SYRINGES, KITS, AND METHODS FOR INTRACUTANEOUS AND/OR SUBCUTANEOUS INJECTION OF PASTES

Abstract

This disclosure includes syringes, kits containing the same, and related methods. Some syringes are pre-loaded with paste and have a syringe body defining a reservoir having an internal first transverse dimension, a paste disposed within the reservoir, the paste having a solids concentration of greater than 50 mg/mL, a needle defining a lumen having an internal second transverse dimension that is smaller than the first transverse dimension, the needle configured to be in fluid communication with the reservoir to allow intracutaneous delivery of the paste, and a plunger and/or piston disposed within the reservoir and configured to be moved to dispense paste from the reservoir through the lumen. Some syringes include a fitting (e.g. Luer fitting) disposed on the syringe body and in fluid communication with the reservoir and a sealing cap disposed on the Luer fitting to seal the reservoir.

Claims

1. A pre-loaded syringe comprising: a syringe body defining a reservoir; a paste disposed within the reservoir, the paste having a solids concentration of greater than 50 mg/mL; a plunger disposed within the reservoir and configured to be moved to dispense paste from the reservoir; a Luer fitting disposed on the syringe body and in fluid communication with the reservoir; and a sealing cap disposed on the Luer fitting to seal the reservoir.

2. The pre-loaded syringe of claim 1, comprising: a needle defining a lumen, the needle configured to be coupled to the syringe body via the Luer fitting to allow intracutaneous delivery of the paste; where the reservoir has an internal first transverse dimension larger than an internal second transverse dimension of the lumen.

3. A pre-loaded syringe comprising: a syringe body defining a reservoir having an internal first transverse dimension; a paste disposed within the reservoir, the paste having a solids concentration of greater than 100 mg/mL; a needle defining a lumen having an internal second transverse dimension that is smaller than the first transverse dimension, the needle configured to be in fluid communication with the reservoir to allow intracutaneous delivery of the paste; and a plunger disposed within the reservoir and configured to be moved to dispense paste from the reservoir through the lumen.

4. The pre-loaded syringe of claim 2 or 3, where the first transverse dimension is 3 to 16 times larger than the second transverse dimension.

5. The pre-loaded syringe of any of claims 2-4, where the first transverse dimension is between 1 and 5 mm.

6. The pre-loaded syringe of any of claims 2-5, where the second transverse dimension is between 0.1 and 0.9 mm.

7. The pre-loaded syringe of any of claims 2-6, where the needle has a size of 18 Gauge or smaller.

8. The pre-loaded syringe of claim 7, where the needle has a size of 27 Gauge or smaller.

9. The pre-loaded syringe of claim 8, where the needle has a size of 30 Gauge.

10. The pre-loaded syringe of any of claims 2-9, where the needle has a length smaller than 50 mm.

11. The pre-loaded syringe of claim 10, where the needle has a length smaller than 40 mm.

12. The pre-loaded syringe of claim 11, where the needle has a length smaller than 13 mm.

13. The pre-loaded syringe of claim 12, where the needle has a length of approximately 6 mm.

14. The pre-loaded syringe of any of claims 1-13, where the paste has a volume of between 15 μL and 1000 μL.

15. The pre-loaded syringe of any of claims 1-14, where the paste has a volume greater than 50 μL.

16. The pre-loaded syringe of claim 15, where the paste has a volume greater than 100 μL.

17. The pre-loaded syringe of any of claims 1-16, where the syringe is configured to dispense paste at a flow rate of greater than 30 μL/s under a force applied to the plunger having a magnitude below 25 N.

18. The pre-loaded syringe of any of claims 1-17, where the syringe is configured to dispense paste at a flow rate of greater than 65 μL/s under a force applied to the plunger having a magnitude below 25 N.

