of the sleeve. The sleeve of the dose indicating member is further in helical threaded engagement with the housing. The dose indicating scale is hence helically-shaped and is provided on an outer circumference of the sleeve. In other words, the consecutive numbers or symbols representing the size of a dose are provided on the outer circumference of the sleeve in a helical manner so that during dose setting or dose dialing a series of increasing or decreasing numbers shows up in a window of the housing. 
     In another embodiment the housing comprises at least a body and a cartridge holder connected to the body. The body accommodates the drive mechanism and the cartridge holder accommodates a cartridge. Typically, the cartridge holder is either transparent or comprises at least one window to provide visual inspection of the cartridge and its content. For a mass manufacturing process it may be of particular benefit to provide a cartridge holder preassembly constituted by the cartridge holder with the cartridge arranged therein and to further provide a body preassembly constituted by the body with the drive mechanism assembled therein or thereto. In a final step of assembly, which could be also denoted as ‘marriage’ the two preassemblies are just connected and mutually interlocked so that the injection device is ready to use or almost ready to use. 
     The injection device may be configured and designed as a disposable device that is intended to be discarded in its entirety once the content of the cartridge has been expelled. With a disposable device the cartridge holder is typically irreleasably connected to the body which means that a detachment of cartridge holder and body after an initial connection thereof implies a destruction of at least one of cartridge holder or body. 
     Apart from that it is also conceivable that the injection device is configured as a reusable device, wherein the cartridge holder and the body are releasably connectable. With a reusable device the drive mechanism is further provided with a reset function so as to return the piston rod into an initial axial position during replacement of a cartridge. 
     According to a further embodiment the cartridge holder comprises a proximal connecting end with an insert section to engage with a receptacle of a distal connecting end of the body. Typically, the cross-section and geometric shapes of the receptacle and of the insert portion mutually match in such a way, that a positive interconnection of receptacle and insert portion can be obtained. Moreover, the insert section may be slidably insertable in axial direction into the receptacle. 
     The insert section may comprise at least one fastening element to positively engage with a complementary-shaped fastening element of the receptacle. Mutually engageable and complementary-shaped fastening elements of the insert section and the receptacle provide an axial interlock of cartridge holder and body. Typically, the insert section is slidably displaceable inside the receptacle until the mutually corresponding fastening elements of insert section and receptacle engage. Once the fastening elements of insert section and receptacle engage the insert section is axially fixed to the receptacle. Hence, upon mutual engagement of fastening elements of the insert section and the receptacle the cartridge holder is axially fixed to the body and vice versa. 
     Furthermore and according to another embodiment the cartridge holder comprises an annular flange section on an outside surface axially confining the insert section in the distal direction. A distal portion of the cartridge holder located distally from the flange section further comprises a diameter that is smaller than the diameter of the insert section. Hence, the cartridge holder may comprise a tapered structure towards the distal end so as to fix and to fasten the cartridge therein. 
     The insert section is axially confined or axially delimited by the radially outwardly extending flange section. The insert section typically comprises or forms a socket portion with an outer diameter that is at least slightly smaller than the outer diameter of the flange section. The receptacle of the body is configured to axially receive the entirety of the insert portion. Hence, the inner diameter of the receptacle matches with the outer diameter of the insert portion so that the insert portion is axially insertable into the receptacle to form the interconnection of cartridge holder and body. The axial extensions of the insert section and of the receptacle mutually match so that the flange section gets in axial abutment with a distally facing axial end face of the sidewall of the body forming the receptacle when the flange section is in a final assembly position inside the receptacle. 
     Moreover, the sidewall of the receptacle comprises a beveled axial end face that is complementary-shaped to a beveled abutment face of the flange portion. The beveled axial end face of the receptacle&#39;s sidewall forms an axial edge or axial end of the receptacle and faces towards the abutment face of the flange portion of the insert section. The beveled axial end face and the beveled abutment face of the receptacle and of the flange portion define an axial abutment of the cartridge holder and the body so as to limit an insert motion of the insert section entering the receptacle. By means of beveled faces the mutual abutment of the sidewall of the receptacle of cartridge holder or body and the correspondingly-shaped flange section of body or cartridge holder inherently provides a tolerance compensation. An axial compression of the beveled surfaces of the flange section and the distal end face of the receptacle leads to a splaying or radial deformation of the sidewalls of the receptacle and/or insert section by way of which a mutual fastening of cartridge holder and body on the basis of positively engaging fastening elements can be facilitated. 
     By reducing the diameter of the cartridge holder from the proximal end towards the distal end, the proximal connecting end of a diameter reduced cartridge holder can be remain substantially unchanged or unaltered compared to a reference cartridge holder configured to accommodate a reference cartridge. By means of diameter reduced distal section the cartridge holder easily provides a radial support and a radial fixing or clamping of a diameter reduced cartridge. 
     According to another embodiment the cartridge holder comprises at least three axially extending inner ribs protruding radially inwardly from an inside surface of the cartridge holder. Said inner ribs are further distributed around the inner circumference of the cartridge holder. Furthermore, they are distributed around the inner circumference of the cartridge holder. It is of particular benefit, when the inner ribs are equidistantly or equiangularly distributed or spaced about the inner circumference of the cartridge holder. The at least three inner ribs may extend substantially parallel in axial direction. They may extend across the flange section. Hence, a proximal end of the inner ribs may be located in the proximal portion of the sleeve while a distal end of the inner ribs may be located in the distal portion of the sleeve. 
     By means of the at least three axially extending inner ribs the flexural strength and mechanical stability of the cartridge holder can be improved. In addition, the inner ribs may provide radial support for the outer circumference of the tubular-shaped cartridge when arranged inside the cartridge holder. In this way the inner ribs effectively act and serve as a radial support structure for the cartridge. Moreover, by means of radially inwardly extending ribs a difference in the outer shape or outer diameter of the proximal portion and the distal portion of the cartridge holder can be effectively reduced. In this way, the difference of the diameter between a standard cartridge and a diameter-reduced cartridge can be compensated by the radial extension of the inner ribs and by the difference in the diameters of the proximal portion and the distal portion of the sleeve. 
     Typically, there are provided more than just three axially extending inner ribs. For instance, there may be provided four, five, six, seven, eight or even more inner ribs typically equally spaced in circumferential direction to provide a multiple radial support for the cartridge positioned inside the cartridge holder. 
     Inner ribs or a constantly reducing inner diameter of the cartridge holder in distal direction further serves to axially guide and to align the cartridge inside the cartridge holder. In this way a well-defined axial guiding and a rather precise alignment of the cartridge along the longitudinal axis of the cartridge holder can be obtained. For a smooth distally directed and repeated displacement of the piston rod in the course of subsequent dose delivery procedures it is of particular benefit when the barrel of the cartridge almost exactly co-aligns with the longitudinal extend of the piston rod. In this way a strain of buckling loads to the piston can be effectively reduced and frictional forces between the piston and the side wall of the barrel of the cartridge can be kept substantially constant over the entire displacement path of the piston inside the barrel. 
     In another aspect the disclosure also relates to a cartridge for an injection device as described above. The cartridge has a tubular-shaped barrel sealed in proximal direction by a piston. The barrel is filled with a liquid medicament to be delivered or to be dispensed by interaction with the injection device. Furthermore, a ratio of an axial length l versus the diameter D 2  of the tubular-shaped body is larger than 5, larger than 8 or larger than 10. Hence, the ratio 
             l     D   ⁢           ⁢   2           
is larger than 5, larger than 8 or larger than 10. Such rather elongated and diameter reduced cartridges are of particular use to provide the intended dosing accuracy or the intended reduction regarding the size of discrete steps of doses to be set and to be dispensed.
 
