Alternate siliconization process to containers and methods of making same

Abstract

In some examples, a syringe coating apparatus comprises a syringe and a centrifuge tube sized to accommodate the syringe. The centrifuge tube includes a reservoir space located at the bottom of the centrifuge tube to collect excess silicone oil during centrifugation. The apparatus may further include a circular support plate configured to center and stabilize the syringe within the centrifuge tube during centrifugation.

Description

TITLE OF INVENTIONALTERNATE SILICONIZATION PROCESS TO CONTAINERS AND METHODS OF MAKING SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 725,114 filed November 26, 2024, the entire contents of which are incorporated by reference herein.FIELD OF THE INVENTION

[0002] The present disclosure relates generally to syringes, such as pre-filled syringes. More specifically, the present disclosure relates to methods for improving the siliconization process of syringes and other devices and methods for assessing proper application thereof.BACKGROUND OF THE INVENTION

[0003] Silicone oil is a biocompatible synthetic lubricant safe for ingestion that is commonly used in pre-filled syringe (PFS) systems to allow for smooth syringe stopper movement while maintaining drug product sterility. Siliconization of pre-filled syringes is desirable for lubrication and improving patient drug delivery experience. The siliconization process lowers the frictional force of plunger stopper movement, allowing for easier injection and reduction in patient pain during drug product administration.

[0004] In recent years, siliconization methods have been the focus of both academic and industrial research due to their impact on patient experience and regulatory compliance. Recent findings of oil migration into drug product formulation and arduous injection due to needle-clogging and protein aggregation have also motivated investigation into the dynamics of silicone oil distribution.

[0005] Current industrial technology for siliconization involves spray coating methodologies. Spray coating through atomization of silicone oil allows for a thin application of the silicone oil. However, spray-coating application has been shown to produce variabilities in the silicone oil layer due to its dropwise application, leading to less consistent performance.

[0006] Moreover, a key factor in the design of current technology is the difficulty in characterization of the distribution of the silicone oil layer or particle formation that occurs. A better understanding of the resulting coating, and effect of stress (e.g., thermal, physical, aging) andplunger force on silicone oil distribution would allow for improved patient experience. The current industry standard is to use reflectometry devices such as Bouncer by Unchained Labs to measure silicone oil layer thickness. However, reflectometry-based measurements have critical limitations for temporally resolved studies of silicone oil dynamics. Measurements with such devices require an empty, dry syringe rendering direct studies of silicone oil within fill finished pre-filled syringes difficult to achieve.

[0007] Thus, there exists a need for devices that improve upon and advance the methods of applying silicone oil onto injectors and syringes, such as pre-filled syringes, and to assess and evaluate the proper application thereof.SUMMARY OF THE INVENTION

[0008] Described herein are syringe-coating systems. In some examples, a syringe-coating system comprises a syringe and a centrifuge tube sized to accommodate the syringe. The centrifuge tube includes a reservoir space located at the bottom of the centrifuge tube to collect excess silicone oil during centrifugation. The apparatus may further include a circular support plate configured to center and stabilize the syringe within the centrifuge tube during centrifugation.

[0009] In certain embodiments of the systems described herein, the syringe is pre-filled with a predetermined amount of silicone oil, the predetermined amount ranging from 0.05 g to 1.0 g. In certain embodiments of the systems described herein, the syringe is pre-filled with a predetermined amount of silicone oil, the predetermined amount ranging from 0.05 g to 0.4 g. In certain embodiments, the predetermined amount is 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g or 1.0 g of silicone oil.

[0010] In certain embodiments of the systems described herein, the circular support plate is configured to ensure circumferential uniform distribution of silicone oil toward a flange end of the syringe during the centrifugation.

[0011] In certain embodiments of the systems described herein, the reservoir space in the centrifuge tube is configured to drain excess silicone oil away from the syringe.

[0012] In certain embodiments, the systems described herein further comprise a centrifuge configured to rotate the syringe at speeds between 1,000 RPM and 10,000 RPM. In certain embodiments, the systems described herein further comprise a centrifuge configured to rotate the syringe at speeds between 1,000 RPM and 4,000 RPM. In certain embodiments, the centrifuge isconfigured to rotate the syringe at about 1,000 RPM, about 2,000 RPM, about 3,000 RPM, about 4,000 RPM, about 5,000 RPM, about 6,000 RPM, about 7,000 RPM, about 8,000 RPM, about 9,000 RPM or about 10,000 RPM. In certain embodiments, the centrifuge is configured to rotate the syringe at 1,000 RPM, 2,000 RPM, 3,000 RPM, 4,000 RPM, 5,000 RPM, 6,000 RPM, 7,000 RPM, 8,000 RPM, 9,000 RPM or 10,000 RPM.

