Downstream plasma treated siliconized plastic syringe barrels and related syringes and methods

Abstract

The presently disclosed subject matter provides a plasma treated plastic syringe barrel having a plasma treated lubricant coating and an inner surface having a reduced number of particles compared to the inner surface of a plastic syringe barrel having an untreated lubricant coating; a plasma treated plastic syringe barrel having a plasma treated lubricant coating and an inner surface having an extremely low particle surface density; a related syringe; a related filled syringe having an extremely low particle content in solution; a method of treating an eye; a method of producing a plastic syringe barrel having a stable lubricating layer; a related method of producing a syringe; a related syringe; and a related method of treating an eye.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 057,284, filed July 27, 2020, the contents of which are incorporated herein by reference in their entirety.

[0003] Statement regarding federally funded research or development

[0004] This invention was developed with government funding granted by the National Eye Institute, a division of the National Institutes of Health, under license number R44EY024461. The United States holds certain rights to this invention. Technical Field

[0005] This invention relates to plastic syringes for delivering drugs. Background Technology

[0006] As the biopharmaceutical market continues to grow, the demand for injectable drug dosage forms is also increasing. Pre-filled syringes and drug products supplied in glass vials for administration using universal syringes are the most common packaging configurations. Syringes are typically made of glass or plastic.

[0007] Current trends regarding pre-filled syringes favor the use of glass pre-filled syringes utilizing calcined silica gel (e.g., Gerrescheimer). Baked-on Glass syringes), pre-filled plastic syringes using chemically cross-linked silicone (Schott). ) and silicone-free plastic syringe systems (e.g., Terumo PLAJEX) TM West Daikyo and BDSterifill TM However, these unassembled, nested pre-filled syringes and associated manufacturing equipment—even without considering the cost of the biopharmaceutical itself—can be costly.

[0008] Compared to pre-filled syringes, user-fillable plastic syringes and assembled generic plastic syringes offer significant cost reductions (sometimes up to 95%) for compound drug products. However, generic plastic syringes are associated with sub-visible particles derived from lubrication to allow the plunger stop to slide within the syringe barrel, and protein aggregation induced by sub-visible silicone oil particles after drug filling. Silicone-modified plastic pre-filled syringes are also associated with silicone oil sub-visible particles; therefore, glass pre-filled syringes continue to account for a large portion (approximately 70%) of the pre-filled syringe market, and product development for plastic pre-filled syringes focuses on silicone-free plastic syringes.

[0009] There remains a need for a simple and safe solution that can take advantage of the stability and safety provided by the lyophilization of biopharmaceuticals in vials, and the extremely low cost of generic plastic syringes for bedside drug administration or compounded drugs, while providing a more stable layer of silicone oil with a minimization of subvisible particulate content.

[0010] Plastic syringes are also used for intravitreal injection into the eye to treat macular degeneration and diabetic retinopathy. These expensive biopharmaceuticals are provided in vials that need to be filled into generic syringes prior to administration. The silicone oils used in these generic syringes introduce particulate contamination into the drug solution injected into the patient's eye. Several complications ranging from elevated intraocular pressure to visual floaters have been reported due to these silicone oil particles. The FDA requires ophthalmic solutions to meet its USP 789 particulate contamination guidelines. USP 789 requires ≥ 10 microns no more than 50 particles / ml and ≥ 25 microns no more than 5 particles / ml. While the biologic solutions in vials must meet the USP 789 requirements, the syringes used to administer these drugs are unregulated and introduce particulate contamination that leads to patient complications. There remains a need for a low particulate plastic syringe for injection of ophthalmic solutions provided in vials. SUMMARY

[0011] The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane-based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species; and wherein the number of particles greater than 8 microns in diameter in the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane-based lubricant coating is reduced by at least 75%, 80%, 85%, 90%, or 95% respectively compared to the interior surface of a plastic syringe barrel with a polysiloxane-based lubricant coating. The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane-based lubricant coating, wherein each plasma treatment comprises a downstream plasma generated at atmospheric pressure; and wherein the number of particles greater than 8 microns in diameter in the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane-based lubricant coating is reduced by at least 75%, 80%, 85%, 90%, or 95% respectively compared to the interior surface of a plastic syringe barrel with a polysiloxane-based lubricant coating.

[0012] The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species; and wherein the surface density of the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane based lubricant coating is < 600 particles per 12 cm 2 , < 500 particles per 12 cm 2 or < 400 particles per 12 cm 2 , wherein the particles are greater than 8 microns in diameter. The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane based lubricant coating, wherein each plasma is a downstream plasma generated at atmospheric pressure; and wherein the surface density of the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane based lubricant coating is < 600 particles per 12 cm 2 , < 500 particles per 12 cm 2 or < 400 particles per 12 cm 2 , wherein the particles are greater than 8 microns in diameter.

[0013] The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species; and wherein the surface density of the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane based lubricant coating is < 100 particles per cm 2 , < 90 particles per cm 2 , < 50 particles per cm 2 , < 40 particles per cm 2 , < 35 particles per cm 2 or < 30 particles per cm 2 , wherein the particles are greater than 8 microns in diameter. The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane based lubricant coating, wherein each plasma treatment comprises a downstream plasma generated at atmospheric pressure; and wherein the surface density of the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane based lubricant coating is < 100 particles per cm 2 , < 90 particles per cm 2 , < 50 particles per cm 2 , < 40 particles per cm2 ≤ 35 particles / cm 2 or ≤ 30 particles / cm 2 wherein the particle diameter is greater than 8 microns.

[0014] The presently disclosed subject matter describes a syringe comprising a plastic syringe barrel, a plunger rod, a plunger stopper, and a needle as described herein. The presently disclosed subject matter describes a syringe comprising a plastic syringe barrel, a luer lock or slip tip, a plunger rod, and a plunger stopper. In some embodiments, the polysiloxane-based lubricant coating is a silicone oil coating. In some embodiments, the plastic syringe barrel comprises about 0.005 mg / cm 2 to about 0.5 mg / cm 2 silicone oil. In some embodiments, the polysiloxane-based lubricant coating is a polydimethylsiloxane coating.

[0015] The presently disclosed subject matter describes a syringe comprising a plastic syringe barrel containing a solution as described herein. In some embodiments, the particle content in the solution is ≤ 50 particles / ml for any particles having a diameter ≥ 10 μm, or ≤ 5 particles / ml for any particles having a diameter ≥ 25 μm. In some embodiments, the syringe comprises a plastic syringe barrel containing a solution comprising an anticoagulant, a vaccine, or a recombinant protein. In some embodiments, the syringe comprises a plastic syringe barrel containing a solution of an anti-VEGF protein. In some embodiments, the syringe comprises a plastic syringe barrel containing a solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab. In some embodiments, the syringe comprises a plastic syringe barrel containing an ophthalmic solution. In some embodiments, the particle content in the ophthalmic solution is ≤ 50 particles / ml for any particles having a diameter ≥ 10 μm, or ≤ 5 particles / ml for any particles having a diameter ≥ 25 μm. In some embodiments, the maximum fill volume of the plastic syringe barrel is 1.0 ml, 0.5 ml, 0.3 ml, 0.25 ml, 0.10 ml, or 0.05 ml.

[0016] The presently disclosed subject matter describes a method of treating an eye comprising intravitreal administration of a solution or an ophthalmic solution to the eye with a syringe as described herein.

[0017] The presently disclosed subject matter describes a method of producing a plastic syringe barrel having a stable layer of silicone oil comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2a plasma treated inner surface of the plastic syringe barrel to form a uniform coating of silicone oil; and exposing the uniform coating of silicone oil to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; wherein the surface density of the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is ≤ 600 particles per 12 cm 2 , ≤ 500 particles per 12 cm 2 or ≤ 400 particles per 12 cm 2 , where the particles are greater than 8 microns in diameter. The presently disclosed subject matter describes a method of producing a plastic syringe barrel with a stable layer of silicone oil comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of silicone oil to the plasma treated inner surface of the plastic syringe barrel to form a uniform coating of silicone oil; and exposing the uniform coating of silicone oil to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; wherein the surface density of the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is ≤ 600 particles per 12 cm 2 , ≤ 500 particles per 12 cm 2 or ≤ 400 particles per 12 cm 2 , where the particles are greater than 8 microns in diameter. In some embodiments, the method further comprises waiting at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour, 2 hours, or 3 hours before exposing the uniform coating of silicone oil to the plasma.

[0018] The presently disclosed subject matter describes a method of producing a plastic syringe barrel with a stable layer of silicone oil comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of silicone oil to the plasma treated inner surface of the plastic syringe barrel to form a uniform coating of silicone oil; and exposing the uniform coating of silicone oil to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; wherein the surface density of the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is ≤ 100 particles per cm 2 , ≤ 90 particles per cm 2 , ≤ 50 particles per cm 2 , ≤ 40 particles per cm 2 , ≤ 35 particles per cm 2 or ≤ 30 particles per cm 2wherein the particles have a diameter greater than 8 microns. The presently disclosed subject matter describes a method of producing a plastic syringe having a stable layer of silicone oil, comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of a silicone oil onto the plasma treated inner surface of the plastic syringe barrel to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; wherein the inner surface of the plasma treated plastic syringe barrel having the plasma treated silicone oil coating has a surface density of < 100 particles / cm 2 , < 90 particles / cm 2 , < 50 particles / cm 2 , < 40 particles / cm 2 , < 35 particles / cm 2 , or < 30 particles / cm 2 , wherein the particles have a diameter greater than 8 microns. In some embodiments, the method further comprises waiting at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour, 2 hours, or 3 hours before exposing the uniform silicone oil coating to the plasma.

[0019] The presently disclosed subject matter describes a method of producing a plastic syringe barrel having a stable layer of silicone oil, comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of a silicone oil onto the plasma treated inner surface of the plastic syringe barrel to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; wherein the inner surface of the plasma treated plastic syringe barrel having the plasma treated silicone oil coating has a reduction in the number of particles having a diameter greater than 8 microns by at least 75%, 80%, 85%, 90%, or 95% compared to the inner surface of the plastic syringe barrel having the silicone oil coating. The presently disclosed subject matter describes a method of producing a plastic syringe having a stable layer of silicone oil, comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2a plasma treated inner surface of the plastic syringe barrel with 0.005 to 0.5 mg / cm2of a silicone oil to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; wherein the number of particles greater than 8 microns in diameter in the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is reduced by at least 75%, 80%, 85%, 90%, or 95% compared to the inner surface of the plastic syringe barrel with the silicone oil coating, respectively. In some embodiments, the method further comprises waiting at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour, 2 hours, or 3 hours before exposing the uniform silicone oil coating to the plasma.

