Patent Publication Number: US-2023146367-A1

Title: Patch for Use with an Injector Device

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is the national stage entry of International Patent Application No. PCT/EP2021/058493, filed on Mar. 31, 2021, and claims priority to Application No. EP 20315111.3, filed on Apr. 3, 2020, the disclosures of which are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates to a patch for placement on skin and for use with an injector device for a medicament. 
     BACKGROUND 
     Injector devices, for example auto-injectors, typically have a sealed container of medicament, and a needle for injection of the medicament into a patient. A plunger or piston within the medicament container can be moved into the medicament container to dispense medicament through the needle for injection to a patient. 
     Some patients may experience discomfort when an injection needle is inserted into the skin at the injection site or during delivery of the medicament. The level of discomfort may vary depending on numerous factors, some relating to the medicament such as the temperature, volume and viscosity of the medicament, some relating to the injector device, such as size and insertion depth of the injection needle, or injection delivery time. Some patients may also feel uncomfortable with the anticipation of the injection process and the feel and sight of an injection needle before and during insertion into the skin. 
     SUMMARY 
     According to the present disclosure, there is provided a patch for placement on the skin and for use with an injector device, the patch comprising a first layer on a first side of the patch, a second layer on a second side of the patch opposite to the first side, a sealed fluid reservoir between the first and second layers, a fluid contained within the fluid reservoir, and a moveable rupturing element configured to pierce and rupture the fluid reservoir to allow release of the fluid out of the fluid reservoir. The patch may also comprise an aperture extending at least partially through the patch to receive an injection needle of an injector device. 
     The fluid reservoir may be defined by the first and second layers. The first and second layers may be separate elements bonded, welded, or otherwise connected together, or the first and second layers may be integrally formed. 
     The rupturing element may be moveable between an initial position and an activated position in which the rupturing element ruptures the fluid reservoir. 
     A biasing arrangement may be configured to bias the rupturing element into the initial position. This may advantageously help towards preventing unintended rupturing of the fluid reservoir. 
     The rupturing element may be disposed within the fluid reservoir. This may advantageously help towards providing a simpler patch to use, and/or avoid unintended contact with the components of the patch. Alternatively, the rupturing element may be disposed outside the fluid reservoir. The rupturing element may be a separate component to the first and second layers. This may advantageously help towards ease and cost reduction of manufacture. 
     The patch may comprise a support member. The rupturing element may be moveably mounted to the support member. This may advantageously help towards controlling relative movement of the rupturing element and support member during use. This may advantageously also help towards supporting an injection device in use with the patch. 
     The rupturing element may be integrally formed with the one of the first and second layers. This may advantageously help towards ease and reduced cost of manufacture. 
     The injection aperture may extend partially through the patch, and may extend through only one of the first and/or second layers of the patch. Alternatively, the injection aperture may extend entirely through the patch, such as through both the first and second layers of the patch. The injection aperture may be configured to receive an injection needle of an injector device, and/or to receive a portion of a body or housing of an injector device. The injection aperture may comprise an abutment or stepped portion such that part of an injector device may be received in the injection aperture until the injector device reaches and contacts the abutment or stepped portion. This may advantageously help towards guiding use of an injection device with the patch. 
     At least one of the first and second layers may comprises a piercable membrane which can be pierced by the rupturing element to rupture the fluid reservoir. 
     The piercable membrane may include one or more regions of weakness at which the piercable membrane is more easily ruptured than at other regions of the piercable membrane. This may advantageously help towards ensuring effective rupturing of the reservoir in use. 
     The at least one region of weakness may comprise a region of reduced thickness in the piercable membrane. 
     The support element and rupturing element may surround the injection aperture. The injection aperture may be formed in one or both of the first and second layers. The injection aperture may be formed through the piercable membrane. This may advantageously help to ensure an injection needle of the injection device enters the skin. Alternatively, the piercable membrane may extend across the injection aperture. In such an embodiment, an injection needle of an injector device may pierce the piercable membrane during use of the patch. This may advantageously help towards ease of reduced cost of manufacture. 
     The injection aperture may extend at least partially through the patch and may comprise an axis. The axis may be defined centrally within the injection aperture. The injection aperture may be disposed substantially centrally on the patch. The support member and rupturing element may be moveable relative to each other in a direction of the injection aperture axis. This may advantageously facilitate movement of the injector device effecting relative movement of the support member and rupturing element. 
     A portion of the patch may comprise a skin-contacting surface, and the patch may further comprise a protective material layer removably adhered over the skin-contacting surface and which is intended to be removed before use of the patch. This may advantageously help protect the patch from external damage before use, and/or prevent contamination of the patch before use. 
     A portion of the patch may comprise a skin-contacting surface, and the skin-contacting surface may comprise an adhesive layer to secure the patch to the skin of a patient. This may advantageously help to secure the patch on the skin before and during use. 
     The patch may include a locking mechanism associated with the rupturing element and configured such that in a locked condition of the locking mechanism, the rupturing element is prevented from being moveable to rupture the fluid reservoir, and in an unlocked condition of the locking mechanism, to rupturing element is moveable to be able to rupture the fluid reservoir. This may advantageously help towards preventing unintended activation of the patch. 
     The locking mechanism may include a release element which is engagable by an injector device, and operable to move the locking mechanism into the unlocked condition when an injector device is pressed against the release element. This may advantageously help towards ensuring the patch is only activated once an injection device is in contact and/or engaged with the patch. 
     The patch may include a stop associated with the rupturing element and configured to restrict movement of the rupturing element beyond a predetermined range of movement. This may advantageously help towards preventing the rupturing element contacting or pressing onto the skin more than an intended degree during use, and to prevent or minimise discomfort in use. 
     The rupturing element may comprise a circular or substantially circular component, such as a circular or elliptical component. The rupturing element may surround a portion of the support member. This may advantageously help towards ease of manufacture and reliability of operation in use, and/or assist in guiding relative movement of the rupturing element and support member during use. 
     The rupturing element may comprise one or more pointed protrusions configured to pierce a component which defines the fluid reservoir in order to rupture the fluid reservoir. 