[0013] In certain embodiments, the systems described herein further comprise a centrifuge configured to generate a silicone oil layer between 0.1 micron and 2 microns in thickness on an interior surface of the syringe.

[0014] In certain embodiments, the systems described herein further comprise a centrifuge configured to generate a silicone oil layer between 0.4 micron and 2 microns in thickness on an interior surface of the syringe. In certain embodiments, the silicon layer is 0.1 microns, 0.2 microns, 0.3 microns, 0.4 microns, 0.5 microns, 0.6 microns, 0.7 microns, 0.8 microns, 0.9 microns, 1.0 microns, 1.1 microns, 1.2 microns, 1.3 microns, 1.4 microns, 1.5 microns, 1.6 microns, 1.7 microns, 1.8 microns, 1.9 microns, or 2.0 microns thick.

[0015] In certain embodiments of the systems described herein, the centrifugation is configured to uniformly distribute the silicone oil on the syringe with a relative standard deviation (RSD%) of 15% or less. In certain embodiments of the systems described herein, the centrifugation is configured to uniformly distribute the silicone oil on the syringe with a relative standard deviation (RSD%) of 11% or less. In certain embodiments of the systems described herein, the centrifugation is configured to uniformly distribute the silicone oil on the syringe with a relative standard deviation (RSD%) of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%.

[0016] In certain embodiments, the systems described herein are operated at a temperature between 20 ° C and 100 ° C. In certain embodiments, the systems described herein are operated at a temperature of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100 ° C.

[0017] Also described herein are methods for coating a syringe. In some examples, a method for coating a syringe with silicone oil, comprises placing a pre-filled syringe containing a predetermined amount of silicone oil into a centrifuge tube; supporting and stabilizing the syringe with a circular support plate to ensure centering within the centrifuge tube; and centrifuging the syringe at a speed between 1,000 RPM and 10,000 RPM to cause uniform distribution of the silicone oil.

[0018] In certain embodiments, centrifuging is performed at a speed of 1,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments,26085 centrifuging is performed at a speed of 2,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 3,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 4,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 5,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 6,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 7,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 8,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 9,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe. In certain embodiments, centrifuging is performed at a speed of 10,000 RPM to cause uniform distribution of silicone oil toward the flange end of the syringe.

[0019] In certain embodiments of the methods described herein, centrifuging is performed for an amount of time necessary to achieve the desired coating. In certain embodiments of the methods described herein, centrifuging is performed between 1 to 30 minutes. In certain embodiments of the methods described herein, centrifuging is performed between 1 and 15 minutes. In certain embodiments of the methods described herein, centrifuging is performed for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 minutes. In certain embodiments of the methods described herein, centrifuging is performed at 4,000 RPM for 10 minutes.

[0020] In certain embodiments, the methods for coating a syringe described herein further comprise the step of allowing excess silicone oil to collect in a reservoir space at a bottom of the centrifuge tube.

[0021] In certain embodiments of the methods described herein, centrifuging is performed at a suitable rate to achieve a silicone oil layer thickness between 0.1 microns and 2.0 microns. In certain embodiments of the methods described herein, centrifuging is performed at a suitable rate to achieve a silicone oil layer thickness between 1.2 microns and 1.6 microns. In certain embodiments of the methods described herein, centrifuging is performed at a suitable rate to achieve a silicone oil layerthickness of 0.1 microns, 0.2 microns, 0.3 microns, 0.4 microns, 0.5 microns, 0.6 microns, 0.7 microns, 0.8 microns, 0.9 microns, 1.0 microns, 1.1 microns, 1.2 microns, 1.3 microns, 1.4 microns, 1.5 microns, 1.6 microns, 1.7 microns, 1.8 microns, 1.9 microns, or 2.0 microns thick.

[0022] In certain embodiments of the methods described herein, centrifuging is performed at a temperature between 20 ° C and 100 ° C. In certain embodiments, centrifuging is performed at a temperature of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100 ° C.

[0023] In certain embodiments, the methods for coating a syringe described herein further comprise the step of assessing the silicone oil distribution using a Bouncer mapping technique to ensure uniformity of a layer of the silicone.

[0024] In certain embodiments, the methods for coating a syringe described herein further comprise pre-heating the silicone oil to reduce viscosity and enhance uniformity of a layer of the silicone oil during centrifuging.

