Description Field of the Invention

The present invention relates to the field of drug delivery devices and systems and in particular to devices and systems adapted to prepare and/or to administer a medicament, preferably a multi-component medicinal fluid.

Background and Prior Art

Numerous medicinal products are provided in liquid form and require particular preparation prior to be administered to a patient. For instance, some medicinal products are provided as a multi-component product that requires mixing of its separate components prior to application. Since the various components of the medicament might be insoluble and/or may separate, e.g. due to different specific masses, a direct and immediate mixing process prior to application is generally required. Moreover, by manufacturing and distributing various components of medicaments in a separate way, shelf life of the medicament and its components may increase and/or transportation and general handling of the components might become less complicated. This way, decomposition of a mixture of multiple components can be effectively prevented. In the course of applying or administering a liquid medicament to a patient, the flow rate of the medicinal fluid is rather low. A mixing of various liquid substances is crucial and gets even more difficult as the geometry of flow through channels decreases. According to the basic principle of fluid dynamics, rather small ducts and channels support a laminar flow whereas an increase in duct size allows for a turbulent flow which is generally advantageous for a mixing purpose.

Objects of the Invention It is therefore an object of the present invention to provide a drug delivery system for preparing and/or administering a medicinal fluid, wherein the fluid compris esnumerous liquid or soluble substances to be mixed prior to application or administering to a patient. It is a further object, to provide a liquid medicinal fluid which is highly homogeneous and which comprises a well-defined composition of various liquid substances. Furthermore, the drug delivery system should be easy to handle and should be inexpensive to manufacture. Summary of the Invention

In a first aspect, the invention provides a drug delivery system for preparing and/or for administering a medicinal fluid. The drug delivery system comprises at least a first reservoir filled with a first liquid substance and further comprises at least a second reservoir filled with a second liquid substance, respectively.

The drug delivery system further comprises a micro mixing device that has at least a first inlet port and which is in fluid-flow communication with at least the first and the second reservoir for mixing first and second substances, respectively in order to obtain the medicinal fluid to be administered. The micro mixing device further has an outlet port to dispense the mixed medicinal fluid to an administering module, which, in turn is adapted to store, to administer or to apply the medicinal fluid to a patient. The micro mixing device is particularly adapted to mix the at least first and second substances with each other, typically by way of emulsifying or dispersion.

By making use of a micro mixing device, even small amounts of a first and a second liquid substance to be provided to an administering module at a

comparatively low flow rate can be mixed on demand, immediately prior to administering the medicinal fluid to a patient. By way of a micro mixing device, at least two liquid substances can be homogeneously mixed with each other, even by taking into account peculiar properties arising from the field of micro fluidics.

Generally, flow channels for the first and/or second liquid substance inside the micro mixing device may scale between a few micrometers up to one millimetre. Preferably, mixing of first and second liquid substances takes place in the micro mixing device featuring channels or ducts having diameters of less than 1 mm, preferably less than 500 pm, less than 300 pm, less than 100 pm or even less than 50 pm or less than 10 pm. By means of a micro mixing device, numerous substances can be mixed on a micrometer scale, thus providing a highly

homogeneous emulsion or dispersion of a multi-component medicinal fluid.

The drug delivery system can be adapted to various application scenarios, in particular for a variety of drug delivery devices, wherein the administering module arranged downstream the micro mixing device may be implemented as a pen-type injection system, as a syringe, as an inhaler, as a vial, as a tube or as a container for receiving and storing the mixed substances.

The internal design and structure of the micro mixing device may individually depend on the substances to be mixed as well as on required flow rates of the medicinal fluid to be mixed therewith.

According to another preferred aspect, the micro mixing device comprises at least a first inlet port and a second inlet port that are both in fluid-flow communication with the first reservoir and the second reservoir, respectively. This way, first and second substances to be mixed by way of the micro mixing device can be fed at different flow rates towards the micro mixing device, thus allowing to universally vary the composition of the medicinal fluid. Hence, the composition of a medicinal fluid can be modified immediately prior to injection or application to a patient.

Furthermore, and according to another aspect, the drug delivery system may be equipped with at least a first pump arranged between the first and/or the second reservoir and the micro mixing device for feeding the micro mixing device with the first and/or second substance, respectively. By way of a pump, preferably by way of a micro pump, flow rates of first and/or second liquid substances can be individually adapted in order to prepare medicinal fluids of various composition downstream of the micro mixing device.

According to an alternative embodiment, a second pump can be arranged downstream of the micro mixing device. In such an arrangement, first and/or second substances might be sucked through the micro mixing device. Depending on the viscosity and the geometry of the drug delivery system, it is even

conceivable to operate the drug delivery system without a pump, such that the flow of first and/or second liquid substance is governed exclusively by gravitation.

