The present disclosure relates to accelerated testing methods and systems of silicone drainage in medical devices, and in particular, syringes used in a medication delivery device.
Syringes are used to deliver medication. Syringes include a barrel extending between a flange and a shoulder that leads to a needle hub. The medication may be contained within the barrel and dispensed by movement of a piston slidable along the inner walls of the barrel. When stored, the syringes have the needle end facing up and the flange end pointing down. Silicone or other substances are disposed along the inner walls of the syringe for lubrication and extended sealing. After syringes have been siliconized, the syringes may be stored for significant periods of time. During this storage time, the initial distribution of silicone may change as the silicone drains from the top to the bottom (that is, from the needle end toward the flange end) under gravity. Understanding these changes due to silicone drainage is necessary to appreciate the effects of changes in silicone distribution of empty syringes during storage on injection functionality and in silicone particulate levels in prefilled syringes once filled with medication. Currently, only empirical methods are available for these types of assessments and the methods require studies with extended durations to document the effects of empty component storage and filled syringe storage over time. These studies can require substantial duration. As an example, it can take over 6 years to study the combined effects of the maximum allowed empty and filled storage times for the syringes, if up to four years for the storage of empty syringe barrels before filling is desired and up to two years for the storage of filled syringes is desired after the maximum empty storage has elapsed. Accordingly, there is a need to understand the silicone drainage from a first principles perspective and to use this understanding to identify a way to accelerate the studies so that useful information can be created in a much shorter time than 6 years and/or overcome one or more of these and other shortcomings of the prior art.
In one embodiment, a testing method for accelerating silicone drainage rate for a siliconized syringe is disclosed. The method includes one or more of the following steps: Placing a syringe including a film of silicone in a predefined orientation into a centrifuge holder of a centrifuge system. The syringe includes a needle end and an opposite, flange end. The predefined orientation of the syringe includes the flange end being disposed farther away from a center axis of the centrifuge system than the needle end or the needle end being disposed farther away from said center axis of the centrifuge system than the flange end. Activating a centrifugation of the centrifugation holder of the centrifuge system with the syringe at a predetermined G-rate and for a predetermined period of a time. Ending the centrifugation of the centrifugation holder with the syringe after the period time has elapsed. Assessing one or more injection functionality parameters of the syringe after the elapsed period of time.
In another embodiment, a testing method for accelerating silicone drainage rate for a siliconized syringe is provided. The method includes one or more of the following steps: Placing a syringe including a film of silicone in a predefined orientation into a centrifuge holder of a centrifuge system. The syringe includes a needle end and an opposite, flange end. The predefined orientation of the syringe includes the flange end being disposed farther away from a center axis of the centrifuge system than the needle end or the needle end being disposed farther away from the center axis of the centrifuge system than the flange end.
Activating a centrifugation of the centrifugation holder of the centrifuge system with the syringe at a predetermined G-rate and for a predetermined period of a time (tfc), wherein the period of time (tfc) is expressed:
where tfg is a gravity drainage time to be simulated and tfc is the centrifuge run time at speed co in the centrifuge system with a rotor arm length of rc, a matching point of z, a length of the syringe of LF, and g is an acceleration due to gravity. Ending the centrifugation of the centrifugation holder with the syringe after the period time has elapsed.
In yet another embodiment, a syringe testing apparatus for a centrifuge system is disclosed. The syringe includes a barrel with a barrel diameter and a flanged end diameter greater than the barrel diameter. The apparatus includes a body defining a plurality of cells extending between an upper end and a lower end of the body. Each of the cells includes a diameter sized to receive a barrel of the syringe but not a flange of the syringe. A base plate includes a plurality of recesses. Each of the recesses is arranged in coaxial alignment with a corresponding cell of the body. Each of the recesses includes a diameter sized greater than the diameter of the cell, and a depth sized to capture a thickness of the flange of the syringe. The base plate includes attachment features for secure attachment to the lower end of the body.