[0025] In some examples, a method for visualizing and analyzing silicone oil distribution in prefilled syringes comprises tagging the silicone oil with a fluorescent dye, applying the tagged silicone oil to a syringe via a centrifugation method, and using fluorescence imaging to observe the distribution and uniformity of the silicone oil layer within the syringe.

[0026] In certain embodiments of the methods described herein, the fluorescent dye is 4,4- Difluoro-l,3,5,7-Tetramethyl-4-Bora-3a,4a-Diaza-s-Indacene (BODIPY), with an excitation wavelength of 505 nm and emission wavelength of 515 nm or a BODIPY derivative. Other BODIPY variants may be used to tag the silicone oil such as (4,4-DifIuoro-l,3,5,7,8-Pentamethyl-4-Bora- 3a,4a-Diaza-s-Indacene) BODIPY with excitation at 493 and emission at 503 and 4,4-Difluoro-5,7- Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Dodecanoic acid, among others.

[0027] In certain embodiments of the methods described herein, the fluorescence imaging is performed in real-time during a syringe production process.

[0028] In certain embodiments of the methods described herein, the BODIPY-tagged silicone oil is applied to the pre-filled syringe at a thickness controlled by centrifugation parameters to achieve a uniform coating.

[0029] In certain embodiments, the methods for visualizing and analyzing silicone oil distribution in pre-filled syringes described herein, further comprises maintaining the concentration of the fluorescent dye at a predetermined ppm level to ensure minimal impact on the flow behavior of the silicone oil.

[0030] In certain embodiments of the methods described herein, the silicone oil layer thickness and distribution are mapped using fluorescent signal intensity for quality control and performance verification.

[0031] In certain embodiments, the methods for visualizing and analyzing silicone oil distribution in pre-filled syringes described herein, further comprises the step of filtering the silicone oil with the fluorescent dye through a 0.45 pm pore-size syringe filter to remove aggregates from the tagged oil.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Various embodiments of the presently disclosed syringes are disclosed herein with reference to the drawings, wherein:

[0033] Fig. l is a schematic front view of a pre-filled syringe;

[0034] Fig. 2A is an embodiment of a system for positioning a syringe inside a centrifuge tube for siliconization.

[0035] Fig. 2B illustrates two Bouncer single line scans comparing two methods of silicone oil application;

[0036] Fig. 2C illustrates two Bouncer mappings of the silicone oil layers from two types of applications;

[0037] Fig. 3 provides photographs showing a series of fluorescent images showcasing the use of BODIPY-tagged silicone oil (green fluorescence) in different syringe systems; and

[0038] Fig. 4 illustrates the chemical structure of BODIPY, a hydrophobic fluorescent dye used to tag silicone oil for visualization of silicone oil dynamics in pre-filled syringes.

[0039] Fig. 5 illustrates results of functional performance testing by Instron measurement as described in Example 4 below, showing results of centrifuge-on siliconization and no annealing, centrifuge siliconization, with 48 h annealing, and spray-on siliconization, solid lines represent break loose glide force of empty syringe, and dashed lines represent break loose extrusion force of water filled syringe.

[0040] Various embodiments are described below with reference to the appended drawings. It is to be appreciated that these drawings depict only some embodiments of the disclosure and are therefore not to be considered limiting of its scope.DETAILED DESCRIPTION OF THE INVENTION

[0041] Despite the various improvements that have been made to pre-filled syringes and the siliconization process, conventional methods suffer from some shortcomings as discussed above.

[0042] Therefore, there is a need for further improvements to the devices and methods used to improve upon and advance the methods of applying silicone oil onto syringes, such as pre-filled syringes, and to assess and evaluate the proper application thereof. Among other advantages, the present disclosure may address one or more of these needs.

[0043] As used herein, the term “proximal,” when used in connection with a component of a syringe or injector, refers to the end of the component closest to the user’s hands when holding the device; whereas the term “distal,” when used in connection with a component of a syringe or injector, refers to the end of the component closest to the needle insertion site during use. Moreover, as used herein, the terms “medicament,” “medication,” and “drug” are used generically interchangeably and it will be understood that the ampoules described herein may be used to store, deliver, or administer vaccines, biologies, therapeutics, medicaments, topical ointments, and the like.