     According to a further embodiment the filling volume of the cartridge confined by the piston and the sidewall of the barrel is smaller than 2 ml, smaller than 1.8 ml or smaller than 1.6 ml. In particular, the filling volume of the cartridge may be substantially around 1.5 ml. In further embodiments the filling volume of the cartridge may be as small as about 1 ml. 
     The barrel typically comprises a tubularly-shaped vitreous material, such like glass. A size reduction of the barrel and hence of the cartridge is of particular use to increase the robustness of the cartridge against mechanical impact. A cartridge with a reduced diameter compared to the reference cartridge may inherently comprise an increased structural rigidity and mechanical stability. It may be less susceptible to fracture or cracking in the event of mechanical impact. 
     In another aspect the disclosure also relates to a method of increasing the dosing accuracy of an injection device. In a first step there is provided an injection device for delivery of a liquid medicament, which injection device has a housing and a drive mechanism. The drive mechanism comprises a piston rod to advance in a distal direction and to butt against a proximally facing surface of a piston of a cartridge. The injection device further has a dose setting member and a dose dispensing member to set and to dispense a dose of the medicament. Said dose may either be a fixed or predefined dose or the dose may be user-settable, i.e. the size of the dose may be individually modified by the user himself. 
     The drive mechanism is configured to advance the piston rod in distal direction by a distance z 1  to dispense a reference volume V 1  of the medicament when operably engaged with a reference cartridge having a reference diameter D 1 . In a second step the method of increasing the dosing accuracy comprises arranging a cartridge inside the housing instead of the reference cartridge, wherein the cartridge has a tubular-shaped barrel filled with a liquid medicament and wherein said barrel is sealed in proximal direction by a piston displaceably arranged inside the barrel. The cartridge has a diameter D 2  that is smaller than the reference diameter D 1 . In this way setting and dispensing of a dose of the medicament of a volume V 2  is enabled, which volume V 2  is smaller than the volume V 1  when the piston rod is advanced in distal direction by the distance z 1 . 
     The present method implies replacement of a standard cartridge by a cartridge with a reduced diameter while still making use of a substantially unaltered injection device. In particular all mechanically interacting components of the drive mechanism of the injection device can remain unaltered so that the drive mechanism provides an unaltered advancing motion of a piston rod during a dose dispensing procedure. It is only by a well-defined reduction of the diameter of the cartridge that the volume of the medicament dispensed per axial displacement of the piston rod is reduced in a well-defined way. 
     It may be then only required to slightly modify the geometric size of a pressure piece at a distal end of the piston rod and to eventually modify the geometry of the cartridge holder if the diameter reduction of the cartridge also reflects on the outer diameter thereof. In addition and in order to provide a correct and matching dose size indicator a dose indicating member may have to be equipped with a re-sized dose indicating scale. The dose indicating member itself and its mechanical interaction with other components of the drive mechanism can remain unaltered. 
     In this way dosing accuracy can be improved and the step size of discreet dose sizes can be reduced without any substantial modifications to the drive mechanism of the injection device. 
     In a further aspect, the injection device is configured as a manually operable injection device, wherein a force for driving the piston rod in distal direction is entirely provided by a user. The drive mechanism may therefore comprise a dose button or a comparable dose dispensing member that is displaceable in proximal direction with respect to the housing during setting of a dose and which is displaceable in distal direction by the user during dispensing of a dose, thereby transferring a distally directed thrust or a driving torque to the piston rod. 
     A displacement path of the dose button or dose dispensing member is directly related to a displacement path of the piston rod. The drive mechanism may provide a linear transmission between the axial displacement of the dose button or dose dispensing member and the piston rod. Hence, the displacement path of the dose button or dose dispensing member is typically larger than the displacement path of the piston rod. But the distally directed thrust provided by the piston rod and acting on the piston of the cartridge may be larger than a thrust or force required to displace the dose button or the dose dispensing member in distal direction for inducing or conducting the injection process. 
     In another aspect, the injection device comprises only cartridge at a time. The injection device and its drive mechanism is configured to operably engage with only one cartridge. The injection device is hence configured as a single-cartridge device. In particular, the cartridge holder of the injection device only receives a single cartridge filled with a medicament. In order to accommodate a cartridge with a reduced diameter in comparison to a reference cartridge the inner diameter of the cartridge holder is also reduced compared to a reference cartridge holder configured to accommodate a reference cartridge. 
     In a further aspect the drive mechanism comprises a single piston rod to engage with the single cartridge accommodated in the injection device. Hence, the injection device only comprises a single drive mechanism. 
     The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, 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,
 
