Stopper with low force for use in an injector

Abstract

The present invention relates to a stopper for an injector for delivery of a pharmaceutical composition and to an injector with the stopper. The stopper has a stopper body with an actuating surface opposite an outlet surface, an axial length between the actuating surface and the outlet surface, and a transverse diameter, which stopper body defines an access diameter, the stopper at an axial location from the actuating surface comprising a deformable sealing element surrounding the stopper body and having an outer diameter, which is larger than the transverse diameter, which deformable sealing element is made from a thermoplastic elastomer and has an axial extension in the range of 5% and 95% of the axial length of the stopper body, and the stopper comprising a cavity at the axial location of the deformable sealing element, the cavity having a lateral extension larger than the access diameter of the stopper body.

Claims

1. An injector for delivery of a pharmaceutical composition, the injector comprising a cylinder having an inner wall, a piston rod, and a stopper having a stopper body with an actuating surface opposite an outlet surface, an axial length between the actuating surface and the outlet surface, and a transverse diameter, the stopper body having a tubular section having an access diameter, the stopper at an axial location from the actuating surface comprising a deformable sealing element made from a thermoplastic elastomer (TPE), which deformable sealing element surrounds the stopper body, has an outer diameter, which is larger than the transverse diameter, and a deformable sealing element axial extension in the range of 5% and 95% of the axial length of the stopper body, which deformable sealing element seals an annular gap between the stopper body and the inner wall of the cylinder, and the stopper comprising a cavity at the axial location of the deformable sealing element, the cavity comprising a compressible fluid and having a lateral extension larger than the access diameter and at least 50% of the outer diameter of the deformable sealing element and a cavity axial extension in the range of 5% to 50% of the axial length of the stopper body, and which cavity is formed at an interface between the stopper body and the piston rod and/or at an interface between the deformable sealing element and the piston rod.

2. The injector according to claim 1, wherein the cavity axial extension is in the range of 10% to 50% of the axial length of the stopper body.

3. The injector according to claim 1, wherein the cavity has a cylindrical, an ellipsoidal or a toroidal shape.

4. The injector according to claim 1, wherein the stopper body comprises an actuating stopper element and an outlet stopper element each comprising a deformable sealing element as defined in claim 1, which actuating stopper element and which outlet stopper element are linked together by a resilient frame, the outlet stopper element being located at a first axial location from the actuating surface, and the actuating stopper element being located at a second axial location from the actuating surface, the stopper having the cavity at the first axial location.

5. The injector according to claim 4, wherein the stopper comprises a second cavity at the second axial location.

6. The injector according to claim 4, wherein the resilient frame has a cylindrical shape.

7. The injector according to claim 1, wherein the deformable sealing element is an O-ring with a recess along the inner diameter of the O-ring so that upon mounting of the O-ring on the stopper body or the piston rod the cavity is formed between the O-ring and the stopper body or between the O-ring and the piston rod at the recess of the O-ring.

8. The injector according to claim 1, wherein the stopper body has a cylindrical shape and the deformable sealing element is comprised on a cylindrical structure for mounting on the stopper body or the piston rod, so that upon mounting of the cylindrical structure on the stopper body or the piston rod, the cavity is formed between the stopper body or the piston rod and the cylindrical structure.

9. The injector according to claim 1, wherein the deformable sealing element has or the stopper body and the deformable sealing element have a Shore A hardness in the range of 30 to 90.

10. The injector according to claim 1, wherein the stopper body is made from a TPE.

11. The injector according to claim 1, wherein the deformable sealing element is at a first axial location from the actuating surface and a cavity at the first axial location and wherein the stopper further comprises a second deformable sealing element at a second axial location from the actuating surface and a second cavity at the second axial location.

12. The injector according to claim 1, wherein the deformable sealing element is at a first axial location from the actuating surface and wherein the stopper further comprises a second deformable sealing element at a second axial location from the actuating surface and the cavity extends between the first axial location and the second axial location.

13. The injector according to claim 1, wherein the outer diameter of the deformable sealing element is in the range of 1.5% to 10% larger than the inner diameter of the cylinder before inserting the stopper into the cylinder.

14. The injector according to claim 1, wherein the deformable sealing element has a Shore A hardness in the range of 30 to 90, and wherein the injector does not comprise an external lubricant.

15. The injector according to claim 1, wherein the cylinder is made from glass.

16. The injector according to claim 1, wherein the cylinder has an inner diameter in the range of 2 mm to 12 mm.

17. The injector according to claim 1, wherein the cylinder is prefilled with a pharmaceutical composition.

18. The injector according to claim 1, wherein the deformable sealing element is convex and the deformable sealing element axial extension is in the range of 5% to 25% of the axial length of the stopper body.

