Patent Description:
Drug delivery devices, such as autoinjectors, on-body injectors, and hand-held injectors, are commonly prescribed for patients to self-administer medication. Such devices typically include a drive mechanism (e.g., a spring) that operates on a prefilled syringe in response to a triggering event, such as the patient pressing a button on the device. The drive mechanism creates a drive force and, additionally, operates on a plunger to deliver the medication subcutaneously via the needle. These drug delivery devices may be constructed as single-use or reusable devices.

Autoinjectors and on-body injectors offer several benefits in drug delivery over conventional syringes, such as simplicity of use. Autoinjectors and on-body injectors are beneficial for delivering drugs with high viscosities. However, as viscosity increases, the drive force required to inject the drug also increases. A large drive force may cause internal pressure build-up within the device, causing the prefilled syringe to fracture during injection. <CIT> discloses a plunger-driven auto injector. <CIT> discloses a firing button for an automatic injection device.

The present disclosure minimizes risk of component failure for drug delivery devices that sustain one or more impact events during injection. Specifically, the present disclosure addresses the impact forces imparted on a reservoir of a spring-loaded drug delivery device. In accordance with one or more aspects described herein, a drug delivery device and a method of manufacturing a drug delivery device may reduce peak internal pressure of a spring-loaded drug delivery device during injection without compromising the drug delivery.

In accordance with a first exemplary aspect, a drug delivery device may include a reservoir having a distal end and a proximal end, a drug delivery member in fluid communication with the distal end of the reservoir, a plunger disposed in and moveable relative to the reservoir, and a plunger rod having a mass MP, a distal end and a proximal end. The plunger rod may be movable from (i) a first position, where the distal end of the plunger rod is spaced apart from the plunger to (ii) a second position, where the distal end of the plunger rod contacts the plunger. The drug delivery device may further include a drive mechanism that is coupled to the proximal end of the plunger rod and that is configured to deliver a drive force FD to move the plunger rod from the first position to the second position. A ratio of the mass of the plunger rod to the drive force of the drive mechanism (MP/FD) may be in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf). In other embodiments, the ratio of the mass of the plunger rod to the drive force of the drive mechanism may be expanded beyond this range.

In accordance with a second exemplary aspect, a drug delivery device may include a housing having a distal end and a proximal end, a drug reservoir disposed in the housing and having a distal end and a proximal end, a drug delivery member in fluid communication with the distal end of the drug reservoir, a plunger disposed in and moveable relative to the drug reservoir, a carrier encasing the drug reservoir, and a plunger rod having a distal end and a proximal end. The plunger rod may be movable from (i) a first position, where the distal end of the plunger rod is spaced apart from the plunger to (ii) a second position, where the distal end of the plunger rod contacts the plunger. The drug delivery device may further include a drive mechanism that is coupled to the proximal end of the plunger rod and that is configured to move the plunger rod from the first position to the second position by a drive force FD. The plunger rod, plunger, carrier, and drug reservoir may be movable from (i) the second position to (ii) a third position, where the carrier contacts the distal end of the housing. The drive mechanism may be configured to move the plunger rod, plunger, carrier, and drug reservoir from the second position to the third position. A ratio of total mass of the plunger rod, plunger, carrier, and drug reservoir MT to drive force FD of the drive mechanism (MT/FD) may be in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf). In other embodiments, the ratio of the mass of the plunger rod, plunger, carrier, and drug reservoir to the drive force of the drive mechanism may be expanded beyond this range.

In accordance with a third exemplary aspect, a drug delivery device may include a housing having a distal end and a proximal end, a drug reservoir disposed in the housing and having a distal end and a proximal end, a drug delivery member in fluid communication with the distal end of the drug reservoir, a plunger disposed in and moveable relative to the drug reservoir, a carrier encasing the drug reservoir, and a plunger rod having a distal end and a proximal end. The plunger rod may be movable from (i) a first position, where the distal end of the plunger rod is spaced apart from the plunger to (ii) a second position, where the distal end of the plunger rod contacts the plunger. The drug delivery device may include a drive mechanism coupled to the proximal end of the plunger rod and is configured to move the plunger rod from the first position to the second position at a first velocity µ<NUM>. A mass of the plunger rod MP may be inversely proportional to a square of the first velocity µ<NUM> of the plunger rod, wherein the plunger rod, plunger, carrier, and drug reservoir are movable from (i) the second position to (ii) a third position, where the carrier contacts the distal end of the housing. The drive mechanism may be configured to move the plunger rod, plunger, carrier, and drug reservoir from the second position to the third position at a second velocity µ<NUM>. A total mass of the plunger rod, plunger, carrier, and drug reservoir MT may be inversely proportional to a square of the second velocity µ<NUM> of the plunger rod, plunger, carrier, and drug reservoir.