wherein in a further embodiment 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,
 
wherein in a further embodiment 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,
 
wherein in a further embodiment 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.
 
     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 derivatives 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-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
     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: 
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
     H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2, 
     des Pro36 Exendin-4(1-39), 
     des Pro36 [Asp28] Exendin-4(1-39), 
     des Pro36 [IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or 
     des Pro36 [Asp28] Exendin-4(1-39), 
     des Pro36 [IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), 
     des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39), 
     wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative; 
     or an Exendin-4 derivative of the sequence 
     des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010), 
     H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2, 
     des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
     H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2, 
     des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, 
     H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, 
     des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, 
     H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, 
     H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2; 
     or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative. 
     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. 
     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. 
     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 β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. 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; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (C H ) and the variable region (V H ). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε 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. 
     In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). 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, κ or λ, is present per antibody in mammals. 
     Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity. 
     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 third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, 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. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates. 
     It will be further apparent to those skilled in the art that various modifications and variations can be made to the present disclosure without departing from the spirit and scope of the disclosure. Further, it is to be noted, that any reference numerals used in the appended claims are not to be construed as limiting the scope of the disclosure. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       In the following, an embodiment of the disclosure is described in detail by making reference to the drawings, in which: 
         FIG. 1  schematically illustrates an interface of cartridge holder, cartridge, body and drive mechanism of an injection device according to the present disclosure, 
         FIG. 2  schematically shows a reference cartridge in longitudinal cross section, 
         FIG. 3  shows a diameter reduced cartridge compared to the reference cartridge, 
         FIG. 4  shows a dose indicating sleeve with a reference dose indicating scale, 
         FIG. 5  shows the dose indicating sleeve with a re-sized dose indicating scale, 
         FIG. 6  shows a further embodiment of a dose indicating sleeve with still another re-sized dose indicating scale, 
         FIG. 7  shows one embodiment of the injection device in an exploded view, and 
         FIG. 8  shows the injection device in a longitudinal cross-section. 
     
