Patent Publication Number: US-2020281815-A1

Title: Mixing and/or Reconstitution System

Description:
The invention refers to a mixing and/or reconstitution system, in particular a drug mixing and/or reconstitution system and a respective method. 
     Certain drugs are ideally administered in a liquid form, injected subcutaneously for the optimal therapeutic effect. However, some of these liquid drugs are unstable, having a shelf life that is relatively short. This can be a problem both for prophylactic treatments, where patients must inject themselves on a regular basis and therefore want to keep a reasonable supply of drug at home, and for emergency treatments, where patients need to keep a supply of the drug to hand but may not need it for weeks or longer. 
     In this case often drugs in a concentrated liquid form or lyophilized (freeze-dried) drugs are used, which usually comprise separate components, namely a powder or liquid which is much more stable and therefore has a long shelf life, and a diluent liquid. These components are typically supplied in separate vials and the user must reconstitute the drug prior to injection. Such reconstitution is often a complex process with many steps. Also, there is the risk during the reconstitution process at various points that, if the user is not careful, the drug can be contaminated. Therefore, there is a need for a system and a method which removes the possibility of user error and provides a well reconstituted drug in a short time. 
     From document U.S. Pat. No. 6,238,372 B1 a fluid control device for use with a syringe and at least one medical vessel is known, wherein the fluid control device comprises three ports, one of it for receiving a syringe, and a rotatable flow control member. There is a need for a system or injection device which reduces the possibility of user error and provides an easy operation with less user steps. 
     The above problem is solved by the system defined in claim  1 . It is further solved by the method defined in claim  13 . 
     According to the invention a mixing and/or reconstitution system comprises in particular
         an adaptor,   an integrated injection device removably attached to the adaptor comprising a switching element,   a first reservoir, containing a first material (for example pre-filled with water), wherein the first material is a fluid, and   a user-operable trigger,
 
wherein the adaptor further comprises
   a first attachment location, e.g. a recess, adapted to attach a vial, wherein the vial contains a second material within a second reservoir, wherein the second material contains a medicament formulation,   a first connection element, e.g. a first needle,   a flow channel providing fluid communication of the switching element and the first connection element,   a sensing arrangement for detecting a pre-defined position of the vial at the first attachment location, and   an interlock element which is adapted to allow operating the trigger by the user in order to establish a fluid communication between the first connection element and the first reservoir (e.g. piercing a membrane sealing the first reservoir by the first needle) only if the sensing arrangement detects the pre-defined position of the vial at the first attachment location.       

