Injection springs for auto-injectors and pre-filled syringes for aging

Abstract

A method for adjusting an autoinjector configured to actuate a pre-filled syringe, the autoinjector having a biasing member having a spring constant, the pre-filled syringe being filled with a volume of therapeutic fluid, the pre-filled syringe including a barrel, a stop, and a needle, the stop having a travel path, the biasing member being arranged to move the stop along the travel path. An autoinjector having an injection spring suitable for aging pre-filled syringes.

Description

[0001] This application is a divisional application of Teva Pharmaceutical International Ltd., with application number 201980076235.X, entitled "Autoinjector and Injection Spring for Prefilled Syringe for Aging", which entered the Chinese national phase on May 19, 2021 (international application date: 20190919, international application number: PCT / IB2019 / 001050).

[0002] Cross-reference to related applications

[0003] This application is a PCT international patent application filed on September 19, 2019, and claims priority to U.S. Provisional Application Serial No. 62 / 734,209 filed on September 20, 2018, the entire contents of which are expressly incorporated herein by reference. Background Technology

[0004] An autoinjector is a device used to automatically administer therapeutic fluids into a patient. The popularity of autoinjectors has increased rapidly in recent years due to various factors. For example, autoinjectors are very convenient for caregivers and patients who self-administer therapeutic fluids. Autoinjectors reduce the number of steps required to manage therapeutic fluids. Furthermore, because autoinjectors are labeled and the syringes are pre-filled by the drug supplier, there is no need to manually fill the syringe using a vial of therapeutic fluid. The use of pre-filled syringes reduces the risks of dosage errors, drug misidentification, and contamination.

[0005] In use, an autoinjector typically contains a pre-filled syringe and has a compression spring or other biasing member for pushing a stop to expel the therapeutic fluid. A button or other actuator is connected to a mechanism for releasing the compression spring, causing it to extend. As the spring extends, it drives a piston rod or plunger, which in turn pushes the stop within the syringe. The stop then expels the therapeutic fluid from the syringe barrel, through the needle, and into the patient's tissue at the administration site.

[0006] Before placing pharmaceutical products such as prefilled syringes and autoinjectors on the market, companies typically must obtain approval from government regulatory agencies (e.g., the U.S. Food and Drug Administration) or similar agencies abroad. For drugs contained in prefilled syringes and delivered via autoinjector systems, pharmaceutical companies are usually required to provide the agency with stability testing reports. These reports may include various information demonstrating normal performance throughout the product's shelf life. Some performance characteristics that must be provided may include dosage accuracy within the expected injection time over the entire product's shelf life.

[0007] Typically, the pre-filled syringe containing the therapeutic fluid is defined early in the development process. An autoinjector is then selected, and the injection time of the pre-filled syringe within the autoinjector must meet the desired injection time. To meet the desired injection time, injection time simulation is usually used. Injection time simulation is typically mathematical in nature and based on the geometry of the pre-filled syringe. The geometry of the pre-filled syringe specifically includes parameters such as needle length, needle diameter, and syringe diameter. This simulation is also often based on drug parameters, such as viscosity. These parameters enable the simulation of the hydrodynamic forces exerted by the fluid on the stop. The Hagen-Poiseuille equation is an example of a formula for modeling hydrodynamics. A stepwise function is typically used to estimate the frictional forces during delivery to simulate the constant release force at the beginning of the injection phase and the constant slip force during the remainder of the injection phase.

[0008] In practice, the frictional force between the stop and the syringe body of the pre-filled syringe is usually considered constant in injection time simulations. This constant force is typically inferred from the measured pressure on the empty pre-filled syringe as the stop moves at a speed corresponding to the desired injection time. Some more complex simulations may estimate the frictional force using the following formula:

[0009] (1)

[0010] Where, μ oil It refers to the viscosity of the lubricant, r. b It is the inner radius of the syringe barrel, l stoper It is the length of the stop that contacts the syringe barrel, d oil It's the thickness of the lubricant. It is the injection speed (linear piston speed, whose length dimension changes with time).

[0011] Typically, for Newtonian fluids, neglecting the pressure drop across the syringe barrel, the Hagen-Poiseuille equations can be used to estimate the fluid dynamics at a given temperature:

[0012] (2)

[0013] Where μ is the viscosity of the fluid, L n It is the length of the needle channel, r b rn is the inner radius of the syringe barrel, and rn is the inner diameter of the needle channel.

[0014] Injection time simulations are often based on characteristics of the autoinjector, such as the feeding force applied by the autoinjector to the stop on the pre-filled syringe barrel. This feeding force is based on the construction and parameters of the autoinjector's injection spring or other structures that power the movement of the autoinjector's injection mechanism. Potential resistance within the autoinjector may also be considered.

[0015] By using these various mathematical models to calculate the force applied to the stop, the injection time can be simulated. The simulated injection time can then be used to verify whether the parameters and construction of the injection spring will provide sufficient force to the stop to achieve the desired injection time. Summary of the Invention

[0016] In general, this patent document aims to define a spring for an autoinjector. Another aspect relates to defining an autoinjector having a defined spring.

[0017] One aspect of this patent document is a method of manufacturing an autoinjector. The method includes: aging a pre-filled syringe having a stop; measuring the force required to move the stop a predetermined distance within the aged pre-filled syringe over a predetermined time period; and selecting a spring having a predetermined spring force that moves the stop a predetermined distance over the predetermined time period.

[0018] One aspect of this patent document is a method of manufacturing an autoinjector for dispensing therapeutic fluid contained in an operable prefilled syringe, the operable prefilled syringe including an operable barrel and an operable stop movably positioned within the operable barrel, the operable stop being movable along an operable travel path from a first operable position to a second operable position, the autoinjector including an injection spring having a spring force configured to apply a dispensing force to the operable stop by driving a piston rod toward the operable stop when the autoinjector is actuated, the dispensing force being at least a portion of the spring force. The method includes: aging a pre-filled syringe at an accelerated rate to form a reference pre-filled syringe, the reference pre-filled syringe including a reference barrel and a reference stop located within the reference barrel; moving the reference stop of the reference pre-filled syringe along a reference travel path from at least a first reference position to at least a second reference position; measuring multiple forces applied to the reference stop and measuring multiple reference stop positions as the reference stop moves along the reference travel path within the reference barrel; generating a force curve, the force curve including when the reference... The system includes at least some forces and reference stop positions measured as the stop moves between the first reference position and the second reference position, wherein at least one of the measured forces is associated with at least one of the measured reference stop positions; and an injection spring is selected such that when the operable stop moves along the operable travel path between the first operable position and the second operable position, the feeding force applied to the operable stop at each position of the operable stop is greater than the force measured at the corresponding reference stop position among the measured reference stop positions.

[0019] Another aspect of this patent document relates to an autoinjector comprising: an aged pre-filled syringe, a stop located within the pre-filled syringe, and an injection spring. The injection spring has a spring force large enough to move the stop a defined distance.

[0020] Another aspect of this patent document is an autoinjector device comprising a pre-filled syringe including: a barrel extending along a longitudinal axis between proximal ends, the barrel having an inner diameter of approximately 8.65 mm; a needle disposed at a distal end of the barrel having an inner diameter of approximately 0.27 mm and a length of approximately 19.5 mm or less, wherein a volume of therapeutic fluid comprising furenate hexamethylenetetramine and having a viscosity of approximately 8.8 cSt at 22°C is held within the barrel; and a stop disposed within the barrel to hold the therapeutic fluid within the barrel, the barrel defining a travel path for the stop having an initial first position for the stop and a final second position for the stop, the first position being the initial position of the stop before delivery of the therapeutic fluid, and the second position being the final position of the stop after delivery of the full dose of the therapeutic fluid. The autoinjector holds a pre-filled syringe. The autoinjector includes an injection spring arranged to apply a feeding force to the stop by driving a piston rod toward the stop. When the autoinjector is actuated, the injection spring is configured to provide an initial feeding force of at least about 20 N to the stop when the stop is in the initial first position, and a final feeding force of at least 12 N to the stop when the stop is in the final second position, the feeding force being at least a portion of the spring force of the injection spring.

[0021] Another aspect of this patent document relates to an autoinjector comprising: an aged pre-filled syringe, a stop within the pre-filled syringe, and an injection spring. The injection spring has a spring force large enough to move the stop a predetermined distance within a predetermined time.

[0022] Another aspect of this patent document is an autoinjector device 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 stop located within the barrel, the barrel defining an inner surface, the barrel having an inner diameter of approximately 8.65 mm, the barrel defining a travel path for the stop having a first position and a second position for the stop, the needle having an inner diameter of approximately 0.27 mm and a length of approximately 19.5 mm or less, a therapeutic fluid being held within the barrel, the viscosity of the therapeutic fluid being approximately 10 cP or less at 22°C. Prior to aging of the pre-filled syringe, the inner surface of the barrel is lubricated with approximately 0.35 mg to approximately 1.1 mg of silicone oil having a viscosity in the range of approximately 500 cSt to approximately 1500 cSt at 25°C. The autoinjector holds the pre-filled syringe. The autoinjector includes a plunger and an injection spring. The plunger engages with the stop, and the injection spring biases the plunger toward the stop. When in the first position, the injection spring has a force determined according to the action in claim 1; a spring force in the range of about 20 N to about 30 N; a stored spring energy in the range of about 0.9 J to about 2 J; a spring constant in the range of about 0.2 N / mm to about 0.4 N / mm; a compression length in the range of about 50 mm to about 100 mm; a stored energy of about 25% more than the minimum spring energy required to move the stop from the first position to the second position without interruption before aging of the pre-filled syringe; and a force sufficient to move the stop from the first position to the second position along the travel path within about 5 seconds to about 25 seconds.

[0023] Another aspect of this patent document relates to an autoinjector comprising: an aged syringe pre-filled with furenal group monoclonal antibody, a stop located within the pre-filled syringe barrel, and an injection spring. The injection spring has a spring force large enough to move the stop a defined distance.

[0024] Another aspect of this patent document is a pre-filled syringe comprising a stop and a therapeutic fluid comprising furenate group monoclonal antibody; and an autoinjector having an injection spring and a piston rod arranged to move the stop 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 position and the second position corresponding to a dose of the therapeutic fluid. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of an exemplary syringe pre-filled with fluid, based on the principles of this disclosure;

[0026] Figure 2 This shows the sequence listing of furenate group monoclonal antibody, which can be loaded into... Figure 1 In the pre-filled syringe shown;

[0027] Figure 3A It is a graph showing the relationship between a set of measured forces and the displacement of the drive component acting on the stop of an unaged pre-filled syringe;

[0028] Figure 3B This is a graph showing the maximum force measured for multiple artificially aged pre-filled syringes;

[0029] Figure 3C It is a graph showing the relationship between a set of measured forces and the displacement of the drive component acting on the stop of a pre-filled syringe that has been artificially aged to 24 months.

[0030] Figure 3D This is a graph showing the injection times observed for pre-filled syringes with multiple natural and artificial aging processes;

[0031] Figure 4A This is a side view showing a partial cross-section of the fixing device used for testing pre-filled syringes;

[0032] Figure 4B This is a side view showing a partial cross-section of an alternative fixing device used for testing pre-filled syringes and autoinjector mechanisms;

[0033] Figure 4C This is a side sectional view of a fixing device used for testing the spring force in an autoinjector;

[0034] Figure 5 It is used for measurement and Figures 4A to 4C A side view of the instrument showing the performance of a pre-filled syringe and an autoinjector used together with the shown fixation device;

[0035] Figure 6 This is a flowchart illustrating the determination process by which the spring constant can be selected for the injection spring of an auto-injector;

[0036] Figure 7 This is a schematic diagram of an exemplary oven used for the artificial aging of one or more pre-filled syringes;

[0037] Figures 8 to 10 Several test procedures are shown, each of which is suitable for execution. Figure 6 The test operation of the determination process in the middle;

[0038] Figure 11 It shows the use Figure 5 The test equipment in the middle performs at least Figures 8 to 10 A flowchart illustrating the methods for movement and measurement operations during the testing process;

[0039] Figure 12 This is a flowchart illustrating the assembly process for assembling an autoinjector;

[0040] Figure 13 The multiple components of the auto-injector are shown, separated from each other for easier viewing;

[0041] Figure 14 yes Figure 13 The cross-section of the autoinjector, which is configured for pre-injection.

[0042] Figure 15 Showing the intermediate injection structure Figure 14 Automatic injectors in the middle;

[0043] Figure 16 Showing the end of the injection structure Figure 14 Automatic injectors in the middle;

[0044] Figure 17 Showing a 90° rotation Figure 16 Automatic injectors in the middle;

[0045] Figure 18 This is a flowchart illustrating the process of using an autoinjector with a pre-filled syringe and a selected injection spring; and

[0046] Figure 19 An auto-injector actuated by a user is shown. Detailed Implementation

[0047] Various embodiments will be described in detail with reference to the accompanying drawings, in which the same reference numerals denote the same parts and components in various views. Reference to the various embodiments does not limit the scope of the appended claims. Furthermore, any examples set forth in this specification are not intended to be limiting, but merely illustrate some of the many possible embodiments of the appended claims.

[0048] Unless otherwise stated or expressly stated in the context of their use, for the purposes of this patent document, the terms “or” and “and” shall mean “and / or”. Terms used in the singular form shall also include the plural form, where appropriate, and vice versa. Unless otherwise stated, or where the use of “one or more” is clearly inappropriate, “a” is used herein to mean “one or more”. Unless otherwise stated, “or” is used to mean “and / or”. The use of “comprising,” “including,” “containing,” “including,” “containing,” “having,” and “having” is interchangeable and not restrictive. The term “for example,” is also not restrictive. For example, the term “comprising” should mean “including but not limited to.”

[0049] Unless explicitly stated otherwise, all ranges provided herein include both the upper and lower limits of the range. Although multiple values ​​are disclosed herein when certain exemplary embodiments are disclosed, other embodiments within the scope of the appended claims may have values ​​other than the specific values ​​disclosed herein or values ​​outside the scope disclosed herein.

[0050] The terms "approximately" or "about" when used with numerical or structural elements provide tolerances typically found during testing and production due to variations and imprecise tolerances caused by factors such as materials and equipment. These terms also provide tolerance to variations in natural and environmental conditions caused by factors such as temperature and humidity changes.

[0051] As used herein, the term "furenate methaneclobe" is used interchangeably to refer to the anti-CGRP antagonist antibody produced by the expression vectors with accessions ATCC PTA-6867 and ATCC PTA-6866. The amino acid sequences of the heavy and light chain variable regions are shown in SEQ ID NO: 1 and 2, respectively. The CDR amino acid sequences of the G1 heavy chain variable region are shown in SEQ ID NO: 7-9 (indicating Kabat and Chothia CDRs). The CDR amino acid sequences of the G1 light chain variable region are shown in SEQ ID NO: 10-12. Exemplary polynucleotides encoding the G1 heavy and light chain variable regions are shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively. The full-length amino acid sequence of the G1 heavy chain is shown in SEQ ID NO: 3. The full-length amino acid sequence of the G1 light chain is shown in SEQ ID NO: 4. Exemplary polynucleotides encoding the full-length G1 heavy and light chains are shown in SEQ ID NO: 3 and SEQ ID NO: 4, respectively. The characterization of G1 is described in PCT Publication No. WO 2007 / 054809 and WHO Drug Information 30(2):280-1(2016), and the above references are incorporated herein by reference in their entirety.

[0052] Figure 1 An exemplary embodiment of a pre-filled syringe 150 is shown, adapted to hold a therapeutic fluid 160 for injection. The pre-filled syringe 150 includes a barrel 151, a needle 155, and a stop 157. The barrel 151 defines an interior 154 sized to accommodate a predetermined amount of fluid 160 (e.g., at least one dose of therapeutic fluid). The fluid 160 is held within the interior 154 of the barrel 151, located between the stop 157 and the needle 155. An example syringe that can be used with the pre-filled syringe 150 is the 2.25 mL EZ-Fill syringe supplied by Ompi (Piombino Dese, Italy). Other types of syringes, and syringes from other manufacturers, can also be used.

[0053] The barrel 151 extends between a distal end 152 and an open proximal end 153. The pre-filled syringe 150 also has a tip 161 at the distal end 152. The barrel 151 defines a proximal-facing shoulder 151a at the distal end 152 of the interior 154, which extends between the barrel 151 and the tip 161.

[0054] The syringe barrel 151 is configured to contain approximately 2.25 mL of fluid. However, other barrel sizes can be used. For example, the barrel 151 can be sized to contain approximately 1 mL of fluid. In other embodiments, the barrel 151 is sized to accommodate a volume of therapeutic fluid 160 in the range of approximately 1 mL to approximately 3 mL, approximately 1 mL to approximately 2.5 mL, or approximately 2 mL to approximately 2.5 mL. Other embodiments of the pre-filled syringe 150 can accommodate other volumes of therapeutic fluid 160.

[0055] Additionally, the syringe barrel 151 has an inner diameter of approximately 8.65 mm or other internal lateral dimensions. However, in alternative embodiments, the barrel 151 may have an inner diameter in the range of approximately 6 mm to approximately 10 mm, or approximately 8.5 mm to approximately 8.8 mm. Other possible embodiments may have an inner diameter other than those in these ranges.