[0044] Reference is now made to FIG. 1, which shows an exemplary prefilled-syringe 100 contained within a needle safety device known in the art. It will be understood that though a needle within a safety device is shown, the disclosure is not thus limited. For example, though a pre-filled syringe with a staked needle is shown, it will be understood that the principles disclosed herein are equally applicable to other types of injectors (e.g., syringes with removable needles, auto-injectors, or on-body (wearable) injectors having needles, etc ). Pre-filled syringe 100 generally comprises two main portions, a plunger rod assembly 110 and a barrel 120. Plunger rod assembly 110 generally extends between a proximal end 112 and a distal end 114, and generally comprises an elongated piston 115 extending between a plunger flange (or press) 117 and a stopper 130.

[0045] A cylindrical barrel 120 extends between proximal end 122 and distal end 124 and comprises a body 125 defining a lumen 126 for accepting a portion of plunger rod assembly 110. Body 125 further comprises a barrel flange 127 adjacent proximal end 122 and defines a reservoir “R” that holds a medicament, drug, saline, or other substance for injecting into a patient’s body. An internally threaded stopper 130 is disposed inside lumen 126 of body 125. In one embodiment, stopper 130 is made of an elastomeric material such as natural rubber, synthetic rubber, thermoplastic elastomers, or combinations thereof, and comprises an opening to receive and mate with a portion of plunger rod assembly 110 by advancing a portion of the plunger rod assemblyinside the barrel lumen 126 and rotating at least one of coupler 119 and stopper 130 relative to the other. Though not shown, a syringe may optionally include a cap 135 disposed over a needle coupled to the distal end of the barrel 120. Once the cap removed, the user may pierce the patient’s skin with the needle, then push on plunger flange 117 to drive the plunger to deliver a medicament through needle into the patient’s body.

[0046] Development of alternative siliconization methods is desirable to improve the performance of PFS delivery systems. A significant challenge in siliconization lies in the inhomogeneity and control of silicone oil layer thickness. Thus, there is a need for innovative methods to 1) produce consistent uniformly coated syringes and / or 2) visualize silicone oil dynamics. In some embodiments, a new technique for creating uniform syringe coating with fine control of silicone oil thickness is contemplated, and this technique may include using centrifuge technology instead of the spray coating and dip-coating techniques.

[0047] In certain embodiments, the instant disclosure shows a new methodology of siliconization by applying amounts of silicone oil to PFS, followed by centrifugation. Through testing of key centrifuge parameters of centrifugation time, speed, and temperature, control of silicone oil layer thickness was readily achieved. Importantly, centrifugation siliconization shows a significant improvement to layer homogeneity. After an annealing step, the centrifuge siliconization method generates a silicone oil layer that is functionally similar to commercial spray-on approach.

[0048] With reference to Figs. 2A-2C, a new method for coating syringe systems using centrifugation techniques will now be described. In some examples, a predetermined amount (e.g., between 0.05 g and 0.4 g) of silicone oil may be added to the interior of a syringe (e.g., within the barrel). In one experiment, 0.1 g of silicone oil was added within the barrel of a 1 mb syringe. The syringes were then transferred to a 50 mb centrifuge tube for centrifugation. Fig. 2A is a photograph of a system 200 for fixturing of a syringe for centrifugation with a 1 mb syringe 210 held in a 50 mb centrifuge tube 220. In this example, the 1 mb syringe 210 is supported by a generally circular support plate 215 that keeps the syringe centered and stable within the centrifuge tube 220. In some examples, the syringe 210 is placed “needle-side” up and centrifugation in this manner may push oil down uniformly toward the flange end 212 of the pre-filled syringe 210. In some examples, a reservoir space 222 in the bottom of the centrifuge tube 220 may allow for excess silicone oil to be drained. Several centrifugation parameters were evaluated for silicone oil distribution from a range of 1,000 - 4,000 RPM (3,739 xg) at 25 to 100 degrees C, and silicone oil layer distribution may beevaluated by an industry standard technique (e.g., Bouncer mapping technique or other). Based on experimentation, it is contemplated that a method of centrifugation coating would include spinning the syringes down at 4,000 RPM (3,739xg) and 25 ° C for 10 minutes to generate a circumferential uniform silicone oil layer between 1 micron and 2 microns thick (e.g., between 1.6 microns and 1.2 microns, or 1.4 microns in thickness).

[0049] Fig. 2B illustrates representative Bouncer single line scans of sprayed-on siliconized syringe 230 (top) and the disclosed centrifugation siliconization 240 (bottom). As seen in Fig. 2B, when comparing representative line scans of the in-line sprayed on method to the centrifugation method, the centrifugation process generated a more uniform silicone oil layer with a Relative Standard Deviation (RSD%) of 11 compared to sprayed on with an RSD% of 24.