     The support member may comprise a substantially planar component, and/or a substantially planar portion, such as a plate or flange portion. The substantially planar portion may extend substantially parallel to one or both of the first and second layers, such as the membrane. This may advantageously help to support the respective layer(s). 
     The patch may comprise one or more fluid passages configured to allow fluid from the reservoir to pass towards the skin, and advantageously configured to allow fluid to flow into contact with the skin. 
     The biasing arrangement may comprise one or more biasing members. The biasing member(s) may be provided on the support member and/or on the rupturing element. The biasing member(s) may be formed integrally with the support member and/or rupturing element, or may be separate component(s) connected to the support member and/or rupturing element, such as by bonding, welding or other means of mechanical fastening. The biasing member(s) may comprise a resilient component and may comprise spring arm(s) and/or coil spring(s). 
     The fluid in the fluid reservoir may comprise a liquid. The fluid in the fluid reservoir may comprise one of an antiseptic, analgesic, anaesthetic, or sterilising agent. The fluid in the fluid reservoir may comprise a liquid which does not include a chemically or pharmacologically active substance. 
     The patch may include a temperature varying arrangement configured to be activated in use of the patch to apply a heating or cooling sensation to the skin of a patient. 
     The patch may further comprise a thermochromic element configured to display a plurality of colours dependent on a temperature of the patch. 
     Also provided is a system comprising a patch as described above, and an injector device for use with the patch, wherein the injector device comprises a housing configured to receive a container of medicament. 
     The injector device may comprise a container of medicament received within the housing. 
     Also provided is a method of use of a patch for placement on the skin and for use with an injector device, the patch comprising a first layer on a first side of the patch, a second layer on a second side of the patch opposite to the first side, a sealed fluid reservoir between the first and second layers, a fluid contained within the fluid reservoir, the method comprising moving a moveable rupturing element to rupture the fluid reservoir to allow release of the fluid out of the fluid reservoir. 
     The method may comprise placement of the patch on the skin. The method may comprise engaging an injector device with the patch, and movement of the moveable rupturing element by means of the injector device engaging with the patch. The method may comprise applying pressure on the patch via the injector device to move the moveable rupturing element. 
     The method may comprise moving the rupturing element between an initial position and an activated position in which the rupturing element ruptures the fluid reservoir. 
     The method may comprise the support member and rupturing element moving relative to each other, and such movement may be in a direction of the injection aperture axis. 
     The method may comprise removing a protective material layer adhered over the skin-contacting surface before use of the patch. 
     The method may comprise securing the patch to the skin with an adhesive layer on a skin contacting surface of the patch. 
     The method may comprise moving a locking mechanism associated with the rupturing element from a locked condition, in which the rupturing element is prevented from being moveable to rupture the fluid reservoir, to an unlocked condition of the locking mechanism, in which the rupturing element is moveable to be able to rupture the fluid reservoir. 
     The method may comprise engaging a release element by an injector device, to move the locking mechanism into the unlocked condition when an injector device is pressed against the release element. 
     These and other aspects of the disclosure will be apparent from and elucidated with reference to the embodiments described hereinafter. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       Embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which: 
         FIG.  1 A  is a schematic side view of an injector device including a removable cap; 
         FIG.  1 B  is a schematic side view of the injector device of  FIG.  1 A , with the cap removed from the housing; 
         FIG.  2    is a perspective view of an injection patch of a first embodiment; 
         FIG.  3    is a side view of the injection patch of  FIG.  2    in place on a patient&#39;s skin and showing an injector device for use with the injection patch; 
         FIG.  4    is a cross-sectional view of the injection patch of  FIG.  2    in an initial position; 
         FIG.  5    is a cross-sectional view of the injection patch of  FIG.  2    in an activated position; 
         FIG.  6    is an exploded perspective view of the injection patch of  FIG.  2    showing the component parts thereof; 
         FIG.  7    is a cross-sectional view of an injection patch of a second embodiment in an initial position; 
         FIG.  8    is a cross-sectional view of the injection patch of  FIG.  7    in an activated position; 
         FIG.  9    is an exploded perspective view of the injection patch of  FIGS.  7  and  8    showing the component parts thereof; 
         FIG.  10    is a cross-sectional view of an injection patch of a third embodiment in an initial position; 
         FIG.  11    is a cross-sectional view of the injection patch of  FIG.  10    in an activated position; 
         FIG.  12    is an enlarged partial cross-sectional view of an injection patch of a fourth embodiment in a locked condition; and 
         FIG.  13    is an enlarged partial cross-sectional view of the injection patch of  FIG.  12    in an unlocked condition. 
     
    
    
     DETAILED DESCRIPTION 
     A drug delivery device, as described herein, may be configured to inject a medicament into a patient. For example, delivery could be sub-cutaneous, intra-muscular, or intravenous. Such a device could be operated by a patient or care-giver, such as a nurse or physician, and can include various types of safety syringe, pen-injector, or auto-injector. The device can include a cartridge-based system that requires piercing a sealed ampule before use. Volumes of medicament delivered with these various devices can range from about 0.5 ml to about 3 ml. Another device can include a large volume device (“LVD”) or patch pump, configured to adhere to a patient&#39;s skin for a period of time (e.g., about 5, 15, 30, 60, or 120 minutes) to deliver a “large” volume of medicament (typically about 2 ml to about 50 ml). Yet another device may comprise a pre-filled syringe within a housing of the device. The syringe may be fixed within the housing or may be moveable within the housing, for example from a retracted position to an operation extended position. 
     In combination with a specific medicament, the presently described devices may also be customized in order to operate within required specifications. For example, the device may be customized to inject a medicament within a certain time period (e.g., about 3 to about 20 seconds for auto-injectors, and about 10 minutes to about 60 minutes for an LVD). Other specifications can include a low or minimal level of discomfort, or to certain conditions related to human factors, shelf-life, expiry, biocompatibility, environmental considerations, etc. Such variations can arise due to various factors, such as, for example, a drug ranging in viscosity from about 3 cP to about 50 cP. Consequently, a drug delivery device will often include a hollow needle ranging from about 25 to about 31 Gauge in size. Common sizes are 17 and 29 Gauge. 
