Injection device with dose setting mechanism having maximum dose stop

Abstract

A dose setting mechanism for a drug delivery device is provided comprising a dose setting member and a further element. Maximum dose stop features are provided on a housing and on the further element.

Claims

1. A dose setting mechanism for a drug delivery device, the mechanism comprising: a housing comprising an internal helical thread, a dose setting member comprising an external surface that engages the internal helical thread of the housing such that the dose setting member is movable relative to the housing to set a dose, a drive sleeve which is at least partially located within the housing and which is moved along a helical path having a rotatory component and a translational component in a first axial direction relative to the housing during dose setting, a threaded piston rod in threaded engagement with the drive sleeve, wherein an inner side of the housing and a proximal flange of the drive sleeve define corresponding stops, wherein the corresponding stops are arranged to abut one another so as to limit the movement of the drive sleeve in the first axial direction during dose setting thereby defining a maximum settable dose, and wherein the dose setting member and the drive sleeve are decoupled during dose dispensing such that the dose setting member is free to rotate relative to the drive sleeve and the piston rod is free to rotate relative to the drive sleeve.

2. The dose setting mechanism according to claim 1, wherein the housing has a first protrusion and the drive sleeve has a second protrusion and wherein the distance between the first and second protrusions defines the maximum settable dose.

3. The dose setting mechanism according to claim 1, wherein the dose setting member and the drive sleeve are coupled during dose setting and wherein the dose setting member and the drive sleeve are rotated together during dose setting.

4. The dose setting mechanism according to claim 1, wherein the piston rod is in direct contact with the drive sleeve.

5. The dose setting mechanism according to claim 1, wherein the dose setting member and the piston rod are decoupled during dose dispensing such that the dose setting member and the piston rod are allowed to move relative to each other during dose dispensing.

6. The dose setting mechanism according to claim 1, further comprising a reservoir containing a medicament, preferably insulin, which reservoir is attached to the housing.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In the following, the invention will be described by a way of examples and with reference to the schematic drawings in which:

(2) FIG. 1 shows a dose setting mechanism similar to that disclosed in EP 1 603 611 B1,

(3) FIG. 2 shows a sectional view of the dose setting mechanism according to a first embodiment of the invention and

(4) FIG. 3 shows a sectional view of the dose setting mechanism of a second embodiment of the invention.

DETAILED DESCRIPTION

(5) Hereinafter, the features of the present invention are described with reference to the drug delivery device shown in FIG. 1 which is similar to the device disclosed in EP 1 603 611 B1.

(6) Although the present invention is described with reference to this specific drug delivery device, the dose setting mechanism may be applicable to other variable dose injection devices, where the maximum dose is limited in a similar manner. In other words, it may equally be applied to any drug delivery device where the maximum dose stop is determined by features of two separate components moving towards one another and making contact when the maximum dose is reached. This could apply both to rotationally moving components, e.g. in a diallable variable dose pen, or axially travelling components, e.g. in a pull-push fixed dose pen. Furthermore, the present invention is described with respect to disposable drug delivery devices, but is applicable also for reusable drug delivery devices.

(7) The drive mechanism 1 shown in FIG. 1 comprises a housing (not shown). A cartridge (reservoir), containing medicinal product, can be mounted to the housing and retained by any suitable means. The cartridge and its retaining means are not shown in FIG. 1. The cartridge may contain a number of doses of a medicinal product and also typically contains a displaceable piston. Displacement of the piston causes the medicinal product to be expelled from the cartridge via a needle (also not shown). The housing or an insert fixed within the housing is provided with a threaded circular opening. A helical thread extends along the inner cylindrical surface of the housing.

(8) The drive mechanism 1 further comprises a piston rod 2, a drive sleeve 3, a dose dial sleeve 4 with a dose knob 5, a button 6, a spring member 7, a nut 8 and a clutch means (not shown). The spring member 7 is provided between a flange 9a formed on the drive sleeve 3 and a front face of the clutch means. The housing or a separate window part 10 may be provided with an internal helical thread engaging the external surface of the dose dial sleeve 4.

(9) The piston rod 2 is of generally circular section. One end of the piston rod is provided with a first thread which is engaged with the thread or formed in the circular opening of the housing or its insert. On the upper end in FIG. 1 the piston rod 2 is provided with a second thread which engages an internal thread formed within the tubular drive sleeve 3. The first thread and the second thread are oppositely disposed and may have a different pitch.