[0020] In some embodiments, the uncharged energized gaseous species comprises excited argon atoms. In some particular embodiments, the plastic is a cyclic olefin polymer (COP), a cyclic olefin copolymer (COC), a polyethylene (PE), a polycarbonate (PC), a polypropylene (PP), or a polyethylene terephthalate (PET). In some embodiments, the plastic syringe has a maximum fill volume of 1.0 ml, 0.5 ml, 0.3 ml, 0.25 ml, 0.10 ml, or 0.05 ml.

[0021] The presently disclosed subject matter describes a method of producing a syringe having a plastic syringe barrel with a stable polysiloxane-based lubricant coating, the method comprising the method of producing a plastic syringe barrel described herein, and assembling the plastic syringe barrel with a plunger rod, a plunger stopper, and a needle. In some embodiments, the plastic syringe barrel contains a solution, and wherein the particle content in the solution is < 50 particles / ml for any particles with a diameter > 10 pm, or < 5 particles / ml for any particles with a diameter > 25 pm.

[0022] The presently disclosed subject matter describes a plastic syringe comprising a plastic barrel, a plunger rod, and a plunger stopper, wherein the plastic barrel has a stable silicone oil coating, and is produced by the steps of: providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm2of a silicone oil to the plasma treated inner surface of the plastic syringe barrel to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a plasma consisting essentially of uncharged energized gaseous species; wherein the surface density of the inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is < 600 particles / 12 cm2, < 500 particles / 12 cm2, or < 400 particles / 12 cm2, respectively. 2 a plasma treated inner surface of the plastic syringe barrel with 0.005 to 0.5 mg / cm2of a silicone oil to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; wherein the number of particles greater than 8 microns in diameter in the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is reduced by at least 75%, 80%, 85%, 90%, or 95% compared to the inner surface of the plastic syringe barrel with the silicone oil coating, respectively. In some embodiments, the method further comprises waiting at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour, 2 hours, or 3 hours before exposing the uniform silicone oil coating to the plasma. 2 a plasma treated inner surface of the plastic syringe barrel with 0.005 to 0.5 mg / cm2of a silicone oil to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; wherein the number of particles greater than 8 microns in diameter in the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating is reduced by at least 75%, 80%, 85%, 90%, or 95% compared to the inner surface of the plastic syringe barrel with the silicone oil coating, respectively. In some embodiments, the method further comprises waiting at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour, 2 hours, or 3 hours before exposing the uniform silicone oil coating to the plasma. 2 ​2 wherein the particle diameter is greater than 8 microns. The presently disclosed subject matter describes a plastic syringe comprising a plastic barrel, a plunger rod, and a plunger stopper, wherein the plastic barrel has a stable silicone oil coating and is produced by the steps of: providing a plastic syringe barrel, exposing the interior surface of the plastic syringe barrel to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of silicone oil onto the plasma treated interior surface of the plastic syringe barrel to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a downstream plasma generated at atmospheric pressure; wherein the interior surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating has a surface density of < 600 particles / 12 cm 2 , < 500 particles / 12 cm 2 , or < 400 particles / 12 cm 2 , respectively, wherein the particle diameter is greater than 8 microns.

[0023] The presently disclosed subject matter describes a plastic syringe comprising a plastic barrel, a plunger rod, and a plunger stopper, wherein the plastic barrel has a stable silicone oil coating and is produced by the steps of: providing a plastic syringe barrel, exposing the interior surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of silicone oil onto the plasma treated interior surface of the plastic syringe barrel to form a uniform silicone oil coating; and exposing the uniform silicone oil coating to a plasma consisting essentially of uncharged energized gaseous species; wherein the interior surface of the plasma treated plastic syringe barrel with the plasma treated silicone oil coating has a surface density of < 100 particles / cm 2 , < 90 particles / cm 2 , < 50 particles / cm 2 , < 40 particles / cm 2 , < 35 particles / cm 2 , or < 30 particles / cm 2 , respectively, wherein the particle diameter is greater than 8 microns. The presently disclosed subject matter describes a plastic syringe comprising a plastic barrel, a plunger rod, and a plunger stopper, wherein the plastic barrel has a stable silicone oil coating and is produced by the steps of: providing a plastic syringe barrel, exposing the interior surface of the plastic syringe barrel to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2a plasma treated inner surface of the plastic syringe barrel with a uniform coating of silicone oil; and exposing the uniform coating of silicone oil to a downstream plasma generated at atmospheric pressure; wherein the surface density of the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated coating of silicone oil is < 100 particles / cm 2 , < 90 particles / cm 2 , < 50 particles / cm 2 , < 40 particles / cm 2 , < 35 particles / cm 2 , or < 30 particles / cm 2 , wherein the particles are greater than 8 microns in diameter.

[0024] The presently disclosed subject matter describes a plastic syringe comprising a plastic barrel, a plunger rod, and a plunger stopper, wherein the plastic barrel has a stable coating of silicone oil and is produced by the steps of: providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of silicone oil to the plasma treated inner surface of the plastic syringe barrel to form a uniform coating of silicone oil; and exposing the uniform coating of silicone oil to a plasma consisting essentially of uncharged energized gaseous species; wherein the number of particles greater than 8 microns in diameter in the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated coating of silicone oil is reduced by at least 75%, 80%, 85%, 90%, or 95% compared to the inner surface of the plastic syringe barrel with the coating of silicone oil. The presently disclosed subject matter describes a plastic syringe comprising a plastic barrel, a plunger rod, and a plunger stopper, wherein the plastic barrel has a stable coating of silicone oil and is produced by the steps of: providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a downstream plasma generated at atmospheric pressure for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of silicone oil to the plasma treated inner surface of the plastic syringe barrel to form a uniform coating of silicone oil; and exposing the uniform coating of silicone oil to a downstream plasma generated at atmospheric pressure; wherein the number of particles greater than 8 microns in diameter in the plasma treated inner surface of the plasma treated plastic syringe barrel with the plasma treated coating of silicone oil is reduced by at least 75%, 80%, 85%, 90%, or 95% compared to the inner surface of the plastic syringe barrel with the coating of silicone oil.

[0025] In some embodiments, the plastic syringe comprises a plastic syringe barrel containing a solution. In some embodiments, the particle content in the solution is < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm. In some embodiments, the plastic syringe comprises a plastic syringe barrel containing a biologic. In some embodiments, the plastic syringe comprises a plastic syringe barrel containing a solution comprising an anticoagulant, a vaccine, or a recombinant protein. In some embodiments, the plastic syringe comprises a plastic syringe barrel containing a solution comprising an anti-VEGF protein. In some embodiments, the plastic syringe comprises a plastic syringe barrel containing a solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab. In some embodiments, the plastic syringe comprises a plastic syringe barrel containing an ophthalmic solution. In some embodiments, the particle content in the ophthalmic solution is < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm.

[0026] The presently disclosed subject matter describes a method of treating an eye comprising intravitreal administration of a solution or an ophthalmic solution to the eye with a syringe produced by the methods described herein.

[0027] Current syringes include a plasma treated plastic syringe barrel and are coated with a plasma treated polysiloxane based lubricant coating, where each plasma treatment consists essentially of an uncharged energized gaseous species, a plunger rod, a plunger stopper, and a needle; where the plastic syringe barrel contains a solution and has a particle content in the solution of < 50 particles / ml for any particles > 10 pm in diameter, or < 5 particles / ml for any particles > 25 pm in diameter. The presently disclosed subject matter describes a method of treating an eye comprising intravitreal administration of a solution to the eye with a syringe. The syringe includes a plasma treated plastic syringe barrel and is coated with a plasma treated polysiloxane based lubricant coating, where each plasma treatment is a downstream plasma generated at atmospheric pressure, consisting of a plunger rod, a plunger stopper, and a needle; where the plastic syringe barrel contains a solution and has a particle content in the solution of < 50 particles / ml for any particles > 10 pm in diameter, or < 5 particles / ml for any particles > 25 pm in diameter. The presently disclosed subject matter describes a method of treating an eye comprising intravitreal administration of a solution to the eye with a syringe. In some embodiments, the solution is an anti-VEGF protein solution. In some embodiments, the solution includes an anticoagulant, a vaccine, or a recombinant protein. In some embodiments, the solution is an ophthalmic solution. In some embodiments, the solution includes pegaptanib, ranibizumab, aflibercept, or bevacizumab. The presently disclosed subject matter describes a syringe including a plasma treated plastic syringe barrel and is coated with a plasma treated polysiloxane based lubricant coating, where each plasma treatment consists essentially of an uncharged energized gaseous species, a luer lock or slip tip, a plunger rod, and a plunger stopper; where the plastic syringe barrel contains a solution and has a particle content in the solution of < 50 particles / ml for any particles > 10 pm in diameter, or < 5 particles / ml for any particles > 25 pm in diameter. The presently disclosed subject matter describes a syringe including a plasma treated plastic syringe barrel and is coated with a plasma treated polysiloxane based lubricant coating, where each plasma treatment is a downstream plasma generated at atmospheric pressure, consisting of a luer lock or slip tip, a plunger rod, and a plunger stopper; where the plastic syringe barrel contains a solution and has a particle content in the solution of < 50 particles / ml for any particles > 10 pm in diameter, or < 5 particles / ml for any particles > 25 pm in diameter.

[0028] The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane-based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species or each plasma treatment is a downstream plasma; and wherein the number of particles greater than 8 microns in diameter in the interior surface of the plasma treated plastic syringe barrel having a plasma treated polysiloxane-based lubricant coating is reduced by at least 75%, 80%, or 95% respectively compared to the interior surface of a plastic syringe barrel having a polysiloxane-based lubricant coating.

[0029] The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated perfluoropolyether lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species or each plasma treatment comprises a downstream plasma; and wherein the surface density of the interior surface of the plasma treated syringe barrel having a plasma treated perfluoropolyether lubricant coating is ≤ 600 particles / 12 cm 2 , ≤ 500 particles / 12 cm 2 , or ≤ 400 particles / 12 cm 2 , where the particles are greater than 8 microns in diameter.

