Silicone-oil-free prefilled syringe

Abstract

The present invention relates to a silicone-oil-free prefilled syringe and a method for manufacturing same. The silicone-oil-free prefilled syringe of the present invention is in a form coated with an acrylate-based amphoteric material containing a phosphorylcholine group, which is a super-hydrophilic material having excellent biocompatibility, on a rubber gasket of a syringe plunger, and has the advantages of being simply manufactured and overcoming physical and biological problems of existing silicone-oil-coated prefilled syringes.

Description

Pre-filled syringe without silicone oil

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0163752 filed November 18, 2024, and all contents disclosed in the document of said Korean patent application are incorporated herein as part of this specification.

[0002] The present invention relates to an internally coated pre-filled syringe, and more specifically, to a pre-filled syringe coated with a polymer material based on an acrylate-based amphoteric monomer material containing a phosphorylcholine group, which is an extremely hydrophilic material, instead of silicone oil.

[0003] Recently, the use of pre-filled syringes, which have medication already loaded inside, is increasing due to reasons such as preventing bacterial contamination, medical accidents, and the rise in direct patient administration. Since pre-filled syringes are transported and stored with the medication already filled in the barrel, they offer various advantages. These include the elimination of the need for mixing or measuring medication at the medical site, the ability to administer accurate dosages without misuse even in emergencies, high hygiene due to reduced risk of contamination, cost savings by minimizing medication waste, and ease of operation that allows even inexperienced users to administer the medication.

[0004] Currently, the most common type of pre-filled syringe is the silicone oil-coated syringe. In these syringes, silicone oil is used as a lubricant to reduce friction between the plunger and the syringe barrel; however, this silicone oil can react with the medication contained within the syringe to form micro-contamination particles (drug aggregates), particularly protein aggregates. Since such micro-contamination particles can affect the safety of the medication, the principle is to discard all pre-filled syringes in which micro-contamination particles larger than a certain size are observed.

[0005] Furthermore, it has been reported that in silicone oil-coated pre-filled syringes, the silicone oil can cause adhesion to the inner tube, leading to excessive initial injection force. Such excessive initial injection force can induce unstable procedures contrary to the user's intent, resulting in patient pain and localized drug overdose. As injection force is a critical evaluation factor for the stable delivery of drugs, improvements in this area are currently necessary.

[0006] To address the aforementioned drawbacks of silicone oil, methods such as spray coating or baking were introduced for its application, but they did not yield significant improvements.

[0007] Therefore, through repeated research on silicone oil substitutes capable of improving the disadvantages of silicone oil coating methods, our research team developed a novel pre-filled syringe that ensures the stability and efficacy of injected drugs by fundamentally blocking the generation of microcontamination particles caused by conventional silicone oils through the use of an acrylate-based amphoteric material containing phosphorylcholine groups, which exhibits excellent lubricity and biocompatibility, while also guaranteeing consistent drug delivery over time and airtightness.

[0008] <Prior Art Literature>

[0009] Published Patent 10-2011-0095399

[0010]

[0011] Accordingly, the inventors conducted multifaceted research to solve the above problem and confirmed that coating the syringe rubber absorber with an acrylate-based amphoteric material containing a phosphorylcholine group instead of the conventionally used silicone oil can resolve the disadvantages of conventional silicone oil-coated pre-filled syringes, such as high initial injection force and the generation of microcontamination particles, thereby completing the present invention.

[0012] The present invention aims to provide a silicone oil-free pre-filled syringe and a method for manufacturing the same.

[0013] The present invention aims to provide a composition for coating a pre-filled syringe comprising an amphoteric monomer material of the acrylate series containing a phosphorylcholine group.

[0014]

[0015] To achieve the above objective, the present invention provides a pre-filled syringe coated with an acrylate-based amphoteric material containing a phosphorylcholine group having excellent biocompatibility and lubricity.

[0016] The acrylate-based amphoteric material containing the above phosphorylcholine group may be selected from MPC (2-Methacryloyloxyethyl phosphorylcholine), APC (Acryloyloxyethyl phosphorylcholine), or a combination thereof.

[0017] According to one embodiment of the present invention, the amphoteric material may be coated by polymerizing by UV treatment, and the concentration of the amphoteric material may be 180 to 300 mM.

