WO2012013585A1

WO2012013585A1 - Co-delivery of two medicaments in a single injection

Info

Publication number: WO2012013585A1
Application number: PCT/EP2011/062604
Authority: WO
Inventors: Alastair Robert Clarke; Matthew John Ekman; Michael James David Heald; Christopher James Smith
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2010-07-26
Filing date: 2011-07-22
Publication date: 2012-02-02

Abstract

An injection system for co-delivery of two medicaments having an adaptor (1) that accepts a mini-syringe (20) containing a first medicament and that accepts an injection device (30) that contains a second medicament, where the mini-syringe (20) connects to the injection device (30) during injection to deliver both medicaments to a patient simultaneously in a single injection.

Description

CO-DELIVERY OF TWO MEDICAMENTS IN A SINGLE INJECTION Field of the Disclosure

Specific embodiments of this disclosure relate to a means for delivering at least two medicaments stored in separate primary packages through a single injection. One medicament is provided in a disposable mini-syringe with attached injection needle and the other medicament(s) is provided in a multiple dose injection device, which can be either disposable or reusable.

Background

Certain disease states require treatment using one or more different medicaments. For example, in some cases it might be beneficial to treat a diabetic with a long-lasting insulin and with a glucagon-like peptide-1 (GLP-1 ), which is derived from the transcription product of the proglucagon gene. GLP-1 is found in the body and is secreted by the intestinal L cell as a gut hormone. GLP-1 possesses several physiological properties that make it (and its analogues) a subject of intensive investigation as a potential treatment of diabetes mellitus.

There are a number of potential problems when delivering two active medicaments or "agents" simultaneously. The two active agents may interact with each other during the long-term, shelf life storage of the formulation. Therefore, it is advantageous to store the active components separately and to only combine them at the point of delivery, e.g. injection or inhalation. However, the process for combining the two agents needs to be simple and convenient for the user to perform reliably.

A further problem is that the quantities and/or proportions of each active agent making up the combination therapy may need to be varied for each user or at different stages of their therapy. For example, one or more actives may require a titration period to gradually increase a patient up to a "maintenance" dose. A further example would be if one active requires a non-adjustable fixed dose while the other one is varied in response to a patient's symptoms or physical condition. This problem means that pre- mixed formulations of multiple active agents may not be suitable as these pre-mixed formulations would have a fixed ratio of the active components, which could not be varied by the healthcare professional or patient.

Accordingly, there exists a strong need to provide devices and methods for the delivery of one or more medicaments. The present disclosure overcomes the above-mentioned problems by providing separate storage containers for the two active agents that are only combined at the point of delivery. The present disclosure also gives the opportunity for varying the quantity of one or both liquid medicaments. For example, one fluid quantity can be varied by changing the properties of the injection device (e.g. dialing a user variable dose or changing the device's "fixed" dose). The second fluid quantity can be changed by manufacturing a variety of mini-syringes, each variant containing a different volume and/or concentration of the second active agent. The user or healthcare professional would then select the most appropriate mini-syringe for a particular treatment regime. These and other advantages will become evident from the following more detailed description of the invention. Problem to be solved

The problem to be solved by the present invention is to provide a mini-syringe, an injection system and a method for operating the injection system where the safety and comfort of the user is increased. SUMMARY

According to an exemplary arrangement a mini-syringe for use with an injection device to co-deliver two medicaments in a single injection is provided. The mini-syringe comprises a housing. The housing may have a distal end. The housing may have a proximal end. The housing may have a central axis, in particular a main longitudinal axis. The housing may be any geometric shape, however, a cylindrical shape is preferred. The housing has a hub that contains a first needle cannula. Inside the housing is a pierceable slideable piston or bung, similar to those rubber pistons found in well-known cartridges of medication designed for use in pen-type injection devices. The distal end of the piston and the distal end of the housing form a distal chamber or first chamber. The distal chamber may store a first medicament, preferably one dose of a first medicament. The first chamber may contain a medicament. Preferably, the first chamber contains a liquid medicament. The proximal end of the piston and the, preferably open, proximal end of the housing form a proximal chamber or second chamber. The proximal chamber is configured to accept the distal end of an injection device. In particular, the proximal chamber may be configured to accept a needle hub of an injection device. The needle hub of the device may be adapted and arranged to receive a needle. According to an embodiment, the proximal chamber, in particular the open end of the proximal chamber, is covered with a pierceable seal. The pierceable seal may maintain sterility of a second or proximal needle assembly. The second needle assembly may be mounted in the piston. The mini-syringe has two needle assemblies. A first needle assembly is connected to the distal end of the housing, preferably positioned parallel to the central axis of the housing. The first needle assembly may have the hub. The hub is preferably integral to the housing. The first needle assembly may comprise the previously mentioned needle cannula. This first needle assembly is in fluid communication with the distal chamber and any medicament contained therein. The mini-syringe may have a needle cap. The needle cap may cover a portion of the first needle assembly. In particular, the needle cap may cover the needle cannula. The needle cap may maintain needle sterility prior to use and may seal the distal end of the distal chamber. The mini-syringe also has the second needle assembly. The second needle assembly may be mounted in the piston. The second needle assembly may be likewise positioned parallel to the central axis. Preferably, the second needle assembly comprises a hub. The hub may be connected or otherwise fixed to the piston. The second needle assembly may have a needle stub, hollow needle cannula, sharpened on both ends. According to an embodiment, the piston in the mini-syringe contains a fluid recess. The fluid recess may be on the distal end of the piston. The fluid recess may be configured to accept a portion of the needle stub, in particular of the distal end of the needle stub, when the needle stub pierces the piston during injection.