In accordance with a fourth exemplary aspect, a method of manufacturing a drug delivery device may include providing a reservoir, a plunger disposed in and moveable relative to the reservoir, and a drive mechanism where the drive mechanism is configured to move a plunger rod by a drive force FD. Further, the method may include selecting a plunger rod having a mass MP based on a ratio of mass of the plunger rod to drive force (MP/FD) in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf), providing the plunger rod having the mass based on the plunger rod mass to drive force ratio, and coupling the plunger rod to the drive mechanism.

In further accordance with any one or more of the foregoing first, second, third, or fourth aspects, a drug delivery device/method of manufacturing a drug delivery device may further include any one or more of the following forms. In a one form of the device, the drive force may be in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and the mass of the plunger rod may be in a range of approximately <NUM> to approximately <NUM>.

In one form of the device, the drive force may be in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and the mass of the plunger rod may be in a range of approximately <NUM> to <NUM>.

In one form of the device, the drive force may be in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and the total mass of the plunger rod, plunger, carrier, and drug reservoir may be in a range of approximately <NUM> to approximately <NUM>.

In one form of the device, the drive force may be in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and the total mass of the plunger rod, plunger, carrier, and drug reservoir may be in a range of <NUM> to approximately <NUM>.

In one form of the device, the reservoir may be a prefilled syringe.

In one form of the device, the mass of the plunger rod may be in a range of approximately <NUM> to approximately <NUM>.

In one form of the device, a mass of the carrier may be in a range of approximately <NUM> to approximately <NUM> and the mass of the plunger rod may be in a range of approximately <NUM> to approximately <NUM>.

In one form, the method may further include providing a housing having a distal end and a proximal end, selecting a carrier having a mass based on a ratio of total mass of the plunger rod, plunger, carrier, and reservoir to drive force (MT/FD) in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf), providing the carrier having the mass based on the ratio of total mass of the plunger rod, plunger, carrier, and reservoir to drive force, and enclosing the reservoir with the carrier.

In one form of the method, providing the drive mechanism may include providing a spring configured to move the plunger rod at a drive force that is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and providing a plunger rod having a mass in a range of approximately <NUM> to approximately <NUM>.

In one form of the method, providing the drive mechanism may incldue providing a spring configured to move the plunger rod at a drive force that is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and providing a plunger rod having a mass in a range of approximately <NUM> to approximately <NUM>.

In one form of the method, providing the drive mechanism may include providing a spring configured to move the plunger rod at a drive force that is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) and providing a plunger rod, plunger, carrier, and reservoir having a total mass in a range of approximately <NUM> to approximately <NUM>.

The drug delivery devices described and illustrated herein are designed to minimize component failure, and, specifically fracture of drug-filled reservoirs during injection. <FIG> illustrate a first example of an autoinjector <NUM>, which sustains one impact event; <FIG> illustrate a second example of an autoinjector <NUM>, which sustains two impact events; and <FIG> illustrates an example of an on-body injector <NUM>, which sustains one impact event. The claimed subject matter may be applied to any force-driven drug delivery device that is susceptible to component failure caused by impact events, or any autoinjector with potential energy stored. As used herein, an "impact event" is used to describe the occurrence of a moving drug delivery device component, e.g. a plunger rod, contacting a stationary drug delivery device component, e.g., a plunger. As will be described further below, these impact events occur in existing drug delivery devices and may cause the drug delivery device to fail.

Turning first to <FIG>, the autoinjector <NUM> includes a reservoir <NUM> configured to contain and/or containing a drug <NUM>, a drug delivery member <NUM> configured to deliver the drug, a plunger rod <NUM> configured to drive a plunger <NUM>, and a drive mechanism <NUM> configured to power drug delivery. The reservoir <NUM>, which may be a prefilled syringe, an empty syringe, or other drug storage container, has a distal end <NUM> and a proximal end <NUM>, where the drug delivery member <NUM> is in fluid communication with the distal end <NUM> of the reservoir <NUM>. <FIG> illustrates the autoinjector <NUM> in a preloaded position where the plunger rod <NUM> is disposed at the proximal end <NUM> of the reservoir <NUM> and spaced way from the plunger <NUM>, which is disposed within the reservoir <NUM> and is movable relative to the reservoir <NUM>. The reservoir <NUM> in this example is a glass syringe and includes a thin-walled glass barrel <NUM> and an annular flange <NUM> located at the proximal end <NUM> of the reservoir <NUM>.

The drug delivery member <NUM> is configured to deliver the stored drug to a patient. The drug delivery member <NUM> has a proximal end <NUM> in fluid communication with the distal end <NUM> of the reservoir <NUM>, and a distal end <NUM> configured to be received within a patient. In <FIG>, the delivery member <NUM> is a needle, but other embodiments of a drug delivery device may include a hard or soft cannula or another component that facilitates fluid communication and delivery of a drug to the patient.