Additional embodiments of the disclosure, as well as features and advantages thereof, will become more apparent by reference to the description herein taken in conjunction with the accompanying drawings. The components in the figures are not necessarily to scale. Moreover, in the figures, like-referenced numerals designate corresponding parts throughout the different views.
For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended.
After syringes have been siliconized, the syringes may be stored for significant periods of time (where the syringes are typically stored with the needle end up and the flange end down, although aspects of the present disclosure are applicable to syringes stored with flange end up and needle end down, or any orientation in between). During this storage time the initial distribution of silicone may change as the silicone drains from the top to the bottom under gravity. Such changes can be understood if the long term performance of the syringes is to be controlled. This disclosure describes a centrifugation approach used to accelerate the current empirical methods that are used to investigate silicone drainage in syringes, which currently takes years to complete. In one form, a method to accelerate aging of siliconized syringes using a centrifuge is described. Fundamental predictive relationships for actual aging and simulated aging by centrifugation are related. Applying the method of centrifugation is useful for rapidly simulating syringe functionality change after long-term storage in the empty state.
By way of illustration, the syringe alone may be used as a medication delivery device or may be used in conjunction with another device which is used to set and to deliver a dose of a medication, such as pen injectors, infusion pumps and auto-injectors. The medication may be any of a type that may be delivered by such a medication delivery device. Syringes may be provided empty or with a medication. The term “medication” refers to one or more therapeutic agents including but not limited to insulins, insulin analogs such as insulin lispro or insulin glargine, insulin derivatives, GLP-1 receptor agonists such as dulaglutide or liraglutide, glucagon, glucagon analogs, glucagon derivatives, gastric inhibitory polypeptide (GIP), GIP analogs, GIP derivatives, oxyntomodulin analogs, oxyntomodulin derivatives, therapeutic antibodies and any therapeutic agent that is capable of delivery by the above device. The medication as used in the device may be formulated with one or more excipients. The device is operated in a manner generally as described above by a patient, caregiver or healthcare professional to deliver medication to a person.
An exemplary syringe 10 is illustrated in
The syringe hub 32 may include a needle extending distally thereform or may be adapted to receive an attachable needle assembly (not shown). A distal end of the syringe barrel 16 along the shoulder portion 32 includes a passageway 38 which is in fluid communication with the chamber 28. An elongate needle cannula 35 (shown in dashed) includes a lumen extending therethrough between its proximal and distal ends 40, 42. Proximal end 40 of the needle cannula 35 is coupled to the distal needle end 14 of the syringe barrel 16 through the passageway 38 to place the needle lumen in fluid communication with the chamber 28. In illustrated example, the needle cannula 35 is securely attached to the syringe body 11 through the use of adhesives or other attachment means. In other examples, the needle may be removably attached to the syringe body 11 such as through needle attachment hub which is permanently attached to the needle cannula and frictionally attached around needle hub 32 of the syringe. For the purposes of this disclosure, the testing of the syringes may involve only the syringe body of syringe 10, with the plunger and piston assembly 15 and needle 35 omitted, which is why these elements are shown dashed.
An exemplary method to accelerate the testing of silicone drainage in syringes is to use centrifugation as a way to replace gravity forces with centrifugal forces that are higher than gravity forces. The resulting silicone drainage from centrifugal forces can be strongly correlated to drainage resulting from gravity, and a centrifugation test can be used to replace the long period of gravity studies, potentially changing the study from years to hours. To this end, a mathematical model that allows for both drainage under gravity and centrifugal forces was created and used to analyze a set of test data from a centrifugation syringe silicone drainage test. This model leads to a quasilinear first order Partial Differential Equation (PDE) that can be solved numerically.