     The mixing and/or reconstitution system according to the invention simplifies the reconstitution and/or mixing of a first and a second material compared to existing devices. The inventive system supports the user in following the correct mixing and/or reconstitution sequence while minimizing the necessary operating steps preventing misuse. Additionally, usage of a high number of separate components is avoided. The adaptor with the injection device and the first reservoir, for example provided by a cartridge, is pre-assembled and may allow long-term storage, in particular if the first fluid material is water. The only separate component is formed by the vial. Simplification of use and prevention of misuse is realized mainly by the interaction of the sensing arrangement and the interlock element of the adaptor. The cooperation of the sensing arrangement and the interlock element makes sure that only if the vial is attached to the adaptor at the pre-defined position, i.e. the correct position, the trigger is allowed to be operated by the user in order to establish a fluid communication between the first connection element and the first reservoir and thereby between the first reservoir containing the fluid material and the second reservoir of the vial containing the second material. After establishing this fluid communication the fluid material contained within the first reservoir is allowed to be transferred from the first reservoir to the second reservoir of the vial for mixing and/or reconstitution. Accordingly, the inventive system provides a pre-defined sequence of steps during use. 
     In one embodiment the first attachment location may be formed as a recess within the adaptor guiding the vial into the pre-defined position. The guiding may be further enhanced by providing a lever, for example at the end of the recess opposite from the first attachment location which guides and/or presses the vial more reliable into the pre-defined position than by the user. 
     The inventive system has the further advantage that the system provides large handling surfaces to hold the system and apply the necessary force for operation. 
     In one embodiment the interlock element may fix the first reservoir in a pre-defined position with regard to the adaptor thereby preventing operation of the trigger which is connected to the first reservoir, for example by a plunger sealing the first reservoir. If the pre-defined position of the vial is detected by the sensing arrangement the interlock element and with it the first reservoir is no longer fixed but movable, for example along the longitudinal direction of the adaptor in order to establish the fluid communication between the first connection element and the first reservoir. 
     The present invention particularly refers to the mixing and/or reconstitution of a first material and a second material, wherein the first material is a fluid, and the second material contains a medicament formulation, where in the second material is a solid material. Reconstitution is the rehydration of a lyophilized (freeze dried) drug (e.g. medicament formulation) by a diluent (e.g. the fluid first material). The term mixing refers to any other intermixing of any first and second material. 
     In one embodiment the first material is a fluid drug component and the second material is a solid drug component. In another embodiment, the second material is a fluid. 
     In one embodiment the adaptor comprises an upper body (housing) and a lower body (housing) attached to each other, for example, by a snap-fit connection in order to reduce production costs. In another embodiment the adaptor is provided with a single piece body (housing). The adaptor may have a basically cylindrical form. 
     In one embodiment the trigger may be the plunger of the injection device or a plunger of a cartridge or a longitudinally movable element, e.g. a plunger, of the adaptor connected to the plunger of the cartridge. In one embodiment the plunger is movable by the user from an initial first position to a second position in which a pre-defined or the full content of the first reservoir is transferred to the vial. At the first position and/or the second position the plunger may be secured to the adaptor using a snap-fit connection. Therefore, the plunger may comprise, for example, a flexible web with a projection and the body, e.g. the upper body, a respective projection at a position of the body of the adaptor corresponding to the first and/or second position of the plunger. 
     In another embodiment the first reservoir is provided by the injection device, for example in form of a syringe, or by a cartridge separate from the injection device. If the first reservoir is provided by the injection device there may be a cartridge forming the first reservoir integrated in the injection device. If the first reservoir is provided by the injection device, it is not necessary to provide a cartridge separate from the injection device for the first material. 
     The first connection element may be formed as a first needle or trocar. 
     In another embodiment the first attachment location comprises a second connection element, e.g. a second needle or trocar or a needle section of a double-ended needle forming the connection element for the first reservoir, which is adapted to establish a fluid communication between the flow channel and the second reservoir of the vial during attachment of the vial at the first attachment location. In the pre-defined position the vial may be attached such at the first attachment location that the second connection element forms a fluid connection with the second reservoir of the vial. In this case the second connection element provides a fluid connection with the flow channel of the adaptor. 
     In another embodiment the sensing arrangement is adapted to take an initial first state and a second state different from the first state and indicating that the vial is in the pre-defined position at the first attachment location. 
     In one embodiment sensing arrangement may be formed in one embodiment by a flexible leg of a cartridge protector forming a latch connection with an element of the adaptor, e.g. a projection at its inner surface. In this embodiment in the initial first state the latch is locked whereas in the second state indicating that the vial is in the pre-defined position the vial, for example its cap, actuates, e.g. bends, the leg such that latch is released. In this embodiment the cartridge protector is fixed by the locked latch in the initial state. In the second state, in which the latch is released, the cartridge protector is movable along the longitudinal direction of the adaptor thereby allowing the first reservoir connected to the cartridge protector to be moved along the longitudinal direction of the adaptor in order to establish the fluid communication between the first connection element and the first reservoir. 
     In another embodiment the sensing arrangement may be formed by a leg projecting from the adaptor, for example within a recess, and a slider connected to the leg. In this embodiment in the initial first state the slider is locked in a first position whereas in the second state indicating that the vial is in the pre-defined position the vial, for example its wall, actuates, e.g. bends, the leg such that slider is moved (slid) a pre-defined distance. In this embodiment the cartridge protector is fixed by the locked slider in the initial state. In the second state the opening of the slider meshes with a respective projection of the adaptor such that the slider is movable along the longitudinal direction of the adaptor thereby allowing the first reservoir connected to the slider to be moved along the longitudinal direction of the adaptor in order to establish the fluid communication between the first connection element and the first reservoir. 
     In a further embodiment the first attachment location comprises at least one fixing element, e.g. a hook, for fixing the vial at the attachment position. This prevents a displacement of the vial during mixing and/or reconstitution. 
     In another embodiment the trigger, e.g. the plunger of the adaptor, comprises a guard allowing access to the plunger of the injection device only if the sensing arrangement detects the pre-defined position of the vial at the first attachment location. 
     In a further embodiment the first connection element may be provided at a second attachment location formed by the adaptor, for example a recess. Alternatively, the first connection element may be provided within the injection device, for example within its housing. The second attachment location realizes a precise attachment of the separate cartridge at the adaptor or an accurate fixation of the first reservoir, for example provided by a cartridge, within the injection device. 
     In another embodiment the switching element is a two-way selector valve comprising an initial first channel (path) and a second channel (path), wherein the first channel provides a fluid communication between a third reservoir of the injection device and the flow channel of the adaptor and the second channel provides a fluid communication between a needle of the injection device and the third reservoir of the injection device, wherein the valve is adapted to switch between the first channel and the second channel. 
     Alternatively, if the first reservoir is provided by the injection device, the switching element is a two-way selector valve comprising an initial first channel (path) and a second channel (path), wherein the first channel provides a fluid communication between first connection element (provided within the injection device) and the flow channel of the adaptor and the second channel provides a fluid communication between a needle of the injection device and the first connection element and thereby the first reservoir, wherein the valve is adapted to switch between the first channel and the second channel. 
     In another embodiment the switching element may be adapted to be switched between the first channel and the second channel using at least one key projecting from the surface of the adaptor, wherein the at least one key is actively connected with the switching element fixing it at the adaptor during moving and/or pivoting of the injection device relative to the adaptor. Switching between the first channel and the second channel may be realized for example by rotation of the injection device relative to the switching element, for example by an angle between 30° and 70°. In one embodiment the switching element is fixed at the housing and the injection device is rotated. Alternatively, the injection device is held fixed and the switching element is rotated, for example by the angle mentioned above. 
     In another embodiment the adaptor comprises a de-aeration channel, e.g. at the second connection element. The channel may be formed as a notch at the outer surface of the connection element, which may be realized as a needle or needle section. This enables venting of the vial during filling the fluid first material into the second reservoir containing the medicament formulation. It is important that the channel has a diameter which is big enough to keep the connection open but small enough to prevent leakage of fluid from the vial. 
     In one embodiment the needle of the injection device may be protected by the adaptor (caused by integration of the injection device into the adaptor) or by a needle shield and/or guard and/or or cap, for example by a folding or sliding sleeve. 
     In one embodiment the injection device may be fixed at the adaptor such that the injection device&#39;s axis is oblique with regard to the axis of the cartridge and/or the vial when attached to the adaptor in order to ease operation of the injection device plunger for drawing the mixed and/or reconstituted material out of the second reservoir into the first reservoir or an injection device reservoir. 
     The injection device may comprise a housing, the first reservoir within an integrated volume or a cartridge or an injection device reservoir (third reservoir), and a drive mechanism for expelling the content of the mixed and/or reconstituted material out of the respective reservoir. 
     In one embodiment the system comprises the vial containing a second material within a second reservoir, wherein the second material contains a medicament formulation. 
     The above task is also solved by the simplified and hence user friendly as well as misuse safe method for mixing and/or reconstitution of a first fluid material and a second material using the above described system comprising the following steps:
         attaching the vial to the first attachment location of the adaptor such that the sensing arrangement detects the vial being placed at the pre-defined position thereby allowing operation of the trigger by the user,   operating the trigger by the user thereby establishing a fluid communication between the first connection element and the first reservoir (e.g. piercing a membrane sealing the first reservoir by the first needle) and emptying the first material into the second reservoir,   waiting a first pre-defined time period and/or swiveling the vial a pre-defined number of times or over a second pre-defined time period,   afterwards by operation of the injection device plunger drawing the mixed and/or reconstituted material out of the second reservoir into the first reservoir or an injection device reservoir.       