[0050] Additionally, by observing the corresponding Bouncer mappings in Fig. 2C., there was evidence that the centrifugation mapping 260 (bottom) shows a more uniform layer as evidenced by the “holes” 252 in the silicone oil layer in the sprayed-on process mapping 250 (top). Thus, experimentation shows that the instant pre-filled syringe siliconization by centrifugation process may perform equal to, or better than, traditional spray on methods. Specifically, the “centrifuged-on” method may provide for a more controlled-thickness silicone oil application by varying centrifuge process parameters such as centrifuge revolutions per minute (RPM), duration (min), and temperature. In some examples, it may also be possible to pre-heat the silicone oil prior to the centrifuge operation to further reduce viscosity toward minimizing the resulting layer thickness. This technique may allow a manufacturer to deliver prescribed silicone oil layer thicknesses on demand in a repeatable and / or reproducible manner. Furthermore, as shown, the centrifuged-on method inherently offers improved uniformity over the traditional spray method in which the number of droplets landing per unit area possesses randomness. This may reduce or eliminate silicone oil nonuniformities that appear as “hot spots” or “holes” in a coating.

[0051] In addition to the method of applying silicone oil via centrifuge, the present disclosure also contemplates a technique to view silicone oil dynamics in syringes by using fluorescence to confirm layer thickness and uniform distribution to verify performance of the siliconization techniques. This visualization process (e.g., by using white light reflectometry and laser interferometry) may be performed to any syringe or instrument that has been coated, including those coated with the centrifugation method, the dip-coating method and / or the spray coating method. In some examples, real-time fluorescent visualization (see exemplary fluorescent images in Fig. 3) may be used as an26085 investigative tool to map silicone oil thickness distribution and flow mechanics as a function of time under various geometrical scenarios, represented by fluorescent signal intensity. This visualization may be accompanied by fluorescent tagging techniques that will be described in greater detail below. The real-time fluorescent visualization may be performed at one or more points in the production cycle, including (i) during stoppering, (ii) stiction formation through stationary stopper as a function of elapsed time, (iii) aspiration force investigation in the shoulder region of the syringe, and / or (iv) studying the interaction of liquid / drug product at the silicone oil-stopper interface, and many other scenarios prevalent to use cases. In Fig. 3, a series of fluorescent images showing BODIPY-tagged silicone oil used to tag vial stoppers and syringes using the centrifuged-on method. BODIPY-tagged silicone oil appears green but is depicted as grey shading in Fig. 3. The left set of images show vial stopper silicone oil distribution, and a uniform layer thickness is visible in a sliced stopper. The middle set of images show centrifuged-on fluorescent silicone oil in glass syringes at various levels. The right set of images show a syringe with untagged silicone oil, which appears white when compared to the image on the far right with the tagged silicone oil. These visualization and characterization techniques may enable technology that allow the manufacturer to quantitate syringe sterile barrier breakage or migration of oil into drug product, understand needle clogging, and / or offer better batch-to-batch consistency. Given its high commercial impact in terms of determining product sterility, syringe quality control, regulatory compliance, and siliconization methods, this technology may allow for better-informed syringe coating and testing.

[0052] To aid in visualization, the silicone oil used in these techniques may be a fluorescently- tagged silicone oil. In some examples, fluorescent tagging may be used as a mode of investigating the distribution of silicone oil and / or silicone oil dynamics as a function of interaction with liquid / drug product contained within the syringe and / or plunger stopper movement. Thus, a series of material characterizations including surface tension and rheometry may be used to compare the mechanical and chemical behaviors of untagged versus tagged silicone oil while minimizing the concentration of fluorophore dye to the ppm level to render the impact of fluorescent tagging innocuous in altering the flow behavior of silicone oil.

[0053] In some examples, 4,4-Difluoro-l,3,5,7-Tetramethyl-4-Bora-3a,4a-Diaza-s-Indacene (C13H15BF2N2) (BODIPY), or a derivative thereof, may be used to tag the silicone oil. In some examples, any BODIPY class of fluorescent molecules for tagging may be used. The dye may be a green-fluorescent dye with excitation at 505 nm and emission at 515 nm that allows for novel26085 visualization of silicone oil dynamics within pre-filled syringes through tagging. Other BODIPY variants may be used to tag the silicone oil such as (4,4-Difluoro-l,3,5,7,8-Pentamethyl-4-Bora- 3a,4a-Diaza-s-Indacene) BODIPY with excitation at 493 and emission at 503 and 4,4-Difluoro-5,7- Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Dodecanoic acid, among others. Additionally, BODIPY is highly hydrophobic, meaning insoluble in water, and remains within nonpolar environments like silicone oil. In some examples, the BODIPY may be tetramethyl-substituted for enhanced hydrophobicity compared to traditional BODIPY. Owing to these characteristics, BODIPY may be utilized to tag silicone oil to understand protein aggregation within drug product. Certain amounts of BODIPY may be mixed with the silicone oil typically used for the siliconization process. This BODIPY-tagged silicone oil may then be filtered through a 0.45 pm pore-size syringe filter to remove BODIPY aggregates from the tagged oil. One example of a chemical structure of the hydrophobic fluorescent dye used in a study is shown in Fig. 4.