[0056] In some examples, the syringe barrel 151 is formed of borosilicate glass. In some examples, the syringe barrel 151 is formed of transparent type I borosilicate glass. For example, the syringe barrel 151 may be composed of a mixture of SiO2, B2O3, Al2O3, Na2O, and CaO. In a more specific example, the syringe barrel 151 is formed of 75% SiO2, 10.5% B2O3, 5% Al2O3, 7% Na2O, and 1.5% CaO. Alternative embodiments may use other mixtures of these materials to form the glass of the syringe barrel 151. Other embodiments may use other types of glass or even materials other than glass to form the syringe barrel 151. For example, the syringe barrel 151 may be formed of plastic. In at least some embodiments, the syringe barrel 151 is a borosilicate glass barrel supplied by Schott Corporation of Elmsford, New York. Syringe barrels 151 from other manufacturers may be used.

[0057] The stop 157 is axially movable in the distal direction along the travel path P within the interior 154 of the syringe barrel 151. The stop 157 has a generally cylindrical body, or a cross-sectional shape similar to the cross-section of the inner surface 156 of the syringe barrel 151. The stop 157 has one or more flanges or ribs 158 extending radially from the body. Furthermore, the stop 157 has a compressed state and an uncompressed state; when the stop 157 is inserted into the syringe barrel 151, the stop 157 is in the compressed state.

[0058] The main body of the stop 157 has a first engagement surface 157a facing the outside of the pre-filled syringe 150 in the proximal direction and a second engagement surface 157b facing the fluid 160 contained within the syringe body 151. The first engagement surface 157a is flat, and during use, the end of the piston rod (e.g., Figures 14 to 17107) Abutting engagement surface 157a. In alternative embodiments, the first engagement surface 157a may include a threaded hole (not shown) or other connection structure (not shown) to allow the stop 157 to be screwed into or otherwise connected to the end of the piston rod in the autoinjector. To move the stop 157 distally within the syringe barrel 151, a feeding force may be applied to the first engagement surface 157a of the stop 157 to push the stop 157 along the travel path P. The body of the stop 157 has a length of approximately 7.7 mm. In alternative embodiments, the stop 157 may have a length ranging from approximately 7.3 mm to approximately 8.1 mm or from approximately 7 mm to approximately 9 mm. Alternative embodiments of the stop 157 may have a length longer than or shorter than these ranges. Additionally, when the stop 157 is in a compressed state, the outer diameter of the body of the stop 157 is approximately 8.95 mm. In some alternative embodiments, the outer diameter of the body is in 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 include a body having an outer diameter not within these ranges. Furthermore, this outer diameter is measured from the base of the flange 158 across the body to the base of the flange 158 located on the opposite side of the body.

[0059] Multiple annular flanges 158 engage the inner surface 156 of the syringe barrel 151. The flanges 158 form a generally airtight seal against the inner surface 156 of the syringe barrel 151 and retain the therapeutic fluid 160 within the interior 154. A stop 157 includes four flanges 158. In alternative embodiments, the stop 157 may have more or fewer flanges 158. For example, the stop 157 may have one flange, two flanges, three flanges, or more than four flanges. Alternative embodiments may also omit the flanges, allowing the entire outer surface 162 between the first engagement surface 157a and the second engagement surface 157b to engage with the inner surface 156 of the syringe barrel 151. In a compressed state, the stop 157 has a diameter or lateral dimension of approximately 8.95 mm. In alternative embodiments, the outer diameter of the stop 157 in a compressed state may range from approximately 6 mm to approximately 10 mm, or from approximately 6.5 mm to approximately 9.5 mm. In some examples, the outer diameter of the stop 157 is the outer diameter extending beyond the largest portion of the stop 157 (e.g., beyond at least one flange 158), and the outer diameter of the stop 157 is at least slightly larger than the inner diameter or internal lateral dimension of the syringe barrel 151 to ensure a seal between the stop 157 and the syringe barrel 151. When in an uncompressed state, at least some possible embodiments of the stop 157 have an outer diameter in the range of about 9.25 mm to about 9.45 mm.

[0060] The stop 157 is formed of rubber such as brominated butyl rubber, but materials other than rubber or brominated butyl rubber can be used to form the stop 157. An exemplary formulation that can be used to form brominated butyl rubber is formulation 4023 / 50 / GREY from West Pharmaceutical Services, Pennsylvania, USA. Other formulations are also possible. In other embodiments, other types of rubber materials or materials other than rubber are used to form the stop 157. Additionally, the stop 157 may have a fluoropolymer coating or a laminated outer surface 162 on its outer surface. In an example, the coating may cover the entire outer surface 162 of the stop 157. In alternative examples, the coating may cover some or all of the second engagement surface 157b, some or all of the flange 158, some or all of the outer surface 162 opposite the inner surface 156 of the syringe barrel 151, some or all of the first engagement surface 157a, or a combination of these surfaces. An example of a fluoropolymer material that can be used to coat the stop 157 is ethylene-tetrafluoroethylene copolymer (ETFE). The advantage of using a fluoropolymer to coat the stop 157 is that the fluoropolymer prevents the absorption or adsorption of the therapeutic fluid 160.

[0061] Materials other than fluoropolymers can be used to coat or laminate the stop 157. An example of an alternative material is silicone. Alternatively, the stop 157 can be coated or laminated with two or more materials. For example, the stop 157 can be coated with a fluoropolymer on the portion of its surface that comes into contact with the therapeutic fluid 160, and coated with silicone oil on the portion of its surface that does not come into contact with the therapeutic fluid 160. The coating on the stop 157 can serve as a lubricant, provide increased biocompatibility with the therapeutic fluid 160, prevent absorption or adsorption of the therapeutic fluid 160 or its components, and a combination of the foregoing effects. In other embodiments, the stop 157 does not have any type of coating or lamination construction.

[0062] In use, the second engagement surface 157b of the stop 157 pushes the fluid 160 toward the needle 155 to expel the fluid 160 from the pre-filled syringe 150. The stop 157 moves along the travel path P from a first position D1 to a second position D2. In an exemplary embodiment, the first position D1 is the position adjacent to the fluid 160 before any dose of therapeutic fluid 160 is delivered, and the second position D2 is the position of the second engagement surface 157b when a full dose of therapeutic fluid 160 has been delivered. When the stop 157 is in the second position D2, the stop 157 is directly adjacent to or even in contact with the shoulder 151a of the syringe barrel 151. In an alternative embodiment, when the stop 157 is in the first position D1, a gap or air bubble may be present between the therapeutic fluid 160 and the stop 157; or, when the stop 157 is in the second position D2, the stop 157 may be spaced apart from the shoulder 151a of the syringe barrel 151.

[0063] The travel path P can be approximately 29.6 mm, and a travel path P of approximately 29.6 mm is sometimes also referred to as a "30 mm" travel path. In alternative embodiments, the travel path P can range from approximately 25.7 mm to approximately 28.2 mm, from approximately 25 mm to approximately 29 mm, or from approximately 25 mm to approximately 40 mm. In some embodiments, the travel path P can be 29.6 mm. In other embodiments, the length of the travel path P can be a distance outside these ranges. The volume of the therapeutic fluid 160 located in the pre-filled syringe 150, held between the first position D1 and the second position D2 of the stop 157, is approximately 1.585 mL, which directly corresponds to the internal volume of the syringe barrel 151 located between the first position D1 and the second position D2. In alternative embodiments, the volume of the fluid 160 located between the first position D1 and the second position D2 of the stop 157 is in the range of approximately 1.51 mL to approximately 1.66 mL. In alternative embodiments, fluid 160 may have different volumes between the first position D1 and the second position D2 of the stop 157. The volume of fluid 160 may correspond to a full dose of therapeutic fluid 160, multiple doses of therapeutic fluid 160, or a partial dose of therapeutic fluid 160.

[0064] The force applied by the autoinjector 140 to the stop 157 is the feeding force. The magnitude of the feeding force required to push the stop 157 in the pre-filled syringe 150 can vary due to a variety of factors. Examples of these factors include the lubricant 159, the geometry and material of the syringe, the geometry and material of the stop, the therapeutic fluid 160 in the pre-filled syringe 150, the required injection time, and other resistances opposing the movement of the stop 157. Additionally, because the stop 157 is compressible, it can absorb some of the feeding force applied to it by the piston rod of the autoinjector 140. If this absorption becomes significant enough to affect the performance of the autoinjector 140, the selected injection spring must have a sufficiently large force to overcome this absorption.

[0065] Lubricant 159 can be disposed along the inner surface 156 of the cylinder 151 to facilitate the movement of the stop 157 within the cylinder 151. As the stop 157 moves along the travel path P, lubricant 159 is disposed between the inner surface 156 of the cylinder 151 and the outer contact surface 162 of the stop 157. Lubricant 159 reduces the frictional force between the outer contact surface 162 of the stop 157 and the inner surface 156 of the cylinder 151.

[0066] The lubricant used to form the lubricant layer 159 is silicone oil. An 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 the inner surface 156 of the syringe barrel 151. The lubricant 159 may cover the entire inner surface 156 of the syringe barrel 151, including the wall of the barrel 151 and the shoulder 151a. In other examples, the lubricant 159 is insufficient to cover the entire inner surface 156 of the pre-filled syringe 150, for example, only along the wall of the barrel 151, or only along the portions of the wall of the barrel 151 extending along the travel path P.

[0067] In at least some embodiments, the lubricant layer 159 has a substantially uniform thickness along the travel path P. Alternatively, the lubricant layer 159 has a substantially uniform thickness along the entire length of the syringe barrel 151. Additionally, in at least some embodiments, the lubricant layer 159 has a substantially uniform thickness around the inner circumference of the syringe barrel 151. In other embodiments, the thickness of the lubricant layer 159 varies along the length of the syringe barrel 151 or along the travel path P. For example, the thickness of the lubricant 159 may gradually thin towards the distal end 152 of the pre-filled syringe barrel 150 compared to the proximal end 153. As discussed in more detail herein, the thickness of the lubricant 159 may have other variations and may also be carried around the syringe barrel 151.

[0068] In a possible embodiment, the thickness of the lubricant layer 159 is approximately 0.5 μm. Other thicknesses are possible. For example, the lubricant layer 159 may have a thickness between approximately 0.1 μm and approximately 1 μm along the travel path P. In other examples, the lubricant layer 159 may have a thickness between approximately 0.1 μm and approximately 0.3 μm along the travel path P.

[0069] In at least some embodiments, the pre-filled syringe 150 includes about 0.7 mg of silicone oil to form lubricant 159. In other embodiments, the amount of silicone oil ranges from about 0.4 mg to about 1.1 mg. In still other embodiments, the amount of silicone oil ranges from about 0.35 mg to about 1.0 mg.

[0070] In an exemplary embodiment, the lubricant forming the lubricant layer 159 has a viscosity of about 1000 cSt at 25°C. In alternative embodiments, the lubricant has a viscosity in the range of about 500 cSt to about 1000 cSt at 25°C, about 100 cSt to about 1000 cSt at 25°C, or less than about 1250 cSt at 25°C. In other embodiments, the lubricant has a viscosity outside these ranges.

[0071] A needle 155 is disposed at the proximal end 152 of the barrel 151 and connected to the tip 161. The needle 155 is secured to the tip 161 using an adhesive. In an alternative embodiment, a hub or other structure is used to connect the needle 155 to the tip 161.

[0072] The needle 155 extends between a first end and a second end. The needle 155 is attached at or near the first end to the distal end 152 of the syringe barrel 151. The second end of the needle 155 may be sufficiently sharp or pointed to facilitate injection at the user's injection site 198 (see [link to injection site 198]). Figure 19 The skin is damaged at point 192. The needle 155 defines a channel 155a in fluid communication with the interior 154 of a pre-filled syringe 150. During operation, fluid 160 flows through the channel 155a to exit the syringe barrel 151. The channel 155a of the needle 155 has an inner diameter or lateral dimension, which is the distance from one point on the outer periphery to another point on the opposite side of the outer periphery. The inner diameter is an example of the lateral dimension when the cross-section of the channel 155a is circular. In this example, the channel 155a has a constant inner diameter or lateral dimension along the length of the needle 155. However, in other embodiments, the inner diameter or lateral dimension may vary along the length of the channel 155a.

[0073] Needle 155 is a stainless steel needle, for example, an AISI 304 grade stainless steel needle supplied by Chirana T. In Jecta in Slovakia. Additionally, needle 155 has the ISO name 4301-304-00-1 and the ISO designation X5CrNi18-9. Other materials can be used to form needle 155. Other embodiments may use needle 155 from other manufacturers, as well as needle 155 with alternative ISO certifications or no certification at all.

[0074] The needle 155 has a length of 19.5 mm. In alternative embodiments, the needle 155 may have a length ranging from about 15 mm to about 25 mm, from 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. Additionally, the needle channel 155a has an inner diameter or internal lateral dimension of 0.27 mm, from about 0.15 mm to about 0.3 mm, from about 0.25 mm to about 0.29 mm, from about 0.21 mm to about 0.3 mm, or less than 0.27 mm. In other embodiments, the needle 155 has an inner diameter of about 0.29 mm or less. Other embodiments have inner diameters narrower or wider than these ranges.

[0075] The therapeutic fluid 160 may contain a drug having a pharmacologically or otherwise active ingredient, a biological agent, a biosimilar, or any other ingredient for treating the body. Depending on the composition of the therapeutic fluid 160 and the prescribed treatment regimen, the therapeutic fluid 160 may have one of a variety of different volumes and viscosities. In at least some possible embodiments, for example, the therapeutic fluid 160 has a volume of approximately 1.585 mL. In other embodiments, the volume of the therapeutic fluid 160 ranges from approximately 1.51 mL to approximately 1.66 mL. In other embodiments, the volume of the therapeutic fluid 160 ranges from approximately 1 mL to approximately 2.25 mL. In other embodiments, a different volume of the therapeutic fluid 160 is loaded in a pre-filled syringe 150.

[0076] Therapeutic fluid 160 may be a liquid pharmaceutical composition comprising furenizumab, ethylenediaminetetraacetic acid disodium dihydrate (EDTA), L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, sucrose, and water for injection. An example of a specific formulation of therapeutic fluid 160 is approximately 225 mg furenizumab, approximately 0.204 mg EDTA, approximately 0.815 mg L-histidine, approximately 3.93 mg L-histidine hydrochloride monohydrate, approximately 0.3 mg polysorbate 80, approximately 99 mg sucrose, and water for injection, with a pH of approximately 5.5. In alternative embodiments, therapeutic fluid 160 may be prepared with a nominal concentration of 150 mg / mL 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, and 1.2 mg / mL LP580, with a pH of 5.5. In some embodiments, at least about 70% of the furenyl hematizumab in the liquid pharmaceutical composition is an IgG2-B disulfide isoform. In some embodiments of any of the compositions provided herein, about 72% of the antibody molecules in the composition are disulfide isoform B, wherein about 22% of the antibody molecules in the composition are IgG2-A / B, and wherein about 6% of the antibody molecules in the composition are IgG2-A disulfide isoform. Other embodiments of the therapeutic fluid 160 (including embodiments of a therapeutic fluid for furenyl hematizumab) may have other formulations including other components. Additionally, the therapeutic fluid 160 may contain pharmaceuticals, biologics, or biosimilars other than furenyl hematizumab.

[0077] The viscosity of the liquid pharmaceutical composition can be approximately 8.8 cSt at 22°C. Other viscosities are possible. For example, the therapeutic fluid 160 can have a viscosity of approximately 4 cSt to approximately 14 cSt at 22°C. In some examples, the therapeutic fluid 160 has a viscosity of approximately 8 cP to approximately 10 cP at 22°C. In some examples, the therapeutic fluid 160 has a viscosity of less than 10 cSt at 22°C.

[0078] Therapeutic fluid 160 can be used to treat or prevent a variety of different temporary or chronic diseases, conditions, or other illnesses. Therapeutic fluid 160 can be used to treat or prevent any disease or condition associated with CGRP (calcitonin gene-related peptide) activity or CGRP upregulation. In one possible embodiment, therapeutic fluid 160 includes a biological agent, such as that used to treat episodic or chronic migraines. For example, therapeutic fluid 160 may include an immunoglobulin G2 (IgG2) monoclonal antibody. In another example, therapeutic fluid 160 includes a humanized IgG2 monoclonal antibody. This antibody may also be expressed in CHO cells. In another example, therapeutic fluid 160 includes an anti-CGRP protein.

[0079] In a more specific example, refer to Figure 2 Therapeutic fluid 160 includes an antibody comprising: a heavy chain variable region V H Structural domain, the heavy chain variable region V H The amino acid sequence of the structural domain has at least 90%, optionally 95%, 97%, 99%, or 100% identity with SEQ ID NO: 1; and the light chain variable region V L Structural domain, the variable region V of the light chain L The amino acid sequence of the domain exhibits at least 90%, optionally 95%, 97%, 99%, or 100%, identity with SEQ ID NO: 2. In some examples, the therapeutic fluid 160 comprises an antibody generated from an expression vector having ATCC accession numbers PTA-6867 and PTA-6866. In another example, the therapeutic fluid 160 comprises furenette monoclonal antibody.

[0080] In other examples, the therapeutic fluid 160 includes an antibody comprising the following CDRs: CDR H1 as set forth in SEQ ID NO: 3; CDR H2 as set forth in SEQ ID NO: 4; CDR H3 as set forth in SEQ ID NO: 5; CDR L1 as set forth in SEQ ID NO: 6; CDR L2 as set forth in SEQ ID NO: 7; and CDRL3 as set forth in SEQ ID NO: 8.

[0081] The therapeutic effect of furenelizumab is durable and can be achieved through relatively infrequent injections. In one embodiment, for example, furenelizumab may be administered approximately once a month or less frequently. In another example, furenelizumab may be administered once every two months or less frequently. In another example, furenelizumab may be administered once every three months or less frequently. In yet another example, furenelizumab may be administered once every four months or less frequently. Furenelizumab is disclosed in more detail in U.S. Patent 8,007,794, published August 30, 2011, entitled “Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide and Methods Using the Same,” the entire contents of which are incorporated herein by reference.