A mathematical model was developed for falling thin film flow drainage in the syringe barrels. The main assumptions involved in building this model are: (1) The film is thick enough that the continuum approach to fluid dynamics is applicable. For example, a value of 1 μm (micron) may be given as a lower bound on the typical length scale for a liquid system in order for the continuum hypothesis to be valid, see Hunter, S. C., 1976, “Mechanics of Continuous Media”, Ellis Horwood Limited Publisher, ISBN 85312-042-0, although testing has demonstrated less than 1 micron. To the contrary, the silicone film in syringes can be much smaller than 1 μm so the validity of extending the continuum approach to such small films was determined when the model results were compared to experimental results, such as shown, for example, in
The model developed covers both the case of gravity induced drainage and centrifugal force induced drainage from a cylindrically shaped syringe, such as the syringe 10, with a film 50 initially of size δo(z), as shown in
In general the initial thickness of film 50 will vary along the length of the syringe barrel 16, although in
where μ is the dynamic viscosity of the liquid, ρ is the density of the liquid, and g is the gravity/centrifugal force. For gravity flow, g(z) is a constant g, but for the centrifuge flow, g(z) is expressed as follows:
g(z)=(rc+z)ω2 (A.2)
where rc is the radius of the centrifuge arm, ω is the angular velocity of the centrifuge in radian/sec and z measures the distance from the end of the centrifuge arm along the syringe.
Given that velocity u is a function of r only, Equation (A.1) can be written with ordinary derivatives rather than partial derivatives. This gives
The equation for α(z) can be written as:
Where β represents the influence of centrifugal force such that β=0 indicates that the flow is under gravity and β=1 indicates that the flow is under centrifugal forces. Combining Equations (A.3) and (A.4) and integrating the combined equation and applying the boundary conditions shown in Equations (A.6) and (A.7). In the following, the explicit dependence of acceleration α on direction z will be assumed and so α(z) will be written simply as acceleration α.
Equation (A.3) can be integrated twice to yield an expression for velocity as a function of density, acceleration, viscosity, and layer thickness once the appropriate bouncary conditions are applied. Here, the boundary conditions are:
where C1 is a constant of integration. C1 can be found from one of the boundary conditions for the velocity u, which is that the shear stress at the boundary of the film 50 is zero. Mathematically this translates to:
when
(equivalent to r=γ R) and γ=(D−2δ)/D
where D is the inside diameter of the syringe barrel 16 surrounding the chamber 28 and δ is the thickness of the film 50.
The second boundary condition is that there is no slip of the liquid at the inner surface of the glass syringe barrel. This gives
u=0 when
(equivalent to r=R)
Integrating Equation (A.3) and applying boundary conditions in Equations (A.6) and (A.7) yields:
Now the velocity profile as a function of r is known, the flowrate of the film 50 can be calculated when the thickness is δ. The flowrate Q in the z direction is given by:
Substituting Equation (A.8) into Equation (A.9) gives:
The integral in Equation (A.10) can be evaluated to yield:
where, by the definition of dimensionless variable γ, see Equation (A.7), γ<1.
Now that the equation for the flowrate Q is provided, as a function of the film thickness, δ, the unsteady state evolution of the film thickness δ as a function of z can be evaluated. An unsteady state mass balance over the slice between z and z+Δz can be written as
The volume in the slice, ΔV, is given by
Equation (A.13) can be simplified to
ΔV=π(Dδ−δ2)Δz. (A.14)
Substituting Equation (A.14) into Equation (A.12) gives as follows.
Dividing both sides of Equation (A.26) by Δz and taking the limit as Δz→0, gives
which can be simplified to
Since film thickness δ<<inside diameter D of the syringe barrel, Equation (A.17) can be simplified further:
where Q is given by Equation (A.11). It is now convenient to introduce another dimensionless ψ where:
Equation (A.18) now becomes:
Substituting Equation (A.11) for Q into Equation (A.20) gives:
Equation (A.21) can be reduced to:
In Equation (A.22) the fact that Ψ is a function of z and s(ψ) is a function of z as well. The ordinary derivatives in Equation (A.22) can be found from Equations (A.4) and (A.21)
The equations for s(ψ) and its derivative can be simplified since film thickness δ<<inside diameter D and so ψ<<1. The function ln(1−x) can be expanded as
Expanding all the terms in the equations for s(ψ) and its derivative gives:
These equations can be simplified to the following by using the leading term in the equations.