[0054] In some experiments, functional testing was performed comparing tagged and untagged silicone oil by a drop shape analyzer, and it was observed that tagging had limited to no effect on silicone oil. The measured contact angle for untagged silicone oil on glass is 10.13 (±0.52) °, which is comparable to the contact angle measurement for BODIPY-tagged silicone oil on glass of 12.66 (±2.62) °. Oil may be transferred between stopper ribs with the push and pull movement of the stopper. The stopper ploughing through the oil to form a thick layer may be readily visible. Interestingly, it was observed that the silicone oil aspirated, creating a suction effect near the dispensing end. Compared to spray-on, our centrifuged-on method is comparably smooth to sprayed- on methodology.EXAMPLESExample 1: Centrifuge Siliconization

[0055] Silicone-oil free (SOF) PFS were first coated with a range of silicone oil from 10 - 400 mg. PFS were first mounted upright in a fixture for weighing on a balance. Silicone oil was most uniform when a predetermined amount of silicone was applied as a uniform ring near the flange of the syringe. After waiting 10 minutes for the silicone oil to drop down towards the needle end, PFS are then transferred to a 50 mL falcon tube with fixturing as shown in Fig. 2A with a foam ring as the support plate to hold the PFS in the center and a vial cap with a hole drilled through to allow silicone oil to flow through upon centrifugation to be captured by a reservoir space in the bottom of the26085 centrifuge tube. Following mounting, PFS were then centrifuged by a Sorvall X4R Pro Series Centrifuge to uniformly distribute the silicone oil across the syringe. Centrifuge parameters of time, speed, and temperature were adjusted to alter resultant siliconization thickness. For any centrifugation performed at elevated temperature, the centrifuge was allowed to reach temperature for 30 minutes before centrifugation.Example 2: Silicone Distribution

[0056] Siliconization thickness and homogeneity were measured by a Bouncer device. Syringes were measured through white light reflectometry and red laser interferometry. Prior to each measurement session, Bouncer measurement was validated by measuring a 500 nm layer thick standard. Syringes were scanned across 10 mm lines with a resolution of 100 points per line at angles of 0, 60, 120, 180, 240, and 300°. Bouncer data was outputted as a map of silicone layer thickness for each scanned line. Silicone oil layer homogeneity is represented by the standard deviation (SD) and the relative standard deviation (RSD) across the entire sample. Percent RSD was calculated by 100 * s / |x|, where 5 is the sample standard deviation and is the sample mean.Example 3: Mechanical TestingBreak-loose Glide Force (BLGF) Testing

[0057] Break-loose glide force (BLGF) testing was performed on an Instron model tester. BLGF testing was performed by pushing a plunger through an empty syringe. PFS were stoppered by hand to target plunger stopper position at a predetermined distance (measured from the top of the flange to the top of the plunger stopper). A 50N load cell was used for increased force measurement sensitivity. Syringes were held in place by a 3D printed fixture and threaded with a plunger rod. The plunger rod was depressed at a speed of 0.01 mm / s to maximize the frictional force for measurement to observe differences more readily in functional performance. The test was set to complete when 20N of force is detected, indicating end of plunger movement. Break loose force and average extrusion force were measured. Raw data was exported for visualization with the Plotly Python library. Traces were aligned to the break loose force peak for comparison across siliconization processes.26085Centrifuged-on Parameter Testing

[0058] Centrifugation siliconization distributes silicone oil uniformly toward the flange end of the PFS, analogous to spin-coating of thin films to attain nano-scale layer thicknesses with a uniform height. Several centrifugation parameters were evaluated for silicone oil distribution from a range of 1,000 - 4,000 RPM (3,739xg) at 20 °C. Initial testing of PFS centrifuging without a fixture resulted in undesirable coating uniformity. A fixture as shown in Fig. 2A was used to achieve uniform coating to prevent tilting and rotation of PFS during centrifugation. Without the fixture, coating results in cases in which silicone oil can spiral along the barrel of the syringe with an RSD of 302%. In contrast, after utilizing a fixture for centrifugation at the same centrifugation settings, the silicone oil layer has an improved RSD of 10%, SD of 67.6nm with a layer thickness of 676 nm. Initially, this fixture was made from cutting foam rings to seat the PFS into the centrifuge tube. With this approach, it was found that spinning the syringes down at 4,000 RPM (3,739 xg) and 20 °C for 10 minutes generated a uniform silicone oil layer 1.4 microns thick.