    
    
     DETAILED DESCRIPTION 
     The injection device  10  as shown in  FIGS. 1, 7 and 8  is configured as a pen-type injector. It comprises an elongated housing  11  extending in a longitudinal or axial direction. Towards a distal direction  1  the injection device  10  comprises a distal housing component denoted as cartridge holder  20 . In the opposite longitudinal direction the housing  11  comprises a second housing component denoted as body  30 . Both housing components, namely cartridge holder  20  and body  30  are of tubular and elongated shape. The cartridge holder  20  is configured to accommodate a cartridge  50  comprising a tubular-shaped barrel  51  and being filled with a liquid medicament  53 . At a distal end the cartridge  50  comprises a pierceable seal  54  typically comprising a pierceable septum of an elastomeric material. 
     At the opposite proximal end the cartridge  50  is sealed by a piston  52  slidably arranged inside the barrel  51  of the cartridge  50 . For dispensing of a dose of the liquid medicament  53  the cartridge holder  20  comprises a threaded socket  19  at its distal end to receive a correspondingly threaded needle assembly with a double-tipped injection needle. A proximal tipped end of the injection needle of the needle assembly, which is presently not illustrated, is configured to pierce the distal seal  54  of the cartridge  50  thereby gaining access to the interior of the cartridge  50 . The distal end of the injection needle is then configured to puncture biological tissue to deliver the medicament. For medicament delivery the piston  52  is to be displaced in distal direction  1  under the action of a distally advancing piston rod  110  of a drive mechanism  5  of the injection device  10 . The drive mechanism  5  is accommodated and fixed in the body  30  of the injection device  10 . 
     The cartridge holder  20  and the body  30  are to be interconnected by means of a positive connection as it is explicitly shown in  FIG. 1 . The cartridge holder  20  comprises a proximal connecting end  21  to irreleasably interconnect with a distal connecting end  31  of the body  30 . The cartridge holder  20  and the body  30  are interconnectable in an interleaved or nested way. In the presently illustrated embodiment the proximal connecting end  21  of the cartridge holder  20  comprises an insert section  22  axially confined in distal direction  1  by a radially outwardly extending flange section  23 . The distal connecting end  31  of the body  30  comprises a receptacle  32  to axially receive the insert section  22  of the cartridge holder  20 . The outer diameter of the insert section  22  exactly matches with the inner diameter of the receptacle  32  so that the insert section  22  can be inserted into the receptacle  32  by means of a sliding motion in proximal direction  2  relative to the body  30 . 
     The sidewall  33  of the receptacle  32  comprises a beveled axial end face  34  that forms a distal end of the body  30 . The flange section  23  on the outer surface  27  of the cartridge holder  20  comprises a complementary-shaped beveled abutment face  24  featuring a geometric shape that matches with the shape of the beveled axial end face  34  of the sidewall  33 . As it is shown in  FIG. 1  the beveled abutment face  24  faces in proximal direction  2  whereas the beveled axial end face  34  faces in distal direction  1 . 
     The flange section  23  divides the cartridge holder  20  into a distal portion  29   a  and a proximal portion  29   b . Distal and proximal portions  29   a ,  29   b  are separated by the flange section  23  having an annular shape and extending around the entire circumference of the cartridge holder  20 . A diameter of the proximal portion  29   a  is smaller than a diameter of the proximal portion  29   b . The proximal portion may coincide with the insert section  22  or may define the insert section  22  of the cartridge holder  20 . In this way, the outer shape of the cartridge holder comprises a radially stepped down portion towards the distal end thereby adapted to the reduced diameter of the cartridge  50  located therein. 
     In order to irreleasably interconnect the cartridge holder  20  and the body  30  in a final assembly or final fastening position F there are provided mutually corresponding fastening elements  35  and  25  on the inside of the receptacle  32  and on the outside of the insert section  22 . The body  30  comprises numerous fastening elements  35  radially inwardly extending from the inside of the sidewall  33  of the receptacle  32 . The fastening elements are configured as snap features or snap protrusions extending radially inwardly from the sidewall  33  of the receptacle  32 . 
     There are provided several e.g. four fastening elements  35  arranged along the inner circumference of the sidewall  33  of the receptacle  32 . The fastening elements  35  are arranged near a flange-like threaded support  36  having a central through opening  37  through which the threaded piston rod  110  extends. The support  36  extends substantially perpendicular to the axial direction and confines the receptacle  32  in proximal direction  2 . The support  36  effectively divides the body  30  into a distal interface section formed by the receptacle  32  and a proximal section to accommodate the mechanical components of the drive mechanism  5 . 
     The fastening elements  35  provided on the inside of the sidewall  33  of the receptacle  32  comprise radially inwardly extending protrusions having a beveled section  35   a  facing in distal direction  1  and extending radially inwardly from the sidewall  33  to the crest of the protruding fastening element  35  to axially abut with a complementary shaped recessed fastening element  25  of the cartridge holder  20 . The fastening element  25  comprises a radially extending recessed portion terminated in proximal direction  2  by a radially extending abutment section to axially abut with the fastening element  35 . When the cartridge holder  20  and the body  30  are arranged in a final assembly configuration or fastening position F an axial interlock  6  between the fastening elements  25 ,  35  and hence between the cartridge holder  20  and the body  30  is established. 