Substituting into Equation (A.22) and simplifying leads to
The final step in the model is to make it dimensionless in direction z and time, t, by normalizing z by Lf (the length of the syringe from the tip nearest the centrifuge center where the film thickness measurements start to the other end of the syringe, as shown in
where now z and t are the dimensionless z and t variables and the model runs from 0<=z<=1 and 0<=t<=1. The equation for α(z) in the dimensionless z form becomes:
and for the derivative it becomes:
The details involved in the derivation of the model equation (1.0) are given in Equations A.1 to A.33.
The final step in the model is to make it dimensionless in z and t by normalizing z by Lf (the length of the syringe from the tip nearest the centrifuge center where the film thickness measurements start to the other end of the syringe) and tf, the total time horizon of the model. Dimensionless z and t lead to the final form of the mathematical model equation:
The model runs from 0<=z<=1 and 0<=t<=1. The equation for α(z) in the dimensionless z form becomes:
and for the derivative it becomes:
Note that in Equation (2.3), the derivative is with respect to the original z, not the dimensionless form of z. Hence the Lf does not appear in Equation (2.3). The form of the model in Equation (2.1) is that of a wave equation where the wave speed VW is given by:
Thus, the speed at which the silicone moves along the syringe barrel is directly proportional to tf, silicone density ρ, the acceleration g when under gravity, and rc when under centrifugal forces. The wave speed is proportional to the square of inside diameter D and ω. The wave speed is inversely proportional to Lf. All of these variables are constant for a given configuration and so these variables will not change the wave speed for a syringe being centrifuged for simulated aging. The variables that will change are z and φ. The wave speed increases as z increases which reflects the longer radius for the centrifugal force. The wave speed also decreases as φ decreases in a quadratic way, whether this is gravity or centrifugal force driven. To this end, as the movement of the silicone proceeds the value of φ tends to fall. The rate at which φ falls depends on φ itself so the biggest change in φ occurs at the earlier times once the movement has started.
The model also indicates how the time should be scaled in order to see the same effect between gravity and centrifugal flow. Denoting the value of tf as tfg for gravity flow and tfc for centrifugal flow, the ratio of tfc to tfg is given by:
In Equation (2.5) a value of z must be chosen, remembering that 0<=z<=1. If z is set=0 to do the scaling in Equation (2.5), the centrifugal force on the entire silicone layer will be underestimated and so the centrifuging time equivalent to a time under gravity will be overestimated. The opposite will occur if z is set to 1. Given that the dependence of the centrifugal force is linear in z, the best value of z to use is likely to be closer to 0.5. If the wave speed depended on the value of φ in a linear way then the best value to use would be 0.5 exactly. In the Example below, the assertion that z=0.5 is better than z=0 or z=1 will be tested. A parameter T_Fct can be defined and used to rewrite Equation (2.5) as:
T_Fct=0.0 will be designated as the Low condition, T_Fct=0.5 will be designated as the Mid condition, and T_Fct=1.0 will be designated as the High condition. These conditions at which the tip (T_Fct=1.0), middle (0.5), and flange (0.0) points are subjected to, such that the aging time matches the corresponding point along the syringe.
Simulations using the model presented here in Equations (2.1) and (2.2) have reproduced experimental drainage in syringes under centrifugal forces.
This model also shows that, based on the first principles of fluid flow under gravity and centrifugal forces, it is possible to scale the time require for a given amount of silicone drainage using Equation (2.6). Simulations have shown that of the three conditions Low, Medium, and High described above, the most accurate scaling for silicone flow is produced by a value of T_Fct=0.5. This matching point can be varied at the selection of the operator using this formula. Matching various points may be preferred if different aspects of the syringe behavior need to be understood. An example can be the use of a spring-driven autoinjector where a thinner silicone layer at the tip might be of more concern due to the higher glide force it may create or increased injection times that may be observed with self-injection devices. In that case it would be better to select a T_Fct of 0 to better match this point.