[0059] A table summary of these results and tested conditions is shown in Table A.

[0060] As shown in Table A, parameter space and results of centrifugation siliconization method demonstrate the effect of centrifuge speed, initial silicone oil application, and centrifuge time on layer thickness and RSD. In this experiment, all samples were heated to 40°C.

[0061] From iterative testing, the thinnest possible layer thickness was targeted, and it was found that centrifugation temperature and time had the largest impact on resultant thickness while initial silicone application amount had a minimal effect. With the goal of targeting ~ 500 nm thickness layers consistent with commercial results, centrifuge speed was only tested at 3000 (1850 nm) and 4000 rpm (1635 nm) (Table A). It was demonstrated that theoretically, centrifuge speed is a26085 parameter that can tune silicone oil thickness as well; however, to generate the thinnest siliconization, all other experiments were performed at 4000 rpm. Temperature was tested at 40°C as a higher temperature lowers the viscosity of the silicone oil, allowing for smoother and thinner siliconization using the in-unit centrifuge temperature control. If desired, the syringes and silicone oil may be pre-heated to a target temperature before centrifugation to improve temperature uniformity. Desirable results of centrifugation siliconization were achieved at 4000 rpm, 40 °C for 30 minutes, generating a PFS with a silicone oil thickness of 401 nm, 12% RSD, 48.12 nm SD. As seen in Fig. 2C, when comparing representative line scans of the in-line sprayed on method to the centrifugation method, the centrifugation process generated a more uniform silicone oil layer with an RSD% of 11 compared to sprayed on with an RSD% of 24 in addition to the lack of a gradient for the centrifuged-on application. When observing the Bouncer mappings, for instance in Fig. 2C, further evidence was found to suggest that centrifugation produces a more uniform layer as evidenced by the lack of “holes” in the silicone oil layer when compared to the spray ed-on process. Iterative testing of centrifugation time and temperature was performed to reach the thinnest silicone oil layer possible to approach thicknesses near spray-on levels. Through centrifugation siliconization, it was possible to generate uniform siliconization with layer thicknesses ranging from 1800 - 400 nm with precision by tuning centrifuge time. Through these characterization methods, it was found that the novel PFS siliconization by centrifugation produces more uniform layers than traditional spray on methods.Example 4: Functionality Testing

[0062] Using the best result conditions from centrifuged-on parameter testing, several SOF PFS for functionality testing were siliconized. As shown by Fig. 5, functionality testing began with centrifuged-on siliconization directly after the centrifugation process and saw an average break loose force of 2.693 N and an average extrusion force of 1.506 N. When compared to the spray-on measurements, centrifuged-on siliconization performs much worse as spray-on has a much lower average break loose force of 1.379 N and an average glide force of 0.276 N. As the glide force is an order of magnitude higher in the centrifuged-on condition, factors beyond simple layer thickness were hypothesized to be responsible. Additionally, initial stopper movement consistently measured 3 peaks, which aligns with the spacing of the stopper ribs, across initial 5mm of travel, indicating that the silicone oil coating was easily rubbed off by the stopper with the centrifuged-on process. Due to26085 these clearly observable differences, it was theorized that simple layer height is not sufficient to account for the differences in functional performance. To remedy and understand the difference in functional performance, centrifuged-on siliconized PFS were annealed at 100 °C for 48 hours before assembly with a plunger. As shown in Fig. 5, a drastic improvement in BLGF with annealing was achieved, similar in performance to spray-on application with an average break loose force of 1.324 N and an average glide force of 0.327 N. These results indicate PFS functional performance is impacted by the age of the coating and that annealing improves the lubricity performance of silicone oil. These findings are in agreement with prior accounts of silicone oil annealing and PFS age.