19. The pre-loaded syringe of any of claims 1-18, where the paste has a solids concentration of greater than 200 mg/mL.

20. The pre-loaded syringe of claim 19, where the paste has a solids concentration of between 425 and 475 mg/mL.

21. The pre-loaded syringe of any of claims 1-20, where the paste has a solids content of between 1% and 99%.

22. The pre-loaded syringe of claim 21, where the paste has a solids content of between 30% and 40%.

23. The pre-loaded syringe of any of claims 1-22, where the paste has a density of between 1.1 and 1.4 g/mL.

24. A kit comprising: a syringe body defining a reservoir having an internal first transverse dimension; and a needle configured to be coupled to the syringe body and defining a lumen having an internal second transverse dimension that is larger than the first transverse dimension; and a paste having a solids concentration of greater than 100 mg/mL.

25. The kit of claim 24, where the paste is disposed within the reservoir.

26. The kit of claim 24 or 25, where the syringe body comprises: a Luer fitting in fluid communication with the reservoir; and a sealing cap disposed on the Luer fitting to seal the reservoir; where the needle is configured to be coupled to the syringe body via the Luer fitting.

27. The kit of any of claims 24-26, where the first transverse dimension is 3 to 16 times larger than the second transverse dimension.

28. The kit of any of claims 24-27, where the first transverse dimension is between 1 and 5 mm.

29. The kit of any of claims 24-28, where the second transverse dimension is between 0.1 and 0.9 mm.

30. The kit of any of claims 24-29, where the needle has a size of 18 Gauge or smaller.

31. The kit of claim 30, where the needle has a size of 27 Gauge or smaller.

32. The kit of claim 31, where the needle has a size of 30 Gauge.

33. The kit of any of claims 24-32, where the needle has a length smaller than 50 mm.

34. The kit of claim 33, where the needle has a length smaller than 40 mm.

35. The kit of claim 34, where the needle has a length smaller than 13 mm.

36. The kit of claim 35, where the needle has a length of approximately 6 mm.

37. The kit of any of claims 24-36, where the reservoir has a volume of between 100 μL and 1000 μL.

38. The kit of any of claims 24-37, comprising a plunger disposed within the reservoir and configured to be moved to dispense paste from the reservoir through the lumen at a flow rate of greater than 30 μL/s under a force applied to the plunger having a magnitude below 25 N.

39. The kit of any of claims 24-38, comprising a plunger disposed within the reservoir and configured to be moved to dispense paste from the reservoir through the lumen at a flow rate of greater than 65 μL/s under a force applied to the plunger having a magnitude below 25 N.

40. The kit of any of claims 24-39, where the paste has a solids concentration of greater than 200 mg/mL.

41. The kit of claim 40, where the paste has a solids concentration of between 425 and 475 mg/mL.

42. The kit of any of claims 24-41, where the paste has a solids content of between 1% and 99%.

43. The kit of claim 42, where the paste has a solids content of between 30% and 40%.

44. The kit of any of claims 24-43, where the paste has a density of between 1.1 and 1.4 g/mL.

45. A method of intracutaneously injecting a volume of paste comprising: moving a plunger of a syringe to dispense paste from a reservoir of the syringe through a lumen of a needle of the syringe, the reservoir having an internal first transverse dimension that is larger than an internal second transverse dimension of the lumen, where the second transverse dimension is between 0.1 and 0.9 mm; where the paste has a solids concentration of greater than 100 mg/L; and where the paste is dispensed at a flow rate of greater than 30 μL/s as the plunger is moved at a rate of between 2 and 40 mm/s.

46. The method of claim 45, comprising disposing the needle into and/or through cutaneous tissue of a patient.

47. The method claim 45 or 46, comprising removing a sealing cap from a Luer fitting of the reservoir.

48. The method of any of claims 45-47, comprising coupling the needle to the reservoir via a Luer fitting disposed on at least one of the needle and the reservoir.

49. The method of any of claims 45-48, where the flow rate of the paste is substantially linearly proportional to the rate of plunger movement.

50. The method of any of claims 45-49, where the first transverse dimension is 3 to 16 times larger than the second transverse dimension.

