Prefilled syringe and autoinjector

Abstract

To provide a prefilled syringe and an autoinjector.SOLUTION: The invention provides a method of adapting an autoinjector configured to actuate a prefilled syringe. The auto injector has a biasing member having a certain spring constant. The prefilled syringe is filled with a certain volume of therapeutic fluid. The prefilled syringe includes a barrel, stopper and a needle. The stopper has a certain path of travel. The biasing member is arranged to move the stopper along the path of travel. Also provided is an autoinjector having an injection spring adapted to an aged prefilled syringe.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed as a PCT International patent application on September 19, 2019, and claims priority to U.S. Provisional Patent Application No. 62 / 734,209, filed September 20, 2018, the entire contents of which are expressly incorporated herein by reference. [Background technology]

[0002] An auto-injector is a device for automatically injecting a therapeutic fluid into a patient's body. Demand for auto-injectors has grown rapidly in recent years due to a variety of factors. For example, auto-injectors are convenient for both caregivers and patients who self-administer therapeutic fluids. Auto-injectors reduce the number of steps required to administer therapeutic fluids. Furthermore, auto-injectors are labeled and the syringes are pre-filled by the drug supplier, eliminating the need to manually fill syringes with vials of therapeutic fluid. The use of pre-filled syringes reduces the risk of dosage errors, misidentification of medication, and contamination.

[0003] During use, an auto-injector is typically loaded with a pre-filled syringe and has a compressed spring or other biasing member to push against a stopper to release the therapeutic fluid. A button or other actuator is connected to a mechanism to release the compressed spring, causing it to expand. As the spring expands, it drives a piston rod or plunger, which in turn pushes against a stopper inside the syringe. The stopper then expels the therapeutic fluid from the syringe barrel, through the needle, and into the patient's tissue at the administration site.

[0004] Before pharmaceutical products such as prefilled syringes and auto-injectors can be marketed, companies typically must obtain approval from a government regulatory agency, such as the U.S. Food and Drug Administration or a similar agency in a foreign country. For drugs contained in prefilled syringes and delivered through auto-injector systems, pharmaceutical companies must provide the agency with stability test reports that contain a variety of information demonstrating adequate performance throughout the product's shelf life. Some of the performance characteristics that must be provided include dose accuracy within the expected injection time throughout the product's shelf life.

[0005] Typically, a prefilled syringe containing the therapeutic fluid is defined early in the development process. An autoinjector is later selected, and the injection time of the prefilled syringe within the autoinjector must match the expected injection time. To match the expected injection time, injection time simulations are typically used. Injection time simulations are typically mathematical in nature and based on the geometry of the prefilled syringe. The geometry of the prefilled syringe includes parameters such as needle length, needle diameter, and barrel diameter, among others. Such simulations are also typically based on pharmaceutical parameters such as viscosity. These parameters allow for the simulation of the hydrodynamic forces that the fluid applies against the stopper. The Hagen-Poiseuille equation is an example of a formula for modeling hydrodynamic forces. Frictional forces during delivery are typically approximated using step-wise functions to simulate a constant sliding yield stress at the beginning of the injection period and a constant sliding equilibrium stress for the remainder of the injection period.

[0006] In practice, the friction force between the stopper and barrel of a filled syringe is typically considered constant in injection time simulations. The constant force is typically extrapolated from the measured ejection force on an empty, filled syringe when the stopper is moved at a speed comparable to that corresponding to the expected injection time. Some more complex simulations can estimate the friction force using the following formula: (1) Ffriction =((2πμ oil r b l stopper ) / d oil )ν In the formula, μ oil is the viscosity of the lubricant, and r b is the inner radius of the syringe barrel, and l stopper is the length of the stopper in contact with the syringe barrel, and d oil is the lubrication thickness and v is the injection velocity (linear piston velocity with length dimension over time).

[0007] Generally, for Newtonian fluids, neglecting the pressure drop across the syringe barrel, the hydrodynamic forces can be estimated at a given temperature using the Hagen-Poiseuille equation: (2) F hydrodynamic =((8πμL n r b 4 ) / r n 4 )ν where μ is the viscosity of the fluid and L n is the length of the needle channel, and r b is the inner radius of the syringe barrel, and r n is the inner radius of the needle channel.

[0008] The flow time simulation is also generally based on the characteristics of the auto-injector, such as the pumping force it exerts on the stopper of the filled syringe barrel. The pumping force is based on the parameters and configuration of the auto-injector's injection spring or other structure that powers the movement of the auto-injector's injection mechanism. Potential resistance forces within the auto-injector may also be considered.

[0009] By calculating the force applied to the stopper using these various mathematical models, the injection time to accomplish an injection can be simulated. The simulated injection time can then be used to verify whether the injection spring parameters and configuration provide sufficient delivery force to the stopper to meet the expected injection time. Summary of the Invention [Problem to be solved by the invention]

[0010] In general, this patent document is directed to determining a spring for an automatic injector. Another aspect is directed to determining an automatic injector having the determined spring. [Means for solving the problem]

[0011] An aspect of this patent document is a method of manufacturing an auto-injector, the method including the steps of aging a pre-filled syringe having a stopper, measuring the force required to move the stopper a determined distance in a determined time within the aged pre-filled syringe, and selecting a spring having a determined spring force that moves the stopper the determined distance in the determined time.

[0012] One aspect of this patent document is a method of manufacturing an automatic injector for delivering a therapeutic fluid stored in an operationally filled syringe, the operationally filled syringe including an operational barrel and an operational stopper movably positioned within the operational barrel, the operational stopper being movable along an operational path from a first operational position to a second operational position, the automatic injector including an injection spring having a spring force, the injection spring configured to apply a delivery force to the operational stopper by driving a piston rod toward the operational stopper upon activation of the automatic injector, the delivery force being at least a portion of the spring force. The method includes the steps of aging a filled syringe at an accelerated rate to form a reference filled syringe, the reference filled syringe including a reference barrel and a reference stopper positioned within the reference barrel; moving the reference stopper of the reference filled syringe along a reference path of travel from at least one first reference position to at least one second reference position; measuring a plurality of applied forces on the reference stopper as the reference stopper moves along the reference path within the reference barrel to determine a plurality of reference stopper positions; and generating an applied force profile. the force profile includes at least some of the reference stop positions and applied forces measured while the reference stop is moving between the first and second reference positions, at least one of the measured applied forces correlating with at least one of the measured reference stop positions; and selecting an injection spring such that a delivery force applied to the operational stop at each position of the operational stop as it moves along its operational path between the first and second operational positions is greater than the measured application force at a corresponding one of the measured reference stop positions.

[0013] Another aspect of this patent document also relates to an automatic injector having an aged pre-filled syringe, a stopper within the pre-filled syringe, and an injection spring, the injection spring having a spring force sufficient to move the stopper a determined distance.

[0014] Another aspect of this patent document is an auto-injector arrangement including a barrel extending along a longitudinal axis between a distal end and a proximal end and having an internal diameter of approximately 8.65 mm; a needle disposed at the distal end of the barrel and having an internal diameter of approximately 0.27 mm and a length of approximately 19.5 mm or less; a therapeutic fluid retained within the barrel, the therapeutic fluid comprising fremanezumab and having a viscosity of approximately 8.8 cSt at 22°C, the volume ranging from approximately 1.51 mL to approximately 1.66 mL; and a stopper disposed within the barrel to retain the therapeutic fluid within the barrel, the barrel defining a travel path for the stopper, the travel path having a first initial position for the stopper and a second initial position for the stopper, the first position being an initial position of the stopper prior to delivery of the therapeutic fluid and the second position being a final position of the stopper upon delivery of a maximum dose of the therapeutic fluid. The auto-injector holds the pre-filled syringe. The automatic injector includes an injection spring arranged to apply a delivery force to the stopper by driving the piston rod toward the stopper, and when the automatic injector is activated, the injection spring is configured to provide an initial delivery force of at least about 20 N to the stopper when the stopper is positioned in a first initial position and a final delivery force of at least 12 N to the stopper when the stopper is positioned in a second final position, the delivery force being at least a portion of the spring force of the injection spring.

[0015] Another aspect of this patent document also relates to an automatic injector having an aged pre-filled syringe, a stopper within the pre-filled syringe, and an injection spring, the injection spring having a spring force sufficient to move the stopper a determined distance within a determined time.

[0016] Another aspect of this patent document is an automatic injector including a pre-filled syringe. The pre-filled syringe includes a barrel at least partially formed of glass, a needle in fluid communication with the barrel, and a stopper positioned within the barrel, the barrel defining an inner surface, the barrel having an inner diameter, the barrel diameter being approximately 8.65 mm, the barrel defining a track for the stopper, the track having a first position for the stopper and a second position for the stopper, the needle having an inner diameter of approximately 0.27 mm and a length of approximately 19.5 mm or less, a therapeutic fluid held within the barrel, the therapeutic fluid having a viscosity of approximately 10 cP at 22°C. About 0.35 mg to about 1.1 mg of silicone oil lubricates the inner surface of the barrel, the silicone oil having a viscosity in the range of approximately 500 cSt at 25°C to approximately 1500 cSt at 25°C before aging of the pre-filled syringe. The automatic injector holds the pre-filled syringe. The automatic injector includes a plunger and an injection spring. The plunger engages with the stopper, and the injection spring biases the plunger toward the stopper. When in a first position, the injection spring has a force determined in accordance with the action of claim 1; a spring force within the range of about 20 N to about 30 N; a stored spring energy within the range of about 0.9 J to about 2 J; a spring constant within the range of about 0.2 N / mm to about 0.4 N / mm; a compressed length within the range of about 50 mm to about 100 mm; a stored energy that is about 25% greater than the minimum spring energy required to move the stopper from the first position to the second position without stalling, prior to aging of the filled syringe; and a force sufficient to move the stopper along a path from the first position to the second position within about 5 seconds to about 25 seconds.

[0017] Another aspect of this patent document also relates to an auto-injector having a syringe pre-filled and aged with fremanezumab, a stopper inside the pre-filled syringe, and an injection spring, the injection spring having a spring force sufficient to move the stopper a determined distance.

[0018] Another aspect of this patent document is an auto-injector having a pre-filled syringe containing a stopper and a therapeutic fluid including fremanezumab, and a piston rod and injection spring arranged to move the stopper from a first position to a second position in about 19 seconds or less with a force of about 30 N or less, wherein the distance between the first and second positions corresponds to one dose of the therapeutic fluid. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 is a schematic diagram of an exemplary syringe pre-filled with fluid in accordance with the principles of the present disclosure. [Figure 2] FIG. 2 shows a sequence listing for fremanezumab that can be loaded into the pre-filled syringe shown in FIG. [Figure 3A] FIG. 3A is a graph plotting a set of measured forces opposing the displacement of a drive member acting on the stopper of an unaged, filled syringe. [Figure 3B] FIG. 3B is a chart showing the maximum applied forces measured for pre-filled syringes of various artificial ages. [Figure 3C] FIG. 3C is a graph plotting a set of measured forces opposing the displacement of the drive member acting against the stoppers of pre-filled syringes artificially aged for up to 24 months. [Figure 3D] FIG. 3D is a chart showing the observed injection times for pre-filled syringes of various natural and artificial ages. [Figure 4A] FIG. 4A is a side elevational view in partial section showing a fixture for testing prefilled syringes. [Figure 4B] FIG. 4B is a side elevational view in partial section showing an alternative fixture for testing prefilled syringes and auto-injector mechanisms. [Figure 4C] FIG. 4C is a side cross-sectional view of a fixture for testing spring forces in an auto-injector. [Figure 5]FIG. 5 is a side elevational view of an instrument intended to test the performance of prefilled syringes and auto-injectors for use with the fixture illustrated in FIGS. 4A-4C. [Figure 6] FIG. 6 is a flow diagram illustrating a decision process by which a spring constant for an injection spring of an auto-injector can be selected. [Figure 7] FIG. 7 is a schematic diagram of an exemplary oven used in artificially aging one or more pre-filled syringes. [Figure 8] FIG. 8 illustrates various test processes, each suitable for implementing the test operations of the decision process of FIG. [Figure 9] FIG. 9 illustrates various test processes, each suitable for implementing the test operations of the decision process of FIG. [Figure 10] FIG. 10 illustrates various test processes, each suitable for implementing the test operations of the decision process of FIG. [Figure 11] FIG. 11 is a flow diagram illustrating a method for performing at least the moving and measuring operations of the testing process of FIGS. 8-10 using the test equipment of FIG. [Figure 12] FIG. 12 is a flow chart illustrating an assembly process for assembling an auto-injector. [Figure 13] FIG. 13 illustrates the components of the auto-injector separated from one another for clarity. [Figure 14] 14 is a cross-sectional view of the auto-injector of FIG. 13 arranged in a pre-injection configuration. [Figure 15] FIG. 15 shows the auto-injector of FIG. 14 in an in-injection configuration. [Figure 16] FIG. 16 shows the auto-injector of FIG. 14 in an end-of-injection configuration. [Figure 17] FIG. 17 shows the auto-injector of FIG. 16 rotated 90 degrees. [Figure 18] FIG. 18 is a flow diagram illustrating a use process for using an auto-injector with a pre-filled syringe and a selected injection spring. [Figure 19]FIG. 19 illustrates the auto-injector being activated by a user. DETAILED DESCRIPTION OF THE INVENTION

[0020] Various embodiments are described with reference to the drawings, where like reference numerals represent like parts and assemblies throughout the several views. Reference to various embodiments does not limit the scope of the appended claims. Moreover, any examples described herein are not intended to be limiting, but merely to set forth some of the many possible embodiments of the appended claims.

[0021] For the purposes of this patent document, the terms "or" and "and" shall mean "and / or" unless otherwise stated or unless a different intention is clear from the context of their use. Wherever applicable, terms used in the singular include the plural as well, and vice versa. The use of "a" herein means "one or more" unless otherwise stated or unless the use of "one or more" is clearly inappropriate. The use of "or" means "and / or" unless otherwise stated. The use of "comprise," "comprises," "comprising," "includes," "including," "having," and "has" are interchangeable and not intended to be limiting. The term "such as" likewise is not intended to be limiting. For example, the term "including" is intended to mean "including, but not limiting to."

[0022] All ranges provided herein are inclusive of the upper and lower range values ​​unless expressly stated otherwise. Although values ​​are disclosed herein when disclosing certain exemplary embodiments, other embodiments within the scope of the pending claims may have the specific values ​​disclosed herein or values ​​that are outside the ranges disclosed herein.

[0023] Terms such as "substantially" or "about" used in connection with values ​​or structural elements define tolerances normally found during testing and production due to variations or imprecise tolerances of factors such as materials and equipment. These terms also define tolerances for variations found in natural and environmental conditions due to factors such as changes in temperature and humidity.

[0024] As used herein, the term "fremanezumab" is used interchangeably to refer to the anti-CGRP antagonist antibody produced by the expression vectors having the deposit numbers ATCC PTA-6867 and ATCC PTA-6866. The amino acid sequences of the heavy and light chain variable regions are set forth in SEQ ID NOS: 1 and 2, respectively. The CDR amino acid sequences of the G1 heavy chain variable region are set forth in SEQ ID NOS: 7-9 (Kabat and Chothia CDRs are labeled). The CDR amino acid sequences of the G1 light chain variable region are set forth in SEQ ID NOS: 10-12. Exemplary polynucleotides encoding the G1 heavy and light chain variable regions are set forth in SEQ ID NOS: 5 and 6, respectively. The full-length G1 heavy chain amino acid sequence is set forth in SEQ ID NOS: 3. The full-length G1 light chain amino acid sequence is set forth in SEQ ID NOS: 4. Exemplary polynucleotides encoding the G1 full-length heavy and light chains are set forth in SEQ ID NOS: 3 and 4, respectively. The characterization of G1 is described in PCT Publication No. WO 2007 / 054809 and WHO Drug Information 30(2):280-1 (2016), which are incorporated by reference in their entireties.

[0025] FIG. 1 shows an exemplary embodiment of a pre-filled syringe 150 suitable for holding a therapeutic fluid 160 for injection. The pre-filled syringe 150 includes a barrel 151, a needle 155, and a stopper 157. The barrel 151 defines an interior 154 sized to hold a predetermined amount of fluid 160 (e.g., at least one dose of the therapeutic fluid). The fluid 160 is held within the interior 154 of the barrel 151 between the stopper 157 and the needle 155. One example of a syringe that can be used as the pre-filled syringe 150 is a 2.25 mL EZ-Fill syringe supplied by Ompi (Piombino Dese, Italy). Other types of syringes can be used, as can syringes from other manufacturers.

[0026] The barrel 151 extends between a distal end 152 and an open proximal end 153. The prefilled syringe 150 similarly has a tip 161 at the distal end 152. The barrel 151 defines a proximal-facing shoulder 151 a at the distal end 152 within an interior 154 that extends between the barrel 151 and the tip 161.

[0027] Syringe barrel 151 is configured to hold approximately 2.25 mL of fluid. However, other barrel sizes may be utilized. For example, barrel 151 may be sized to hold approximately 1 mL of fluid. In other embodiments, barrel 151 is sized for therapeutic fluid 160 volumes ranging from about 1 mL to about 3 mL, from about 1 mL to about 2.5 mL, or from about 2 mL to about 2.5 mL. Other embodiments of prefilled syringe 150 may hold other volumes of therapeutic fluid 160.

[0028] Additionally, syringe barrel 151 has an inner diameter or other internal transverse dimension of approximately 8.65 mm. However, in alternative embodiments, barrel 151 can have an inner diameter within the range of approximately 6 mm to approximately 10 mm, or approximately 8.5 mm to approximately 8.8 mm. Still other contemplated embodiments can have inner diameters outside of these ranges.

[0029] In some embodiments, syringe barrel 151 is formed from borosilicate glass. In some embodiments, syringe barrel 151 is formed from transparent Type I borosilicate glass. For example, syringe barrel 151 may be composed of a mixture of SiO, BO, AlO, NaO, and CaO. In a more specific example, syringe barrel 151 is formed using 75% SiO, 10.5% BO, 5% AlO, 7% NaO, and 1.5% CaO. Alternative embodiments involving other mixtures of these materials can be used to form the glass for syringe barrel 151. In other embodiments, other types of glass, or even materials other than glass, can be used to form syringe barrel 151. For example, syringe barrel 151 can be formed from plastic. In at least some embodiments, syringe barrel 151 is a borosilicate glass barrel supplied by Schott Corporation of Elmsford, NY. Syringe barrels 151 from other manufacturers can also be used.

[0030] Stopper 157 is axially movable distally within interior 154 of barrel 151 along a path of travel P. Stopper 157 has a main body that is substantially cylindrical or otherwise has a cross-sectional shape similar to the cross-section of inner surface 156 for barrel 151. Stopper 157 has one or more flanges or ribs 158 extending radially from the main body. Additionally, stopper 157 has a compressed state and an uncompressed state, with stopper 157 being in the compressed state when inserted into syringe barrel 151.

[0031] The main body of the stopper 157 has a first engagement surface 157a that faces proximally toward the exterior of the prefilled syringe 150 and a second engagement surface 157b that faces the fluid 160 stored inside the barrel 151. The first engagement surface 157a is flat, and the end of a piston rod (e.g., 107 in FIGS. 14-17) abuts against the engagement surface 157a during use. In an alternative embodiment, the first engagement surface 157a includes a threaded hole (not shown) or other coupling structure (not shown) so that the stopper 157 can be threaded onto or otherwise coupled to the end of a piston rod in an auto-injector. To move the stopper 157 distally within the syringe barrel 151, a delivery force can be applied to the first engagement surface 157a of the stopper 157, pushing the stopper 157 along a path of travel P. The main body of the stopper 157 has a length of approximately 7.7 mm. In alternative embodiments, stopper 157 may have a length within the range of about 7.3 mm to about 8.1 mm, or about 7 mm to about 9 mm. Alternative embodiments of stopper 157 may have lengths longer or shorter than these ranges. Furthermore, the outer diameter of the main body of stopper 157 when in a compressed state is about 8.95 mm. In some alternative embodiments, the outer diameter of the main body is within the range of about 8.85 mm to about 9.05 mm, or about 5.5 mm to about 9.5 mm. Alternative embodiments may have a main body with an outer diameter outside these ranges. Furthermore, the outer diameter is measured from the base of flange 158 through the main body to the base of flange 158 on the opposite side of the main body.