[0082] Therapeutic Fluid 160 can also be used to treat or prevent other conditions such as cluster headaches, post-traumatic headaches, fibromyalgia, and interstitial cystitis / bladder pain syndrome (ICBPS).

[0083] In some embodiments, the shelf life of therapeutic fluid 160 is expected to be approximately 24 months when stored between 2°C and 8°C. In an example, the shelf life of therapeutic fluid 160 is expected to be approximately 2 years when stored at 5°C. In other embodiments, the shelf life of therapeutic fluid 160 is expected to be at least 12 months when stored between 2°C and 8°C. In some instances, the shelf life of therapeutic fluid 160 is expected to be at least 18 months when stored between 2°C and 8°C. In some examples, the shelf life of therapeutic fluid 160 is expected to be at least 30 months when stored between 2°C and 8°C. In some examples, the shelf life of therapeutic fluid 160 is expected to be at least 36 months when stored between 2°C and 8°C. In some examples, the shelf life of therapeutic fluid 160 is expected to be at least 6 months when stored between 2°C and 8°C. In some examples, when stored between 2°C and 8°C, the expected shelf life of therapeutic fluid 160 is at least 9 months.

[0084] Conventional injection time simulations for the prefilled syringe 150 have been found to have several drawbacks. For example, many aspects of the prefilled syringe 150 change over time, and given sufficient time, some of these changes can cause significant problems with the performance of the prefilled syringe 150 and the autoinjector 140 in which it is mounted. Current injection time simulations typically do not account for many of these variations, which may include changes in the prefilled syringe 150 that can increase resistance to the movement of the stop 157 within the syringe barrel 151.

[0085] Compared to the pre-filled syringe 150 before the change, the increased resistance may be significant enough to slow the speed of the syringe stop 157 within the syringe barrel 151. Sometimes, the increased resistance leading to slower injection speeds can cause patient discomfort. Slow injections may also cause impatient users 190 of the self-administered therapeutic fluid 160 to prematurely pull the needle 155 out of their bodies, resulting in incomplete delivery of the fluid 160. In another embodiment, the movement of the stop 157 may even stop, resulting in only a partial dose being delivered.

[0086] Friction and hydrodynamics are examples of resistance that impede the movement of the stop 157 and can affect the release force and sliding force, thus affecting injection time and dosage accuracy. The release force is the magnitude of the force required to move the stop 157, while the sliding force is the magnitude of the force required to maintain the movement of the stop 157. Friction can exist between the stop 157 and the syringe barrel 151. Other types of friction may also impede the movement of the stop 157. Hydrodynamics is the force required to push fluid 160 through the barrel 151 into the needle 155 and then through the needle 155.

[0087] Over time, several changes may occur, and the friction between the stop 157 and the syringe barrel 151 may increase. For example, the lubricant 159 in the syringe barrel 151 or on the stop 157 may deteriorate or become damaged, whether due to time or due to interaction with the components of the therapeutic fluid 160. Deterioration of the lubricant 159 may lead to an increase in its viscosity. This deterioration may also cause the lubricant layer 159 on the barrel wall 156 to thin over time. Furthermore, since the lubricant 159 is a fluid and flows along the barrel wall 156 over time, this may cause changes in the thickness of the lubricant 159, resulting in an area of ​​increased friction along the travel path P of the stop, as the lubricant 159 thins or disappears completely.

[0088] There are also other examples of changes that can increase hydrodynamic forces. For instance, some therapeutic fluid 160 may change over time. The therapeutic fluid 160 may aggregate or crystallize over time, forming larger clumps that may become lodged in the channel 155a of the hypodermic needle 155. The blockage caused by these clumps may increase the hydrodynamic force required for the fluid 160 to pass through the needle 155. This results in greater resistance that impedes the movement of the stop 157.

[0089] If developers of therapeutic fluids or pre-filled syringes want to use real-world data to design autoinjectors or for regulatory approval, they can choose to test pre-filled syringes that have aged to at least the required shelf life. The problem with using 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.

[0090] Waiting a long time until the natural shelf life of the therapeutic fluid expires before submitting a regulatory approval application for a drug delivered by an autoinjector can significantly delay the drug approval process and the time it takes for pharmaceutical companies to bring the therapeutic fluid to market. As a result, potentially life-changing or even life-saving drugs are delayed in reaching patients. Furthermore, this delay makes it more difficult for pharmaceutical companies to recoup the huge investments required to research and find successful drugs. To expedite the regulatory approval process, pharmaceutical companies can use simulations or accelerated aging to replicate the effects of time. For example, pharmaceutical companies can use mathematical models to approximate the performance of a pre-filled syringe after a certain period of time. In another example, pharmaceutical companies heat the pre-filled syringe at a predetermined temperature and for a predetermined period of time to simulate aging. The relationship between the length of time the pre-filled syringe is heated and the actual non-accelerated time can be defined according to the Arrhenius equation:

[0091] (3) K = Ae -EA / (RT)

[0092] Where "K" is the rate constant, "T" is the absolute temperature (in Kelvin), and "Ae" is the absolute temperature. -EA " is a constant for a given reaction, and "R" is a universal gas constant.

[0093] Artificial aging of the pre-filled syringe 150 or therapeutic fluid 160 has been found to potentially lead to complications during stability testing. For example, during stability testing using artificially aged pre-filled syringes 150 and autoinjectors (e.g., [missing information]), aging was observed in [missing information] Figures 13 to 17 The combination of the autoinjector 140 shown may lead to various operational failures, including failure to inject within the expected injection time. Artificial aging of the pre-filled syringe 150 has also been found to result in higher-than-expected resistance applied to the stop 157. For example, at the end of the injection stroke along the travel path P, the resistance applied to the stop 157 is higher than expected. Therefore, as the simulated aging time increases, the injection spring 109 used in standard autoinjector devices cannot consistently and successfully operate the autoinjector using the artificially aged pre-filled syringe 150.

[0094] In particular, it was found that heating the pre-filled syringe 150 amplifies certain changes that occur over time. For example, heating causes changes in the pre-filled syringe 150 to occur at a faster rate than changes in the pre-filled syringe 150 during the equivalent time period of natural aging. For example, compared to a pre-filled syringe 150 that ages naturally for 24 months at an unaccelerated rate, a pre-filled syringe 150 subjected to accelerated aging by heating over a simulated 24-month period will exhibit greater magnitude and even more types of changes, such as changes in the thickness of the lubricant layer 159, a greater reduction in the viscosity of the lubricant, greater variations in the thickness of the lubricant layer 159, more interaction between the therapeutic fluid 160 and the lubricant, and so on.

[0095] All these amplified changes that occur during artificial aging or accelerated aging unnaturally increase friction and hydrodynamics compared to naturally aged pre-filled syringes 150. When an artificially aged pre-filled syringe 150 with increased resistance to movement of the stop 157 is combined with an autoinjector (e.g., autoinjector 140, described in more detail herein), operational failures may occur, including failure to inject the therapeutic fluid 160 within the intended injection time or even injection interruption. However, pharmaceutical companies must demonstrate that the autoinjector 140 is capable of moving the stop 157 to deliver the full dose of the therapeutic fluid 160 without interruption for a reasonable period of time. To achieve an effective control path by allowing artificial aging and meeting stability requirements, adaptation of the autoinjector 140 is recommended herein. An injection spring 109 for the autoinjector 140 is used, which has sufficient spring force to meet acceptable delivery specifications for the artificially aged pre-filled syringe 150. However, it should be noted that pre-filled syringes used in commercially available autoinjectors undergo natural aging. In addition, it should be noted that unnecessarily increasing the spring force is usually not beneficial, as it may cause discomfort, bruising, or breakage of the pre-filled syringe.

[0096] exist Figures 3A to 3D The diagram shown illustrates an example of this problem with artificially aged pre-filled syringes 150. In order to produce Figures 3A to 3DThe data shown indicates that the pre-filled syringe 150 used is a 2.25 mL EZ-Fill syringe with an inner barrel diameter of approximately 8.65 mm. The EZ-Fill syringe was supplied by Ompi of Piombino Dese, Italy. The stop 157 is a FluroTec plunger from West Pharmaceutical Services of Exton, Pennsylvania, USA. The needle 155 is an AISI 304 grade stainless steel needle supplied by Chirana T. Injecta of Slovakia, with an inner diameter of approximately 0.27 mm and a length of approximately 19.5 mm. The syringe barrel 151 is lubricated with 0.7 mg of silicone oil, which has a viscosity of 1000 cSt at 25°C. The therapeutic fluid 160, contained in the pre-filled syringe 150, consists of approximately 1.585 mL of a Freeman formulation prepared 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, at a pH of 5.5. The therapeutic fluid 160 has a viscosity of 8.8 cSt at 22°C. Multiple unaged pre-filled syringes 150 were tested. The travel path P of the stop 157 in the syringe body 151 (corresponding to the extrusion volume of the therapeutic fluid 160) is approximately 30 mm.

[0097] Figure 3A This is a graph showing the relationship between the force acting on the syringe stop 157 of an unaged, pre-filled syringe 150 and the displacement of the stop 157 when the stop 157 moves at a constant speed. This graph can be used as a reference. Figure 4A and Figure 5 The test equipment shown was used to obtain the force. The y-axis displays the force applied to the stop 157 in Newtons (N). Because the stop 157 moves at a substantially constant speed, this force is approximately equal to the resistance that prevents the stop 157 from moving. The displacement is the displacement of the stop 157 from its first (initial) position at the start of injection to its second (final) position. Figure 3A The diagram shows that the maximum resistance during the movement of the stop 157 is about 8N until just before the displacement reaches about 30mm, which corresponds to the stop 157 reaching and impacting the shoulder 151a in the syringe barrel 151.

[0098] Figure 3BThis is a bar graph showing the maximum force applied to the stop 157 of a pre-filled syringe 150 undergoing accelerated aging. The pre-filled syringe 150 exposed to accelerated aging was heated at 40°C for a period equal to the simulated desired natural aging time. For each pre-filled syringe 150, the stop 157 was pressed to expel therapeutic fluid 160 at a constant rate, and the force applied to the stop 157 was measured. The force applied to the stop 157 is equal to or corresponds to the force that impedes the movement of the stop 157. This curve is based on a reference... Figure 4A and Figure 5 The test equipment shown obtained the force. The y-axis displays the maximum force, in Newtons, acting on the syringe stop 157 as it moves at a constant speed to deliver a dose of therapeutic fluid 160. The x-axis displays the simulated aging time of the pre-filled syringe 150 after accelerated aging. The first bar shows the maximum force before accelerated aging. The second bar shows the maximum force of the pre-filled syringe 150 after a simulated aging time of 3 months (T3). The third bar shows the maximum force of the pre-filled syringe 150 after a simulated aging time of 6 months (T6). The fourth bar shows the maximum force of the pre-filled syringe 150 after a simulated aging time of 9 months (T9). The fifth bar shows the maximum force of the pre-filled syringe 150 after a simulated aging time of 14 months (T14). The sixth bar shows the maximum force of the pre-filled syringe 150 after a simulated aging time of 24 months (T24).

[0099] As can be seen, the maximum force measured when moving the stop 157 gradually increased to approximately 14 N during the test, which is significantly greater than the 8 N measured with the unaged pre-filled syringe 150. Each bar in the graph represents a group of pre-filled syringes 150 tested at each simulated aging time, and shows the range of the measured maximum force for that group, from the highest measured maximum force to the lowest measured maximum force. Each bar also shows a box representing the middle two quartiles or the middle 50% of the measured force.

[0100] Figure 3C This is a graph plotting the relationship between the force applied to the syringe stop 157 of a pre-filled syringe 150 and the displacement of the stop 157 after a simulated aging period of 24 months. The pre-filled syringe 150 exposed to accelerated aging conditions was heated at 40°C, equivalent to simulating a desired period of natural aging. For each pre-filled syringe 150, the stop 157 was pressed to expel the therapeutic fluid 160 at a constant speed, and the force applied to the stop 157 was measured. The force applied to the stop 157 is equal to or corresponds to the force that opposes the movement of the stop 157. The y-axis shows the force applied to the stop 157 in Newtons (N). This graph is based on a reference... Figure 4A and Figure 5 The force was obtained using the described testing equipment. Because the stop 157 moves at a substantially constant speed, the force is approximately equal to the resistance acting to prevent the stop 157 from moving. The displacement is the displacement from the first position of the stop 157 at the start of injection to the final position of the stop 157. Figure 3C The chart shows that the maximum resistance is about 14N during the movement of the stop 157 until the displacement is exactly 30mm. The displacement of exactly 30mm corresponds to the stop 157 reaching and impacting the shoulder 151a of the syringe barrel 151.

[0101] As in Figure 3B and 3C As can be seen, for a pre-filled syringe 150 with a simulated or accelerated aging life of 24 months, the peak force or maximum force required to move the stop 157 by a distance of 30 mm is in the range of approximately 13 N to approximately 14 N. This peak force for the accelerated-aging pre-filled syringe 150 contrasts sharply with the mere 8 N to 9 N peak force required to move the stop 157 of a naturally aged pre-filled syringe 150. Figure 3A As shown in the figures, these graphs demonstrate that the force required to move the stop 157 of the artificially aged pre-filled syringe 150 used for testing is significantly increased compared to that of a naturally aged pre-filled syringe 150.

[0102] Figure 3D This is a bar chart showing the injection time or the time required to move the stop 157 from the first position D1 to the second position D2 for both naturally aged and accelerated-aged pre-filled syringes 150. The y-axis displays the injection time (in seconds), and the x-axis displays the lifespan of the pre-filled syringe 150. Data for naturally aged pre-filled syringes 150 is displayed as unshaded bars, while data for accelerated-aged pre-filled syringes 150 is displayed as shaded bars. To generate... Figure 3DThe data in the figure shows that an autoinjector 140 with a pre-filled syringe 150 is mounted in a fixture that keeps the autoinjector 140 upright with the needle 155 pointing downwards. A container is placed under the autoinjector 140 to collect the fluid 160 as it is dispensed. The autoinjector 140 is activated. A stopwatch is manually started while the autoinjector 140 is activated and stopped immediately when the therapeutic fluid 160 stops flowing from the needle 155. A digital stopwatch with an accuracy of one-hundredth of a second is used. Eight samples of naturally aged pre-filled syringes 150 were tested at 0 months, 1 month, 6 months, 9 months, 13 months, 19 months, and 24 months. Four samples of accelerated-aging pre-filled syringes 150 were tested at 12 months, 24 months, and 48 months. Each bar on the graph represents a group of pre-filled syringes 150 tested under the natural or simulated aging conditions indicated on the graph, and shows the range of injection times for each group from the longest to the shortest injection time. Each bar also displays a box representing the middle two quartiles or the middle 50% of the injection time.

[0103] At 12 months, the naturally aged pre-filled syringe 150 had an injection time ranging from approximately 18.6 s to approximately 20.8 s, while the accelerated-aged pre-filled syringe 150 had an injection time ranging from approximately 16.4 s to approximately 39.3 s. At 24 months, the naturally aged pre-filled syringe 150 had an injection time ranging from approximately 18 s to approximately 21 s, while the accelerated-aged pre-filled syringe 150 had an injection time ranging from approximately 19.4 s to approximately 46.3 s. It can be seen that the delivery time of the naturally aged pre-filled syringe 150 remains relatively stable throughout its lifespan. Until the aging time of the pre-filled syringe 150 is approximately 9 months, the delivery time of the artificially aged pre-filled syringe 150 is comparable to that of the naturally aged pre-filled syringe 150. After this aging time, the delivery time for the full dose begins to increase rapidly for the artificially aged pre-filled syringe 150. During 24 months of simulated aging, the delivery time may exceed 45 seconds, which exceeds the target delivery time.

[0104] The tests and results above indicate that artificial aging of the prefilled syringe 150 may lead to an increase in the force required to complete the injection. In some cases, artificial aging of the prefilled syringe 150 may result in an increase in the force required to complete the injection within the desired or predetermined time period (e.g., from about 5 seconds to about 19 seconds).

[0105] As a solution to these operational failures, the autoinjector 140 can be manufactured using an injection spring 109, which is strong enough to accommodate the higher compressive force on the stop 157 of the artificially aged pre-filled syringe 150. That is, the injection spring 109 may require a sufficiently high spring constant K and compressive force to overcome the increased resistance, particularly at the end of injection, generated by the artificially aged pre-filled syringe 150, where the stop 157 approaches the second position D2 and the resistance is significantly greater than at the start of injection. Figure 3B As shown. However, increasing the strength of the injection spring 109 may cause discomfort or even bruising to the patient. It may also damage the syringe 150. Therefore, it is not desirable to use an injection spring 109 with a force greater than required.

[0106] The following tests can be used to determine suitable spring parameters for the injection spring 109 of the autoinjector 140 used to inject therapeutic fluid 160 from an artificially aged pre-filled syringe 150. For example, the tests can determine a sufficiently strong feeding force that causes the syringe stop 157 to shift completely along the entire travel 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 stop 157, and a reference needle 155. The pre-filled syringe 150 actually used in the autoinjector 140 to deliver therapeutic fluid 160 to the patient is an operable pre-filled syringe 150 having an operable barrel 151, an operable stop 157, and an operable needle 155. The reference pre-filled syringe 150 is substantially similar to the operating pre-filled syringe 150. To ensure proper performance of the operable pre-filled syringe 150, the reference pre-filled syringe 150 and the operable pre-filled syringe 150 are approximately the same size and made of the same material or a material that provides the same performance characteristics. In alternative embodiments, the reference pre-filled syringe 150 and the operable pre-filled syringe 150 may have different parameters. For example, the reference pre-filled syringe 150 may have parameters that provide greater resistance to the movement of the stop 157, ensuring that the designed injection spring 109 will still provide adequate feeding force throughout the entire range of spring compression, so that the autoinjector 140 will inject the full dose of the therapeutic fluid 160 within a defined time.