51. The method of any of claims 45-50, where the first transverse dimension is between 1 and 5 mm.

52. The method of any of claims 45-51, where the second transverse dimension is between 0.1 and 0.9 mm.

53. The method of any of claims 45-52, where the needle has a size of 18 Gauge or smaller.

54. The method of claim 53, where the needle has a size of 27 Gauge or smaller.

55. The method claim 54, where the needle has a size of 30 Gauge.

56. The method of any of claims 45-55, where the needle has a length smaller than 50 mm.

57. The method of claim 56, where the needle has a length smaller than 40 mm.

58. The method of claim 57, where the needle has a length smaller than 13 mm.

59. The method of claim 58, where the needle has a length of approximately 6 mm.

60. The method of any of claims 45-59, where the injected volume of paste is greater than 10 μL.

61. The method of claim 60, where the injected volume of paste is between 15 μL and 1200 μL.

62. The method of claim 61, where the injected volume of paste is between 30 μL and 100 μL.

63. The method of any of claims 45-62, where the paste has a solids concentration of greater than 200 mg/mL.

64. The method of claim 63, where the paste has a solids concentration of between 425 and 475 mg/mL.

65. The method of any of claims 45-64, where the paste has a solids content of between 1% and 99%.

66. The method of claim 65, where the paste has a solids content of between 30% and 40%.

67. The method of any of claims 45-66, where the paste has a density of between 1.1 and 1.4 g/mL.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The following drawings illustrate by way of example and not limitation. For the sake of brevity and clarity, every feature of a given structure is not always labeled in every figure in which that structure appears. Identical reference numbers do not necessarily indicate an identical structure. Rather, the same reference number may be used to indicate a similar feature or a feature with similar functionality, as may non-identical reference numbers. The figures are drawn to scale (unless otherwise noted), meaning the sizes of the depicted elements are accurate relative to each other for at least the embodiment depicted in the figures.

[0057] FIG. 1 is a diagram of a conventional syringe, showing various exemplary contributions to injection force.

[0058] FIG. 2A is a side-view of one embodiment of the present pre-loaded syringes, showing a removable needle.

[0059] FIG. 2B is a side view of the embodiment of FIG. 2A, showing a sealing cap.

[0060] FIGS. 2C and 2D are cross-sectional end views of a reservoir and a needle, respectively, of the embodiment of FIG. 2A.

[0061] FIG. 3 is a graph of injection force versus plunger movement for various syringe reservoir volumes at first flow rate.

[0062] FIG. 4 is a graph of injection force versus plunger movement for various syringe reservoir volumes at a second flow rate.

[0063] FIG. 5 is a graph of average injection force versus syringe reservoir cross-sectional area at the first and second flow rates.

[0064] FIG. 6 is a graph of injection force versus plunger movement for a syringe at the first flow rate.

[0065] FIG. 7 is a top view of one embodiment of the present kits.

[0066] FIG. 8 depict a paste that exhibited both partial and complete clogging while delivered from a 4.6 mm reservoir through a 27G UTW, 6 mm needle at a volumetric flow rate of 33.3 μL/sec.

[0067] FIG. 9 depicts the force required to deliver the paste from the syringes which was measured using a texture analyzer (where the force required to drive the plunger is plotted against the plunger distance).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0068] U.S. Pat. No. 8,790,679, to the extent not inconsistent with the present disclosure, is expressly incorporated by reference herein, in its entirety.

[0069] Referring now to the drawings, and more particularly to FIG. 1, shown is a diagram of a conventional syringe 10, showing various exemplary contributions to injection force (e.g., a force required to cause flow from a syringe, typically applied to a syringe plunger). In this diagram, syringe 10 is shown having a reservoir 14 (containing a substance 18), a needle 22, and a plunger 26. As shown, the total force required to dispense fluid (e.g., including paste, viscous Newtonian and/or non-Newtonian and/or thixotropic fluids, and/or the like) is generally a combination of forces generated within and/or near three particular regions: reservoir exit 30, needle 22, and reservoir/plunger interface 34. For example, at reservoir exit 30, the cross-sectional area through which substance 18 may flow can sharply decrease, which may result in viscous resistance as the substance is forced to flow through reservoir exit 30 and into needle 22. Such viscous resistance can also be present in flow through needle 22 (e.g., which has a relatively small cross-sectional area when compared to reservoir 14). And, in the depicted example, plunger 26 is configured to directly interface with reservoir 14 at reservoir/plunger interface 34 (e.g., a sealed and/or friction fit interface), and frictional forces may occur as plunger is moved relative to reservoir 14. These viscous and/or frictional injection force contributions may be additive to provide the total injection force for a given syringe 10 containing a given substance 18.