[0032] A plurality of annular flanges 158 engage the inner surface 156 of the syringe barrel 151. The flanges 158 create a substantially airtight seal against the inner surface 156 of the syringe barrel 151 to retain the therapeutic fluid 160 within the interior 154. The stopper 157 includes four flanges 158. In alternative embodiments, the stopper 157 may have more or fewer flanges 158. For example, the stopper 157 may have one flange, two flanges, three flanges, or more than four flanges. Alternative embodiments may also include no flanges, such that the entire outer surface 162 between the first and second engagement surfaces 157a, 157b engages the inner surface 156 of the syringe barrel 151. In a compressed state, the stopper 157 has an outer diameter or cross dimension of approximately 8.95 mm. In alternative embodiments, the outer diameter of stopper 157 in its compressed state can be in the range of about 6 mm to about 10 mm, or about 6.5 mm to about 9.5 mm. In some examples, the outer diameter of stopper 157 is the outer diameter across the largest portion of stopper 157 (e.g., across at least one of flanges 158) and is at least slightly larger than the inner diameter or inner transverse dimension of syringe barrel 151 to ensure a seal between the stopper and the barrel. When in its uncompressed state, at least some contemplated embodiments of stopper 157 have an outer diameter in the range of about 9.25 mm to about 9.45 mm.

[0033] Stopper 157 is formed from a rubber such as bromobutyl rubber, although materials other than rubber or bromobutyl can be used to form stopper 157. An exemplary formulation that can be used to form bromobutyl rubber is formulation 4023 / 50 / GREY manufactured by West Pharmaceutical Services, PA, USA. In other embodiments, materials such as other types of rubber or non-rubber materials are used to form stopper 157. Additionally, stopper 157 can have a fluoropolymer coating or laminated outer surface 162 thereof. In one example, the coating can cover the entire outer surface 162 of stopper 157. In alternative examples, the coating can cover part or all of second engagement surface 157b, part or all of flange 158, part or all of the portion of outer surface 162 that faces inner surface 156 of syringe barrel 151, part or all of first engagement surface 157a, or a combination of these surfaces. Ethylene tetrafluoroethylene (ETFE) is one example of a fluoropolymer material that can be used to coat the stopper 157. The advantage of coating the stopper 157 with a fluoropolymer is that it prevents absorption or adsorption of the therapeutic fluid 160.

[0034] It is possible to coat or laminate the stopper 157 with materials other than fluoropolymers. One example of an alternative material is silicone. Alternatively, the stopper 157 can be coated or laminated with two or more materials. For example, the stopper 157 can have a fluoropolymer coating on the surface portion that contacts the therapeutic fluid 160 and a silicone oil coating on the surface portion that does not contact the therapeutic fluid 160. The coating on the stopper 157 can act as a lubricant, provide increased biocompatibility with the therapeutic fluid 160, prevent absorption or adsorption of the therapeutic fluid 160 or its components, or a combination thereof. In yet other embodiments, the stopper 157 does not have any type of coating or lamination.

[0035] During use, the second engagement surface 157b of the stopper 157 pushes the fluid 160 toward the needle 155, expelling the fluid 160 from the pre-filled syringe 150. The stopper 157 is moved from a first position D1 along the path of travel P to a second position D2 along the path of travel P. In the exemplary embodiment, the first position D1 is adjacent to the fluid 160 before any amount of a dose of the therapeutic fluid 160 has been delivered, and the second position D2 is the location of the second engagement surface 157b once delivery of the entire dose of the therapeutic fluid 160 has been completed. When in the second position D2, the stopper 157 is directly adjacent to or even touching the shoulder 151a of the syringe barrel 151. In an alternative embodiment, when the stopper 157 is in the first position D1, there may be gaps or air bubbles between the stopper 157 and the therapeutic fluid 160, or when the stopper 157 is in the second position D2, the stopper 157 may be isolated from the shoulder 151a of the syringe barrel 151.

[0036] The path of travel P may be approximately 29.6 mm, sometimes referred to as a "30 mm" path of travel. In alternative embodiments, the path of travel P may be within a range of approximately 25.7 mm to approximately 28.2 mm, approximately 25 mm to approximately 29 mm, or approximately 25 mm to approximately 40 mm. In some embodiments, the path of travel P may be 29.6 mm. In other embodiments, the length of the path of travel P may be a distance outside these ranges. The volume of therapeutic fluid 160 within pre-filled syringe 150 held between first and second positions D1, D2 of stopper 157 is approximately 1.585 mL, which directly corresponds to the internal volume of syringe barrel 151 between first and second positions D1, D2. In alternative embodiments, the volume of fluid 160 between first and second positions D1, D2 of stopper 157 is within a range of approximately 1.51 mL to approximately 1.66 mL. Alternate embodiments can have different volumes of fluid 160 between the first and second positions D1, D2 of stopper 157. The volume of fluid 160 can correspond to one full dose of therapeutic fluid 160, multiple doses of therapeutic fluid 160, or partial doses of therapeutic fluid 160.

[0037] The force applied by the auto-injector 140 to the stopper 157 is the delivery force. The amount of delivery force required to push the stopper 157 within the pre-filled syringe 150 can vary due to a variety of factors, including lubrication 159, syringe geometry and material, stopper geometry and material, the therapeutic fluid 160 within the pre-filled syringe 150, the desired injection time, and other resisting forces opposing movement of the stopper 157. Additionally, because the stopper 157 is compressible, it may absorb some of the delivery force applied to it by the piston rod of the auto-injector 140. The selected injection spring must have sufficient force to overcome this absorption if it becomes significant enough to affect the performance of the auto-injector 140.

[0038] Lubrication 159 may be disposed along the inner surface 156 of the barrel 151 to facilitate movement of the stopper 157 within the barrel 151. The lubrication 159 is disposed between the inner surface 156 of the barrel 151 and the outer contact surface 162 of the stopper 157 as the stopper 157 moves along the path of travel P. The lubrication 159 reduces friction between the outer contact surface 162 of the stopper 157 and the inner surface 156 of the barrel 151.

[0039] The lubricant used to form lubricating layer 159 is silicone oil. One example of a silicone oil that can be used is polydimethylsiloxane. In alternative embodiments, a lubricant other than silicone oil, a silicone oil other than polydimethylsiloxane, or any other suitable lubricant is used to lubricate inner surface 156 of barrel 151. Lubricant 159 can cover the entire inner surface 156 of syringe barrel 151, including the wall and shoulder 151 a of barrel 151. In example embodiments, lubricant 159 covers less than the entire inner surface 156 of filled syringe 150, such as only along the wall of barrel 151 or only along the portion of the wall of barrel 151 that extends along path of travel P.

[0040] In at least some embodiments, lubricious layer 159 has a substantially uniform thickness along path of travel P. Alternatively, lubricious layer 159 has a substantially uniform thickness along substantially the entire length of syringe barrel 151. Further, in at least some embodiments, lubricious layer 159 has a substantially uniform thickness around the inner circumference of syringe barrel 151. In other embodiments, the thickness of lubricious layer 159 varies across the length of syringe barrel 151 or along path of travel P. For example, the thickness of lubrication 159 may be gradually thinner toward distal end 152 of pre-filled syringe 150 compared to proximal end 153 of pre-filled syringe 150. As discussed in more detail herein, the thickness of lubrication 159 can vary in other ways and can also be carried around the circumference of syringe barrel 151.

[0041] In a contemplated embodiment, the thickness of the lubricating layer 159 is about 0.5 μm. Other thicknesses are possible. For example, the lubricating layer 159 may have a thickness along the path of travel P of about 0.1 μm to about 1 μm. In other examples, the lubricating layer 159 may have a thickness along the path of travel P of about 0.1 μm to about 0.3 μm.

[0042] In at least some embodiments, prefilled syringe 150 includes about 0.7 mg of silicone oil to form lubricating layer 159. In other embodiments, the amount of silicone oil is in the range of about 0.4 mg to about 1.1 mg. In still other embodiments, the amount of silicone oil is in the range of about 0.35 mg to about 1.0 mg.

[0043] In an exemplary embodiment, the lubricant forming lubricating layer 159 has a viscosity of about 1000 cSt at 25° C. In alternative embodiments, the lubricant has a viscosity between about 500 cSt and about 1000 cSt at 25° C., between about 100 cSt and about 1000 cSt at 25° C., or less than about 1250 cSt at 25° C. In still other embodiments, the lubricant has a viscosity outside these ranges.

[0044] Needle 155 is disposed at distal end 152 of barrel 151 and is coupled to tip 161. Needle 155 is secured to tip 161 using an adhesive. In an alternative embodiment, needle 155 is coupled to tip 161 using a hub or other structure.

[0045] The needle 155 extends between a first end and a second end. The needle 155 is coupled to the distal end 152 of the syringe barrel 151 at or adjacent the first end of the needle 155. The second end of the needle 155 may be sufficiently pointed or sharp to assist in breaching the skin 192 at an injection site 198 of a user 190 (see FIG. 19 ). The needle 155 defines a channel 155a in fluid communication with the interior 154 of the pre-filled syringe 150. During operation, the fluid 160 flows through the channel 155a and exits the syringe barrel 151. The channel 155a of the needle 155 has an inner diameter or transverse dimension that is the distance from one point on its periphery to another point on the opposite side of its periphery. The inner diameter is an example of a transverse dimension when the cross-section of the channel 155a is circular. In one embodiment, channel 155a has a constant inner diameter or cross-sectional dimension along the length of needle 155. However, in other embodiments, the inner diameter or cross-sectional dimension may vary along the length of channel 155a.

[0046] The needle 155 is a stainless steel needle, such as an AISI 304 grade stainless steel needle supplied by Chirana T. Injecta, Slovakia. Additionally, the needle 155 has the ISO designation 4301-304-00-1 and the ISO designation X5CrNi18-9. Other materials can be used to form the needle 155. Other embodiments may use needles 155 from other manufacturers and needles 155 with alternative ISO certifications or no certification at all.

[0047] Needle 155 has a length of 19.5 mm. In alternative embodiments, needle 155 can have a length within the range of about 15 mm to about 25 mm, about 18.3 mm to about 20.7 mm, or less than 19.5 mm. Other embodiments may have needle lengths longer or shorter than these ranges. Furthermore, needle channel 155a has an inner diameter or inner transverse dimension of 0.27 mm, about 0.15 mm to about 0.3 mm, about 0.25 mm to about 0.29 mm, about 0.21 mm to about 0.3 mm, or less than 0.27 mm. In other embodiments, needle 155 has an inner diameter of about 0.29 mm or less. Other embodiments have an inner diameter narrower or wider than these ranges.

[0048] Therapeutic fluid 160 may contain a pharmaceutical having a pharmacological or other active ingredient, a biologic, a biosimilar, or any other composition for treating the body. Depending on the composition of therapeutic fluid 160 and the prescribed treatment, therapeutic fluid 160 may have one of a variety of different volumes and viscosities. For example, in at least some contemplated embodiments, therapeutic fluid 160 has a volume of approximately 1.585 mL. In other embodiments, the volume of therapeutic fluid 160 is within a range of approximately 1.51 mL to approximately 1.66 mL. In other embodiments, the volume of therapeutic fluid 160 is within a range of approximately 1 mL to approximately 2.25 mL. In still other embodiments, other volumes of therapeutic fluid 160 are loaded into prefilled syringe 150.

[0049] Therapeutic fluid 160 may be a liquid pharmaceutical composition including fremanezumab, disodium ethylenediaminetetraacetic acid dihydrate (EDTA), L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, sucrose, and water for injection. One specific formulation of therapeutic fluid 160 is about 225 mg fremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidine hydrochloride monohydrate, about 0.3 mg polysorbate 80, about 99 mg sucrose, and water for injection at a pH of about 5.5. In one alternative embodiment, the therapeutic fluid 160 may be formulated at a nominal concentration of 150 mg / mL in 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, 1.2 mg / mL P580, pH 5.5. In some embodiments, at least about 70% of the fremanezumab in the liquid pharmaceutical composition is of the IgG2-B disulfide isotype. In some embodiments of any of the compositions provided herein, about 72% of the antibody molecules in the composition are of the disulfide isotype B, wherein about 22% of the antibody molecules in the composition are of the IgG2-A / B disulfide isotype, and about 6% of the antibody molecules in the composition are of the IgG2-A disulfide isotype. Other embodiments of the therapeutic fluid 160 may be other formulations containing other components. Additionally, the therapeutic fluid 160 may comprise a pharmaceutical, biologic, or biosimilar product other than fremanezumab.

[0050] The viscosity of the liquid pharmaceutical composition may be about 8.8 cSt at 22° C. Other viscosities are possible. For example, the therapeutic fluid 160 may have a viscosity in the range of about 4 cSt at 22° C. to about 14 cSt at 22° C. In some embodiments, the therapeutic fluid 160 has a viscosity in the range of about 8 cP at 22° C. to about 10 cP at 22° C. In some embodiments, the therapeutic fluid 160 has a viscosity of less than about 10 cSt at 22° C.

[0051] Therapeutic fluid 160 can be used for the treatment or prevention of a variety of different transient or chronic diseases, conditions, or other illnesses. Therapeutic fluid 160 can be used for the treatment or prevention of any disease or disorder linked to CGRP (calcitonin gene-related peptide) activity or CGRP upregulation. In one contemplated embodiment, therapeutic fluid 160 includes a biologic, such as for the treatment of episodic or chronic migraines. For example, therapeutic fluid 160 can include an immunoglobulin G2 (IgG2) monoclonal antibody. In another example, therapeutic fluid 160 includes a humanized IgG2 monoclonal antibody. The antibody can also be expressed in CHO cells. In another example, therapeutic fluid 160 includes an anti-CGRP protein.

[0052] In a more specific embodiment, referring to FIG. 2, the therapeutic fluid 160 comprises a heavy chain variable region V whose amino acid sequence is at least 90%, optionally 95%, 97%, 99% or 100% identical to SEQ ID NO:1. H a light chain variable region V domain, and a light chain variable region V whose amino acid sequence is at least 90%, optionally 95%, 97%, 99% or 100% identical to SEQ ID NO:2 L In some embodiments, therapeutic fluid 160 comprises an antibody produced by an expression vector having ATCC deposit numbers PTA-6867 and PTA-6866. In other embodiments, therapeutic fluid 160 comprises fremanezumab.

[0053] In other examples, the therapeutic fluid 160 comprises an antibody comprising the following CDRs: CDR H1 set forth in SEQ ID NO:3; CDR H2 set forth in SEQ ID NO:4; CDR H3 set forth in SEQ ID NO:5; CDR L1 set forth in SEQ ID NO:6; CDR L2 set forth in SEQ ID NO:7; and CDR L3 set forth in SEQ ID NO:8.

[0054] The therapeutic effect of fremanezumab is long-lasting, allowing it to be administered by relatively infrequent injections. For example, in one embodiment, fremanezumab can be administered about once a month or less. In another embodiment, fremanezumab can be administered about once every two months or less. In another embodiment, fremanezumab can be administered about once every three months or less. In another embodiment, fremanezumab can be administered about once every four months or less. Fremanezumab is disclosed in more detail in U.S. Patent No. 8,007,794, issued August 30, 2011, entitled "Antagonist Antibodies to Calcitonin Gene-Related Peptide and Methods of Use Thereof," the entire disclosure of which is incorporated herein by reference.

[0055] Therapeutic fluid 160 can also be used to treat or prevent other conditions such as cluster headaches, post-traumatic headaches, fibromyalgia, and interstitial cystitis / painful bladder syndrome (ICBPS).

[0056] In some implementations, the therapeutic fluid 160 is expected to have a shelf life of approximately 24 months when stored between 2°C and 8°C. In one example, the therapeutic fluid 160 is expected to have a shelf life of approximately 2 years when stored at 5°C. In other embodiments, the therapeutic fluid 160 is expected to have a shelf life of at least 12 months when stored between 2°C and 8°C. In some examples, the therapeutic fluid 160 is expected to have a shelf life of at least 18 months when stored between 2°C and 8°C. In some examples, the therapeutic fluid 160 is expected to have a shelf life of at least 30 months when stored between 2°C and 8°C. In some examples, the therapeutic fluid 160 is expected to have a shelf life of at least 36 months when stored between 2°C and 8°C. In some examples, the therapeutic fluid 160 is expected to have a shelf life of at least 6 months when stored between 2°C and 8°C. In some embodiments, the therapeutic fluid 160 is expected to have a shelf life of at least 9 months when stored at 2°C to 8°C.

[0057] It has been discovered that conventional injection time simulations of pre-filled syringe 150 have several disadvantages. For example, several aspects of pre-filled syringe 150 change over time, and over sufficient time, some of these changes can cause significant problems in the performance of pre-filled syringe 150 and the auto-injector 140 into which pre-filled syringe 150 is assembled. Many of these changes are not generally taken into account in current injection time simulations, and these include changes to pre-filled syringe 150 that increase the resistance forces that oppose movement of stopper 157 inside syringe barrel 151.

[0058] The increased resistance may be sufficient to slow the velocity of the syringe stopper 157 within the syringe barrel 151 compared to the filled syringe 150 before the change occurred. The injection rate resulting from these increased resistance may sometimes be uncomfortable for the patient. A slow injection rate could also result in an impatient user 190 self-administering the therapeutic fluid 160 prematurely withdrawing the needle 155 from their body, resulting in incomplete delivery of the fluid 160. In yet another embodiment, the motion of the stopper 157 may even stall, resulting in only a partial dose being delivered.

[0059] Friction and hydrodynamic forces are examples of resistive forces that oppose movement of the stopper 157 and can affect the sliding yield stress and sliding equilibrium stress, and therefore injection time and dose accuracy. The sliding yield stress is the amount of force required to move the stopper 157, and the sliding equilibrium stress is the amount of force required to maintain movement of the stopper 157. Friction may exist between the stopper 157 and the syringe barrel 151. Other types of friction may similarly oppose movement of the stopper 157. Hydrodynamic forces are the force required to push the fluid 160 through the barrel 151 into the needle 155 and then through the needle 155.

[0060] There are several changes that can occur over time that can increase friction between the stopper 157 and the syringe barrel 151. For example, the lubrication 159 in the syringe barrel 151 or on the stopper 157 can deteriorate or fail, either due to time or due to interaction with components of the therapeutic fluid 160. Deterioration of the lubrication 159 can increase the viscosity of the lubrication 159. Deterioration can also thin the lubrication layer 159 on the barrel wall 156 over time. Additionally, the lubrication 159 is a fluid and will flow along the barrel wall 156 over time, which can cause variations in the thickness of the lubrication 159, resulting in areas of increased friction along the path of travel P of the stopper as the lubrication layer 159 thins or disappears entirely.

[0061] There are also several examples of changes that can increase hydrodynamic forces. For example, some therapeutic fluids 160 may change over time. Over time, the therapeutic fluid 160 may aggregate or crystallize to form larger clumps that may become lodged within the channel 155a of the hypodermic needle 155. The blockages created by these clumps may increase the hydrodynamic forces required to move the fluid 160 through the needle 155. As a result, there is greater resistance to movement of the stopper 157.

[0062] If developers of therapeutic fluids or pre-filled syringes want to use current real-world data to design auto-injectors or for use in regulatory approval, they may choose to test pre-filled syringes that have been aged for at least as long as the desired shelf life. One problem with using current real-world data is that many therapeutic fluids and pre-filled syringes are expected to have long shelf lives, some as long as 24 months or even longer.