     Another advantage of the above inventive method is that establishing a fluid communication between the first connection element and the first reservoir and emptying the first material into the second reservoir is provided within one step by a continuous actuation of the trigger (e.g. movement into the longitudinal direction of the adaptor) once the operation of the trigger is allowed. 
     In one embodiment the vial is pressed to the first attachment location using a lever. The lever reduces the necessary user force needed by the user to establish a fluid communication between the first connection element and the first reservoir. 
     In one embodiment the method comprises the additional step that prior administration of the mixed and/or reconstituted material the injection device is detached from the adaptor and the two-way switching element is switched from the first channel to the second channel. 
     The term “medicament” or “medicament formulation”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, 
     wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
 
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
 
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
 
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
 
     Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin. 
     Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin. 
     Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2. 
     Exendin-4 derivatives are for example selected from the following list of compounds:
     H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,   H-(Lys)5-des Pro36, des Pro37 Exendin-4)1-39)-NH2,   des Pro36 Exendin-4)1-39),   des Pro36 [Asp28] Exendin-4)1-39),   des Pro36 [IsoAsp28] Exendin-4)1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4)1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4)1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4)1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4)1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4)1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4)1-39); or   des Pro36 [Asp28] Exendin-4)1-39),   des Pro36 [IsoAsp28] Exendin-4)1-39),   des Pro36 [Met(O)14, Asp28] Exendin-4)1-39),   des Pro36 [Met(O)14, IsoAsp28] Exendin-4)1-39),   des Pro36 [Trp(O2)25, Asp28] Exendin-4)1-39),   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4)1-39),   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4)1-39),   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4)1-39),
 
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
 
or an Exendin-4 derivative of the sequence
   des Pro36 Exendin-4)1-39)-Lys6-NH2 (AVE0010),   H-(Lys)6-des Pro36 [Asp28] Exendin-4)1-39)-Lys6-NH2,   des Asp28 Pro36, Pro37, Pro38Exendin-4)1-39)-NH2,   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4)1-39)-NH2,   H-Asn-(Glu)5des Pro36, Pro37, Prop38 [Asp28] Exendin-4)1-39)-NH2,   des Pro36, Pro37, Pro38 [Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4)1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4)1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4)1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4)1-39)-NH2,   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4)1-39)-Lys6-NH2,   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4)1-39)-NH2,   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4)1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4)1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O) 14 , Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4)1-39)-Lys6-NH2,   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4)1-39)-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4)1-39)-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4)1-39)-NH2,   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4)1-39)-(Lys)6-NH2,   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4)S1-39)-(Lys)6-NH2,   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4)1-39)-(Lys)6-NH2;
 
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
   

     Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin. 
     A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. 
     Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. 
     The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about  220  amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. 
     There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, 
     IgG, and IgM antibodies, respectively. 
     Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. 
     In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. 
     Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity. 
     An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv). 
     Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington&#39;s Pharmaceutical Sciences”  17 . ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology. 
     Pharmaceutically acceptable solvates are for example hydrates. 
    
    
     
       Non-limiting, exemplary embodiments will now be described with reference to the accompanying drawings, in which: 
         FIG. 1  shows a principle sketch of a sectional view of first embodiment of a mixing and/or reconstitution system without vial; 
         FIG. 2  shows a perspective side view of the first embodiment of a mixing and/or reconstitution system in an initial state without vial; 
         FIG. 3  shows a perspective side view of an upper body of the system of  FIG. 2 ; 
         FIG. 4  shows a perspective side view of a lower body of the system of  FIG. 2 ; 
         FIG. 5  shows a perspective side view of a plunger of the system of  FIG. 2 ; 
         FIG. 6  shows a perspective side view of a cartridge protector of the system of  FIG. 2 ; 
         FIG. 7  shows a perspective side view of an attachment element of the system of  FIG. 2 ; 
         FIG. 8  shows a perspective side view of a valve of the system of  FIG. 2 ; 
         FIG. 9  shows a perspective side view of a syringe of the system of  FIG. 2 ; 
         FIG. 10  shows a perspective side view of a needle with protection element of the system of  FIG. 2 ; 
         FIG. 11  shows a perspective side view of a cartridge of the system of  FIG. 2 ; 
         FIG. 12  shows a perspective side view of a vial used for the system of  FIG. 2 ; 
         FIG. 13  shows a perspective bottom view of the upper body of the system of  FIG. 2 ; 
         FIG. 14  shows another perspective side view of system of  FIG. 2  with vial; 
         FIG. 15  shows a sectional view of the system of  FIG. 2  with vial; 
         FIG. 16  shows a perspective side view of the system of  FIG. 2  during a first step of the mixing and/or reconstitution method; 
         FIG. 17  shows an enlarged detail of a sectional view of the system of the system of  FIG. 2 ; 
         FIG. 18  shows the detail of  FIG. 17  during a first step of the mixing and/or reconstitution method; 
         FIG. 19  shows the detail of  FIG. 17  during a second step of the mixing and/or reconstitution method; 
         FIG. 20  shows an enlarged detail of a sectional view of the system of the system of 
         FIG. 2  during a third step of the mixing and/or reconstitution method; 
         FIG. 21  shows an enlarged detail of  FIG. 20 ; 
         FIG. 22  shows an enlarged detail of a sectional view of the lower body of the system of  FIG. 2 ; 
         FIG. 23  shows a perspective side view of the system of  FIG. 2  during the third step of the mixing and/or reconstitution method depicted in  FIGS. 20 and 21 ; 
         FIG. 24  shows a perspective side view of the system of  FIG. 2  at the end of the third step of the mixing and/or reconstitution method; 
         FIG. 25  a detail of  FIG. 24 ; 
         FIGS. 26-28  details of a sectional view of the system of  FIG. 2  during the third step of the mixing and/or reconstitution method; 
         FIG. 29  shows a perspective side view of the system of  FIG. 2  during a fourth step of the mixing and/or reconstitution method; 
         FIGS. 30-31  shows perspective side views of the system of  FIG. 2  during a fifth step of the mixing and/or reconstitution method; 
         FIG. 32  shows a detail of a sectional view of the system of  FIG. 2  during the fifth step of the mixing and/or reconstitution method; 
         FIGS. 33-34  shows perspective side views of the system of  FIG. 2  during a sixth step of the mixing and/or reconstitution method; 
         FIG. 35  shows a perspective side view of the system of  FIG. 2  during a seventh step of the mixing and/or reconstitution method; 
         FIG. 36  the view of  FIG. 33 ; 
         FIG. 37  shows a sectional view of the system of  FIG. 33 or 36 ; 
         FIGS. 38-39  show another sectional views of the system of  FIG. 33 or 36 ; 
         FIG. 40  shows a sectional view of the system of  FIG. 34 ; 
         FIGS. 41-42  shows a sectional view of the system of  FIG. 2  during assembly; 
         FIG. 43  shows a detail of the sectional view of  FIG. 43 ; 
         FIG. 44  shows a sectional view of a second embodiment of a mixing and/or reconstitution system with vial; 
         FIG. 45  shows another sectional view of the system of  FIG. 44 ; 
         FIG. 46  shows a sectional view of a third embodiment of a mixing and/or reconstitution system with vial; 
         FIG. 47  shows a sectional view of the system of  FIG. 46  during a first step of the mixing and/or reconstitution method; 
         FIG. 48  shows a sectional view of the system of  FIG. 46  during a second step of the mixing and/or reconstitution method; 
         FIG. 49  shows a sectional view of the system of  FIG. 46  during a third step of the mixing and/or reconstitution method; 
         FIG. 50  shows a sectional view of a fourth embodiment of a mixing and/or reconstitution system with vial; 
         FIG. 51  shows a sectional view of the system of  FIG. 50  in an initial state and during a first to third step of the mixing and/or reconstitution method; 
         FIG. 52  shows a sectional view of the system of  FIG. 50  during a fourth to seventh step of the mixing and/or reconstitution method; 
         FIGS. 53-56  shows a sectional view of the system of  FIG. 50  during the first to fourth step of the mixing and/or reconstitution method in more detail; 
         FIGS. 57-58  shows sectional views of the valve of the system of  FIG. 50  in more detail; 
         FIGS. 59-60  shows sectional views of another cartridge protector for use with the above systems; 
         FIG. 61  shows a sectional view of the slider of the system of  FIG. 50  in detail; 
         FIG. 62  shows a sectional view of the valve of the system of  FIG. 2  in detail; and 
         FIG. 63  shows a perspective side view of the lower body of the system of  FIG. 3  in detail. 
     