The drive mechanism <NUM> of this version includes a compressed coil spring <NUM> coupled to a proximal end <NUM> of the plunger rod <NUM>. The drive mechanism <NUM> is configured to deliver an initial force of the drive mechanism <NUM>, referred herein as the drive force FD, to move the plunger rod <NUM> from the preloaded position, also referred herein as a first position where the plunger rod <NUM> is a distance X from the plunger <NUM>, to a second position where a distal end <NUM> of the plunger rod16 makes contact with a proximal end <NUM> of the plunger <NUM>, as shown in <FIG>. At the impact event shown in <FIG>, the drive force FD initially causes the plunger rod <NUM> to impart an impact force on the plunger <NUM>, before causing the plunger <NUM> to move linearly along a longitudinal axis A of the autoinjector <NUM>, and through the reservoir <NUM>. In this case, the longitudinal axis A coincides with a longitudinal axis of the reservoir <NUM>. As the plunger <NUM> moves through the reservoir <NUM>, a stopper located at the distal end <NUM> of the plunger <NUM> is configured to sealingly and slidably engage an inner wall of the glass barrel <NUM> to push the drug through the reservoir <NUM> and out through an open end of the drug delivery member <NUM>. The term "drive force" may be a surrogate for the energy expended during the acceleration of the moving components, i.e. the plunger rod <NUM>.

An actuator <NUM> oppositely located from the delivery member <NUM> is configured to activate the drive mechanism <NUM>. In the example illustrated in <FIG>, the actuator <NUM> includes a button <NUM> and an actuator spring <NUM> and is configured to trigger the delivery of the drug to the patient by releasing the drive mechanism <NUM>. In the preloaded position, the coil spring <NUM> of the drive mechanism <NUM> is compressed between an annular flange <NUM> of the plunger rod <NUM> and a rear cap <NUM> of the autoinjector <NUM>. When the button <NUM> is pressed by the patient or a healthcare provider, the button <NUM> moves against the actuator spring <NUM> to release a lock tab <NUM> carried by the button <NUM> from a recess <NUM> in the plunger rod <NUM>, and also releases the annular flange <NUM> of the plunger rod <NUM>. As seen in <FIG>, this releases the plunger rod <NUM> and allows the drive mechanism <NUM> to force the plunger rod <NUM> down relative to the orientation of <FIG> and <FIG> and ultimately to contact and impact the plunger <NUM>. Subsequent to the impact event shown in <FIG>, the spring <NUM> biases the annular flange <NUM> in a distal direction, thereby moving the plunger rod <NUM> along the longitudinal axis A toward the distal end <NUM> of the reservoir <NUM>. In another embodiment, the actuator <NUM> may be a soft switch that activates a motor that drives the plunger rod <NUM>.

A patient may hold the drug delivery device <NUM> by a housing <NUM> which encloses the reservoir <NUM>, drive mechanism <NUM>, and plunger rod <NUM>. The housing <NUM> is open at a distal end <NUM> and is closed at a proximal end <NUM>. The housing <NUM> may be constructed as a single, unitary component or constructed from multiple components or sections that are combined into a single, integral unit. As illustrated in <FIG>, the housing <NUM> may be attached to a needle shield <NUM> that is moveable relative to the distal end <NUM> of the delivery member <NUM>. A removable sterile barrier <NUM> can also be disposed about the distal end <NUM> of the delivery member <NUM>. The needle shield <NUM> may be biased in the distal direction by a biasing member (e.g., a spring), which is not shown.

To illustrate the impact event of the first example autoinjector <NUM>, the method of operating the autoinjector <NUM> is described sequentially with reference to <FIG>. Prior to activating the actuator <NUM>, the patient or healthcare provider may initially remove the removable sterile barrier <NUM>, exposing the delivery member <NUM>, and may press the needle shield <NUM> against the skin of the patient. The reaction force exerted by the patient's skin may push the needle shield <NUM> in and away from the distal end <NUM> of the drug delivery member <NUM> until the needle shield <NUM> reaches a position inside the housing <NUM>, as shown in <FIG>.

The patient or healthcare provider may then press the actuator button <NUM> of the actuator <NUM> to activate the drive mechanism <NUM>, which drives the plunger rod <NUM> toward the plunger <NUM>. As a result, the plunger rod <NUM> moves distance X from the first position shown in <FIG> to a second position shown in <FIG> where the distal end <NUM> of the plunger rod <NUM> initially impacts the proximal end <NUM> of the plunger <NUM>. The drive mechanism <NUM> then drives the plunger <NUM> toward the distal end <NUM> of the syringe <NUM> to discharge the drug from the reservoir <NUM> and into the patient via the delivery member <NUM>. The reservoir <NUM> remains stationary relative to the distal end <NUM> of the housing <NUM> as the plunger rod <NUM> and plunger <NUM> move through the reservoir <NUM>. When delivery of the drug is complete, and/or when the plunger <NUM> has completed its delivery stroke, the patient or healthcare provider may remove the autoinjector <NUM> from the patient's skin.