[0030] The presently disclosed subject matter describes a plastic syringe barrel comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated perfluoropolyether lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species or each plasma treatment comprises a downstream plasma; and wherein the surface density of the interior surface of the plasma treated plastic syringe barrel having a plasma treated perfluoropolyether lubricant coating is ≤ 100 particles / cm 2 , ≤ 90 particles / cm 2 , ≤ 50 particles / cm 2 , ≤ 40 particles / cm 2 , ≤ 35 particles / cm 2 , or ≤ 30 particles / cm 2 , where the particles are greater than 8 microns in diameter.

[0031] The presently disclosed subject matter describes a syringe comprising a plastic syringe barrel, a plunger rod, a plunger stopper, and a needle as described herein. The presently disclosed subject matter describes a syringe comprising a plastic syringe barrel, a plunger rod, a plunger stopper, and a luer lock or slip tip. In some embodiments, the plastic syringe contains a solution. In some embodiments, the particle content in the solution is < 50 particles / ml for any particle with a diameter > 10 pm, or < 5 particles / ml for any particle with a diameter > 25 pm. In some embodiments, the plastic syringe barrel contains a solution comprising an anticoagulant, a vaccine, or a recombinant protein. In some embodiments, the plastic syringe barrel contains an anti-VEGF protein solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab. In some embodiments, the plastic syringe contains an ophthalmic solution. In some embodiments, the particle content in the ophthalmic solution is < 50 particles / ml for any particle with a diameter > 10 pm, or < 5 particles / ml for any particle with a diameter > 25 pm. The presently disclosed subject matter describes a method of treating an eye comprising intravitreal administration of a solution or an ophthalmic solution to the eye with a syringe as described herein.

[0032] The presently disclosed subject matter describes a method of producing a plastic syringe barrel with a stable lubricating layer comprising providing a plastic syringe barrel, exposing an inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; applying 0.005 to 0.5 mg / cm 2 of perfluoropolyether onto the plasma-treated inner surface of the plastic syringe barrel to form a uniform perfluoropolyether coating; and exposing the uniform perfluoropolyether coating to a plasma consisting essentially of uncharged energized gaseous species for 0.1 to 10 seconds; wherein the inner surface of the plasma-treated plastic syringe barrel with the plasma-treated perfluoropolyether coating has a surface density of < 600 particles / 12 cm 2 , < 500 particles / 12 cm 2 , < 400 particles / 12 cm 2 , < 100 particles / cm 2 , < 90 particles / cm 2 , < 50 particles / cm 2 , < 40 particles / cm 2 , < 35 particles / cm 2 , or < 30 particles / cm 2 , where the particles are greater than 8 microns in diameter.

[0033] The presently disclosed subject matter describes a syringe comprising a plasma treated plastic syringe barrel and coated with a plasma treated perfluoropolyether lubricant coating, wherein each plasma treatment consists essentially of an uncharged energized gaseous species, a plunger rod, a plunger stopper, and a needle; wherein the plastic syringe barrel contains a solution, and the particle content in the solution is < 50 particles / ml for any particles with a diameter > 10 pm, or < 5 particles / ml for any particles with a diameter > 25 pm. The presently disclosed subject matter describes a method of treating an eye comprising intravitreal administration of a solution to the eye with a syringe described herein. In some embodiments, the solution comprises an anticoagulant, a vaccine, or a recombinant protein, wherein the solution is an ophthalmic solution, wherein the solution is an anti-VEGF protein solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab.

[0034] The presently disclosed subject matter describes a syringe comprising a plasma treated plastic syringe barrel and coated with a plasma treated perfluoropolyether lubricant coating, wherein each plasma treatment consists essentially of an uncharged energized gaseous species, a luer slip or a luer lock, a plunger rod, and a plunger stopper; wherein the plastic syringe barrel contains a solution, and the particle content in the solution is < 50 particles / ml for any particles with a diameter > 10 pm, or < 5 particles / ml for any particles with a diameter > 25 pm. BRIEF DESCRIPTION OF DRAWINGS

[0035] The accompanying drawings incorporated herein and forming a part of the specification, illustrate various embodiments of the present application and together with the description serve to explain the principles of the application. In the drawings, like reference characters refer to like or functionally similar elements.

[0036] FIG. 1A is an exploded perspective view of a syringe (left) and an inset of a luer slip (top) and a luer lock (bottom).

[0037] Figure 1B is a cross-sectional view of a plastic syringe barrel and a syringe tip (left), and a cross-sectional view showing various surfaces (right).

[0038] Figure 1C-1 is a bright field image of the inner surface of an empty / unfilled COP syringe barrel without any coating.

[0039] Figure 1C-2 is a corresponding dark field image of the inner surface of an empty / unfilled COP syringe barrel without any coating (left), and a magnified view of a portion of these dark field images (right).

[0040] Figure 1D-1is a bright field image of the interior surface of a COP syringe barrel that is empty / unfilled after spraying 1000 cSt silicone oil onto the interior surface of the COP syringe barrel.

[0041] Figure 1D-2 is a corresponding dark field image of the interior surface of an empty / unfilled COP syringe barrel with sprayed silicone oil (left), and a magnified view of a portion of these dark field images (right).

[0042] Figure 1E-1 is a bright field image of the interior surface of an empty / unfilled plasma treated COP syringe barrel with plasma treated silicone oil according to an embodiment of the present application. The plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species.

[0043] Figure 1E-2 is a corresponding dark field image of the interior surface of an empty / unfilled plasma treated COP syringe barrel with plasma treated silicone oil according to an embodiment of the present application. The plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species.

[0044] Figure 1F-1 is a magnified bright field image of the interior surface of an empty / unfilled COP syringe barrel without any coating (left), the interior surface of an empty / unfilled COP syringe barrel with sprayed silicone oil (middle), and the interior surface of an empty / unfilled plasma treated COP syringe with plasma treated silicone oil, where the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species (right) according to an embodiment of the present application.

[0045] Figure 1F-2 is a magnified dark field image of the interior surface of an empty / unfilled COP syringe barrel without any coating (left), the interior surface of an empty / unfilled COP syringe barrel with sprayed silicone oil (middle), and the interior surface of an empty / unfilled plasma treated COP syringe with plasma treated silicone oil, where the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species (right) according to an embodiment of the present application.

[0046] Figure G-1 is a bright field image of the interior surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil.

[0047] Figure G-2 is the respective dark field images of the interior surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (left), and a magnified view of a portion of these dark field images (right).

[0048] Figure 1H-1 is a bright field image of the interior surface of an empty / unfilled COP syringe barrel with downstream plasma treated silicone oil.

[0049] Figure 1H-2 is the respective dark field images of the empty / unfilled interior surface of a COP syringe barrel with downstream plasma treated silicone oil (left), and a magnified view of a portion of these dark field images (right).

[0050] Figure 1I is a dark field image of the interior surface of an empty / unfilled COP syringe barrel without any coating (left), the interior surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (middle), and the interior surface of an empty / unfilled plasma treated COP syringe with plasma treated silicone oil, wherein the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species (right) according to embodiments of the present application.

[0051] Figure 1J is a dark field image of the interior surface of an empty / unfilled COP syringe barrel without any coating (left), the interior surface of an empty / unfilled COP syringe barrel with downstream plasma treated silicone oil (middle), and the interior surface of an empty / unfilled plasma treated COP syringe with plasma treated silicone oil, wherein the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species (right) according to embodiments of the present application.

[0052] Figure 1K is a dark field image (left) and a bright field image (right) of the interior surface of an empty / unfilled COP syringe barrel without any coating.

[0053] Figure 1L is a dark field image (left) and a bright field image (right) of the interior surface of an empty / unfilled COP syringe barrel after spraying 1000 cSt silicone oil.

[0054] Figure 1Mare brightfield images (left) and darkfield images (middle) of the interior surface of an empty / unfilled plasma-treated COP syringe barrel having a plasma-treated silicone oil according to embodiments of the present application (left) and magnified views of portions of these darkfield images (right). The plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species.

[0055] Figure 2 is a bar graph comparing particle concentration (particles / mL) of ≥5 pm particles between the following sources of biological solution: BD U100 insulin syringes filled with BD U100 insulin syringes filled with Exel U100 insulin syringes filled with and generic 0.25 ml syringes treated according to the methods described herein and filled with .

[0056] Figure 3A is a bar graph comparing particle concentration (particles / mL) of ≥10 pm particles between the following sources of biological solution: BD U100 insulin syringes filled with BD U100 insulin syringes filled with Exel U100 insulin syringes filled with and generic 0.25 ml syringes treated according to the methods described herein and filled with . Figure 3B is a magnified view of the bar graph in Figure 3A .

[0057] Figure 4A is a bar graph comparing particle concentration (particles / mL) of ≥25 pm particles between the following sources of biological solution: BD U100 insulin syringes filled with BD U100 insulin syringes filled with Exel U100 insulin syringes filled with and generic 0.25 ml syringes treated according to the methods described herein and filled with . Figure 4B is a magnified view of the bar graph in Figure 4A .

[0058] Figure 5 is a bar graph comparing particle concentration (particles / mL) of ≥5 pm particles between the following sources of biological solution: BD U100 insulin syringes filled with BD U100 insulin syringes filled with filtered BD U100 insulin syringes filled with and generic 0.25 ml syringes treated according to the methods described herein and filled with filtered A universal 0.25ml syringe.

[0059] Figure 6 This is a bar graph comparing the particle concentration (particle count / mL) of ≥10μm particles among the following biological solution sources: directly from vials. Filtered directly from the vial Processed and filled according to the method described in this article A universal 0.25ml syringe, and a filter-treated and filled syringe according to the method described herein. A universal 0.25ml syringe.

[0060] Figure 7 This is a bar graph comparing the particle concentration (particle count / mL) of ≥25μm particles among the following biological solution sources: directly from vials. Filtered directly from the vial Processed and filled according to the method described in this article A universal 0.25ml syringe, and a filter-treated and filled syringe according to the method described herein. A universal 0.25ml syringe. Detailed Implementation

[0061] While the invention may be embodied in many different forms, it should be understood that this disclosure is intended to provide for embodiments that embody the principles of the invention, and such embodiments are not intended to limit the invention to the preferred embodiments described herein and / or those illustrated herein. The claimed subject matter may also be embodied in other ways, incorporating other existing or future techniques, including different steps or elements similar to those described in this document. Furthermore, although the term “step” may be used herein to imply different aspects of the method employed, it should not be construed as implying any particular order of the various steps disclosed herein, unless the order of the steps is explicitly described.