    
    
     A first embodiment of an inventive mixing and/or reconstitution system is shown in a concept sketch in  FIG. 1  and in  FIGS. 2 to 43, 59, 60, 62 and 63  also referring to the respective mixing and/or reconstitution method. 
     The system comprises an adaptor  100  with a first recess  101  for a vial  160 , a cartridge  120  accommodated within a second recess  102  of the adaptor  100  and an injection device in form of a syringe  140  accommodated within a third recess  103  of the adaptor  100 . Further, the adaptor  100  may be formed as a single-piece as shown in  FIG. 1  or, alternatively, may comprise an upper body  100   a  and a lower body  100   b  as depicted in  FIGS. 2 to 43 . The upper and lower bodies  100   a ,  100   b  may be fixed together by a snap-fit connection  130  which is shown in  FIG. 13 . 
     The syringe  140  may be an empty 3 ml syringe and the cartridge  120  may be a 3 ml cartridge pre-filled with 2 ml water. As a vial  160  a standard 20 ml vial may be used. 
     The adaptor  100  is an elongated, basically cylindrical component which may be placed with its lower end surface on a desk such that its longitudinal direction runs perpendicular to the desk surface. The first and second cylindrical recesses  101 ,  102  are accommodated one above the other along a longitudinal direction, wherein the first recess  101  may be accommodated below the second recess  102  as shown in  FIGS. 1 and 2 , for example. The third cylindrical recess  103  for the syringe  140  is located in parallel to the first and second recesses  101 ,  102 . 
     The cylindrical recess  101  for the vial  160  may comprise one or more hooks  105  in order to fix the vial  160  when it is accommodated within the recess  101 . Each hook  105  may be formed as a projection slanting slightly in the upper direction in order to obstruct the vial from dropping out of the first recess  101 . 
     On the upper end of the first recess a double-ended needle or trocar  107  is provided within a horizontal rib  104  of the lower body  100   b . The lower end  107   a  projects into the first recess  101  from above, whereas the upper end of the double-ended needle  107  projects into the second recess  102  from underneath. The vertical flow channel  109  of the double-ended needle  107  is connected with a horizontal flow channel  108  running within the horizontal rib  104  of the lower body  100   b  (see e.g.  FIG. 15 ). 
     The second recess  102  comprises the cylindrical cartridge  120  which contains the cartridge reservoir  121 . The cartridge reservoir  121  is closed at its lower end by a cap  122  comprising a membrane  123  (see  FIG. 11 , for example). At the upper end the cartridge reservoir  121  is closed by a plug  125 . The cartridge  120  contains within its reservoir  121  a first fluid material for mixture and/or reconstitution with the second material provided by the vial. The cartridge  120  is slidably fixed within the second recess  102 . In an initial state the cartridge  120  is accommodated such within the second recess  102  that an interlock element in form of a cartridge protector  114  keeps the lower end of the cartridge  120  with the membrane  123  in a certain distance from the upper end of the needle  107  so that the needle  107  cannot pierce the membrane  123 . 
     The cartridge protector  114 , which is shown in detail in  FIG. 6 , comprises a central flange  115  which receives the lower end of the cartridge  120 , in particular its cap  122 . This is shown in detail for example in  FIG. 17 . In the center of the flange  115  an opening  116  is provided so that the needle  107  may pierce the membrane  123  when the cartridge protector  114  is moved into the direction of the needle. The cartridge protector  114  further comprises for example three legs  117  projecting from the flange  115 , wherein each leg has a front end (lower end)  117   a . Additionally, each leg  117  comprises at its inner surface a recess  118  with an upper edge  118   a  which are engaged with respective projections  104   a  of the horizontal rib  104  of the lower body  100   b  in an initial state (see also  FIG. 59 ). In the initial state the cartridge protector  114  supports the cartridge  120  at a pre-defined distance from the upper end of the needle  107  as indicated above. The legs  117  of the cartridge protector  114  point into downward direction and are slightly flexible with regard to a transversal force. They are provided such within the lower body  100   b  of the adaptor  100  that their front ends  117   a  project into the first recess  101 . 
     At the upper end of the upper body  100   a  of the adaptor  100  there is a trigger in form of a plunger  110  which is slidable along the outer surface of the upper body  100   a  ( FIGS. 2 to 43 ) or of the adaptor  100  ( FIG. 1 ) between an initial first position shown in  FIG. 23  and a second end position shown in  FIG. 24 . In the second position the lower end face  110   b  of the plunger  110  arrives at the stop surface  100   c  of the upper body  100   b  of the adaptor  100  (see  FIG. 25 ). The plunger  110  is basically formed as a hollow cylinder closed at its upper end that caps the second recess  102  of the adaptor  100  containing the cartridge  120 . The plunger further comprises a cylindrical rod  110   c  projecting from the inner surface of the upper end downwards as shown in  FIG. 26 . The lower end face of the rod  110   c  abuts on the plug  125  of the cartridge  120 . 
     As shown in  FIG. 25  the lower portion of the shell of the plunger  110  further comprises a flexible web  110   a  with a tangential projection. The web  110   a  meshes with projections  119  of the upper body  100   a  accommodated along the longitudinal direction of the adaptor forming together two snap-fit connections in a first initial position shown in  FIG. 23  and in a second end position of the plunger  110  shown in  FIGS. 24 and 25 . 
     In the embodiment shown in  FIG. 1  the plunger  110  further comprises a guard  112  covering and thereby protecting the upper end of the syringe  140  in the initial position of the plunger  110 . 
     The syringe  140  accommodated within the third recess  103  of the adaptor  100  comprises a syringe reservoir  141 , a handle  143  and a plunger  144 . In the initial position the plug  145  fixed at the lower end of the plunger  144  is in its lowest position so that the volume of the syringe reservoir  141  is almost zero as shown in  FIG. 1 or 20 , for example. In the initial state the syringe reservoir  141  is empty. The syringe  140  further comprises an attachment element  150  containing a two-way selector valve  155  as a switching element at the lower end of the syringe reservoir  141 . The syringe further comprises a needle  170  with protection element as shown in  FIGS. 2 and 10 , for example. Alternatively, the needle may be integrated within and protected by the adaptor  100  body as shown in  FIG. 1 . The needle  170  is attached to the attachment element  150 . 
     The attachment element  150  is formed as a basically cylindrical element and is shown in detail in  FIG. 7 . The attachment element  150  comprises a through-going cylindrical channel  151  extending along the longitudinal direction of the attachment element  150  from the upper to the lower end of the attachment element  150 . The central portion of the attachment element  150  is formed by a vertical opening  153  accommodating the valve  155 . The axis of the cylindrical opening  153  runs perpendicular to the axis of the channel  151 . The attachment element  150  further comprises an attachment section  152  at its lower end at which the needle  170  may be fixed. At its upper end the attachment element  150  is connected to the syringe reservoir  141  as shown, for example, in  FIG. 20 . From this Fig. it can be derived that the upper section of the flow channel  151  is connected to the syringe reservoir  141  forming a fluid connection. 