     The delivery devices described herein can also include one or more automated functions. For example, one or more of combining the needle and cartridge, needle insertion, medicament injection, and needle retraction can be automated. Energy for one or more automation steps can be provided by one or more energy sources. Energy sources can include, for example, mechanical, pneumatic, chemical, or electrical energy. For example, mechanical energy sources can include springs, levers, elastomers, or other mechanical mechanisms to store or release energy. One or more energy sources can be combined into a single device. Devices can further include gears, valves, or other mechanisms to convert energy into movement of one or more components of a device. 
     The one or more automated functions of an auto-injector may each be activated via an activation mechanism. Such an activation mechanism can include an actuator, for example, one or more of a button, a lever, a needle sleeve, or other activation component. Activation of an automated function may be a one-step or multi-step process. That is, a user may need to activate one or more activation components in order to cause the automated function. For example, in a one-step process, a user may depress a needle sleeve against their body in order to cause injection of a medicament. Other devices may require a multi-step activation of an automated function. For example, a user may be required to depress a button and retract a needle shield in order to cause injection. 
     In addition, activation of one automated function may activate one or more subsequent automated functions, thereby forming an activation sequence. For example, activation of a first automated function may activate at least two of combining the needle and cartridge, needle insertion, medicament injection, and needle retraction. Some devices may also require a specific sequence of steps to cause the one or more automated functions to occur. Other devices may operate with a sequence of independent steps. 
     Some delivery devices can include one or more functions of a safety syringe, pen-injector, or auto-injector. For example, a delivery device could include a mechanical energy source configured to automatically inject a medicament (as typically found in an auto-injector) and a dose setting mechanism (as typically found in a pen-injector). 
     An exemplary drug delivery device  10  is shown in  FIGS.  1 A and  1 B . Device  10 , as described above, is configured to inject a medicament into a patient&#39;s body. Device  10  includes a housing  11  which typically contains a cartridge or pre-filled syringe that defines a reservoir containing the medicament to be injected, and the components required to facilitate one or more steps of the delivery process. 
     The device  10  can also include a cap  12  that can be detachably mounted to the housing  11 . Typically, a user must remove cap  12  from housing  11  before device  10  can be operated. 
     As shown, housing  11  is substantially cylindrical and has a substantially constant diameter along the longitudinal axis A-A. The housing  11  has a distal region D and a proximal region P. 
     The term “distal” refers to a location that is relatively closer to a site of injection, and the term “proximal” refers to a location that is relatively further away from the injection site. 
     Device  10  can also include a needle sleeve  19  coupled to housing  11  to permit movement of sleeve  19  relative to housing  11 . For example, sleeve  19  can move in a longitudinal direction parallel to longitudinal axis A-A. Specifically, movement of sleeve  19  in a proximal direction can permit a needle  17  to extend from distal region D of housing  11 . 
     Insertion of needle  17  can occur via several mechanisms. For example, needle  17  may be fixedly located relative to housing  11  and initially be located within an extended needle sleeve  19 . Proximal movement of sleeve  19  by placing a distal end of sleeve  19  against a patient&#39;s body and moving housing  11  in a distal direction will uncover the distal end of needle  17 . Such relative movement allows the distal end of needle  17  to extend into the patient&#39;s body. Such insertion is termed “manual” insertion as needle  17  is manually inserted via the patient&#39;s manual movement of housing  11  relative to sleeve  19 . 
     Another form of insertion is “automated”, whereby needle  17  moves relative to housing  11 . Such insertion can be triggered by movement of sleeve  19  or by another form of activation, such as, for example, a button  13 . As shown in  FIGS.  1 A and  1 B , button  13  is located at a proximal end of housing  11 . However, in other embodiments, button  13  could be located on a side of housing  11 . 
     Other manual or automated features can include drug injection or needle retraction, or both. Injection is the process by which a bung or piston  14  is moved from a proximal location to a more distal location within the reservoir of the cartridge  18  in order to force a medicament from the cartridge  18  through needle  17 . In some embodiments, a drive spring (not shown) is under compression before device  10  is activated. A proximal end of the drive spring can be fixed within proximal region P of housing  11 , and a distal end of the drive spring can be configured to apply a compressive force to a proximal surface of piston  14 . Following activation, at least part of the energy stored in the drive spring can be applied to the proximal surface of piston  14 . This compressive force can act on piston  14  to move it in a distal direction. Such distal movement acts to compress the liquid medicament within the cartridge  18 , forcing it out of needle  17 . 
     Following injection, needle  17  can be retracted within sleeve  19  or housing  11 . Retraction can occur when sleeve  19  moves distally as a user removes device  10  from a patient&#39;s body. This can occur as needle  17  remains fixedly located relative to housing  11 . Once a distal end of sleeve  19  has moved past a distal end of needle  17 , and needle  17  is covered, sleeve  19  can be locked. Such locking can include locking any proximal movement of sleeve  19  relative to housing  11 . 
     Another form of needle retraction can occur if needle  17  is moved relative to housing  11 . Such movement can occur if the cartridge  18  within housing  11  is moved in a proximal direction relative to housing  11 . This proximal movement can be achieved by using a retraction spring (not shown), located in distal region D. A compressed retraction spring, when activated, can supply sufficient force to the cartridge  18  to move it in a proximal direction. Following sufficient retraction, any relative movement between needle  17  and housing  11  can be locked with a locking mechanism. In addition, button  13  or other components of device  10  can be locked as required. 
       FIGS.  2  to  6    show an injection patch  20  of a first embodiment, suitable for use with an injector device, such as the injector device  10  shown in  FIGS.  1 A and  1 B . The injection patch  20  comprises a first layer  21  and a second layer  22 . The first layer is disposed on a first side of the patch  20  which, in use, is intended to lie in contact with, or at least proximate, the skin S of a patient. The second layer  22  is disposed on an opposite side of the patch  20  from the first layer  21 , and is on a side of the patch  20  that, in use, faces away from the skin of a user. In the exemplary embodiment shown, the first layer  21  comprises a membrane  21  and the second layer  22  comprises an open cup-shaped housing  22  defining an interior space. The membrane  21  is attached and sealed across an opening of the housing  22  to seal an enclosed interior space  23  between the first and second layers of the membrane  21  and the housing  22 . The inner space  23  comprises a fluid reservoir containing a fluid. That is, the sealed fluid reservoir  23  is defined between the first and second layers  21 ,  22 . In the first exemplary embodiment, the fluid reservoir is defined by the first and second layers  21 ,  22 , although in alternative embodiments envisaged within the scope of the present disclosure, the reservoir  23  may be defined by other layers or components of the patch  20 . Such alternative embodiments may comprise the reservoir disposed between the first and second layers  21 ,  22 . 