[0070] As will be described below, it may be shown that injection force and/or flow resistance for a given syringe, needle, and/or substance combination can be substantially dominated by viscous effects near a reservoir exit (e.g., 30), for example, due to the sharp change in cross-sectional area proximate this region. Further, it has been observed that in pastes containing cohesive, micronized powders that are highly susceptible to forming robust aggregates (where an aggregate is comprised of two or more powder particles that have not been completely dispersed during mixing) may exhibit partial, and/or complete clogging during delivery of the paste from the syringe reservoir and into the needle. Complete clogging results in the total obstruction of fluid flow from the device. In contrast, partial clogging does not result in the complete obstruction of fluid flow, but may be noted as an abrupt increase in force/pressure during delivery resulting in a discontinuity during fluid delivery. FIG. 8 depicts a paste that exhibited both partial and complete clogging while delivered from a 4.6 mm reservoir through a 27G UTW, 6 mm needle at a volumetric flow rate of 33.3 μL/sec.

[0071] FIG. 2A-2D depict a first embodiment of the present pre-loaded syringes, designated by the reference numeral 38. In the embodiment shown, pre-loaded syringe 38 comprises a syringe body 42 defining a reservoir 46 having an internal first transverse dimension (e.g., diameter) 50. In this embodiment, reservoir 46 comprises a substantially circular cross-section; however, in other embodiments, reservoir 46 can comprise any suitable cross-section, such as, for example, square, rectangular, and/or otherwise polygonal, circular, elliptical, and/or otherwise rounded, and/or the like, and the cross-section need not be constant from one end of the reservoir to the other. Table 1 provides non-limiting examples of dimensions for reservoirs which may be suitable for use in some embodiments of the present syringes.

TABLE-US-00001 TABLE 1 Illustrative Reservoir Dimensions Consistent with Some Embodiments of the Present Syringes. Example 1 Example 2 Example 3 Example 4 Reservoir 100 250 500 1000 Volume (μL) Internal 1.46 2.30 3.30 4.61 Diameter (mm) Cross-sectional 1.67 4.15 8.55 16.69 Area (mm.sup.2)
Reservoirs of the present disclosure may have volumes, internal diameters (e.g., first transverse dimension 50), cross-sectional areas, and/or the like, that are less than, between any two of, or greater than any one of any value listed in TABLE 1, above.

[0072] In the embodiment shown, syringe 38 comprises a Luer fitting 54 (e.g., disposed on syringe body 42) in fluid communication with reservoir 46. In the depicted embodiment, Luer fitting 54 is configured to allow removable coupling of a needle 58 with syringe body 42, for example, to allow intracutaneous delivery of a paste 62 (described in more detail below) from the reservoir through the needle. In this way, embodiments of the present pre-loaded syringes can be provided without a needle attached to the syringe body and can allow a clinician to select, replace, change, and/or the like needles, as may be desired. In the embodiment shown, syringe 38 comprises a sealing cap 66 configured to seal reservoir 46 (e.g., which can be removably coupled to syringe body 42, for example, via Luer fitting 54). Sealing cap 66 can function to seal the reservoir to prevent inadvertent loss, contamination, and/or the like of paste 62, and can be removed from the reservoir to allow attachment of needle 58. Other embodiments of the present pre-loaded syringes can be provided with a needle 58 attached to syringe body 42, and Luer fitting 54 and sealing cap 66 may be omitted.

[0073] In the embodiment shown, needle 58 is configured to be in fluid communication with reservoir 46 to allow intracutaneous delivery of paste 62. In this embodiment, needle 58 defines a lumen 70 having an internal second transverse dimension 74 that is smaller than first transverse dimension 50 of reservoir 46. For example, in this embodiment, first transverse dimension 50 is 3 to 16 times larger than second transverse dimension 74. However, in other embodiments, first transverse dimension 50 can be between any two of or greater than any one of 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 times second transverse dimension 74. For further example, in this embodiment, first transverse dimension 50 is between 1 and 5 mm, and second transverse dimension 74 is between 0.1 and 0.9 mm.