     The valve  155  is formed by a cylindrical element with a longitudinal axis  156  and comprises a first channel  157  and a second channel  158  (see  FIGS. 8, 39 and 40 ). 
     The two-way selector valve  155  is pivotable accommodated within the vertical opening  153  of the attachment element  150 . The valve  155  may be rotated with respect to the attachment element  150  by rotation of the syringe  140 , for example by an angle between 30° and 70°. This is facilitated by two elongated projections  106  and one conical projection  106   a  shown in  FIG. 63  which mesh with respective recesses of the valve  155  as shown in  FIGS. 8 and 62 . As one can derive from  FIG. 8  a recess  159  at the outer surface of the attachment element  155  cooperate with the elongated recess  106  of the lower body  100   b . Further, as depicted in  FIG. 62 , the conical projection  106   a  meshes with a respective central and conical recess of the valve. This projection  106   a  further forms the connection of a first channel  157  of the valve with the horizontal channel  108  of the adaptor  100 . The first channel  157  is an angled channel (e.g. angle 90°) which in an initial state of the adaptor  100  forms a fluid connection between the upper section of the channel  151  of the attachment element  150  (and thereby the syringe reservoir  141 ) and the horizontal channel  108  of the adaptor  100  as best shown in  FIG. 62 . The second channel  158  of the valve  155  (depicted for example in  FIGS. 8 and 40 ) forms a fluid connection between the upper section of the channel  151  (and thereby the syringe reservoir  141 ) and the lower section of the channel  151  of the attachment element  150  (and thereby the needle  107  attached to the attachment element  150 ) when the valve  155  is switched to a rotated position. The rotation (switch) of the valve  155  relative to the attachment element  150  is explained in detail below. 
     The system further comprises a vial  160  which has the form of a bottle and contains a vial reservoir  161  which is closed on one end by the vial body and sealed on the other end by a cap  162  with a membrane  163 . The vial  160  is depicted in detail in  FIG. 12 , for example. In an initial state the vial  160  is separate from the adaptor  100  at which the cartridge  120  is fixed within the second recess  102  and the syringe  140  within the third recess  103 . The vial  160  may be stored separately from the adaptor  100  with syringe  140  and cartridge  120 . The vial contains in its reservoir  161  a second material with a medicament formulation which is to be mixed and/or reconstituted with the first material contained within the cartridge reservoir  121 . 
     The needle  170  may comprise a protection element as depicted in  FIG. 10  and attached to the attachment section  152  of the attachment element  150  of the syringe  140 . It comprises a needle cap protecting the needle so that user injury is prevented prior and after injection. The needle cap may be removed or pulled off prior administration of a mixed and/or reconstituted material  165  contained in the syringe reservoir  141  after mixing and/or reconstitution using the inventive system. 
     In the following the mixing and/or reconstitution method is explained in detail with regard to the first embodiment. For the mixing and/or reconstitution the pre-fixed system as shown in  FIG. 2  in its initial state is used (comprising the adaptor  100 , the cartridge  120  and the syringe  140 ) together with the vial  160  (see  FIG. 12 ). As indicated above the cartridge  120  comprises the fluid component for mixing and/or reconstitution, whereas the vial  160  comprises the solid or lyophilized component. 
     The inventive system provides a highly user friendly operation which is also very safe with regard to unintentional misuse. The system is constructed such that the vial may be stored separately from the system comprising the adaptor  100 , the cartridge  120  and the syringe  140 . 
     In the first step the vial  160  is inserted into the first recess  101  as shown in  FIG. 16 . At the end of the insertion the cap  162  with the membrane  163  of the vial  160  is pressed against the lower end  107   a  of the double-ended needle  107  as indicated by arrow  191  in  FIG. 18  so that the membrane  163  is pierced by this needle end  107   a  until the cap  162  reaches respective stop surfaces at the rib  104  of the lower body  100   b  (see  FIGS. 18 and 19 ). 
     At the same time detecting a pre-defined (correct) position of the vial  160  (in which the membrane  163  of the vial is fully pierced by the lower end  107   a  of the needle  170 ) by the sensing arrangement comprising the cartridge protector  114  and the lower body  100   b , particularly its rib  104 , the lower ends  170   a  of the cartridge protector  114  are bent sidewards by the cap  162  of the vial  160  as indicated by arrow  192  and dashed line  194  in  FIGS. 18 and 19 . The bending of the legs  117  is because the cap  162  has a slightly bigger cross section than the inner distance of the legs  117 . As soon as the lower end  117   a  of each leg  117  is bent to the side (see the dashed line  194  in  FIGS. 18 and 19 ) by a sufficient amount the recess  118  and edge  118   a  de-latch from the engagement with the projection  104   a  of the rib  104  of the lower body  100   b . Due to the de-engagement of the cartridge protector  114  from the adaptor  100  lower body  100   b  the cartridge protector  114  is no longer fixed to and supported by the adaptor  100  but allowed to slide into longitudinal direction, particularly downwards. In other words, the amount of bending of the cartridge protector  114  legs  117  indicates the pre-defined correct position of the vial  160  after insertion of the vial  160  into the first recess  101 . In case the position of the vial  160  does not correspond to the pre-defined position the operation of the trigger (plunger  110 ) is prevented (or locked) by the interlock element (cartridge protector  114 ) as the cartridge  120  cannot move due to the firm support of interlock element (cartridge protector  114 ) by the adaptor  100 . As soon as the pre-defined position of the vial  160  is reached after insertion into the first recess  101 , the now de-latched and slidable interlock element (cartridge protector  114 ) allows operating of the trigger (plunger  110 ). 
     In a third step, as soon as the vial is in the pre-defined position, the user presses the trigger (plunger  110 ) downwards as shown in  FIG. 20  by arrow  194  or in  FIG. 23 or 26  by arrow  198 . Thereby, the plunger  110  slides from its initial position shown in  FIG. 23  to its end position shown in  FIG. 24 . The user needs to press the plunger  110  with such a force that the flexible web  110   a  comes out of engagement with and overrides the projection  119  as shown in  FIG. 23 . In the end position of the plunger  110  the second projection  119  at a lower end of the upper body  100   a  catches into place as shown in  FIGS. 24 and 25  engaging the web  110   a  and preventing retraction of the plunger  110 . Further, in the second end position, the lower end face  110   b  of plunger  110  arrives at a respective stop surface  100   c  of the upper body  100   b.    
     With the downward movement of the plunger  110  the rod  110   c  of the plunger is pulled down driving the now slidable and no longer locked cartridge  120  into downward direction as indicated by arrow  191  in  FIGS. 26 and 27 . As soon as the cap  122  of the cartridge  120  reaches the upper end of the double-ended needle  107  the needle  107  pierces the membrane  123  so that a fluid connection is established between the cartridge reservoir  121  and the vertical channel  109  of the double-ended needle  107  and thereby the horizontal channel  108  as well. The end position of the cartridge  120  within the second recess  102  where the lower surface of the flange  115  of the cartridge protector  114  abuts the upper surface of rib  104  is shown in  FIG. 27 . 