     The fluid within the reservoir  23  of the exemplary embodiment may comprise a sterilising agent, for example alcohol or other liquid with sterilising properties. The fluid may additionally or alternatively comprise an analgesic or anaesthetic to reduce the sensation of an injection by an injection needle of an injector device  10  during use of the patch  20  (described in more detail hereafter). The fluid is advantageously a liquid. The liquid may comprise the substances and/or properties mentioned above. The liquid may alternatively comprise an inert substance, or a substance that does not have chemical, biological or pharmacologically active properties. In one embodiment, the liquid may comprise water. 
     The patch  20  includes in injection aperture  24  extending through the patch  20 . The injection aperture  24  is configured for an injection needle  17  of an injector device  10  to extend through the injection aperture  24  during an injection process. The injection aperture  24  is provided by a cylindrical wall  25  portion of the housing  22  and a correspondingly shaped hole  26  in the membrane  21 . The membrane  21  is sealed to an end surface of the cylindrical wall  25  around the hole  26 . 
     The patch  20  includes a moveable rupturing element  27  disposed within the fluid reservoir  23 . The rupturing element  27  comprises a ring shaped body  28  with a plurality of pointed protrusions  29 . The protrusions  29  are directed towards the membrane  21 . The patch  20  further comprises a support member  30  about which the rupturing element  27  is moveably mounted. The support member  30  comprises a hollow cylindrical portion  31  and a flange  32  extending radially from one end of the hollow cylindrical portion  31  proximate the membrane  21 . The rupturing element  27  is disposed around the hollow cylindrical portion  31  of the support member  30  and is moveable relative to the support member  30  about their common axis X-X (see  FIG.  6   ) from an initial position, shown in  FIG.  4   , to an activated position, shown in  FIG.  5   . 
     A biasing arrangement  33  is provided and configured to bias the rupturing element  27  into the initial position. In the exemplary embodiment shown, the biasing arrangement  33  comprises a biasing element  33  in the form of a plurality of resilient arms  33 . These extend through slots  34  in the rupturing element  27 . The slots  34  are configured such that as the rupturing element  27  moves from the initial position to the activated position, the resilient arms  33  are deflected and exert a force on the rupturing element  27  biasing it in a direction towards the initial position. 
     The cylindrical wall  25  of the housing  22  is disposed within the hollow cylindrical portion  31  of the support member  30 . The membrane  21  is sealed around a peripheral edge of the housing  22  and around the end surface of the hollow cylindrical portion  31  as described above, such that the support member  30  and rupturing element  27  are sealed within the fluid reservoir  23 . 
     In the exemplary embodiment, the membrane  21  comprises a skin-contacting surface of the patch  20 . An adhesive  35  is provided on an outwardly-facing surface of the membrane  21  to enable the patch  20  to be adhered to the skin S of a patient. A protective material layer  36  is provided on the membrane  21 . The protective material layer  36  is removable from the membrane  21  before use of the patch  20 , but serves to protect the membrane  21  from contact, contamination or damage prior to use, for example during manufacture, transport and storage of the patch  20 . Advantageously, the protective material layer  36  is of a greater thickness than the membrane  21 . The protective material layer  36  may also be made of a tougher or more structurally resilient material than that of the membrane  21 . 
     The membrane  21  includes a weakened region  37 . The weakened region  37  is located in the location of the protrusions  29  of the rupturing element  27  when the rupturing element  27  is in the activated position. The weakened region  37  is shown as a single circular region, but may alternatively comprise a plurality of discrete regions or any suitable shape or size. The weakened region  37  may be formed integrally with the membrane  21 , and may comprise a region of reduced thickness of the material of the membrane  21 , or a region demarcated by one or more lines of weakening in the material of the membrane  21 , such as score lines or lines of reduced material thickness. Alternatively, the weakened region  37  may comprise an aperture in the membrane  21  and a portion of a different rupturable material bonded over the aperture. 
     The support member  30  and rupturing element  27  are provided with a stop arrangement  38  which defines the position of the rupturing element  27  relative to the support member  30  in the activated position and prevents further movement of the rupturing element  27  relative to the support member  30  beyond the activated position. In the exemplary embodiment shown, the stop arrangement  38  comprises a plurality of posts  39  extending from the flange  32 . In the activated position of the rupturing element  27 , the rupturing element  27  abuts the posts  39 , thereby preventing further movement of the rupturing element  27  beyond the activated position. 
     Use of the patch  20  of the first embodiment will now be described. A user first removes the protective material layer  36  exposing the adhesive layer  35 . The user then places the patch  20  on the patient&#39;s skin at the intended injection site, with the location of the intended injection in the middle of the hole  26  in the membrane  21  and aligned with the injection aperture  24 . (Herein, a user may comprise the patient in the context of a self-administered medicament, or may comprise a health care professional in the case of a health care professional administering medicament to a patient). The adhesive layer  35  helps retain the patch  20  in position on the patient&#39;s skin. 
     The user then prepares the injector device  10  for administering an injection, and places the distal end of the injector device  10  on the patch  20  with the axis A-A of the injector device  10  aligned with the axis X-X of the rupturing element  27  and hollow cylindrical portion  31  of the support member  30 . The user then presses the injector device  10  down onto the patch  20 , which causes an upper portion of the housing  22  to deform towards the skin of the patient and the rupturing element  27  to move from the initial position shown in  FIG.  4   , to the activated position shown in  FIG.  5   . The pointed protrusions  29  of the rupturing element  27  pierce the membrane  21 . The piercing is facilitated by the protrusions  29  being located facing the weakened regions  37  of the membrane  21  such that those regions of the membrane  21  are relatively easily pierced. 