[0074] In the embodiment shown, needle 58 is a 27 Gauge needle; however in other embodiments, needle 58 can comprise any suitable size, such as, for example, 18 Gauge or smaller (where smaller refers to a needle with a smaller internal diameter, or alternatively, a larger gauge), 27 Gauge or smaller, 30 Gauge or smaller, or sizes larger than 18 Gauge, and can comprise any suitable wall size (e.g., ultra-thin wall, thin wall, regular wall, and/or the like). To illustrate, a 30 Gauge regular wall needle can have approximately the same median internal diameter (e.g., second transverse dimension 74) as a 33 Gauge ultra-thin wall needle. Needles that are 30 Gauge and smaller are typically considered pain-free, as some patients may not experience discomfort (or any sensation) when the cutaneous tissue is pierced. Needles of the present disclosure can comprise any suitable length, such as, for example, smaller than 50 mm, smaller than 40 mm, smaller than 10 mm, approximately 6 mm, 6 mm, and/or any other suitable length. For example, needles of the present disclosure can comprise a length that is greater than any one of or between any two of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, or larger mm.

[0075] In the depicted embodiment, syringe 38 comprises a plunger 78 disposed within reservoir 46 and configured to be moved (e.g., relative to the reservoir) to dispense paste 62 from the reservoir.

[0076] In the embodiment shown, paste 62 is disposed within reservoir 46 (e.g., syringe 38 is pre-loaded). The reservoir 46 may be made of any material that is suitable for the intended application and that is compatible with the paste 62. Non-limiting examples of reservoir materials include glass (e.g. borosilicate glass) and plastics (e.g. polypropylene, polycarbonate, polystyrene, etc). As described above, reservoir 46 can comprise any suitable dimensions, and any suitable volume of the reservoir may comprise paste 62. For example, in some embodiments, paste 62 has a volume of between 15 μL and 1000 μL. In some embodiments, the paste can have a volume greater than 50 μL, and in some embodiments, the paste can have a volume greater than 100 μL. In some embodiments, the paste can have a volume greater than 1000 μL, and in some embodiments, the paste can have a volume greater than 2000 μL. A volume of paste 62 disposed within reservoir 46 may sometimes be referred to as an injection volume (e.g., if substantially all of the volume of paste is to be injected and/or dispensed from the syringe).

[0077] Pastes suitable for use with the present syringes can comprise any suitable material properties (e.g., solids concentrations, solids content, viscosity profile, density, and/or the like). For example, paste 62 can comprise a solids concentration of greater than 100 mg/mL, greater than 200 mg/mL, or between 300 and 500 mg/mL (e.g., greater than any one of or between any two of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or greater mg/mL). For further example, paste 62 can comprise a solids content (e.g., a mass of powder relative to a total mass of the paste) of between 30% and 40% (e.g., 35%) (e.g., greater than any one of, or between any two of 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 or more %). For yet further example, paste 62 can comprise a density of between 1.1 and 1.4 g/mL (e.g., 1.25 g/mL) (e.g., greater than any one of or between any two of 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, or larger g/mL).

[0078] In certain aspects a suitable paste may be a protein paste having a solids content of 35%, a density of 1.3 g/mL, and a solids concentration of approximately 450 mg/mL. In one example, such a paste can be tested, characterized, or optimized by dispensing the paste from a variety of syringes (e.g., having reservoirs with various first transverse dimensions 50 and/or volumes), each equipped with a 27 Gauge ultra-thin wall needle 58 (e.g., having a second transverse dimension 74 of 0.3 mm).

[0079] Flow resistance within a needle 58 (e.g., opposing an injection force) can be dependent on volumetric flow rate of a fluid (e.g., paste 62) through the needle, and this volumetric flow rate can also be equal to the volumetric flow rate of the fluid through a reservoir 46 in communication with the needle (e.g., allowing for conservation of mass). If fluid flow rate is matched for syringes having reservoirs with varying dimensions and/or volumes, but substantially identical needles, the flow resistance within the needle for each syringe can be substantially the same as the flow resistance within the needles of the other syringes, and thus any differences in total injection force amongst the syringes may be dominated by viscous effects near the reservoir exits of the syringes (e.g., 30).