     When the plunger  110  is further pushed down by the user as shown in  FIG. 20  by arrow  194  or in  FIG. 27  by arrow  198  the first fluid material contained within the cartridge reservoir  121  is driven by the plunger  125  into the vial reservoir  161  through the vertical flow channel  109  of the double-ended needle  107 . This is depicted in  FIGS. 20 and 27  by arrow  195 . Due to the inner pressure within the horizontal flow channel  108  or the adjacent channels  157  of the valve  155  and  151  of the attachment element  150  the first material is driven to the vial  160  only. This is depicted by the dashed line  196  in  FIGS. 20 and 21 . Because the membrane  163  of the vial  160  is pierced prior the membrane  123  of the cartridge  120  the vacuum in the vial reservoir  161  is equalized. Further, the cartridge protector  114  ensures that only if the vial  160  is in the correct position the cartridge  120  may be pierced and cartridge reservoir  121  may be emptied. This ensures correct operation of the system. 
     After piercing of the cartridge all three components (i.e. the cartridge  120 , the vial  160  and the syringe  140 ) are connected by the flow channel composed of the flow channel  151  of the attachment element  150 , the horizontal flow channel  108  and the vertical flow channel  109  of the double-ended needle. Emptying of the cartridge  120  creates an excess pressure within the vial (if not vented) which may move the syringe  140  or the bung  125  of the cartridge  120  (in one embodiment the cartridge  120  cannot be moved when the plunger  110  is locked in the second end position). In order to prevent excess pressure within the vial reservoir  161  the double-ended needle  107  comprises a de-aeration notch  107   b  at the outer surface of its lower end  107   a  which is depicted in  FIGS. 21 and 22 . The excess air within the vial reservoir  161  leaves the vial reservoir  161  along the de-aeration notch  107   b  as depicted in  FIG. 21  by the dashed line  197 . For correct operation the notch  107   b  shall have a diameter which is big enough to keep the membrane  163  of the vial  160  open but small enough to prevent leakage of liquid from the vial reservoir  161 . 
     The user presses the plunger  110  as long as the cartridge reservoir  121  is fully emptied into the vial  160  and the end position of the plunger  110  is reached as shown in  FIGS. 24, 25 and 28 . 
     In the next step, in order to fully mix and/or reconstitute the first and the second material contained within the vial reservoir  161  the system is swiveled or pivoted back and forth as shown by arrows  200  in  FIG. 29  over a pre-defined time period. The fully mixed and/or reconstituted material is depicted with reference number  165 . In one embodiment, the content of the vial reservoir  161  is visible through to large windows in the lower body  100   b  of the adaptor  100  so that the user may observe the correct mixing and/or reconstitution process. 
     In the next step the system may be reversed as shown in  FIG. 30 . However, alternatively, the reversal is not mandatory. In this step, the plunger  144  of the syringe  140  is pulled as shown by arrow  193  in  FIG. 30  such that the mixed and/or reconstituted material  165  contained within the vial reservoir  161  is drawn into the syringe reservoir  141 . The mixed and/or reconstituted material  165  flows along the channel  109  of the double-ended needle  107 , the horizontal channel  108 , the first channel  157  of the valve  155  and the upper section of the channel  151  of the attachment element  150  (in the reverse position of the system shown in  FIGS. 30 to 32  this section appears to be the lower section of the channel  151 ) as depicted in  FIG. 32  by arrow  201 . The end position of the system of this step is shown in  FIG. 31 . In the end position the whole mixed and/or reconstituted material  165  is contained within the syringe reservoir  141 . 
     In the following step, the system may be reversed again as shown in  FIG. 33 . Further, the syringe  140  is turned around a horizontal axis corresponding to the longitudinal axis  156  of the valve  155  (see  FIG. 8 ) as shown in  FIG. 34  by arrow  201 . In this step the upper portion of the syringe  140  comprising the syringe reservoir  141  is detached from the third recess  103   a  within the upper body  100   a  and the lower portion of the syringe  140  comprising the needle  170  from the third recess  103   b  within the lower body  100   b . Further, the valve  155  is kept fixed at the lower body  100   b  of the adaptor  100  and the syringe  140  and with it the attachment element  150  are rotated such that there is a relative rotation of the valve  155  and the attachment element  150  causing that the first channel  157  of the valve  155  is closed and that the second channel  158  is opened as indicated in  FIGS. 39 and 40 . The mechanical fixation of the valve  155  is provided by the elongated projections  106  at the intermediate portion  103   c  of the third recess  103  at the lower housing  100   b  as shown in  FIGS. 38 and 63  which cooperate with the recesses  159  of the valve  155  (see  FIG. 8 ). In the pivoted position of the valve  155  relative to the attachment element  150  there is a fluid connection between the syringe reservoir  141  and the needle through the second channel  158  of the valve  155  as depicted in  FIG. 40  by arrow  203 . This allows the administration of the mixed and/or reconstituted material  165  accommodated within the syringe reservoir  141  by needle  170 . The mixing and/or reconstitution method is thereby finished and the syringe is ready to use. 
     In order to administrate the mixed and/or reconstituted material  165  the syringe  140  is pulled from the adaptor  100  in horizontal direction as indicated by arrow  202  in  FIG. 35 . Further, the user may remove the needle cap prior using the syringe  140  for injection. By the removal of the syringe  140  form the adaptor  100  the valve  155  is released from the projections  106 ,  106   a.    
     Finally, with regard to  FIGS. 41 to 43  it shall be explained that during assembly of the inventive system the attachment element  150  is fixed at the upper body  100   a  by a slant  106   b  which presses the attachment element  150  against the body  100   a  to seal the transition between the first channel  157  of the valve  155  and the vertical flow channel  108  of the upper body  100   a  and to provide a stiff connection between the syringe  140  and the adaptor  100 . 
     In  FIGS. 44 and 45  a second embodiment of an inventive system is depicted which basically works analogously to the first embodiment shown in  FIGS. 1 to 43 . The adaptor  100 ′ of the second embodiment differs from the adaptor  100  shown in  FIG. 1  therein that the flow channel  108   a  of the second embodiment has two horizontal sections and one vertical section whereas the flow channel  108  of the first embodiment is horizontal only and has no vertical section. The flow channel  108   a  of the second embodiment with the adaptor  100 ′ is longer due to a misalignment of the syringe  140  and the double-ended needle  107 . Additionally, this embodiment may further comprise anti-slip foot elements  100   d  provided at the lower end of adaptor  100 ′. 
     A third embodiment of an inventive system is provided and depicted in  FIGS. 46 to 49 . The system of the third embodiment basically corresponds to the system depicted in  FIG. 1 . In contrast to the embodiment of  FIG. 1  the syringe is provided within the third recess  103  in a reversed position. Further, the first recess  101  is provided with a swivel-mounted lever  180  on one side of its lower end and a handle  181  projecting laterally from the other side of its lower end. 