     The pierced membrane  21  allows the fluid from within the fluid reservoir  23  to be released onto the patient&#39;s skin at and around the injection site. Depending on the formulation of the liquid within the fluid reservoir, the released fluid may help to sterilised the injection site, and/or reduce the patient&#39;s sensation of touch or pain at the injection site. Thereby, subsequent progression of the injection process, in which the injection needle  17  extends through the injection aperture  24  and into the patient&#39;s skin S, is ensured to be in a sterile region of skin, and/or causes the patient a reduced discomfort as the needle  17  enters the skin and the medicament injection process progresses. The sensation of fluid from the ruptured reservoir  23  on the skin may provide a sensory distraction from the injection sensation, without active anaesthetic action. For example, if the fluid in the reservoir is water. The patch  20 , and thereby the fluid within the reservoir, may be heated or cooled prior to use to provide a warming or cooling sensation on the skin in use, helping distraction from injection sensation. The fluid within the reservoir may alternatively comprise a pressurised gas such that sensation of gas release upon rupturing of the reservoir provides a distracting sensation. The quick pressure drop may also provide a cooling sensation. The fluid may yet further comprise a liquid that evaporates upon release from the reservoir  23 , again further providing a cooling sensation to the skin at the injection site. 
     The posts  39  of the stop arrangement  38  abut the rupturing element  27  in the activated position and prevented the rupturing element  27  from moving beyond the activation position. The stop arrangement  38  thereby serves to prevent the protrusions  29  of the rupturing element  27  extending further through the membrane  21  which may otherwise cause them to press more firmly onto the patient&#39;s skin. This thereby helps towards preventing discomfort for the patient being caused by an unwanted degree of contact with the protrusions  29 . 
     A patch  20  of a second embodiment of the disclosure is shown in  FIGS.  7  to  9   , and comprises a number of the same features as the patch  20  of the first embodiment, such features retaining the same reference numerals. A difference with the patch  20  of the second embodiment is that the patch  20  of the second embodiment does not include a rupturing element or support member disposed inside the fluid reservoir  23  defined by the housing  22  and membrane  21 . The patch  20  of the second embodiment does include a rupturing element  27  and a support member  30  although these components are disposed outside the fluid reservoir  23 . 
     The rupturing element  27  of the patch  20  of the second embodiment comprises a plate spaced from and substantially parallel to the membrane  21 . The rupturing element  27  includes a plurality of pointed protrusions  29  extending from a surface of the plate proximate to the membrane  21  and extending in a direction towards the membrane  21 . The support member  30  also comprises a plate, and is disposed between the rupturing element  27  and the membrane  21 . The support element  30  includes a plurality of holes  40  located corresponding to the locations of the protrusions  29  on the adjacent rupturing element  27 . The rupturing element  27  and the support member  30  respectively include a central hole  41 ,  42  aligned with the injection aperture  24  defined by the cylindrical wall  25  of the housing  22  and the hole  26  in the membrane  21 . 
     The rupturing element  27  is moveably mounted to the support member  30 . The rupturing element  27  is advantageously coupled to the support member  30  by one or more resilient coupling members  43 . Such resilient coupling members  43  may comprise one or more springs or other suitable deflectable elements such as resilient arms or other portions of deflectable material bonded to the rupturing element  27  and to the support member  30 , such as a foam or elastomeric block or other shaped element. Alternatively, the resilient coupling members  43  may be formed integrally with one of the rupturing element  27  and the support member  30  and bonded to the other of the rupturing element  27  and the support member  30 . Yet further, the resilient coupling members  43  may be formed integrally with both the rupturing element  27  and the support member  30 . 
     The rupturing element  27  is moveable between an initial position (shown in  FIG.  7   ) to an activated position (shown in  FIG.  8   ). The resilient coupling members  43  serve as a biasing arrangement  33  to bias the rupturing element  27  towards the initial position. In the initial position, the protrusions  29  are spaced from the membrane  21 . The rupturing element  27  is moveable against a biasing force of the resilient coupling members  43  to the activated position, in which the protrusions  29  extend through the holes  40  in the support member  30  and into contact with the membrane  21  to pierce the membrane  21 . 
     In the exemplary embodiment, a surface of the rupturing element  27  facing away from the membrane  21  comprises a skin-contacting surface of the patch  20 . An adhesive  35  is provided on the outwardly-facing surface of the rupturing element  27  to enable the patch  20  to be adhered to the skin of a patient. A protective material layer  36  is provided on the outwardly facing surface of the rupturing element  27 . The protective material layer  36  is removable from the rupturing element  27  before use of the patch  20 , but serves to protect the skin-contacting surface of the rupturing element  27 , and the adjacent membrane  21  from contact, contamination or damage prior to use, for example during manufacture, transport and storage of the patch  20 . 
     As with the patch  20  of the first embodiment, the membrane  21  advantageously includes weakened regions  37  located facing the protrusions  29  of the rupturing element  27 . The weakened regions  37  may be formed integrally with the membrane  21 , and may comprise a region of reduced thickness of the material of the membrane  21 , or a region demarcated by one or more lines of weakening in the material of the membrane  21 , such as score lines or lines of reduced material thickness. Alternatively, the weakened region  37  may comprise an aperture in the membrane  21  and a portion of a different rupturable material bonded over the aperture. 
     Use of the patch  20  of the second embodiment will now be described, and is similar to the method of use of the patch  20  of the first embodiment, and so like method steps will not be repeated. 
     After a user has placed the patch  20  on the patient&#39;s skin and prepared the injector device  10  for administering an injection, the distal end of the injector device  10  is placed on the patch  20  with the axis A-A of the injector device  10  aligned with injection aperture  24 . The user then presses the injector device  10  down onto the patch  20 , which causes the rupturing element  27  to move from the initial position shown in  FIG.  7   , to the activated position against the biasing force of the resilient coupling members  43 . In the activated position, the pointed protrusions  29  of the rupturing element  27  extend through the holes  40  in the support member  30  and pierce the membrane  21 . The piercing is facilitated by the protrusions  29  being located facing the weakened regions  37  of the membrane  21  such that those regions of the membrane are relatively easily pierced. 