Because the centrifugal force is a linear function of the distance from the center of the centrifuge but the acceleration due to gravity is effectively a constant, a small ratio of the centrifuge arm length to syringe barrel length will lead to in accurate scaling. The system described here refers to systems where this ratio is at least 4:1.
Note that one skilled in the art can apply other approaches to developing the model based on the key assumptions described above to achieve similar modelling results while the principles are based on the key assumptions and the approach outlined in the steps that follow the model development. For example, a model can be developed using Cartesian coordinates and assuming that because the film is very thin, the flow is planar rather than cylindrical. In this case, equation (A.3) becomes:
and if we assume that the glass surface corresponds to y=0, the two boundary conditions equivalent to (A.6) and (A.7) become:
and u=0 at y=0 (B.3)
Here Equations (B.2) and (B.3) are equivalent to (A.6) and (A.7) in the cylindrical coordinate model.
Integrating twice and applying the boundary conditions yields the equivalent to equation (A.8):
The equivalent to equation (A.10) becomes:
Evaluating the integral yields the result that is equivalent to (A.11):
The volume slice described in (A.14) becomes:
ΔV=πDδΔz (B.7)
This means that Equation (A.18) is exactly the same here:
Because flat geometry is assumed, the dimensionless term Ψ is less meaningful. Therefore, the equivalent to equation (2.4) is displayed below in terms of δ and not Ψ:
Equation (3.0) can be integrated numerically in time to obtain a relationship for δ(z,t), given an initially known silicone distribution of δ(z,t0).
In a preliminary test, a set of 20 syringes, of a configuration such as the ones described herein, were divided into two groups. The first group was designated as samples 1 to 10 and the second as samples 11 to 20. The samples 1 to 10 were centrifuged for a time equivalent to 2 years of gravity flow and the samples 11 to 20 were centrifuged for a time equivalent of 1 year of gravity flow. A layer film including silicone was measured pre and post centrifugation using various test methods, such as, for example, an analytical method to characterize sprayed-on silicone oil layer thickness distribution in empty prefilled syringes using instruments, also referred to as a RapID. The measurement device reported the thickness at z distances of 0 to 49 mm in 1 mm increments. At each z point the device measures 9 points along the circumference. These 9 points were averaged to give the average silicone layer thickness at each z point.
Any centrifuge system may be used for the test. In one example, the centrifuge system 100 includes a Jouan KR4-22 (S/N 403100041) centrifuge, such as shown in
The operational characteristics of the rotor 120 of centrifuge system 100, that is the speed, whether constant or variable, or other features, are controlled by a system controller 130, shown as dashed to indicate it is housed within the system housing 122. The system controller 130 includes at least one processor 132 in electric communication with and internal memory 134 (e.g., internal flash memory, on-board electrically erasable and programmable read-only memory (EEPROM), etc.) and a power source, such as a voltage source. The system controller 130 may be coupled to a variety of operational sensors 136 that are integrated with the centrifuge and includes control logic operative to perform the operations described herein to control operations of the centrifuge, such as the revolution rate and operational time. The processor 132 includes controls logic operative to perform the operations described herein, including starting and stopping the centrifuge. Note that other control mechanisms may be selected, provided that they control the acceleration and time adequately to effect the simulation described heretofore.