Based on the requirements of the drug and the force generated by the drive mechanism <NUM> (i.e. a high viscosity drug requires a higher drive force to move the plunger through the reservoir), the plunger rod <NUM> may indirectly or directly impart an impact force onto the barrel <NUM> of the reservoir <NUM> when the plunger rod <NUM> impacts the plunger <NUM>. If the plunger <NUM> is placed lower in the reservoir <NUM> such that the distance X increases, the impact becomes more important, i.e., more likely to be the cause of breakage. Here, plunger depth refers to a distance between a top of the flange <NUM> to the proximal end <NUM> of the plunger <NUM>. Accordingly, "lower" refers to the plunger <NUM> being farther away from the flange <NUM> and closer to the delivery member <NUM>. A load from the impact event generates pressure waves in the drug <NUM> that propagate through the glass barrel <NUM>. For the combination of materials and geometries typical of glass syringes, a pressure wave will "couple" to the glass barrel <NUM> of the reservoir <NUM> as it propagates axially. This coupling results in a reduction of wave speed, and radial motion of the syringe. The coupled wave oscillates through the barrel <NUM> and may cause the barrel <NUM> to fracture.

To reduce pressure propagation throughout the glass barrel <NUM> with a given drive force FD, the mass MP of the plunger rod <NUM> may be increased by a mass multiplier. More specifically, the mass MP of the plunger rod <NUM> may be increased based on a ratio MP / FD of the mass MP of the plunger rod <NUM> to the drive force FD of the drive mechanism <NUM>. The internal pressure of the reservoir <NUM> decreases when the ratio MP /FD is in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf). For example, if the drive force FD is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf), then the mass MP of the plunger rod <NUM> may be in a range of approximately <NUM> to approximately <NUM>, and preferably between <NUM> to <NUM>. In another example, if the drive force FD is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf), then the mass MP of the plunger rod <NUM> may be in a range of approximately <NUM> to approximately <NUM>, and preferably between <NUM> to <NUM>. The ranges in mass of the plunger rod <NUM> do not affect drug delivery time, i.e. the time from activation to completion. The principal intended to be captured is that the mass of the plunger rod MP and/or other moving components is maximized to mitigate the potential negative consequences of impact.

Impact force is also related to the velocity of the plunger rod <NUM> as it moves from the first position to the second position. To minimize the impact and instances of reservoir <NUM> fracture while maintaining delivery injection time, the plunger rod <NUM> of the drug delivery device <NUM> moves from the first position to the second position at a velocity µ<NUM> that is approximately proportional to the inverse square root of the mass MP-<NUM>/<NUM> of the plunger rod <NUM>. According to this relationship, an increase in the mass MP of the plunger rod <NUM> reduces the velocity at which the plunger rod <NUM> travels through the reservoir <NUM>, and therefore reduces force of impact imparted onto the plunger <NUM>. A lower impact force at the first impact event minimizes risk of internal pressure build-up in the reservoir that causes component fracture. In a preferred example, the mass MP of the plunger rod <NUM> may be increased two to three times depending on the drive force FD of the drive mechanism <NUM>. For example, if a conventional plunger rod is about <NUM> grams, then the mass may be increased to mass in a range of approximately <NUM> to <NUM> grams, and preferably between <NUM> and <NUM> grams.

Turning now to <FIG>, a second example autoinjector <NUM> includes a reservoir <NUM> configured to contain and/or contains a drug <NUM>, a drug delivery member <NUM> configured to deliver the drug, a plunger rod <NUM> configured to drive a plunger <NUM>, and a drive mechanism <NUM> configured to power drug delivery. The reservoir <NUM>, which may be a prefilled syringe, an empty syringe, or other drug storage container, has a distal end <NUM> and a proximal end <NUM>, where the drug delivery member <NUM> is in fluid communication with the distal end <NUM> of the reservoir <NUM>. <FIG> illustrates the autoinjector <NUM> in a preloaded position where the plunger rod <NUM> is disposed at the proximal end <NUM> of the reservoir <NUM> and spaced way from the plunger <NUM>, which is disposed within the reservoir <NUM> and is movable relative to the reservoir <NUM>. The reservoir <NUM> in this example is a glass syringe and includes a thin-walled glass barrel <NUM>, an annular flange <NUM> located at the proximal end <NUM>, and a shoulder <NUM> disposed at the distal end <NUM> of the reservoir <NUM>.

An actuator <NUM> oppositely located from the delivery member <NUM> is configured to activate the drive mechanism <NUM>. In the example illustrated in <FIG>, the actuator <NUM> includes a button <NUM> and an actuator spring <NUM> and is configured to trigger the delivery of the drug to the patient by releasing the drive mechanism <NUM> as described above and in relation to the previously illustrated autoinjector <NUM>.

A patient may hold the drug delivery device <NUM> by a housing <NUM> which encloses the reservoir <NUM>, drive mechanism <NUM>, and plunger rod <NUM>. The housing <NUM> is open at a distal end <NUM> and is closed at a proximal end <NUM> with a rear cap <NUM>. The housing <NUM> may be constructed as a single, unitary component or constructed from multiple components or sections that are combined into a single, integral unit. The distal end <NUM> of the delivery member <NUM> is configured to extend beyond the distal end <NUM> of the housing <NUM> as illustrated in <FIG>. A conical end <NUM> is located at the distal end <NUM> of the housing <NUM> and has a tapered shape. As will be discussed below, the tapered shape of the conical end <NUM> provides a stopping surface for the carrier <NUM> at the second impact event.