The present disclosure also relates to an adaptor. The adaptor may be used with the mini-syringe during co-delivery of two liquid medicaments. The adaptor may be either reusable or disposable. The adaptor may comprise a housing. The housing may have a first compartment. The housing may have a second compartment. The first compartment may be configured to accept a mini-syringe as generally described above. The first compartment may have a side window opening. The side window opening may allow the mini-syringe to be inserted into the adaptor and to be ejected when the exhausted of medicament. In particular, the mini-syringe may be insertable perpendicularly with respect to a main longitudinal axis of the adaptor via the side window opening. The second compartment may be configured to accept an injection device, for example a pen-type multi-dose device capable of a single or variable dose setting. The second compartment may have a proximal opening. The proximal opening may allow insertion of the device into the second compartment. The device may be inserted along the main longitudinal axis of the adaptor via the proximal opening. The device may be a reusable or a disposable device. For convenience and to assist in performing the injection, the adaptor may have finger flanges. The finger flanges may be attached to the housing. In particular, the finger flanges may be attached to the housing adjacent the proximal opening. There may also be a needle opening in the first compartment. The needle opening may be designed to accept the first needle assembly attached to the mini-syringe. The adaptor may comprise at least one of, preferably a plurality of back stops, e.g. protrusions. The back stops are preferably located in the first compartment, preferably in the proximal end of the first compartment. The back stops may be used to prevent axial movement of the mini-syringe in a proximal direction. This is especially desirable when removing the injection device from the adaptor after an injection is completed and to assist in separating the mini-syringe from the injection device.

According to an embodiment, the adaptor and the injection device are an integrated assembly. Particularly in the case where both the adaptor component and the injection device are disposable, it may be preferable to provide these two separate components as a single integrated assembly. The single integrated assembly would function in the same manner as the separate components described, however, the integrated assembly would either be designed such that it was not possible for the user to separate the injection device from the adaptor or the injection device and adaptor would be manufactured as a single assembly. The integrated assembly offers a convenient benefit to the user in terms of reduced user steps compared to the user assembly of two separate components, thereby obviating certain operational steps as described below. Alternatively, the adaptor and the mini syringe could provide a one-piece disposable component. Again this assembly would either be designed such that it was not possible for the user to separate the mini syringe from the adaptor or the mini syringe and adaptor would be manufactured as a single assembly. One convenience benefit for the user would be the reduced number of parts that need to be assembled prior to use, furthermore the bigger part provides for improved handling capabilities, e.g. for users with manual handicaps.

According to an embodiment, the injection device has a reservoir of medicament. The reservoir preferably holds a plurality of doses of the medicament. The reservoir may be sealed with a septum. The device may have a dose dialing module.

According to the present disclosure a mini-syringe for use with an injection device to co- deliver two medicaments in a single injection is provided. The injection device could be a multiple use injection device, preferably a pen-type multi-dose injection device. The injection device could be a reusable or disposable device. A disposable device is an injection device that is preloaded with medicament and cannot be reloaded with new medicament after the initial medicament is exhausted. The device may be a fixed dose or a variable dose device, but in either case it is a multi-dose device. The injection device is fully operable in itself requiring only an injection needle to be mounted, e.g. a standard pen needle, in order to perform administration of a medicament. This offers a convenience benefit to the user in terms of injection device to be used. A user could use an injection device for a mono therapy and the same device could be used for a combination therapy when used in conjunction with a mini-syringe according to the present disclosure.

A further feature of the disclosure is that both medicaments may be delivered via one injection needle and in one injection step. This offers a convenient benefit to the user in terms of reduced user steps compared to administering two separate injections. This convenience benefit may also result in improved compliance with the prescribed therapy, particularly for users who find injections unpleasant.

The integrated needle of the mini-syringe may also mean that the user does not have to manually attach a needle to either the adaptor housing or to the injection device. The manual attachment of the needle is often one of the most difficult tasks for the user to perform and, if performed incorrectly, may result in a poor seal between needle and septum and/or damage to the septum, which in turn can result in leaking of medicament and inaccurate doses.