[0018] According to one embodiment of the present invention, the pre-filled syringe of the present invention is a pre-filled syringe capable of being filled with a drug or a tissue repair agent, and may be filled with at least one therapeutic drug or tissue repair agent inside, and may not be filled with a therapeutic agent.

[0019] The therapeutic drug or tissue repair agent that can be filled into the above-mentioned pre-filled syringe may be selected from stem cells and stem cell-derived active ingredients, natural polysaccharides derived from microorganisms or plants, heterologous or homologous collagen preparations, fish-derived gene extracts, blood coagulation factors, cytokines, growth factors, hormones, signal transduction molecules, vaccines, antibody therapeutics, antibody-drug conjugates, and combinations thereof.

[0020] According to one embodiment of the present invention, the present invention provides a method for manufacturing a pre-filled syringe comprising the step of applying a polymerization solution containing an acrylate-based amphoteric monomer material containing a phosphorylcholine group and a crosslinking agent to the rubber absorber of a syringe and UV treating it.

[0021] In the above manufacturing method, the amphoteric monomer material may be selected from MPC (2-Methacryloyloxyethyl phosphorylcholine), APC (Acryloyloxyethyl phosphorylcholine), or a combination thereof, and the concentration of the amphoteric monomer material is 180 to 300 mM.

[0022] According to one embodiment of the present invention, the crosslinking agent included in the polymerization solution is one or more selected from the group consisting of dipentaerythritol hexaacrylate (DPHA), ethylene glycol diacrylate (EGDA), ethylene glycol dimethacrylate (EGDMA), allyl methacrylate (AMA), acetoacetoxyethyl methacrylate (AAEM), isocyanatoethyl methacrylate (IEM), isobutyl methacrylate (IBMA), normal butyl methacrylate (BMA), and combinations thereof.

[0023] According to one embodiment of the present invention, the proportion of the crosslinking agent included in the polymerization solution is 1 to 2% based on the molar concentration of the amphoteric monomer material.

[0024] According to one embodiment of the present invention, the present invention provides a composition for coating a pre-filled syringe comprising an amphoteric monomer of the acrylate series containing a phosphorylcholine group.

[0025] According to one embodiment of the present invention, the amphoteric monomer material is selected from MPC (2-Methacryloyloxyethyl phosphorylcholine), APC (Acryloyloxyethyl phosphorylcholine), or a combination thereof.

[0026] According to one embodiment of the present invention, the concentration of the amphoteric monomer material is 180 to 300 mM.

[0027] According to one embodiment of the present invention, the coating composition additionally comprises a crosslinking agent, wherein the crosslinking agent is 1 to 2% based on the molar concentration of the amphoteric monomer material.

[0028]

[0029] According to the present invention, by coating the rubber absorber inside a pre-filled syringe with an amphoteric acrylate-based material containing phosphorylcholine groups that exhibits excellent biocompatibility and lubricity, it is possible to secure a constant injection force and stable airtightness, which are essential physical elements of a pre-filled syringe. Furthermore, the pre-filled syringe of the present invention has the effect of significantly reducing the generation of microparticles compared to conventional silicone oil-coated pre-filled syringes, thereby ensuring the safety and efficacy of the drug.

[0030] Additionally, the method for manufacturing a pre-filled syringe according to the present invention has the effect of simplifying the process by utilizing a simplified manufacturing method of polymerizing and coating through UV.

[0031]

[0032] Figure 1 is a conceptual diagram of a pre-filled syringe with MPC coating technology applied.

[0033] Figure 2 shows the results of an analysis of syringe operability according to the initiator, coating agent concentration, and UV irradiation time for MPC coating on the rubber suction surface inside the syringe.

[0034] Figures 3a and 3b are the results of infrared spectroscopic analysis of a rubber absorber surface-coated with MPC.

[0035] Figures 4a and 4b show the results of the hydrophilicity analysis of a rubber absorber surface-coated with MPC.

[0036] Figures 5a and 5b show the microsurface morphology and elemental composition analysis results of the rubber absorber.

[0037] Figures 6a and 6b show the results of particle size analysis of microcontamination particles generated in the injection solution.

[0038] Figure 7 shows the results of the syringe airtightness evaluation.

[0039] Figures 8a and 8b show the results of a comparative evaluation of the injection force of the syringe.

