Medicament delivery device with two drive springs

Abstract

A medicament delivery device includes a case, a first plunger, a second plunger arranged telescopically with the first plunger, a first drive spring biasing the second plunger relative to the case, and a second drive spring biasing the first plunger relative to the second plunger.

Claims

1. A medicament delivery device comprising: a case; a drive mechanism comprising a first drive member and a second drive member, the drive mechanism arranged to act on a stopper of a syringe to displace the stopper and dispense a medicament; a first drive spring arranged in the case and bearing against the second drive member, wherein the first drive spring is configured to move the first drive member and the second drive member relative to the case to displace the stopper within the syringe and dispense the medicament when the second drive member is released; and a second drive spring arranged in the case and bearing against the first drive member, wherein the second drive spring is configured to move the first drive member relative to the case to displace the stopper within the syringe and dispense the medicament when the first drive member is released.

2. The medicament delivery device of claim 1, wherein a proximal end of the first drive spring bears against the case.

3. The medicament delivery device of claim 2, wherein a distal end of the first drive spring bears against the second drive member.

4. The medicament delivery device of claim 1, wherein a proximal end of the second drive spring bears against the second drive member.

5. The medicament delivery device of claim 4, wherein a distal end of the second drive spring bears against the first drive member.

6. The medicament delivery device of claim 1, wherein the first drive member and the second drive member are telescoped relative to one another.

7. The medicament delivery device of claim 6, wherein the first drive member is telescoped within the second drive member.

8. The medicament delivery device of claim 1, wherein the first drive spring bears against the second drive member such that the first drive member and the second drive member move distally relative to the case when the second drive member is released.

9. The medicament delivery device of claim 1, wherein the second drive spring bears against the first drive member such that the first drive member moves distally relative to the case when the first drive member is released.

10. The medicament delivery device of claim 9, wherein the second drive member is configured to be released after the first drive member is released.

11. The medicament delivery device of claim 1, further comprising a trigger button operable by a user, wherein the first drive member and the second drive member are configured to be released after the trigger button is displaced.

12. The medicament delivery device of claim 1, further comprising an arm adapted to engage the second drive member, wherein the arm is configured to be deflected to release the second drive member.

13. A drive mechanism for a medicament delivery device, the drive mechanism comprising: a first drive member arranged to bear on a stopper of a syringe such that the stopper displaces and dispenses a medicament when the first drive member is moved relative to a case of the medicament delivery device; a second drive member; a first drive spring bearing against the second drive member, wherein the first drive spring is configured to move the first drive member and the second drive member relative to the case of the medicament delivery device when the second drive member is released; and a second drive spring bearing against the first drive member, wherein the second drive spring is configured to move the first drive member relative to the case of the medicament delivery device when the first drive member is released, wherein the syringe is fixed within the case with respect to movement in a distal direction, and wherein the distal direction corresponds to a direction into which the stopper is displaced relative to the case to dispense the medicament.

14. The drive mechanism of claim 13, wherein a distal end of the first drive spring is bearing against the second drive member.

15. The drive mechanism of claim 13, wherein a distal end of the second drive spring is bearing against the first drive member.

16. The drive mechanism of claim 13, wherein the first drive spring bears against the second drive member such that the first drive member and the second drive member move distally relative to the case of the medicament delivery device when the second drive member is released.

17. The drive mechanism of claim 13, wherein the first drive member and the second drive member are telescoped relative to one another.

18. The drive mechanism of claim 17, wherein the first drive member is telescoped within the second drive member.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein:

(2) FIG. 1 is a schematic longitudinal section of an exemplary embodiment of a medicament delivery device prior to use,

(3) FIG. 2 is a schematic longitudinal section an exemplary embodiment of a medicament delivery device during use,

(4) FIG. 3 is a schematic longitudinal section of an exemplary embodiment of a medicament delivery device during use,

(5) FIG. 4 is a schematic longitudinal section of an exemplary embodiment of a medicament delivery device during use, and

(6) FIG. 5 is a schematic longitudinal section of an exemplary embodiment of a medicament delivery device after use.

(7) Corresponding parts are marked with the same reference symbols in all figures.

DETAILED DESCRIPTION

(8) FIG. 1 is a schematic longitudinal section of an exemplary embodiment of an medicament delivery device 1 prior to use. The medicament delivery device 1 comprises a case 2 adapted to receive a medicament container (e.g., a syringe 3) with a needle 4. The syringe 3 is fixed within the case 2 with respect to movement in the distal direction D, for example by a rib 26 supporting the syringe 3 at a distal end 27. Alternatively, the syringe 3 could be supported at a finger flange 28. A stopper 5 is arranged to seal a proximal end of the syringe 3 and to displace a liquid medicament M from the syringe 3 through the needle 4 when being moved in a distal direction D within the syringe 3. A needle shroud 6 is telescoped with the case 2, axially movable relative the case 2 between an extended shroud position ESP, in which the needle 4 is covered and a retracted shroud position RSP in which the needle 4 is exposed. A detent or a spring (not illustrated) may be arranged to bias the needle shroud 6 in the extended shroud position ESP.