19. The injector according to claim 1, wherein the stopper body has a diameter in the range of 50% to 90% of the outer diameter of the deformable sealing element.

20. The injector according to claim 1, wherein the deformable sealing element is convex and is further defined by an angle between the stopper body and the deformable sealing element, which angle is the range of 120° to 160°.

21. The injector according to claim 1, wherein the deformable sealing element is convex and an actuating contact angle facing the actuating surface of the stopper is formed between the inner wall of the cylinder and the deformable sealing element, which actuating contact angle is in the range of 5° to 60°.

22. The injector according to claim 1, wherein the deformable sealing element is convex and an outlet contact angle facing the outlet surface of the stopper is formed between the inner wall of the cylinder and the deformable sealing element, which outlet contact angle is in the range of 5° to 60°.

23. The injector according to claim 1, wherein the deformable sealing element is convex and an actuating contact angle facing the actuating surface of the stopper is formed between the inner wall of the cylinder and the deformable sealing element, and an outlet contact angle facing the outlet surface of the stopper is formed between the inner wall of the cylinder and the deformable sealing element, which actuating contact angle and outlet contact angle are independently in the range of 5° to 60°.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) In the following the invention will be explained in greater detail with the aid of examples and with reference to the schematic drawings, in which

(2) FIG. 1 shows a stopper of the prior art;

(3) FIG. 2 shows a cross-sectional view of a stopper of the invention;

(4) FIG. 3 shows a cross-sectional view of an injector of the invention;

(5) FIG. 4 shows a cross-sectional view of a stopper of the invention with a piston rod;

(6) FIG. 5 shows a cross-sectional view of a stopper of the invention with a piston rod;

(7) FIG. 6 shows a cross-sectional view of a stopper of the invention;

(8) FIG. 7 shows a cross-sectional view of a stopper of the invention;

(9) FIG. 8 shows a cross-sectional view and a top view of a stopper of the invention;

(10) FIG. 9 shows a cross-sectional view and a top view of a stopper of the invention;

(11) FIG. 10 shows a cross-sectional view and a top view of a stopper of the invention;

(12) FIG. 11 shows an embodiment of a stopper of the invention having a resilient frame;

(13) FIG. 12 shows an embodiment of a stopper of the invention having a resilient frame;

(14) FIG. 13 shows an embodiment of a stopper of the invention having a resilient frame;

(15) FIG. 14 shows several embodiments of stoppers of the invention;

(16) FIG. 15 shows embodiments of stoppers of the invention;

(17) FIG. 16 shows an embodiment of a piston rod of the invention

(18) FIG. 17 shows an embodiment of a stopper of the invention.

(19) It should be understood that combinations of the features in the various embodiments are also contemplated, and that the various features, details and embodiments may be combined into other embodiments.

(20) Reference to the figures serves to explain the invention and should not be construed as limiting the features to the specific embodiments as depicted.

DETAILED DESCRIPTION OF THE INVENTION

(21) The present invention relates to stoppers for injectors for delivery of a pharmaceutical composition and to injectors. The present invention will now be described in greater detail with reference to the appended drawings. Certain figures are depicted as “cross-sectional views” of the injectors of the invention, where the injector in the “cross-sectional view” is depicted at an angle of 90° compared to the injector otherwise depicted. Certain figures depict side views of injectors of the invention. These side views do not depict the outlet of the injectors but it is to be understood that the injector of the invention will have an outlet, e.g. fitted with a hypodermic needle.

(22) FIG. 1 shows an example of a stopper 1001 of the prior art. The stopper 1001 has a piston body 1002 with and an actuating end 1003 and an outlet end 1004, and the actuating end 1003 comprises a tubular section 1007 having an internal helical thread 1008. The stopper 1001 comprises two deformable sealing elements 1005. The stopper 1001 has a solid section 1006. The stopper 1001 thus exerts substantial force from the solid elastomeric material 1006 via the deformable sealing element 1005 and towards the container inner wall (not shown) dictating the use of lubrication means for satisfactory injection functionality causing significant disadvantages.