[0080] Volumetric flow rate can depend on the cross-sectional area (e.g., first transverse dimension 50) of the reservoir and plunger 78 velocity. Thus, volumetric flow rates between syringes with differing reservoirs may be matched by varying applied plunger velocities amongst the syringes. For example, syringes having reservoirs with smaller internal transverse dimensions (e.g. 100 μL volume reservoirs) can require higher plunger velocities than syringes having reservoirs with larger internal transverse dimensions (e.g. 1000 μL volume reservoirs) to attain a given flow rate. For further example, for four illustrative syringes having reservoirs of varying volumes and internal dimensions, TABLE 2 provides respective plunger velocities required to achieve two particular volumetric flow rates: 33.3 μL/s and 67.0 μL/s.

TABLE-US-00002 TABLE 2 Plunger Velocities at Two Illustrative Flow Rates for Reservoirs Consistent with Some Embodiments of the Present Syringes. 33.3 μL/s 67.0 μL/s Reservoir Volume Plunger Velocity Plunger Velocity (μL) (mm/s) (mm/s) 100 19.91 40.00 250 8.02 16.12 500 3.90 7.83 1000 2.00 4.01

[0081] As shown, some embodiments of the present syringes (e.g., 38) are configured to dispense paste at a flow rate of greater than 30 μL/s as plunger 78 is moved at a rate of between 2 and 40 mm/s. Also, as shown in the depicted examples, flow rate of paste is substantially linearly proportional to the rate of plunger movement.

[0082] FIG. 3 and FIG. 4 are graphs that depict injection force (ordinate; units provided in Newtons) versus plunger movement (abscissa; units provided in millimeters) for syringes represented in TABLES 1 and 2, at flow rates represented in TABLE 2. As shown, for a given flow rate, syringes having reservoirs with smaller internal transverse dimensions 50 may produce smoother (e.g., flatter) injection force curves with lower injection force magnitudes than those observed for syringes having reservoirs with larger internal transverse dimensions. One implication of smoother injection force curves is the absence of clogging during paste flow from the reservoir into the needle. As flow rate is increased, syringes having reservoirs with smaller internal transverse dimensions may experience a smaller increase in injection force than syringes with reservoirs with larger internal transverse dimensions. Additionally, syringes having reservoirs with smaller internal transverse dimensions have been noted to be less susceptible to either partial or complete clogging.

[0083] FIG. 5 is a graph of average injection force versus syringe reservoir cross-sectional area for the syringes represented in TABLES 1 and 2, at the flow rates represented in TABLE 2. As shown, syringes having reservoirs with smaller internal transverse dimensions may require less injection force than syringes having larger internal transverse dimensions at a given flow rate, and/or may be less susceptible to increases in injection force, which may be induced by flow rate increases and/or clog formation.

[0084] FIG. 6 is a graph of injection forces versus plunger movement for a syringe having a reservoir 46 with a first internal transverse dimension 50 of 1.03 mm, a needle 58 having a lumen 70 with a second internal transverse dimension 74 of 0.160 mm (e.g., a 30 Gauge needle), and a length of 13 mm, at a plunger 78 velocity of 40 mm/s to produce a flow rate of 33.3 μL/s, dispensing the 35% solids content protein paste described above. As shown, the injection force curve is smooth (i.e. free of clog formation), with a magnitude of 5.38 N.

[0085] Typically, the upper limit for manual injection force (e.g., considering patient and/or clinician comfort) is approximately 25 N. As shown, some embodiments of the present syringes are configured to dispense paste (e.g., 62) at a flow rate of greater than 30 μL/s under a force (e.g., an injection force) applied to the plunger having a magnitude of below 25 N (e.g., less than 20, 15, 10, or 5 N). Some embodiments are configured to dispense paste at a flow rate of greater than 65 μL/s under a force applied to the plunger having a magnitude below 25 N (e.g., less than 20, 15, 10, or 5 N).