[0063] Waiting this long to submit an application for regulatory approval for a drug delivered by an auto-injector until after the therapeutic fluid's natural shelf life can significantly delay the approval process for the medication and the time when pharmaceutical companies can bring the therapeutic fluid to market. This results in delays in potentially life-changing or life-saving medications reaching patients. Furthermore, this delay makes it more difficult for pharmaceutical companies to recoup the significant investments required to research and discover successful medications. To speed up the regulatory approval process, pharmaceutical companies can use aging simulation or acceleration to replicate the effects of time. For example, pharmaceutical companies can use mathematical modeling to approximate the performance of a pre-filled syringe after a certain period of time. In another example, pharmaceutical companies heat a pre-filled syringe at a determined temperature and for a determined period of time to simulate aging. The relationship between the length of time the pre-filled syringe is heated and the actual unaccelerated length of time can be defined according to the following Arrhenius calculation: (3) K=A e -EA / (RT) where "K" is the rate constant, "T" is the absolute temperature (in Kelvin), and "A e -EA " is a constant for a given reaction and "R" is the universal gas constant.

[0064] It has been discovered that artificial aging of the prefilled syringe 150 or therapeutic fluid 160 can create complications during stability testing. For example, during stability testing using artificial aging, it was discovered that the combination of an aged prefilled syringe 150 and an auto-injector (e.g., the auto-injector 140 shown in FIGS. 13-17) can result in various operational failures, including an inability to inject within the intended injection time. Furthermore, it was discovered that artificial aging of the prefilled syringe 150 leads to greater than expected resistance forces on the stopper 157. For example, the resistance forces exerted on the stopper 157 along the path of travel P toward the end of the injection stroke were greater than expected. Thus, the injection spring 109 used in standard auto-injector devices failed to consistently operate the auto-injector with the artificially aged prefilled syringe 150 as simulated aging increased.

[0065] In particular, it has been discovered that heating the pre-filled syringe 150 exaggerates certain changes that occur over time. For example, heating causes changes to the pre-filled syringe 150 to occur more quickly than would occur in an equivalent time period due to natural aging. For example, compared to a pre-filled syringe 150 that has been naturally aged at an unaccelerated rate for 24 months, a pre-filled syringe 150 that has been subjected to accelerated aging simulated by heating for 24 months exhibits a greater magnitude of changes and more types of changes, such as changes to the thickness of the lubricating layer 159, a greater decrease in the viscosity of the lubricant, a greater variation in the thickness of the lubricating layer 159, and more interactions between the therapeutic fluid 160 and the lubricant.

[0066] All of these exaggerated changes that occur during artificial or accelerated aging result in unnatural increases in friction and hydrodynamic forces compared to a naturally aged pre-filled syringe 150. When an artificially aged pre-filled syringe 150 with increased resistance to movement of the stopper 157 is combined with an auto-injector (such as the auto-injector 140 described in more detail herein), operational malfunctions may occur, including failure to inject the therapeutic fluid 160 within the intended injection time and even stalling of the injection. Nevertheless, pharmaceutical companies must demonstrate data that the auto-injector 140 is capable of moving the stopper 157 in a reasonable time to deliver the full dose of therapeutic fluid 160 and avoid stalling. To allow for a viable regulatory pathway by allowing for artificial aging and meeting stability requirements, adaptations of the auto-injector 140 are proposed herein. An injection spring 109 for the auto-injector 140 is used that has a spring force sufficient to meet acceptable delivery specifications for the artificially aged pre-filled syringe 150. However, it is noted that pre-filled syringes used in commercially available auto-injectors will naturally age. It is further noted that unnecessarily increasing the spring force is generally not beneficial as it may cause some discomfort, pain to the patient, or lead to breakage of the pre-filled syringe.

[0067] An example of this problem for an artificially aged prefilled syringe 150 is illustrated in the diagrams shown in Figures 3A-3D. For purposes of generating the data shown in Figures 3A-3D, the prefilled syringe 150 used was an EZ-Fill syringe with a barrel inner diameter of approximately 8.65 mm and a capacity of 2.25 mL supplied by Ompi, Piombino Dese, Italy; the stopper 157 was a FluroTec plunger manufactured by West Pharmaceutical Services PA, Inc., Exton, PA, USA; and the needle 155 was a Grade AISI 304 stainless steel needle with an inner diameter of approximately 0.27 mm and a length of approximately 19.5 mm supplied by Chirana T. Injecta, Slovakia. The syringe barrel 151 was lubricated with 0.7 mg of silicone oil having a viscosity of approximately 1000 cSt at 25°C. The therapeutic fluid 160 loaded into the pre-filled syringe 150 consisted of approximately 1.585 mL of a fremanezumab formulation formulated at a nominal concentration of 150 mg / mL in 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, and 1.2 mg / mL P580, pH 5.5. The therapeutic fluid 160 had a viscosity of 8.8 cSt at 22° C. A number of unaged pre-filled syringes 150 were tested. The path of travel P of the stopper 157 within the barrel 151 corresponding to the extrusion of the therapeutic fluid 160 is approximately 30 mm.

[0068] FIG. 3A is a graph plotting the displacement of stopper 157 versus the force exerted on syringe stopper 157 of an unaged, filled syringe 150 as stopper 157 is moved at a constant velocity. This graph can be obtained using the test equipment described with reference to FIGS. 4A and 5. The y-axis represents the force exerted on stopper 157, measured in Newtons N. Because stopper 157 is moved at a substantially constant velocity, this applied force is substantially equal to the resistive force acting against the movement of stopper 157. The displacement is from a first (initial) position of stopper 157 at the start of injection to a second (final) position of stopper 157. The diagram in FIG. 3A shows that the maximum resistive force during movement of stopper 157 is approximately 8 N until just before a displacement of approximately 30 mm is reached, corresponding to stopper 157 reaching and striking shoulder 151 a in syringe barrel 151.

[0069] FIG. 3B is a bar graph showing the maximum force exerted on the stopper 157 of a filled syringe 150 subjected to accelerated aging. The filled syringes 150 exposed to accelerated aging were heated at 40° C. for an equivalent period of time to simulate the desired natural aging. For each filled syringe 150, the stopper 157 was pressed to expel the therapeutic fluid 160 at a constant rate, and the force exerted against the stopper 157 was measured. The force exerted against the stopper 157 is equivalent to or corresponds to the force resisting movement of the stopper 157. The graph was obtained using the test equipment described with reference to FIGS. 4 and 5. The y-axis represents the maximum force in Newtons exerted against the syringe stopper 157 while being moved to deliver a dose of therapeutic fluid 160 at a constant rate. The x-axis represents the simulated age of the filled syringe 150 after undergoing accelerated aging. The first bar shows the maximum application force before accelerated aging. The second bar shows the maximum application force for a filled syringe 150 having a simulated age of 3 months (T3). The third bar shows the maximum application force for a filled syringe 150 having a simulated age of 6 months (T6). The fourth bar shows the maximum application force for a filled syringe 150 having a simulated age of 9 months (T9). The fifth bar shows the maximum application force for a filled syringe 150 having a simulated age of 14 months (T14). The sixth bar shows the maximum application force for a filled syringe 150 having a simulated age of 24 months (T24).

[0070] As can be seen, the maximum force measured while moving stopper 157 during testing progressively increases to approximately 14 N, much greater than the 8 N measured for unaged filled syringes 150. Each bar on the graph represents a group of filled syringes 150 tested at each simulated age and shows the range of measured applied forces for that group, from the highest maximum applied force measured for that group to the lowest maximum applied force measured for that group. Each bar also presents boxes representing the middle two quartiles, or middle 50%, of the measured applied forces.

[0071] FIG. 3C is a graph plotting the force exerted against the syringe stopper 157 versus the displacement of the stopper 157 for pre-filled syringes 150 having a simulated age of 24 months. The pre-filled syringes 150 subjected to accelerated aging were heated at 40° C. for an equivalent period of time to simulate the desired natural aging. For each pre-filled syringe 150, the stopper 157 was pressed to expel the therapeutic fluid 160 at a constant rate, and the force exerted against the stopper 157 was measured. The force exerted against the stopper 157 is equivalent to or corresponds to the force resisting the movement of the stopper 157. The y-axis represents the force exerted against the stopper 157, measured in Newtons (N). The graph was obtained using the test equipment described with reference to FIGS. 4A and 5. Because stopper 157 moves at a substantially constant velocity, this force is substantially equal to the resistive force acting against the movement of stopper 157. This displacement is from the first position of stopper 157 at the start of the injection to the final position of stopper 157. The diagram in Figure 3C shows that the maximum resistive force during the movement of stopper 157 is approximately 14 N, just before reaching a displacement of 30 mm, which corresponds to stopper 157 reaching and striking shoulder 151 a in syringe barrel 151.

[0072] 3B and 3C, the peak or maximum force required to move the stopper 157 a distance of 30 mm for the filled syringe 150 having a simulated or accelerated age of 24 months was in the range of about 13 N to about 14 N. The peak force for the accelerated aged filled syringe 150 contrasts sharply with the peak force of only 8 N to 9 N required to move the stopper 157 of the naturally aged filled syringe 150, as shown in FIG. 3A. These graphs demonstrate a significant increase in the force required to move the stopper 157 for the artificially aged filled syringe 150 used in the testing, compared to the naturally aged filled syringe 150.

[0073] FIG. 3D is a bar graph showing the injection time, or the time it takes to move the stopper 157 from a first position D1 to a second position D2, for a filled syringe 150 that has undergone natural aging and a filled syringe 150 that has undergone accelerated aging. The y-axis represents the injection time in seconds, and the x-axis represents the age of the filled syringe 150. Data for the filled syringe 150 that has undergone natural aging is shown as a solid bar, and data for the filled syringe 150 that has undergone accelerated aging is shown as a solid bar. To generate the data in FIG. 3D, the autoinjector 140 with the filled syringe 150 was assembled in a jig that held the autoinjector 140 upright with the needle 155 pointing downward. A container was placed under the autoinjector 140 to collect the fluid 160 as it was being dispensed. The autoinjector 140 was activated. A stopwatch was manually started upon activation of the auto-injector 140 and stopped immediately when therapeutic fluid 160 ceased flowing from the needle 155. A digital stopclock accurate to within one-hundredth of a second was used. Eight samples of naturally aged pre-filled syringes 150 were tested at zero, one, six, nine, thirteen, nineteen, and twenty-four months. Four samples of accelerated aged pre-filled syringes 150 were tested at twelve, twenty-four, and forty-eight months. Each bar on the chart represents a group of pre-filled syringes 150 tested at natural or simulated ages, as labeled on the chart, and shows the range of injection times for each group, from longest to shortest. Each bar also displays boxes representing the middle two quartiles, or middle fifties, of injection times.

[0074] At 12 months, the naturally aged prefilled syringes 150 had injection times ranging from about 18.6 seconds to about 20.8 seconds, while the accelerated aged prefilled syringes 150 had injection times ranging from about 16.4 seconds to about 39.3 seconds. At 24 months, the naturally aged prefilled syringes 150 had injection times ranging from about 18 seconds to about 21 seconds, while the accelerated aged prefilled syringes 150 had injection times ranging from about 19.4 seconds to about 46.3 seconds. As can be seen, the delivery times of the naturally aged prefilled syringes 150 remain relatively constant throughout the life of the prefilled syringes 150. The delivery times for the accelerated aged prefilled syringes 150 are comparable to the delivery times of the naturally aged prefilled syringes 150 until the prefilled syringes 150 are about 9 months old. After this age, the time to deliver the full dose begins to increase rapidly for the accelerated aged pre-filled syringe 150. At 24 months of simulated aging, the delivery time can reach over 45 seconds, exceeding the target delivery time.

[0075] The above tests and results indicate that accelerated aging of the pre-filled syringe 150 can result in an increase in the force required to complete an injection. In some cases, artificial aging of the pre-filled syringe 150 can result in an increase in the force required to complete an injection within a desired or determined time (e.g., from about 5 seconds to about 19 seconds).

[0076] As one solution to these operational problems, the auto-injector 140 may be manufactured with an injection spring 109 strong enough to accommodate the higher thrust force on the stopper 157 of the artificially aged pre-filled syringe 150. That is, the injection spring 109 may require a sufficiently high spring constant K and compression to overcome the increased resistance force generated by the artificially aged pre-filled syringe 150, particularly at the end of the injection as the stopper 157 approaches the second position D2 and the resistance force becomes significantly greater than the resistance force at the start of the injection, as seen in FIG. 3B . However, increasing the strength of the injection spring 109 may lead to discomfort and even pain for the patient. Increased strength may also lead to breakage of the syringe 150. Therefore, using an injection spring 109 with more power than necessary is undesirable.

[0077] The tests described below can be used to determine suitable spring parameters for the injection spring 109 of an auto-injector 140 used to inject a therapeutic fluid 160 from an artificially aged pre-filled syringe 150. For example, the tests can determine a delivery force strong enough to completely displace a syringe stopper 157 along the entire path P within a predetermined time. The artificially aged pre-filled syringe 150 used in these tests forms a reference pre-filled syringe 150 having a reference barrel 151, a reference stopper 157, and a reference needle 155. The pre-filled syringe 150 currently used in an auto-injector 140 to deliver a therapeutic fluid 160 to a patient is an operational pre-filled syringe 150 having an operational barrel 151, an operational stopper 157, and an operational needle 155. The reference pre-filled syringe 150 is substantially similar to the operational pre-filled syringe 150. To ensure proper performance of the filled syringe 150 during operation, the reference filled syringe 150 and the operational filled syringe 150 have substantially the same dimensions and are made of the same material or materials that provide the same performance characteristics. In alternative embodiments, the reference filled syringe 150 and the operational filled syringe 150 can have different parameters. For example, the reference filled syringe 150 can have parameters that provide a more resistant force against movement of the stopper 157, ensuring that the designed injection spring 109 still provides a suitable amount of delivery force throughout the entire spring compression range, thereby ensuring that the auto-injector 140 will inject the entire dose of therapeutic fluid 160 within a determined time period.

[0078] 4A and 4B illustrate a fixture for testing the injection of a pre-filled syringe 150 to determine whether the injection spring 109 has sufficient force to meet performance standards for regulatory approval of the pre-filled syringe 150 and auto-injector 140. FIG. 4A illustrates a fixture 315 for holding a pre-filled syringe 150, as well as the principle of the test. The fixture 315 includes a syringe support frame 316 having a bottom support 316a, side supports 316b, and a top plate 316c. The syringe support frame 316 has sufficient thickness and rigidity so that it does not bend or compress under the application of the forces used in the test. The top plate 316c defines a hole 316d that is large enough to allow the syringe barrel 151 to pass through the hole 316d, but not so large that the syringe flange 158 at the proximal end 153 of the filled syringe 150 passes through the hole 316d. In this manner, the filled syringe 150 is supported by the top plate 316c with the needle 155 pointing downward. A drive rod 314 is aligned with and has an end that engages the first engagement surface 157a of the syringe stopper 157. A second, opposite end of the drive rod 314 is coupled to testing equipment configured to move the drive rod 314 at a substantially constant velocity. The drive rod 314 is also attached to a measurement device, such as a load cell 315 (see, e.g., FIG. 5), positioned to measure the force applied to the drive rod 314 as it moves.

[0079] The needle 155 is positioned in or over a collection container 318 to collect the therapeutic fluid 160 as it is expelled from the pre-filled syringe 150. Collecting the therapeutic fluid 160 allows for a comparison of the amount of fluid 160 loaded into the pre-filled syringe 150 before testing with the amount of fluid 160 expelled from the pre-filled syringe 150 after testing. Alternatively, the tip 161 of the needle 155 can be inserted into a mass to simulate an injection into a patient's body. Inserting the tip 161 of the needle 155 into a mass allows the testing device to include resistance to flow in measuring the total resistance acting against the movement of the syringe stopper 157. Examples of masses into which an injection can be simulated include cadaver tissue, animal tissue such as porcine tissue, and synthetic tissue.

[0080] During testing, the drive rod 314 is advanced or pushed against the stopper 157 at a constant rate and to push the stopper 157 a determined distance. In at least some contemplated embodiments, the determined distance corresponds to movement of the stopper 157 from a first position D1 to a second position D2 to deliver the full dose of therapeutic fluid 160. The rate at which the drive rod 314 is pushed downward is selected to simulate the desired timing for injection of a pre-filled syringe 150 within the auto-injector 140. In some embodiments, the drive rod 314 is advanced from the first position D1 to the second position D2 in a time period ranging from about 5 seconds to about 12 seconds.

[0081] As drive rod 314 is advanced toward syringe stopper 157, load cell 315 measures the force applied to drive rod 314 and the relative position of drive rod 314 is measured. The displacement of drive rod 314 is substantially equal to the displacement of syringe stopper 157. At each force measurement, the force measurement and the displacement of drive rod 314 are recorded.

[0082] During testing, the force applied to the drive rod 314 to advance or push the syringe stopper 157 is the applied force F eThe force resisting the movement of the stopper 157 due to friction, fluid dynamics, and any forces resisting the movement of the stopper 157 is the resistive force Fr. Because the stopper 157 moves at a substantially constant velocity during the test, the applied force is substantially equal to the resistive force. The applied force may vary during the advancement of the stopper 157 due to changes in the resistive force acting against the movement of the stopper 157.

[0083] 4B illustrates an alternative fixture 319 for testing a pre-filled syringe 150 in combination with an auto-injector 140. This embodiment is substantially similar to the fixture in FIG. 4A and includes a syringe support frame 316 that supports a pre-filled syringe 150. Additionally, a clamp 317 is assembled on a top plate 316c of the syringe frame 316 and includes first and second opposing jaws 317a, 317b. The first and second jaws 317a, 317b each define opposing contours, such as semi-circular notches, that are shaped to receive and securely hold a portion of the auto-injector 140 when the jaws 317a, 317b are closed. In operation, the auto-injector 140, with its injection spring 109 removed, is assembled into the clamp 317 and positioned so that the piston rod 107 from the auto-injector 140 is axially aligned with the syringe barrel 151. The piston rod 107 is inserted into the syringe barrel 151 such that the end of the piston rod 107 for the auto-injector 140 engages the first engagement surface 157a of the stopper 157.

[0084] As described in more detail herein, the auto-injector 140 includes a subassembly that moves in response to decompression of the injection spring 109. The subassembly includes structure for advancing the piston rod 107. The subassembly may also include additional movement structure and secondary spring mechanisms that are also moved or driven by the injection spring 109 as it decompresses. In an exemplary embodiment, the entire auto-injector 140, except for the injection spring 109, can be assembled into the clamp 317, provided that access exists for inserting the drive rod 314 into the auto-injector 140 so that it can engage and move the piston rod 107 and other auto-injector components that operate in response to movement of the piston rod 107. Alternatively, the subassembly can be removed from or otherwise exposed by the auto-injector 140 and assembled into the clamp 317 without the components of the auto-injector 140 that are not operated by the injection spring 109.

[0085] A drive rod 314, coupled to the test instrument, engages and moves the piston rod 107 a determined distance at a constant velocity. In at least some embodiments, the determined distance corresponds to the distance the stopper 157 must travel from the first position D1 to the second position D2 to deliver the full dose of therapeutic fluid 160. The applied force to the drive rod 314 and the displacement of the drive rod 314 are recorded. In this test setup, the measured force may correspond to all resistive forces, including friction within the filled syringe 150, hydrodynamic forces, friction within the subassembly, any force required to compress the secondary spring within the subassembly, and any other resistive forces acting against the movement of the stopper 157 and the movement of the subassembly.

[0086] 4C illustrates a fixture 320 for testing an auto-injector 140 to determine the spring strength of the injection spring 109. This is used to simulate the operation of the auto-injector 140 and measure the delivery force of the piston rod 107 as the injection spring 109 decompresses. This is useful for verifying proper operation of the auto-injector 140 after the injection spring 109 has been selected as described in more detail herein.

[0087] The fixture 320 includes a base 321 that can be secured to a workbench 324 for stability during testing. The base 321 is secured to the workbench 324 using bolts 326a, 326b. A tube 327 extends upward from the base 321 and defines a cavity 323 sized to accommodate the auto-injector 140. The length of the cavity 323 is approximately the same length as the housing 104 for the auto-injector 140, but may be longer or shorter in various embodiments. The cross-sectional shape and area of ​​the cavity 323 are sized to allow the auto-injector 140 to slide into the cavity 323 while still securely holding the auto-injector 140 without twisting or wobbling. A cap 322 is secured onto the top end of the tube 327 to encase and secure the auto-injector 140 within the cavity 323. Cap 322 defines a bore 325 axially aligned with cavity 323 and sized to accommodate drive rod 314 .