Delivering both medicaments via a single needle also ensures that they are delivered to the same subcutaneous site. This may be an advantage if the safety or efficacy of the combination therapy is improved by the interaction of the two active agents in the body or at the injection site. The contents of the mini-syringe may be effectively flushed by the medicament expelled from the injection device.

The one "fixed" dose in the mini-syringe could be varied by providing the mini-syringe in a number of different active agent strengths. For example, the concentration or volume of the active agent could be increased or decreased accordingly. In this way, the dose strength could be adjusted to a patient's needs, including during any drug titration periods that may be required. The injection device of the system of the present disclosure could deliver a user variable dose or could equally be a "fixed-dose" injection device. Transferring the dose from the injection device to the mini-syringe before advancing the mini-syringe bung or piston might be important if the medicament from the injection pen is being used to flush out a smaller volume of medicament from the mini-syringe. It is believed that the fluid from the injection device should be transferred from the injection device into the mini-syringe before the bung or piston of the mini-syringe begins to advance. There are a number of reasons for this. Firstly, most injection devices, especially pen-type designs, feature some degree of mechanical advantage, i.e. a system of gearing or different thread pitches, that reduces the force required on the injection button to cause the bung to advance. Secondly, the bung diameter of the mini- syringe is greater than the bung diameter of the injection pen cartridge. This means that an equal force applied to both bungs will result in a lower pressure being created in the mini-syringe compared to the pressure in the injection device cartridge or reservoir.

The design of the mini-syringe, adaptor and injection device can also influence the sequential order of the injection. To further increase the likelihood that the injection device will transfer its dose to the mini-syringe prior to movement of the mini-syringe bung, the diameter of the tubing or cannula used to make the double-ended needle stub can be increased. This will reduce the resistance of the needle and allow the fluid held in the reservoir or cartridge of the injection device to pass more easily into the mini- syringe. However, if the delivery sequence of the medicaments is also important for reasons of efficacy, then it would also be possible to design the reverse situation where the mini-syringe is emptied before the fluid is delivered from the injection pen. This could be achieved by introducing friction or mechanical detents into the system, particularly in either the injection device or the reusable housing. For example, a mechanical detent at the beginning of the injection pen button dispense stroke could increase the force required to deliver medicament from the injection pen and cause the mini-syringe content to be expelled first. Once the mini-syringe reaches the end of its stroke, the applied force would then overcome the detent causing the injection pen to dispense.

In one embodiment an injection system comprises a mini-syringe, and adaptor, and an injection device, wherein a second compartment of the adaptor is configured to enable distal movement of the injection device relative to a housing of the adaptor upon pushing on an injection button of the injection device such that

- The piston of the mini-syringe is moved to discharge the content of the first distal chamber of the mini-syringe;

- the piston of the mini-syringe and septum of the reservoir of the injections device are pierced by the needle stub of the mini-syringe establishing fluid communication between the injection device and the first needle at the distal end of the mini-syringe;

- medicament from the injection device can be discharged through said first needle.

A further aspect relates to an injection system for co-delivery of two medicaments. The injection system may comprise the previously described mini-syringe. The injection system may comprise the previously described injection device. The injection system may comprise the previously described adaptor. The adaptor may comprise the housing having the first compartment and the second compartment. The first compartment may be configured to accept the mini-syringe. The second compartment may be configured to accept the device.

The present disclosure also relates to a method for operating the previously described injection system and, in particular, of delivering two medicaments stored in separate primary packages. In a first step, the injection device may be loaded into the adaptor, preferably via the proximal opening of the second compartment. The injection device, in particular the reservoir of the device may hold a first medicament. In a next step, the mini-syringe may be loaded into the adaptor, preferably via the side window opening of the first compartment. The mini-syringe, in particular the first compartment, may hold a second medicament. Alternatively, the mini-syringe may be loaded first into the adaptor and, afterwards, the injection device may be loaded into the adaptor. In a further step, a dose to be injected may be dialled using the dose dialing module of the device. Afterwards, the injection device may be pushed distally relative to the adaptor housing such that the distal end of the injection device may cause the seal of the mini-syringe to tear open and such that needle stub may pierce through the piston of the mini-syringe and the septum of the reservoir. Piercing of the needle stub through the piston and the septum may establish fluid connection between the device and the mini-syringe. In particular, piercing of the needle stub through the piston and the septum may enable transfer of the first medicament in the reservoir or of at least a dose of the first medicament in the reservoir from the device into the distal chamber of the mini-syringe holding already the second medicament. In a next step, an injection button of the device is pushed for delivering the two medicaments, i.e. the medicament of the mini-syringe and the medicament initially held in the reservoir of the device, from the distal chamber to a user. Afterwards, the injection device may be pushed further distally in the adaptor housing by pushing onto the injection button such that the piston may reach the distal end of the distal chamber and such that the dose delivery may be completed. The injection device may then be pulled proximally to an initial position within the adaptor housing such that the needle stub may be removed from the septum. The back stops may prevent the mini-syringe from moving proximally. In a last step, the mini-syringe may be ejected from the adaptor, preferably in the direction perpendicular to the main longitudinal axis of the adaptor via the side window opening. Now, the injection system may be ready for introducing a new mini-syringe into the first compartment, for example.