[0107] Figure 4A and Figure 4B A fixing device is shown, which is used to test the injection of the prefilled syringe 150 to determine that the injection spring 109 has sufficient force to meet the performance standards for regulatory approval of the prefilled syringe 150 and the autoinjector 140. Figure 4AA fixing device 315 for holding the pre-filled syringe 150 is shown, and the test principle is also explained. The fixing device 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 to prevent bending or compression under the applied forces used in the test. The top plate 316c defines an aperture 316d large enough that the syringe barrel 151 will pass through it, but not so large that the syringe flange 158 at the proximal end 153 of the pre-filled syringe 150 will fit through the aperture 316d. In this way, the pre-filled syringe 150 is supported by the top plate 316c, and the needle 155 points downwards. A drive rod 314 aligns with a first engagement surface 157a of a syringe stop 157 and has an end that engages with the first engagement surface 157a of the syringe stop 157. The opposite second end of the drive rod 314 is coupled to a test device configured to move the drive rod 314 at a substantially constant speed. The drive rod 314 is also attached to a device such as a load sensor 315 (see, for example, Figure 5 A measuring device, such as a measuring device, is positioned to measure the force applied to the drive rod 314 as it moves.

[0108] The needle 155 is positioned in or above the 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 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, ensuring that the full dose is expelled during testing. Alternatively, the tip 161 of the needle 155 can be inserted into a clump to simulate injection into a patient. Inserting the tip 161 of the needle 155 into a clump allows the test device to include resistance to flow in a measurement of the total resistance to movement of the syringe stop 157. Examples of clumps that can simulate injection include cadaveric tissue, animal tissue (e.g., pig tissue), and synthetic tissue.

[0109] During testing, the drive lever 314 advances or pushes against the stop 157 to push it to a consistent speed and a defined distance. In at least some possible embodiments, the defined distance corresponds to the stop 157 moving from a first position D1 to a second position D2 to deliver the full dose of therapeutic fluid 160. The speed at which the drive lever 314 is pushed down is selected to simulate the desired timing of injection of a pre-filled syringe 150 within an autoinjector 140. In some embodiments, the drive lever 314 advances from the first position D1 to the second position D2 over a time range of approximately 5 seconds to approximately 12 seconds.

[0110] As the drive rod 314 advances against the syringe stop 157, the load sensor 315 measures the force applied to the drive rod 314, and the relative position of the drive rod 314 is also measured. The displacement of the drive rod 314 will be approximately equal to the displacement of the syringe stop 157. The force measurement result and the displacement of the drive rod 314 are recorded each time a force measurement is performed.

[0111] During the test, the force applied to the drive rod 314 to advance or push the syringe stop 157 is the force F. e The force that hinders the movement of the stop 157 due to friction, hydrodynamic forces, and any force that hinders the movement of the stop 157 constitutes the resistance F. r Because the stop 157 moves at a roughly constant speed during the test, the force will be approximately equal to the resistance. However, due to the changing resistance that hinders the movement of the stop 157, the force may change as the stop 157 moves forward.

[0112] Figure 4B An alternative fixing device 319 is shown for testing a pre-filled syringe 150 used in conjunction with an autoinjector 140. This embodiment is generally similar to... Figure 4A The device includes a fixing device and a syringe support frame 316 that supports the pre-filled syringe 150. Additionally, a clamp 317 is mounted on the top plate 316c of the syringe frame 316 and includes opposing first jaws 317a and second jaws 317b. Each of the first jaws 317a and second jaws 317b defines an opposing profile, such as a semi-circular cut, shaped to receive and securely hold a portion of the autoinjector 140 when the jaws 317a, 317b are closed. In operation, the injection spring 109 of the autoinjector 140 is removed and the autoinjector 140 is mounted in the clamp 317 and positioned such that the piston rod 107 from the autoinjector 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 autoinjector 140 engages with the first engagement surface 157a of the stop 157.

[0113] As described in more detail herein, the autoinjector 140 includes a sub-assembly that moves in response to the decompression of the injection spring 109. This sub-assembly will include a structure for advancing the piston rod 107. The sub-assembly may also include additional moving structures and a secondary spring mechanism that is also moved or driven by the injection spring 109 when it decompresses. In an exemplary embodiment, the entire autoinjector 140, excluding the injection spring 109, can be mounted in the clamp 317 if the drive rod 314 can be inserted into the autoinjector 140 to engage and move the piston rod 107 and other autoinjector components that operate in response to the movement of the piston rod 107. Alternatively, where no components of the autoinjector 140 not operated by the injection spring 109 are required, the sub-assembly can be removed from the autoinjector 140 or otherwise exposed and mounted in the clamp 317.

[0114] A drive rod 314 connected to the test equipment engages at a constant speed and moves the piston rod 107 a defined distance. In at least some embodiments, this defined distance corresponds to the distance the stop 157 moves from a first position D1 to a second position D2 to deliver the full dose of the therapeutic fluid 160. The force applied 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 total resistance, which includes friction in the pre-filled syringe 150, hydrodynamic forces, friction in the subassembly, any force required to compress the secondary spring in the subassembly, and other resistances that impede the movement of the stop 157 and the subassembly.

[0115] Figure 4C A fixture 320 is shown for testing an autoinjector 140 to determine the spring strength of the injection spring 109. The fixture 320 is used to simulate the operation of the autoinjector 140 and measure the feeding force of the piston rod 107 when the injection spring 109 is decompressed. As described in more detail herein, it is useful to verify the correct operation of the autoinjector 140 after selecting the injection spring 109.

[0116] The fixing device 320 includes a base 321 that can be fixed to a workbench 324 for stability during testing. The base 321 is secured to the workbench 324 using bolts 326a and 326b. A tube 327 extends upward from the base 321 and defines a cavity 323 sized to receive an autoinjector 140. The length of the cavity 323 is approximately the same as the length of the housing 104 for the autoinjector 140, but in various embodiments the cavity 323 may be longer or shorter. The cross-sectional shape and dimensions of the cavity 323 are configured to allow the autoinjector 140 to slide into the cavity 323, but to remain securely held in place without twisting or wobbling. A cap 322 is fixed to the top end of the tube 327 to close and secure the autoinjector 140 within the cavity 323. The cap 322 defines an aperture 325 axially aligned with the cavity 323 and sized to receive a drive rod 314.

[0117] As explained in more detail herein, the autoinjector 140 has a housing 102 and a cap sleeve 103 retracted into the housing 102 (see, for example, Figures 13 to 17 Slide the cap sleeve 103 into the housing 102 to prepare the autoinjector 140 for firing, allowing the internal piston rod 107 to move freely. To test the autoinjector 140 in the fixture 320, remove the pre-filled syringe 150 from the autoinjector 140, exposing the piston rod 107. Then, insert the autoinjector 140 into the cavity 323 and orient it such that the cap sleeve 103 points upward and extends from the top of the tube 327. Place the cap 322 over the end of the tube 327. Then, insert the drive rod 314 through the hole 325 and into the autoinjector 140 such that the end of the drive rod 314 engages with the end of the piston rod 107. The opposite second end of the drive rod 314 is coupled to a test device configured to move the drive rod 314 at a substantially constant speed. The drive rod 314 is also attached to, for example, a load sensor 315 (see, for example, Figure 5 A measuring device, such as a measuring device, is positioned to measure the force applied to the drive rod 314 as it moves.

[0118] Then, the cap 322 is pushed down until the cap sleeve 103 retracts into the housing 102, which prepares the autoinjector 140 to fire and releases the injection spring 109 for decompression, and moves the piston rod 107. The cap 322 is locked onto the end of the tube 327, thus holding the cap 322 in place. Any suitable mechanism can be used to hold the cap 322 in place. For example, the cap 322 can be screwed onto the end of the tube 327. Alternatively, the tube 327 may include a key projecting from the side of the retaining device 320, and the cap 322 may include an L-shaped groove that receives the key and holds the cap 322 in place. The methods and test apparatus disclosed herein can also be used to test alternative embodiments of spring-driven autoinjectors.

[0119] At the start of the test, the injection spring 109 is compressed and the piston rod 107 is in a position corresponding to the stop 157 in its first position. The drive rod 314 is then raised at a constant speed by a predetermined distance. In at least some possible embodiments, the predetermined distance corresponds to the stop 157 moving from the first position D1 to a second position D2 to deliver the full dose of the therapeutic fluid 160. For example, the drive rod 314 may be raised by approximately 30 mm. Furthermore, the speed at which the drive rod 314 is raised is selected to simulate the desired timing of injection of the pre-filled syringe 150 within the autoinjector 140. As the drive rod 314 rises and the piston rod 107 advances, the load sensor 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 will be approximately equal to the displacement of the syringe stop 157. The force measurement and the displacement of the drive rod 314 are recorded at each force measurement to form a delivery force curve. Such force measurement results can be used to verify that when the piston rod 107 advances between the position corresponding to the first position D1 of the stop 157 and the position corresponding to the second position D2 of the stop 157, the injection spring 109 applies the desired feeding force to the piston rod 107.

[0120] Although the retaining device 320 is shown as holding the autoinjector 140 with the telescopic sleeve 103 so that the autoinjector 140 is ready to fire and the piston rod 107 is free to move, the retaining device 320 can be adapted to hold and fire an autoinjector 140 with alternative mechanisms, such as buttons, knobs, levers, and slide buttons.

[0121] Figure 5 Show Figure 4AThe fixture 315 shown is located in the test apparatus for operating the drive rod 314 and measuring the performance of the pre-filled syringe 150. In this apparatus, the general-purpose test mechanism 310 has a crosshead 312 that can move up and down and can move at a constant and defined speed. The fixture 316 is mounted in the general-purpose test mechanism 310 and positioned such that the drive rod 314 is axially aligned with the crosshead 312. A load sensor 315 is located between the drive rod 314 and the crosshead 312 and measures the force acting on the drive rod 314 when the crosshead 312 moves downward toward or otherwise toward the stop 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 described herein, the linear movement of the crosshead 312 and the drive rod 314 will be approximately equal to the linear movement of the syringe stop 157. Although the fixture 316 shown in the illustration is used in conjunction with the general-purpose test equipment 310, it should be understood that... Figure 4B The fixing device 319 shown and Figure 4C The fixture 320 shown can be used in a substantially similar manner with the general-purpose test mechanism 310 and the drive rod 314.

[0122] The load sensor 315, gauge, and general-purpose testing mechanism 310 are operated by a programmable controller 311, such as a computer. This programmable controller controls the movement of the crosshead 312 and records the output from the load sensor 315. The gauge is an instrument used for measuring distance. Measurements from the load sensor 315 and the gauge are synchronized, such that the force recorded during force measurement is correlated with the displacement of the drive rod 314 / stop 157. The force and displacement measurements form a force curve, which correlates the measured force with the displacement of the drive rod 314 and stop 157. This data can be used to generate... Figures 3A to 3C The graphs and tables shown are similar to those shown. The computer controller 311 can also record the time interval for each measurement and the total time required for the stop 157 to fully move to deliver the full dose of the therapeutic fluid 160.

[0123] The load sensor 315 can be any type of instrument or sensor for measuring force, such as a strain gauge or piezoelectric cell. The gauge can be any type of instrument for measuring distance, including light-, laser-, and magnetic measuring instruments. Because the motor driving the crosshead 312 is a stepper motor, and the distance is determined by the number of steps during the rotation of the armature on the motor, the gauge can also be virtual. An example of a general-purpose test mechanism 310 that can be used is the MultiTest 2.5-I tension meter available from Mecmesin Ltd. in the UK. An example of the load sensor 315 can be 25N or 200N. An example of the control software can be Emperor v1.18. Other general-purpose mechanisms that can be used to measure force and displacement can be used. In operation and as described herein, the programmable controller 311 controls the general-purpose test mechanism 310 to move the crosshead 312 at a substantially constant speed. Alternative embodiments may apply acceleration or deceleration to the movement of the crosshead 312. In alternative testing equipment, the retaining device 320 for holding the pre-filled syringe 150 and the autoinjector 140 can be used with the general-purpose testing equipment 310.

[0124] The injection spring 109 for the autoinjector 140 is desired to have sufficient force to apply a feeding force to the stop 157 and to operate the relevant sub-components in the autoinjector 140 for a defined time period (e.g., approximately 19 seconds) even when the prefilled syringe 150 is subjected to accelerated aging, thus allowing the specifications of spring 109 to be used in regulatory approval processes. Particularly because the effects of natural aging are less significant than those of artificial aging, spring 109 is also desired to be not excessively strong and not deliver the therapeutic fluid 160 too quickly for a commercially viable combination of autoinjector 140 and prefilled syringe 150. The feeding force is a portion of the spring force applied to the stop 157 during operation of the autoinjector 140; the remainder of the spring force operates any sub-components also driven by the injection spring 109.

[0125] Figures 6 to 11Various methods are shown for determining that the injection spring 109 has sufficient stored energy to perform the following actions: (i) moving the syringe stop 157 a desired distance along the travel path P within a defined time; (ii) having sufficient stored energy to maintain a relatively stable speed of movement when the stop 157 approaches the second position D2, to prevent the stop 157 from stalling; and (iii) operating components in the autoinjector 140, other than the piston rod 107, also driven by the injection spring 109. Examples of components in the autoinjector 140 driven by the injection spring 109 include the piston rod 107, the retaining pin 106, and the retaining sleeve 108, wherein the spring 109 holds these components distally against the biasing force of the cap sleeve spring 110. In yet another alternative embodiment, the only structure that moves by the decompression of the injection spring 109 is the syringe stop 157 itself. A portion of the syringe force applied to the stop 157 by the piston rod 107 is the feeding force. The spring force is the operating force used to operate the remaining parts of the mechanism in the autoinjector 140, excluding the piston rod 107.

[0126] Figure 6 This is a flowchart illustrating a determination process 200, through which parameters can be selected for the injection spring 109 of the autoinjector 140. Examples of parameters for the injection spring 109 include spring constant, uncompressed spring length, and compressed spring length. The determination process 200 includes an aging operation 202, a testing operation 204, and a selection operation 206. The determination process 200 may optionally include a second selection operation 208.

[0127] In aging operation 202, one or more pre-filled syringes 150 (e.g., Figure 1 The pre-filled syringe 150 shown is aged for at least a simulated aging time equal to the expected shelf life of the therapeutic fluid 160 and the pre-filled syringe 150. Figure 7 As shown, in some embodiments, a heat source is used to artificially age the pre-filled syringe 150 or the therapeutic fluid 160. For example, one or more syringes 150 pre-filled with the therapeutic fluid 160 may be placed inside 182 of an oven 180. In some embodiments, humidity is not controlled during the artificial aging process. In other embodiments, humidity is controlled during the artificial aging process.

[0128] To accelerate the aging of 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 the simulated aging time. 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 may be heated at a temperature of about 5°C, about 25°C, or about 40°C. Each sample group 170 is held at the predetermined temperature for a different time period (e.g., several minutes, several days, several weeks, several months, several years). The temperature and duration of heating the pre-filled syringes 150 can be determined according to the Arrhenius equation (1). The number of pre-filled syringes 150 heated to accelerate aging depends on the number of samples tested against the selected injection spring 109. The more samples tested, the more data available for selecting the spring 109. In addition, multiple groups of pre-filled syringes 150 may be heated at different temperatures or tested for different durations. Heating different groups of pre-filled syringes 150 in this manner allows for the use of data simulating different shelf lives and different environments during the selection process of spring 109.

[0129] In test operation 204, one or more force tests may be performed on the aged pre-filled syringe 150 using any suitable test technique, including those described in more detail herein (see, for example, Figure 4A , Figure 4B and Figure 5 Typically, the one or more tests include measuring one or more forces F applied to the stop 157 of each pre-filled syringe 150 as each pre-filled syringe 150 moves from a first position D1 to a second position D2 and is dispensed with therapeutic fluid 160. e The force measurement results are correlated with the corresponding position (i.e. displacement) of the stop 157 along the travel path P.

[0130] In some embodiments, the force is measured to move only the stop 157 of the prefilled syringe 150 (see, for example, Figure 4A and Figure 5 In other examples, measurements are taken of other components driven by the injection spring that move the stop 157 via the piston rod and simultaneously operate the autoinjector (see, for example, Figure 4B and Figure 5 The force of action.

[0131] In operation 206, the measured forces are analyzed to determine the injection spring 109, which has sufficient energy to transmit an appropriate amount of force and suitable parameters for operation within an autoinjector. The spring force is determined according to Hooke's Law:

[0132] (4) F spring =K(l 0-X )

[0133] Among them, F spring "K" is the force of the spring, "K" is the spring constant of a specific injection spring, 10 is the uncompressed spring length, and x is the current spring length.