[0088] As described in more detail herein, the auto-injector 140 includes a housing 102 and a cover sleeve 103 nested within the housing 102 (see, e.g., FIGS. 13-17). Sliding the cover sleeve 103 into the housing 102 cocks the auto-injector 140, thereby allowing the internal piston rod 107 to move freely. To test the auto-injector 140 in the fixture 320, the pre-filled syringe 150 is removed from the auto-injector 140, exposing the piston rod 107. The auto-injector 140 is then inserted into the cavity 323 and oriented so that the cover sleeve 103 faces upward and extends from the top of the tube 327. A cap 322 is placed over the end of the tube 327. The drive rod 314 is then inserted into the bore 325 and into the auto-injector 140 so that the end of the drive rod 314 engages the end of the piston rod 107. A second, opposite end of the drive rod 314 is coupled to testing equipment configured to move the drive rod 314 at a substantially constant velocity. The drive rod 314 is also attached to measurement equipment, such as a load cell 315, positioned to measure the force applied to the drive rod 314 as it moves (see, for example, FIG. 5).

[0089] The cap 322 is then pushed down until the cover sleeve 103 snaps into the housing 102, cocking the auto-injector 140 and decompressing the injection spring 109, allowing the piston rod 107 to move freely. The cap 322 locks onto the end of the tube 327 so that it remains in place. Any suitable mechanism can be used to secure the cap 322 in place. For example, the cap 322 can be threaded onto the end of the tube 327. Alternatively, the tube 327 can include a key that protrudes from the side of the fixture 320, and the cap 322 can include an L-shaped slot that receives the key and holds the cap 322 in place. The methods and testing apparatus disclosed herein can also be used to test alternative embodiments of spring-activated auto-injectors.

[0090] At the start of the test, the injection spring 109 is compressed and the piston rod 107 is in a position corresponding to the stopper 157 in a first position. The drive rod 314 is then raised at a constant rate a determined distance. In at least some contemplated embodiments, the determined distance corresponds to the movement of the stopper 157 from the first position D1 to the second position D2 to deliver the full dose of therapeutic fluid 160. For example, the drive rod 314 may be raised approximately 30 mm. Furthermore, the rate of lift of the drive rod 314 is selected to simulate the desired timing for injection of the pre-filled syringe 150 within the auto-injector 140. As the drive rod 314 is raised and the piston rod 107 advances, the load cell 315 measures the force applied to the drive rod 314 and the relative position of the drive rod 314. The displacement of the drive rod 314 is substantially equal to the displacement of the syringe stopper 157. At each force measurement, the force measurement and displacement of the drive rod 314 are recorded to form a delivery force profile. Such force measurements can be used to verify that the injection spring 109 is exerting the desired delivery force on the piston rod 107 as it advances between positions corresponding to the first and second positions D1, D2 of the stopper 157.

[0091] Although the jig 320 is illustrated as holding an auto-injector 140 having a telescoping sleeve 103 for cocking the auto-injector 140 and allowing the piston rod 107 to move freely, it can be adapted to hold and cock auto-injectors 140 having alternative mechanisms such as push buttons, knobs, levers and sliding buttons.

[0092] FIG. 5 illustrates the fixture 315 shown in FIG. 4A in a test setup for operating the drive rod 314 and measuring the performance of the filled syringe 150. In this setup, a universal testing machine 310 has a crosshead 312 that can move up and down and at a constant, determined speed. A fixture 316 is assembled within the universal testing machine 310 and positioned so that the drive rod 314 is axially aligned with the crosshead 312. A load cell 315 is positioned between the drive rod 314 and the crosshead 312 to measure the force exerted on the drive rod 314 as the crosshead 312 moves downward or otherwise advances toward the stopper 157. Additionally, a gauge for measuring the displacement of the crosshead 312 or the drive rod 314 is positioned and configured to measure the movement of the crosshead 312. As noted herein, the linear movement of the crosshead 312 and drive rod 314 is substantially equal to the linear movement of the syringe stopper 157. Although fixture 316 is shown in use with universal testing machine 310, it should be appreciated that fixture 319 illustrated in FIG. 4B and fixture 320 illustrated in FIG. 4C can also be used in a substantially similar manner with universal testing machine 310 and piston rod 314.

[0093] The load cell 315, gauge, and universal testing machine 310 are operated by a programmable controller 311, such as a computer, which controls the movement of the crosshead 312 and records the output from the load cell 315 into a gauge for measuring distance. Measurements from the load cell 315 and gauge are synchronized to correlate the recorded applied force with the displacement of the drive rod 314 / stopper 157 at the time the force measurement is made. The force and displacement measurements form a force profile that correlates the measured force with the displacement of the drive rod 314 and stopper 157. This data can be used to generate graphs and charts similar to those illustrated in FIGS. 3A-3C. The computer controller 311 can also record the time interval for each measurement made and the total time it took to fully displace the stopper 157 for delivery of the full dose of therapeutic fluid 160.

[0094] The load cell 315 can be any type of instrument or sensor that measures force, such as a strain gauge or piezoelectric cell. The gauge can be any type of instrument for measuring distance, including optical, laser, and magnetic-based instruments. It is also contemplated that the gauge can be a virtual gauge, in that the motor driving the crosshead 312 is a stepper motor, and the distance is determined by the number of steps in the rotation of the armature on the motor. An example of a usable universal testing machine 310 is the Multi Test 2.5-I Tensometer, available from Mecmesin, UK. An example of a load cell 315 can be 25 N or 200 N. An example of control software can be Emperor v1.18. Other universal machines adaptable for measuring force and displacement can also be used. In operation, as discussed herein, the programmable controller 311 controls the universal testing machine 310 to move the crosshead 312 at a substantially constant velocity. Alternative embodiments can apply acceleration or deceleration to the movement of the crosshead 312. In an alternative test setup, a fixture 320 that holds both the pre-filled syringe 150 and the auto-injector 140 can be used with a universal test machine 310 .

[0095] It is desirable to select an injection spring 109 for the auto-injector 140 that has sufficient force to exert a pumping force against the stopper 157 and simultaneously actuate associated subassemblies within the auto-injector 140 within a determined time, such as approximately 19 seconds, when the pre-filled syringe 150 is subjected to accelerated aging so that the spring 109 specifications can be used in the regulatory approval process. Similarly, it is desirable to select a spring 109 that does not have an excessively strong spring force for a commercialized auto-injector 140 and pre-filled syringe 150 combination and does not deliver therapeutic fluid 160 too rapidly, especially since the effects of natural aging are not as significant as with artificial aging. The pumping force is a portion of the spring force exerted against the stopper 157 during operation of the auto-injector 140, with the remainder of the spring force acting on any subassemblies also driven by the injection spring 109.

[0096] 6-11 illustrate various methods for determining an injection spring 109 that has sufficient stored energy to (i) move the syringe stopper 157 a desired distance along path of travel P within a determined time period, (ii) maintain a relatively steady rate of motion as the stopper 157 approaches second position D2 to prevent the stopper 157 from stalling, and (iii) operate components within the auto-injector 140 other than the piston rod 107 that are also powered by the injection spring 109. Examples of components within the auto-injector 140 that are powered by the injection spring 109 include the piston rod 107, the retaining pin 106, and the retaining sleeve 108, which the spring 109 holds distally against the bias of the cover sleeve spring 110. In yet another alternative embodiment, the only structure moved by decompression of the injection spring 109 is the syringe stopper 157 itself. The portion of the syringe force that is applied to the stopper 157 through the piston rod 107 is the delivery force. The remaining portion of the spring force that is used to operate the mechanisms within the auto-injector 140 other than the piston rod 107 is the actuation force.

[0097] 6 is a flow diagram illustrating a decision process 200 by which parameters for the injection spring 109 of the auto-injector 140 can be selected. Examples of parameters for the injection spring 109 include a spring constant, an uncompressed spring length, and a compressed spring length. The decision process 200 includes an aging operation 202, a testing operation 204, and a selection operation 206. The decision process 200 may optionally include a second selection operation 208.

[0098] In the aging operation 202, one or more pre-filled syringes 150, such as the pre-filled syringe 150 shown in FIG. 1, may be aged to a simulated age at least equal to a desired shelf life for the therapeutic fluid 160 and the pre-filled syringe 150. As shown in FIG. 7, in some implementations, the pre-filled syringe 150 or the therapeutic fluid 160 is artificially aged using a heat source. For example, one or more syringes 150 pre-filled with the therapeutic fluid 160 may be placed in the interior 182 of an oven 180. In some implementations, humidity is not controlled during the artificial aging process. In other implementations, humidity is controlled during the artificial aging process.

[0099] To accelerate aging for the pre-filled syringes 150, one or more pre-filled syringes 150 are placed in an oven 180 at a predetermined temperature. The higher the temperature, the faster the pre-filled syringes 150 age to a simulated age. In some embodiments, the pre-filled syringes 150 are heated at a temperature ranging from about 20°C to about 60°C. For example, the pre-filled syringes 150 can be heated at a temperature of about 5°C, about 25°C, or about 40°C. Each of the sample sets 170 is maintained at the predetermined temperature for a different period of time (e.g., minutes, days, weeks, months, or years). The temperature and length of time for heating the pre-filled syringes 150 can be determined according to the arenium calculation of Equation (1). The number of pre-filled syringes 150 heated for accelerated aging depends on the number of samples to be tested for selection of the injection spring 109. The more samples tested, the more data available for selecting the spring 109. Additionally, sets of pre-filled syringes 150 can be heated at different temperatures or tested for different lengths of time. Heating different sets of pre-filled syringes 150 in this manner allows data simulating different shelf lives and different conditions to be used in the spring 109 selection process.

[0100] In test operation 204, one or more force tests may be performed on the aged filled syringes 150 using any suitable testing technique, including those illustrated in more detail herein (see, e.g., FIGS. 4A, 4B, and 5). Generally, the test or tests include one or more applied forces F applied to the stopper 157 of each filled syringe 150 as the stopper 157 moves from a first position D1 to a second position D2 and as the therapeutic fluid 160 is delivered. e The applied force measurements are correlated with the corresponding position (i.e., displacement) of the stopper 157 along the path of travel P.

[0101] In some embodiments, the force applied to move only the stopper 157 of the pre-filled syringe 150 is measured (see, e.g., FIGS. 4A and 5). In other examples, the force applied to move the stopper 157 via a piston rod that simultaneously moves other components of an injection spring-powered auto-injector is measured (see, e.g., FIGS. 4B and 5).

[0102] In a selection operation 206, the measured applied force is analyzed to determine an injection spring 109 that has sufficient energy to deliver a suitable amount of force while at the same time having suitable parameters for operation within the auto-injector. The spring force is determined according to Hooke's law as follows: (4) F spring =K(l0-x) In the formula, F spring where is the spring force, "K" is the spring constant of the particular injection spring, l0 is the uncompressed spring length, and x is the current spring length.

[0103] In the following, the term spring compression or spring compression in a determined state will be used to refer to the difference between the length of the spring in said determined state and the uncompressed length of the spring. In at least some embodiments, such as the automatic injector 140, a gap exists between the piston rod 107 and the stopper 157 at the beginning of operation. At the beginning of operation, the injection spring 109 must decompress slightly to engage the piston rod 107 against the stopper 157. In these embodiments, the spring length at the beginning of operation (before activation of the automatic injector 140) is the initial spring length l when the piston rod 107 contacts the stopper 157 and begins to push the stopper 157 from its first position D1. i In these embodiments, the transmission power may also be modeled as: (5) F d =K(C i -x stopper ), where C i =l0-l i In the formula, C i is the initial compression of the spring, and l i is the length of the spring when the piston rod engages with the stopper and the stopper is in the initial position, and x stopper is the displacement of the stopper relative to the first initial position of the stopper. Furthermore, the stored energy available to deliver medication within the auto-injector can be modeled as:

number

[0104] Because equations (4) and (5) are linear equations, the spring force for injection spring 109 can be represented by a straight line plotting decreasing force against increasing displacement in the graph shown in FIG. 3C. In one contemplated embodiment, the measured applied force can be used to determine a suitable spring 109. In this embodiment, the reference force F used to calculate the spring force is ref may be the maximum applied force measured as the drive rod 314 of the testing instrument 310 moves the stopper 157 from the first position D1 to the second position D2. For an accelerated aged filled syringe 150 as disclosed herein, this maximum applied force may be the sliding equilibrium stress measured as the stopper 157 approaches the second position D2, as illustrated in FIG. 3C . In other embodiments or situations, the maximum applied force may be the sliding equilibrium stress as the stopper 157 moves along the intermediate portion of the path of travel P. In still other embodiments or situations, the maximum applied force may be the sliding yield stress as the stopper 157 begins its movement from the first position D1.

[0105] One additional condition that may be used to determine the spring parameters (e.g., spring constant, compressed length, uncompressed length) may be that the final spring force must be 50% or more of the initial spring force, which is the spring force of the injection spring 109 when the piston rod 107 initially engages the stopper 157 at the first position D1. In other embodiments, the final spring force must be 60%, 70%, 80%, or 90% or more of the initial spring force. These design specifications and parameters for the injection spring 109 may lead to several alternatives for a suitable spring 109. Other conditions, such as market availability and price, may then be considered when selecting the injection spring 109. In some embodiments, selecting a suitable spring 109 may involve maximizing a utility function that includes one or more of the conditions described herein. In some embodiments, the injection spring 109 has a spring force in the range of about 20 N to about 40 N when the stopper 157 is in the first position D1 and engaged by the piston rod 107. In some embodiments, the injection spring 109 has a spring force in the range of about 20 N to about 30 N when the stopper 157 is in the first position D1 and engaged by the piston rod 107. Furthermore, in some embodiments, the injection spring 109 can have a spring force in the range of about 14 N to about 20 N when the stopper 157 is in the second position D2. Furthermore, in some embodiments, the injection spring 109 can have a spring force in the range of about 15 N to about 18 N when the stopper 157 is in the second position D2.

[0106] In some embodiments, multiple measured applied forces can be used to determine a suitable spring 109. For example, an initial applied force (sliding yield stress) can be used in conjunction with the applied force at the end of path P to determine a suitable spring 109. In another example, a baseline energy for moving stopper 157 within a filled syringe 150 can be calculated based on measured force profiles obtained by moving stopper 157 using the apparatus depicted in FIGS. 4-5. The baseline energy can be calculated for stopper 157 moving within one or more aged reference filled syringes 150 or one or more unaged filled syringes 150. In at least some embodiments, the selected spring 109 will have a stored energy that is approximately 25% greater than the baseline stored energy when stopper 157 is in first position D1 and engaged by piston rod 107. In other contemplated embodiments, the stored energy is approximately 20%, 30%, 40%, 50%, or 60% greater than the baseline stored energy. Thus, a possible design parameter for some embodiments is for injection spring 109 to have about 25% more stored energy when stopper 157 is in first position D1 and engaged by piston rod 107 than is actually required to move stopper 157 in unaged filled syringe 150 from first position D1 to second position D2 without stalling. In some embodiments, the stored energy in injection spring 109 is in the range of about 0.9 J to about 2 J when stopper 157 is in first position D1 and engaged by piston rod 107.

[0107] Furthermore, to ensure proper movement of the stopper 157, it is beneficial for the delivery force when the stopper 157 reaches the second position D2 to be as high as possible. By having this high delivery force in the second position D2, the risk of stalling at the end of dose delivery is reduced. Furthermore, it is beneficial for the initial delivery force to be as low as possible to avoid a high initial shock. As a result, some possible embodiments have an injection spring 109 with a longer initial spring compression length rather than an injection spring 109 with a high spring constant. In some embodiments, the spring parameters can be selected to maximize the initial spring compression length and minimize the spring constant of the injection spring 109. In other words, if multiple spring parameters are considered to provide a suitable spring 109, the spring 109 with the lowest spring constant and the highest initial compression is preferred.

[0108] In some embodiments, the initial spring compression length is in the range of about 50 mm to about 100 mm, and the spring constant is in the range of about 0.2 N / mm to about 0.4 N / mm. In alternative embodiments, the initial spring compression length is in the range of about 75 mm to about 95 mm, and the spring constant is in the range of about 0.28 N / mm to about 0.32 N / mm. In another example, the spring constant is about 0.3 N / mm.

[0109] Once the spring parameters have been determined, an injection spring 109 is selected that will cause the piston rod 107 of the automatic injector 140 to exert a delivery force on the syringe stopper 157 that is greater than the maximum measured force, such that the injection spring 109 has sufficient force to overcome all resisting forces acting against the movement of the stopper 157 and move the stopper 157 to the second position D2 within the determined time.

[0110] Additionally, in some embodiments, parameters for the injection spring 109 are selected based on a maximum applied force measured during testing of a pre-filled syringe 150 exposed to accelerated aging. In other examples, parameters for the injection spring 109 are selected based on multiple applied forces measured during testing. For example, the spring constant, uncompressed spring length, and compressed spring length can be calculated based on or for multiple applied forces, which can provide a more favorable gradient of spring force as the spring 109 uncompresses.

[0111] Additionally, the embodiments shown herein use a helical spring for the injection spring 109. The helical spring is a linear velocity spring; other embodiments may use other types of springs 109, such as a conical spring, a constant force spring, a variable force spring, a torsion spring, a gas spring, or a hydraulic spring. Hooke's Law for springs such as gas springs and hydraulic springs is not linear. However, Hooke's Law is substantially linear throughout the first portion of the displacement of the gas or hydraulic spring, and the spring force can still be approximated using Equation (4) or a similar linear relationship. In alternative embodiments, suitable mathematical relationships and models other than Hooke's Law can be used to determine the force for springs, including linear and nonlinear springs.

[0112] 8-10 illustrate various test processes 220, 230, 240 that are each suitable for implementing the test operation 204 of the decision process 200. In some implementations, the test processes 220, 230, 240 are implemented using automated or semi-automated test equipment, such as the test equipment 310 described herein in connection with Figures 4A, 4B, and 5. A suitable process for using the test equipment 310 is described in more detail herein with reference to Figure 11.

[0113] Each of the testing processes 220, 230, 240 can be performed on the pre-filled syringe 150 either alone or in combination with the auto-injector 140 or components thereof. In some embodiments, the testing device 310 acts directly on the stopper 157 of the pre-filled syringe 150. In other embodiments, the testing device 310 acts on the drive member 314 (e.g., piston rod 107) of the auto-injector 140, which is operatively coupled to the syringe stopper 157.

[0114] The pre-filled syringe 150 may be naturally aged or artificially aged. Each of the testing processes 220, 230, 240 may also be performed on an unaged pre-filled syringe 150. In some embodiments, the testing processes 220, 230, 240 are performed on a pre-filled syringe 150 that is pre-filled with a therapeutic fluid 160. In other embodiments, the testing processes 220, 230, 240 are performed on a syringe 150 that is pre-filled with another type of fluid (e.g., saline or water).

[0115] 8 is a flow diagram illustrating a first test process 220 suitable for implementing the test operation 204 of the decision process 200. The first test process 220 includes a move operation 222, a measure operation 224, and a decide operation 226.

[0116] In movement operation 222, stopper 157 of filled syringe 150 is moved distally within syringe barrel 151 at a constant speed along path of travel P. For example, stopper 157 may be moved along path of travel P from a first position (e.g., proximal position, initial position) D1 to a second position (e.g., distal position, bottomed-out position) D2.