     The proximal end of the cartridge holder  20  comprises a beveled edge  38  at its outer circumference that engages with the beveled section  35   a  of the protrusion  35  as the insert section  22  is urged in proximal direction  2  into the receptacle  32 . The beveled edge  38  is at least located in an angular position on the proximal end of the insert section  22  that matches with an angular position of the respective fastening element  25 . The beveled edge facilitates mutual assembly and induces an elastic deformation of both, the sidewall  33  of the receptacle  32  and of the insert section  22 . The mutually corresponding fastening elements  25 ,  35  of cartridge holder  20  and body  30  are subject to tensile stress and to compressive stress during insertion of the insert section  22  into the receptacle  32 , respectively. 
     Since the outer diameter of the insert section  22  matches with the inner diameter of the receptacle  32  an insert and fastening procedure requires elastic deformation of the housing component&#39;s cartridge holder  20  and body  30  due to the shape of the mutually corresponding fastening elements  25 ,  35 . The housing components, cartridge holder  20  and body  30  are typically single pieced and are made by way of injection molding of a thermoplastic material. 
     During mutual assembly, the receptacle  32  and its sidewall  33  experiences a radially outwardly directed load or stress leading to tensile forces in circumferential direction inside the sidewall  33 . Correspondingly, the insert section  22  experiences a radially inwardly directed pressure leading to compressive stress in circumferential direction inside the insert section  22 . Since thermoplastic materials are more sensitive to tensile than to compressive stress it is of particular benefit, that weakening recessed structures are provided in the insert section of the cartridge holder  20 . The radially inwardly extending protrusions of the fastening elements  35  of the body provide a structural reinforcement so that the sidewall  33  in the region of the fastening elements  35  is less susceptible in response to tensile loads that may arise during an assembly procedure. 
     The recessed fastening elements  25  provided in the insert section  22  of the cartridge holder  20  are configured as blind holes or pocket holes and do not completely intersect the wall structure of the insert section  22 . Hence, a radial depth D of the recesses  25  is smaller than the thickness of the sidewall  26  of the insert section  22 . Making use blind recesses or pocket holes instead of through openings also enhances and improves the mechanical stability and resistivity against mechanical loads present on the respective fastening element  25  during assembly. As a result a rather rigid, tight and long-term mechanically stable irreleasable connection of cartridge holder  20  and body  30  is provided. 
     As it is further indicated in  FIG. 1  there are also provided inner ribs  140  protruding radially inwardly from an inside surface  28  of the cartridge holder  20 . The inner ribs  140  also extend in axial direction. They comprise a beveled proximal end  146 . There may be provided numerous, e.g. 5, 6 or even 8 or 10 inner ribs  140  along the inner circumference of the inside surface  28  of the cartridge holder  20 . The inner ribs  140  may equidistantly or equiangularly spaced in circumferential or tangential direction so as to provide a radial support for the cartridge  50  arranged inside the sleeve  29 . 
     By way of the radially inwardly extending inner ribs  140  any differences of an outer diameter of the diameter reduced cartridge  50  and an inner diameter of the cartridge holder  20  can be effectively compensated. By means of the beveled proximal ends  146  insertion of the cartridge  50  from a proximal end in distal direction  1  and into the hollow cartridge holder  20  can be facilitated. Also here a mutual radial centering and mutual radial displacement of the cartridge  50  relative to the cartridge holder  20  is obtained as the distal end of the cartridge  50  engages and slides along the beveled proximal ends  146  of the inner ribs  140 . 
     In  FIGS. 2 and 3  two different cartridges, namely a reference cartridge  150  and a cartridge  50  in accordance with the present disclosure are illustrated, respectively. Both cartridges  50 ,  150  comprise a tubular-shaped barrel  51 ,  151  extending in a longitudinal direction that coincides with a cylindrical symmetry axis of the barrels  51 ,  151 . In an axial distal direction  1  the barrels  51 ,  151  are sealed by a distal seal  54 ,  154 , typically comprising a pierceable septum fixed to a diameter reduced neck portion  56 ,  156 . Typically, the pierceable seal  54 ,  154  is fixed to a distal end of the barrel  51 ,  151  by means of a crimped metal cap typically made of aluminum. 
     As it is further illustrated in  FIGS. 2 and 3  the pierceable seal  54 ,  154  can be axially penetrated by a needle  58 . The needle  58  is typically part of a needle assembly comprising a sleeve-shaped needle hub having a fastening structure that is correspondingly-shaped to the threaded socket  19  of the cartridge holder  20 . The proximal end of the needle  58  is insertable through a central through opening of the cartridge holder  20  co-aligned with the pierceable sealing  54 ,  154 . In this way the proximal tipped end  59  of the needle  58  can be positioned inside the interior volume of the cartridge  50 ,  150 , thereby providing a fluid channel for the liquid medicament  53  located inside the cartridge  50 ,  150 . 
     Towards their proximal end the cartridges  50 ,  150  are sealed by means of a piston  52 ,  152  typically made of an elastomeric material, such like a natural or synthetic rubber. The piston  52 ,  152  serves as a proximal seal of the barrel  51 ,  151 . It is displaceable in distal direction  1  under the action of the distally advancing piston rod  110 . For injecting of a dose of a predefined size, for instance for injecting of a dose of a reference volume V 1  the piston  152  is displaced in distal direction  1  by a distance z 1  as shown in  FIG. 2 . The reference volume V 1  is determined by the inner reference diameter D 1  of the reference cartridge  150  and the axial displacement distance z 1 . Hence, the reference volume 
     