[0062] Embodiments of the invention will now be described more fully below with reference to the accompanying drawings, which illustrate some, but not all, of the embodiments of the invention. In fact, the invention may be embodied in many different forms and should not be construed as limited to the embodiments described herein; rather, these embodiments are provided so that this disclosure satisfies applicable legal requirements. The same numerals refer to elements throughout. Further details of the embodiments of the invention will be apparent to those skilled in the art. Although the invention has been described based on these preferred embodiments, it will be apparent to those skilled in the art that certain modifications, variations, and alternative constructions will be readily apparent while still remaining within the spirit and scope of the invention.

[0063] The presently disclosed subject matter will now be described in greater detail.

[0064] Figure 1A-1 is an exploded perspective view of an exemplary syringe 20 (left) and illustrations of a luer slip tip (top) and a luer lock tip (bottom). FIG. 1A shows a plastic syringe barrel 1, a syringe tip 2, a plunger rod 3 that is inserted into the plastic syringe barrel and is movable forward or backward along the length of the plastic syringe barrel, a plunger stopper or seal 4 that is connected to the front of the plunger rod 3 and that makes an airtight contact with a portion of the inner surface of the plastic syringe barrel as the plunger rod is moved forward or backward, a needle 6 and a needle hub 5 that are connected to the syringe tip 2, and a needle safety cap 7. In other embodiments, the syringe 20 does not include the needle 6, the needle hub 5 that connects the syringe tip 2, and the needle safety cap 7. The illustrations of FIG. 1A show two configurations of the syringe tip 2: a luer lock tip 8 and a slip tip 9. The luer lock tip 8 provides a male threaded hub so that a female needle hub is screwed onto the luer lock tip. The slip tip 9 provides a male threaded hub that is configured so that a female needle hub is slid onto and mounted to the slip tip. In one embodiment, the syringe includes a plastic syringe barrel, a plunger rod, a plunger stopper, and a needle. In one embodiment, the needle is a fixed needle or is pre-connected to the syringe barrel. In one embodiment, the needle is glued to the syringe barrel. In one embodiment, the syringe includes a plastic syringe barrel, a luer lock or slip tip, a plunger rod, and a plunger stopper.

[0065] Figure 1A-2 is an image of an exemplary syringe that includes a plastic syringe barrel 1, a syringe tip 2, a plunger rod 3, a plunger stopper 4, and a fixed (or pre-connected) needle 6a, a needle safety cap 7, and a plunger back cover 15 (left); and an image of the exemplary syringe with the needle safety cap 7 and the plunger back cover 15 assembled or on (right).

[0066] Figure 1B is a cross-sectional view of a plastic syringe barrel 1 and a syringe tip 15 (left). The plastic syringe barrel 1 includes a proximal end 10, a distal end 11, and a cylindrical wall 12 that extends between the proximal and distal ends. The cylindrical wall 12 of the syringe barrel has an inner surface 13 and defines a chamber 14 for receiving a substance (e.g., a solution). According to embodiments of the present invention, the inner surface 13 is an inner surface of a plasma-treated plastic syringe barrel having a plasma-treated silicone oil coating, or an inner surface of a plasma-treated plastic syringe barrel coated with a plasma-treated polysiloxane-based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species. See, e.g., FIG. 1G and FIG. 1H. Figure 1BThe right side cross-sectional view illustrates the various surfaces: the interior surface of the plastic syringe barrel 17 to be plasma treated and the interior space of the plastic syringe barrel 18, the plasma treated plastic syringe barrel 19, the uniform polysiloxane-based lubricant coating 20 to be plasma treated (e.g., uniform silicone oil coating), the interior surface of the plasma treated plastic syringe barrel from which the surface density particle images and measurements are taken 21 having a plasma treated polysiloxane-based lubricant coating (e.g., plasma treated plastic syringe barrel having a plasma treated silicone oil coating), and the plasma treated polysiloxane-based lubricant coating 22. The syringe barrel chamber 14 can be pre-filled with a drug in dry or liquid form, an ophthalmic solution, a biologic, or any other substance including water or diluent for reconstituting a drug. The distal end 11 of the syringe barrel is connected to a syringe tip 15 having a passageway 16 that extends through the distal end 11 of the syringe barrel and communicates with the syringe barrel chamber 14. The plunger rod 3 (shown in FIG. 1A) can extend into the proximal end 10 of the plastic syringe barrel 1 with the plunger stopper 4 sliding in fluid-tightly engaging fashion within the cylindrical wall 12 of the chamber 14.

[0067] Described herein are exemplary embodiments of a method of generating a plastic syringe barrel having a stable polysiloxane-based lubricating layer, the method comprising the steps of: providing a plastic syringe barrel, exposing an interior surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species; applying a polysiloxane-based lubricant coating to the plasma treated interior surface of the plastic syringe barrel to form a uniform polysiloxane-based lubricant coating; and exposing the uniform polysiloxane-based lubricant coating to a plasma consisting essentially of uncharged energized gaseous species. The method surprisingly results in a plasma treated plastic syringe barrel having a plasma treated polysiloxane-based lubricant coating on the interior surface of the plasma treated plastic syringe barrel with a very low surface density of particles, wherein the plastic syringe barrel is unfilled or empty. In one embodiment, the number of particles having a diameter greater than 8 microns in the interior surface of the plasma treated plastic syringe barrel having a plasma treated polysiloxane-based lubricant coating is reduced by at least 95% compared to the interior surface of a plastic syringe barrel having a polysiloxane-based lubricant coating. In one embodiment, the interior surface of the plasma treated plastic syringe barrel having a plasma treated polysiloxane-based lubricant coating has a surface density of < 600 particles per 12 cm 2 of the interior surface of a 1 ml plastic syringe barrel, and the term "12 cm 2 " is the approximate total surface area of the interior surface of a 1 ml plastic syringe barrel, and the term "12 cm 2” generally encompasses the total surface area of the inner surface of a 1 ml plastic syringe barrel of various configurations). In one embodiment, the surface density of the inner surface of a plasma treated plastic syringe barrel with a plasma treated polysiloxane based lubricant coating is < 30 particles / cm 2 where the particle diameter is greater than 8 microns.

[0068] While it is well known that plasma treatment of plastics can enhance the wettability of fluids with reactive functional groups or polarity, plasma treatment of plastic surfaces is not common in industry practice because the additional processing step is inconvenient without any known significant advantage or superior lubricant stability. Importantly, one skilled in the art would not expect to plasma treat a plastic with a commonly used silicone oil lubricant to enhance wettability, as silicone oil lubricants are non-polar and do not have any reactive functional groups. Plastic materials such as polypropylene and other cyclic olefin polymers commonly used to manufacture syringes are difficult to bond because they are hydrophobic, have poor surface wettability (low surface energy), do not have any surface reactive functional groups, and are non-polar. This non-reactive or inert nature of these plastics is very important to maintain the stability of pharmaceutical products in direct contact with the plastic materials. Downstream plasma treatment of plastics slightly improves the surface energy of the plastic by creating functional groups on the surface, thereby improving wettability; however, because silicone oil is non-polar, does not have any functional groups, one skilled in the art would expect the slight change in plastic wettability to only provide incremental improvement in silicone oil wettability, and not further improve the chemical bonding between the plastic and the silicone oil. Because there is no adhesion between the silicone oil and the plastic surface, the lubricant is easily displaced under mechanical or chemical stress. Mechanical stress refers to the movement of the plunger rod in the syringe barrel, while chemical stress is the contact of a polar fluid such as an aqueous pharmaceutical product. Due to the large difference in surface energy between an aqueous solution and a non-polar and inert silicone oil, the lubricant tends to retract into droplets on the plastic surface to reduce the surface area of contact between the silicone oil and the pharmaceutical fluid. Because there is no permanent chemical bond between the silicone oil and the plastic, the silicone oil can easily migrate on the plastic surface or from the plastic surface into the pharmaceutical solution. Consistent with these expectations, product development for plastic syringes has moved away from using silicone oil or plasma treatment. This is evident in industry product development that has generally focused on silicone-free plastic syringes (e.g. West Daikyo Crystal Zenith ) as well as plastic syringes that use chemically cross-linked reaction silicone oils (e.g. Schott Biotec ).

[0069] The disclosures herein demonstrate the unexpected result that the combination of plastic plasma treatment described herein first increases the wettability of the silicone oil such that the silicone layer is flat as a thin film rather than discrete droplets or islands that rest on the surface, and then a subsequent plasma treatment of the lubricating layer as described herein, which results in permanent cross-linking of the lubricating film to produce a permanent coating rather than cross-linked particles. The plasma-induced cross-linking of the lubricant prevents further flowability of the silicone oil, such that the silicone oil remains a uniform coating even under the mechanical or chemical stresses described above. This in turn provides the unexpected result of a silicone oil lubricated plastic syringe barrel having an extremely low number of particles on the inner surface, and a filled silicone oil lubricated plastic syringe barrel having an extremely low number of particles in solution.

[0070] As used herein, "a plasma consisting essentially of uncharged energized gaseous species" means a plasma limited to the recited uncharged energized gaseous species and possibly charged energized gaseous species that do not materially affect the basic and novel characteristics of a plasma consisting essentially of uncharged energized gaseous species. These basic and novel characteristics are capable of producing at least one of the following, as applicable or recited in the corresponding claims: a silicone lubricated plastic syringe barrel having an inner surface with a reduction of at least 95% in the number of particles having a diameter greater than 8 microns compared to the inner surface of a plastic syringe barrel having a coating of a polysiloxane-based lubricant; a silicone lubricated plastic syringe barrel having an inner surface with a surface density of < 600 particles per 12 cm 2 2 of a silicone lubricated plastic syringe barrel having an inner surface with a surface density of < 50 particles per cm 2 of a silicone lubricated plastic syringe barrel having an inner surface with a surface density of < 50 particles per cm 2 of a silicone lubricated plastic syringe barrel having an inner surface with a surface density of < 50 particles per cm

[0071] In one embodiment, the uncharged energized gaseous species includes energized argon atoms. In one embodiment, the reactive gas is oxygen. In another embodiment, the reactive gas is air. In another embodiment, a mixture of the reactive gas and argon is used. In one embodiment, the method includes exposing the inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 seconds to 10 seconds; and applying 0.005 mg / cm 2 2 of a silicone lubricated plastic syringe barrel having an inner surface with a surface density of < 50 particles per cm 2 of a silicone lubricated plastic syringe barrel having an inner surface with a surface density of < 50 particles per cm

[0072] In one embodiment, the plastic syringe barrel is composed of cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyethylene (PE), polycarbonate (PC), polypropylene (PP), or polyethylene terephthalate (PET). In one embodiment, the plastic syringe barrel has a maximum fill volume of 10 ml, 3 ml, 1 ml, 0.5 ml, 0.3 ml, 0.25 ml, 0.10 ml, or 0.05 ml.