     In order to place the vial  160  within in the first recess of the adaptor  100 ″ of the third embodiment the vial may be slid into the first recess  101  from the side as shown in  FIG. 47  by arrow  206 . In order to correctly position the vial  160  within the first recess  101  subsequently, as depicted in  FIG. 48 , the lever  208  is pivoted into the direction of the handle  181  as shown by arrow  208  in  FIG. 48  thereby moving the vial  160  upwards into the direction of the lower end  107   a  of the needle  107 . The final position of the vial within the first recess  101  is shown in  FIG. 49 . As soon as the pre-defined (correct) position is reached the cartridge protector  114  is triggered such that the cartridge  120  is allowed to move down into the direction of the needle  107  to establish a fluid connection between the cartridge reservoir  121  and the vial reservoir  161  by piercing the membrane of the cartridge  120 . Afterwards, as shown in  FIG. 49 , a plunger  126  of the cartridge (instead of the plunger  110  of the adaptor as in the first embodiment) may be pressed downwards in order to establish this fluid connection and to empty the first material of the cartridge reservoir  121  into the vial reservoir  161 . During these steps the lever  180  keeps closed with the handle  181  thereby fixing the vial  160  in the pre-defined (correct) position within the first recess  101 . 
     A fourth embodiment of an inventive system and method is depicted in  FIGS. 50 to 58 and 61  comprising an adaptor  300 , an injection device  340  and a vial  360 . In this embodiment the system does not comprise a cartridge separate from the injection device but is formed by the reservoir  341  of the cartridge of the injection device  340 , wherein the cartridge is integrated in the injection device  340 . Accordingly, the adaptor  300  comprises a first recess  301  and a second recess  303 , wherein the first recess  301  is adapted to receive the vial  360  and the second recess accommodated in parallel to the first recess  301  is adapted to fix the injection device  340 . As depicted in  FIG. 50  the injection device  340  comprises analogously to the first embodiment a valve  355  within a vertical opening. Additionally, at the lower end of the injection device  340  a needle  370  is attached. The adaptor  300  further comprises at the lower end of the first recess  301  a needle  306  pointing upwards. The injection device  340  comprises a second needle  307  pointing upwards as well. In an initial state the second needle  307  does not pierce a membrane at an attachment portion  348  of the cartridge reservoir  341  which is ensured by a slider  346  supporting the attachment portion  348  and the cartridge reservoir  341 . At its inner and lower side surface the first recess  301  comprises a leg  385  which is connected to the slider  346  of the injection device  340 , wherein the leg  385  together with the slider  346  form the sensing arrangement for detecting a pre-defined position of the vial  360  within the first recess  301 . The slider  346  forming the interlock element is shown in more detail in  FIG. 61 . The slider  346  supports the cartridge reservoir  341  and its attachment portion  348  in an initial state such that it has a pre-defined distance with regard to the upper end of the needle  307 . The flow channel of the needle  306  is connected via a horizontal channel  308  within the adaptor  300  with the first channel  357  of the valve  355  (see  FIG. 57 a   ) and b) and  FIG. 58 ) as a switching element and the flow channel of the needle  307 . 
     The mixing and/or reconstitution method is now explained referring particularly to  FIGS. 51 to 56 . 
     The initial state of the inventive system according to this embodiment is depicted in  FIG. 51 a   ). For facilitating the mixing and/or reconstitution of the first fluid material contained in cartridge reservoir  341  and the second material contained in the vial reservoir  361  in the first step shown in  FIG. 51 b   ) the vial  360  is inserted into the first recess  301 , wherein the cap of the vial  360  faces downwards. The movement direction of the vial  360  is depicted in  FIG. 51 b   ) by arrow  206 . During insertion of the vial  360  the lever  380  is open (see  FIG. 53 ). In order to position the vial  360  correctly within the first recess  301 , afterwards, as shown in  FIG. 51 c   ) by arrow  207  the lever  380  is pivoted into the direction of handle  381  so that the recess  301  is closed thereby moving the vial  360  further downwards and pierce the membrane sealing the vial reservoir  361  by the needle  360 . This step is shown in an enlarged drawing in  FIG. 54 . The  FIG. 54  further shows that by the side wall of the vial  360  the leg  385  is pushed sideways into the direction of the injection device  340 . Thereby, as shown in  FIG. 61 , the slider  346 , which is connected to the leg  385 , is moved horizontally as indicated by arrow  214  in  FIG. 61 . Hence, the slider  346  is moved so far that openings  346   a  within the slider (which were initially disengaged) now engage with respective projections  348  of the injection device  340  so that the slider  346  is allowed to move downwards. The final lower position of slider  346  is shown in  FIG. 54 . 
     If now the user, if the slider  346  is in the lower position indicating that the vial is correctly at a pre-defined position adjusted within the first recess  301 , presses the plunger  344  of the injection device as depicted in  FIG. 51 d   ) by arrow  209  or  FIG. 55  by arrow  212  the attachment portion  348  and the cartridge reservoir  341  are moved down so that the needle  307  pierces the membrane sealing the cartridge reservoir  341  thereby establishing a fluid connection between the cartridge reservoir  341  and the vial reservoir  361 . Accordingly, by further pressing the plunger  344  the first fluid material contained within the cartridge reservoir  341  is emptied via the flow channel of the needle  307 , the first channel  357  of the valve  355 , the horizontal flow channel  308  and the flow channel of the needle  306  into the vial reservoir  361  as depicted in  FIG. 51 d   ) and  FIG. 55 . 
     In the next step, the user may wait and slowly swivel (see arrows  210 ) the system in order to mix and/or reconstitute the first and second material within the vial reservoir  361  as shown in  FIG. 52 a   ). 
     In the next step, as shown in  FIG. 52 b   ) the fully mixed and/or reconstituted material  365  is drawn back into the cartridge reservoir  341  by pulling the plunger  344  of the injection device  340  as depicted by arrow  211  in  FIG. 52 b   ). As one can derive from  FIG. 56  showing the same step the mixed and/or reconstituted material  365  uses the same flow channel as in the step shown in  FIG. 54 . The mixing and/or reconstitution method is herewith finished providing a injection device filled with the mixed and/or reconstituted material  365 . 
     In order to administer the mixed and/or reconstituted material  365 , afterwards, as depicted in  FIG. 52 c   ), the injection device is detached from the adaptor  300 , for example by unscrewing the injection device and pulling (see arrows  215 ,  216 ). Now, as indicated in  FIG. 52 d   ) the injection device is ready to administrate the mixed and/or reconstituted material  365 . For that the valve  355  must be switched into the second position, for example by a screw driver. Switching means, for example, rotation of the valve  355  with respect to the injection device  340  so that a second flow channel  358  connects the cartridge reservoir  341  and the needle  370  as depicted in  FIGS. 57 and 58 . The two-way selector valve  355  works analogously to the first embodiment shown in  FIGS. 1 to 43 . Unlike the first embodiment the valve  355  may be switched by an external tool. 
     LIST OF REFERENCE NUMBERS 
     