(23) FIG. 2 shows an embodiment of a stopper 1 of the invention, and in FIG. 3 the stopper 1 has been inserted into an injector 21 of the invention. The depicted stoppers 1 are injection moulded as single pieces from a thermoplastic elastomer (TPE). In FIG. 4 and FIG. 5 the stopper 1 is depicted with different embodiments of a piston rod 10. The stopper 1 has a stopper body 2 with an actuating surface 3 opposite an outlet surface 4, and an axial length between the actuating surface 3 and the outlet surface 4. The stopper body 2 has a transverse diameter, and the stopper body 2 defines an access diameter. At an axial location from the actuating surface 3 the stopper 1 comprising a deformable sealing element 5 surrounding the stopper body 2 and having an outer diameter, which is larger than the transverse diameter. The deformable sealing element 5 has an axial extension in the range of 5% and 95% of the axial length of the stopper body 2. When inserted into a cylinder 22 of a syringe 21 the deformable sealing element 5 abuts the inner wall 23 of the cylinder 22 so that the deformable sealing element 5 seals an annular gap between the inner wall 23 and the stopper body 2. The stopper 1 is depicted with a supporting sealing element 51, which also abuts the inner wall 23. When a supporting sealing element 51 is present it will typically have a smaller diameter than the diameter of the deformable sealing element 5, which has a lateral extension, a diameter, in the depicted embodiment, larger than the access diameter of the stopper body 2. The supporting sealing element 51 can prevent tilting of the stopper 1 when the stopper 1 is mounted in the cylinder 22. The deformable sealing element 5 is made from a TPE; in the embodiment shown, the TPE is a non-lubricated Evoprene G970 (Mexichem Specialty Compounds).

(24) A tubular section 7 extends from the actuating surface 3, and the tubular section 7 has in internal helical thread 71 representing an engagement device for engaging a complementary engagement device of the engagement section 11 of the piston rod 10. Thus, the cavity 6 is formed in the interface between the terminal site 13 of the engagement section 11 of the piston rod 10 and the deformable sealing element 5 when the piston rod 10 is inserted into the tubular section 7. Specifically, the complementary engagement device is an external helical thread 14. The internal helical thread 71 defines has a minimum diameter and a maximum diameter defined by the helix. The minimum diameter of the helix will, in this embodiment, be the access diameter defined by the stopper body 2.

(25) The piston rod 10 will normally be made from a hard polymeric material. The piston rods 10, as depicted, have a ridge 12, which has a larger diameter than the largest diameter of the helix of the internal helical thread 71, but smaller than the inner diameter of the cylinder 22. Thereby, the ridge 12 defines how deep into the tubular section 7 the engagement section 11 of the piston rod 10 can be inserted. When the engagement section 11 of the piston rod 10 has been fully inserted into the tubular section 7, i.e. in the embodiments shown the engagement section 11 is screwed into the tubular section 7, a cavity 6 is formed between the terminal site 13 of the piston rod 10. The cavity 6 may thus be a cylindrical cavity 6 as shown in FIG. 4 or a toroidal cavity 6 as shown in FIG. 5. In both cases the cavity 6 has a lateral extension, e.g. a diameter, larger than the access diameter of the stopper body 2.

(26) FIG. 6 shows an embodiment of the stopper 1, where the stopper 1 has a cavity 6 at the axial location of a deformable sealing element 5 closest to the outlet surface 4 of the stopper 1, which cavity 6 is open to the outlet surface 4.

(27) FIG. 7 shows an embodiment of the stopper 1, where the stopper 1 has a cavity 6, which is enclosed in the TPE of the stopper. The stopper 1 may for example be injection moulded as two pieces, where one piece is the stopper body 2 having an open cavity 6 as depicted in FIG. 6 an another piece is a tip that can be attached to the stopper body 2 so that the cavity 6 is enclosed between the material of the tip and the stopper body 2 after welding. The stopper 1 in FIG. 7 does not have a tubular section 7 but a stopper body 2 having a tubular section 7 can also be prepared with an enclosed cavity 6 as shown in FIG. 7.

(28) FIG. 8, FIG. 9 and FIG. 10 show embodiments of the stopper 1, where the cavity 6 has a toroidal shape. In the top panels, the stoppers 1 are depicted in a cross-sectional view and in the bottom panels, the stoppers 1 are depicted in a top view. In all three embodiments shown, the stoppers 1 are preferably prepared by injection moulding as single pieces of a TPE. In FIG. 8 and FIG. 9 the tubular section 7 has a protrusion 72 at the bottom of the tubular section 7, which protrusion 72 extends into the tubular section 7. Thereby, toroidal cavities 6 will be formed when the piston rod (now shown in FIG. 8 and FIG. 9) is inserted into the tubular section 7. In FIG. 9 the protrusion 72 is shaped to form a toroidal cavity 7 shaped to form two subcavities so that the cavity 7 has the shape of an interrupted cylindrical shell. In FIG. 10 the tubular section 7 is separated from the cavity 6, which is instead formed to extend from the outlet surface 4 and into the stopper body 2.