[0073] The method of manufacturing a plastic syringe barrel with a stable silicone oil layer includes exposing the interior surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species. In one embodiment, the plasma consisting essentially of uncharged energized gaseous species is a downstream plasma generated, for example, by the configuration for plasma processes described in U.S. Patent No. 9133412. The downstream plasma configuration described in U.S. Patent No. 9133412 generates a gas stream with a mixture of uncharged energized gaseous species and charged species at one location, then flows the filtered or separated gas plasma rich in uncharged energized gaseous species “downstream” to a second location where the article is plasma treated. U.S. Patent No. 9133412 describes treating lubricants with a downstream plasma and further describes that thermal and electronic energy can be released locally by the energized gaseous species by creating reactive sites between lubricant molecules, almost instantaneously or through a continuous reaction process, which can produce the desired material properties.

[0074] The downstream plasma consisting essentially of uncharged energized gaseous species is different from the atmospheric plasma processes described in U.S. Patent No. 7553529 and the vacuum plasma processes described in U.S. Patent Application No. 14 / 347677 and U.S. US4767414; all of which describe a direct ionization plasma radiation process that can result in retaining embedded charges at or near the treated surface and altering the material properties of the treated surface in different ways.

[0075] In one embodiment, the uncharged energized gaseous species includes high-energy neutrals, radicals, neutral atoms or molecules formed from the combination of electrons and ions, or excited noble gas atoms. In one embodiment, the radicals are reactive gas atoms or polymerizable gas atoms.

[0076] In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated in part from an initial gas stream comprising an inert gas. In one embodiment, the inert gas is helium, neon, argon, or krypton. In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated in part from an initial gas stream comprising an oxidizing gas. In one embodiment, the oxidizing gas is air, oxygen, carbon dioxide, carbon monoxide, water vapor, or mixtures thereof. In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated in part from an initial gas stream comprising a non-oxidizing gas. In one embodiment, the non-oxidizing gas is nitrogen or hydrogen. In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated in part from an initial gas stream comprising a mixture of gases.

[0077] In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated in part from a gas plasma and a mixture of charged and uncharged energized gaseous species generated by microwave energy, high voltage direct current (DC), radio frequency (RF) power sources, or thermal activation processes such as passing the gas over a catalytic surface or heated wire. Examples of devices that generate energized gaseous species include a capacitively coupled plasma generation device with two opposing electrodes, an inductively coupled plasma generation device with a coil surrounding the gas stream, a microwave generator electrically coupled to a power source to generate electromagnetic radiation that energizes the gas stream, a catalyst comprising a wire or other electrically resistive material coupled to a power source.

[0078] In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated in part by one or more electrostatic or electromagnetic fields separating or filtering uncharged energized gaseous species from ions, electrons, and other charged species by electrical grounding (e.g., with one or more wires, grids, meshes, or any other structure known in the art that is electrically conductive and can be electrically grounded) or by neutralizing charged species in the gas stream by recombination in a transfer zone.

[0079] In one embodiment, the downstream plasma or plasma consisting essentially of uncharged energized gaseous species is generated at a vacuum (typically less than about 200 Torr) or about atmospheric pressure (typically about 760 Torr).

[0080] The method of producing a plastic syringe barrel with a stable polysiloxane-based lubricant further includes applying the polysiloxane-based lubricant to the plasma treated interior surface of the plastic syringe barrel to form a uniform polysiloxane-based lubricant coating. In one embodiment, the method includes applying 0.005 mg / cm 2 to 0.05 mg / cm 2A polysiloxane-based lubricant is applied to a plasma treated interior surface of a plastic syringe barrel. In one embodiment, the polysiloxane-based compound is a silicone oil of dimethylpolysiloxane having the following general chemical structure:

[0081]

[0082] The number of repeating siloxane units (n) in the polymer chain will determine the molecular weight and viscosity of the silicone oil. As the number of siloxane units increases, the polymer becomes longer and both the molecular weight and viscosity increase. Generally, the useful viscosity range of the silicone oil at ambient temperature is about 5 to 100,000 centistokes. Preferably, the polysiloxane-based lubricant has a viscosity of about 1000 to 12500 centistokes at ambient temperature. Preferably, the polysiloxane-based lubricant is polydimethylsiloxane (PDMS) which is 1000 centistokes at ambient temperature. In another embodiment, the method includes the use of other non-silicon inert lubricants. These include inert fluorine-containing chemical lubricants such as perfluoropolyethers (PFPE). Representative examples of commercially available PFPE include Fomblin® Y series lubricants from Solvay Solexis; Krytox® series lubricants from E. I. du Pont de Nemours and Company; and Fomblin Fomblin series lubricants; Krytox® series lubricants from E. I. du Pont de Nemours and Company; and series lubricants; and Krytox® from Daikin Industries, Ltd. Uniform coating can be achieved by pre-heating the lubricant, adding a solvent, or mechanically wiping the lubricant after spraying.

[0083] The lubricant can be used in a diluted or non-diluted form, or a combination of diluted and non-diluted lubricants can be used. In embodiments, the silicone oil lubricant is applied as an aqueous dispersion or emulsion. Any suitable solvent can be used as a diluent that is compatible with the lubricant or combination of lubricants used. The lubricant can be diluted to facilitate the application of a thin film of the lubricant onto the surface of the object. The amount or weight percentage of the lubricant in the lubricant-solvent solution is not essential to the performance of the present application. When a solvent is used, the weight percentage of the lubricant in the solvent can be greater than or equal to about 0.1%, for example, 1%, 10%, 20%, 30%, 40%, and 50%. The weight percentage of the lubricant in the solvent can also be less than or equal to about 95%, for example, 90%, 80%, 70%, and 60%. The diluent solvent evaporates prior to exposure to a downstream plasma or a plasma consisting essentially of uncharged energized gas species.

[0084] The method of producing a plastic syringe barrel with a stable polysiloxane-based lubricant further comprises exposing the uniform coating of silicone oil to a downstream plasma or a downstream plasma consisting essentially of uncharged energized gaseous species. The term "plasma consisting essentially of uncharged energized gaseous species" is as described above. In one embodiment, the surface density of the inner surface of the plasma treated plastic syringe barrel with a plasma treated polysiloxane-based lubricant coating is < 600 particles per 12 cm 2 (for any particles greater than 8 microns in diameter). In one embodiment, the surface density of the inner surface of the plasma treated plastic syringe barrel with a plasma treated polysiloxane-based lubricant coating is < 40 particles per cm 2 (for any particles greater than 8 microns in diameter). In one embodiment, the resulting inner surface of the plasma treated plastic syringe barrel with a plasma treated polysiloxane-based lubricant coating has at least a 95% reduction in the number of particles compared to the inner surface of a plastic syringe barrel with silicone oil.

[0085] In another embodiment, the method of producing a plastic syringe barrel with a stable polysiloxane-based lubricant layer further comprises assembling the plastic syringe barrel with a stable polysiloxane-based lubricant layer with a plunger rod, a plunger stopper, and a needle. The plastic syringes according to embodiments of the present application are particularly advantageous for user-fillable syringes (which require more plunger rod movement to aspirate and deliver the drug) and pre-filled ophthalmic syringes (which are regulated to ensure very low sub-visible particle content) due to the surprising and extremely low particle counts on the inner surface of the syringe and in the solution.

[0086] In one embodiment, the syringe contains a solution comprising a biologic. In one embodiment, the syringe contains an ophthalmic solution. In one embodiment, the syringe contains an ophthalmic solution or a solution comprising a biologic, and the particle content of the solution is < 50 particles per ml for any particles > 10 μm in diameter, or < 5 particles per ml for any particles > 25 μm in diameter.

[0087] Described herein are exemplary embodiments of a plastic syringe comprising a plastic barrel, a plunger rod, a plunger stopper, and a needle, wherein the plastic barrel has a stable polysiloxane-based lubricant layer and is produced by exposing the inner surface of the plastic syringe barrel to a plasma consisting essentially of uncharged energized gaseous species for 0.1 seconds to 10 seconds; applying 0.005 mg / cm 2 to 0.5 mg / cm 2a plasma treated inner surface of the plastic syringe barrel is exposed to a plasma consisting essentially of uncharged energized gaseous species. Advantageously, the surface density of particles having a diameter greater than 8 microns in the plasma treated inner surface of the plasma treated plastic syringe barrel having the plasma treated polysiloxane-based lubricant coating is < 600 particles per 12 cm 2 . Advantageously, the surface density of particles having a diameter greater than 8 microns in the plasma treated inner surface of the plasma treated plastic syringe barrel having the plasma treated polysiloxane-based lubricant coating is < 40 particles per cm 2 . Advantageously, the number of particles in the plasma treated inner surface of the plasma treated plastic syringe barrel having the plasma treated silicone oil is reduced by at least 95% compared to the inner surface of a plastic syringe barrel having silicone oil.

[0088] Described herein are exemplary embodiments comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane-based lubricant coating, wherein each plasma is a downstream plasma generated at atmospheric pressure; and wherein the surface density of the plasma treated inner surface of the plasma treated plastic syringe barrel having the plasma treated polysiloxane-based lubricant coating is < 600 particles per 12 cm 2 , < 500 particles per 12 cm 2 , or < 400 particles per 12 cm 2 , respectively, wherein the particles have a diameter greater than 8 microns.

[0089] Further described herein are exemplary embodiments comprising a syringe comprising a plastic syringe barrel that is plasma treated and coated with a plasma treated polysiloxane-based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species; and wherein the surface density of the plasma treated inner surface of the plasma treated plastic syringe barrel having the plasma treated polysiloxane-based lubricant coating is < 100 particles per cm 2 , < 90 particles per cm 2 , < 50 particles per cm 2 , < 40 particles per cm 2 , < 35 particles per cm 2 , or < 30 particles per cm 2 , respectively, wherein the particles have a diameter greater than 8 microns; the syringe further comprising a plunger rod, a plunger stopper, and a needle.