(9) A drive mechanism 7 is arranged to act on the stopper 5 for displacing it within the syringe 3. In an exemplary embodiment, the drive mechanism 7 comprises a first plunger 8 telescoped with a second plunger 9. In the exemplary embodiment shown in FIG. 1, the first plunger 8 is telescoped within the second plunger 9. A first drive spring 10 (e.g., a compression spring) is arranged within the case 2, proximally grounded in the case 2 and distally bearing against the second plunger 9, biasing the second plunger 9 in the distal direction D relative to the case 2. A second drive spring 11 (e.g., a compression spring) is arranged, in the exemplary embodiment, within the second plunger 9, proximally grounded in the second plunger 9 and distally bearing against the first plunger 8, biasing the first plunger 8 in the distal direction D with respect to the second plunger 9 against the stopper 5.

(10) A plunger release mechanism 12 is arranged for selectively preventing and allowing release of the first plunger 8 and second plunger 9 for performing an injection. In an exemplary embodiment, the plunger release mechanism 12 comprises a sleeve 13 protruding distally from a proximal end wall 14 of the case 2 into the case 2. The second plunger 9 is adapted to be telescoped within the sleeve 13. In an exemplary embodiment, one or more spline/groove combinations may be formed on the second plunger 9 and the sleeve 13 to prevent rotation of the second plunger 9 relative to the sleeve 13.

(11) In an exemplary embodiment, the sleeve 13 includes at least one compliant first arm 15 having a retention boss 16 adapted to engage a first opening 17 in the second plunger 9. In an exemplary embodiment, the first arm 15 is radially deflectable and biased radially outward. In an exemplary embodiment, at least one of the first retention boss 16 and the first opening 17 may be ramped for radially outwardly deflecting the first retention boss 16 due to the force of the first drive spring 10.

(12) In an exemplary embodiment, a trigger button 18 is slidably arranged relative the case 2 and arranged on the proximal end wall 14. Button walls 19 protrude from a proximal surface of the trigger button 18 through the proximal end wall 14 into the case 2. The button walls 19 are arranged to outwardly support the first retention bosses 16 when the trigger button 18 is in an extended button position EBP. When the trigger button 18 is depressed and moved in the distal direction D into a depressed button position DBP a second opening 20 in the button wall 19 is axially aligned with the first retention boss 16 thus allowing radial outward deflection thereof.

(13) Furthermore, in an exemplary embodiment, the second plunger 9 includes at least one compliant plunger beam 21 with a second retention boss 22 adapted to protrude from the second plunger 9 in a proximal direction P inwardly of the sleeve 13 and deflectable and biased in a radially outward direction. The second retention boss 22 is adapted to engage a retention surface 23 on the first plunger 8. In an exemplary embodiment, at least one of the second retention boss 22 and the retention surface 23 may be ramped for radially outwardly deflecting the second retention boss 22 due to the force of the second drive spring 11. The sleeve 13 is arranged to outwardly support the second retention bosses 22 when the second plunger 9 is in a proximal plunger position PPP such that the second retention boss 22 cannot disengage the retention surface 23.

(14) When the second plunger 9 is moved in the distal direction D into a distal plunger position OPP, the second retention boss 22 moves distally beyond an end of the sleeve 13, allowing radial outward deflection of the second retention boss 22. In another exemplary embodiment, the retention surface 23 may be replaced with an opening or a recess.

(15) In an exemplary embodiment the plunger beam 21 may be arranged on the second plunger 9 by a live hinge 24.

(16) In the initial state prior to use as illustrated in FIG. 1 the needle shroud 6 is in the extended shroud position ESP, the trigger button 18 is in the extended button position EBP, the first retention boss 16 keeps the second plunger 9 in the proximal plunger position PPP and the second retention boss 22 is engaged to the retention surface 23 preventing release of the first plunger 8.

(17) An exemplary sequence of operation of the medicament delivery device 1 is as follows:

(18) The needle shroud 6 is moved in the proximal direction P into the retracted shroud position RSP thereby exposing the needle 4. This may be achieved by placing the medicament delivery device 1 against an injection site and applying sufficient force to retract the needle shroud 6. Thus the needle 4 is inserted into the injection site.

(19) FIG. 2 is a schematic longitudinal section of the medicament delivery device 1 with the needle shroud 6 in the retracted shroud position RSP.

(20) The user may push the trigger button 18 moving it from the extended button position EBP into the depressed button position DBP.

(21) FIG. 3 is a schematic longitudinal section of the medicament delivery device 1 with the trigger button 18 in the depressed button position DBP.