[0134] In the following text, the term "spring compression" or "spring compression in a defined state" is used to refer to the difference between the uncompressed length of the spring and the length of the spring in the defined state. In at least some embodiments, such as the autoinjector 140, a gap exists between the piston rod 107 and the stop 157 at the start of operation. At the start of operation, the injection spring 109 must be slightly decompressed so that the piston rod 107 rests against the stop 157. In these embodiments, the spring length at the start of operation (before the autoinjector 140 is actuated) is greater than the initial spring length l when the piston rod 107 abuts against the stop 157 and begins to push the stop 157 from its first position D1. i Short. In these embodiments, the feeding force can also be modeled as:

[0135] (5)F d =K(Ci-x) stopper ), where C i =l0-l i

[0136] Among them, C i It is the initial compressive force of the spring, l i It is the length of the spring when the piston rod engages the stop and the stop is in the initial position, and x is the length of the spring. stopper This is the displacement of the stop relative to its initial first position. Furthermore, the stored energy that can be used to dispense medication from the autoinjector can be modeled as:

[0137] (6) By using these equations, the spring constant and uncompressed spring length for the injection spring 109 can be selected to provide sufficient feeding force to the stop 157, thereby enabling the stop 157 to successfully move a displacement along the travel path P, a displacement at least long enough to deliver the full dose of the therapeutic fluid 160 within the desired time. It should be noted that the initial spring length depends on the geometry of the autoinjector 140, such as the spring length at the start of operation (i.e., the assembled spring length or the length to be fired) and the clearance between the piston rod 107 and the stop 157 in its initial position.

[0138] Because equations (4) and (5) are linear, therefore in Figure 3CThe spring force of the injection spring 109 can be represented by plotting a line showing the force decreasing with increasing displacement in the graph shown. In a possible embodiment, the appropriate spring 109 can be determined using the measured force. In this embodiment, the reference force F used to calculate the spring force is... ref The maximum force can be the maximum force measured when the drive rod 314 of the test device 310 moves the stop 157 from the first position D1 to the second position D2. For the accelerated aging pre-filled syringe 150 disclosed herein, the maximum force can be the sliding force measured when the stop 157 approaches the second position D2, such as... Figure 3C As shown. In other embodiments or cases, the maximum force may be a sliding force as the stop 157 moves along the middle portion of the travel path P. In other embodiments or cases, the maximum force may be a release force when the stop 157 begins to move from the first position D1.

[0139] Additional conditions that can be used to determine the spring parameters (e.g., spring constant, compressed length, uncompressed length) may include: the final spring force should be no less than 50% of the initial spring force, which is the spring force of the injection spring 109 when the piston rod 107 first engages the stop 157 at the first position D1. In other embodiments, the final spring force should be no less than 60%, 70%, 80%, or 90% of the initial spring force. These design specifications and parameters of the injection spring 109 may result in several selections of 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 mentioned 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 stop 157 is in the first position D1 and engaged by the piston rod 107. In one embodiment, when the stop 157 is in the first position D1 and engaged by the piston rod 107, the injection spring 109 has a spring force in the range of about 20 N to about 30 N. Additionally, in some embodiments, when the stop 157 is in the second position D2, the injection spring 109 may have a spring force in the range of about 14 N to about 20 N. Furthermore, in some embodiments, when the stop 157 is in the second position D2, the injection spring 109 may have a spring force in the range of about 15 N to about 18 N.

[0140] In some embodiments, a suitable spring 109 can be determined using multiple measured forces. For example, the initial force (release force) can be used together with the force at the end of the travel path P to determine the suitable spring 109. In another example, it can be based on the use of, as shown in Figure 4 to Figure 5The measured force curve obtained from the movement stop 157 of the device shown is used to calculate the reference energy for moving the stop 157 within the pre-filled syringe 150. The reference energy can be calculated for the stop 157 moving within one or more aged reference pre-filled syringes 150 or one or more unaged pre-filled syringes 150. In at least some embodiments, when the stop 157 is in the first position D1 and engaged by the piston rod 107, the selected spring 109 will have stored energy that is about 25% of or about 25% more than the reference stored energy. In other possible embodiments, the stored energy is about 20%, 30%, 40%, 50%, or 60% of the reference stored energy, or about 20%, 30%, 40%, 50%, or 60% more than the reference stored energy. Therefore, for some embodiments, a possible design parameter is that, when the stop 157 is in the first position D1 and engaged by the piston rod 107, the injection spring 109 has approximately 25% more stored energy than the energy actually required to move the stop 157 in the unaged pre-filled syringe 150 from the first position D1 to the second position D2 without interruption. In some embodiments, the stored energy in the injection spring 109 is in the range of approximately 0.9 J to approximately 2 J when the stop 157 is in the first position D1 and engaged by the piston rod 107.

[0141] Furthermore, it has been found that, in order to ensure proper movement of the stop 157, it is advantageous to have the highest possible feed force when the stop 157 reaches the second position D2. Having this higher feed force at the second position D2 reduces the risk of pauses at the end of dose delivery. Additionally, it has been found that it is advantageous to have the lowest possible initial feed force to avoid a high initial shock. As a result, some possible embodiments have an injection spring 109 having a longer initial spring compression length than injection springs 109 with a higher spring constant. In some embodiments, spring parameters can be selected to maximize the initial spring compression length of the injection spring 109 and minimize the spring constant. In other words, when multiple spring parameters will provide a suitable spring 109, the spring 109 with the lowest spring constant and the highest initial compression is preferred.

[0142] 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 an alternative embodiment, 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.

[0143] Once the spring parameters are determined, an injection spring 109 is selected that will cause the piston rod 107 of the auto-injector 140 to apply a feeding force greater than the measured maximum force to the stop 157 of the injector, such that the injection spring 109 will overcome all resistance to the movement of the stop 157 and have sufficient force to move the stop 157 to the second position D2 within a defined time.

[0144] Additionally, in some embodiments, the parameters for the injection spring 109 are selected based on the maximum force measured during testing with the pre-filled syringe 150 exposed to accelerated aging. In other examples, the parameters for the injection spring 109 are selected based on multiple forces measured during testing. For example, the spring constant, the uncompressed spring length, and the compressed spring length can be calculated based on or for multiple forces; these multiple forces can provide a more favorable spring force slope when the spring 109 is decompressed.

[0145] Additionally, the embodiments shown herein use a helical spring as the injection spring 109. The helical spring is a linear stiffness coefficient spring. Other embodiments may use other types of springs 109, such as conical springs, constant force springs, variable force springs, torsion springs, gas springs, or hydraulic springs. Hooke's law is not linear for springs such as gas springs and hydraulic springs. However, Hooke's law is approximately linear over the first portion of the displacement of a gas spring or hydraulic spring, and the spring force can still be approximated using equation (4) or similar linear relationships. In alternative embodiments, appropriate mathematical relationships and models other than Hooke's law may be used to determine the force of the spring (including linear and nonlinear springs).

[0146] Figures 8 to 10 Multiple test procedures 220, 230, and 240 are illustrated, each of which is suitable for performing test operation 204 of determination procedure 200. In some embodiments, methods such as those described herein are used. Figure 4A , Figure 4B and Figure 5 The described test equipment 310, or similar automated or semi-automated test equipment, is used to implement test processes 220, 230, and 240. References will be made herein. Figure 11 To describe in more detail the appropriate procedure for using test equipment 310.

[0147] Each test procedure 220, 230, 240 can be performed individually on the pre-filled syringe 150 or in combination with the autoinjector 140 or components thereof. In some examples, the test device 310 acts directly on the stop 157 of the pre-filled syringe 150. In other examples, the test device 310 acts on the drive member 314 (e.g., piston rod 107) of the autoinjector 140, which is operatively coupled to the syringe stop 157.

[0148] The pre-filled syringe 150 can be naturally aged or artificially aged. Each test procedure 220, 230, 240 can also be performed on an unaged pre-filled syringe 150. In some examples, test procedures 220, 230, 240 are performed on a pre-filled syringe 150 pre-filled with a therapeutic fluid 160. In other examples, test procedures 220, 230, 240 are performed on a syringe 150 pre-filled with other types of fluids (e.g., saline or water).

[0149] Figure 8 This is a flowchart illustrating a first test procedure 220 suitable for performing test operations 204 of determination procedure 200. The first test procedure 220 includes a movement operation 222, a measurement operation 224, and a determination operation 226.

[0150] In movement operation 222, the stop 157 of the prefilled syringe 150 moves distally along the travel path P within the syringe barrel 151 at a constant speed. For example, the stop 157 can move along the travel path P from a first position (e.g., proximal position, initial position) D1 to a second position (e.g., distal position, bottoming position) D2.

[0151] In some embodiments, during actual injection using the autoinjector 140, a constant speed is selected to match the displacement speed of the stop 157, which moves from a first position D1 to a second position D2, and the full dose of fluid 160 is held in the syringe barrel 151 between the first position D1 and the second position D2. For example, a constant speed can be selected to simulate a desired injection time in the range of about 5 seconds to about 19 seconds. Another embodiment can select a constant speed to simulate an injection time in the range of about 5 seconds to about 12 seconds. Another embodiment can select a constant speed to simulate an injection time in the range of about 6 seconds to about 20 seconds. Another embodiment can select a constant speed to simulate an injection time in the range of about 8 seconds to about 15 seconds. Another embodiment can select a constant speed to simulate an injection time in the range of about 15 seconds to about 25 seconds. In some examples, a constant speed can be selected to simulate an injection time in the range of about 17 seconds to about 22 seconds. In one example, a constant speed can be selected to simulate an injection time of about 12 seconds. In the examples, a constant speed can be selected to simulate an injection time of approximately 8 seconds. In the examples, a constant speed can be selected to simulate an injection time of approximately 18 seconds. In the examples, a constant speed can be selected to simulate an injection time of approximately 19 seconds. In the examples, a constant speed can be selected to simulate an injection time of approximately 20 seconds. In some examples, the constant speed is selected to be in the range of approximately 60 mm / min to approximately 360 mm / min. In other embodiments, the constant speed is selected to be between approximately 150 mm / min and approximately 200 mm / min. In some examples, the constant speed can be selected to be between approximately 80 mm / min and approximately 90 mm / min. In the examples, the constant speed is selected to be approximately 150 mm / min. In the examples, the constant speed is selected to be approximately 86 mm / min. In the examples, the constant speed is selected to be approximately 175 mm / min.

[0152] Measurement operation 224 measures one or more forces applied to the stop 157, causing the stop 157 to move distally at a constant speed along a travel path P. In some embodiments, the force used to initiate the movement of the stop 157 relative to the syringe barrel 151 (i.e., a release force) is measured. In other embodiments, the force used to maintain the movement of the stop 157 along the travel path P within the syringe barrel 151 (i.e., a sliding force) is measured. For example, the maximum force applied during the movement of the stop 157 along the travel path P (i.e., the maximum sliding force) can be measured. In some examples, the displacement of the stop 157 is measured simultaneously with the force measurement.

[0153] In determination operation 226, a reference force is determined for calculating a suitable spring 109. In some embodiments of selection operation 206, the reference force is used to select a spring constant, an uncompressed spring length, or a compressed spring length.

[0154] In some embodiments, the reference force is the maximum or peak force that the injection spring 109 needs to overcome to move the stop 157 along the travel path P between the first position D1 and the second position D2. Therefore, the reference force is not less than the measured force applied to the stop 157 to overcome any resistance opposite to the distal movement of the stop 157 along the travel path P. In some embodiments, the reference force is equal to the measured maximum force. In other embodiments, the reference force may be greater than the measured maximum force. In other embodiments, the reference force may be less than the measured maximum force. For example, the measured maximum force may be measured at a displacement outside the range of the first position D1 and the second position D2 of the stop 157.

[0155] In other embodiments, the reference force is also determined based on the resistance generated by the components of the autoinjector 140. For example, the reference force may also take into account one or more frictional forces generated by the movement between two or more components of the autoinjector 140 (e.g., Figures 13 to 17 The piston rod 107, support member 105, indicator sleeve 111, and retaining sleeve 108 are shown. In this example, the reference force may also include moving or operating one or more components of the autoinjector 140 (e.g., retaining pin 106, retaining sleeve 108) to overcome another spring 109 (e.g., Figures 13 to 17 The force required to bias the cap sleeve spring 110 in the autoinjector. The resistance generated by the autoinjector 140 can be measured, calculated or otherwise estimated separately.

[0156] Figure 9 This is a flowchart illustrating a second possible test procedure 230 suitable for performing test operations 204 of determination procedure 200. The second test procedure 230 includes a movement operation 232, a measurement operation 234, and a determination operation 236. The movement operation 232 of the second test procedure 230 is the same as or substantially the same as the movement operation 222 of the first test procedure 220.

[0157] Except for acquiring multiple force measurements along the travel path P, measurement operation 234 is substantially the same as measurement operation 224 of the first test procedure 220. Each force measurement is associated with a corresponding displacement of the stop 157 along the travel path P. In some embodiments, force measurements are performed twice along the travel path P (e.g., at a first position D1 and a second position D2). In other embodiments, force measurements are performed three or more times along the travel path P. In some examples, forces are measured at constant intervals along the travel path P. In some examples, forces are measured continuously along the travel path P.

[0158] In some embodiments, the displacement of the drive rod 314, corresponding to the displacement of the plunger 157, is also measured. The displacement can be measured simultaneously with each force measurement. In some embodiments, the displacement and force measurements can be correlated to form a force curve.

[0159] Except for determining two or more reference forces, determination operation 236 is the same as or substantially the same as determination operation 226 of the first test procedure 220. For example, one determined reference force may correspond to a release force, while another determined reference force may correspond to a measured maximum sliding force. In other embodiments, two or more determined reference forces may correspond to different measured sliding forces. In other embodiments, one determined reference force may correspond to a sliding force or a release force, while another determined reference force may correspond to the displacement of the piston rod 107 of the autoinjector 140 outside the displacement range of the stop 157. For example, the determined reference force may correspond to the force required to begin moving the piston rod 107 before it engages with the stop 157.

[0160] In some embodiments, at least one reference force is determined based on a measured force used to push the stop 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 measured forces or frictional forces related to the movement of the autoinjector 140 or the operation of its internal components. In yet another possible embodiment, at least one reference force is determined corresponding to a measured force used to operate the internal components of the autoinjector 140 and push the stop 157.

[0161] Figure 10 This is a flowchart illustrating a third test process 240 suitable for performing test operation 204 of determination process 200. The third test process 240 determines spring parameters such that the injection spring 109 with the determined spring parameters can successfully drive the stop 157 along the travel path P. The third test process 240 includes a movement operation 242, a measurement operation 244, a determination operation 246, a calculation operation 248, and a selection operation 250.

[0162] The movement operation 242 in the third test process 240 is the same as or substantially the same as the movement operation 222 in the first test process 220.

[0163] In some embodiments, measurement operation 244 is the same as or substantially the same as measurement operation 224 of the first test process 220. In other embodiments, measurement operation 244 is the same as or substantially the same as measurement operation 234 of the second test process 230.

[0164] In some embodiments, the determination operation 246 is the same as or substantially the same as the determination operation 226 of the first test process 220. In other embodiments, the determination operation 246 is the same as or substantially the same as the determination operation 236 of the second test process 230.

[0165] Calculation operation 248 determines the corresponding spring constant, uncompressed spring length, or compressed spring length for each of the one or more reference forces determined in determination operation 246. These spring parameters are calculated based on the determined reference force (which is equal to or otherwise corresponds to the measured force) and the corresponding displacement of the stop 157. The calculated spring parameters are "reference spring parameters".

[0166] In some embodiments, assuming the uncompressed spring length and the geometry of the autoinjector, calculation operation 248 determines the minimum spring constant required to generate a force sufficient to drive the stop 157 along the travel path P at the corresponding displacement position of the stop 157. In other embodiments, calculation operation 248 determines the minimum spring constant required to generate the required force and overcome the resistance generated by the autoinjector 140. In some embodiments, the uncompressed spring length is also determined by calculation operation 248. In some embodiments, calculation operation 248 determines both the minimum spring constant and the maximum uncompressed spring length. In other embodiments, calculation operation 248 may determine the maximum spring constant.

[0167] The second determination operation 250 compares the reference spring parameters determined in the calculation operation 248 to determine the optimal spring parameters. The optimal spring parameters can be selected based on various criteria, such as desired injection time, desired spring force, spring cost, and the geometry of the autoinjector 140.

[0168] Figure 11 Flowchart 260 shows the process for using Figure 4A , Figure 4B and Figure 5The test device 310 performs at least the movement operations 222, 232, 242 and measurement operations 224, 234, 244 of the test processes 220, 230, 240. In some embodiments, the test device 310 includes a tension meter or other mechanism for measuring the force applied to the syringe stop 157. As described above, the test device 310 may include a frame 316 for holding the pre-filled syringe 150.

[0169] In some examples, the operations in flowchart 260 and other flowcharts, as well as those discussed herein, are performed on a single pre-filled syringe 150. However, in other examples, the operations in flowchart 260 are performed on multiple pre-filled syringes 150. In some examples, the operations can be performed on pre-filled syringes 150 with various aging times (e.g., natural or artificial aging). In some examples, the operations can be performed on unaged pre-filled syringes 150. In some examples, the operations in flowchart 260 are implemented using the pre-filled syringe 150 itself. In other examples, the operations can be implemented using the pre-filled syringe 150 in conjunction with one or more components of the autoinjector 140.

[0170] In some examples, it can also be like Figure 4B As shown, multiple portions of the autoinjector 140 (e.g., multiple portions of the drive assembly) are mounted onto the test device 310. In such an example, the frame 316 may be adapted to hold components of the autoinjector 140. For example, an additional clamp 317 may be mounted onto the frame 316 to hold the drive member 314 (e.g., piston rod 107), the entire autoinjector 140, or a portion thereof. In such an example, the drive rod 314 of the test device 310 is operatively coupled to the stop 157 via the drive member 314 of the autoinjector 140.