       
         
           
             
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     The drive mechanism  5  of the injection device  10  is configured to set and to dispense a reference volume V 1  of the medicament  53 . Hence, for dispensing of the reference volume V 1  the drive mechanism  5  is configured to displace the piston rod  110  by a distance z 1 . 
     According to the present disclosure the drive mechanism  5  and hence almost the entire injection device  10  configured and designed for a reference cartridge  150  is now used with a different cartridge  50  as shown in  FIG. 3 . In comparison to the reference cartridge  150  the cartridge  50  is also of tubular shape but comprises an inner diameter D 2  that is smaller than the reference diameter D 1 . For injecting of a smaller dose compared to the reference volume V 1  also here a correspondingly size reduced piston  51  is to be displaced in distal direction by the same distance z 1 . Due to the reduced diameter D 2  compared to the reference diameter D 1  the dispensed volume V 2  is smaller than the reference volume V 1 . The ejected volume V 2  calculates as 
     
       
         
           
             
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     In this way a size reduced dose of the medicament  53  can be dispensed and injected via the injection needle  58  by making use of one and the same drive mechanism  5 . There may be situations and configurations of the drive mechanism  5 , where the smallest discrete displacement z 1  of the piston rod  110  corresponds or defines a minimum reference volume V 1  in the range of 1 IU. By reducing the diameter of the cartridge from D 1  to D 2  the minimum dispensable size of a dose to be dispensed can be reduced to values smaller than 1 IU. If for instance the area of the inner cross-section of the reference cartridge  150  is divided by 2 with the cartridge  50  the minimum dose size to be dispensed by means of the drive mechanism  5  will be divided by 2. A minimum dose size as well as a discrete step size of selectable doses may then equal e.g. 0.5 IU. 
     As it is further shown in  FIG. 3 , the diameter reduced cartridge  50  comprises a ratio of an axial length l over the diameter D 2  that is larger than 5, larger than 8 or even larger than 10. Moreover, a total filling volume confined by the piston  52  and the sidewall of the barrel  51  is typically smaller than 2 ml, smaller than 1.8 ml or smaller than 1.6 ml. It may be as small as 1.5 ml or as small as 1 ml. Reducing the diameter of the barrel  51  compared to the reference barrel  151  is further beneficial in terms of a static or dynamic friction between the piston  52  and the inside facing sidewall of the barrel  51 . In effect, the total sealing surface on the outer circumference of the piston  52  is reduced compared to the piston  152 . In this way, static as well as dynamic friction between the piston  52  and the barrel  51  is typically smaller than dynamic and static friction of the piston  152  and the barrel  151 . In effect, dispensing forces that have to be applied to a proximal thrust receiving surface  55  of the piston  52  can be effectively reduced. This is particularly beneficial to increase a handling comfort and ease of use of the injection device. 
     In  FIGS. 7 and 8  one embodiment of an injection device  10  is illustrated comprising a drive mechanism  5  that has been commercially distributed over years and which is described in detail in the following documents: WO 2004/078239 A1, WO 2004/078240 A2 and WO 2004/078241 A1. The injection device  10  is of disposable type. Hence, when the medicament  53  contained in the cartridge  50  has been dispensed or used up the entire device  10  is intended to be discarded. Therefore, the cartridge holder  20  to accommodate the cartridge  50  is irreleasably connectable to the proximal housing component, hence to the body  30 . A cap  40  to cover the cartridge holder  20  extending distally from the body  30  is releasably interconnectable with the cartridge holder  20 . 
     The drive mechanism  5  comprises numerous mechanically interacting components. The flange like support  36  of the body  30  comprises a threaded through opening  37  threadedly engaged with a distal thread  112  of the piston rod  110 . The distal end of the piston rod  110  comprises a bearing  115  on which a pressure foot  116  is free to rotate with the longitudinal axis of the piston rod  110  as an axis of rotation. The pressure foot  116  is configured to axially abut against the proximally facing thrust receiving surface of the piston  52  of the cartridge  50 . During a dispensing action the piston rod  110  rotates relative to the body  30  thereby experiencing a distally directed advancing motion relative to the body  30  and hence relative to the barrel  51  of the cartridge  50 . As a consequence, the piston  52  of the cartridge  50  is displaced in distal direction by a well-defined distance due to the threaded engagement of the piston rod  110  with the body  30 . 
     The piston rod  110  is further provided with a second thread  114  at its proximal end. The distal thread  112  and the proximal thread  114  are oppositely handed. 
     There is further provided a drive sleeve  100  having a hollow interior to receive the piston rod  20 . The drive sleeve  100  comprises an inner thread threadedly engaged with the proximal thread  114  of the piston rod  110 . Moreover, the drive sleeve  100  comprises an outer threaded section  105  at its distal end. The threaded section is axially confined between a distal flange portion  102  and another flange portion  104  located at a predefined axial distance from the distal flange portion  102 . Between the two flange portions  102 ,  104  there is provided a last dose limiting member  106  in form of a semi-circular nut having an internal thread matching the threaded section  105  of the drive sleeve  100 . 
     The last dose limiting member  106  further comprises a radial recess or protrusion at its outer circumference to engage with a complementary-shaped recess or protrusion at an inside of the sidewall  33  of the body  30 . In this way the last dose limiting member  106  is splined to the body  30 . A rotation of the drive sleeve  100  in a dose incrementing or clockwise direction during consecutive dose setting procedures leads to an accumulative axial displacement of the last dose limiting member  106  relative to the drive sleeve  100 . There is further provided an annular spring  96  that is in axial abutment with a proximally facing surface of the flange portion  104 . Moreover, there is provided a tubular-shaped clutch member  90 . At a first end the clutch member  90  is provided with a series of circumferentially directed saw teeth. Towards a second opposite end of the clutch member  90  there is located a radially inwardly directed flange. 
     Furthermore, there is provided a dose dial or dose indicating sleeve  80 . The dose indicating sleeve  80  is provided outside of the spring  96  and the clutch member  90  and is located radially inward of the body  30 . A helical groove  81  is provided about an outer surface of the dose indicating sleeve  80 . The body  30  is provided with a window  44  through which a part of the outer surface of the dose indicating sleeve  80  can be seen. The body  30  is further provided with a helical rib at an inside sidewall portion of an insert piece  70 , which helical rib is to be seated in the helical groove  81  of the dose indicating sleeve  80 . The tubular shaped insert piece  70  is inserted into the proximal end of the body  30 . It is rotationally and axially fixed to the body  30 . There are provided first and second stops on the body  30  to limit a dose setting procedure during which the dose indicating sleeve  80  is rotated in a helical motion relative to the body  30 . 