The medicaments may both be liquid or, alternatively, one or more of the medicaments may be a powder, suspension or slurry. In one embodiment the mini-syringe could be filled with a powdered medicament that is either dissolved or entrained in the second medicament of the injection device as the second medicament is injected through the mini-syringe. In the broadest scope, these medicaments could be delivered via a number of routes of administration, for example needle based injections (as described), needle-free injection, inhalation etc. For example, an inhaler version of the present disclosure might replace the mini-syringe with a mini-container that connects to an MDI or DPI inhaler. The mouthpiece would be part of the mini-container. The patient would inhale through the mini container, actuating the MDI or DPI inhaler as normal. As the air and medicament passes through the mini-container the second medicament, contained in the mini-container, would become entrained in the airflow and delivered to the patient. Alternative embodiments of the mini-syringe include various methods of containing and expelling the medicament from the mini-syringe. For example, the medicament could be contained in a flexible container. The double-ended needle stub would pierce this container in much the same manner as the described rubber bung or piston is pierced. Medicament from the injection device would then be delivered into the flexible container, expelling liquid from the integrated needle. Further advancement of the injection device would then cause the flexible container to collapse, thereby expelling the remaining volume. Likewise, alternative uses of the mini-syringe concept could include connecting the mini- syringe to a single use injection device such as a prefilled syringe. This would enable a combination injection to be administered without the need for a "dual chamber cartridge". The mini-syringe and pre-filled syringe could then be filled separately using standard filling equipment without the risk of one medicament contamination the other either during manufacture or storage. In one such embodiment, the single use injection device could be a prefilled syringe with its own integrated needle stub. In this embodiment, the mini-syringe would not have the double-ended needle stub component. The mini- syringe would attach to the front of the pre-filled syringe and the integrated needle stub would pierce the bung of the mini-syringe. The injection would then proceed as per the described embodiment. The fluid would be expelled from the prefilled syringe into the mini-syringe, causing a mixture of medicament to be expelled from the integrated needle of the mini-syringe. Once the prefilled syringe is empty the pre-filled syringe would then press against the bung of the mini-syringe and cause the bung to advance, thereby expelling the remaining medicament. In a further single-use embodiment, the mini-syringe retains the double-ended needle stub and the pre-filled syringe features a septum seal rather than an integrated needle stub. The injection would then proceed as described in the other embodiments. According to a preferred embodiment, a mini-syringe is provided which is adapted for use with an injection device to co-deliver two medicaments in a single injection. The mini-syringe comprises a housing having a distal end and a proximal end. The mini- syringe comprises a pierceable piston slideably positioned inside the housing forming a distal chamberand a proximal chamber within the housing. The mini-syringe comprises a first needle assembly connected to the distal end of the housing and being in fluid communication with the distal chamber and a second needle assembly mounted in the piston.

According to a preferred embodiment, a mini-syringe for use with an injection device to co-deliver two medicaments in a single injection is provided. The mini-syringe comprises a housing having a distal end and a proximal end and a central axis. The mini-syringe comprises a pierceable piston slideably positioned inside the housing forming a distal chamber and proximal chamber within the housing. The mini-syringe comprises a first needle assembly connected to the distal end of the housing parallel to the central axis and in fluid communication with the distal chamber and a second needle assembly mounted in the piston parallel to the central axis.

According to a preferred embodiment, an adaptor for use in co-delivery of two medicaments is provided. The adaptor comprises a housing having a first compartment and a second compartment, where the first compartment is configured to accept a mini- syringe and having a window opening to allow insertion of the mini-syringe into the first compartment, where the second compartment has a proximal opening and is configured to accept an injection device. The adaptor comprises a needle opening in the first compartment to accept a needle assembly attached to the mini-syringe. The adaptor comprises back stops in the first compartment to prevent axial movement of the mini- syringe in a proximal direction.

According to a preferred embodiment, an injection system for co-delivery of two medicaments is provided. The injection system comprises the previously described mini-syringe. The injection system comprises an injection device. The injection system comprises an adaptor comprising a housing having a first compartment and a second compartment, wherein the first compartment is configured to accept the mini-syringe, and wherein the second compartment is configured to accept the device.

According to a preferred embodiment, an injection system for co-delivery of two medicaments is provided. The injection system comprises a mini-syringe comprising, a housing having a distal end and a proximal end, a pierceable piston slideably position inside the housing forming a distal chamber and proximal chamber within the housing, a first needle assembly connected to the distal end of the housing and in fluid communication with the distal chamber, and a second needle assembly mounted in the piston. The injection system comprises an adapter comprising a housing having a first compartment and a second compartment, where the first compartment is configured to accept the mini-syringe and having a side window opening to allow insertion of the mini- syringe into the first compartment, where the second compartment has a proximal opening and is configured to accept an injection device.