(10) The drive sleeve 3 extends about the piston rod 2. The drive sleeve is generally cylindrical with two flanges 9a, 9b provided on its lower end in FIG. 1. The two flanges 9a, 9b are spaced a distance along their drive sleeve with an external helical thread provided on the outer part of the drive sleeve between the two flanges. The nut is located between the drive sleeve and the housing and disposed between the two flanges of the drive sleeve. The nut 8 can be either a half-nut or a full-nut. The nut has an internal thread that is engaged with the external thread of the drive sleeve 3. The outer surface of the nut 8 and an internal surface of the housing are keyed together by means of longitudinally directed splines to prevent relative rotation between the nut 8 and the housing, while allowing relative longitudinal movement there between.

(11) The spring member 7 is disposed about the drive sleeve 3 on the side facing away from the nut 8 of the upper flange 9a in FIG. 1. The metal spring 7 may be formed as an undulated or a bent washer. The outer surface of the spring 7 and an internal surface of the housing are keyed together by means of longitudinally directed splines to prevent relative rotation between the spring 7 and the housing, while allowing relative longitudinal movement there between.

(12) The clutch means (not shown) may be designed as a sleeve which is disposed about the drive sleeve 3 within the dose dial sleeve 4. The clutch means may have means for engaging the spring 7 on its lower side in FIG. 1 and means for engaging dose dial sleeve 4 and/or dose knob 5 on its upper side in FIG. 1. Such means for engaging the further components of the dose setting mechanism can include corresponding teeth. Spring 7 biases the clutch means into engagement with the dose dial sleeve 4 and/or dose knob 5. Further, the clutch means and the drive sleeve 3 may be keyed together such that the drive sleeve 3 follows a rotation of the clutch means while allowing relative longitudinal movement there between. The engagement between the spring 7 and the clutch means is preferably designed such that the clutch means may perform a relative rotational movement with respect to spring 7 if the clutch means is in engagement with the dose dial sleeve 4 or dose knob 5.

(13) The dose knob 5 is designed as a dose dial grip which is fixed to the dose dial sleeve 4. The dose knob 5 has a grippable surface allowing a user to dial a dose by rotating the dose knob 5 which thus forms a dose setting member. The dose dial sleeve 4 and the dose knob 5 both have a central opening on the upper side in FIG. 1 to receive a pin of button 6 which acts on the clutch means allowing to push the clutch means towards flange 9a of the drive sleeve against the force of spring 7.

(14) Operation of the drive mechanism in accordance with the mechanism shown in FIG. 1 will now be described.

(15) To dial a dose, a user rotates the dose knob 5. The spring member 7 applies an axial force to the clutch means in the upwards direction in FIG. 1. The force exerted by the spring 7 couples the clutch means to the dose knob 5 for rotation. As the dose knob 5 is rotated, the associated dose dial sleeve 4, the drive sleeve 3 and the clutch means all rotate in unison.

(16) Audible and tactile feedback of the dose being dialled is provided by the spring 7 and the clutch means. The spring 7 cannot rotate with respect to the housing, so the spring deforms allowing the teeth or the like of the clutch means to jump over the e.g. teethed spring 7 producing an audible and tactile ‘click’.

(17) The helical thread of the dose dial sleeve 4 and the internal helical thread of the drive sleeve 3 have the same lead. This allows the dose dial sleeve 4 to advance along the thread of the housing or its insert 10 at the same rate as the drive sleeve 3 advances along the thread of the piston rod 2. Rotation of the piston rod 2 is prevented due to the opposing direction of the threads of the piston rod 2. The further thread of the piston rod 2 is engaged with the thread of the housing or its insert and so the piston rod 2 does not move with respect to the housing while a dose is dialed.

(18) The nut 8, keyed to the housing, is advanced along the external thread of the drive sleeve 3 by the rotation of the drive sleeve 3. When a user has dialed a quantity of medicinal product that is equivalent to the deliverable volume of the cartridge, the nut 8 reaches a position where it abuts the upper flange 9a of the drive sleeve 3. A radial stop formed on the surface of the nut 8 contacts a radial stop on the surface of the flange 9a of the drive sleeve 3, preventing both the nut 8 and the drive sleeve 3 from being rotated further.

(19) Should a user inadvertently dial a quantity greater than the desired dosage, the drive mechanism 1 allows the dosage to be corrected without dispense of medicinal product from the cartridge. The dose knob 5 is counter-rotated. This causes the system to act in reverse.

(20) When the desired dose has been dialled, the user may then dispense this dose by depressing the button 6 in the direction of the first end (lower end in FIG. 1) of the drive mechanism 1. The button 6 applies pressure to the clutch means, displacing same axially with respect to the dose knob 5. This causes the clutch means to disengage from the dose knob 5. However, the clutch means remains keyed in rotation to the drive sleeve 3. The dose knob 5 and associated dose dial sleeve 4 are now free to rotate (guided by the helical thread of the housing).