In still another embodiment, first and/or second reservoirs are coupled with respective first and/or second drive mechanisms for feeding the first and/or the second substance to the respective inlet ports of the micro mixing device. For instance, when first and/or second reservoirs comprise a syringe-like configuration, wherein by way of displacement of a moveable piston a certain amount of first and/or second liquid substances can be expelled from respective first and/or second reservoirs, a first and/or second pump may be effectively replaced. Hence, by a respective drive mechanism, first and/or second liquid substances can be urged through the micro mixing device.

It is of further advantage, when the administering module comprises an injection device or wherein the administering module comprises a cartridge that is adapted to receive and to store the prepared medicinal fluid. Such a cartridge is preferably adapted to be disposed inside a drug delivery device for dispensing a dose of the medicinal fluid e.g. by way of injection. In particular, the injection device may comprise a pen-type injector or may comprise a perfusor arrangement adapted to constantly provide a medicinal fluid to a patient on the basis of a well-defined and controlled flow rate. According to a further preferred embodiment, the micro mixing device is of passive type. Hence, the mixing process in the micro mixing device relies mainly on molecular diffusion and chaotic advection. Molecular diffusion can be generally improved by increasing the contact surface between the various fluids and by decreasing the diffusion path between them. Chaotic advection can for instance be implemented by manipulating the laminar flow in the micro channels of the micro mixing device. In general, various micro mixing principles can be applied here. The micro mixing device may comprise a basic T-mixer, a Y-mixer or may implement the concept of parallel lamination and/or the concept of hydraulic focussing.

In a further embodiment, the micro mixing device and the mixing effect to be achieved therewith may be based on lamination, injection, chaotic advection and/or droplet generation. With a lamination based micro mixing device, an inlet stream is divided into numerous substreams that are joined into one stream as laminae, wherein the flow in the micro mixing device is usually driven by pressure but may also be generated by electro-osmosis. In contrast to parallel lamination micro mixing, also a serial lamination mixer geometry can be applied here. Typical serial lamination mixer principles are join- split-join; split-join; split-split-join and/or multiple intersecting micro channels.

Hence, with serial lamination mixers, an inlet stream is consecutively split and joined, typically in different directions. With injection mixers, only a solute flow is split into many streams and is injected into a solvent flow. On top of one stream is arranged an array of nozzles, which create a number of micro plumes of the solute. These plumes increase the contact surface and decrease the mixing path.

For generating chaotic advection in a micro mixing device it is generally beneficial to insert obstacles in a mixing channel. Moreover, it is conceivable to make use of zig-zag micro channel structures to produce recirculation around respective turns. Also, depending on the Reynolds number, respective mixing channels or mixing chambers of the micro mixing device may comprise a so-called modified Tesla structure, C-shape; L-shape or a twisted micro channel shape.

Generally, the drug delivery system is not restricted to a single micro mixing device. The system may comprise numerous micro mixing devices, that can be arranged parallel and/or serial for parallelly or sequentially mixing various

substances and their intermediate products.

Moreover, the drug delivery system is also not constricted to passive type micro mixing devices. Generally, also micro mixing devices of active type can be universally implemented here. Active micro mixing devices may for instance be based on serial or sequential segmentation, tailor dispersion, pressure disturbance, electrohydrodynamic disturbance, dielectrophoretic disturbance, electrokinetic disturbance, acoustic and/or thermal disturbance and/or on the basis of integrated microstirrer in a mixing chamber. With active micro mixing devices, at least the flow of one substance to be mixed with another one is occasionally or regularly stopped, e.g. by way of a micro pump or similar devices adapted to control a flow of a mixing substance. For instance electrical conductors may generate a magnetic field, that may stimulate movement of magnetic beads, which, in turn may improve the mixing significantly. Mechanical disturbances may also be generated by an integrated magnetic microstirrer that is placed at the interface between two liquids in a T- mixer. Electrohydrodynamic disturbances can be achieved by electrodes placed along a mixing channel, wherein by changing the voltage and frequency on the electrodes has a significant influence on the mixing of the substances.

By way of dielectrophoretic disturbance, wherein a non-uniform electrical field is generated around the particles to be mixed, said particles may move towards and away from an electrode. Among the variety of fundamental mixing principles to be applied with micro mixing devices, for instance by applying thermal energy, a temperature gradient can be generated across a number of parallel channels in order to investigate the temperature dependence of the substances to be mixed with each other.

According to another preferred aspect, the micro mixing device comprises a polymer based substrate material. Alternatively or additionally, the micro mixing device may be manufactured on the basis of silicon and/or glass. Moreover, the micro mixing device may comprise steel or other metals inert to the substances to be mixed. It may for instance also comprise titanium.