[0040]

[0041] The present invention relates to a pre-filled syringe comprising an outer cap, a syringe barrel, a rubber suction cup, a backstop, and a syringe plunger (Fig. 1). The syringe barrel includes an outlet, and the rubber suction cup is coupled with the syringe plunger and arranged inside the syringe barrel to define a variable volume space through which the front surface of the rubber suction cup and the syringe barrel can discharge fluid through the outlet. The outlet is connected to an injection needle or other accessory for connection to another device.

[0042] A rubber suction attached to one end of a syringe plunger may be manufactured from rubber, silicone, or other suitable elastic material. The suction may be substantially cylindrical and may include one or more outer circumferential ribs around the outer surface of the suction, and the suction and ribs enable the ribs to achieve a substantially fluid-tight seal together with the inner surface of the syringe body. The front surface of the suction may have any suitable shape, for example, substantially flat, substantially conical, or hemispherical. While the outer circumferential ribs included in the rubber suction have an advantageous effect on maintaining sterility, an increase in the number of ribs may increase friction between the suction and the syringe body, thereby reducing user convenience.

[0043] While it is common practice to coat the inside of syringes with silicone oil to overcome the aforementioned problems and ensure airtightness and lubrication, the solidification of the internal silicone oil can require excessive initial injection force. In this case, moving the plunger may require too much force, which may cause issues for some users. For instance, if significant force is required to move or maintain the suction using the plunger, setting the correct administration volume or delivering the volume smoothly can become more difficult. Furthermore, excessive initial injection force can lead to infusion volume imbalance and patient pain.

[0044] In addition, micro-contamination particles often occur in the inner barrel of the syringe due to the silicone oil used in the pre-filled syringe. These micro-contamination particles are formed when the silicone oil coated on the inner barrel combines with the drug and aggregates; they are primarily found in pre-filled syringes filled with protein drugs. In particular, micro-contamination particles found inside pre-filled syringes filled with protein drugs can cause side effects such as unnecessary immune reactions, as well as cause changes in the concentration of the filled drug. Therefore, if micro-contamination particles exceeding a certain size or value are observed in a pre-filled syringe, the safety of the drug is compromised, and thus, the principle is to discard the entire quantity.

[0045] Accordingly, in the present invention, to maximize lubricity by replacing conventionally used silicone oil, a “material having an amphoteric ionic functional group having an acrylate group” is coated onto the rubber absorber of a syringe. The “material having an amphoteric ionic functional group having an acrylate group” refers to an acrylate-based monomer that exhibits amphoteric characteristics by having a cation and an anion coexist within a single molecule. Since the material exhibiting amphoteric characteristics forms strong hydrogen bonds with water molecules due to positive and negative charges, it has high biocompatibility and lubricity, effectively preventing the adhesion of non-specific proteins or cells. Furthermore, in the present invention, since the coating is applied only to the rubber absorber and not to the inside of the syringe inner tube, contact between the coating material and the drug filled into the syringe can be minimized.

[0046] In this specification, “acrylate-based amphoteric substance,” “substance having an amphoteric ionic functional group having an acrylate group,” “acrylate-based monomer exhibiting amphoteric ionic properties,” or “acrylate-based amphoteric monomer substance” are all used interchangeably with the same meaning.

[0047] The coating method of the present invention includes the step of applying a polymerization solution containing an amphoteric ionic monomer having an acrylate group and a crosslinking agent to a rubber absorber adsorbed with a photoinitiator, and then applying UV light. When polymerizing by applying UV light in this manner, there is an advantage in that the coating can be effectively applied without deforming the structure of the rubber absorber. In the case of thermal polymerization, which is a general polymerization method, processing must be performed at high temperatures and for a long time, which can deform the structure of the rubber absorber and / or inner tube, potentially causing problems such as syringe airtightness.

[0048] In the present invention, the amphoteric monomer having the acrylate group is an acrylate-series monomer containing a phosphorylcholine (PC) functional group containing phosphorus and nitrogen, which is connected in any form, and specifically is selected from 2-Methacryloyloxyethyl Phosphorylcholine (MPC) or Acryloyloxyethyl Phosphorylcholine (APC), but is not limited thereto.