[0171] At actuation operation 266, the test device 310 applies a force to the syringe stop 157. In some examples, actuation operation 266 includes advancing (e.g., lowering) the drive rod 314 of the test device 310 toward the stop 157. In some examples, the drive rod 314 moves automatically. In other examples, the drive rod 314 is moved manually. In some examples, the drive rod 314 moves at a constant speed.

[0172] In this example, the drive rod 314 is attached to a 25N load sensor. In other embodiments, the drive rod 314 is attached to a 200N load sensor. Other load sensors with sufficient sensitivity range to measure the forces that can be applied to the drive rod 314 are possible.

[0173] As the stop 157 moves along the travel path P, measurement operation 268 measures the force exerted by the drive rod 314 on the stop 157 once or multiple times. For example, the testing device 310 can automatically measure the force exerted by the drive rod 314. The testing device 310 also tracks the displacement of the drive rod 314, which is directly related to the displacement of the syringe stop 157. Therefore, measurement operation 268 results in one or more force readings, each associated with a determined displacement of the stop 157.

[0174] In one example, force measurement can be performed when the stop 157 initially moves relative to the syringe barrel 151. In another example, force measurement can be performed when the stop 157 approaches or reaches the end of the travel path P. In yet another example, force measurements can be performed multiple times along the travel path P at periodic intervals or distances. In yet another example, force measurements are performed continuously along the travel path P.

[0175] Figure 12 It is a flowchart illustrating the assembly of an autoinjector (such as...) Figures 13 to 17 The assembly process 280 of the autoinjector 140, which has features such as Figure 1 The assembly process 280 includes a pre-filled syringe 150 and a selected injection spring 109. The assembly process 280 includes at least an acquisition operation 284, a first installation operation 286, and a second installation operation 288. The assembly process 280 may optionally include a selection operation 282.

[0176] In selection operation 282, user 190 selects the spring constant of the injection spring 109 to be installed in autoinjector 140 to drive injection into pre-filled syringe 150. Even if the pre-filled syringe 150 has been artificially aged, a spring constant sufficient to drive injection into the pre-filled syringe 150 must be selected. User 190 can select the spring constant using any of the determination process 200 or testing processes 220, 230, 240 described herein.

[0177] At operation 284, user 190 selects an injection spring 109 with selected spring parameters. The selected injection spring 109 generates a biasing force sufficient to drive the syringe stop 157 within the syringe barrel 151 entirely along the travel path P. In some examples, the selected injection spring 109 generates a biasing force sufficient to drive the stop 157 entirely along the travel path P and perform other operations within the autoinjector 140. For example, the selected injection spring 109 is strong enough to bias the retaining pin 106 and retaining barrel 108 proximally, thereby loading the cap sleeve spring 110 and driving the stop 157 along the travel path P.

[0178] In some embodiments, the selected injection spring 109 is a compression spring. In some examples, the selected injection spring 109 is a linear spring. In other examples, the selected injection spring 109 is a variable stiffness coefficient spring. In other examples, the selected injection spring 109 is a constant force spring. In other embodiments, the selected injection spring 109 is a mechanical gas spring, a pneumatic spring, or a hydraulic spring.

[0179] In the first installation operation 286, the selected injection spring 109 is installed in the autoinjector 140. For example, the selected injection spring 109 may be disposed as part of the autoinjector 140 within the outer body 102 of the autoinjector 140. In some examples, the selected injection spring 109 is aligned with the piston rod 107 (see, for example, see...). Figure 14 In the example, the selected injection spring 109 is compressed between the piston rod 107 and the retaining pin 106 (see, for example, see...). Figure 14 ).

[0180] In the second installation operation 288, the pre-filled syringe 150 is installed in the autoinjector 140. For example, the pre-filled syringe 150 can be installed on the syringe holder 101 in the outer body 102.

[0181] Figures 13 to 17 Indicates suitability for injection Figure 1 An exemplary autoinjector 140 with a pre-filled syringe 150. Figure 13 The components of the autoinjector 140 are shown, disassembled for easy viewing. Figure 14 yes Figure 13 The cross-section of the autoinjector 140 is shown, and the autoinjector 140 is configured for pre-injection. Figure 15 Showing the intermediate injection structure Figure 14 The automatic injector 140 in the middle. Figure 16 Showing the structure at the end of injection Figure 14 The automatic injector 140 in the middle. Figure 17 Showing a 90° rotation Figure 16 The automatic injector 140 is described herein. Although exemplary embodiments of the automatic injector 140 are disclosed and illustrated herein, any suitable spring-driven automatic injector may be used with the devices and methods disclosed herein.

[0182] The autoinjector 140 has a distal end 141 and a proximal end 142 (see...) Figure 14 The autoinjector 140 is actuated by pushing the distal end 141 against the body of the patient 180 at the injection site 198. The autoinjector 140 is held at the injection site 198 until a dose of therapeutic fluid 160 has been expelled from the pre-filled syringe 150.

[0183] The autoinjector 140 includes a housing 102 and an end cap 112 mounted at a proximal end 142 of the housing 102. The autoinjector 140 also includes a syringe holder 101 disposed within the housing 102. The syringe holder 101 and the end cap 112 are fixed relative to the housing 102. The syringe holder 101 is configured to hold a pre-filled syringe, for example... Figure 1 The pre-filled syringe 150.

[0184] The cover sleeve 103 is mounted on the distal end 141 of the outer casing 102. The cover sleeve 103 is in the extended position relative to the outer casing 102. Figure 14 ) and retraction position ( Figure 15 The cap sleeve 103 can slide telescopically between the two positions. When in the extended position, the cap sleeve 103 surrounds the syringe needle 155 of the pre-filled syringe 150. Moving the cap sleeve 103 to the retracted position exposes the syringe needle 155.

[0185] A cover sleeve spring 110 extends between a first end 110a and a second end 110b. When the cover sleeve 103 extends, the cover sleeve spring 110 extends to a first length between the first end 110a and the second end 110b. When the cover sleeve 103 retracts, the cover sleeve spring 110 is compressed to a second length between the first end 110a and the second end 110b. The second length is shorter than the first length. The cover sleeve spring 110 biases the cover sleeve 103 to the extended position. The cover sleeve 103 is able to move to the retracted position against the biasing force of the spring 110, thereby compressing the spring 110. In the example shown, the spring 110 is a helical spring. However, in other examples, the spring 110 may be a gas-driven spring, a pneumatic spring, a hydraulic spring, or any other type of spring.

[0186] The needle cap remover 104 is initially disposed on the cap sleeve 103 and engages with the housing 102. When the needle cap remover 104 engages the cap sleeve 103 and the housing 102, the needle cap remover 104 prevents the cap sleeve 103 from moving to the retracted position. The needle cap remover 104 clamps a rigid needle guard initially disposed around the needle 155 of the prefilled syringe 150. When removed from the autoinjector 140, the needle cap remover 104 actuates the rigid needle guard, thereby removing the rigid needle guard from the syringe needle 155.

[0187] A support member 105 is disposed within the housing 102 near the syringe holder 101. The support member 105 is axially and rotatably fixed to the end cap 112. The distal end of the support member 105 abuts against the proximal end of the syringe holder 101.

[0188] The drive assembly is located within the housing 102 near the syringe holder 101. This drive assembly includes an injection spring 109 and a sub-assembly biased by the injection spring 109. In the example shown, the injection spring 109 is a helical spring with a variable force. However, in other examples, the injection spring 109 may be a conical spring, a torsion spring, a gas-driven 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.

[0189] The actuator or subassembly includes at least a piston rod 107 aligned with a stop 157 of the prefilled syringe 150. The piston rod 107 is axially movable within the outer body 102 along a travel distance between a firing position and a bottoming position. In the firing position, the piston rod 107 is spaced proximally from the prefilled syringe stop 157. In the bottoming position, the piston rod 107 presses the stop 157 against a proximal-facing shoulder 151a within the interior 154 of the prefilled syringe 150.

[0190] Because the piston rod 107 is separated from the stop 157 when in the ready-to-fire position, the injection spring 109 will not immediately apply a feeding force to the stop 157 upon release and expansion. The injection spring 109 will slightly decompress, advancing the piston rod 107 a short distance until it engages the stop 157. Once the piston rod 107 engages the stop 157, the injection spring 109 will continue to decompress, but resistance from the prefilled syringe 150 (e.g., resistance and hydrodynamics) will act to impede the movement of the stop 157, and thus impede the decompression of the injection spring 109.

[0191] The injection spring 109 extends between a first end 109a and a second end 109b. When the piston rod 107 is positioned in the firing position (see...), the injection spring 109 extends between a first end 109a and a second end 109b. Figure 14 The injection spring 109 is compressed to a first firing length between the first end 109a and the second end 109b. When the piston rod 107 is in the bottoming position (see...), Figure 16 The injection spring 109 extends to a second length between the first end 109a and the second end 109b. The second length is longer than the first length.

[0192] The injection spring 109 applies a force to distally bias the piston rod 107 toward the bottom-out position. In the example, 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 may rest against the inner shoulder of the piston rod 107 to distally bias the piston rod 107. The first length may be approximately 72 mm, and the second length may be approximately 106 mm. The injection spring 109 may have an uncompressed length of approximately 157 mm. The constant of the injection spring 109 may be approximately 0.30 N / mm.

[0193] In some examples, the subassembly also includes a retaining pin 106. An injection spring 109 biases proximally toward the end cap 112 against the retaining pin 106. For example, a second end 109b of the injection spring 109 may rest against an inner shoulder of the retaining pin 106. In some examples, the injection spring 109 is sandwiched between the piston rod 107 and the retaining pin 106. In this example, the injection spring 109 biases proximally against the retaining pin 106 while simultaneously biasing distally against the piston rod 107.

[0194] The retaining pin 106 has a locking configuration and a releasing configuration. In the locked 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, overcoming the bias of the injection spring 109. In some examples, the retaining pin 106 holds the piston rod 107 in a ready-to-fire position, overcoming the bias of the injection spring 109. In the releasing configuration, the retaining pin 106 releases the piston rod 107 to generate relative movement between the piston rod 107 and the retaining pin 106.

[0195] Specifically, the retaining pin 106 of the drive assembly includes an arm 106a extending from a fixed end 106d to a free end 106c. The fixed end 106d is attached to a base 106e. The free end 106c defines a stop member 106b that moves radially when the arm 106a bends. In some examples, the base 106e is sized to extend into the piston rod 107. In some examples, the base 106e is sized to extend through at least a portion of the injection spring 109, such that the injection spring 109 coils around the base 106e.

[0196] The piston rod 107 defines a recess 107a in which a stop member 106b of the retaining pin 106 can be disposed. Therefore, when the arm 106a is bent radially inward, the retaining pin 106 is locked, such that the stop member 106b engages with the recess 107a to hold the piston rod 107 in a firing position. When the arm 106a is bent radially outward to move the stop member 106b away from the recess 107a, the retaining pin 106 changes to a release configuration.

[0197] Retaining sleeve 108 surrounds a portion of retaining pin 106. Retaining sleeve 108 is axially movable between a distal position and a proximal position. When in the distal position, retaining sleeve 108 holds retaining pin 106 in a locking configuration (see [link]). Figure 14 Specifically, the retaining sleeve 108 is radially aligned with the arm 106a and has a sufficiently small internal lateral dimension to inhibit outward radial bending of the arm 106a. Therefore, the retaining sleeve 108 prevents the stop member 106b of the retaining pin 106 from moving outward radially from the notch 107a of the piston rod 107. When in the proximal position, the retaining sleeve 108 is axially offset from the stop member 106b, thereby allowing the retaining pin 106 to transition to a release configuration.

[0198] Prior to injection, the retaining sleeve 108 is biased to a distal position by a cap sleeve spring 110 extending to a second length. In some examples, the cap sleeve spring 110 biases the cap sleeve 103 via the retaining sleeve 108. For example, a first end 110a of the cap sleeve spring 110 abuts the retaining sleeve 108, which abuts the proximal end of the cap sleeve 103. Movement of the cap sleeve 103 to a retracted position pushes the retaining sleeve 108 to the proximal position and compresses the cap sleeve spring 110 to the second length.

[0199] In some embodiments, the retaining sleeve 108 has a telescopic configuration. For example, the retaining sleeve 108 may include an outer body 108a and an inner body 108b (see [link to documentation]). Figure 16 The inner body 108b is disposed around the support member 105. The inner body 108b is rotatably fixed 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. The first end 110a of the cover sleeve spring 103 abuts against the outer body 108a to bias distally to retain the sleeve 108.

[0200] The outer body 108a and the inner body 108b are rotatably fixed together. The outer body 108a and the inner body 108b engage with each other to move axially together as a single unit from a distal position to a proximal position. For example, the inner body 108b has helical teeth, and the outer body 108a is sized to accommodate a slot containing these helical teeth. The helical teeth extend through the slot to be driven by the outer body 108a in the proximal direction. When the outer body 108a moves to the distal end of the inner body 108b, the helical teeth disengage from the slot in a cam-like manner.

[0201] The indicator sleeve 111 is disposed within the housing 102, close to the syringe holder 101. As will be described in more detail herein, the interaction between the indicator sleeve 111 and other components within the housing 102 produces noise (e.g., a clicking sound), which audibly indicates the stage of injection (e.g., the start and end of injection).

[0202] The indicator sleeve 111 is axially movable relative to the housing 102 between a proximal and distal position. For example, the indicator sleeve 111 has a wing 111b that slides in a slot 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 this example, a second end 110b of the cover sleeve spring 110 abuts a portion of the indicator sleeve 111. Therefore, the cover sleeve spring 110 is clamped between the retaining sleeve 108 and the indicator sleeve 111. In one example, the cover sleeve spring 110 is clamped between the outer body 108a of the retaining sleeve 108 and the wing 111b of the indicator sleeve 111.

[0203] The indicator sleeve 111 restricts 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 a stop member 106b of the retaining pin 106 straddles during axial movement of the retaining pin 106 between respective distal and proximal positions. The engagement between the stop member 106b and the groove restricts distal movement of the retaining pin 106 relative to the indicator sleeve 111, which in turn restricts distal movement of the retaining pin 106 relative to the support member 105, which is axially fixed relative to the outer body 102.

[0204] The indicator sleeve 111 selectively engages the piston rod 107. For example, the indicator sleeve 111 may have one or more arms 111c, each arm having a pawl 111d at its free end. The arms 111c are bent to allow the pawl 111d to move radially relative to the piston rod 107. The pawl 111d is sized to engage in a corresponding slot 107c defined in the piston rod 107.

[0205] Figure 14 An autoinjector 140 in a pre-injection configuration is shown. The needle cap remover 104 and rigid needle guard have been removed. The syringe stop 157 is positioned at a first position D1 along a travel path P within the pre-filled syringe 150. The piston rod 107 is held proximally away from the syringe stop 157 by a retaining pin 106.

[0206] The retaining pin 106 and piston rod 107 are positioned relative to each other such that the stop member 106b of the retaining pin 106 is radially aligned with the recess 107a of the piston rod 107. A retaining sleeve 108 is disposed at a distal position, wherein 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 at this distal position. Therefore, the retaining sleeve 108 presses the stop member 106b into the recess 107a and prevents the stop member 106b from radially moving out of the recess 107a.

[0207] The indicator sleeve 111 is also disposed at the distal position. The pawl 111d of the indicator sleeve 111 is disposed within the 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 pawl 111d. The internal lateral dimension of the inner body 108b of the retaining sleeve 108 is small enough to retain the pawl 111d within the slot 107c when radially aligned with it.

[0208] like Figure 15 As shown, injection begins with the proximal movement of the cap sleeve 103 relative to the housing 102 to the retracted position. The proximal end of the cap sleeve 103 abuts against the retaining sleeve 108 (e.g., the outer body 108a of the retaining sleeve 108) and pushes 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. Therefore, the biasing force of the injection spring 109 acting on the piston rod 107 is sufficient to cause the stop member 106b to disengage from the recess 107a in the piston rod 107 in a cam-like manner.

[0209] Therefore, under the bias of the injection spring 109, the piston rod 107 can move freely distally toward the stop 157 of the pre-filled syringe 150. Upon distal movement, the piston rod 107 engages the stop 157 of the pre-filled syringe 150 and pushes the stop 157 distally along the travel path P within the syringe barrel 151. The distal movement of the stop 157 forces fluid 160 through the needle 155 at the distal end 152 of the pre-filled syringe 150.

[0210] Releasing the stop member 106b from the notch 107a of the piston rod 107 also releases the retaining pin 106 to allow movement relative to the piston rod 107. In some embodiments, the injection spring 109 biases the retaining pin 106 proximally toward the end cap 112.

[0211] The retaining member 106b of the retaining pin 106 engages the proximal end of the inner body 108b of the retaining sleeve 108. During this proximal movement, the retaining pin 106 drives the inner body 108b of the retaining sleeve 108 until the inner body 108b abuts against the support member 105. The impact between the inner body 108b of the retaining sleeve 108 and the support member 105 generates noise (e.g., a first click), which provides an audible indication that injection has begun.

[0212] The stop member 106b prevents the inner body 108b of the retaining sleeve 108 from moving back to the distal position (see [link]). Figure 16 The stop member 106b does not engage with the outer body 108a of the retaining sleeve 108. Therefore, the outer body 108a can move distally on the stop member 106b (see...). Figure 16 ).

[0213] As the piston rod 107 begins to move distally, it actuates the indicator sleeve 111 through the engagement between the pawl 111d and the slot 107c. Thus, the piston rod 107 overcomes the bias of the cover sleeve spring 110 to move the indicator sleeve 111 to the distal position. The engagement between the wing 111b of the indicator sleeve 111 and the support member 105 prevents further distal movement of the indicator sleeve 111.