[0117] In some implementations, the constant speed is selected to match the speed of displacement of the stopper 157 during an actual injection using the auto-injector 140, in which the stopper 157 is moved from a first position D1 to a second position D2, and the entire dose of fluid 160 is retained within the syringe barrel 151 between the first and second positions D1, D2. For example, the constant speed may be selected to simulate a desired injection time in the range of about 5 seconds to about 19 seconds. In another embodiment, the constant speed may be selected to simulate an injection time in the range of about 5 seconds to about 12 seconds. In another embodiment, the constant speed may be selected to simulate an injection time in the range of about 6 seconds to about 20 seconds. In another embodiment, the constant speed may be selected to simulate an injection time in the range of about 8 seconds to about 15 seconds. In another embodiment, the constant speed may be selected to simulate an injection time in the range of about 15 seconds to about 25 seconds. In some examples, the constant speed can be selected to simulate an injection time in the range of about 17 seconds to about 22 seconds. In one example, the constant speed can be selected to simulate an injection time of about 12 seconds. In one embodiment, the constant speed can be selected to simulate an injection time of about 8 seconds. In one embodiment, the constant speed can be selected to simulate an injection time of about 18 seconds. In one embodiment, the constant speed can be selected to simulate an injection time of about 19 seconds. In one embodiment, the constant speed can be selected to simulate an injection time of about 20 seconds. In some embodiments, the constant speed can be selected to be between about 60 mm / min and about 360 mm / min. In other embodiments, the constant speed can be selected to be between about 150 mm / min and about 200 mm / min. In some embodiments, the constant speed can be selected to be between about 80 mm / min and about 90 mm / min. In one embodiment, the constant speed can be selected to be about 150 mm / min. In one embodiment, the constant speed can be selected to be about 86 mm / min. In one embodiment, the constant speed can be selected to be about 175 mm / min.

[0118] Measurement operation 224 measures one or more applied forces against stopper 157 to move stopper 157 distally at a constant velocity along path P. In some embodiments, the applied force (i.e., sliding yield stress) used to initiate motion of stopper 157 relative to syringe barrel 151 is measured. In other embodiments, the applied force (i.e., sliding equilibrium stress) used to maintain motion of stopper 157 along path P within syringe barrel 151 is measured. For example, the maximum applied force (i.e., maximum sliding equilibrium stress) during movement of stopper 157 along path P can be measured. In some embodiments, the displacement of stopper 157 is measured simultaneously with measuring the applied forces.

[0119] A determining operation 226 determines a reference force for use in calculating a preferred spring 109. In some embodiments of the selecting operation 206, the reference force is used to select a spring constant, an uncompressed spring length, or a compressed spring length.

[0120] In some embodiments, the reference force is the maximum or peak force that the injection spring 109 must overcome to move the stopper 157 between the first and second positions D1, D2 along the path of travel P. Thus, the reference force is equal to or greater than the measured force being applied to the stopper 157 to overcome any resistance opposing distal movement of the stopper 157 along the path of travel P. In some embodiments, the reference force is equal to the maximum measured force and can be used to determine parameters for the injection spring 109. In other embodiments, the reference force can be greater than the maximum measured force. In yet other embodiments, the reference force can be less than the maximum measured force. For example, the maximum measured force could be measurable for the stopper 157 at a displacement outside the range of the first and second positions D1, D2.

[0121] In other embodiments, the reference force may also be determined based on a resistive force generated by a component of the auto-injector 140. For example, the reference force may also take into account one or more frictional forces generated by movement between two or more components of the auto-injector 140 (e.g., the piston rod 107, the support member 105, the indicator sleeve 111, and the retaining sleeve 108 shown in FIGS. 13-17). In one example, the reference force may also include the force required to move or operate one or more components of the auto-injector 140 (e.g., the retaining pin 106, the retaining sleeve 108) against the bias of another spring 109 (e.g., the cover sleeve spring 110 in FIGS. 13-17). The resistive force generated by the auto-injector 140 may be separately measured, calculated, or otherwise estimated.

[0122] 9 is a flow diagram illustrating a second possible test process 230 suitable for implementing the test operation 204 of the decision process 200. The second test process 230 includes a move operation 232, a measure operation 234, and a decide operation 236. The move operation 232 of the second test process 230 is the same as or substantially the same as the move operation 222 of the first test process 220.

[0123] The measuring operation 234 is substantially the same as the measuring operation 224 of the first testing process 220, except that multiple applied force measurements are made along the path of travel P. Each applied force measurement is associated with a corresponding displacement of the stopper 157 along the path of travel P. In some implementations, two applied force measurements are made along the path of travel P (e.g., at a first position D1 and a second position D2). In other embodiments, three or more applied force measurements are made along the path of travel P. In some examples, the applied force is measured at regular intervals along the path of travel P. In some examples, the applied force is measured continuously along the path of travel P.

[0124] In some embodiments, the displacement of the drive rod 314, which corresponds to the displacement of the plunger 157, is also measured. The displacement may be measured at the same time that each measurement of applied force is made. In some embodiments, the displacement and applied force measurements may be correlated to form a force profile.

[0125] Determining operation 236 is the same as or substantially the same as determining operation 226 of first testing process 220, except that two or more reference forces are determined. For example, one determined reference force may correspond to a sliding yield stress, and another determined reference force may correspond to a maximum measured sliding equilibrium stress. In other embodiments, the two or more determined reference forces may correspond to different measured sliding equilibrium stresses. In other embodiments, a determined reference force may correspond to a sliding equilibrium stress or a sliding yield stress, and another determined reference may correspond to a displacement of piston rod 107 for auto-injector 140 that is outside the range of displacement of stopper 157. For example, a determined reference force may correspond to a force required to initiate movement of piston rod 107 before engaging stopper 157.

[0126] In some embodiments, at least one reference force is determined based on a measured applied force to push the stopper 157 from a first position D1 to a second position D2 within the syringe barrel 151, and at least another reference force is determined based on a measured force or friction associated with the movement or operation of an internal component of the auto-injector 140. In yet another contemplated embodiment, at least one reference force is determined that corresponds to a measured applied force to move an internal component of the auto-injector 140 and push the stopper 157.

[0127] 10 is a flow diagram illustrating a third test process 240 that is suitable for implementing the test operation 204 of the determination process 200. The third test process 240 determines spring parameters such that the injection spring 109 having the determined spring parameters can successfully drive the stopper 157 along the path of travel P. The third test process 240 includes a move operation 242, a measure operation 244, a determine operation 246, a calculate operation 248, and a select operation 250.

[0128] The transfer operation 242 of the third testing process 240 is the same as or substantially the same as the transfer operation 222 of the first testing process 220 .

[0129] In some implementations, the measurement operation 244 is the same as or substantially the same as the measurement operation 224 of the first test process 220. In other embodiments, the measurement operation 244 is the same as or substantially the same as the measurement operation 234 of the second test process 230.

[0130] In some implementations, the measuring operation 246 is the same as or substantially the same as the determining operation 226 of the first test process 220. In other implementations, the determining operation 246 is the same as or substantially the same as the determining operation 236 of the second test process 230.

[0131] Calculating operation 248 determines a corresponding spring constant, uncompressed spring length, or compressed spring length for each of the one or more reference forces determined in determining operation 246. These spring parameters are calculated based on the determined reference forces (which are equal to or otherwise correspond to the measured applied forces) and the corresponding displacements of stopper 157. The calculated spring parameters are "reference spring parameters."

[0132] In some embodiments, given the uncompressed spring length and auto-injector geometry, calculating operation 248 determines the minimum spring constant needed to generate a force at the corresponding displacement position of stopper 157 sufficient to drive stopper 157 along path of travel P. In other embodiments, calculating operation 248 determines the minimum spring constant needed to generate the required force and overcome the resistance force generated by auto-injector 140. In some embodiments, the uncompressed spring length is also determined by calculating operation 248. In some embodiments, calculating operation 248 determines a minimum spring constant and a maximum uncompressed spring length. In other embodiments, calculating operation 248 may determine a maximum spring constant.

[0133] A second determining operation 250 determines optimal spring parameters by comparing the reference spring parameters determined in calculating operation 248. The optimal spring parameters may be selected based on a variety of different criteria, such as desired injection time, desired spring force, spring cost, and the geometry of the auto-injector 140.

[0134] 11 is a flow chart 260 illustrating a method for performing at least the moving operations 222, 232, 242 and measuring operations 224, 234, 244 of the testing processes 220, 230, 240 using the testing equipment 310 of FIGS. 4A, 4B, and 5. In some implementations, the testing equipment 310 includes a tensiometer or other mechanism for measuring the applied force on the syringe stopper 157. As mentioned above, the testing equipment 310 may include a frame 316 for holding the filled syringe 150.

[0135] In some embodiments, the operations of flowchart 260 and other flowcharts and operations discussed herein are performed for a single pre-filled syringe 150. However, in other embodiments, the operations of flowchart 260 are performed for multiple pre-filled syringes 150. In some embodiments, the operations may be performed for pre-filled syringes 150 of various ages (natural or artificial). In some embodiments, the operations may be performed on unaged pre-filled syringes 150. In some embodiments, the operations of flowchart 260 are implemented using a pre-filled syringe 150 alone. In other embodiments, the operations may be implemented using a pre-filled syringe 150 in combination with one or more components of an auto-injector 140.

[0136] In some embodiments, a portion of the auto-injector 140 (e.g., a portion of the drive assembly) may be assembled to the testing instrument 310, as shown in FIG. 4B. In such embodiments, the frame 316 may be adapted to hold the auto-injector 140 components. For example, an additional clamp 317 may be assembled to the frame 316 to hold the drive member 314 (e.g., piston rod 107) of the auto-injector 140, the entire auto-injector 140, or a portion thereof. In such embodiments, the drive rod 314 of the testing instrument 310 is operably coupled to the stopper 157 via the drive member 314 of the auto-injector 140.

[0137] In an actuation operation 266, the test instrument 310 generates an acting force on the syringe stopper 157. In some embodiments, the actuation operation 266 includes advancing (e.g., lowering) the drive rod 314 of the test instrument 310 toward the stopper 157. In some embodiments, the drive rod 314 is moved automatically. In other embodiments, the drive rod 314 is moved manually. In some embodiments, the drive rod 314 is moved at a constant velocity.

[0138] In one embodiment, drive rod 314 is attached to a 25 N load cell. In another embodiment, drive rod 314 is attached to a 200 N load cell. Other load cells with a sensitivity range sufficient to measure forces that can be applied to drive rod 314 are possible.

[0139] Measuring operation 268 makes one or more measurements of the force being exerted by drive rod 314 on stopper 157 as stopper 157 moves along path of travel P. For example, test instrument 310 can automatically perform the measurements of the force exerted by drive rod 314. Test instrument 310 also tracks the displacement of drive rod 314, which is directly related to the displacement of syringe stopper 157. Thus, measuring operation 268 results in one or more force readings, each correlated to a determined displacement of stopper 157.

[0140] In one embodiment, a force measurement can be taken when stopper 157 first moves relative to syringe barrel 151. In another embodiment, a force measurement can be taken when stopper 157 approaches or reaches the end of path P. In another embodiment, multiple force measurements can be taken at periodic intervals or distances along path P. In another embodiment, force measurements are taken continuously along path P.

[0141] Figure 12 is a flow diagram illustrating an assembly process 280 for assembling an auto-injector, such as the auto-injector 140 of Figures 13-17, with a pre-filled syringe, such as the pre-filled syringe 150 of Figure 1, and a selected injection spring 109. The assembly process 280 includes at least an obtaining operation 284, a first placing operation 286, and a second placing operation 288. The assembly process 280 may optionally include a selecting operation 282.

[0142] In selection operation 282, the user 190 selects a spring constant for the injection spring 109 to be installed in the auto-injector 140 to drive the injection of the pre-filled syringe 150. The spring constant is selected to be sufficient to drive the injection of the pre-filled syringe 150 even if the pre-filled syringe 150 has been artificially aged. The user 190 can select the spring constant using either the decision process 200 or the testing processes 220, 230, 240 described herein.

[0143] In obtain operation 284, the user 190 selects an injection spring 109 having selected spring parameters. The selected injection spring 109 generates a biasing force that is at least sufficient to drive the syringe stopper 157 completely along the path of travel P within the syringe barrel 151. In some embodiments, the selected injection spring 109 generates a biasing force sufficient to drive the stopper 157 completely along the path of travel P and to perform other operations within the auto-injector 140. For example, the selected injection spring 109 has sufficient strength to bias the retaining pin 106 and retaining sleeve 108 to a proximal position, load the cover sleeve spring 110, and drive the stopper 157 along the path of travel P.

[0144] In some implementations, the selected injection spring 109 is a compression spring. In some embodiments, the selected injection spring 109 is a linear rate spring. In other embodiments, the selected injection spring 109 is a variable rate spring. In yet other embodiments, the selected injection spring 109 is a constant force spring. In other implementations, the selected injection spring 109 is a mechanical gas spring, a pneumatic spring, or a hydraulic spring.

[0145] In a first installation operation 286, the selected injection spring 109 is installed within the auto-injector 140. For example, the selected injection spring 109 may be disposed within the outer body 102 of the auto-injector 140 as part of the drive assembly. In some embodiments, the selected injection spring 109 is aligned with the piston rod 107 (see, e.g., FIG. 14). In one embodiment, the selected injection spring 109 is compressed between the piston rod 107 and the retaining pin 106 (see, e.g., FIG. 14).

[0146] In a second installation operation 288, the pre-filled syringe 150 is installed into the auto-injector 140. For example, the pre-filled syringe 150 may be assembled in the syringe holder 101 inside the outer body 102.

[0147] 13-17 illustrate an exemplary auto-injector 140 suitable for injecting the pre-filled syringe 150 of FIG. 1. FIG. 13 illustrates the components of the auto-injector 140 separated from one another for clarity. FIG. 14 is a cross-sectional view of the auto-injector 140 of FIG. 13, with the auto-injector 140 positioned in a pre-injection configuration. FIG. 15 illustrates the auto-injector 140 of FIG. 14 in an in-injection configuration. FIG. 16 illustrates the auto-injector 140 of FIG. 14 in an end-of-injection configuration. FIG. 17 illustrates the auto-injector 140 of FIG. 16 rotated 90 degrees. Although exemplary embodiments of the auto-injector 140 are disclosed and illustrated herein, any suitable spring-actuated auto-injector may be used with the devices and methods disclosed herein.

[0148] The auto-injector 140 has a distal end 141 and a proximal end 142 (see FIG. 14). The auto-injector 140 is activated by pressing the distal end 141 against the body of the patient 180 at the injection site 198. The auto-injector 140 is held at the injection site 198 until the dose of therapeutic fluid 160 has been expelled from the pre-filled syringe 150.

[0149] The auto-injector 140 includes an outer housing 102 and an end cap 112 assembled to the proximal end 142 of the outer housing 102. The auto-injector 140 also includes a syringe holder 101 disposed within the outer housing 102. The syringe holder 101 and the end cap 112 are stationary relative to the housing 102. The syringe holder 101 is configured to hold a pre-filled syringe, such as the pre-filled syringe 150 of FIG. 1 .

[0150] A cover sleeve 103 is assembled to the distal end 141 of the outer housing 102. The cover sleeve 103 is telescopically slidable relative to the outer housing 102 between an extended position (FIG. 14) and a retracted position (FIG. 15). When in the extended position, the cover sleeve 103 surrounds the syringe needle 155 of the prefilled syringe 150. When the cover sleeve 103 is moved to the retracted position, the syringe needle 155 is exposed.

[0151] A cover sleeve spring 110 extends between a first end 110a and a second end 110b. The cover sleeve spring 110 extends a first length between the first and second ends 110a, 110b when the cover sleeve 103 is expanded. The cover sleeve spring 110 compresses to a second length between the first and second ends 110a, 110b when the cover sleeve 103 is contracted. The second length is shorter than the first length. The cover sleeve spring 110 biases the cover sleeve 103 toward the expanded position. The cover sleeve 103 can be moved to a contracted position against the bias of the spring 110 to compress the spring 110. In the illustrated embodiment, the spring 110 is a helical coil spring. However, in other embodiments, the spring 110 can be a gas spring, a pneumatic spring, a hydraulic spring, or any other type of spring.

[0152] The needle cap remover 104 is initially positioned over the cover sleeve 103 and engages the outer housing 102. The needle cap remover 104 engages the cover sleeve 103 and the outer housing 102 while preventing the cover sleeve 103 from moving to a retracted position. The needle cap remover 104 initially grasps a rigid needle shield that is positioned around the needle 155 of the pre-filled syringe 150. When removed from the auto-injector 140, the needle cap remover 104 takes the rigid needle shield with it and removes it from the syringe needle 155.

[0153] A support member 105 is disposed within outer housing 102 proximal to syringe holder 101. Support member 105 is axially and rotationally fixed relative to end cap 112. The distal end of support member 105 abuts against the proximal end of syringe holder 101.

[0154] The drive assembly is disposed within the outer housing 102 proximal to the syringe holder 101. The drive assembly includes an injection spring 109 and a subassembly biased by the injection spring 109. In the illustrated embodiment, the injection spring 109 is a helical coil spring having a variable force. However, in other embodiments, the injection spring 109 may be a conical spring, a torsion spring, a gas spring, a pneumatic spring, a hydraulic spring, or any other type of variable or constant force spring. The injection spring 109 may also be any other injection spring 109 or structure that biases the piston rod 107 toward the distal end 141 of the auto-injector 140.

[0155] The drive mechanism or subassembly includes at least one piston rod 107 aligned with a stopper 157 of the filled syringe 150. The piston rod 107 is axially movable within the outer body 102 along a travel distance between a cocked position and a bottomed-out position. When in the cocked position, the piston rod 107 is spaced proximally from the filled syringe stopper 157. When in the bottomed-out position, the piston rod 107 presses the stopper 157 against a proximally facing shoulder 151 a within the interior 154 of the filled syringe 150.

[0156] Because the piston rod 107 is spaced from the stopper 157 when in the cocked position, the injection spring 109 does not immediately exert a delivery force on the stopper 157 upon release and deployment of the spring 109. The injection spring 109 decompresses slightly, advancing the piston rod 107 a short distance until it engages the stopper 157. Once the piston rod 107 engages the stopper 157, the injection spring 109 continues to decompress, but resistance forces from the filled syringe 150, such as resistance and hydrodynamic forces, act against the movement of the stopper 157 and therefore against the decompression of the injection spring 109.

[0157] The injection spring 109 extends between a first end 109a and a second end 109b. The injection spring 109 is compressed to a first cocking length between the first and second ends 109a, 109b when the piston rod 107 is positioned in the cocked position (see FIG. 14). The injection spring 109 is expanded to a second length between the first end 109a and the second end 109b when the piston rod 107 is positioned in the bottomed-out position. The second length is longer than the first length.

[0158] The injection spring 109 applies a force to bias the piston rod 107 distally toward the bottomed-out position. In one embodiment, the injection spring 109 is disposed within the hollow interior of the piston rod 107. For example, a first end 109a of the injection spring 109 can press against an inner shoulder of the piston rod 107 to bias the piston rod 107 distally. The first length can be approximately 72 mm, and the second length can be approximately 106 mm. The injection spring 109 can have an uncompressed length of approximately 157 mm. The constant of the injection spring 109 can be approximately 0.30 N / mm.

[0159] In some embodiments, the subassembly also includes a retaining pin 106. An injection spring 109 biases the retaining pin 106 proximally toward the end cap 112. For example, a second end 109b of the injection spring 109 can press against an inner shoulder of the retaining pin 106. In some embodiments, the injection spring 109 is sandwiched between the piston rod 107 and the retaining pin 106. In one embodiment, the injection spring 109 biases the retaining pin 106 proximally while biasing the piston rod 107 distally.

[0160] The retaining pin 106 has a locking configuration and a release configuration. When in the locking configuration, the retaining pin 106 engages the piston rod 107 to hold the piston rod 107 in an axially fixed position relative to the retaining pin 106 against the bias of the injection spring 109. In some embodiments, the retaining pin 106 holds the piston rod 107 in a cocked position against the bias of the injection spring 109. When in the release configuration, the retaining pin 106 releases the piston rod 107 to allow relative movement between the piston rod 107 and the retaining pin 106.