In one example, a centrifuge system includes a body, a rotor rotatable relative to the body about a center axis by a motor, a compartment associated with the rotor, one or more syringes having a film of silicone arranged in the compartment in a predefined orientation where a flange end of the syringe is disposed farther away from the center axis than a needle end of the syringe, and a controller operably coupled to the motor, the controller configured to: activate a centrifugation of the syringe at a predetermined G rate and for a period of a centrifuge run time (tfc), wherein the simulation time is expressed: tfg/tfc=((r_C+zL_F)ω{circumflex over ( )}2)/g), where tfg is a gravity drainage time to be simulated and tfc is a centrifuge run time at speed ω in the centrifuge system with a rotor arm length of rc, a matching point of z, a length of the syringe of LF, and g is an acceleration due to gravity. In one example, the ratio of the rotor arm length to a syringe length is greater than or equal to 4:1. The predetermined G rate is constant or is variable. The product of zLf can be multiplied by a T_fct factor, wherein T_fct factor is a value between 0 and 1. In one example, T_fct factor is 0.5. The system may include a bucket fixture configured to retain the syringe in the predefined orientation, wherein the compartment is configured to receive the bucket fixture. The bucket fixture may include a body defining a plurality of holding cells having a diameter sized to receive a barrel of the syringe and sized to not receive the flange end of the syringe, and a base plate defining a plurality of recesses arranged in coaxial alignment with a corresponding holding cell of the body, each of the recesses having a diameter sized greater than the diameter of the holding cell and sized to receive the flange end of the syringe, and a depth sized to capture a thickness of the flange end of the syringe, the base plate including attachment features for secure attachment to the lower end of the body.
An exemplary embodiment of a fixture bucket assembly 200 is shown in
The syringes are placed within the holding cells 235 with the flange end away from the center of the rotor. The syringe's placement in the fixture bucket is shown in
Such as shown in
One example of a testing method, referred to as 1900, for accelerating silicone drainage rate for an empty pre-filled siliconized syringe is shown in
where tfg is the gravity drainage time to be simulated and tfc is the centrifuge run time at speed ω in a centrifuge with an arm length of rc, a matching point of z, a syringe length of LF, and g is the acceleration due to gravity. In other examples, said parameters includes any one of break-loose force, glide force, total silicone content, silicone layer profile, self-injection device injection time, or any combination thereof.
The assessment in step 1940 may be accomplished by filling (which optionally can be air for assessing syringe break loose and plunger glide forces) and plungering the syringe, then testing with a suitable fixture and force-displacement test stand to determine break-loose force and glide force. A suitable description can be found in ISO 11040. Silicone content can be accomplished by any relevant analytical method, including gravimetrically weighing empty syringe both pre- and post-solvent extraction to remove the silicone and drying to remove the solvent. Alternatively, the solvent can also be collected and assayed to determine the quantity of silicone extracted. For determining the silicone layer profile, an analytical method to characterize sprayed-on silicone oil layers in empty prefilled syringes may be used, such as, with reference to PDA J Pharm Sci Technol. 2018 May-June; 72(3):278-297. doi: 10.5731/pdajpst.2017.007997. Epub 2018 Jan. 17.
One of the benefits of the method is the provision of accelerated data for clinical trials. Another of the benefits is to enable better and faster data set for drug filing. Results may lead to changes in container enclosure system or lubrication profile. The testing method provides a use of centrifugation to model long term effect of gravity pull.
An example test method, such as method 1900, is performed with the centrifuged system 100. An example of the data resulting from applying the method is shown in FIG. to, which shows the pre- and post-silicone layer profiles, the silicone layer thickness in nanometer vs. distance in the z direction in millimeters for equivalent of 2 years, for sample 4. The first curve 1000 is the initial (pre centrifugation) silicone profile and the second curve 1010 is the silicone profile after (post) centrifugation for the equivalent of 2 years. In the test configuration, the position z=0 is at the open end of the syringe where the measurements start, in this case, with the RapID. With RapID, measurements are from about 1 mm inside the flange (the “zero” on the graph in
The initial pre silicone layer, the silicone layer thickness in nanometers vs. distance in the z direction in millimeters, for samples 11-20 is shown in
Parameter Specification for the Model
Using the above geometrical information, the centrifugation time equivalent to a gravity falling time of 1 year and 2 years can be found based on the ratio of the centrifugal acceleration to the acceleration due to gravity. Results of the Centrifuge time calculations are shown in Table 2.