The drive mechanism <NUM> includes a compressed coil spring <NUM> coupled to a proximal end <NUM> of the plunger rod <NUM>. The drive mechanism <NUM> is configured to deliver a drive force FD to move the plunger rod <NUM> from the preloaded position, also referred herein as a first position where the plunger rod <NUM> is a distance Y from the plunger <NUM>, to a second position where a distal end <NUM> of the plunger <NUM> makes contact with a proximal end <NUM> of the plunger <NUM>, as shown in <FIG>. At the first impact event, the plunger rod <NUM> contacts the plunger <NUM> and initially imparts and impact force onto the plunger <NUM>. The drive force FD then causes the plunger <NUM> to move the glass barrel <NUM> of the reservoir <NUM> linearly along a longitudinal axis A of the autoinjector <NUM>. The frictional force between the plunger <NUM> and the glass barrel <NUM> causes the reservoir <NUM>, along with the plunger rod <NUM> and plunger <NUM>, to move in the distal direction. The shoulder <NUM> of the reservoir <NUM> is in contact with a distal end <NUM> of the carrier <NUM> and carries the carrier <NUM> from the second position illustrated in <FIG> to a third position illustrated in <FIG>. The carrier <NUM> stops moving in the distal direction when the distal end <NUM> of the carrier <NUM> contacts an inner surface <NUM> of the conical end <NUM> of the housing <NUM>. At this point, the momentum of the plunger rod <NUM> against the plunger <NUM> overcomes the frictional force between the plunger <NUM> and the glass barrel <NUM> and the plunger rod <NUM> and the plunger <NUM> are moveable through the reservoir <NUM> relative to the reservoir <NUM>, carrier <NUM>, and housing <NUM>. The plunger <NUM> has a stopper at its distal end <NUM> and is configured to sealingly and slidably engage an inner wall of the reservoir <NUM> to discharge (e.g., eject) the drug from the reservoir <NUM> into the patient via the delivery member <NUM>.

To illustrate the two impact events of the second example autoinjector <NUM>, the method of operating the autoinjector <NUM> is described sequentially with reference to <FIG>. Initially, the patient or healthcare provider places the autoinjector <NUM> against the patient's skin, and presses the activation button <NUM> or otherwise initiates the actuator <NUM>. The actuator <NUM> releases the compressed spring <NUM>, which drives the plunger rod <NUM> from the first position illustrated in <FIG> to the second position illustrated in <FIG> where a distal end <NUM> of the plunger rod <NUM> impacts a proximal end <NUM> of the plunger <NUM>. <FIG> illustrates the moment of the first impact event when the moving plunger rod <NUM> impacts the stationary plunger <NUM>. After the first impact, the plunger rod <NUM> and plunger <NUM> advance both the reservoir <NUM> and the carrier <NUM> toward the conical end <NUM> of the housing <NUM>. As illustrated in <FIG>, the distal end <NUM> of the delivery member <NUM> extends through the open end of the housing <NUM> so that it may be inserted into the skin of the patient. Concurrently with the extension of the needle <NUM>, the distal end <NUM> of the syringe carrier <NUM> contacts a point on the inside surface <NUM> of the conical end <NUM> of the housing <NUM>, and remains in contact with the inside surface <NUM> while the plunger rod <NUM> and plunger <NUM> continue to advance in the distal direction to expel the drug into the patient.

Analysis of the autoinjector <NUM> using high-speed video has revealed that the two impact events impart significant impact forces to the reservoir <NUM>. The first event occurs when the moving plunger rod <NUM> comes in contact with the stationary plunger <NUM> upon initial activation of the autoinjector <NUM>. The load generates pressure waves that propagate through the fluid column. For the combination of materials and geometries typical of glass syringes, a pressure wave will "couple" to the glass barrel <NUM> as it propagates axially. This coupling results in a reduction of wave speed, and radial motion of the syringe <NUM>. The second impact event occurs when the moving carrier <NUM> contacts the stationary conical end <NUM> of the housing <NUM>. The forces of either or both of these two impacts can fracture the syringe barrel <NUM>.