     A dose dial grip  66  is disposed about an outer surface of the proximal end of the dose indicating sleeve  80 . An outer diameter of the dose dial  66  typically corresponds to the outer diameter of the body  30 . The dose dial  66  is secured to the dose indicating sleeve  80  to prevent relative movement therebetween. The dose dial  66  is provided with a central opening. 
     Furthermore, a dose button  60  of generally T-shape is provided at a proximal end of the injection device  10 . A stem  62  of the dose button  60  extends through the opening in the dose dial  66  through an inner diameter of extensions of the drive sleeve  100  and into a receiving recess at the proximal end of the piston rod  110 . The stem  62  is retained for limited axial movement in the drive sleeve  100  and against rotation with respect thereto. A head  64  of the dose button  60  is generally circular. A skirt extends from a periphery of the head  64  and is further adapted to be seated in a proximally accessible annular recess of the dose dial  66 . 
     To dial a dose a user rotates the dose dial  66 . With the spring  96  also acting as a clicker and the clutch member  90  engaged, the drive sleeve  100  the spring or clicker  96 , the clutch member  90  and the dose indicating sleeve  80  rotate with the dose dial  66 . Audible and tactile feedback of the dose being dialed is provided by the spring  96  and by the clutch member  90 . Torque is transmitted through saw teeth between the spring  96  and the clutch member  90 . The helical groove  81  on the dose indicating sleeve  80  and a helical groove in the drive sleeve  100  have the same lead. This allows the dose indicating sleeve  80  to extend from the body  30  and the drive sleeve  100  to climb the piston rod  110  at the same rate. At a limit of travel a radial stop on the dose indicating sleeve  80  engages either with a first stop or a second stop provided on the body  30  to prevent further movement. Rotation of the piston rod  110  is prevented due to the opposing directions of the overall and driven threads on the piston rod  110 . 
     The last dose limiting member  106  keyed to the body is advanced along the threaded section  105  by the rotation of the drive sleeve  100 . When a final dose dispensed position is reached, a radial stop formed on a surface of the last dose limiting member  106  abuts a radial stop on the flange portion  104  of the drive sleeve  100 , preventing both, the last dose limiting member  106  and the drive sleeve  100  from rotating further. 
     Should a user inadvertently dial beyond the desired dosage, the pen-injector  10  allows the dosage to be dialed down without dispense of the medicament from the cartridge  50 . For this the dose dial  66  is simply counter-rotated. This causes the system to act in reverse. A flexible arm of the spring or clicker  96  then acts as a ratchet preventing the spring  96  from rotating. The torque transmitted through the clutch member  90  causes the saw teeth to ride over one another to create the clicks corresponding to dialed dose reduction. Typically, the saw teeth are so disposed that a circumferential extent of each saw tooth corresponds to a unit dose. 
     When the desired dose has been dialed the user may simply dispense the set dose by depressing the dose button  60 . This displaces the clutch member  90  axially with respect to the dose indicating sleeve  80  causing dog teeth thereof to disengage. However, the clutch member  90  remains keyed in rotation to the drive sleeve  100 . The dose indicating sleeve  80  and the dose dial  66  are now free to rotate in accordance with the helical groove  81 . 
     The axial movement deforms the flexible arm of the spring  96  to ensure the saw teeth cannot be overhauled during dispense. This prevents the drive sleeve  100  from rotating with respect to the body  30  though it is still free to move axially with respect thereto. The deformation is subsequently used to urge the spring  96  and the clutch member  90  back along the drive sleeve  100  to restore the connection between the clutch member  90  and the dose indicating sleeve  80  when the distally directed dispensing pressure is removed from the dose button  60 . 
     The longitudinal axial movement of the drive sleeve  100  causes the piston rod  110  to rotate through the through opening  37  of the support  36  of the body, thereby to advance the piston  52  in the cartridge  50 . Once the dialed dose has been dispensed, the dose indicating sleeve  80  is prevented from further rotation by contact of a plurality of members extending from the dose dial  66  with a corresponding plurality of stops. A zero dose position is finally determined by the abutment of one of axially extending edges of members of the dose indicating sleeve  80  with a corresponding stop of the body  30 . 
     The drive mechanism  5  as described above is only exemplary for one of a plurality of differently configured drive mechanisms that are generally implementable in a disposable pen-injector. Hence, one concept of the present disclosure, namely to modify, in particular, to reduce the diameter of a cartridge by means of a respective cartridge replacement is generally implementable with a large variety and with almost all types of injection devices comprising a cartridge filled with a medicament and being sealed by a piston for expelling of a dose of the medicament. 
     When replacing a standard or reference cartridge  150  by a diameter reduced cartridge  50  all mechanically interacting components of the drive mechanism  5  may remain unchanged or unmodified. This is also valid for the dimensions and the geometry of the dose indicating member  80 , presently configured as a dose indicating sleeve  88 . In  FIG. 4 , one example of a dose indicating sleeve  88  provided with a reference dose indicating scale  182  is shown in comparison to the location of the dose indicating window  44  of the body  30 . As can be seen from  FIG. 4 , the dose indicating sleeve  88  comprises a helical structure on its outer circumference having the shape and form of a helical groove  81 . Accordingly, the outer circumference of the tubular-shaped dose indicating sleeve  88  is provided with a reference dose indicating scale  182  with consecutive integer numbers 1, 2, 3, 4 and so on representing integer IU. 
     When making use of a diameter reduced cartridge  50  the reference dose indicating scale  182  on the outer circumference of the dose indicating sleeve  88  has to be replaced by a resized dose indicating scale  82  or  84  as shown for instance in  FIGS. 5 and 6 , respectively. The dose indicating scale  82  as shown in  FIG. 5  is applicable when the inner cross-section of the cartridge  50  is reduced by a factor 2 compared to the inner cross-section of the reference cartridge  150 . Consequently, the numbers of the reference dose indicating scale are divided by the factor 2. The dose indicating scale  82  of the dose indicating sleeve  88  is configured to show a sequence of numbers such like 0.1, 1, 1.5, 2, and so on. 
     In  FIG. 6  another resized dose indicating scale  84  is presented that is applicable when the inner cross-section of the reference cartridge  150  is divided by a factor 10. Such a resized dose indicating scale  84  on the outer circumference of a geometrically unmodified dose indicating sleeve  88  is provided a sequence of consecutive numbers such as 0.1, 0.2, 0.3, 0.4 and so on. 
     LIST OF REFERENCE NUMBERS 
     