The radius used for the centrifugal acceleration is (rC+T_Fct*Lf). There are three sets of calculations shown in Table 2. The first set assumes that the representative value of z to use for the calculations is z=0 (T_Fct=0.0). The results show that for 1 year a centrifugation time of 6.26 hours should be used and for 2 years it should be 12.51 hours. If the value of T_Fct=0.5 is used as the representative point for the centrifuge acceleration calculations then these times are 5.59 hours and 11.17 hours respectively. Finally if the value of T_Fct=1.0 is used as the representative point for the centrifuge acceleration calculations then these times are 5.07 hours and 10.09 hours respectively.
Results
The results of general centrifugation can be demonstrated using the methods described herein. Results can be determined and characterized using the following categories, as shown in Table 3.
The results in
For each sample the following charts can be viewed. In
The next sections look at summary of the results across all the samples.
It is possible to model the drainage of the silicone layer in syringes using a centrifuge to accelerate the drainage and get results that agree reasonably well with experiment especially for longer periods of time. Given also that the model shows that the predicted results using a centrifuge, which has a large enough radius to minimize the effects of acceleration variation along the syringe, are similar to the results obtained under gravity drainage using an equivalent centrifugation time, it can be concluded that accelerated testing of silicone drainage using a centrifuge running for an equivalent drainage time will reproduce drainage under gravity. Further the results show that the best point to use to estimate silicone drainage from the syringe over time comes by matching the centrifugal force at the point that is halfway along the syringe length and that other matching points may be more appropriate for a specific combination of syringe properties of concern (silicone layer thickness, glide force, etc.) and a specific application (i.e. a manual prefilled syringe, an autoinjector, or a bolus injector).
To clarify the use of and to hereby provide notice to the public, the phrases “at least one of <A>, <B>, . . . and <N>” or “at least one of <A>, <B>, . . . <N>, or combinations thereof” or “<A>, <B>, . . . and/or <N>” are defined by the Applicant in the broadest sense, superseding any other implied definitions hereinbefore or hereinafter unless expressly asserted by the Applicant to the contrary, to mean one or more elements selected from the group comprising A, B, . . . and N. In other words, the phrases mean any combination of one or more of the elements A, B, . . . or N including any one element alone or the one element in combination with one or more of the other elements which may also include, in combination, additional elements not listed.
While various embodiments have been described, it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible. Accordingly, the embodiments described herein are examples, not the only possible embodiments and implementations. Furthermore, the advantages described above are not necessarily the only advantages, and it is not necessarily expected that all of the described advantages will be achieved with every embodiment.
Various aspects are described in this disclosure, which include, but are not limited to, the following aspects:
1. A testing method for accelerating silicone drainage rate for a siliconized syringe, comprising: placing a syringe including a film of silicone in a predefined orientation into a centrifuge holder of a centrifuge system, the syringe including a needle end and an opposite, flange end, the predefined orientation of the syringe including the flange end being disposed farther away from a center axis of the centrifuge system than the needle end or the needle end being disposed farther away from the center axis of the centrifuge system than the flange end; activating a centrifugation of the centrifugation holder of the centrifuge system with the syringe at a predetermined G-rate and for a predetermined period of a time; ending the centrifugation of the centrifugation holder with the syringe after the period time has elapsed; and assessing one or more injection functionality parameters of the syringe after the elapsed period of time.
2. The testing method of aspect 1, wherein the film of the syringe includes a non-cross-linked silicone.
3. The testing method of any one of the preceding aspects, wherein the time elapsed is expressed as (t)=[(intended simulation time) (acceleration due to gravity)]÷[(square of centrifuge revolution rate)(Distance from center of rotor hub to matching point on the syringe barrel)].
4. The testing method of any one of the preceding aspects, wherein a ratio of a length of a rotor arm of the centrifuge system to a length of a barrel of the syringe is greater than or equal to 4:1.