To reduce pressure propagation throughout the glass barrel <NUM> with a given drive force FD, the mass of the plunger rod MP may be increased by a mass multiplier as described above. Additionally, the mass of the carrier <NUM> may be increased based on a ratio MT /FD of the total mass MT of an impact system <NUM>, i.e. the plunger rod <NUM>, plunger <NUM>, reservoir <NUM>, and carrier <NUM>, to the drive force FD of the drive mechanism <NUM>. The internal pressure of the reservoir <NUM> reaches a safe pressure value when the ratio MT /FD of total mass MT to drive force FD is in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf). For example, if the drive force FD is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf), then the mass MT of the impact system <NUM> may be in a range of approximately <NUM> to approximately <NUM>, and preferably between <NUM> to <NUM>. In another example, if the drive force FD is in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf), then the mass MT of the impact system <NUM> may be in a range of approximately <NUM> to approximately <NUM>, and preferably between <NUM> to <NUM>. In other embodiments, the mass of the plunger <NUM>, the mass of the reservoir <NUM>, the mass of the carrier <NUM>, the mass of the plunger rod <NUM>, or any combination of all or one of the components of the impact system <NUM> may be increased so that the total combined mass MT of the impact system <NUM> to drive force FD ratio is within the desired range. As used herein, the term "impact system" refers to the components included in the second impact event, and according to the example illustrated in <FIG>, the "impact system" includes the plunger rod <NUM>, the plunger <NUM>, the reservoir <NUM>, and the carrier <NUM>. As used herein, the term "safe pressure value" refers to a range of internal pressure values of the autoinjector <NUM> that may be equal to or below peak pressure values.

Increase in impact force also relates to the velocity µ<NUM> of the plunger rod <NUM> as it moves from the first position to the second position, and the velocity µ<NUM> of the impact system <NUM> as it travels from the second position to the third position. To minimize the occurrences of fracture of the reservoir <NUM>, the mass MP of a conventional plunger rod <NUM> may be increased to minimize the velocity µ<NUM> of the plunger rod <NUM> when the plunger rod <NUM> impacts the plunger <NUM> at the first impact event, as described above. Additionally, the mass of the carrier <NUM> may be increased to reduce the velocity µ<NUM> of the impact system <NUM> as the impact system <NUM> moves from the second position to the third position. In a preferred form, the total mass MT of the impact system <NUM> increases such that the velocity µ<NUM> of the impact system <NUM> is proportional to the inverse square root of the mass MT-<NUM>/<NUM> of the impact system <NUM>. By reducing the velocity µ<NUM> , the force of impact imparted onto the conical end <NUM> of the housing <NUM> at the second impact event is reduced. The mass MT of the impact system <NUM> may be increased up to three times the mass of a conventional impact system, depending on the drive force FD of the drive mechanism <NUM>.

While the drive mechanisms <NUM>, <NUM> of the two autoinjectors <NUM>, <NUM> thus far disclosed are described as including coil springs <NUM>, <NUM>, alternative versions of the drive mechanisms <NUM>, <NUM> can include other force generating means including, for example, pressurized gas, chemical reaction devices, materials undergoing phase changes, etc. Moreover, other types of springs other than coil springs could be utilized if desired.

The improvements to conventional drug delivery devices disclosed herein may be applied to another drug delivery device, such as an on-body drug delivery device shown in <FIG>. For example, a mass of a plunger rod <NUM> of an on-body injector <NUM> may be increased relative to the drive force FD of a drive mechanism <NUM> to avoid component failure. <FIG> illustrates a wearable on-body drug delivery device <NUM>. The device <NUM> may include a housing <NUM> that can be attached to a patient. The drug delivery device <NUM> includes a reservoir <NUM>, a drive <NUM>, and a drug delivery member <NUM>. The reservoir <NUM> may be defined at least in part by a rigid-walled cylinder <NUM> having a distal end <NUM> and a proximal end <NUM>. A plunger <NUM> is disposed within the reservoir <NUM> and fitted to move along a longitudinal axis B of the reservoir <NUM> between the proximal end <NUM> and the distal end <NUM> to force a drug out of the reservoir <NUM> and into a drug delivery member <NUM>. The drug delivery member <NUM> is in fluid communication with the reservoir <NUM> at a proximal end <NUM> of the drug delivery member <NUM>.

The drive mechanism <NUM> may be similar in structure and operation to the drive mechanism <NUM>, <NUM> for moving the plunger rod <NUM>, <NUM> along the syringe <NUM>, <NUM>, as described above with reference to <FIG>. The drive mechanism <NUM>, which may include a spring, is coupled to a proximal end <NUM> of a plunger rod <NUM>. A distal end <NUM> of the plunger rod <NUM> is spaced a distance Z from a proximal end <NUM> of the plunger <NUM>. In operation, the drive mechanism <NUM> drives the plunger rod <NUM> toward the plunger <NUM>. The plunger rod <NUM> is configured to make contact with the proximal end <NUM> of the plunger <NUM> and to urge the plunger <NUM> along the B axis through the reservoir <NUM>. Other drive mechanisms, such as pressurized gases, chemical reaction devices, materials undergoing phase changes and the like, may also be used to apply a drive force FD to the plunger rod <NUM> to move the plunger <NUM> along the cylinder <NUM>.