     As with the patch  20  of the first embodiment, the pierced membrane allows the fluid from within the fluid reservoir  23  to be released onto the patient&#39;s skin at and around the injection site, with the associated advantageous effects described above. The patch  20  of the second embodiment may include one or more fluid passages  44  formed in the rupturing element  27  to enhance flow of a fluid from within the fluid reservoir  23  into contact with the skin S of the patient. 
     In a variant of the second embodiment intended within the scope of the present disclosure, fluid the reservoir may be disposed between the support plate  30  and the rupturing element  27 . In such an alternative embodiment, relative movement of the rupturing element  27  towards the support plate  30  would similarly cause the piercing of the surface of the fluid reservoir  23  to release fluid therefrom. The support plate  30  and rupturing element  27  may be separate components connected together, or may be integrally formed components moveable relative to one another. The support plate  30  and rupturing element  27  may be connected by one or more resilient coupling members which act as a biasing arrangement biasing the support member  30  away from the rupturing element  27 . 
     A patch  20  of a third embodiment of the disclosure is shown in  FIGS.  10  and  11   , and comprises a number of the same features as the patches  20  of the first and second embodiments, such features retaining the same reference numerals. The patch  20  of the third embodiment includes at least one rupturing element  27  disposed inside the fluid reservoir  23  which is defined by the housing  22  and membrane  21 . The exemplary embodiment shown includes a plurality of rupturing elements  27 . The rupturing elements  27  are provided extending from an interior surface of the housing  22  and are directed towards the membrane  21 . 
     The rupturing elements  27  of the patch  20  of the third embodiment comprise protections  27  including pointed protrusions  29  at a tip of the protection  27  disposed proximate the membrane  21 . The rupturing elements may be attached to the housing  22 , or may be formed integrally with the housing  22 , the latter being advantageous for ease and cost of manufacture. 
     The housing  22  is advantageously formed of a material to provide some structural strength to the patch  20 , and some resistance to deformation of the housing  22  (as may also be the case with the patches  20  of the previously-described embodiments). Any suitable material may be chosen to provide the desired structural properties of the housing  22 , such as metal or plastics, in an appropriate material thickness. The patch  20  is deformable between an initial position (shown in  FIG.  10   ) to an activated position (shown in  FIG.  11   ). As such, the rupturing elements  27  are moveable between an initial position to an activated position. The resilience of the housing  22  results in the rupturing elements  27  being biased into the initial position, and so as such, the patch  20  of the third embodiment includes a biasing arrangement  33  configured to bias the rupturing elements  27  into the initial position. 
     In the initial position, the protrusions  29  are spaced from the membrane  21 . The rupturing elements  27  are moveable against a biasing force of the resilient housing  22  to the activated position, in which the protrusions  29  contact and pierce the membrane  21 . 
     In the exemplary embodiment, a surface of the membrane  21  comprises a skin-contacting surface of the patch  20 . An adhesive  35  is provided on the outwardly-facing surface of the membrane  21  to enable the patch  20  to be adhered to the skin of a patient. A protective material layer  36  is provided on the outwardly facing surface of the membrane  21 . The protective material layer  36  is removable from the membrane  21  before use of the patch  20 , but serves to protect the membrane from contact, contamination or damage prior to use, for example during manufacture, transport and storage of the patch  20 . 
     As with the patches  20  of the first and second embodiments, the membrane  21  advantageously includes one or more weakened regions  37  located facing the protrusions  29  of the rupturing elements  27 . The weakened regions  37  may be formed integrally with the membrane  21 , and may comprise a region of reduced thickness of the material of the membrane  21 , or a region demarcated by one or more lines of weakening in the material of the membrane  21 , such as score lines or lines of reduced material thickness. Alternatively, the weakened regions  37  may comprise an aperture in the membrane  21  and a portion of a different rupturable material bonded over the aperture. 
     Use of the patch  20  of the third embodiment will now be described, and is similar to the method of use of the patch  20  of the first and second embodiments, and so like method steps will not be repeated. 
     After a user has placed the patch  20  on the patient&#39;s skin and prepared the injector device  10  for administering an injection, the distal end of the injector device  10  is placed on the patch  20  with the axis A-A of the injector device  10  aligned with injection aperture  24 . The user then presses the injector device  10  down onto the patch  20 , which causes the housing  22  to deform from the initial position to the activated position against the biasing force of the resilient deformable housing  22 . Thereby, the rupturing elements  27  to move towards the membrane  21  such that the pointed protrusions  29  pierce the membrane  21 . The piercing is facilitated by the protrusions  29  being located facing the weakened regions  37  of the membrane  21  such that those regions of the membrane are relatively easily pierced. 
     As with the patches  20  of the first and second embodiments, the pierced membrane  21  allows the fluid from within the fluid reservoir  23  to be released onto the patient&#39;s skin at and around the injection site, with the associated advantageous effects described above. 
       FIGS.  12  and  13    illustrate an enlarged view of a portion of a patch  20  of a fourth embodiment, and is similar to the patch of the first embodiment. A difference with the patch  20  of the fourth embodiment is that the patch  20  includes a locking mechanism  46 . The locking mechanism  46  is associated with the rupturing element  27  and is configured such that in a locked condition, the rupturing element  27  is prevented from being moveable to rupture the fluid reservoir  23 . In an unlocked condition, the rupturing element  27  is moveable to be able to rupture the fluid reservoir  23 . 
     In the patch  20  of the exemplary fourth embodiment, the locking mechanism  46  is shown in a locked condition in  FIG.  12   , and in an unlocked condition in  FIG.  13   . The locking mechanism  46  comprises a pivotable locking arm  47  which in the locked condition, is engaged in a recess  48  in the rupturing element  27 . The locking arm  47  is pivotably coupled to the cylindrical wall  25  of the housing  22 , but alternatively may be pivotably coupled to the support member  30 , for example to the hollow cylindrical portion  31  of the support member  30 . In the locked condition, the locking arm  47  prevents the rupturing element  27  from moving relative to the housing  22  and the support member  30 . 
     The locking arm  47  can be pivoted into the unlocked condition, in which the locking arm  47  is out of engagement with the recess  48  in the rupturing element  27 . This renders the rupturing element  27  able to move relative to the housing  22  and the support member  30 , and so the patch  20  to be used as described above. 