5. The testing method of any one of the preceding aspects, wherein one of the parameters includes a break-loose force.
6. The testing method of any one of the preceding aspects, wherein one of the parameters includes a glide force.
7. The testing method of any one of the preceding aspects, wherein one of the parameters includes a silicone content.
8. The testing method of any one of the preceding aspects, wherein one of the parameters includes a silicone layer profile.
9. The testing method of any one of the preceding aspects, wherein one of the parameters includes an injection time of said syringe.
10. The testing method of any one of the preceding aspects, wherein the predetermined G-rate is constant.
11. The testing method of any one of the preceding aspects, wherein the predetermined G-rate is variable.
12. A testing method for accelerating silicone drainage rate for a siliconized syringe, including: placing a syringe including a film of silicone in a predefined orientation into a centrifuge holder of a centrifuge system, the syringe including a needle end and an opposite, flange end, the predefined orientation of the syringe including the flange end being disposed farther away from a center axis of the centrifuge system than the needle end or the needle end being disposed farther away from the center axis of the centrifuge system than the flange end; activating a centrifugation of the centrifugation holder of the centrifuge system with the syringe at a predetermined G-rate and for a predetermined period of a time (tfc), wherein the period of time (tfc) is expressed:
where tfg is a gravity drainage time to be simulated and tfc is the centrifuge run time at speed ω in the centrifuge system with a rotor arm length of rc, a matching point of z, a length of the syringe of LF, and g is an acceleration due to gravity; and ending the centrifugation of the centrifugation holder with the syringe after the period time has elapsed
13. The testing method of aspect 12, wherein a ratio of a length of a rotor arm of the centrifuge system to a length of a barrel of the syringe is greater than or equal to 4:1.
14. The testing method of any one of aspects 12-13, wherein the predetermined G-rate is constant.
15. The testing method of any one of aspects 12-13, wherein the predetermined G-rate is variable
16. The testing method of any one of aspects 12-15, further including assessing one or more injection functionality parameters of the syringe after the elapsed period of time.
17. The testing method of aspect 16, wherein one of the parameters includes at least one of a break-loose force, a glide force, a silicone content, and a silicone layer profile.
18. The testing method of aspect 16, wherein one of the parameters includes an injection time of the syringe, which may be a self-injection syringe device, also referred to as an autoinjector.
19. A syringe testing apparatus for a centrifuge system, the syringe having a barrel with a barrel diameter and a flanged end diameter greater than the barrel diameter, the apparatus including: a body defining a plurality of cells extending between an upper end and a lower end of the body, each of the cells having a diameter sized to receive a barrel of the syringe but not a flange of the syringe; and a base plate defining a plurality of recesses, each of the recesses arranged in coaxial alignment with a corresponding cell of the body, each of the recesses having a diameter sized greater than the diameter of the cell, and a depth sized to capture a thickness of the flange of the syringe, the base plate including attachment features for secure attachment to the lower end of the body.
20. The syringe testing apparatus of aspect 19, wherein each of the holding cells has a syringe shape configuration.
This application claims benefit to U.S. provisional application No. 62/573,843, filed Oct. 18, 2017, which is hereby incorporated herein by reference in its entirety.
Filing Document | Filing Date | Country | Kind |
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PCT/US2018/055331 | 10/11/2018 | WO | 00 |
Publishing Document | Publishing Date | Country | Kind |
---|---|---|---|
WO2019/079088 | 4/25/2019 | WO | A |
Number | Name | Date | Kind |
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10269117 | Matayoshi | Apr 2019 | B1 |
20130209766 | Felts | Aug 2013 | A1 |
20150335823 | Weikart | Nov 2015 | A1 |
20170108451 | Gertz | Apr 2017 | A1 |
20190231986 | Devaraneni | Aug 2019 | A1 |
Number | Date | Country |
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0173363 | Oct 2001 | WO |
2017086366 | May 2017 | WO |
Number | Date | Country | |
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20200016324 A1 | Jan 2020 | US |
Number | Date | Country | |
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62573843 | Oct 2017 | US |