         
           1  distal direction 
           2  proximal direction 
           5  drive mechanism 
           6  axial interlock 
           10  injection device 
           11  housing 
           19  threaded socket 
           20  cartridge holder 
           21  proximal connecting end 
           22  insert section 
           23  flange section 
           24  abutment face
       fastening element   
     
           26  sidewall 
           27  outside surface 
           28  inside surface 
           29   a  distal portion 
           29   b  proximal portion 
           30  body 
           31  distal connecting end 
           32  receptacle 
           33  sidewall 
           34  end face 
           35  fastening element 
           35   a  beveled section 
           36  support 
           37  through opening 
           38  beveled edge 
           40  cap 
           44  window 
           50  cartridge 
           51  barrel 
           52  piston 
           53  medicament 
           54  distal seal 
           55  surface 
           56  neck portion 
           58  needle 
           59  proximal end 
           60  dose button 
           62  stem 
           64  head 
           66  dose dial 
           70  insert piece 
           80  dose indicating member 
           81  helical groove 
           82  dose indicating scale 
           84  dose indicating scale 
           88  dose indicating sleeve 
           90  clutch member 
           96  spring 
           100  drive sleeve 
           102  distal flange portion 
           104  flange portion 
           105  threaded section 
           106  last dose limiting member 
           110  piston rod 
           112  distal thread 
           114  proximal thread 
           115  bearing 
           116  pressure foot 
           150  cartridge 
           151  barrel 
           152  piston 
           154  distal seal 
           156  neck portion 
           182  reference dose indicating scale