[0161] Specifically, the drive assembly retaining pin 106 includes an arm 106a extending from a fixed end 106d to a free end 106c. The fixed end 106d is attached to a base portion 106e. The free end 106c defines a stop member 106b that moves radially when the arm 106a is bent. In some embodiments, the base portion 106e is sized to extend within the piston rod 107. In some embodiments, the base portion 106e is sized to extend through at least a portion of the injection spring 109 such that the injection spring 109 spirals around the base portion 106e.

[0162] The piston rod 107 defines a recess 107a into which the stop member 106b of the retaining pin 106 can fit. The retaining pin 106 is thus disposed in a locked configuration when the arms 106a are bent radially inward, such that the stop member 106b engages the recess 107a to retain the piston rod 107 in a cocked position. The retaining pin 106 transitions to a released configuration when the arms 106a are bent radially outward to move the stop member 106b away from the recess 107a.

[0163] The retaining sleeve 108 surrounds a portion of the retaining pin 106. The retaining sleeve 108 moves axially between a distal position and a proximal position. When in the distal position, the retaining sleeve 108 retains the retaining pin 106 in a locked configuration (see FIG. 14 ). Specifically, the retaining sleeve 108 is radially aligned with the arms 106 a and has an inner cross dimension small enough to prevent outward radial bending of the arms 106 a. Thus, the retaining sleeve 108 prevents outward radial movement of the stop members 106 b of the retaining pin 106 from the recesses 107 a of the piston rod 107. When in the proximal position, the retaining sleeve 108 is axially offset from the stop members 106 b, thereby allowing the retaining pin 106 to transition to the unlocked configuration.

[0164] Prior to injection, the retaining sleeve 108 is biased to a distal position by the cover sleeve spring 110, which has expanded to a second length. In some embodiments, the cover sleeve spring 110 biases the cover sleeve 103 through the retaining sleeve 108. For example, a first end 110a of the cover sleeve spring 110 abuts the retaining sleeve 108, which abuts the proximal end of the cover sleeve 103. Movement of the cover sleeve 103 to the retracted position pushes the retaining sleeve 108 to a proximal position, compressing the cover sleeve spring 110 to the second length.

[0165] In some implementations, the retaining sleeve 108 has a telescoping configuration. For example, the retaining sleeve 108 can include an outer body 108a and an inner body 108b (see FIG. 16 ). The inner body 108b is disposed around the support member 105. The inner body 108b is rotationally fixed relative to the support member 105 but is axially movable relative to the support member 105. The outer body 108a is disposed around the inner body 108b. A first end 110a of the cover sleeve spring 103 abuts the outer body 108a to bias the retaining sleeve 108 distally.

[0166] The outer body 108a and the inner body 108b are rotationally fixed together. The outer body 108a and the inner body 108b snap fit together and move axially together as a unit from a distal position to a proximal position. For example, the inner body 108b has angled teeth, and the outer body 108a defines slots sized to accommodate the angled teeth. The angled teeth extend through the slots and are entrained by the outer body 108a in the proximal direction. The angled teeth cam out of the slots as the outer body 108a is moved distally from the inner body 108b.

[0167] An indicator sleeve 111 is disposed within outer housing 102 proximal to syringe holder 101. As described in more detail herein, interaction between indicator sleeve 111 and other components within outer housing 102 produces noises (e.g., clicks) that audibly indicate stages of the injection (e.g., the start and end of the injection).

[0168] The indicator sleeve 111 is axially movable relative to the outer housing 102 between a proximal position and a distal position. For example, the indicator sleeve 111 has wings 111b that slide within slots 105a defined in the support member 105 to limit axial movement between the indicator sleeve 111 and the support member 105. The indicator sleeve 111 is biased to the proximal position by a cover sleeve spring 110. In one embodiment, a second end 110b of the cover sleeve spring 110 abuts a portion of the indicator sleeve 111. Thus, the cover sleeve spring 110 is sandwiched between the retaining sleeve 108 and the indicator sleeve 111. In one embodiment, the cover sleeve spring 110 is sandwiched between the outer body 108a of the retaining sleeve 108 and the wings 111b of the indicator sleeve 111.

[0169] The indicator sleeve 111 limits the axial movement of the retaining pin 106 relative to the outer body 102. For example, the indicator sleeve 111 defines a groove in which the stop member 106b of the retaining pin 106 rides during axial movement of the retaining pin 106 between its respective distal and proximal positions. Engagement between the stop member 106b and the groove limits the distal movement of the retaining pin 106 relative to the indicator sleeve 111, which in turn limits the distal movement of the retaining pin 106 relative to the support member 105, which is axially fixed relative to the outer body 102.

[0170] The indicator sleeve 111 selectively engages the piston rod 107. For example, the indicator sleeve 111 can have one or more arms 111c with detents 111d at their free ends. The arms 111c flex to move the detents 111d radially relative to the piston rod 107. The detents 111d are sized to snap into corresponding slots 107c defined in the piston rod 107.

[0171] 14 illustrates the auto-injector 140 in a pre-injection configuration. The needle cap remover 104 and rigid needle shield have been removed. The syringe stopper 157 is positioned at a first position D1 along path of travel P within the pre-filled syringe 150. The piston rod 107 is held at a proximal spaced location from the syringe stopper 157 by a retaining pin 106.

[0172] The retaining pin 106 and piston rod 107 are positioned such that the stop member 106b of the retaining pin 106 is radially aligned with the recess 107a of the piston rod 107 relative to one another. The retaining sleeve 108 is disposed in a distal position such that the retaining sleeve 108 (e.g., the inner body 108b of the retaining sleeve 108) is radially aligned with the stop member 106b of the retaining pin 106. Thus, the retaining sleeve 108 presses the stop member 106b into the recess 107a and prevents radial movement of the stop member 106b out of the recess 107a.

[0173] The indicator sleeve 111 is similarly disposed within the distal position. A detent 111d of the indicator sleeve 111 is disposed within a slot 107c of the piston rod 107. The retaining sleeve 108 (e.g., the inner body 108b of the retaining sleeve 108) is radially aligned with the detent 111d. The inner transverse dimension of the inner body 108b of the retaining sleeve 108 is small enough to retain the detent 111d within the slot 107c when radially aligned with the detent 111d.

[0174] 15, injection is initiated by proximal movement of the cover sleeve 103 relative to the housing 102 toward a retracted position. The proximal end of the cover sleeve 103 abuts the retaining sleeve 108 (e.g., the outer body 108a of the retaining sleeve 108), pushing the retaining sleeve 108 to its proximal position. When in the proximal position, the retaining sleeve 108 is not radially aligned with the stop member 106b of the retaining pin 106. Thus, the bias of the injection spring 109 acting on the piston rod 107 is sufficient to cam the stop member 106b out of the recess 107a in the piston rod 107.

[0175] Thus, the piston rod 107 is free to move distally under the bias of the injection spring 109 toward the stopper 157 of the prefilled syringe 150. During distal movement, the piston rod 107 engages the stopper 157 of the prefilled syringe 150 and pushes the stopper 157 distally along a path of travel P within the syringe barrel 151. The distal movement of the stopper 157 pushes fluid 160 through the needle 155 at the distal end 152 of the prefilled syringe 150.

[0176] Releasing the stopper member 106b from the recess 107a in the piston rod 107 also releases the retaining pin 106 for movement relative to the piston rod 107. In some implementations, an injection spring 109 biases the retaining pin 106 proximally toward the end cap 112.

[0177] The stop member 106b of the retaining pin 106 engages the distal end of the inner body 108b of the retaining sleeve 108. During this proximal movement, the retaining pin 106 entrains the inner body 108b of the retaining sleeve 108 until the inner body 108b abuts the support member 105. The impact between the inner body 108b of the retaining sleeve 108 and the support member 105 creates a noise (e.g., a first click) that provides an audible indication that the injection has begun.

[0178] The stop member 106b prevents the inner body 108b of the retaining sleeve 108 from moving back to a distal position (see FIG. 16). The stop member 106b does not engage the outer body 108a of the retaining sleeve 108. Thus, the outer body 108a can move distally over the stop member 106b (see FIG. 16).

[0179] When the piston rod 107 begins to move distally, it entrains the indicator sleeve 111 through the engagement between the detent 111 d and the slot 107 c. Thus, the piston rod 107 moves the indicator sleeve 111 to a distal position against the bias of the cover sleeve spring 110. The engagement between the wings 111 b of the indicator sleeve 111 and the support member 105 prohibits further distal movement of the indicator sleeve 111.

[0180] When the indicator sleeve 111 is positioned in a distal position, the detent 111d is axially offset from the retaining sleeve 108, which is positioned in a proximal position (see FIG. 17). Thus, the detent 111d is free to cam out of the slot 107c of the piston rod 107, thereby allowing the piston rod 107 to continue distal movement due to the injection spring 109. When moved radially outward, the detent 111d engages the distal end (e.g., inner body 108a) of the retaining sleeve 108, thereby preventing proximal movement of the indicator sleeve 111. The body of the piston rod 107 prevents radially inward deflection of the arm 111c and detent 111d during injection.

[0181] 16, the piston rod 107 moves the stopper 157 within the syringe barrel 151 until the stopper 157 reaches a bottomed-out position (e.g., at the proximally-facing shoulder 151a) within the syringe barrel 151. The injection spring 109 continues to urge the piston rod 107 against the stopper 157 when the stopper 157 is disposed in the bottomed-out position.

[0182] After the injection is completed, the automatic injector 140 is moved away from the injection site 198. The cover sleeve 103 biases distally onto the needle 155. Specifically, the cover sleeve spring 110 biases the outer body 108a of the retaining sleeve 108 distally. The stop member 106b of the retaining pin 106 prevents distal movement of the inner body 108b of the retaining sleeve 108. Thus, the outer body 108a moves distally relative to the inner body 108b until the inner body 108b and the outer body 108a axially lock relative to one another. For example, a detent on the inner body 108b may snap into a recess defined by the outer body 108a.

[0183] Distal movement of the outer body 108a of the retaining sleeve 108 pushes the cover sleeve 103 to the extended position. The outer body 108a is locked against proximal movement by the inner body 108b. The outer body 108a abuts the cover sleeve 103 to prevent proximal movement of the cover sleeve 103 back to the retracted position. Thus, the cover sleeve 103 is locked in the extended position covering the syringe needle 155.

[0184] 17, when the piston rod 107 reaches the bottom-out position, a notch 107d defined in the proximal end of the piston rod 107 aligns with a detent 111d on the indicator sleeve 111. The notch 107d allows the detent 111d to cam radially inward and disengage from the retaining sleeve 108. By releasing the detent 111d from the retaining sleeve 108, the indicator sleeve 111 is freed to move back to the proximal position under the bias of the cover sleeve spring 110. The cover sleeve spring 110 urges the indicator sleeve 111 proximally against the end cap 112, which creates another noise (e.g., a second click) that provides an audible indication that the injection is complete.

[0185] An example of an auto-injector suitable for use with the devices, methods, and uses disclosed herein includes the YpsoMate® brand auto-injector available from Yypsomed AG, Burgdof, Switzerland. Further details regarding exemplary auto-injectors suitable for use in activating pre-filled syringes can be found in U.S. Patent Application Publication No. 2016 / 0008541, the disclosure of which is incorporated herein by reference. The methods, devices, and uses disclosed herein can be used with any type of auto-injector that injects a therapeutic fluid from a pre-filled syringe.

[0186] The auto-injectors and pre-filled syringes disclosed herein, including those pre-filled with the therapeutic fluids disclosed herein, are intended for use as medications for treating or preventing migraines and other diseases, conditions, chronic illnesses and disorders, and for other therapeutic uses. The pre-filled syringes and auto-injectors may be sold as a single unit with the pre-filled syringe already inserted into the auto-injector. Alternatively, the pre-filled syringes and auto-injectors can be sold as kits, where the pre-filled syringe and auto-injector are either separate from one another but combined in the same packaging material, or sold together in separate packages, with the pre-filled syringe in one package or box and the auto-injector in a different package or box.

[0187] FIG. 18 is a flow chart illustrating a usage process 290 for using the auto-injector 140 with a pre-filled syringe 150 and a selected injection spring 109. The disclosed methods and devices can be used periodically or on a continuous schedule, as desired. For example, they can be used once a day, once a week, once a month, not more than once a month, not more than once every two months, not more than once every three months, or not more than once every four months. FIG. 19 illustrates the auto-injector 140 being activated by a user 190. The usage process 290 includes at least an aligning operation 294, a pressing operation 296, and a holding operation 298. The usage process 290 may optionally include an obtaining operation 292.

[0188] In an obtain operation 292, the user 190 obtains an auto-injector 140 that stores a pre-filled syringe 150. The auto-injector 140 includes an injection spring 109 that has a spring constant that is sufficient to drive the injection of the pre-filled syringe 150 even if the pre-filled syringe 150 is aged. The injection spring 109 also has sufficient strength to perform other operations within the auto-injector 140 in addition to biasing the stopper 157 (e.g., loading the cover sleeve spring 110).

[0189] In an alignment operation 294 , the distal end 141 of the auto-injector 140 is aligned with an injection site 198 on the body 192 of the user 190 .

[0190] In a pushing action 296, the distal end 141 of the auto-injector 140 is pressed against the injection site 198 (see FIG. 19 ). For example, the user 190 can push the outer body 102 of the auto-injector 140 distally toward the injection site 198 as the cover sleeve 103 retracts into the outer body 102 to expose the needle 155. As described herein, the retraction of the cover sleeve 103 into the body 102 automatically activates the drive assembly to trigger an injection of the pre-filled syringe 150.

[0191] In a holding action 298, the user 190 holds the auto-injector 140 at the injection site 198 with the cover sleeve 103 retracted into the outer body 102 until the end of the injection, which in some embodiments is indicated by an audible noise (e.g., a click) generated by the auto-injector 140.

[0192] The methods, devices and uses disclosed herein have many aspects, including the following.

[0193] One embodiment is a method of adapting an auto-injector configured to actuate a pre-filled syringe, the auto-injector having an injection spring with a fixed spring constant, the pre-filled syringe being filled with a fixed volume of therapeutic fluid, the pre-filled syringe including a barrel, a stopper, and a needle, the stopper having a fixed path of travel, the injection spring being arranged to move the stopper along the path of travel, the method comprising: aging the pre-filled syringe at an accelerated rate to form an aged pre-filled syringe; The method includes the steps of: moving a stopper within the barrel of the aged pre-filled syringe at a predetermined speed to at least one second position; measuring a plurality of forces exerted on the stopper as the stopper moves within the barrel along a path of travel; determining a resistance force opposing movement of the stopper along the path of travel, the resistance force corresponding to the plurality of forces; and selecting a spring constant for an injection spring, wherein the act of selecting the spring constant includes selecting the spring constant to correspond to the resistance force.

[0194] Another aspect is a method in which an operational filled syringe includes an operational barrel and an operational stopper movably positioned within the operational barrel, the operational stopper being movable along an operational path from a first operational position to a second operational position, and the automatic injector includes an injection spring having a spring force, the injection spring configured to apply a delivery force to the operational stopper by driving a piston rod toward the operational stopper upon activation of the automatic injector, the delivery force being at least a portion of the spring force, the method comprising: aging the filled syringe at an accelerated rate to form a reference filled syringe, the reference filled syringe including a reference barrel and a reference stopper positioned within the reference barrel; moving the reference stopper of the reference filled syringe along a reference path from at least one first reference position to at least one second reference position; measuring a plurality of applied forces applied to the reference stopper as the reference stopper moves along the reference path within the reference barrel and measuring a plurality of reference stopper positions; generating an applied force profile, the applied force profile including at least some of the applied forces and reference stopper positions measured while the reference stopper was moving between the first and second reference positions, at least one of the measured applied forces being correlated with at least one of the measured reference stopper positions; and selecting an injection spring such that a delivery force applied to the operational stopper at each position of the operational stopper as the operational stopper moves along the operational path between the first and second operational positions is greater than a measured application force at a corresponding one of the measured reference stopper positions.

[0195] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting an injection spring includes selecting a measured force from the force profile and selecting at least one spring parameter, the selected at least one spring parameter corresponding to the selected force.

[0196] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting at least one spring parameter comprises selecting a spring constant of the injection spring and an uncompressed length of the injection spring.

[0197] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting at least one spring parameter includes selecting a first compression spring length and spring constant corresponding to a reference stop at a first reference position along the reference path of travel.

[0198] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein selecting at least one spring parameter includes selecting a second compression spring length and spring constant corresponding to a reference stop located at a position along the reference path of travel that corresponds to a measured maximum force in the force profile.

[0199] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein when the stopper is in the second, final position, the selected spring has a pumping force that is greater than about 50% of the pumping force when the stopper is in the first, initial position.

[0200] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the predetermined speed corresponds to a speed within a range of about 5 seconds to about 19 seconds required to move the operational stop from a first operational position to a second operational position along the operational path.

[0201] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the plunger is operably coupled to the stopper, and the act of moving the stopper includes moving the plunger, and the act of measuring the plurality of forces exerted on the stopper includes measuring the plurality of forces exerted on the plunger.

[0202] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the act of determining the sliding equilibrium stress includes determining a sliding equilibrium stress required to move the stopper from a first position to a second position along the path of travel within a determined time.

[0203] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining the first resistance force includes measuring the first resistance force when moving the stopper from the first position.

[0204] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining the resistive force includes determining a resistive force selected from the group of sliding yield stress, maximum sliding equilibrium stress, or combinations thereof.

[0205] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining the resistive force includes determining a resistive force selected from the group consisting of a sliding yield stress, a maximum sliding equilibrium stress, or a combination thereof.

[0206] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein determining the resistance forces includes determining at least first and second resistance forces, the first resistance force being a sliding yield stress and the second resistance force being a minimum sliding equilibrium stress for moving the stopper along the path of travel from a first position at the beginning of the path of travel to a second position at the end of the path of travel without stalling.

[0207] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined time is in the range of about 5 seconds to about 25 seconds.

[0208] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the act of determining the minimum sliding equilibrium stress includes determining the minimum sliding equilibrium stress required to move the stopper along the path of travel from the first position to the second position within about 5 seconds to about 25 seconds.

[0209] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the aged filled syringe holds a determined volume of therapeutic fluid between a first position and a second position, and the act of determining the minimum sliding equilibrium stress required to move the reference stopper along the path from the first position to the second position without stalling includes expelling the determined volume of therapeutic fluid from the aged filled syringe.

[0210] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined volume is in the range of about 1.51 mL to about 1.66 mL.

[0211] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the automatic injector includes a subassembly, the subassembly movable in response to decompression of an injection spring and arranged to selectively move a stopper, and wherein the act of selecting a spring constant includes selecting the spring constant to correspond to at least a first resistive force, a second resistive force, and a third resistive force, the third resistive force resisting movement of the subassembly.

[0212] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein moving the stopper within the barrel of the aged pre-filled syringe includes moving a subassembly of the auto-injector.

[0213] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the automatic injector includes a subassembly, the subassembly operable in response to decompression of an injection spring, and at least a portion of the subassembly arranged to selectively move the stopper, and wherein the act of selecting a spring constant includes selecting the spring constant to correspond to a force sufficiently strong to operate the subassembly and move the stopper from the first position to the second position without stalling.

[0214] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein moving the stopper within the barrel of the aged pre-filled syringe includes moving a subassembly of the auto-injector.

[0215] Another aspect is a method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid comprises an antibody.

[0216] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the antibody comprises a humanized monoclonal antibody.

[0217] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the humanized monoclonal antibody comprises an immunoglobulin G2 (IgG2) antibody.

[0218] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the humanized monoclonal antibody comprises an anti-calcitonin gene-related peptide antibody.

[0219] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid has a viscosity in the range of about 4 cSt to about 14 cSt at 22°C.

[0220] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid comprises fremanezumab and has a viscosity in the range of about 4 cSt to about 14 cSt at 22° C.

[0221] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the pre-filled syringe comprises an inner surface, and the pre-filled syringe further comprises a lubricant on the inner surface.

[0222] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the lubricant comprises silicone oil.

[0223] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the lubricant comprises polydimethylsiloxane.

[0224] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil coats the interior surface of the barrel and the pre-filled syringe has a coating thickness of about 0.1 μm to about 0.3 μm before aging.