[0214] When the indicator sleeve 111 is in the distal position, the pawl 111d disengages from the retaining sleeve 108 (see [reference]). Figure 17 The retaining sleeve 108 is positioned proximally, axially offset. Therefore, the pawl 111d freely disengages from the slot 107c of the piston rod 107 in a cam-like manner, allowing the piston rod 107 to continue moving distally via the injection spring 109. When moving radially outward, the pawl 111d engages with the distal end of the piston rod 107 (e.g., the inner body 108a), preventing proximal movement of the indicator sleeve 111. The body of the piston rod 107 prevents radial inward deflection of the arm 111c and the pawl 111d during injection.

[0215] like Figure 16 As shown, the piston rod 107 moves the stop 157 within the syringe barrel 151 until the stop 157 (e.g., at the proximal shoulder 151a) touches the bottom within the syringe barrel 151. When the stop 157 is in the bottomed-out position, the injection spring 109 continues to press the piston rod 107 against the stop 157.

[0216] After injection, the autoinjector 140 is removed from the injection site 198. The cap sleeve 103 is biased distally on the needle tip 155. Specifically, the cap sleeve spring 110 biases distally to retain the outer body 108a of the sleeve 108. The stop member 106b of the retaining pin 106 prevents the inner body 108b of the retaining sleeve 108 from moving distally. Therefore, the outer body 108a moves distally relative to the inner body 108b until the inner body 108b and the outer body 108a are axially locked relative to each other. For example, a pawl on the inner body 108b can engage in a notch defined by the outer body 108a.

[0217] The distal movement of the outer body 108a of the retaining sleeve 108 pushes the cap sleeve 103 to the extended position. The outer body 108a is locked by the inner body 108b to prevent it from moving proximally. The outer body 108a abuts the cap sleeve 103 to prevent the cap sleeve 103 from moving proximally back to the retracted position. Thus, the cap sleeve 103 is locked in the extended position covering the syringe needle 155.

[0218] like Figure 17 As shown, when the piston rod 107 reaches the bottom position, a groove 107d defined at the proximal end of the piston rod 107 aligns with the pawl 111d of the indicator sleeve 111. The groove 107d allows the pawl 111d to disengage radially inward in a cam-like manner, thereby disengaging from the retaining sleeve 108. Releasing the pawl 111d from the retaining sleeve 108 releases the indicator sleeve 111, allowing it to move back to the proximal position under the bias of the cap sleeve spring 110. The cap sleeve spring 110 presses the indicator sleeve 111 proximally against the end cap 112, which produces another noise (e.g., a second click) that provides an audible indication that the injection has ended.

[0219] Examples of autoinjectors suitable for the devices, methods, and uses disclosed herein include those available from Yypsomed AG of Burgdof, Switzerland. Brand of autoinjectors. Further details regarding exemplary autoinjectors suitable for actuating pre-filled syringes can be found in U.S. Publication No. 2016 / 0008541, the entire disclosure of which is incorporated herein by reference. The methods, apparatus, and uses disclosed herein can be used with any type of autoinjector for injecting therapeutic fluids from pre-filled syringes.

[0220] The autoinjectors and pre-filled syringes disclosed herein (including those pre-filled with the therapeutic fluids disclosed herein) are intended for use as medicines for the treatment or prevention of migraines and other diseases, conditions, chronic illnesses, disabilities, and other therapeutic purposes. The pre-filled syringes and autoinjectors may be sold as a single unit having a pre-filled syringe already inserted into the autoinjector. Alternatively, the pre-filled syringes and autoinjectors may be sold as kits, wherein the pre-filled syringes and autoinjectors may be sold separately but in the same package, or together but separately packaged, with the pre-filled syringes in one package or box and the autoinjectors in a different package or box.

[0221] Figure 18 This is a flowchart illustrating a usage process 290 for using an autoinjector 140 with a pre-filled syringe 150 and a selected injection spring 109. The disclosed methods and apparatus can be used as needed, periodically, or based on a continuous schedule. For example, the disclosed methods and apparatus can be used on a schedule of once a day, once a week, once a month, or no more than once a month, once every two months, once every three months, or once every four months. Figure 19 An autoinjector 140 actuated by user 190 is shown. The use process 290 includes at least an alignment operation 294, a pressing operation 296, and a holding operation 298. The use process 290 may optionally include an acquisition operation 292.

[0222] At acquisition operation 292, user 190 acquires an autoinjector 140 containing a pre-filled syringe 150. The autoinjector 140 includes an injection spring 109 having a spring constant sufficient to drive the pre-filled syringe 150 for injection even if it has aged. In addition to the bias stop 157, the injection spring 109 is also strong enough to perform other operations within the autoinjector 140 (e.g., loading the cap sleeve spring 110).

[0223] At alignment operation 294, the proximal end 141 of the autoinjector 140 is aligned with the injection site 198 on the body 192 of the user 190.

[0224] At point 296, the proximal end 141 of the autoinjector 140 presses against the injection site 198 (see [link]). Figure 19 For example, when the cap sleeve 103 retracts into the outer body 102 to expose the needle 155, the user 190 can push the outer body 102 of the autoinjector 140 distally toward the injection site 198. As described herein, the retraction of the cap sleeve 103 into the body 102 automatically actuates the drive assembly to trigger injection of the pre-filled syringe 150.

[0225] At position 298, with the cap sleeve 103 retracted into the outer body 102, the user 190 holds the autoinjector 140 at the injection site 198 until the injection is complete. In some examples, an audible noise (e.g., a click) generated by the autoinjector 140 indicates the end of the injection.

[0226] The methods, apparatus, and uses disclosed herein have many aspects, including the following.

[0227] One aspect is a method for adapting an autoinjector configured to actuate a pre-filled syringe having an injection spring having a spring constant, the pre-filled syringe being filled with a volume of therapeutic fluid, the pre-filled syringe including a barrel, a stop, and a needle, the stop having a travel path, the injection spring being arranged to move the stop along the travel path, the method comprising: aging the pre-filled syringe at an accelerated rate to form an aged pre-filled syringe; moving the stop at a predetermined speed from at least a first position along the travel path to at least a second position along the travel path within the barrel of the aged pre-filled syringe; measuring a plurality of forces applied to the stop as the stop moves along the travel path within the barrel; determining a resistance that impedes the movement of the stop along the travel path, the resistance corresponding to the plurality of forces; and selecting a spring constant for the injection spring, the action of selecting the spring constant including selecting a spring constant corresponding to the resistance.

[0228] Another aspect is a method, used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein an operable prefilled syringe includes an operable barrel and an operable stop positioned within the operable barrel, the operable stop being movable along an operable travel from a first operable position to a second operable position, the autoinjector including an injection spring having a spring force configured to apply a feeding force to the operable stop by driving a piston rod toward the operable stop when the autoinjector is actuated, the feeding force being at least a portion of the spring force, the method comprising: aging the prefilled syringe at an accelerated rate to form a reference prefilled syringe including a reference barrel and a reference stop positioned within the reference barrel; and moving the reference stop of the reference prefilled syringe along a reference travel path from at least a first... The reference position is moved to at least a second reference position; as the reference stop moves along the reference travel path within the reference cylinder, multiple forces applied to the reference stop are measured and multiple reference stop positions are measured; a force curve is generated, the force curve including at least some forces and reference stop positions measured as the reference stop moves between the first reference position and the second reference position, wherein at least one of the measured forces is associated with at least one of the measured reference stop positions; and an injection spring is selected such that, as the operable stop moves along the operable travel path between the first operable position and the second operable position, the feeding force applied to the operable stop at each position of the operable stop is greater than the force measured at the corresponding reference stop position of the measured reference stop position.

[0229] Another aspect is a method that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein selecting the injection spring includes: selecting a measured force from a force curve; and selecting at least one spring parameter corresponding to the selected force.

[0230] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein selecting at least one spring parameter includes selecting a spring constant for the injection spring and an uncompressed length for the injection spring.

[0231] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein selecting at least one spring parameter includes selecting a spring constant and a first compression spring length corresponding to a reference stop at a first reference position along a reference travel path.

[0232] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein selecting at least one spring parameter includes selecting a spring constant and a second compression spring length that corresponds to a reference stop at a location along a reference travel path corresponding to the maximum force measured in the force curve.

[0233] Another aspect is a method that uses alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the selected spring has a feeding force that is approximately 50% greater when the stop is in the final second position than when the stop is in the initial first position.

[0234] Another aspect is a method, used alone or in combination with the implementation examples and aspects disclosed herein, wherein the predetermined speed corresponds to the speed required to move the operable stop from a first operable position to a second operable position along an operable travel path in the range of about 5 seconds to about 19 seconds.

[0235] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein a plunger is operatively connected to a stop, and an action of moving the stop includes moving the plunger, and an action of measuring a plurality of forces applied to the stop includes measuring a plurality of forces applied to the plunger.

[0236] Another aspect is a method that can be used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the action of determining the sliding force includes determining the sliding force required to move the stop from a first position to a second position along the travel path within a defined amount of time.

[0237] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein determining the first resistance includes determining the first resistance when the stop is removed from the first position.

[0238] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein determining the resistance includes determining the resistance selected from the group consisting of: release force, maximum sliding force, or a combination thereof.

[0239] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein determining the resistance includes determining a resistance selected from the group consisting of a release force, a maximum sliding force, or a combination thereof.

[0240] Another aspect is a method that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein determining the resistance includes determining at least a first resistance and a second resistance, the first resistance being a release force and the second resistance being a minimum sliding force for causing the stop to move along the travel path from a first position at the beginning of the travel path to a second position at the end of the travel path without stopping.

[0241] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the determination of the amount takes place in the range of about 5 seconds to about 25 seconds.

[0242] Another aspect is a method that can be used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the action of determining the minimum sliding force includes determining the minimum sliding force required to move the stop from a first position to a second position along the travel path within a range of about 5 seconds to about 25 seconds.

[0243] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein an aged pre-filled syringe is held between a first position and a second position with a defined volume of therapeutic fluid, and the action of determining the minimum sliding force required to move the stop along the travel path from the first position to the second position without interruption includes discharging a defined volume of therapeutic fluid from the aged pre-filled syringe.

[0244] Another aspect is a method, alone or in combination with the implementation examples and aspects disclosed herein, wherein the determined volume is in the range of about 1.51 mL to about 1.66 mL.

[0245] Another aspect is a method used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the autoinjector includes a sub-assembly capable of moving in response to the decompression of an injection spring, the sub-assembly being arranged to selectively move a stop, the action of selecting a spring constant including: selecting a spring constant corresponding to at least a first resistance, a second resistance, and a third resistance, the third resistance impeding movement of the sub-assembly.

[0246] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein a stop within the barrel of a movable, aged, pre-filled syringe comprises a sub-assembly of a movable autoinjector.

[0247] Another aspect is a method, used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the autoinjector includes a sub-assembly capable of operating in response to the decompression of an injection spring, at least a portion of the sub-assembly being arranged to selectively move a stop, the action of selecting a spring constant including: selecting a spring constant corresponding to a force strong enough to operate the sub-assembly and move the stop from a first position to a second position without interruption.

[0248] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein a stop within the barrel of a movable, aged, pre-filled syringe comprises a sub-assembly of a movable autoinjector.

[0249] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the therapeutic fluid contains an antibody.

[0250] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the antibody comprises a humanized monoclonal antibody.

[0251] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the humanized monoclonal antibody includes an immunoglobulin G2 (IgG2) antibody.

[0252] Another aspect is a method, alone or in combination with the preparation methods and aspects disclosed herein, wherein the humanized monoclonal antibody includes a peptide antibody associated with the calcitonin gene.

[0253] Another aspect is a method that is used alone or in arbitrary combination with the foregoing 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.

[0254] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the therapeutic fluid comprises furenyl hexamethylenetetramine and has a viscosity in the range of about 4 cSt to about 14 cSt at 22°C.

[0255] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe includes an inner surface, and the prefilled syringe also includes a lubricant located on the inner surface.

[0256] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the lubricant comprises silicone oil.

[0257] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the lubricant comprises polydimethylsiloxane.

[0258] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein silicone oil is coated on the inner surface of the barrel and the coating thickness is between about 0.1 μm and about 0.3 μm prior to aging of the pre-filled syringe.

[0259] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the lubricant comprises between about 0.35 mg and about 1.1 mg of silicone oil prior to aging of the pre-filled syringe.

[0260] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity between about 500 cSt and about 1500 cSt at 25°C prior to aging of the pre-filled syringe.

[0261] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein aging the pre-filled syringe includes heating the pre-filled syringe for a defined time period.

[0262] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the determined time period is calculated according to the Arrhenius equation.

[0263] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the determined time period is calculated according to the Arrhenius equation; and the determined time period for heating the pre-filled syringe includes heating the pre-filled syringe at a temperature in the range of about 20°C to about 60°C.

[0264] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe has a volume selected from the group consisting of about 1 mL to about 2.25 mL.

[0265] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe has a volume selected from the group consisting of about 1 mL to about 2.25 mL.

[0266] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the distance between a first reference position of the reference stop and a second reference position of the reference stop is in the range of about 25.7 mm to about 30 mm.

[0267] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the distance between a first position of the stop and a second position of the stop is in the range of about 35 mm to about 55 mm.

[0268] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the needle defines a channel having a diameter in the range of about 0.15 mm to about 0.3 mm.

[0269] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the channel defined by the needle has a length ranging from about 15 mm to about 25 mm.

[0270] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the cylinder comprises glass.

[0271] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the cylinder comprises borosilicate glass.

[0272] Another aspect is a method that is used alone or in arbitrary combination with the foregoing embodiments and aspects disclosed herein, wherein the barrel of the prefilled syringe has an inner diameter in the range of about 6 mm to about 10 mm.

[0273] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the stop comprises an ethylene-tetrafluoroethylene copolymer.

[0274] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is a spring selected from the group consisting of: variable force springs, constant force springs, helical springs, conical springs, torsion springs, gas springs, hydraulic springs, and combinations thereof.

[0275] Another aspect is a method that is used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is a spring selected from the group consisting of: variable force springs, constant force springs, helical springs, conical springs, torsion springs, gas springs, hydraulic springs, and combinations thereof.

[0276] Another aspect is an autoinjector for actuating, alone or in combination with the foregoing embodiments and aspects disclosed herein, a pre-filled syringe containing a dose of therapeutic fluid, wherein the therapeutic fluid includes furenal monoclonal antibody, and the autoinjector is manufactured by a process comprising: any combination of the foregoing actions; selecting a spring having a selected spring constant; and assembling the autoinjector with the selected spring.

[0277] Another aspect is an autoinjector, used alone or in any combination with the foregoing embodiments and aspects disclosed herein, the autoinjector device comprising: a pre-filled syringe including a barrel extending along a longitudinal axis between a proximal end and a distal end, the barrel having an inner diameter of approximately 8.65 mm; a needle disposed at the distal end of the barrel, the needle having an inner diameter of approximately 0.21 mm and a length of approximately 20 mm or less, a therapeutic fluid being held within the barrel, the therapeutic fluid having a viscosity of approximately 14 cS at 22°C. t or lower; a stop disposed within a barrel to retain fluid within the barrel, the barrel defining a path of travel for the stop having a first position and a second position for the stop, the therapeutic fluid comprising furenate group monoclonal antibody; and an autoinjector holding the pre-filled syringe, the autoinjector comprising a plunger and an injection spring, the plunger engaging the stop and the injection spring biasing the plunger toward the stop, the injection spring having a spring force of at least approximately 20 N when the stop is in the first position.

[0278] Another aspect is an autoinjector, used alone or in any combination with the foregoing embodiments and aspects disclosed herein, the autoinjector device comprising: a pre-filled syringe including a barrel extending along a longitudinal axis between a proximal and a distal end, the barrel having an inner diameter of approximately 8.65 mm; a needle disposed at the distal end of the barrel, the needle having an inner diameter of approximately 0.27 mm and a length of approximately 19.5 mm or less, the volume of a therapeutic fluid held within the barrel ranging from approximately 1.51 mL to approximately 1.66 mL, the therapeutic fluid comprising furenette hexamethylenetetramine, the viscosity of the therapeutic fluid being approximately 8.8 cSt at 22°C; and a stop disposed within the barrel to retain the therapeutic fluid within the barrel, the barrel defining a path of travel for the stop. The travel path has an initial first position for the stop and a final second position for the stop, the first position being the initial position of the stop before delivery of the therapeutic fluid, and the second position being the final position of the stop when the full dose of the therapeutic fluid has been delivered; and an autoinjector holding the pre-filled syringe, the autoinjector including an injection spring arranged to apply a feeding force to the stop by driving a piston rod toward the stop, wherein, when the autoinjector is actuated, the injection spring is configured to provide an initial feeding force of at least about 20 N to the stop when the stop is in the initial first position, and to provide a final feeding force of about 12 N or more to the stop when the stop is in the final second position, the feeding force being at least a portion of the spring force of the injection spring.

[0279] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final feeding force of at least 12.5 N to the stop when the stop is in the final second position.

[0280] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final feeding force of at least 14 N to the stop when the stop is in the final second position.

[0281] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final feeding force of at least 12N to the stop when the stop is in the final second position, and the pre-filled syringe has an accelerated aging time of approximately 24 months.

[0282] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing 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 stop is in the initial first position.

[0283] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final feeding force in the range of about 12N to about 20N when the stop is in the final second position.