         
           100 ,  100 ′,  100 ″ adaptor 
           100   a  upper body 
           100   b  lower body 
           100   c  stop surface 
           100   d  foot element 
           101  first recess 
           102  second recess 
           103  third recess 
           103   a  third recess within the upper body  100   a    
           103   b  third recess within the lower body  100   b    
           103   c  intermediate portion 
           104  rib 
           104   a  projection 
           105  hook 
           106  projection 
           106   a  central projection 
           106   b  slant 
           107  double-ended needle 
           107   a  lower end of needle  107   
           107   b  de-aeration notch 
           108  horizontal flow channel 
           108   a  flow channel 
           109  vertical flow channel 
           110  plunger 
           110   a  web 
           110   b  lower end face of plunger  110   
           110   c  rod 
           111  handle 
           112  guard 
           113  snap fit 
           114  cartridge protector 
           115  flange 
           116  opening 
           117  leg 
           117   a  front end of leg 
           118  recess 
           118   a  edge 
           119  projection 
           120  cartridge 
           121  cartridge reservoir 
           122  cap 
           123  membrane 
           125  plug 
           126  plunger 
           140  syringe 
           141  syringe reservoir 
           143  handle 
           144  plunger 
           145  plug 
           148  attachment portion 
           150  attachment element 
           151  channel 
           152  attachment section 
           153  vertical opening 
           155  valve 
           156  longitudinal axis 
           157  first channel 
           158  second channel 
           159  recess 
           160  vial 
           161  vial reservoir 
           162  cap 
           163  membrane 
           165  mixture/constituted formulation 
           170  needle with protection element 
           180  lever 
           181  handle 
           191 ,  192 ,  193 ,  195 ,  198 ,  199 ,  200 ,  201 ,  202  arrow 
           203 ,  205 ,  206 ,  207 ,  208 ,  209 ,  210 ,  211 ,  212 ,  213  arrow 
           214 ,  215 ,  216  arrow 
           194 ,  196 ,  197 ,  201  dashed line 
           300  adaptor 
           301  first recess 
           303  second recess 
           306 ,  307  needle 
           308  flow channel 
           340  injection device 
           341  cartridge reservoir 
           344  plunger 
           345  plug 
           346  slider 
           346   a  opening 
           347  housing of the injection device  340   
           348  attachment portion 
           349  injection device channel 
           355  valve 
           357  first channel 
           358  second channel 
           360  vial 
           361  vial reservoir 
           365  mixture/constituted formulation 
           370  first needle 
           380  lever 
           381  handle 
           385  leg