A method of manufacturing a drug delivery device, e.g. drug delivery devices <NUM>, <NUM>, <NUM> illustrated in <FIG> described herein, includes providing a reservoir, which may be a conventional syringe (see <FIG>) or a cylinder (see <FIG>), a plunger disposed within and moveable relative to the reservoir, and a drive mechanism configured to move a plunger rod by a drive force FD. To avoid component fracture, the method includes selecting a plunger rod having a mass MP based on a ratio MP/FD of mass MP of the plunger rod to drive force FD in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf). Once a suitable plunger rod has been manufactured or selected based on the desired mass, the plunger rod is provided and coupled to the drive mechanism. To manufacture a drug delivery device that sustains at least two impact events, a housing having a distal end and a proximal end is provided. The method further includes selecting a carrier having a mass based on a ratio of total mass MT of the impact system, i.e. total combined mass of the plunger rod, plunger, reservoir, and carrier, to drive force FD (MT/FD) in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf). Once a suitable carrier has been manufactured or selected based on the overall mass of the impact system <NUM>, the carrier is provided to the device by enclosing the reservoir within the carrier.

Autoinjectors and on-body injectors provide sufficient drive power to facilitate delivery of viscous drugs at high injection speeds with little human effort. Just as each type of drug delivery device may be useful for a particular drug or patient, different types of drive mechanisms with varying power capabilities may be suitable for injecting particular types of drugs. To illustrate the method of the present disclosure, two types of drug delivery devices (a "one impact event device" and a "two impact event device") and two types of drive mechanisms may be chosen based on a particular drug.

To manufacture a drug delivery device that sustains one impact event without component failure, the method may include providing a spring that is configured to provide a drive force in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf). For this drive mechanism, a plunger rod having a mass in a range of approximately <NUM> to approximately <NUM> may be provided. In another example, the method may include providing a spring that is configured to provide a drive force in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf). For this drive mechanism, a plunger rod having a mass in a range of approximately <NUM> to approximately <NUM> may be provided.

To manufacture a drug delivery device that sustains at least two impact events without component failure, such as the autoinjector <NUM> in <FIG>, the method may include providing a spring that is configured to provide a drive force to the impact system, i.e. the plunger rod, the plunger, the carrier, and the reservoir, in a range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf). For this particular drive mechanism, an impact system may be provided that has a total mass in a range of approximately <NUM> to approximately <NUM>. If a drive force in the range of approximately <NUM> N (<NUM> kgf) to approximately <NUM> N (<NUM> kgf) is required, an impact system may be provided that has a total mass in a range of approximately <NUM> to approximately <NUM>. The drug delivery device according to the present disclosure is not limited to the drug delivery devices <NUM>, <NUM>, <NUM> illustrated in <FIG>, but may be any drug delivery device that is susceptible to component failure due to impact events.

The components of the drug delivery device, and specifically the plunger rod <NUM>, <NUM>, <NUM>, plunger <NUM>, <NUM>, <NUM>, reservoir <NUM>, <NUM>, <NUM>, and carrier <NUM>, may each be made from a material higher in density than materials conventionally used for these components. The drug delivery device may be made too meet the mass to drive force ratio of the present disclosure. Alternatively, existing drug delivery devices may be modified to meet the desired performance ratio by providing small weights or additives to the components or by replacing new components to existing devices. The components may be made of an AVF-type plastic, polymer, steel, and/or a combination of suitable materials.

The above description describes various systems and methods for use with a drug delivery device. It should be clear that the drug delivery device and method can further comprise use of a medicament listed below with the caveat that the following list should neither be considered to be all inclusive nor limiting. The medicament will be contained in a reservoir. In some instances, the reservoir is a primary container that is either filled or pre-filled for treatment with the medicament. The primary container can be a cartridge or a pre-filled syringe.

For example, the drug delivery device or more specifically the reservoir of the device may be filled with colony stimulating factors, such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the drug delivery device may be used with various pharmaceutical products, such as an erythropoiesis stimulating agent (ESA), which may be in a liquid or a lyophilized form. An ESA is any molecule that stimulates erythropoiesis, such as Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxy polyethylene glycol-epoetin beta), Hematide®, MRK-<NUM>, INS-<NUM>, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well as the molecules or variants or analogs thereof as disclosed in the following patents or patent applications : <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; and <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>.

An ESA can be an erythropoiesis stimulating protein. As used herein, "erythropoiesis stimulating protein" means any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to and causing dimerization of the receptor. Erythropoiesis stimulating proteins include erythropoietin and variants, analogs, or derivatives thereof that bind to and activate erythropoietin receptor; antibodies that bind to erythropoietin receptor and activate the receptor; or peptides that bind to and activate erythropoietin receptor. Erythropoiesis stimulating proteins include, but are not limited to, epoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta, and analogs thereof, pegylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1/hematide), and mimetic antibodies. Exemplary erythropoiesis stimulating proteins include erythropoietin, darbepoetin, erythropoietin agonist variants, and peptides or antibodies that bind and activate erythropoietin receptor (and include compounds reported in <CIT>and <CIT>) as well as erythropoietin molecules or variants or analogs thereof as disclosed in the following patents or patent applications: <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; and <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>.