[0090] Further described herein are exemplary embodiments of a syringe comprising a plastic syringe barrel comprising a plasma treated and coated with a plasma treated polysiloxane based lubricant coating, wherein each plasma treatment consists essentially of uncharged energized gaseous species; and wherein the surface density of the interior surface of the plasma treated plastic syringe barrel with the plasma treated polysiloxane based lubricant coating is < 100 particles / cm 2 , < 90 particles / cm 2 , < 50 particles / cm 2 , < 40 particles / cm 2 , < 35 particles / cm 2 , or < 30 particles / cm 2 , wherein the particles are greater than 8 microns in diameter; the syringe further comprising a luer lock, a sliding stopper, a plunger rod, and a plunger stopper. In one embodiment, a plastic syringe barrel having a capacity of 0.25 ml comprises about 50 micrograms to about 500 micrograms of silicone oil. In one embodiment, the plastic barrel contains a solution, and the particle content in the solution is < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm. In one embodiment, the plastic barrel contains a solution comprising a biologic. In one embodiment, the biologic is an anticoagulant, a vaccine, or a recombinant protein. In one embodiment, the biologic is pegaptanib, ranibizumab, aflibercept, or bevacizumab. In one embodiment, the plastic barrel contains an ophthalmic solution, and the particle content in the ophthalmic solution is < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm. In one embodiment, the maximum fill volume of the plastic syringe barrel is 1 ml, 0.5 ml, 0.3 ml, 0.25 ml, 0.10 ml, or 0.05 ml. Further described herein are methods of treating an eye comprising intravitreal administration of an ophthalmic solution to an eye with a plastic syringe according to the embodiments described herein.

[0091] Example 1: Extremely low particle counts on the interior surface of plastic syringe barrels

[0092] Materials / Methods:

[0093] COP syringe barrels, downstream plasma treated COP syringe barrels with spray on silicone oil, and downstream plasma treated COP syringe barrels with downstream plasma treated silicone oil were prepared.

[0094] Step 1 : Plasma treatment of COP syringe barrel

[0095] A 1 ml COP syringe barrel was treated with downstream plasma.

[0096] a. Syringe format - 1 ml Luer lock.

[0097] b. Gas used - Argon.

[0098] c. Gas flow - 3 standard liters per minute, continuous flow through the syringe barrel. The pressure inside the syringe barrel was approximately atmospheric pressure because no head cap was installed on the syringe during downstream plasma treatment. The gas flow direction started from the flange end and the gas was blown out from the luer end. The syringe was allowed to purge with argon for 2 seconds.

[0099] d. Downstream plasma was initiated for 1.5 seconds.

[0100] Step 2: Application of silicone oil to two plasma treated COP syringe barrels

[0101] A 1 ml COP syringe barrel was treated with downstream plasma.

[0102] Step 3: Plasma treatment of COP syringe barrels with silicone oil

[0103] a. Gas used - Argon.

[0104] b. Gas flow - 3 standard liters per minute, continuous flow through the syringe barrel. The pressure inside the syringe barrel was approximately atmospheric pressure because no head cap was installed on the syringe during downstream plasma treatment. The gas flow direction started from the flange end and the gas was blown out from the luer end. The syringe was allowed to purge with argon for 2 seconds.

[0105] c. Downstream plasma was initiated for 0.5 seconds.

[0106] Zebrasci Flex-S imaging:

[0107] The inner surface of each of the sample COP syringe barrels was imaged using the ZebraSci Flex S benchtop combined spray system, method, and algorithm. The imaging system imaged each syringe barrel and took multiple high-resolution images of the syringe (note that for the plasma treated COP syringe barrels that were sprayed with silicone oil, the images were taken after the silicone oil was applied). The imaging system utilized a backlight paired with a photomask and camera, the mask created a light pattern with alternating dark and light zones to enable detection of changes in refractive index. Bright field images were created where light was reflected into the camera and dark field images were created where light was reflected away from the camera. The imaging system identified edge definitions of silicone oil droplets or particles on the surface through multiple images stitched together to show the entire mapped surface of the syringe. In each of FIGS. 1C-H and Figure 1J In each of FIGS. 1C-H and

[0108] Example 1a : Sample: Empty / Unfilled Uncoated COP Syringe Barrel (No Step), Empty / Unfilled COP Syringe Barrel with Sprayed Silicone Oil (COP Syringe Barrel treated with Step 2), and Empty / Unfilled Downstream Plasma Treated COP Syringe Barrel with Downstream Plasma Treated Silicone Oil (COP Syringe Barrel treated with Steps 1-3). For the COP Syringe Barrel with Sprayed Silicone Oil, the ZebraSci images were taken 0-10 minutes after spraying. For the Downstream Plasma Treated COP Syringe Barrel with Downstream Plasma Treated Silicone Oil - time shift between Step 2 and 3 was 30 minutes to 1 hour. The inner surface of the syringe barrel was imaged using the ZebraSci Flex S benchtop combined spray system, method, and algorithm.

[0109] Example 1b: Sample: Empty / Unfilled Downstream Plasma Treated COP Syringe Barrel with Downstream Plasma Treated Silicone Oil (COP Syringe Barrel treated with Steps 1 and 2); Empty / Unfilled COP Syringe Barrel with Downstream Plasma Treated Silicone Oil (COP Syringe Barrel treated with Steps 2 and 3); Empty / Unfilled Downstream Plasma Treated COP Syringe Barrel with Downstream Plasma Treated Silicone Oil (COP Syringe Barrel treated with Steps 1-3). For the Downstream Plasma Treated COP Syringe Barrel with Downstream Plasma Treated Silicone Oil - time shift between Step 2 and 3 was 0-10 minutes. The inner surface of the syringe barrel was imaged using the ZebraSci Flex S benchtop combined spray system, method, and algorithm.

[0110] Predictive Example 1c:Samples: Multiple downstream plasma treated COP syringe barrels with downstream plasma treated silicone oil (COP syringe barrels treated with steps 1-3). Test processing times, including the following:

[0111]

[0112] The interior surface of the syringe barrels were imaged using the Zebra Sci Flex S benchtop combination spray system, method, and algorithm.

[0113] Particle count in solution was measured: Syringes were filled with water for injection (WFI). Particles in solution were measured using the light block method with the Accusizer 780 instrument and microflow imaging with the MFI 5200 instrument. Measurements were taken according to the standard USP particulate matter measurement protocol or the recommended settings of the instrument manufacturer. The particle test included filling the syringe to 0.05 ml through the syringe needle, dispensing the solution into a clean tube at time 0, diluting the contents to 5 ml with WFI, letting the tube stand for about 1 hour to reduce air bubbles, and vortex mixing the tube before measurement. The particle analysis of the MFI included analyzing the images to identify particle types. Silicone oil droplets had an aspect ratio > 0.85; other particles had an aspect ratio < 85. Unique processing times will further improve and further reduce the particle count in solution as the short time shift between step 1 and step 2 enables the use of the surface functional groups created, and the longer time shift between step 2 and step 3 enables the silicone oil to flatten out on the surface before the final plasma treatment.

[0114] Example 1d: Calculation of surface density particle count:

[0115] Samples: Uncoated COP syringe barrels (no steps), COP syringe barrels with spray silicone oil (COP syringe barrels treated with step 2), and downstream plasma treated COP syringe barrels with downstream plasma treated silicone oil (COP syringe barrels treated with steps 1-3).

[0116] Images of the interior surface of these syringe barrel samples were obtained using the Flex S benchtop combination spray system, method, and algorithm, and the images were then further characterized by the system to count the number of particles and provide a surface density measurement of particles / cm2. The system resolution for particle counting was 7.33 microns / pixel; therefore, the smallest particle size measured was 7.33 microns. 2

[0117] Example 1a Results:

[0118] ​Images of the inner surface of an empty / unfilled uncoated COP syringe barrel, the inner surface of an empty / unfilled COP syringe barrel with sprayed silicone oil, and the inner surface of an empty / unfilled downstream plasma treated COP syringe barrel with downstream plasma treated silicone oil are shown below. Features caused by silicone oil droplets (white) are more easily visualized in the dark field images. These droplets present on the surface are referred to as particles on the surface.

[0119] Figure 1C-1 is a bright field image of the inner surface of an empty / unfilled COP syringe barrel without any coating.

[0120] Figure 1C-2 is the corresponding dark field image (left) of the inner surface of an empty / unfilled COP syringe barrel without any coating, and a magnified view (right) of a portion of these dark field images.

[0121] Figure 1D-1 is a bright field image of the inner surface of an empty / unfilled COP syringe barrel after spraying 1000 cSt silicone oil.

[0122] Figure 1D-2 is the corresponding dark field image (left) of the inner surface of an empty / unfilled COP syringe barrel with sprayed silicone oil, and a magnified view (right) of a portion of these dark field images. Microdroplets of silicone oil are shown in abundance, which are considered as droplet features on the inner surface of the syringe.

[0123] Figure 1E-1 is a bright field image of the inner surface of an empty / unfilled plasma treated COP syringe barrel with plasma treated silicone oil according to embodiments of the present application. The plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species.

[0124] Figure 1E-2 is the corresponding dark field image (left) of the inner surface of an empty / unfilled plasma treated COP syringe barrel with plasma treated silicone oil according to embodiments of the present application, and a magnified view (right) of a portion of these dark field images. The plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species.

[0125] Figure 1F-1is an enlarged bright field image of the inner surface of an empty / unfilled COP syringe barrel with plasma treated silicone oil (right) according to embodiments of the present application, where the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species.

[0126] Figure 1F-2 is an enlarged dark field image of the inner surface of an empty / unfilled COP syringe barrel with plasma treated silicone oil (right) according to embodiments of the present application, where the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species. As shown, the inner surface of the empty / unfilled plasma treated COP syringe with plasma treated silicone oil is surprisingly comparable to the inner surface of the empty / unfilled plasma treated COP syringe barrel without any coating (which has no silicone oil droplets). As shown, the particles in the inner surface of the empty / unfilled plasma treated COP syringe barrel with plasma treated silicone oil are surprisingly reduced by at least 95% compared to the inner surface of the empty / unfilled COP syringe barrel with sprayed silicone oil.