[0086] Thus, using embodiments of the present syringes, pastes may be intracutaneously and/or subcutaneously delivered through relatively thin needles (e.g., from 18 Gauge to 30 Gauge, or smaller), using relatively small injection forces (e.g., from 25 N to 5 N, or smaller).

[0087] In addition to enabling low injection forces for manual injection, alternative embodiments of the invention enable pastes to be smoothly delivered (i.e. free of partial and/or complete clogging) intracutaneously and/or subcutaneously through relatively thin needles via auto-injectors, where the force driving the plunger/piston is partially or completely provided by an external source (i.e. the energy to displace the piston/plunger and deliver the paste is not provided directly by the patient/clinician). Such an external energy source may be a compressed spring or a compressed gas that drives the piston/plunger of the auto-injector device when the patient activates the device via, for example, the press of a button.

[0088] Some embodiments of the present syringes can be configured to provide for any suitable injection force, flow rate, plunger velocity, and/or the like, for example, by varying paste viscosity, solids concentration, solids content, density, and/or the like, needle size, Gauge, length, lumen interior transverse dimension, and/or the like, syringe reservoir size, volume, cross-sectional area, interior transverse dimension, and/or the like.

[0089] FIG. 7 depicts an embodiment 82 of the present kits. Syringes of the present kits can comprise any and/or all of the features described above for syringe 38. As shown, kit 82 comprises a syringe (e.g., 38), depicted with needle 58 separated from syringe body 42 (e.g., with sealing cap 66 sealing reservoir 46). In the embodiment shown, kit 82 comprises one or more needles (e.g., 58) (e.g., to allow a clinician to select, change, replace, and/or the like needles). In the depicted embodiment, kit 82 comprises one or more containers 86 that can be used to store paste (e.g., 62) (e.g., such that an assembled syringe 38 (e.g., with a needle 58 attached to syringe body 42) can be loaded with paste, for example, by puncturing a seal of a container 86 with the needle and drawing plunger 78 away from syringe body 42). However, in some embodiments, syringe 38 may be pre-loaded (e.g., as described above).

[0090] Some embodiments of the present methods for intracutaneously injecting a volume of paste (e.g., 62) comprise moving a plunger (e.g., 78) of a syringe (e.g., 38) to dispense paste from a reservoir (e.g., 46) of the syringe through a lumen (e.g., 70) of a needle (e.g., 58) of the syringe, the reservoir having an internal first transverse dimension (e.g., 50) that is larger than an internal second transverse dimension (e.g., 74) of the lumen, where the second transverse dimension is between 0.1 and 0.9 mm, where the paste has a solids concentration of greater than 100 mg/L, and where the paste is dispensed at a flow rate of greater than 30 L/s as the plunger is moved at a rate of between 2 and 40 mm/s. Some methods comprise removing a sealing cap (e.g., 66) from a fitting (e.g., a Luer fitting 54) of the reservoir. Some methods comprise coupling the needle to the reservoir via a Luer fitting disposed on at least one of the needle and the reservoir. Some methods comprise disposing the needle into and/or through cutaneous tissue of a patient.

[0091] In some methods, the injected volume of paste is greater than 10 μL. In some methods, the injected volume of paste is between 15, 500, or 1000 μL to 1200, 2000, or 3000 μL. In some methods, the injected volume of paste is between 30 μL and 100 μL.

[0092] The above specification and examples provide a complete description of the structure and use of illustrative embodiments. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this invention. As such, the various illustrative embodiments of the methods and systems are not intended to be limited to the particular forms disclosed. Rather, they include all modifications and alternatives falling within the scope of the claims, and embodiments other than the one shown may include some or all of the features of the depicted embodiment. For example, elements may be omitted or combined as a unitary structure, and/or connections may be substituted. Further, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and/or functions, and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.

[0093] The claims are not intended to include, and should not be interpreted to include, means-plus- or step-plus-function limitations, unless such a limitation is explicitly recited in a given claim using the phrase(s) “means for” or “step for,” respectively.