According to a preferred embodiment, a method for operating the previously described injection system is provided. The method comprises the step of loading the injection device into the adaptor. The method comprises the step of loading the mini-syringe into the adaptor. The method comprises the step of dialling a dose to be injected using the dose dialing module. The method comprises the step of pushing the injection device distally relative to the adaptor housing such that the distal end of the injection device causes the seal of the mini-syringe to tear open and such that needle stub pierces through the piston of the mini-syringe and the septum of the reservoir.

These as well as other advantages of various aspects of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings.

The scope of the invention is defined by the content of the claims. The invention is not limited to specific embodiments but comprises any combination of elements of different embodiments. Moreover, the invention comprises any combination of claims and any combination of features disclosed by the claims. BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are described herein with reference to the drawings, in which: Figure 1 illustrates one embodiment of the adaptor;

Figure 2 illustrates one type of injection device that can be used with the adaptor and the mini-syringe;

Figure 3 illustrates one embodiment of the mini-syringe;

Figure 4 illustrates the system with the mini-syringe and injection device loaded into the adaptor;

Figure 5 illustrates the system of Figure 4 immediately before the injection is given;

Figure 6 illustrates the system during the injection;

Figure 7 illustrates the system when the injection is completed; and Figure 8 illustrates the system when the injection device has been pulled axially in the proximal direction to disengage it from the mini-syringe and the mini-syringe being discarded through the window opening. DETAILED DESCRIPTION

Referring to Figure 1 there is shown adaptor 1 , which is preferably designed as a reusable device for each injection that requires the use of a mini-syringe. The adaptor 1 has a housing 8 with a proximal end 2 and a distal end 3, and having two compartments internally, a distal compartment 9 and a proximal compartment 5. A side window opening 4 provides access to the distal compartment 9 and permits side loading of a mini-syringe 20 (see Fig. 3). A needle opening 6 located at the distal end of the distal compartment 9 accommodates a diameter of a needle hub 23 of mini-syringe 20. A proximal opening 1 1 is of sufficient diameter and provides access to an appropriate injection device 30 to the proximal compartment 5.

Back stops 10 (see cut away of adaptor in Fig. 5) located inside the housing 8 at the proximal end of the distal compartment 9 prevent the mini-syringe from travelling backwards (proximally) into the proximal compartment 5 of the adaptor 1 . The back stops 10 define a diameter or opening that is sufficient to allow a distal hub 31 of the injection device 30 (see Fig. 2) to pass through and to engage a proximal chamber 27 of mini-syringe 20. Finger flanges 7 are optionally included and can be attached to or can be integral with the adaptor housing 8. The finger flanges 7 are located near the proximal opening 1 1 to assist the user when gripping the housing 8 during dose administration.

Additional adaptor features (not shown) might include connectors, stops, splines, ribs, grooves, or other design features to engage a specific design of an injection device 30, even those features that would prevent the insertion of a non-appropriate design of an injection device 30. Also possible are features to retain the injection device 20 in a rearward (proximal) position prior to the insertion of the mini-syringe 20 and possibly to return the injection device 30 to this position once the injection is complete when the user releases an injection button 51 of the device 30 (see Fig. 2). Such retention features could include a spring, or other biasing means, and would be designed to locate the injection device 30 in an initial position behind the back stops 10 so that the insertion of the mini-syringe 20 is not impeded by the presence of the injection device 30. It is also possible that this retention feature could be employed as a needle retraction/needle safety feature. The adaptor housing 8 could be designed to accommodate the mini-syringe 20 in a manner where a first needle assembly 22, 23 of the mini-syringe 20 (see needle 22 and needle hub 23 in Figure 2) is hidden prior to and after use. An initial advancing movement of the injection device 30 within housing 8, compressing the spring in the retention feature, could cause the mini-syringe 20 to advance, thus exposing the needle 22. Once the injection is complete and the user releases the injection button 51 , the spring would push the mini-syringe 20 and the injection device 30 backwards (in the proximal direction) and cause the needle 22 to retract. The retention feature and housing mechanism for the mini-syringe 20 could be designed in a manner that only allows the needle 22 to advance once and then, once retracted, prevents the needle 22 from a further advancing movement.

The mini-syringe 20 as shown in Figure 3 is a self-contained, preferably disposable, miniature injection device. The mini-syringe 20 contains a piston 29 (otherwise known as a "bung") positioned slideably within a housing 24. The mini-syringe 20 has a distal chamber 25 and a proximal chamber 27 separated and defined by piston 29. The proximal chamber 27 may be covered with a seal 26, which can maintain the sterility of a needle stub 40 until use. A cover or protective cap 28 surrounds and maintains the sterility of the first needle assembly 22, 23.