(21) The axial movement of the clutch means deforms the spring member 7 and couples e.g. the teeth at the lower end of the clutch means to the spring 7 preventing relative rotation there between. This prevents the drive sleeve 3 from rotating with respect to the housing, though it is still free to move axially with respect thereto.

(22) Pressure applied to the button 6 thus causes the dose knob 5 and the associated dose dial sleeve 4 to rotate into the housing. Under this pressure the clutch means, the spring 7 and the drive sleeve 3 are moved axially in the direction of the lower end of the drive mechanism 1 in FIG. 1, but they do not rotate. The axial movement of the drive sleeve 3 causes the piston rod 2 to rotate though the threaded opening in the housing or its insert, thereby to advance the piston within the cartridge, causing the medicinal product to be expelled from the cartridge. The selected dose is fully delivered as the dose knob 5 returns to a position where it abuts the housing.

(23) When pressure is removed from the button 6, the deformation of the spring member 7 is used to urge the clutch means back along the drive sleeve 3 to re-couple the clutch means with the dose knob 5. The drive mechanism is thus reset in preparation to dial a subsequent dose.

(24) A first embodiment of the invention is shown in the sectional view of FIG. 2 with the components described above with respect to FIG. 1 essentially corresponding to those shown in FIG. 2. Thus, same reference numerals are used to denominate identical parts. In FIG. 2 a tubular housing 11 is shown surrounding dose dial sleeve 4 and drive sleeve 3.

(25) On the inner side of the tubular housing 11, a flange-like protrusion 12 is provided forming a first stop means for limiting the axial movement of drive sleeve 3 within the housing 11. The protrusion 12 is designed such that the flange 9a of the drive sleeve abuts flange 12 if the drive sleeve 3 is moved in the upwards direction of FIG. 2 during dose setting. In other words, the user may dial a dose as described above with respect to FIG. 1 which causes the drive sleeve 3 to be moved along a helical path defined by the threads on the piston rod 2 and the corresponding threads within drive sleeve 3. However, the distance the drive sleeve 3 is allowed to travel during this dialling movement is limited by flange 12 of the housing 11. As dialling a dose is limited by flange 12, the position of flange 12 relative to flange 9a of the drive sleeve 3 defines the maximum settable dose of the dose setting mechanism 1.

(26) The position of flange 12 and/or the position of flange 9a of the drive sleeve 3 may be varied to preselect a different maximum settable dose for the dose setting mechanism 1.

(27) As an alternative to the embodiment shown in FIG. 2, further elements of the drive sleeve 3 may be used as a stop means for abutting flange 12 to define a maximum settable dose.

(28) A second embodiment of the present invention is shown in FIG. 3 which again generally corresponds to the dose setting mechanism shown in FIG. 1. The embodiment shown in FIG. 3 differs from the embodiment of FIG. 2 in that no additional flange 12 is provided on the inner side of the housing 11 thus allowing drive sleeve 3 to move freely within housing 11.

(29) As mentioned above with respect to FIG. 1 spring 7 and the internal surface of the housing 11 are keyed together by means of longitudinally directed splines to prevent a relative rotation between spring 7 and the housing 11 while allowing relative longitudinal movement there between. In the embodiment shown in FIG. 3 said splines comprise a protrusion 13 formed on the outer surface of spring 7 and a longitudinal groove 14 formed on the internal surface of housing 11. The length of groove 14 is limited, thus allowing only a limited longitudinal movement of spring 7 relative to housing 11. In other words, protrusion 13 and groove 14 form corresponding stop means which limit the movement of the dose setting mechanism during dose dialling. Hence, the length of groove 14 defines a maximum settable dose of the dose setting mechanism 1.

(30) The term “medicament”, as used herein, preferably means a pharmaceutical formulation containing at least one pharmaceutically active compound,

(31) 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,

(32) 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,

(33) 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,

(34) 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.

(35) 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.

(36) 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-carboxyhepta-decanoyl) human insulin.

(37) 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.

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

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

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

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

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

(43) des Pro36 [IsoAsp28] Exendin-4(1-39),

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

(45) des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

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

(47) des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

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

(49) des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or

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

(51) des Pro36 [IsoAsp28] Exendin-4(1-39),

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

(53) des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

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

(55) des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

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

(57) des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

(58) wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(86) des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

(87) H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys).sub.6-NH2,

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

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

(90) 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.

(91) 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.

(92) 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.

(93) 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.

(94) 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.

(95) Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and 6 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.

(96) 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.

(97) 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.

(98) 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 crystallizable 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).

(99) 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.

(100) Pharmaceutically acceptable solvates are for example hydrates.