EXAMPLES

[0094] The following examples as well as the figures are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples or figures represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

A Spray Dried Powder Containing a Monoclonal Antibody

[0095] A spray dried powder containing a monoclonal antibody (where the dried powder contained approximately 70% (w/w) protein) was used to prepare a high-concentration paste formulation by blending the powder with Miglyol 812 to yield a homogeneous two-phase suspension of mAb powder particles dispersed in a non-solvent. The final paste concentration contained 1.6 mL of fluid per gram of powder. As the density of Miglyol at 25° C. is 0.95 g/mL, the solids content of the resulting paste was approximately 40%. The measured density of the paste was 1.12 g/mL and the corresponding solids concentration was 448 mg/mL.

[0096] This paste was loaded into glass syringes with varying internal diameters, and delivered through 27G, UTW 6-mm needles (median internal diameter=300 μm) affixed to the syringes via a Luer-lock fitting. The force required to deliver the paste from the syringes was measured using a texture analyzer (force is plotted against the plunger distance).

[0097] As shown in the table below, when the same paste is delivered at the same volumetric flow rate through the same needle, the syringe possessing the narrower internal transverse dimension greatly reduces the force required to deliver the concentrated, high-viscosity paste. The lower injection force facilitates delivery and improves the overall ease-of-administration.

[0098] The mean injection glide force for N=3 replicates for each syringe are shown in Table 3:

TABLE-US-00003 TABLE 3 Syringe Plunger Velocity Flow Rate Replicate 1 Replicate 2 Replicate 3 Average StDev 0.50 mL 7.83 mm/sec 66.7 μL/sec 12.15 N 12.51 N 12.49 N 12.38 N 0.20 N 1.00 mL 4.01 mm/sec 66.7 μL/sec 22.44 N 22.30 N 22.58 N 22.44 N 0.14 N

Example 2

A Model Paste Containing Milled Excipient Powder

[0099] A model paste containing only excipient particles was prepared by blending micronized lactose particles (D.sub.50≦10 μm) with triacetin (a triglyceride with viscosity of approximately 18 cP at 25° C.) to prepare a two-phase composition with 38% solids content. The measured density of the paste was 1.24 g/mL and the corresponding solids concentration was approximately 470 mg/mL. The lactose-triacetin paste was loaded into glass syringes with varying internal diameters, and delivered through 30G (30 gauge), regular wall needles (median internal diameter=160 μm) of 0.5 inch length affixed to the syringes via a Luer-lock fitting. The force required to deliver the paste from the syringes was measured using a texture analyzer (where the force required to drive the plunger is plotted against the plunger distance)(FIG. 9).

[0100] As shown in the table below, when the same paste is delivered at the same volumetric flow rate through the same needle, syringes possessing a narrower internal transverse dimension greatly reduce the force required to deliver the concentrated, high-viscosity paste. The lower injection force facilitates delivery and improves the overall ease-of-administration.

TABLE-US-00004 TABLE 4 Needle Syringe Barrel Lumen Internal Plunger Volumetric Replicate Diameter Diameter Velocity Flow Rate 3 0.160 mm 1.03 mm 40.00 mm/sec  33.3 μL/sec  3.6 N 0.160 mm 1.46 mm 19.91 mm/sec  33.3 μL/sec  7.2 N 0.160 mm 2.30 mm 8.02 mm/sec 33.3 μL/sec 16.2 N 0.160 mm 3.30 mm 3.90 mm/sec 33.3 μL/sec 26.6 N 0.160 mm 4.61 mm 2.00 mm/sec 33.3 μL/sec 51.4 N

[0101] Further, the smoothness of the injection force profiles of the lactose-triacetin paste were noted to improve as the internal diameter of the syringe barrel decreased, reflecting a reduced tendency for partial clogging during paste delivery. This feature is particularly important for the delivery of two-phase composition such as pastes, where the particulate matter can render the composition susceptible to partial and/or complete clogging during delivery through narrow internal diameter needles, as the highly cohesive powder particles may not be completely disrupted, despite the application of high-shear mixing techniques. Accordingly, an equally important feature of the disclosed invention is the ability to deliver highly-concentrated two-phase compositions through narrow-internal diameter needles commonly used for intracutaneous injection without the formation of partial and/or complete clogging.