The housing 24 of the mini-syringe 20 may be a cylindrical body or any other geometric shape suitable for defining a fluid reservoir and for attaching the needle hub 23 into which the integrated needle cannula 22 can be attached. The housing 24 can be manufactured from glass or other drug contact suitable material. The integrated injection needle 22 can be any needle cannula suitable for subcutaneous or intramuscular injection and it is connected directly to the distal chamber 25 and in fluid communication with a medicament contained therein. The term "medicament", as used herein, preferably 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 proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody, 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 derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N- palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl- LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N- palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; Β29-Ν-(ω- carboxyheptadecanoyl)-des(B30) human insulin and B29-N-( -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- lle-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 [lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, lsoAsp28] Exendin-4(1 -39); or des Pro36 [Asp28] Exendin-4(1 -39),

des Pro36 [lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Trp(02)25, lsoAsp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, Asp28] Exendin-4(1 -39),

des Pro36 [Met(0)14 Trp(02)25, lsoAsp28] 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(02)25, Asp28] Exendin-4(1 -39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Trp(02)25] Exendin-4(1 -39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-NH2, des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Met(0)14, Asp28] Exendin-4(1 -39)-Lys6-NH2,

des Met(0)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1 -39)-NH2,

H-(Lys)6-desPro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-NH2, des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-Lys6-des Pro36 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25] Exendin-4(1 -39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] Exendin-4(1 -39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)- NH2,

des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(1 -39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)25, Asp28] Exendin-4(S1 -39)- (Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Trp(02)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, 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.

Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCI 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'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.

Piston 29 can be made of rubber or other material capable of sliding within housing 24 and forming a liquid seal between distal chamber 25 and proximal chamber 27. The piston may contain a hollow 41 on the non-fluid side to accommodate the double-ended needle stub 40. The walls of the hollow section of the piston 29 are in an interference fit to a hub 21 of the double-ended needle stub 40. The walls thus provide a means for retaining the needle stub 40 in a "bung non-pierced" position (as illustrated in Fig. 3) and for guiding the needle stub 40 as it is advanced to a "bung pierced" position, as illustrated in Figs. 6 & 7. The double-ended needle stub 40 is comprised of a small length of tubing or needle cannula designed with end geometries suitable for piercing the piston 29 on one end and for piercing a septum 33 (see Fig. 2) of the injection device cartridge 34 on the distal end thereof. The needle stub 40 is mounted in the hub 21 that provides a means for retaining and guiding the needle stub. The hub 21 also determines the exposed length of the two ends of the needle stub 40 and, hence, how far the stub 40 will protrude into both piston 29 and cartridge septum 33.

The sterile seal 26 of the mini-syringe 20 is preferably designed to be opened automatically, e.g. by cutting, tearing or peeling, when the injection device 30 is advanced within adaptor 1 by the user. This opening of seal 26 may be assisted by features such as angled surfaces on the end of the injection device 30 or features inside the adaptor 1 . Preferably, the opening of the sterile seal 26 will be designed in a manner whereby the exposed, and therefore non-sterile, surface of the sterile seal 26 does not come into contact with the needle stub 40. Alternatively the exposed surface of the sterile seal 26 could be sterilized prior to use, e.g. swabbed with alcohol. A further alternative is that sterile seal 26 is designed to be peeled off by the user prior to use.

Piston 29 may also contain a small recess 42 on the fluid side of the piston 29 to accommodate the sharpened distal tip of needle stub 40. This recess 42 allows the needle stub 40 to pierce the piston 29 without protruding far beyond it. This will allow the bung or piston 29 to travel further without the needle stub 40 contacting the distal end of distal chamber 25 and, therefore, reducing the dead volume of the mini-syringe 20.

The mini-syringe injection system will be designed to operate in conjunction with a multiple use injection device, preferably a pen-type multi-dose injection device, similar to what is illustrated in Fig. 2. The injection device 30 could be a reusable or disposable device. By disposable device it is meant an injection device that is obtained from the manufacturer and which is preloaded with medicament and cannot be reloaded with new medicament after the initial medicament is exhausted. The device may be a fixed dose or a settable dose device, but in either case it is a multi-dose device.

A typical injection device 30 contains the cartridge 34 or other reservoir of medication. This cartridge 34 is typically cylindrical in shape and is usually manufactured in glass. The cartridge 34 is sealed at one end with a rubber bung 35 and at the other end by rubber septum 33. The injection pen 30 is designed to deliver multiple injections. It therefore has features, for example a screw thread, which are used to attach a disposable injection needle. This injection needle is designed to pierce the cartridge septum 33 and to provide fluid communication between the contents of the cartridge 34 and the subcutaneous region of the patient. The medicament is expelled by a delivery mechanism 32 (see Figure 4) in the injection device 30 that causes the rubber bung 35 to advance. The delivery mechanism 32 is typically powered by a manual action of the user. However, the delivery mechanism 32 may also be powered by other means such as a spring, compressed gas or electrical energy (not explicitly shown).