Among a variety of materials applicable to manufacture micro mixing devices, polymers and polymeric fabrication techniques seem to be favourable, both in terms of biocompatibility and in terms of production costs. Polymeric material can be easily prepared and manipulated, e.g. by polymeric bulk micro machining, such as hot embossing, injection moulding, casting and laser ablation.

Especially by making use of polymer based micro mixing devices, the drug delivery system becomes applicable and affordable for numerous mixing applications for medical substances.

According to a further but independent aspect, the invention also provides a method of preparing and/or administering a medicinal fluid, wherein the method comprises the steps of:

1 . providing at least a first reservoir filled with a first liquid substance,

2. proving at least a second reservoir filled with a second liquid substance, and 3. mixing the at least first and second substances by means of a micro mixing device to obtain and/or to prepare the medicinal fluid prior to dispense the medicinal fluid via an outlet port to an administering module, like a syringe, a perfusor, an inhaler, an vial, a container or the like.

The term ..medicament" or "medicinal product", as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, a antibody, 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 exedin-3 or exedin-4 or an analogue or derivative of exedin-3 or exedin-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-G lu-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 [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

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 Exedin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 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.

It will be further apparent to those skilled in the pertinent art that various

modifications and variations can be made to the present invention without

departing from the spirit and scope of the invention. Further, it is to be noted, that any reference signs used in the appended claims are not to be construed as lim iting the scope of the present invention.

Brief Description of the Drawings

In the following, preferred embodiments of the invention will be explained in greater detail by making reference to the drawings in which:

Figure 1 schematically illustrates a drug delivery system according to a first embodiment, Figure 2 shows a drug delivery system according to a second embodiment, and

Figure 3 is illustrative of a third embodiment, wherein a pump is arranged

downstream a m icro m ixing device. Detailed Description

The schematic illustration according to Figure 1 shows a drug delivery system 1 0 comprising a first reservoir 12 filled with a first liquid substance and further comprising a second reservoir 14 filled with a second liquid substance. Both substances are to be fed through respective channels or ducts 16, 1 8 to a micro m ixing device 20. In order to control the fluid flow of first and second substances, a pump 22 is arranged downstream the first and second reservoirs 12, 14 but upstream the m icro m ixing device 20. By way of the m icro m ixing device 20, the at least first and second substances can be mutually m ixed and may be dispensed in form of a homogeneous emulsion or dispersion to an adm inistering module 32. The channels or ducts providing a fluid-flow communication between first and second reservoirs 12, 14 and the m icro m ixing device 20 merge upstream of the pump 22. The feeding or flow rate of the substances contained in first and second reservoirs, respectively, is therefore substantially constant. Downstream of the pump 22, the combined fluids of the first and second reservoir 12, 14 are fed towards the m icro m ixing device 20 via an inlet port 26. By way of the m icro m ixing device 20, the at least two substances are emulsified and/or dispersed in order to produce a homogeneous medicinal product to be fed through the outlet port 30 to the adm inistering module 32. The adm inistering module 32 may comprise a cartridge for a drug delivery device, such as a pen-type injector or a perfusor. The cartridge may be adapted to be inserted into a respective drug delivery device when disconnected from the outlet port 30. Sim ilar, first and/or second reservoirs 12, 14 may be disconnected or reconnected from or with the respective ducts 16, 1 8, for instance in order to replace an empty reservoir 12, 14 by a filled one.

In the configuration as depicted in Figure 2, the first and/or the second duct 16, 1 8 are provided with a separate pump 22, 24. Additionally, the m icro m ixing device 20 comprises two separate inlet ports 26, 28, each of which being separately connected to the first and the second pump 22, 24, respectively.

In this embodiment, a composition of the medicinal product to be m ixed by the m icro m ixing device 20 can be arbitrarily modified, e.g. by changing the flow rates of first and/or second pumps 22, 24, respectively.

Instead or additional to the pumps 22, 24 the first and/or second reservoirs 12, 14 can be equipped with first and/or second drive mechanisms 36, 38 that allow to expel or to urge the respective liquid substance contained in said reservoirs 12 , 14 into the ducts or flow channels 16, 1 8.

In still another embodiment as depicted in Figure 3, a single pump 34 is arranged downstream of the micro mixing device 20. This way, first and/or second substances can be sucked through the channel system 16, 18 into and through the micro mixing device 20.

List of Reference Numerals

10 drug delivery system

12 reservoir

14 reservoir

16 flow channel

18 flow channel

20 micro mixing device

22 pump

24 pump

26 inlet port

28 inlet port

30 outlet port

32 administering module

34 pump

36 drive mechanism

38 drive mechanism