(22) Due to depression of the trigger button 18 into the depressed button position DBP the second opening 20 in the button wall 19 is axially aligned with the first retention boss 16 thus allowing radial outward deflection of the first arm 15 thereof under force from the first drive spring 10. The second plunger 9 is thus released and moved in the distal direction D by the first drive spring 10. Due to the second drive spring 11 biasing the first plunger 8 in the distal direction D relative to the second plunger 9, the first plunger 8 moves with the second plunger 9 and in turn displaces the stopper 5 within the syringe 3 thus starting delivery of the medicament M through the injection needle 4 in a first injection stroke. The second plunger 9 continues to move until it reaches its distal plunger position OPP and abuts a stop in the case 2. When the second plunger 9 impacts the stop, a feedback (e.g., tactile and/or audible) may be provided to indicate that an injection is approximately half finished.

(23) FIG. 4 is a schematic longitudinal section of the medicament delivery device 1 at the end of the first injection stroke with the second plunger 9 in the distal plunger position OPP.

(24) As the second plunger 9 is moved in the distal plunger position OPP, the second retention boss 22 moves distally beyond the distal end of the sleeve 13 thus allowing radial outward deflection of the second arm 21 and disengagement of the retention boss 22 and the sleeve 13 under the force of the second drive spring 11. In this position, the retention boss 22 may distally abut a proximal end of the sleeve 13. The first plunger 8 is thus released and moved in the distal direction D by the second drive spring 11 and continues displacing the stopper 5 within the syringe 3 thus completing delivery of the medicament M through the injection needle 4 in a second injection stroke. The retention surface 23 of the first plunger 8 may impact the second plunger 9 at the end of the second injection stroke to provide a second feedback (e.g., tactile and/or audible) that an injection is finished.

(25) FIG. 5 is a schematic longitudinal section of the medicament delivery device at the end of the second injection stroke.

(26) In an alternative embodiment the second plunger 9 may be arranged to engage the stopper 5. In this embodiment the first drive spring 10 is arranged within the case 2, proximally grounded in the case 2 and distally bearing against the first plunger 8 thus biasing the first plunger 8 in the distal direction D relative the case 2. The second drive spring 11 is arranged within the second plunger 9, proximally grounded in the first plunger 8 and distally bearing against the second plunger 9 thus biasing the second plunger 9 in the distal direction D with respect to the first plunger 8 against the stopper 5.

(27) In an alternative embodiment the drive mechanism 7 may comprise more than two plungers slidably arranged with respect to each other and biased against each other by springs. In this embodiment a respective number of retention bosses would be arranged for a phased release of the plungers.

(28) The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, 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.

(29) 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 praline 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.

(30) 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-(w-carboxyheptadecanoyl)-des(B30)human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.

(31) Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-GIu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-GIn-Met-GIu-GIu-GIu-Ala-Val-Arg-Leu-Phe-lIe-Glu- Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

(32) Exendin-4 derivatives are for example selected from the following list of compounds:

(33) H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

(34) H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

(35) des Pro36 Exendin-4(1-39),

(36) des Pro36 [Asp28] Exendin-4(1-39),

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

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

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

(40) des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

(41) des Pro36 [Trp(O2)25, lsoAsp28] Exendin-4(1-39),

(42) des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), des

(43) Pro36 [Met(O)14 Trp(O2)25, lsoAsp28] Exendin-4(1-39); or

(44) des Pro36 [Asp28] Exendin-4(1-39),

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

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

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

(48) des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

(49) des Pro36 [Trp(O2)25, lsoAsp28] Exendin-4(1-39),

(50) des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

(51) des Pro36 [Met(O)14 Trp(O2)25, lsoAsp28] Exendin-4(1-39), wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;

(52) or an Exendin-4 derivative of the sequence

(53) des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),

(54) H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,

(55) des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,

(56) H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,

(57) H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,

(58) des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

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

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

(61) H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

(62) H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,

(63) H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,

(64) H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,

(65) des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

(66) H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

(67) H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

(68) H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,

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

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

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

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

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

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

(75) H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

(76) H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,

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

(78) H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,

(79) 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,

(80) H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;

(81) or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.

(82) 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.

(83) 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.

(84) 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 (lg) monomer (containing only one lg unit); secreted antibodies can also be dimeric with two lg units as with lgA, tetrameric with four lg units like teleost fish lgM, or pentameric with five lg units, like mammalian lgM.

(85) The lg 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 lg 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 13 sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.

(86) There are five types of mammalian lg heavy chain denoted by a, o, £, y, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in lgA, lgD, lgE, lgG, and lgM antibodies, respectively.

(87) Distinct heavy chains differ in size and composition; a and y contain approximately 450 amino acids and o approximately 500 amino acids, while μ and £ 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 y, a and o have a constant region composed of three tandem lg domains, and a hinge region for added flexibility; heavy chains μ and £ 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 lg domain.

(88) In mammals, there are two types of immunoglobulin light chain denoted by ‘A and K. 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, K or ‘A, is present per antibody in mammals.

(89) 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.

(90) 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 lg 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 (Fe). The Fe 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).

(91) 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's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.

(92) Pharmaceutically acceptable solvates are for example hydrates.

(93) Those of skill in the art will understand that modifications (additions and/or removals) of various components of the apparatuses, methods and/or systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.