The injection system can be designed to work with currently marketed pen-type injection devices 30 or may be designed to work only with only a particular design of injection device 30. This could be achieved by including specific features on the injection device 30 that engage matching or complementary features on either the adaptor housing 8 or the mini-syringe 20. One reason for restricting the use of the mini-syringe injection system to a particular injection device 30 is to ensure dose accuracy of the medicament delivered from the injection pen 30. When using one embodiment of the injection system, the medicament in the injection device 30 is transferred into the mini-syringe 20. At the end of the delivery, the mini-syringe 20 will contain a certain amount of medicament, most likely medicament from the injection device 30 that cannot be expelled because it is in the residual volume of the mini-syringe 20 (the volume that cannot be expelled by advancing the piston 29). Therefore, it may be preferable to use an injection pen 30 that is designed to deliver a dose that is increased from the label claim by an amount equal to the residual volume of the mini-syringe 20. If a user were to use this modified injection device 30 without the mini-syringe 20 attached, he would receive a small overdose compared to the nominally requested dose. Therefore, it would be preferable if the modified injection device 30 was designed such that it was not compatible with standard injection needles, but could only be used in conjunction with the mini-syringe 20.

Illustrative operation steps for using the injection system of the present disclosure include the following;

1 . Referring to Figs. 4-8, a user loads injection device 30 into adaptor 1 . The user inserts the injection device 30 from the proximal end 2 of the adaptor 1 , in particular via the proximal opening 1 1 (see Figure 1 ).

2. The user loads mini-syringe 20 through the side window opening 4 of adaptor 1 .

3. The user dials the dose to be injected using a dial sleeve of delivery mechanism 32 by turning the injection button 51 on the pen-type device 30.

4. The user removes the cover or protective cap 28 from the mini-syringe 20.

5. The user inserts the needle 22 into the skin 50. Fig. 5 illustrates this step and provides a cut-away of the adaptor 1 to show the relationship of the mini-syringe 20 to the distal end of the injection device 30.

6. The user actuates a proximal surface 36 of the injection button 51 to press the injection button 51 inwards (distally). This causes the injection device 30 to be pushed forward (distally) relative to the adaptor housing 8. The distal end of the injection device 30 causes the sterile seal 26 of the mini-syringe 20 to tear open. As the injection device 30 is pushed further forwards, the double-ended needle stub 40 pierces through mini- syringe piston 29 and the cartridge septum 33 of the injection device 30. In particular, the distal end of needle stub 40 is pushed into recess 42 to enable fluid communication with the distal chamber 25. As the injection button 51 is pushed in, medicament in the cartridge 34 begins to transfer from the pen device 30 into the distal chamber 25 of the mini-syringe 20 and mixes with the medicament originally present in the mini-syringe 20. This causes the fluid pressure to increase in the mini-syringe 20 and the delivery of the two mixed medicaments 52 (see Figure 6) begins through needle 22 and into the patient. Once the injection button 51 has been pushed fully forwards to its final position relative to the body of injection device 30, a volume equal to the dose set has been expelled from the injection device 30. However, the dose of the two medicaments will have been only partially delivered through the needle 22. The remainder of the dose of the two medicaments remains in the distal chamber 25 of the mini syringe 20.

7. The user continues pushing onto the proximal surface 36 of injection button 51 , causing the pen device 30 to be pushed forward in the adaptor housing 8. This, in turn, advances the piston 29 of the mini-syringe 20 distally inside housing 24 while delivery of the remaining mixed medicaments 52 in distal chamber 25 continues.

8. The piston 29 reaches the distal end of the mini-syringe 20 distal chamber 25 and the dose delivery is completed.

9. The user removes the needle 22 from the skin 50. 10. The user then pulls the pen device 30 in a backward direction (proximally) to the initial position within the adaptor housing 8. The back stops 10 in the housing 8 prevent the mini-syringe 20 from moving backwards, thus facilitating the removal of the needle stub 40 from the cartridge septum 33.

1 1 . A Rotation of the adaptor 1 , as indicated by arrow 53 to position the adaptor 1 such that the side window opening 4 faces downward causes the mini-syringe 20 to be ejected from the adaptor 1 , preferably directly into a sharps container for safe disposal.

Exemplary embodiments of the present invention have been described. Those skilled in the art will understand, however, that changes and modifications may be made to these embodiments without departing from the true scope and spirit of the present invention, which is defined by the claims.