(29) FIG. 11, FIG. 12 and FIG. 13 show embodiments of the stopper 1 having a resilient frame 83. These stoppers are preferably made as single pieces by injection moulding of a TPE. In FIG. 11 the stopper 1 is shown at different angles at 90° relative to each other in the a and b panels, respectively. In FIG. 12 and FIG. 13 panels a show the stoppers 1 and in panels b the stoppers 1 are inserted into cylinders 22 of injectors 21. Thus, the stopper 1 has an actuating stopper element 81 and an outlet stopper element 82, which are linked together by the resilient frame 83. The actuating stopper element 81 and the outlet stopper element 82 abut the inner wall 23 of the cylinder 22 and seal a gap between the inner wall 23 of the cylinder 22 and the stopper body 2 thereby creating a compressible section 84 between the actuating stopper element 81 and the outlet stopper element 82. The embodiments depicted have cavities 6 at both deformable sealing elements 6. In FIG. 12 and FIG. 13 panels b show how the resilient frame 83, which has a cylindrical shape, can deform upon application of a force as depicted with an arrow. The arrows thus represent the force occurring when the piston rod 10 is pushed toward the outlet end of the cylinder 22. The stopper 1 in FIG. 12 has a piston rod 10 with an engagement section 11 having a terminal site 13 with a larger diameter than the tubular section 7 so that the terminal site 13 functions as a barb that can pull the stopper 1 back and thereby fill the cylinder 22 of the injector 21.

(30) FIG. 14 shows several embodiments of the stopper 1 having a cavity 6 enclosed in the stopper body 2, and in FIG. 15 similar stoppers 1 are shown with cavities 6 having different diameters, in the left and right panels, respectively, where arrows indicate the force exerted on the inner wall 23 of the cylinder 22 via the deformable sealing element 5. Thus, the smaller the diameter of the cavity 6 the larger the force on the inner wall 23 and thereby the higher the break loose force (BLF). Therefore, the lateral extension of the cavity 6 should be at least 50% of the outer diameter of the deformable sealing element 5. If the lateral extension of the cavity 6 is below 50% of the outer diameter of the deformable sealing element 5 a sufficiently low BLF may not be possible to avoid lubrication of the stopper.

(31) FIG. 16 shows how the cavity 6 may be integrated in a piston rod 10. Thus for example, the piston rod 10 may have a cylindrical section with an integrated stopper 1. Alternatively, the piston rod 10 may have a cylindrical section corresponding to the engagement section 11, which is surrounded by an O-ring made of a TPE the O-ring having a recess thereby providing the cavity 6 when mounted on the piston rod 10. In yet a further embodiment, the piston rod 10 may have a cylindrical section corresponding to the engagement section 11, which is surrounded by a sleeve made from a TPE, the sleeve comprising one, two or more deformable sealing elements 5 with cavities 6 formed between the inner surface of the sleeve and the outer surface of the engagement section part of the piston rod 10.

(32) A further embodiment of the stopper 1 of the invention is shown in FIG. 17. In this embodiment, the stopper has two deformable sealing elements 5, which share a toroidal cavity 6 extending from the actuating surface 3 of the stopper 1. Thus, the cavity 6 extends between the axial locations of the deformable sealing elements 5. The stopper 1 has a supporting deformable sealing element 51.

EXAMPLES

Example 1

(33) The stopper depicted in FIG. 2 was prepared by injection moulding from the TPE material Evoprene G970 (Mexichem Specialty Compounds). The stopper had two deformable sealing elements. The stopper was mounted in 1.0 ml non-lubricated borosilicate glass cylinder of 6.35 mm inner diameter with 27 G staked needle and provided to the test facility as pre-filled glass injectors with the integrated needle and stored at 23° C., 50% relative humidity (RH) until testing began. The tests involved analysis of the BLF and the glide force in Water for Injection (WFI) and an aqueous solution of Tween. Testing was based on ISO 7886-3:2005 Annex B Sterile hypodermic injectors for single use—Part 3: Autodisable injectors for fixed-dose immunisation, Test method for forces required to operate plunger. The specific conditions involved emptying the injectors with measurement of forces during the initial 5 mm at a test rate of 100 mm/min in an Instron mechanical testing machine equipped with 100 N load cell. The test results are shown in Table 2.