[0284] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is configured to provide a final feeding force in the range of about 12.5 N to about 20 N when the stop is in the final second position.

[0285] Another aspect is an autoinjector that, when used alone or in any combination with the foregoing embodiments and aspects disclosed herein, has an actual stored spring energy of the injection spring that is at least about 25% greater than the minimum stored spring energy required to move the stop from the first position to the second position without stopping the unaged prefilled syringe.

[0286] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring has stored energy in the range of about 0.9 J to about 2 J when the injection spring is in a first position.

[0287] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing 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 compression length in the range of about 50 mm to about 100 mm when in an initial first position.

[0288] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing 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 compression length in the range of about 75 mm to about 95 mm when in an initial first position.

[0289] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring has a spring force sufficient to move the stop from a first position to a second position along a travel path within about 5 seconds to about 25 seconds.

[0290] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein: the barrel of the prefilled syringe comprises glass and defines an inner surface; and prior to aging, the prefilled syringe further comprises silicone oil on the inner surface of about 0.4 mg to about 1.1 mg.

[0291] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is configured to move the stop along the travel path from the first position to the second position within a range of about 5 seconds to about 19 seconds.

[0292] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the silicone oil has a viscosity between about 500 cSt and about 1500 cSt at 25°C prior to aging of the pre-filled syringe.

[0293] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing 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.

[0294] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the stop has a length in the range of about 7.3 mm to about 8.1 mm.

[0295] Another aspect is an autoinjector used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein a stop has a compressed state and an uncompressed state, and the stop comprises: a body that is generally cylindrical and has a diameter in the uncompressed state ranging from about 8.85 mm to about 9.05 mm; and at least one annular rib extending radially from the body, the annular rib having a diameter in the uncompressed state ranging from about 9.25 mm to about 9.45 mm.

[0296] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein a portion of the stop is coated with ethylene tetrafluoroethylene copolymer and another portion of the stop is coated with silicone resin.

[0297] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the distance between a first position for a stop and a final second position for the stop is in the range of about 25.7 mm to about 30 mm.

[0298] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing 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.

[0299] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing 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.

[0300] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the therapeutic fluid has a viscosity in the range of about 4 cSt to about 10 cSt at 22°C.

[0301] Another aspect is an autoinjector that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein, wherein the injection spring is determined by the action of claim 1.

[0302] Another aspect is an autoinjector, used alone or in any combination with the foregoing embodiments and aspects disclosed herein, the autoinjector device comprising: a pre-filled syringe including a body at least partially formed of glass, a needle in fluid communication with the body, and a stop located within the body, the body defining an inner surface, the body having an inner diameter of approximately 8.65 mm and a volume of approximately 2.25 mL, the body defining a path of travel for the stop having a first position and a second position for the stop, the needle having an inner diameter of approximately 0.21 mm and a length of approximately 20 mm or less, a therapeutic fluid held within the body, the therapeutic fluid having a viscosity of approximately 10 cP or less at 22°C, the therapeutic fluid comprising furenidine monoclonal antibody. The following are provided: a silicone oil of about 0.35 mg to about 1.1 mg lubricating the inner surface of the syringe body, the silicone oil having a viscosity of about 500 cSt to about 1500 cSt at 25°C prior to aging of the pre-filled syringe; and an autoinjector holding the pre-filled syringe, the autoinjector comprising a plunger and an injection spring, the plunger engaging the stop and the injection spring biasing the plunger toward the stop; the injection spring, when in the first position: having a force determined according to the action of claim 1; in the range of about 20 N to about 30 N; about 25% more than the spring force required to move the stop from the first position to the second position without interruption prior to aging of the pre-filled syringe; and having a force sufficient to move the stop from the first position to the second position along a travel path in about 5 seconds to about 25 seconds.

[0303] Another aspect is an autoinjector device for actuating, alone or in combination with the foregoing embodiments and aspects disclosed herein, a pre-filled syringe containing a dose of a therapeutic fluid comprising a humanized monoclonal antibody against immunoglobulin G2 (IgG2), the autoinjector being prepared by a process comprising: aging the pre-filled syringe to form an aged pre-filled syringe; moving a stop within the barrel of the aged pre-filled syringe at a predetermined speed from at least a first position along a travel path to at least a second position along a travel path; measuring a plurality of forces applied to the stop as the stop moves along the travel path within the barrel; determining at least a first resistance and a second resistance that impede movement of the stop along the travel path, the first and second resistances corresponding to the plurality of forces; selecting a spring constant of the injection spring, the action of selecting the spring constant comprising selecting a spring constant corresponding to at least one of the first and second resistances; selecting a spring having the selected spring constant; and assembling the autoinjector with the selected spring.

[0304] Another aspect is an autoinjector device configured to deliver fluid from a syringe by moving a stop within the syringe barrel, either alone or in any combination with the foregoing embodiments and aspects disclosed herein. The autoinjector device includes: a syringe barrel having an empty state and a filled state, the empty state preceding the filled state, the syringe maintaining a dose of therapeutic fluid in the filled state, the therapeutic fluid comprising a humanized monoclonal antibody against immunoglobulin G2 (IgG2); a stop located within the syringe barrel having a travel path between a first position and a second position, the dose of the therapeutic fluid being substantially between the first and second positions; and an injection spring having a spring constant providing a first spring force at least 25% greater than a second spring force, the first spring force corresponding to the minimum spring force required to move the stop from the first position to the second position when the barrel is filled, and the second spring force corresponding to the minimum spring force required to move the stop from the first position to the second position when the barrel is empty.

[0305] Another aspect is an autoinjector device configured to move a stop within the syringe barrel, either alone or in any combination with the foregoing embodiments and aspects disclosed herein, to deliver fluid from the syringe. The autoinjector device includes: a pre-filled syringe having an unaged state and an aged state, wherein, when in the filled state, the pre-filled syringe maintains a dose of therapeutic fluid comprising a humanized monoclonal antibody against immunoglobulin G2 (IgG2); a stop located within the pre-filled syringe having a travel path between a first position and a second position, the dose of the therapeutic fluid being substantially between the first and second positions; and an injection spring having a spring constant providing a first spring force, the first spring force being at least 25% greater than a second spring force, the first spring force corresponding to the minimum spring force required to move the stop from the first position to the second position when the pre-filled syringe is in the aged state, and the second spring force corresponding to the minimum spring force required to move the stop from the first position to the second position when the pre-filled syringe is in the unaged state.

[0306] Another aspect is a pre-filled syringe assembly that can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein for use as a medicine for the treatment or prevention of migraines.

[0307] Another aspect is a pre-filled syringe comprising furenate hematoxylin and taurine, which can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein for use as a medicine for the treatment or prevention of migraines.

[0308] Another aspect is a pre-filled syringe containing a therapeutic fluid, including furenyl hexamethylenetetramine, which can be used alone or in any combination with the foregoing embodiments and aspects disclosed herein for use as a medicament for the treatment or prevention of migraines.

[0309] Another aspect is a pre-filled syringe containing a therapeutic fluid comprising furenidine hexamethylenetetramine and formulated at a nominal concentration of 150 mg / mL with 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, 1.2 mg / mL P580, and a pH of 5.5. This pre-filled syringe is used alone or in any combination with the foregoing embodiments and aspects disclosed herein for use as a medicine for the treatment or prevention of migraines.

[0310] Another aspect is a pre-filled syringe comprising furenate hematoxylin and succinate, which is used alone or in any combination with the foregoing embodiments and aspects disclosed herein for use as a medicament for the treatment or prevention of migraines. The pre-filled syringe is filled with a therapeutic fluid prepared at a nominal concentration of 150 mg / mL with 16 mM histidine, 6.6% sucrose, 0.136 mg / mL EDTA, 1.2 mg / mL P580, and a pH of 5.5.

[0311] Another aspect is a pre-filled syringe containing furenate hematoxylin and taurine, which is used according to a continuous schedule of no more than once every two months, for the purpose of treating or preventing migraines, and is used alone or in any combination with the foregoing embodiments and aspects.

[0312] Another aspect is a pre-filled syringe containing furenate hematoxylin and taurine, which is used according to a continuous schedule of no more than once every three months as a medicine for the treatment or prevention of migraines, which is used alone or in any combination with the foregoing embodiments and aspects.

[0313] Another aspect is a pre-filled syringe containing furenate hematoxylin and taurine, which is used according to a continuous schedule of no more than once every four months for use as a medicine for the treatment or prevention of migraines, which is used alone or in any combination with the foregoing embodiments and aspects.

[0314] Another aspect is an autoinjector, which can be used alone or in any combination with the foregoing embodiments and aspects, comprising: a pre-filled syringe including a stop and a therapeutic fluid including furenal group monoclonal antibody; and an autoinjector having an injection spring and a piston rod arranged to move the stop 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 a dose of the therapeutic fluid.

[0315] The various embodiments described above are provided by way of illustration only and should not be construed as limiting the appended claims. Those skilled in the art will readily recognize that various modifications and alterations can be made without following the exemplary embodiments and applications illustrated and described herein, and without departing from the true spirit and scope of the appended claims. It is intended that any such modifications and equivalents be included within the scope of the claims.

Claims

1. An auto-injector apparatus comprising: a syringe comprising: a barrel comprising an inner surface and a lubricant on the inner surface; a therapeutic fluid held within the barrel, the therapeutic fluid comprising a calcitonin gene-related peptide antibody comprising a heavy chain variable region and a light chain variable region, an amino acid sequence of the heavy chain variable region being at least 90% identical to SEQ ID NO: 1, an amino acid sequence of the light chain variable region being at least 90% identical to SEQ ID NO: 2; and a stopper disposed within the barrel, the stopper configured to move axially within the barrel between an initial position and a final position to expel at least some of the therapeutic fluid from the syringe; and an auto-injector configured to hold the syringe, the auto-injector comprising: a rod configured to abut the stopper; and an injection spring configured to drive the rod to move the stopper from the initial position to the final position, wherein: the injection spring is configured to move the stopper from the initial position to the final position over a period of time between 5 seconds and 19 seconds, the injection spring is configured to provide an initial priming force between 20 N and 30 N when the stopper is in the initial position, the injection spring is configured to provide a final priming force that is at least 50% of the initial priming force when the stopper is in the final position, and a distance between the initial position and the final position corresponds to a dose of the therapeutic fluid.

2. An auto-injector apparatus according to claim 1, wherein, an amino acid sequence of the heavy chain variable region is at least 95% identical to SEQ ID NO: 1, and an amino acid sequence of the light chain variable region is at least 95% identical to SEQ ID NO:

2.

3. An auto-injector apparatus according to claim 2, wherein, an amino acid sequence of the heavy chain variable region is 100% identical to SEQ ID NO: 1, and an amino acid sequence of the light chain variable region is 100% identical to SEQ ID NO:

2.

4. The auto-injector apparatus of claim 1, wherein, the therapeutic fluid comprises a liquid pharmaceutical composition comprising: 225 mg of a calcitonin gene-related peptide antibody comprising a heavy chain variable region and a light chain variable region, an amino acid sequence of the heavy chain variable region being 100% identical to SEQ ID NO: 1, an amino acid sequence of the light chain variable region being 100% identical to SEQ ID NO: 2; 0.204 mg of disodium edetate dihydrate; 0.815 mg of L-histidine; 3.93 mg of L-histidine hydrochloride monohydrate; 0.3 mg of polysorbate 80; 99 mg of sucrose; and water, wherein the liquid pharmaceutical composition for injection has a pH of 5.

5.

5. The auto-injector apparatus of claim 1, wherein: the therapeutic fluid is aged for 24 months, and the injection spring is configured to provide an initial priming force between 20 N and 30 N when the stopper is in the initial position, the injection spring is configured to provide a final priming force that is at least 50% of the initial priming force when the stopper is in the final position, and a distance between the initial position and the final position corresponds to a dose of the therapeutic fluid. The injection spring is configured to move the stopper from the initial position to the final position throughout the shelf life of the therapeutic fluid.

6. An auto-injector apparatus according to claim 5, wherein, The shelf life is 24 months.

7. The auto-injector apparatus of claim 1, wherein, The injection spring has a stored energy between 0.9 J and 2 J when the stopper is in the initial position.

8. An auto-injector apparatus according to claim 7, wherein, The injection spring has a stored spring constant between 0.2 N / mm and 0.4 N / mm and a compression length between 50 mm and 100 mm when the stopper is in the initial position.

9. An auto-injector apparatus according to claim 8, wherein, The stored spring constant is between 0.28 N / mm and 0.32 N / mm and the compression length is between 75 mm and 95 mm.

10. The auto-injector device of claim 1, wherein: the therapeutic fluid is unaged, and the lubricant is a silicone oil.

11. The auto-injector apparatus of claim 1, wherein, The stopper is coated with a first coating comprising an ethylene-tetrafluoroethylene copolymer and a second coating comprising a silicone resin, and The first coating coats a first portion of the stopper and the second coating coats a second portion of the stopper different from the first portion of the stopper.

12. The auto-injector device of claim 1, wherein: the syringe is unaged, and an actual stored spring energy of the injection spring when the stopper is in the initial position is 25% greater than a minimum stored spring energy required to move the stopper from the initial position to the final position without stalling the syringe.

13. The auto-injector apparatus of claim 1, wherein, The syringe has an inner diameter between 8.5 mm and 8.8 mm.

14. An auto-injector apparatus according to claim 13, wherein, The syringe further comprises a needle having a length of 19.5 mm or less.

15. An auto-injector apparatus as defined in claim 14, wherein, The needle has an inner diameter between 0.21 mm and 0.3 mm.

16. The auto-injector device of claim 1, wherein: the therapeutic fluid has a volume between 1.51 mL to 1.66 mL, and the therapeutic fluid has a viscosity between 8 cP to 10 cP at 22 °C.

17. An auto-injector device, comprising: a syringe, the syringe comprising: 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, the therapeutic fluid comprising a calcitonin gene-related peptide antibody having a viscosity of 10 cP or less at 22 °C, the calcitonin gene-related peptide antibody comprising a heavy chain variable region and a light chain variable region, an amino acid sequence of the heavy chain variable region being at least 90% identical to SEQ ID NO: 1, an amino acid sequence of the light chain variable region being at least 90% identical to SEQ ID NO: 2; a needle disposed at the distal end of the barrel, the needle having a length of 19.5 mm or less; and a stopper disposed within the barrel, the stopper configured to move axially within the barrel along a travel path to expel at least some of the therapeutic fluid from the syringe, the travel path 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; and an automatic injector holding the syringe, the automatic injector comprising: a rod configured to abut the stopper; and an injection spring configured to drive the rod into abutment with the stopper to apply a dosing force to the stopper, wherein: the injection spring is configured to provide an initial dosing force between 20 N and 30 N when the stopper is in the initial position, and the injection spring is configured to provide a final dosing force between 12 N and 20 N when the stopper is in the final position, the injection spring is configured to move the stopper from the initial position to the final position over a period of time between 5 seconds and 19 seconds, and a distance between the initial position and the final position corresponds to a dose of the therapeutic fluid.

18. An auto-injector apparatus as defined in claim 17, wherein, the amino acid sequence of the heavy chain variable region is at least 95% identical to SEQ ID NO: 1 and the amino acid sequence of the light chain variable region is at least 95% identical to SEQ ID NO:

2.

19. An auto-injector apparatus as defined in claim 18, wherein, the amino acid sequence of the heavy chain variable region is 100% identical to SEQ ID NO: 1 and the amino acid sequence of the light chain variable region is 100% identical to SEQ ID NO:

2.

20. The auto-injector apparatus of claim 17, wherein, the therapeutic fluid comprises a liquid pharmaceutical composition comprising: 225 mg of a calcitonin gene-related peptide antibody comprising a heavy chain variable region and a light chain variable region, the amino acid sequence of the heavy chain variable region is 100% identical to SEQ ID NO: 1 and the amino acid sequence of the light chain variable region is 100% identical to SEQ ID NO: 2; 0.204 mg of disodium edetate dihydrate; 0.815 mg of L-histidine; 3.93 mg of L-histidine hydrochloride monohydrate; 0.3 mg of polysorbate 80; 99 mg of sucrose; and water, wherein the liquid pharmaceutical composition for injection has a pH of 5.

5.

21. The automatic injector device of claim 17, wherein: the therapeutic fluid is aged for 24 months, and the injection spring is configured to move the stopper from the initial position to the final position over the entire shelf life of the therapeutic fluid.

22. An auto-injector apparatus as defined in claim 21, wherein, the shelf life is 24 months.

23. The auto-injector apparatus of claim 17, wherein, the injection spring has a stored energy between 0.9 J and 2 J when the stopper is in the initial position.

24. The auto-injector apparatus of claim 17, wherein, The injection spring has a stored spring constant between 0.2 N / mm and 0.4 N / mm and a compression length between 50 mm and 100 mm when the stopper is in the initial position.

25. An auto-injector apparatus as defined in claim 24, wherein, The stored spring constant is between 0.28 N / mm and 0.32 N / mm and the compression length is between 75 mm and 95 mm.

26. The auto-injector apparatus of claim 17, wherein: The syringe is not aged, and The actual stored spring energy of the injection spring when the stopper is in the initial position is 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.

27. The auto-injector apparatus of claim 17, wherein, The syringe has an inner diameter between 8.5 mm and 8.8 mm.

28. The auto-injector apparatus of claim 17, wherein, The needle has an inner diameter between 0.21 mm and 0.3 mm.

29. The auto-injector apparatus of claim 17, wherein, The therapeutic fluid has a viscosity between 8 cP and 10 cP at 22 °C.

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