[0225] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the lubricant comprises from about 0.35 mg to about 1.1 mg of silicone oil prior to aging of the pre-filled syringe.

[0226] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity of between about 500 cSt and about 1500 cSt at 25° C. prior to aging of the pre-filled syringe.

[0227] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein aging the filled syringe comprises heating the filled syringe for a determined period of time.

[0228] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined time is calculated according to the Arrhenius equation.

[0229] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the determined time is calculated according to the Arrhenius equation; and heating the filled syringe for the determined time comprises heating the filled syringe at a temperature within the range of about 20°C to about 60°C.

[0230] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the pre-filled syringe has a volume selected from the group of about 1 mL and about 2.25 mL.

[0231] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the pre-filled syringe has a volume selected from the group consisting of about 1 mL and about 2.25 mL.

[0232] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the distance between the first reference position of the reference stopper and the second reference position of the reference stopper is in the range of about 25.7 mm to about 30 mm.

[0233] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the distance between the first position of the stopper and the second position of the stopper is between about 35 mm and about 55 mm.

[0234] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the needle defines a channel, and the channel has a diameter in the range of about 0.15 mm to about 0.3 mm.

[0235] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the channel defined by the needle has a length in the range of about 15 mm to about 25 mm.

[0236] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel comprises glass.

[0237] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel comprises borosilicate glass.

[0238] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the barrel of the pre-filled syringe has an inner diameter in the range of about 6 mm to about 10 mm.

[0239] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the stopper comprises ethylene tetrafluoroethylene.

[0240] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is a spring selected from the group of a variable force spring, a constant force spring, a helical spring, a conical spring, a torsion spring, a gas spring, a hydraulic spring, and combinations thereof.

[0241] Another aspect is the method, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is a spring selected from the group consisting of a variable force spring, a constant force spring, a helical spring, a conical spring, a torsion spring, a gas spring, a hydraulic spring, and combinations thereof.

[0242] Another aspect is an auto-injector device for actuating a pre-filled syringe containing a dosage of a therapeutic fluid, the therapeutic fluid including fremanezumab, and the auto-injector manufactured by a process including any combination of the actions described above; selecting a spring having a selected spring constant; and assembling the selected spring and the auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein.

[0243] Another aspect is a pre-filled syringe comprising an automatic injector arrangement including a barrel extending along a longitudinal axis between a distal end and a proximal end and having an internal diameter of about 8.65 mm, a needle disposed at the distal end of the barrel and having an internal diameter of about 0.21 mm and a length of about 20 mm or less, a therapeutic fluid held within the barrel and having a viscosity in the range of about 14 cSt or less at 22° C., and a stopper disposed within the barrel to retain the therapeutic fluid within the barrel, wherein the barrel defines a travel path for the stopper, and the travel path defines a first travel path for the stopper. an auto-injector, alone or in any combination with the preceding embodiments and aspects disclosed herein, comprising: a pre-filled syringe having a first position and a second position for a stopper, the therapeutic fluid containing fremanezumab; and an auto-injector holding the pre-filled syringe and including a plunger and an injection spring, the plunger engaging the stopper, the injection spring biasing the plunger toward the stopper, the injection spring having a spring force of at least about 20 N when the stopper is positioned in the first position.

[0244] Another embodiment is a pre-filled syringe comprising: an auto-injector arrangement including a barrel extending along a longitudinal axis between a distal end and a proximal end and having an internal diameter of about 8.65 mm; a needle disposed at the distal end of the barrel and having an internal diameter of about 0.27 mm and a length of about 19.5 mm or less; a therapeutic fluid retained within the barrel, the therapeutic fluid comprising fremanezumab and having a viscosity of about 8.8 cSt at 22° C., and having a volume in the range of about 1.51 mL to about 1.66 mL; and a stopper disposed within the barrel to retain the therapeutic fluid within the barrel, wherein the barrel defines a travel path for the stopper, the travel path having a first initial position for the stopper and a second final position for the stopper, the first position being an initial position of the stopper prior to delivery of the therapeutic fluid and the second position being a maximum use position for the therapeutic fluid. an automatic injector, alone or in any combination with the preceding embodiments and aspects disclosed herein, comprising: a filled syringe, the stopper being in a final position at the time of dose delivery; and an injection spring arranged to hold the filled syringe and apply a delivery force to the stopper by driving a piston rod toward the stopper, wherein when the automatic injector is activated, the injection spring is configured to provide an initial delivery force to the stopper of at least about 20 N when the stopper is positioned in a first initial position and a final delivery force to the stopper of at least 12 N when the stopper is positioned in a second final position, the delivery force being at least a portion of the spring force of the injection spring.

[0245] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final delivery force of at least 12.5 N against the stopper when the stopper is positioned in the second, final position.

[0246] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final delivery force of at least 14 N against the stopper when the stopper is positioned in the second, final position.

[0247] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final delivery force of at least 12 N against the stopper when the stopper is positioned in the second, final position, and the filled syringe has an accelerated aging of about 24 months.

[0248] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a spring force in the range of about 20 N to about 30 N when the stopper is positioned in the first, initial position.

[0249] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final delivery force in the range of about 12 N to about 20 N when the stopper is positioned in the second, final position.

[0250] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final delivery force in the range of about 12.5 N to about 20 N when the stopper is positioned in the second, final position.

[0251] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein when the stopper is in the first initial position, the actual stored spring energy of the injection spring is at least about 25% greater than the minimum stored spring energy required to move the unaged filled syringe from the first initial position to the second final position without stalling the stopper.

[0252] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a stored energy in the range of about 0.9 J to about 2 J when the injection spring is in the first position.

[0253] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a spring constant in the range of about 0.2 N / mm to about 0.4 N / mm and a compressed length in the range of about 50 mm to about 100 mm when in the first, initial position.

[0254] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has a spring constant in the range of about 0.28 N / mm to about 0.32 N / mm and a compressed length in the range of about 75 mm to about 95 mm when in the first, initial position.

[0255] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring has sufficient force to move the stopper along the path from the first position to the second position within about 5 seconds to about 25 seconds.

[0256] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the pre-filled syringe comprises glass and defines an interior surface; and, prior to aging of the pre-filled syringe, the pre-filled syringe further comprises from about 0.4 mg to about 1.1 mg of silicone oil on the interior surface.

[0257] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the injection spring is configured to move the stopper along a travel path from a first initial position to a second final position within a range of about 5 seconds to about 19 seconds.

[0258] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity of about 500 cSt to about 1500 cSt at 25° C. prior to aging of the pre-filled syringe.

[0259] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity of about 1000 cSt at 25° C. prior to aging of the pre-filled syringe.

[0260] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the stopper has a length in the range of about 7.3 mm to about 8.1 mm.

[0261] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the stopper has a compressed state and an uncompressed state, and the stopper includes: a main body that is substantially cylindrical and has a diameter in the uncompressed state in the range of about 8.85 mm to about 9.05 mm; and at least one annular rib extending radially from the main body and having an outer diameter in the uncompressed state in the range of about 9.25 mm to about 9.45 mm.

[0262] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein a portion of the stopper is coated with ethylene tetrafluoroethylene and a portion of the stopper is coated with silicone.

[0263] Another aspect is the auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the distance between the first position for the stopper and the second position for the stopper is in the range of about 25.7 mm to about 30 mm.

[0264] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the reference pre-filled syringe has a volume selected from the group of about 1 mL and about 2.25 mL.

[0265] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the pre-filled syringe has a volume selected from the group consisting of about 1 mL and about 2.25 mL.

[0266] Another aspect is an auto-injector, alone or in any combination with the previous embodiments and aspects disclosed herein, wherein the therapeutic fluid has a viscosity of about 4 cSt to about 10 cSt at 22°C.

[0267] Another aspect is an automatic injector, wherein the injection spring is determined according to the actions of claim 1, alone or in any combination with the previous embodiments and aspects disclosed herein.

[0268] Another embodiment is an auto-injector arrangement comprising: a barrel formed at least partially from glass; a needle in fluid communication with the barrel; and a stopper positioned within the barrel, the barrel defining an interior surface, the barrel having an inner diameter, the barrel having a diameter of about 8.65 mm and a volume of 2.25 mL, the barrel defining a track for the stopper, the track having a first position for the stopper and a second position for the stopper, the needle having an inner diameter of about 0.21 mm and a length of about 20 mm or less, a therapeutic fluid held within the barrel, the therapeutic fluid having a viscosity of about 10 cP at 22° C., the therapeutic fluid comprising fremanezumab; and about 0.35 mg to about 1.1 mg of silicone oil lubricating the interior surface of the barrel, the silicone oil having a viscosity of about 500 cP at 25° C. before aging of the filled syringe. and a silicone oil having a viscosity of about 1000 cSt to about 1500 cSt; an auto-injector holding a pre-filled syringe and including a plunger and an injection spring, the plunger engaging a stopper and the injection spring biasing the plunger toward the stopper, the injection spring, when in a first position, having a force determined in accordance with the actions of claim 1; in the range of about 20 N to about 30 N; and about 25% greater than the spring force required to move the stopper from the first position to the second position without stalling prior to aging of the pre-filled syringe; and the force is sufficient to move the stopper along a path from the first position to the second position within about 5 seconds to about 25 seconds.

[0269] Another aspect is an auto-injector device for actuating a pre-filled syringe containing a dosage of a therapeutic fluid, the therapeutic fluid comprising an immunoglobulin G2 (IgG2) humanized monoclonal antibody, the auto-injector including the steps of: aging the pre-filled syringe to form an aged pre-filled syringe; moving a stopper within the barrel of the aged pre-filled syringe at a predetermined speed from at least one first position along a path of travel to at least one second position along the path of travel; measuring a plurality of forces exerted on the stopper as the stopper moves within the barrel along the path of travel; and measuring the forces exerted on the stopper along the path of travel. An automatic injector device, alone or in any combination with the previous embodiments and aspects disclosed herein, manufactured by a process including the operations of: determining at least first and second resistance forces opposing movement of the topper, the first and second resistance forces corresponding to a plurality of acting forces; selecting a spring constant for an injection spring, the act of selecting the spring constant including selecting the spring constant to correspond to at least one of the first and second resistance forces; selecting a spring having the selected spring constant; and assembling the automatic injector and the selected spring.

[0270] Another aspect is an auto-injector device configured to move a stopper within a barrel of a syringe to effect delivery of a fluid from the syringe, the auto-injector device comprising: a syringe barrel having an empty state and a full state, the empty state occurring before the full state, wherein the syringe holds a dose of a therapeutic fluid, the therapeutic fluid comprising an immunoglobulin G2 (IgG2) humanized monoclonal antibody; and a stopper positioned within the syringe barrel and having a path of travel between a first position and a second position, wherein the dose of therapeutic fluid is positioned substantially between the first and second positions. an injection spring having a spring constant providing an injection spring with a first spring force that is at least 25% greater than a second spring force, the first spring force corresponding to a minimum spring force required to move the stopper from the first position to the second position when the barrel is in a full state, and the second spring force corresponding to a minimum spring force required to move the stopper from the first position to the second position when the barrel is in an empty state, alone or in any combination with the previous embodiments and aspects disclosed herein.

[0271] Another aspect is an auto-injector device configured to move a stopper within a barrel of a syringe to effect delivery of a fluid from the syringe, the auto-injector device comprising: a pre-filled syringe having an unaged state and an aged state, the pre-filled syringe holding a dose of a therapeutic fluid when in a full state, the therapeutic fluid comprising an immunoglobulin G2 (IgG2) humanized monoclonal antibody; and a stopper positioned within the pre-filled syringe and having a path of travel between a first position and a second position, the stopper having a path of travel between a first position and a second position, the dose of therapeutic fluid being positioned substantially between the first and second positions. an injection spring having a spring constant providing an injection spring with a first spring force that is at least 25% greater than a second spring force, the first spring force corresponding to a minimum spring force required to move the stopper from the first position to the second position when the filled syringe is in an aged state, and the second spring force corresponding to a minimum spring force required to move the stopper from the first position to the second position when the filled syringe is in an unaged state, alone or in any combination with the previous embodiments and aspects disclosed herein.

[0272] Another aspect is the combination of a pre-filled syringe, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament for treating or preventing migraine headaches.

[0273] Another aspect is a pre-filled syringe containing fremanezumab, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament for treating or preventing migraine headaches.

[0274] Another aspect is a pre-filled syringe containing a therapeutic fluid comprising fremanezumab, alone or in any combination with the previous embodiments and aspects disclosed herein, for use as a medicament for treating or preventing migraine headaches.

[0275] Another aspect is a pre-filled syringe for use as a medicament for treating or preventing migraine headache, containing a therapeutic fluid comprising fremanezumab and formulated at a nominal concentration of 150 mg / mL in 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, 1.2 mg / mL P580, pH 5.5, alone or in any combination with the previous embodiments and aspects disclosed herein.

[0276] Another aspect is a pre-filled syringe containing fremanezumab in any combination with an auto-injector for use as a medicament for treating or preventing migraine headaches, the pre-filled syringe being filled with a therapeutic fluid formulated at a nominal concentration of 150 mg / mL in 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, 1.2 mg / mL P580, pH 5.5, alone or in any combination with the previous embodiments and aspects disclosed herein.

[0277] Another aspect is a pre-filled syringe containing fremanezumab for use as a medicament for treating or preventing migraine headaches according to a continuous schedule of no more than once every two months, either alone or in any combination with the preceding embodiments and aspects.

[0278] Another aspect is a pre-filled syringe containing fremanezumab for use as a medicament for treating or preventing migraine headaches according to a continuous schedule of no more than once every three months, either alone or in any combination with the preceding embodiments and aspects.

[0279] Another aspect is a pre-filled syringe containing fremanezumab for use as a medicament for treating or preventing migraine headaches according to a continuous schedule of no more than once every four months, either alone or in any combination with the preceding embodiments and aspects.

[0280] Another aspect is an auto-injector, either alone or in any combination with the preceding embodiments and aspects, comprising: a pre-filled syringe containing a stopper and a therapeutic fluid including fremanezumab; and an auto-injector having a piston rod and injection spring arranged to move the stopper from a first position to a second position in about 19 seconds or less with a force of about 30 N or less, wherein the distance between the first position and the second position corresponds to a dose of the therapeutic fluid.