[0127] Example 1b results:

[0128] Images of the inner surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (COP syringe barrel treated with steps 1 and 2), the inner surface of an empty / unfilled COP syringe barrel with downstream plasma treated silicone oil (COP syringe barrel treated with steps 2 and 3), and the inner surface of an empty / unfilled downstream plasma treated COP syringe barrel with downstream plasma treated silicone oil (COP syringe barrel treated with steps 1 to 3) are shown in the following figures. Features caused by silicone oil droplets (white) are more easily visualized in the dark field images. These droplets present on the surface are referred to as particles on the surface.

[0129] Figure G-1 is a bright field image of the inner surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil.

[0130] FIG. G-2 is a corresponding dark field image of the interior surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (left), and a magnified view of a portion of these dark field images (right).

[0131] Figure 1H-1 is a bright field image of the interior surface of an empty / unfilled COP syringe barrel with downstream plasma treated silicone oil.

[0132] Figure 1H-2 is a corresponding dark field image of the interior surface of an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (left), and a magnified view of a portion of these dark field images (right)

[0133] Figure 1I is a dark field image of the interior surface of an empty / unfilled COP syringe barrel without any coating (left), an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (middle), and an empty / unfilled plasma treated COP syringe with plasma treated silicone oil, wherein the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species (right) according to embodiments of the present application.

[0134] Figure 1J is a dark field image of the interior surface of an empty / unfilled COP syringe barrel without any coating (left), an empty / unfilled downstream plasma treated COP syringe barrel with sprayed silicone oil (middle), and an empty / unfilled plasma treated COP syringe with plasma treated silicone oil, wherein the plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil are each a plasma treatment consisting essentially of uncharged energized gaseous species (right) according to embodiments of the present application.

[0135] Example 1d results:

[0136] The following surface density particle counts were obtained: interior surface of an empty / unfilled uncoated COP syringe barrel (no steps), interior surface of an empty / unfilled COP syringe barrel with sprayed silicone oil (COP syringe barrel treated with Step 2), and interior surface of an empty / unfilled downstream plasma treated COP syringe barrel with downstream plasma treated silicone oil (COP syringe barrel treated with Steps 1-3).

[0137] Figure 1Kare dark field (left) and bright field (right) images of the interior surface of an empty COP syringe barrel without any coating. On the interior surface of the empty uncoated COP syringe barrel, the corresponding surface density particle count was 3 particles / cm 2 .

[0138] Figure 1L are dark field (left) and bright field (right) images of the interior surface of an empty COP syringe barrel after spraying 1000 cSt silicone oil. On the interior surface of the empty COP syringe barrel with sprayed silicone oil, the corresponding surface density particle count was 31,419 particles / cm 2 .

[0139] Figure 1M are bright field (left) and dark field (right) images of the interior surface of an empty plasma treated COP syringe barrel with plasma treated silicone oil according to embodiments of the present application, and a magnified view of a portion of these dark field images (right). The plasma treatment of the COP syringe barrel and the plasma treatment of the silicone oil were each a plasma treatment consisting essentially of uncharged energized gaseous species. On the interior surface of the empty downstream plasma treated COP syringe barrel with downstream plasma treated silicone oil, the corresponding surface density particle count was 30 particles / cm 2 .

[0140] Example 2 - Particle counting using WFI

[0141] The testing was performed on 0.25 mL polypropylene syringes with a 31G needle attached. The syringe types tested were:

[0142] - Becton Dickenson U100 insulin syringes, and

[0143] - generic 0.25 ml StaClear syringes as embodiments of the present application and treated as described below.

[0144] The 0.25 ml polypropylene syringes were treated according to the following steps:

[0145] - the plastic barrel (without any silicone oil lubricant) was treated with a downstream plasma consisting essentially of uncharged energized gaseous species. Argon gas was purged into the syringe barrel at a rate of 3 standard liters per minute. After a purging time of at least 1 second of gas flow, the downstream plasma was energized for a treatment time of 1.5 seconds.

[0146] - Dow Corning DC360 silicone oil with a viscosity of 1000 cSt was applied to the downstream plasma treated inner surface of a plastic syringe barrel using an IVEK Sonicair spray equipment. The nozzle was heated to 150 Fahrenheit (about 66 Celsius) and 0.15 microliters of total lubricant was sprayed evenly inside the syringe barrel at a speed of 0.15 microliters / second. The syringe was moved in a vertical direction simultaneously with the spray trigger so that the nozzle was inserted into the syringe barrel to evenly cover the spray.

[0147] - The lubricated inner surface of the plastic syringe was then treated with a downstream plasma consisting essentially of uncharged energized gas species. Argon gas was purged into the syringe barrel at a rate of 3 standard liters / minute. After a purge time of at least 1 second of gas flow, the downstream plasma was energized for a treatment time of 0.5 seconds.

[0148] Ten syringes of each type were filled with water for injection (WFI). Light block and microflow imaging using an Accusizer 780 apparatus and MFI 5200 apparatus were used to measure particles in the solutions. Measurements were made according to standard USP particulate matter measurement protocols or instrument manufacturer’s recommended settings. The particle testing included filling the syringes to 0.05 ml through the syringe needle, dispensing the solution into a clean tube at time 0, diluting the contents to 5 ml with WFI, letting the tube stand for about 1 hour to reduce air bubbles, and vortex mixing the tube before measurement. The particle analysis of the MFI included analyzing the images to identify particle types. Silicone oil droplets had an aspect ratio > 0.85; other particles had an aspect ratio < 85.

[0149] Table 1 below reports the light block measurements of cumulative particle concentration (number of particles / mL) of >2 pm particles, >5 pm particles, >10 pm particles, >25 pm particles, and >50 pm particles between the following sources of solution: WFI stock solution in a clean container, BD U100 insulin syringes filled with WFI, and generic (StaClear) 0.25 ml syringes treated according to the above method and filled with WFI.

[0150] Table 1: Light block method

[0151] Particle size WFI StaClear BD 2 μιη 4 1,980 13,200 5 μιη 2 220 6,030 10 μιη 1 10 1,940 25 μιη 0 0 100 50 μιη 0 0 40

[0152] Table 2 below reports the MFI method measurements of cumulative particle concentration (number of particles / mL) of >2 pm particles, >5 pm particles, >10 pm particles, >25 pm particles, and >50 pm particles between the following sources of solution: WFI stock solution in a clean container, BD U100 insulin syringes filled with WFI, and StaClear generic 0.25 ml syringes treated according to the above method and filled with WFI.

[0153] Table 2: Microflow Imaging

[0154] Particle size WFI StaClear BD 2 μιη 16 9,300 157,380 5 μιη 5 230 26,980 10 μιη 2 0 3,427 25 μιη 0 0 237 50 μιη 0 0 3

[0155] Example 3 - Particle counting using Avastin

[0156] The testing was performed on a 0.25 mL polypropylene syringe with a 31G needle attached. Avastin (bevacizumab) was supplied packaged in 4 ml glass vials. The syringe types tested were:

[0157] - Becton Dickenson U100 insulin syringe,

[0158] - Exel U100 insulin syringe, and

[0159] - (TL) generic 0.25 ml syringe

[0160] The generic 0.25 ml syringe was treated according to the teachings outlined in Example 1:

[0161] 32 syringes of each syringe type were filled with 25 mg / ml bevacizumab The particles in solution were measured by microflow imaging using a MFI5200 instrument. The MFI 5200 instrument is capable of measuring particles in the 1 pm to 70 pm particle size range and differentiating between subvisible particles (protein aggregates, silicon microdroplets or air bubbles) by subpopulation.

[0162] a. First, the Avastin solution in the vial was tested for particles in order to obtain a baseline measurement of the particles before filling the solution into the syringe. 0.1 ml of Avastin was pipetted from the vial into another clean container. The container was allowed to stand for 1 hour to eliminate any air bubbles. The solution in the clean container was then vortexed to the minimum setting using a vortex mixer to suspend any particles back into solution. This solution was then introduced into the MFI instrument for particle measurement. This result gave the baseline particle content in the Avastin stock solution.

[0163] b. Syringe testing - the Avastin was filled through the syringe needle to the 0.1 ml graduation on the syringe.

[0164] c. Within one minute, the Avastin from the filled syringe was expelled into a clean and particle free container.

[0165] d. After the Avastin solution was expelled into the container, it was allowed to stand for 1 hour to eliminate any air bubbles.

[0166] e. The fluid was mixed using a vortex mixer to the minimum setting before measurement to suspend any generated particles back into solution.

[0167] f.The solution is then introduced into the MFI instrument for particle measurement.

[0168] Particle analysis includes analyzing the images to identify particle types. The silicone oil droplets have an aspect ratio > 0.85; other particles have an aspect ratio < 85. The MFI instrument can apply an aspect ratio filter to determine spherical particles, which are typically lubricant particles or other shapes associated with protein aggregates. Figures 2-7

[0169] Figure 2 is a bar graph comparing particle concentration (number of particles / mL) of > 5 pm particles between the following sources of biological solution: vial of BD U100 insulin syringe filled with Exel U100 insulin syringe filled with and a generic 0.25 ml syringe (TL) treated and filled with according to the teachings of this example. As shown in Figure 2 , the generic 0.25 ml syringe of TL surprisingly had a total of 1330 particles (silicone particles and other particles) / mL for any particles having a diameter > 5 pm.

[0170] Figure 3A is a bar graph comparing particle concentration (number of particles / mL) of > 10 pm particles between the following sources of biological solution: vial of BD U100 insulin syringe filled with Exel U100 insulin syringe filled with and a generic 0.25 ml syringe (TL) treated and filled with according to the method described in this example. As shown in Figure 3A and Figure 3B which is a zoomed-in view of the bar graph in Figure 3A , the generic 0.25 ml syringe of TL surprisingly had a total of 50 particles (silicone particles and other particles) / mL for any particles having a diameter > 10 pm.

[0171] Figure 4A is a bar graph comparing particle concentration (number of particles / mL) of > 25 pm particles between the following sources of biological solution: vial of stock solution, BD U100 insulin syringe filled with Exel U100 insulin syringe filled with and a generic 0.25 ml syringe (TL) treated and filled with ​Universal 0.25ml syringe (TL). For example... Figure 4A and Figure 4B (yes Figure 4A As shown in the enlarged view of the medium bar graph, for any particles with a diameter ≥25 μm, the TL universal 0.25 ml syringe surprisingly has a total of <7 particles (silicone particles and other particles) / mL. This is because the Avastin stock solution itself does not meet the USP 789 guideline regarding particle size. ≥ The number of particles with a diameter of 10 micrometers is less than 50 / ml, and the particle size is... ≥ The number of 25-micron particles is less than 5 per ml, therefore the Avastin solution needs to be filtered.