(34) TABLE-US-00002 TABLE 2 BLF test results for 1 ml injector, 2- deformable sealing elements stopper. Test conditions Number of Glide force, N 23° C., 50% RH replicates Average BLF (N) 2-30 mm WFI 4 10 (1)  5.2 (1.9) Tween solution 4 9.2 (0.7) 3.7 (0.7)

(35) For comparison stoppers were prepared having only a single deformable sealing element and the tests were repeated. The results are shown in Table 3.

(36) TABLE-US-00003 TABLE 3 BLF test results for 1 ml injector, 1-deformable sealing element stopper. Test conditions Number of Glide force, N 23° C., 50% RH replicates Average BLF (N) 2-30 mm WFI 4 6.2 (0.2) 2.1 (0.4) Tween solution 4 5.0 (0.2) 1.6 (0.7)

(37) In Table 2 and Table 3, the numbers in brackets represent the standard deviations. Glide force gives the average forces for displacements between 2 mm and 30 mm. The average and standard deviation are computed for all data curves combined.

(38) Thus, the stopper of the invention provided consistently low BLF values and also low glide force.

(39) The same stoppers and glass injectors, i.e. stoppers having 1 deformable sealing element and stoppers having 2 deformable sealing elements, were also tested for Cylinder closure integrity (CCI). Specifically, the injectors were prefilled with blue dye solution prepared according to the guidelines in ASTM F 1929, and the tests were based on Pharmaceutical Package Integrity, Parenteral Drug Association's Technical Report No. 27, 1998. The injectors were laid on absorbent paper in a desiccator with the vacuum profile shown in Table 4 and Table 5.

(40) TABLE-US-00004 TABLE 4 CCI test results for 1 ml injector, 1-deformable sealing element stopper Inspection Inspection Inspection after −25 mbar, after −35 mbar, after −100 mbar, 10 min 10 min 10 min No leaking No leaking No leaking

(41) TABLE-US-00005 TABLE 5 CCI test results for 1 ml injector, 2-deformable sealing element stopper Inspection Inspection Inspection after −25 mbar, after −35 mbar, after −100 mbar, 10 min 10 min 10 min No leaking No leaking No leaking

(42) No leaking indicates that the injection system can contain the dye during the vacuum challenges. Thus, the stoppers of the invention provide injectors complying with CCI requirements, also when the stopper has only a single deformable sealing element.

Example 2

(43) Further experiments were conducted with the 1 ml injectors with either the one or two deformable sealing element stoppers to test the CCI and BLF over a period of time of up to 4 weeks. In contrast to Example 1, the injectors had cylinders of cyclic olefin polymer (COP). The injectors with the integrated needle were pre-filled with solutions of 0.10% surfactant (Tween80) in water and stored at 23° C., 50% relative humidity (RH) until testing began.

(44) The area around the stopper was observed immediately after filling the injectors and after 1 hour, 1 week, 2 weeks and 4 weeks. No leakage was observed for any specimen and it was concluded that the injectors comply with CCI requirements.

(45) For the measurements of BLF values, the injectors were tested with a stroke speed of 100 mm/min over 28 mm. The BLF values are shown in Table 6.

(46) TABLE-US-00006 TABLE 6 BLF values over time Immediately 1 week after 2 weeks after 4 weeks after Specimen after filling filling filling filling 1 deformable 9.9 10.8 9.4 10.0 sealing element 2 deformable 12.7 14.6 13.7 13.5 sealing elements

(47) Thus, no significant development in BLF values was observed over a period of 4 weeks, which shows that the stopper of the invention is suited for use in a pre-filled injector. In all cases the BLF values were within an acceptable range.

REFERENCE NUMERALS

(48) 1001 Prior art stopper 1002 Piston body of prior art stopper 1003 Actuating end of prior art stopper 1004 Outlet end of prior art stopper 1005 Sealing element of prior art stopper 1006 Solid section of prior art stopper 1007 Tubular section of prior art stopper 1008 Internal helical thread of prior art stopper 1 Stopper of the invention 2 Stopper body 3 Actuating surface 4 Outlet surface 5 Deformable sealing element 51 Supporting sealing element 6 Cavity 7 Tubular section 71 Internal helical thread 72 Protrusion 81 Actuating stopper element 82 Outlet stopper element 83 Resilient frame 84 Compressible section 10 Piston rod 11 Engagement section 12 Ridge 13 Terminal site of piston rod 14 External helical thread 21 Injector 22 Cylinder 23 Inner wall of the cylinder