[0281] The various embodiments described above are provided by way of example only and should not be construed as limiting the appended claims. Those skilled in the art will readily recognize various modifications and changes that can be made without departing from the true spirit and scope of the following claims without departing from the exemplary embodiments and fields of application illustrated and described herein. All such modifications and equivalents are intended to be included within the scope of the claims. The present disclosure also includes the following aspects. [Aspect 1] 1. A method of manufacturing an automatic injector for delivering a therapeutic fluid stored in an operational pre-filled syringe, the operational pre-filled syringe including an operational barrel and an operational stopper movably positioned within the operational barrel, the operational stopper being movable along an operational path from a first operational position to a second operational position, the automatic injector including an injection spring having a spring force, the injection spring configured to apply a delivery force to the operational stopper by driving a piston rod toward the operational stopper upon actuation of the automatic injector, the delivery force being at least a portion of the spring force, the method comprising: aging the filled syringe at an accelerated rate to form a reference filled syringe, the reference filled syringe including a reference barrel and a reference stopper positioned within the reference barrel; moving the reference stopper of the reference filled syringe along a reference path of travel from at least one first reference position to at least one second reference position; measuring a plurality of forces applied to the reference stopper as the reference stopper moves along the reference path within the reference barrel to measure a plurality of reference stopper positions; generating an applied force profile, the applied force profile including at least some of the applied forces and reference stop positions measured while the reference stop is moving between the first and second reference positions, at least one of the measured applied forces being correlated with at least one of the measured reference stop positions; selecting the injection spring such that the delivery force applied to the operational stop at each position of the operational stop as it moves along an operational path between the first and second operational positions is greater than the measured application force at a corresponding one of the measured reference stop positions; A method comprising: [Aspect 2] 2. The method of claim 1, wherein selecting the injection spring comprises selecting a measured force from the force profile and selecting at least one spring parameter, the selected at least one spring parameter corresponding to the selected force. Aspect 3 3. The method of aspect 2, wherein selecting the at least one spring parameter comprises selecting a spring constant of the injection spring and an uncompressed length of the injection spring. Aspect 4 The method of aspect 2, wherein selecting at least one spring parameter includes selecting a first compression spring length and spring constant corresponding to the reference stopper at the first reference position along the reference path of travel. Aspect 5 The method of aspect 2, wherein selecting at least one spring parameter includes selecting a second compression spring length and spring constant corresponding to the reference stopper located at a position along the reference path of travel that corresponds to a measured maximum force in the force profile. Aspect 6 6. The method of claim 5, wherein the selected spring has a pumping force when the stopper is in the second position that is greater than about 50% of the pumping force when the stopper is in the first position. Aspect 7 2. The method of claim 1, wherein the predetermined speed corresponds to a speed within a range of about 5 seconds to about 19 seconds required to move the operational stopper along the operational path from the first operational position to the second operational position. Aspect 8 The method of aspect 1, wherein the reference-filled syringe holds a determined volume of therapeutic fluid between the first reference position and the second reference position, and the act of moving the reference stopper along the reference path from the first reference position to the second reference position includes a step of releasing the determined volume of therapeutic fluid from the reference-filled syringe. Aspect 9 Aspect 9. The method of aspect 8, wherein the determined volume of therapeutic fluid in the reference syringe is substantially equal to the determined volume of therapeutic fluid held in the operational filled syringe. Aspect 10 9. The method of claim 8, wherein the determined volume is in the range of about 1.51 mL to about 1.66 mL. Aspect 11 2. The method of embodiment 1, wherein the therapeutic fluid comprises fremanezumab. Aspect 12 2. The method of embodiment 1, wherein the reference barrel of the reference pre-filled syringe comprises an inner surface, and wherein the reference pre-filled syringe further comprises a lubricant on the inner surface. Aspect 13 13. The method of claim 12, wherein the lubricant in the reference pre-filled syringe comprises from about 0.35 mg to about 1.1 mg of silicone oil prior to aging of the reference pre-filled syringe. Aspect 14 14. The method of claim 13, wherein the silicone oil has a viscosity of between about 500 cSt at 25° C. and about 1500 cSt at 25° C. prior to aging of the reference filled syringe. Aspect 15 2. The method of aspect 1, wherein aging the reference-filled syringe comprises heating the reference-filled syringe for a determined amount of time. Aspect 16 the determined time is calculated according to the Arrhenius equation; 16. The method of claim 15, wherein heating the reference-filled syringe for a determined period of time comprises heating the reference-filled syringe at a temperature within a range of about 20°C to about 60°C. Aspect 17 2. The method of embodiment 1, wherein the reference barrel of the reference pre-filled syringe has a volume selected from the group of about 1 mL and about 2.25 mL. Aspect 18 2. The method according to embodiment 1, wherein the distance between the first reference position of the reference stopper and the second reference position of the reference stopper is within a range of approximately 25.7 mm to approximately 30 mm. Aspect 19 2. The method of embodiment 1, wherein the reference pre-filled syringe comprises a reference needle, the reference needle defining a channel, the channel having a diameter in the range of about 0.15 mm to about 0.3 mm. Aspect 20 20. The method of embodiment 19, wherein the channel defined by the reference needle has a length in the range of about 15 mm to about 25 mm. Aspect 21 2. The method of embodiment 1, wherein the reference barrel comprises glass. Aspect 22 2. The method of embodiment 1, wherein the reference stopper comprises ethylene tetrafluoroethylene. Aspect 23 2. The method of embodiment 1, wherein the operational filled syringe is substantially similar to the reference filled syringe. Aspect 24 2. The method of embodiment 1, wherein the injection spring is a spring selected from the group of a variable force spring, a constant force spring, a helical spring, a conical spring, a torsion spring, a gas spring, a hydraulic spring, and combinations thereof. Aspect 25 1. An auto-injector device for activating an operational pre-filled syringe containing a dosage of a therapeutic fluid, the therapeutic fluid including fremanezumab, the auto-injector comprising: the action of aspect 1; assembling the selected injection spring with the automatic injector; 1. An auto-injector device manufactured by a process comprising: Aspect 26 a pre-filled syringe comprising: a barrel extending along a longitudinal axis between a distal end and a proximal end and having an internal diameter of approximately 8.65 mm; a needle disposed at the distal end of the barrel and having an internal diameter of approximately 0.27 mm and a length of approximately 19.5 mm or less; a therapeutic fluid retained within the barrel, the therapeutic fluid comprising fremanezumab and having a viscosity of approximately 8.8 cSt at 22°C, and having a volume ranging from approximately 1.51 mL to approximately 1.66 mL; and a stopper disposed within the barrel to retain the therapeutic fluid within the barrel, the barrel defining a path for the stopper, the path having a first initial position for the stopper and a second final position for the stopper, the first position being an initial position of the stopper prior to delivery of the therapeutic fluid and the second position being a final position of the stopper upon delivery of a maximum dose of the therapeutic fluid; an automatic injector including an injection spring configured to hold the filled syringe and to apply a delivery force to the stopper by driving a piston rod toward the stopper, wherein when the automatic injector is activated, the injection spring is configured to provide an initial delivery force to the stopper of at least about 20 N when the stopper is positioned in a first initial position and a final delivery force to the stopper of at least 12 N when the stopper is positioned in the second final position, the delivery force being at least a portion of the spring force of the injection spring; 12. An autoinjector device comprising: Aspect 27 27. The automatic injector device of claim 26, wherein the injection spring is configured to provide a final delivery force of at least 12.5 N against the stopper when the stopper is positioned in the second final position. Aspect 28 28. The automatic injector device of claim 27, wherein the injection spring is configured to provide a final delivery force of at least 14 N to the stopper when the stopper is positioned in the second final position. Aspect 29 27. The automatic injector device of claim 26, wherein the injection spring is configured to provide a final delivery force of at least 12 N against the stopper when the stopper is positioned in the second final position and the filled syringe has an accelerated age of approximately 24 months. Aspect 30 27. The automatic injector device of claim 26, wherein the injection spring is configured to provide an initial delivery force in a range of about 20 N to about 40 N when the stopper is positioned in the first initial position. Aspect 31 27. The automatic injector device of claim 26, wherein the injection spring is configured to provide a final delivery force in a range of about 12 N to about 20 N when the stopper is positioned in the second final position. Aspect 32 27. The automatic injector device of claim 26, wherein when the stopper is in the first position, the actual stored spring energy of the injection spring is at least 25% greater than the minimum stored spring energy required to move the stopper from the first initial position to the second final position without stalling an unaged filled syringe. Aspect 33 27. The automatic injector device of aspect 26, wherein the injection spring has a stored energy in a range of about 0.9 J to about 2 J when the injection spring is in the first initial position. Aspect 34 34. The automatic injector device of embodiment 33, wherein the injection spring has a spring constant in the range of about 0.2 N / mm to about 0.4 N / mm and a compressed length in the range of about 50 mm to about 100 mm when in the first initial position. Aspect 35 35. The automatic injector device of embodiment 34, wherein the injection spring has a spring constant in the range of about 0.28 N / mm to about 0.32 N / mm and a compressed length in the range of about 75 mm to about 95 mm when in the first initial position. Aspect 36 36. The automatic injector device of claim 35, wherein the injection spring is configured to move the stopper along the path from the first initial position to the second final position within a range of about 5 seconds to about 19 seconds. Aspect 37 the prefilled syringe comprises glass and defines an interior surface; and 27. The auto-injector device of claim 26, wherein the pre-filled syringe further comprises about 0.4 mg to about 1.1 mg of silicone oil on the interior surface prior to aging of the pre-filled syringe. Aspect 38 38. The auto-injector device of embodiment 37, wherein the silicone oil has a viscosity of about 1000 cSt at 25° C. prior to aging of the pre-filled syringe. Aspect 39 27. The auto-injector device of embodiment 26, wherein the stopper has a length in the range of about 7.3 mm to about 8.1 mm. Aspect 40 The stopper has a compressed state and an uncompressed state, the stopper comprising: a main body that is substantially cylindrical and has a diameter in an uncompressed state within the range of about 8.85 mm to about 9.05 mm; at least one annular rib extending radially from the main body and having an outer diameter in an uncompressed state within the range of about 9.25 mm to about 9.45 mm; 40. The auto-injector device of embodiment 39, comprising: Aspect 41 40. The auto-injector device of embodiment 39, wherein a portion of the stopper is coated with ethylene tetrafluoroethylene and a portion of the stopper is coated with silicone. Aspect 42 27. The automatic injector device of claim 26, wherein the distance between the first position for the stopper and the second final position for the stopper is in the range of about 25.7 mm to about 30 mm. Aspect 43 27. The automatic injector device of claim 26, wherein the injection spring is determined according to the action of claim 1. Aspect 44 a pre-filled syringe comprising: a barrel at least partially formed of glass; a needle in fluid communication with the barrel; and a stopper positioned within the barrel, the barrel defining an interior surface; the barrel having an inner diameter, the barrel having a diameter of about 8.65 mm; the barrel defining a path for the stopper, the path having a first position for the stopper and a second position for the stopper; the needle having an inner diameter of about 0.27 mm and a length of about 19.5 mm or less; a therapeutic fluid held within the barrel, the therapeutic fluid having a viscosity of about 10 cP at 22°C; lubricating the interior surface of the barrel, from about 0.35 mg to about 1.1 mg of silicone oil, the silicone oil having a viscosity in the range of from about 500 cSt at 25° C. to about 1500 cSt at 25° C. before aging of the filled syringe; an automatic injector holding the prefilled syringe and including a plunger and an injection spring, wherein the plunger engages the stopper and the injection spring biases the plunger toward the stopper, when the injection spring is in the first position; having a force determined according to the action of aspect 1; having a spring force in the range of about 20 N to about 30 N; and When the stopper is positioned at the first position; having a stored spring energy in the range of about 0.9 J to about 2 J; having a spring constant in the range of about 0.2 N / mm to about 0.4 N / mm and a compressed length in the range of about 50 mm to about 100 mm; having stored energy that is approximately 25% greater than the minimum spring energy required to move the stopper from the first position to the second position without stalling, prior to aging of the filled syringe; an auto-injector having sufficient force to move the stopper along the path from the first position to the second position within about 5 seconds to about 25 seconds; 12. An autoinjector device comprising: Aspect 45 a pre-filled syringe comprising a stopper and a therapeutic fluid comprising fremanezumab; and an automatic injector having a piston rod and an injection spring arranged to move the stopper from a first position to a second position in about 19 seconds or less with a force of about 30 N or less, the distance between the first and second positions corresponding to one dose of the therapeutic fluid; 12. An autoinjector device comprising:

Claims

1. 1. An auto-injector device, comprising:

1. A pre-filled syringe, comprising: a barrel including a proximal end and a distal end, extending along a longitudinal axis between the proximal end and the distal end, the barrel having an inner diameter of between 8.5 mm and 8.8 mm; a needle disposed at the distal end of the barrel, the needle having an inner diameter between 0.25 mm and 0.29 mm and a length of 19.5 mm or less; a therapeutic fluid held within the barrel, the therapeutic fluid comprising an anti-calcitonin gene-related peptide (anti-CGRP) antibody, the anti-CGRP antibody comprising a heavy chain variable region whose amino acid sequence is at least 90% identical to SEQ ID NO:1 and a light chain variable region whose amino acid sequence is at least 90% identical to SEQ ID NO:2, the therapeutic fluid having a volume in the range of 1.51 mL to 1.66 mL and a viscosity of 8 cP at 22°C to 10 cP at 22°C; a pre-filled syringe including a stopper disposed within the barrel, the stopper configured to move axially within the barrel along a path of travel between a first position and a second position to expel at least a portion of the volume of the therapeutic fluid from the pre-filled syringe, the first position being an initial position of the stopper prior to delivery of the therapeutic fluid and the second position being a final position of the stopper upon completion of delivery of the therapeutic fluid; an automatic injector holding the pre-filled syringe, the automatic injector comprising: a piston rod configured adjacent to the stopper; an injection spring configured to urge the piston rod against the stopper to apply a delivery force to the stopper; 1. An auto-injector device comprising: When the automatic injector is activated, the injection spring is configured to provide an initial delivery force of at least 20N to 30N when the stopper is positioned in the first position, and a final delivery force of 12N to 20N to move the stopper to the second position; the initial delivery force is greater than the final delivery force; The automatic injector device, wherein the delivery force is at least a portion of the spring force of the injection spring.

2. 2. The automatic injector device of claim 1, wherein the heavy chain variable region is at least 95% identical in amino acid sequence to SEQ ID NO:1 and the light chain variable region is at least 95% identical in amino acid sequence to SEQ ID NO:

2.

3. 3. The automatic injector device of claim 2, wherein the heavy chain variable region is 100% identical in amino acid sequence to SEQ ID NO:1 and the light chain variable region is 100% identical in amino acid sequence to SEQ ID NO:

2.

4. The auto-injector further comprises a housing; 10. The automatic injector device of claim 1, wherein the automatic injector holds the pre-filled syringe stationary relative to the housing.

5. 5. The automatic injector device of claim 4, wherein the automatic injector is configured to hold the pre-filled syringe stationary relative to the housing between actuation of the automatic injector and delivery of the therapeutic fluid.

6. The auto-injector further includes a housing and a cover sleeve; 2. The automatic injector device of claim 1, wherein the cover sleeve is configured to move proximally axially into the housing when the automatic injector is in an enabled state and is pressed against a puncture site by pressure applied to the housing to release the needle, which is immobile relative to the housing, and puncture the puncture site.

7. 2. The automatic injector device of claim 1, wherein the injection spring is within the barrel when the stopper is in the second position.

8. 2. The automatic injector device of claim 1, wherein a distal end of the injection spring is adjacent to the stopper while the stopper is moving from the first position to the second position.

9. 1. An auto-injector device, comprising:

1. A pre-filled syringe, comprising: a barrel including a proximal end and a distal end, extending along a longitudinal axis between the proximal end and the distal end, the barrel having an inner diameter of between 8.5 mm and 8.8 mm; a needle disposed at the distal end of the barrel, the needle having an inner diameter between 0.25 mm and 0.29 mm and a length of 19.5 mm or less; a therapeutic fluid held within the barrel, the therapeutic fluid comprising fremanezumab, the therapeutic fluid having a volume in the range of 1.51 mL to 1.66 mL and a viscosity of 8 cP at 22° C. to 10 cP at 22° C.; a pre-filled syringe including a stopper disposed within the barrel, the stopper configured to move axially within the barrel along a path of travel between a first position and a second position to expel at least a portion of the volume of the therapeutic fluid from the pre-filled syringe, the first position being an initial position of the stopper prior to delivery of the therapeutic fluid and the second position being a final position of the stopper upon completion of delivery of the therapeutic fluid; an automatic injector holding the pre-filled syringe, the automatic injector comprising: a piston rod configured adjacent to the stopper; an injection spring configured to urge the piston rod against the stopper to apply a delivery force to the stopper; 1. An auto-injector device comprising: When the automatic injector is activated, the injection spring is configured to provide an initial delivery force of at least 20N to 30N when the stopper is positioned in the first position, and a final delivery force of 12N to 20N to move the stopper to the second position; the initial delivery force is greater than the final delivery force; The automatic injector device, wherein the delivery force is at least a portion of the spring force of the injection spring.

10. 10. The auto-injector device of claim 9, wherein the pre-filled syringe is aged for up to 24 months.

11. the pre-filled syringe is unaged; 10. The automatic injector device of claim 9, wherein the actual stored spring energy of the injection spring when the stopper is in the initial position is at least 25% greater than the minimum stored spring energy required to move the stopper from the first position to the second position without stalling the filled syringe.

12. 10. The automatic injector device of claim 9, wherein the injection spring has a stored energy of between 0.9 J and 2 J when the stopper is in the first position.

13. When the stopper is in the first position, the injection spring a spring constant between 0.2 N / mm and 0.4 N / mm; 13. The automatic injector device of claim 12, having a compressed length of between 50 mm and 100 mm.

14. 14. The automatic injector device of claim 13, wherein the spring constant is between 0.28 N / mm and 0.32 N / mm and the compressed length is in the range of 75 mm to 95 mm.

15. 10. The automatic injector device of claim 9, wherein the injection spring is configured to move the stopper along the path from the first position to the second position within a range of 5 seconds to 19 seconds.

16. the pre-filled syringe is unaged; the barrel of the prefilled syringe comprises glass and defines an interior surface; 10. The automatic injector device of claim 9, wherein the pre-filled syringe further comprises a lubricant on the inner surface.

17. 17. The automatic injector device of claim 16, wherein the lubricant is disposed on the inner surface as a layer having a thickness of 0.1 μm to 1 μm.

18. 17. The automatic injector device of claim 16, wherein the lubricant is silicone oil.

19. 19. The auto-injector device of claim 18, wherein the silicone oil comprises between 0.4 mg and 1.1 mg of silicone oil.

20. 10. The automatic injector device of claim 9, wherein the stopper has a length of between 7.3 mm and 8.1 mm.

21. The stopper is configured to compress to a compressed state and relax to an uncompressed state, the stopper comprising: a main body that is substantially cylindrical and has a diameter in an uncompressed state between 8.85 mm and 9.05 mm; at least one annular rib extending radially from the main body and having an outer diameter in an uncompressed state between 9.25 mm and 9.45 mm; 21. The automatic injector device of claim 20, comprising:

22. 21. The automatic injector device of claim 20, wherein a portion of the stopper is coated with ethylene tetrafluoroethylene and another portion of the stopper is coated with silicone.

23. 10. The automatic injector device of claim 9, wherein the distance between the first position and the second position is between 25.7 mm and 30 mm.

24. The auto-injector further comprises a housing; 10. The automatic injector device of claim 9, wherein the automatic injector holds a pre-filled syringe stationary relative to the housing.

25. The auto-injector is configured to hold the pre-filled syringe stationary relative to the housing between actuation of the auto-injector and delivery of the therapeutic fluid.

25. The automatic injector device of claim 24.

26. The auto-injector further includes a housing and a cover sleeve; 10. The automatic injector device of claim 9, wherein the cover sleeve is configured to move proximally axially within the housing when the automatic injector is in an enabled state and is pressed against a puncture site by pressure applied to the housing to release the needle, which is immobile relative to the housing, and puncture the puncture site.

27. 10. The automatic injector device of claim 9, wherein the injection spring is within the barrel when the stopper is in the second position.

28. 10. The automatic injector device of claim 9, wherein a distal end of the injection spring is adjacent to the stopper while the stopper is moving from the first position to the second position.

29. The auto-injector further includes a cover sleeve spring; 10. The automatic injector device of claim 9, wherein the injection spring is concentrically disposed within the cover sleeve spring.

30. 1. An auto-injector device, comprising: A syringe, a barrel having a proximal end and a distal end and extending along a longitudinal axis between the proximal end and the distal end, the barrel containing 1 mL of a therapeutic fluid comprising an anti-calcitonin gene-related peptide (anti-CGRP) antibody and having a viscosity of 10 cP or less at 22° C.; a needle disposed at the distal end of the barrel, the needle having a length of 19.5 mm or less; a syringe including: a stopper disposed within the barrel, the stopper configured to move axially within the barrel along a path of travel to expel at least a portion of 1 mL of the therapeutic fluid from the syringe, the path of travel including an initial position of the stopper prior to delivery of the therapeutic fluid and a final position of the stopper at the end of delivery of the therapeutic fluid; an automatic injector holding the syringe, the automatic injector comprising: a rod configured adjacent to the stopper; an injection spring configured to urge the rod against the stopper to apply a delivery force to the stopper; 1. An auto-injector device comprising: the injection spring is configured to provide an initial force of 20N to 30N when the stopper is positioned in the initial position, and the injection spring is configured to provide a final force of 12N to 20N when the stopper is in the final position.

31. 31. The automatic injector device of claim 30, wherein the injection spring has a stored energy of between 0.9 J and 2 J before the automatic injector is actuated.

32. 32. The automatic injector device of claim 31, wherein the injection spring, before the automatic injector is actuated, has a storage spring constant of between 0.2 N / mm and 0.4 N / mm and a compressed length of between 50 mm and 100 mm.

33. 33. The automatic injector device of claim 32, wherein the storage spring constant is between 0.28 N / mm and 0.32 N / mm.

34. the syringe is unaged; 31. The automatic injector device of claim 30, wherein the actual stored spring energy of the injection spring when the stopper is in the initial position is at least 25% greater than the minimum stored spring energy required to move the stopper from the initial position to the final position without stalling the syringe.

35. 31. The automatic injector device of claim 30, wherein the injection spring is configured to move the stopper, via the rod, from the initial position to the final position in between 5 and 19 seconds.

36. 31. The automatic injector device of claim 30, wherein the stopper has a length of between 7 mm and 9 mm.

37. 31. The automatic injector device of claim 30, wherein a portion of the stopper is coated with ethylene tetrafluoroethylene and another portion of the stopper is coated with silicone.

38. 31. The automatic injector device of claim 30, wherein the distance between the initial position and the final position corresponds to a single dose of the therapeutic fluid.

39. 31. The automatic injector device of claim 30, wherein the distance between the initial position and the final position is between 25 mm and 40 mm.

40. 31. The auto-injector device of claim 30, wherein the auto-injector is configured to house the syringe.

41. 31. The automatic injector device of claim 30, wherein the syringe defines a shoulder adjacent a distal end of the syringe.

42. 42. The automatic injector device of claim 41, wherein the stopper abuts a shoulder of the syringe when the stopper is in the final position.

43. 43. The automatic injector device of claim 42, wherein the stopper is spaced from a shoulder of the syringe when the stopper is in the final position.

44. 42. The automatic injector device of claim 41, wherein the stopper contacts a shoulder of the syringe when the stopper is in the final position.

45. 31. The automatic injector device of claim 30, wherein when the stopper is in the initial position, the stopper is adjacent to the therapeutic fluid in the barrel before any amount of the therapeutic fluid is dispensed.

46. 46. ​​The automatic injector device of claim 45, wherein when the stopper is in the initial position, the stopper is proximal to the therapeutic fluid within the barrel before any amount of the therapeutic fluid has been dispensed.

47. 31. The automatic injector device of claim 30, wherein the injection spring is configured to provide the initial force and the final force to the stopper via the rod.

48. 31. The automatic injector device of claim 30, wherein the needle has an inner diameter of between 0.21 mm and 0.3 mm.

49. 49. The automatic injector device of claim 48, wherein the needle has an inner diameter of between 0.25 mm and 0.29 mm.

50. 50. The automatic injector device of claim 49, wherein the needle has an inner diameter of 0.27 mm.

51. 31. The auto-injector device of claim 30, wherein the syringe is aged for up to 12 months.

52. 52. The automatic injector device of claim 51, wherein the syringe is aged for up to 24 months.

53. the syringe is unaged; the syringe barrel comprises glass and defines an interior surface; 31. The automatic injector device of claim 30, wherein the syringe further comprises a lubricant on the inner surface.

54. 54. The automatic injector device of claim 53, wherein the lubricant is disposed on the inner surface as a layer having a thickness of between 0.1 μm and 1 μm.

55. 54. The automatic injector device of claim 53, wherein the lubricant is silicone oil.

56. 56. The automatic injector device of claim 55, wherein the silicone oil comprises between 0.4 mg and 1.1 mg of silicone oil on the inner surface.

57. 57. The automatic injector device of claim 56, wherein the silicone oil has a viscosity of 1000 cSt at 25°C.

58. 31. The automatic injector device of claim 30, wherein the injection spring is within the barrel when the stopper is in the final position.

59. 31. The automatic injector device of claim 30, wherein a distal end of the injection spring is adjacent to the stopper during movement of the stopper from the initial position to the final position.

60. the injection spring is a first spring of the automatic injector; the automatic injector has a second spring; 31. The automatic injector device of claim 30, wherein the uncompressed length of the first spring is greater than the uncompressed length of the second spring.

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