[0172] Example 4 - Using filtered Perform particle counting

[0173] like Figure 4A As shown, in the small bottle The solution has a certain particle count. In this embodiment, the solution from the vial is filtered through a 5μm filter needle before filling the syringe. Solution.

[0174] In this embodiment, 0.25 ml universal syringes (TL) were processed according to the coating conditions described in Example 1. A total of 64 syringes were divided into two groups. One group was filled with unfiltered Avastin solution in vials, and the second group was filled with filtered Avastin solution.

[0175] Measure the baseline particle content in the Avastin solutions before and after filtration. For unfiltered Avastin, remove 0.1 ml from the vial and transfer it to a clean, particle-free container. For filtered Avastin, withdraw 0.1 ml of solution from the vial through a BD 5-micron filter needle and transfer it to a clean, particle-free container. Let both containers stand for 1 hour to eliminate air bubbles. Vortex them using minimal settings before introducing them into the MFI for measurement to resuspend any particles back into the solution. This constitutes the baseline particle content for unfiltered and filtered Avastin.

[0176] 32 0.25ml syringes were filled with 25mg / ml bevacizumab in TL according to the teaching treatment. Fill 32 0.25ml syringes prepared according to the instructions with 25mg / ml bevacizumab filtered through a 5μm filter needle to the 0.1ml mark. To the 0.1 ml mark. Perform MFI measurements on both sets of syringes following the steps outlined in Example 2.

[0177] Figure 5 This is a bar graph comparing the particle concentration (particle count / mL) of ≥5μm particles among the following biological solution sources: from vials stock solution, filtered solution, treated and filled according to the teachings of Example 1 with General 0.25 ml syringes (TL) treated and filled according to the teachings of Example 1 with filtered Figure 5 General 0.25 ml syringes (TL-F) treated and filled according to the teachings of Example 1 with filtered As shown in had a reduced total particle count. Furthermore, for any particles having a diameter > 5 pm, General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered had a total of 812 particles (silica particles and other particles) / mL, surprisingly.

[0178] Figure 6 is a bar graph comparing the particle concentration (number of particles / mL) of > 10 pm particles between the following sources of biological solution: stock solution from a vial, filtered stock solution from a vial, filtered General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered Figure 6 As shown in had a reduced total particle count. Furthermore, for any particles having a diameter > 10 pm, General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered had a total of < 30 particles (silica particles and other particles) / mL, surprisingly.

[0179] Figure 7 is a bar graph comparing the particle concentration (number of particles / mL) of > 25 pm particles between the following sources of biological solution: stock solution from a vial, filtered stock solution from a vial, filtered General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered Figure 7 As shown in had a reduced total particle count. Furthermore, for any particles having a diameter > 25 pm, General 0.25 ml syringes treated and filled according to the teachings of Example 1 with filtered​​ a total of <3 particles (silica particles and other particles) per mL.

Claims

1. A plastic syringe barrel comprising: a plastic syringe barrel that is downstream plasma treated and coated with a downstream plasma treated polysiloxane-based lubricant coating; and the inner surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating thereon has a surface density of < 50 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles.

2. The plastic syringe barrel of claim 1, wherein the interior surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating has a surface density of < 40 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is void of particles when counted.

3. The plastic syringe barrel of claim 1, wherein the interior surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating has a surface density of < 35 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is void of particles when counted.

4. The plastic syringe barrel of claim 1, wherein the interior surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating has a surface density of < 30 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is void of particles when counted.

5. The plastic syringe barrel of claim 1, wherein the plastic syringe barrel comprises about 0.005 mg / cm 2 to about 0.5 mg / cm 2 silicone oil.

6. The plastic syringe barrel of claim 1, wherein the polysiloxane-based lubricant coating is a silicone oil coating.

7. The plastic syringe barrel of claim 1, wherein the polysiloxane-based lubricant coating is polydimethylsiloxane.

8. The plastic syringe barrel of claim 1, wherein the plastic syringe barrel has a maximum fill volume of 1.0 ml, 0.5 ml, 0.3 ml, 0.25 ml, 0.10 ml, or 0.05 ml.

9. A syringe comprising: the plastic syringe barrel of claim 1, a plunger rod, a plunger stopper, and a needle.

10. The syringe of claim 9, wherein the plastic syringe barrel contains a solution.

11. The syringe of claim 9, wherein the plastic syringe barrel contains a solution comprising an anticoagulant, a vaccine, or a recombinant protein.

12. The syringe of claim 9, wherein the plastic syringe barrel contains an anti-VEGF protein solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab.

13. The syringe of claim 9, wherein the plastic syringe barrel contains an ophthalmic solution.

14. The syringe of claim 13, wherein the ophthalmic solution has a particle content of < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm.

15. The syringe of claim 10, wherein the solution has a particle content of < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm.

16. A syringe comprising: the plastic syringe barrel of claim 1, a luer lock or slip tip, a plunger rod, and a plunger stopper.

17. The syringe of claim 16, wherein the plastic syringe barrel contains a solution.

18. The syringe of claim 16, wherein the plastic syringe barrel contains a solution comprising an anticoagulant, a vaccine, or a recombinant protein.

19. The syringe of claim 16, wherein the plastic syringe barrel contains an anti-VEGF protein solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab.

20. The syringe of claim 16, wherein the plastic syringe barrel contains an ophthalmic solution.

21. The syringe of claim 20, wherein the ophthalmic solution has a particle content of < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm.

22. The syringe of claim 17, wherein the particle content of the solution is < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm.

23. Use of the syringe of any one of claims 9-22 in the manufacture of a solution for treatment of the eye or an ophthalmic solution.

24. A method of producing a plastic syringe barrel having a stable silicone oil layer, comprising: providing a plastic syringe barrel, exposing the inner surface of the plastic syringe barrel to a downstream plasma for 0.1 to 10 seconds; and from 0.005 to 0.5 mg / cm 2 of silicone oil is applied to the downstream plasma treated inner surface of the plastic syringe barrel to form a uniform silicone oil coating; exposing the uniform silicone oil coating to a downstream plasma for 0.1 to 10 seconds; 28. The method of any one of claims 24-27, wherein the downstream plasma comprises excited argon atoms. wherein the inner surface of the downstream plasma treated plastic syringe barrel having a downstream plasma treated silicone oil coating has a surface density of < 50 particles / cm 2 wherein the particles are greater than 8 microns in diameter and wherein the plastic syringe barrel is empty when counting particles.

25. The method of claim 24, wherein the inner surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated silicone oil coating has a surface density of < 40 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles.

26. The method of claim 24, wherein the inner surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated silicone oil coating has a surface density of < 35 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles.

27. The method of claim 24, wherein the inner surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated silicone oil coating has a surface density of < 30 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles.

29. The method of any one of claims 24-27, wherein the plastic is cyclic olefin polymer (COP), cyclic olefin copolymer (COC), polyethylene (PE), polycarbonate (PC), polypropylene (PP), or polyethylene terephthalate (PET).

30. The method of any one of claims 24-27, wherein the plastic syringe barrel has a maximum fill volume of 1.0 ml, 0.5 ml, 0.3 ml, 0.25 ml, 0.10 ml, or 0.05 ml.

31. The method of any one of claims 24-27, wherein the plastic is cyclic olefin polymer (COP).

32. The method of claim 24, wherein the method further comprises waiting at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1 hour, 2 hours, or 3 hours before exposing the uniform silicone oil coating to the downstream plasma.

33. A method of producing a syringe having a plastic syringe barrel with a stable polysiloxane-based lubricant coating, comprising: the method of any one of claims 24-32, and assembling the plastic syringe barrel with a plunger rod, a plunger stopper, and a needle.

34. The method of claim 33, wherein the plastic syringe barrel contains a solution, and wherein the particle content of the solution is < 50 particles / ml for any particles having a diameter > 10 pm, or < 5 particles / ml for any particles having a diameter > 25 pm.

35. A plastic syringe comprising a plastic syringe barrel, a plunger rod, and a plunger stopper, wherein the plastic syringe barrel has a stable silicone oil coating, and is produced by: providing a plastic syringe barrel, exposing the inner surface of the plastic syringe barrel to a downstream plasma for 0.1 to 10 seconds; and exposing the uniform silicone oil coating to a downstream plasma; from 0.005 to 0.5 mg / cm 2 of silicone oil is applied to the downstream plasma treated inner surface of the plastic syringe barrel to form a uniform silicone oil coating; 39. The plastic syringe of claim 35, wherein the plastic syringe barrel contains a solution.

40. The plastic syringe of claim 35, wherein the plastic syringe barrel contains a solution comprising an anticoagulant, a vaccine, or a recombinant protein. the inner surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated silicone oil coating thereon has a surface density of < 50 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles.

36. The plastic syringe of claim 35, wherein the interior surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating has a surface density of < 40 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles.

37. The plastic syringe of claim 35, wherein the interior surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating has a surface density of < 35 particles / cm 2 wherein the particles are greater than 8 microns in diameter and wherein the plastic syringe barrel is free of particles when counted.

38. The plastic syringe of claim 35, wherein the interior surface of the downstream plasma treated plastic syringe barrel having the downstream plasma treated polysiloxane based lubricant coating has a surface density of < 30 particles / cm 2 wherein the particle diameter is greater than 8 microns, and wherein the plastic syringe barrel is empty when counting particles. ​ ​ 41. The plastic syringe of claim 35, wherein the plastic syringe barrel contains an anti-VEGF protein solution comprising pegaptanib, ranibizumab, aflibercept, or bevacizumab.

42. The plastic syringe of claim 35, wherein the plastic syringe barrel contains an ophthalmic solution.

43. The plastic syringe of claim 42, wherein the ophthalmic solution has a particle content of < 50 particles / ml for any particles having a diameter > 10 μm, or < 5 particles / ml for any particles having a diameter > 25 μm.

44. The plastic syringe of claim 39, wherein the solution has a particle content of < 50 particles / ml for any particles having a diameter > 10 μm, or < 5 particles / ml for any particles having a diameter > 25 μm.

45. Use of the plastic syringe of any one of claims 35-44 in the manufacture of a solution for treating the eye or an ophthalmic solution.

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