REFERENCE NUMERALS

1 adaptor

2 proximal end

3 distal end

4 side window opening

5 proximal or second compartment

6 needle opening

7 finger flange

8 housing

9 distal or first compartment

10 back stop

1 1 proximal opening

20 mini-syringe

21 hub

22 needle

23 needle hub

24 housing

25 distal chamber

26 seal

27 proximal chamber

28 cover

29 piston

30 injection device distal hub delivery mechanism septum

cartridge

rubber bung proximal surface needle stub hollow

recess

skin

injection button mixed medicament arrow

Claims

1 . A mini-syringe (20) adapted for use with an injection device (30) to co-deliver two medicaments in a single injection, wherein the mini-syringe (20) comprises:

a housing (24) having a distal end and a proximal end;

a pierceable piston (29) slideably positioned inside the housing (24) forming a first distal chamber (25) containing medicament and a proximal chamber (27) within the housing (24);

a first needle assembly (22, 23) suitable for subcutaneous or intramuscular injection connected to the distal end of the housing (24) and being in fluid communication with the distal chamber (25); and

a second needle assembly (21 , 40) comprising a hub (21 ) fixed to the piston (29) and a needle cannula or stub (40) which is sharpened on both ends.

2. The mini-syringe (20) of claim 1 ,

wherein the first chamber (25) contains a liquid medicament.

3. The mini-syringe (20) of claim 1 or claim 2,

wherein the proximal chamber (27) is covered with a pierceable seal (26) that maintains sterility of the second needle assembly (21 , 40).

4. The mini-syringe (20) according to any of the previous claims wherein the needle stub (40) is configured to pierce through the piston (29).

5. The mini-syringe (20) according to any of the previous claims,

where the proximal chamber (27) is configured to accept a needle hub of the injection device (30).

6. The mini-syringe (20) according to claim 4 or claim 5,

where the piston (29) contains a fluid recess (42) arranged on its distal end, wherein the fluid recess (42) is configured to accept a portion of the needle stub (40) during injection.

7. An injection system for co-delivery of two medicaments comprising

- the mini-syringe (20) according to any of claims 1 to 6;

- an injection device (30);

- an adaptor (1 ) comprising a housing (8) having a first compartment (9) and a second compartment (5), wherein the first compartment (9) is configured to accept the mini- syringe (20), and wherein the second compartment (5) is configured to accept the device (30), wherein the first compartment (9) has a window opening (4) to allow insertion of the mini-syringe (20) into the first compartment (9).

8. The injection system of claim 7,

wherein the second compartment (5) has a proximal opening (1 1 ) to allow insertion of the injection device (30).

9. The injection system of claim 7 or claim 8,

wherein the adaptor (10) comprises a needle opening (6) in the first compartment (9) configured to accept the first needle assembly (22, 23) attached to the mini-syringe (20); and

back stops (10) arranged in the first compartment (9) configured to prevent axial movement of the mini-syringe (20) in a proximal direction with respect to the first compartment (9).

10. The injection system according to any of claims 7 to 9,

wherein the injection device (30) has a reservoir (34) of medicament sealed with a septum (33), and wherein the device (30) has a dose dialing module (32).

11. The injection system according to any of claims 7 to 10,

wherein the adaptor (1 ) and the injection device (30) are an integrated assembly.

12. An injection system according to any of the claims 7 to 11 , wherein the second compartment (5) is configured to enable distal movement of the injection device (30) relative to the housing (8) upon pushing on an injection button (51 ) of the device (30) such that

- the piston (29) is moved to discharge the medicament from the first distal chamber (25) of the mini-syringe (20);

- the piston (29) of the mini-syringe (20) and the septum (33) of the reservoir (34) are pierced by the needle stub (40) establishing fluid communication between the injection device (30) and the first needle (22) at the distal end of the mini-syringe (20); - medicament from the injection device (30) can be discharged through said first needle (22).

13. A method for operating the injection system according to any of claims 7 to 12 comprising the steps of:

-Loading the injection device (30) into the adaptor (1 );

- Loading the mini-syringe (20) into the adaptor (1 );

- Dialling a dose to be injected using the dose dialing module (32);

- Pushing the injection device (30) distally relative to the adaptor housing (8) such that the distal end of the injection device (30) causes the seal (26) of the mini-syringe (20) to tear open and such that needle stub (40) pierces through the piston (29) of the mini- syringe (20) and the septum (33) of the reservoir (34).

14. The method of claim 13,

wherein piercing of the needle stub (40) through the piston (29) and the septum (33) enables transfer of the medicament in the reservoir (34) from the device (30) into the distal chamber (25) of the mini-syringe (20).

15. The method of claim 12 or claim 13,

further comprising the steps of:

- Pushing onto an injection button (51 ) of the device (30) for delivering the two medicaments from the distal chamber (25) to a user; - Further pushing the injection device (30) distally in the adaptor housing (8) by pushing onto the injection button (51 ) such that the piston (29) reaches the distal end of the distal chamber (25) and such that the dose delivery is completed;

- Pulling the injection device (30) proximally to an initial position within the adaptor housing (8) such that the needle stub (40) is removed from the septum (33), wherein the back stops (10) prevent the mini-syringe (20) from moving proximally;

- Ejecting the mini-syringe (20) from the adaptor (1 ).