     The locking arm  47  may be manually moved from the locked condition to the unlocked condition by a user, for example by pressing the locking arm  47  with a finger. Alternatively, the locking arm  47  may be engaged by an injector device  10  being inserted into the injection aperture  24 , and so the locking mechanism  46  rendered in the unlocked condition upon use of the patch  20  with an injector device  10 . The locking mechanism  46  may therefore advantageously prevent accidental rupturing of the fluid reservoir  23  prior to use by a user, for example during manufacture, packaging, transport or storage. 
     The locking mechanism  46  shown in  FIGS.  12  and  13    is one exemplary locking mechanism and alternative locking mechanisms are envisaged within the scope of the present disclosure. For example, other configurations of release elements other than the illustrated locking arm  47  may be provided. Such alternative release elements may comprise a sprung tab disengageable with the rupturing element, or a releasable pawl. Furthermore, and of the above described embodiments of patch  20  may include a locking mechanism, for example, with a release element comprising a breakable connection, such as a frangible pin extending between two components of the patch  20  which move relative to each other as the respective rupturing element  27  moves from the initial position to the activated position. 
     Although exemplary embodiments of patch  20  are described above, it will be appreciated that variations and alternatives are anticipated within the scope of the present disclosure, which are intended to fall within the scope of the appended claims. In the embodiments described, the membrane  21  comprises one or more weakened regions  37  which may advantageously facilitate rupturing of the fluid reservoir  23  by the rupturing element(s)  27 . However, the membrane may optionally not include such weakened regions  37  within the scope of the present disclosure, and a membrane material and thickness may be appropriately selected such that the rupturing element(s)  27  may adequately pierce the membrane  21  without the presence of such weakened regions. 
     The protective material layer  36  advantageously may protect the membrane  21  or other skin-contacting surface of the patch  20  (such as the surface of the rupturing element in the second embodiment) from contact, contamination or damage prior to use of the patch  20 , as described above. However, such protective layer  36  is not essential and may optionally be omitted in alternative embodiments. 
     The patch  20  may include an adhesive  35  on a skin-contacting surface, to facilitate the patch  20  locating in position on a patient&#39;s skin during an injection process. However, in an alternative embodiment, the adhesive  35  may be omitted. 
     The embodiments of patch  20  described above include a hole  26  in the membrane  21  through which a needle  17  of an injector device  10  may extend during use of the patch  20  in an injection process. However, alternative embodiments intended within the scope of the present disclosure may not include such hole  26 , and the membrane  21  may comprise a continuous layer of material. Such an alternative may advantageously help ease of manufacture as alignment of the hole  26  with an injection aperture  24 /cylindrical wall of a housing  25  would not be required. Furthermore, the membrane  21  may be easily pierced by the injection needle  17 , thereby not presenting a problem to performing the injection process. 
     In the exemplary embodiments of patch  20  described above, the fluid in the fluid reservoir is described as possibly comprising a sterilising agent, antiseptic, analgesic or anaesthetic. However, it is intended that alternative fluids may be provided in the reservoir. In some embodiments, the function of the patch  20  may be to provide a distracting or comforting sensation to the patient&#39;s skin during the injection process. Such sensation may be provided by cooling or heating the skin. As such, the fluid may be any fluid capable of being heated or cooled such that upon contact with the patient&#39;s skin, the heat or cool sensation is detected by the patient as a distraction to the injection sensation. Such heating or cooling of the fluid may be achieved by heating or cooling the patch  20  before use. Such fluid may comprise any suitable fluid and may comprise an inert fluid, such as water for example. Such fluid may also comprise a fluid that endothermically or exothermically reacts with atmosphere once the reservoir is ruptured, to cool or heat the patient&#39;s skin S. Such fluid may also act to cool the patient&#39;s skin evaporatively once released from the reservoir onto the patient&#39;s skin, for example alcohol. 
     In embodiments in which the patch  20  includes a heating or cooling function to a patient&#39;s skin, the patch  20  may optionally include a temperature indicator, such as a thermochromic portion or other temperature indicating means. Such temperature indicator may change colour, or display a graphic or indicia when the temperature of the patch  20  or the patient&#39;s skin alters by a predetermined amount, or when a threshold temperature is achieved. This may, for example, be useful to indicate to a patient that the injection process can be initiated. Such an exemplary temperature indicator is shown as a thermochromic portion  45  in the patch  20  shown in  FIG.  2   . 
     Although the biasing arrangement  33  of the first embodiment is illustrated in the form of resilient arms  33 , alternative biasing arrangements may be provided, for example one or more springs or other suitable deflectable element(s) such one or more portions of deflectable material such as foam or elastomeric blocks or other shaped elements. In various embodiments of patch  20  described herein, comprising biasing arrangements  33  associated with the rupturing elements  27 , the rupturing elements  27  may advantageously be biased to return to the initial position upon release of a force which moved the respective rupturing element from the initial position to the activated position. 
     In the first embodiment of patch  20 , a stop arrangement  38  is provided, by the stop posts  39 . However, alternative configurations of stop arrangements are envisaged, which may comprise a biasing means or arms being in a fully deflected state (such as the resilient arms  33  being at a maximum deflected state). In the patch  20  of the second embodiment, the stop arrangement may be provided by the resilient coupling members  43  being compressed to a maximum extent, or alternatively when the plate of the rupturing element  27  being in contact with the plate of the support member  30 . 
     The patch  20  of the second embodiment illustrated and described above, includes one arrangement of rupturing mechanism for rupturing the fluid reservoir  23 . However, alternative configurations of external rupturing elements are intended within the scope of the present disclosure. 
     The exemplary embodiments of patch  20  described and illustrated herein include an injection aperture  24  through which an injection needle  17  extends during use of the patch  20  in an injection process. This may at least partially conceal the injection needle  17  from view of the patient during an injection process. This may be advantageous for patients who are anxious about injections and needles and thereby may help relax the patient during an injection process. In some embodiments, the material of construction of the patch  20 , such as the second layer/housing  22 , may comprise an opaque material to further help conceal the injection needle  17  from view of a patient. Alternatively, however, the material of construction of the patch  20 , such as the second layer/housing  22 , may comprise a translucent or semi-translucent material to enable fluid within the fluid reservoir to be visible by the patient. This may help to make operation of the patch  20 , including rupturing of the reservoir and release of the fluid therein, be visible to a patient. This may provide reassurance of operation to the patient. 