[0063] It is to be understood that the embodiments described herein are merely illustrative of the principles and applications of the present disclosure. For example, it may be possible to generate a thinner layer by first spraying-on for a thin layer and then smoothen the layer by the centrifugation process. Moreover, certain components or steps of a method of using the device are optional, and the disclosure contemplates various configurations and combinations of the steps disclosed herein. Additionally, as used herein, the term “coupleable” refers to two or more components that cooperate, join or engage one another. It will be understood that where two or more components are said to be “coupled” or “coupleable” that they may also be unitarily or integrally formed. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present disclosure as defined by the appended claims.

[0064] It will be appreciated that the various dependent claims and the features set forth therein can be combined in different ways than presented in the initial claims. It will also be appreciated that the features described in connection with individual embodiments may be shared with others of the described embodiments.

Claims

CLAIMS1. A syringe-coating system, comprising: a syringe; a centrifuge tube sized to accommodate the syringe, the centrifuge tube having a reservoir space located at the bottom of the centrifuge tube to collect excess silicone oil during centrifugation; and a circular support plate configured to center and stabilize the syringe within the centrifuge tube during centrifugation.

2. The system of claim 1, wherein the syringe is pre-filled with a predetermined amount of silicone oil, the predetermined amount ranging from 0.05 g to 0.4 g.

3. The system of claim 1 or claim 2, wherein the circular support plate is configured to ensure circumferential uniform distribution of silicone oil toward a flange end of the syringe during the centrifugation.

4. The system of any one of claims 1-3, wherein the reservoir space in the centrifuge tube is configured to drain excess silicone oil away from the syringe.

5. The system of any one of claims 1-4, further comprising a centrifuge configured to rotate the syringe at speeds between 1,000 RPM and 4,000 RPM.

6. The system of any one of claims 1-5, further comprising a centrifuge configured to generate a silicone oil layer between 0.4 micron and 2 microns in thickness on an interior surface of the syringe.

7. The system of claim 2, wherein the centrifugation is configured to uniformly distribute the silicone oil on the syringe with a relative standard deviation (RSD%) of 11% or less.

8. A method for coating a syringe with silicone oil, comprising:placing a pre-filled syringe containing a predetermined amount of silicone oil into a centrifuge tube; supporting and stabilizing the syringe with a circular support plate to ensure centering within the centrifuge tube; and centrifuging the syringe at a speed between 1,000 RPM and 10,000 RPM to cause uniform distribution of the silicone oil.

9. The method of claim 8, further comprising the step of allowing excess silicone oil to collect in a reservoir space at a bottom of the centrifuge tube.

10. The method of claim 8 or claim 9, wherein centrifuging is performed at 4,000 RPM for 10 minutes.

11. The method of claim 8 or claim 9, wherein centrifuging is performed at a suitable rate to achieve a silicone oil layer thickness between 1.2 microns and 1.6 microns.

12. The method of any one of claims 8-11, further comprising the step of assessing the silicone oil distribution using a Bouncer mapping technique to ensure uniformity of a layer of the silicone.

13. The method of any one of claims 8-12, further comprising pre-heating the silicone oil to reduce viscosity and enhance uniformity of a layer of the silicone oil during centrifuging.

14. A method for visualizing and analyzing silicone oil distribution in a pre-filled syringe, comprising: tagging the silicone oil with a fluorescent dye; loading the silicone oil with the fluorescent dye into the pre-filled syringe; applying the tagged silicone oil to the syringe via a centrifugation method; and using fluorescence imaging to observe distribution and / or uniformity of a silicone oil layer within the pre-filled syringe.

15. The method of claim 14, wherein the fluorescent dye is 4,4-Difluoro-l,3,5,7- Tetramethyl-4-Bora-3a,4a-Diaza-s-Indacene (BODIPY), with an excitation wavelength of 505 nm and emission wavelength of 515 nm.

16. The method of claim 14 or claim 15, wherein the fluorescence imaging is performed in real-time during a syringe production process.

17. The method of claim 15, wherein the BODIPY-tagged silicone oil is applied to the prefilled syringe at a thickness controlled by centrifugation parameters to achieve a uniform coating.

18. The method of any one of claims 14-17, further comprising maintaining the concentration of the fluorescent dye at a predetermined ppm level to ensure minimal impact on the flow behavior of the silicone oil.

19. The method of any one of claims 14-18, wherein the silicone oil layer thickness and distribution are mapped using fluorescent signal intensity for quality control and performance verification.

20. The method of any one of claims 14-19, further comprising the step of filtering the silicone oil with the fluorescent dye through a 0.45 pm pore-size syringe filter to remove aggregates from the tagged oil.

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