Examples of other pharmaceutical products for use with the device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); other biological agents such as Enbrel® (etanercept, TNF-receptor /Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim , G-CSF, hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such as Sensipar® (cinacalcet). The device may also be used with a therapeutic antibody, a polypeptide, a protein or other chemical, such as an iron, for example, ferumoxytol, iron dextrans, ferric glyconate, and iron sucrose. The pharmaceutical product may be in liquid form, or reconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins set forth below, including fusions, fragments, analogs, variants or derivatives thereof:.

Also included can be a sclerostin antibody, such as but not limited to romosozumab, blosozumab, or BPS <NUM> (Novartis). Further included can be therapeutics such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX or XGEVA. Additionally, included in the device can be a monoclonal antibody (IgG) that binds human Proprotein Convertase Subtilisin/Kexin Type <NUM> (PCSK9). Such PCSK9 specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab), as well as molecules, variants, analogs or derivatives thereof as disclosed in the following patents or patent applications: <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>.

Also included can be talimogene laherparepvec or another oncolytic HSV for the treatment of melanoma or other cancers. Examples of oncolytic HSV include, but are not limited to talimogene laherparepvec (<CIT> and <CIT>); OncoVEXGALV/CD (<CIT>); OrienX010 (<NPL>); G207, <NUM>; NV1020; NV12023; NV1034 and NV1042 (<NPL>).

Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural processes. TIMP-<NUM> is expressed by various cells or and is present in the extracellular matrix; it inhibits all the major cartilage-degrading metalloproteases, and may play a role in role in many degradative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequence of TIMP-<NUM>, and the nucleic acid sequence of a DNA that encodes TIMP-<NUM>, are disclosed in <CIT>. Description of TIMP mutations can be found in <CIT> and <CIT>.

Also included are antagonistic antibodies for human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecule that target the CGRP receptor and other headache targets. Further information concerning these molecules can be found in <CIT>.

Additionally, bispecific T cell engager (BiTE®) antibodies, e.g. BLINCYTO® (blinatumomab), can be used in the device. Alternatively, included can be an APJ large molecule agonist e.g., apelin or analogues thereof in the device. Information relating to such molecules can be found in PCT Publication No. <CIT>.

In certain embodiments, the medicament comprises a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody. Examples of anti-TSLP antibodies that may be used in such embodiments include, but are not limited to, those described in <CIT>, and <CIT>, and <CIT>. Examples of anti-TSLP receptor antibodies include, but are not limited to, those described in <CIT>. In particularly preferred embodiments, the medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated as A5 within <CIT>.

At least some of the techniques of this disclosure similarly can be applied to other drug delivery devices. For example, drug delivery devices generally suitable for simulation using the techniques of this disclosure can include hand-held injectors or on-body injectors. More generally, the techniques of this disclosure can be applied to devices in which a component that advances a liquid drug (or another liquid) uses coil compression, torsion, or another type of mechanical energy storage. Moreover, these techniques can be applied to non-mechanical systems such as propellant-driven systems.

Although the autoinjectors, on-body injector, systems, methods, and elements thereof, have been described in terms of exemplary embodiments, they are not limited thereto. The detailed description is to be construed as exemplary only and does not describe every possible embodiment of the invention because describing every possible embodiment would be impractical, if not impossible. Numerous alternative embodiments could be implemented, using either current technology or technology developed after the filing date of this patent that would still fall within the scope of the claims defining the invention.

Claim 1:
A drug delivery device (<NUM>, <NUM>, <NUM>) comprising:
a housing (<NUM>, <NUM>, <NUM>) having a distal end (<NUM>, <NUM>, <NUM>) and a proximal end (<NUM>, <NUM>, <NUM>);
a reservoir (<NUM>, <NUM>, <NUM>) having a distal end and a proximal end;
a carrier (<NUM>) encasing the reservoir;
a drug delivery member (<NUM>, <NUM>, <NUM>) in fluid communication with the distal end of the reservoir;
a plunger (<NUM>, <NUM>, <NUM>) disposed in and moveable relative to the reservoir;
a plunger rod (<NUM>, <NUM>, <NUM>) having a mass MP, a distal end (<NUM>, <NUM>, <NUM>) and a proximal end (<NUM>, <NUM>, <NUM>), the plunger rod being movable from (i) a first position, where the distal end of the plunger rod is spaced apart from the plunger to (ii) a second position, where the distal end of the plunger rod contacts the plunger; and
a drive mechanism (<NUM>, <NUM>, <NUM>) coupled to the proximal end of the plunger rod, the drive mechanism being configured to deliver a drive force FD to move the plunger rod from the first position to the second position,
wherein a ratio of the mass of the plunger rod to the drive force of the drive mechanism (MP/FD) is in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf);
wherein the plunger rod, plunger, carrier, and reservoir have a total combined mass MT; and
wherein a ratio of the total combined mass MT of the plunger rod, plunger, carrier, and reservoir to the drive force FD of the drive mechanism (MT/FD) is in a range of approximately a value greater than <NUM>/N (<NUM>/kgf) to approximately <NUM>/N (<NUM>/kgf).