     The embodiments of patch  20 , with the exemplary injection apertures  24 , may also advantageously help locate an injector device  10  at the injection site during use by a patient. This can help toward preventing incorrect use or alignment of the injector device  10 , or damage or injury by the injector device during use. 
     The exemplary embodiments of patch  20  described above, comprise a fluid reservoir  23  defined by the first and second layers  21 ,  22  of the patch  20 . However, in alternative embodiments intended within the scope of the present disclosure, a fluid reservoir  23  may be provided between the first and second layers, but within a further layer or layers of material, for example within a balloon or pocket of fluid disposed between the first and second layers of the patch  20 . As such, a rupturing element may be disposed between the first and second layers of the patch, but outside of the fluid reservoir. 
     The exemplary embodiments of patch  20  described above, comprise an injection aperture  24 . However, in alternative embodiments intended within the scope of the present disclosure, the injection aperture may be omitted. In use of such an alternative configuration of patch  20 , the needle  17  of an injector device  10  may pierce through the body of the patch  20  before piercing the patient&#39;s skin S at the injection site. 
     As used herein, the term “rupture” is intended to mean break, burst, tear, puncture or otherwise jeopardise the integrity of the sealed state of the sealed fluid reservoir to permit relese of the fluid contained therein from the reservoir. 
     The various exemplary embodiments of patch  20  described herein, with various optional features mentioned above, may advantageously serve to provide one or more patient benefits of injection pain reduction, distraction from injection needle sensation, even of only by use of the patch  20  per se, needle anxiety reduction, and generally provide improved patient usability and acceptance of use of injector devices. 
     The terms “drug” or “medicament” are used herein to describe one or more pharmaceutically active compounds. As described below, a drug or medicament can include at least one small or large molecule, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Exemplary pharmaceutically active compounds may include small molecules; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more of these drugs are also contemplated. 
     The term “drug delivery device” shall encompass any type of device or system configured to dispense a drug into a human or animal body. Without limitation, a drug delivery device may be an injector device (e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for intraocular, subcutaneous, intramuscular, or intravascular delivery), skin patch (e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal or pulmonary), implantable (e.g., coated stent, capsule), or feeding systems for the gastro-intestinal tract. The presently described drugs may be particularly useful with injector devices that include a needle, e.g., a small gauge needle. 
     The drug or medicament may be contained in a primary package or “drug container” adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other vessel configured to provide a suitable chamber for storage (e.g., short- or long-term storage) of one or more pharmaceutically active compounds. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years. Storage may occur at room temperature (e.g., about 20° C.), or refrigerated temperatures (e.g., from about −4° C. to about 4° C.). In some instances, the drug container may be or may include a dual-chamber cartridge configured to store two or more components of a drug formulation (e.g., a drug and a diluent, or two different types of drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components of the drug or medicament prior to and/or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body. 
     The drug delivery devices and drugs described herein can be used for the treatment and/or prophylaxis of many different types of disorders. Exemplary disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further exemplary disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. 
     Exemplary drugs for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the term “derivative” refers to any substance which is sufficiently structurally similar to the original substance so as to have substantially similar functionality or activity (e.g., therapeutic effectiveness). 
     Exemplary insulin analogues are Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); 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. 
     Exemplary 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-gamma-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N—(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyhepta-decanoyl) human insulin. Exemplary GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, for example: Lixisenatide/AVE0010/ZP10/Lyxumia, Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993 (a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-Xten. 
     An exemplary oligonucleotide is, for example: mipomersen/Kynamro, a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia. 
     Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine. 
     Exemplary hormones include hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin. 
     Exemplary polysaccharides include 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 polysaccharide, 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. An example of a hyaluronic acid derivative is Hylan G-F 20/Synvisc, a sodium hyaluronate. 
     The term “antibody”, as used herein, refers to an immunoglobulin molecule or an antigen-binding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab′)2 fragments, which retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. 
     The terms “fragment” or “antibody fragment” refer to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy and/or light chain polypeptide) that does not comprise a full-length antibody polypeptide, but that still comprises at least a portion of a full-length antibody polypeptide that is capable of binding to an antigen. Antibody fragments can comprise a cleaved portion of a full length antibody polypeptide, although the term is not limited to such cleaved fragments. Antibody fragments that are useful in the present disclosure include, for example, Fab fragments, F(ab′)2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), minibodies, chelating recombinant antibodies, tribodies or bibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins, camelized antibodies, and VHH containing antibodies. Additional examples of antigen-binding antibody fragments are known in the art. 
     The terms “Complementarity-determining region” or “CDR” refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term “framework region” refers to amino acid sequences within the variable region of both heavy and light chain polypeptides that are not CDR sequences, and are primarily responsible for maintaining correct positioning of the CDR sequences to permit antigen binding. Although the framework regions themselves typically do not directly participate in antigen binding, as is known in the art, certain residues within the framework regions of certain antibodies can directly participate in antigen binding or can affect the ability of one or more amino acids in CDRs to interact with antigen. 
     Exemplary antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab). 
     The compounds described herein may be used in pharmaceutical formulations comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may also be used in pharmaceutical formulations that include one or more other active pharmaceutical ingredients or in pharmaceutical formulations in which the present compound or a pharmaceutically acceptable salt thereof is the only active ingredient. Accordingly, the pharmaceutical formulations of the present disclosure encompass any formulation made by admixing a compound described herein and a pharmaceutically acceptable carrier. 
     Pharmaceutically acceptable salts of any drug described herein are also contemplated for use in drug delivery devices. 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 an alkali or alkaline earth metal, 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 known to those of skill in the arts. 
     Pharmaceutically acceptable solvates are for example hydrates or alkanolates such as methanolates or ethanolates. 
     Those of skill in the art will understand that modifications (additions and/or removals) of various components of the substances, formulations, apparatuses, methods, systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.