[0049] The above-mentioned crosslinking agent may be any one selected from the group consisting of dipentaerythritol hexaacrylate (DPHA), ethylene glycol diacrylate (EGDA), ethylene glycol dimethacrylate (EGDMA), allyl methacrylate (AMA), acetoacetoxyethyl methacrylate (AAEM), isocyanatoethyl methacrylate (IEM), isobutyl methacrylate (IBMA), normal butyl methacrylate (BMA), and combinations thereof, and specifically may be ethylene glycol diacrylate (EGDA) or ethylene glycol dimethacrylate (EGDMA), but is not limited thereto.

[0050] The concentration of the amphoteric monomer having an acrylate group containing a phosphorylcholine group included in the polymerization solution of the present invention is 180 to 300 mM. It can be seen that if the concentration of the monomer is less than 180 mM or greater than 300 mM, the injection operability of the syringe after coating is poor. In addition, the ratio of the crosslinking agent included at this time is 1 to 2% based on the molar concentration of the monomer. If the ratio of the crosslinking agent is less than 1% based on the molar concentration of the monomer, crosslinking is not sufficiently performed, so the desired coating strength is not obtained, and if it exceeds 2%, excessive crosslinking causes excessive hardening, resulting in poor internal coating of the coated syringe.

[0051] In the present invention, the conditions for applying UV can be appropriately selected and adjusted for UV intensity and time. In one embodiment of the present invention, effective coating efficiency was observed when the UV intensity was 1020 J / cm² and the treatment was performed for 60 minutes. However, while the treatment time can be reduced when the UV intensity is higher, increasing the treatment time when the UV intensity is lower is not desirable because it causes moisture to evaporate before the polymerization reaction is completely finished.

[0052] In the present invention, the syringe coating method involves coating a coating solution onto a rubber suction device, and a method is used to ensure the operability of the syringe by pushing the lubricated rubber suction device into the syringe barrel. The above coating method has the advantage of being simple to operate and not requiring the inside of the syringe to be coated separately. Conventional methods involve coating the entire syringe barrel with silicone oil, which has the disadvantage of causing physical and biological problems due to the formation of fine contaminant particles resulting from the aggregation of the drug and silicone oil, or the fixation of the silicone oil.

[0053] The initial injection force of the MPC-coated syringe of the present invention shows a constant trend even over a long period (4 weeks), whereas the silicone oil-coated syringe showed a tendency for the initial injection force to rise sharply and then decline rapidly. Furthermore, it can be seen that the MPC-coated syringe of the present invention possesses superior effects, such as high airtightness and non-detection of fine particles, compared to the silicone oil-coated syringe.

[0054] In the present invention, the pre-filled syringe of the present invention may be provided with a therapeutic drug or a tissue repair agent pre-filled. The therapeutic agent or tissue repair agent may be selected from stem cells and stem cell-derived active ingredients, natural polysaccharides derived from microorganisms or plants, collagen and / or hyaluronic acid preparations, fish-derived gene extracts, blood coagulation factors, cytokines, growth factors, hormones, signaling molecules, vaccines, antibody therapeutic agents, antibody-drug conjugates, and combinations thereof.

[0055] The above stem cells may be plant stem cells or animal stem cells, and the above stem cell-derived active active ingredients may include stem cell pulverized material, exosomes isolated from stem cells, stem cell culture medium, stem cell culture concentrate, and proteins such as various growth factors, cytokines, and collagen isolated from stem cells or their culture medium.

[0056] Natural polysaccharides derived from microorganisms, plants, or algae are high-molecular-weight substances in which sugars are linked by glycosidic bonds, and have recently been recognized as new bioactive polymers exhibiting various functions such as improving immune function and anti-inflammatory effects.

[0057] Collagen preparations may be of heterologous or homologous origin and may additionally contain extracellular matrix components such as hyaluronic acid and elastin.

[0058] The pre-filled syringe of the present invention is advantageous for filling protein preparations because no microcontamination particles caused by protein aggregation are observed.

[0059] In the present invention, a kit containing the pre-filled syringe of the present invention may be provided. Additionally, after internal coating of the syringe, a drug may be injected using a drug filler, and then the pre-filled syringe kit may be constructed through high-pressure sterilization and packaging. In one embodiment of the present invention, such a kit contains the pre-filled syringe in a blister pack. The blister pack itself may be sterilized internally. Additionally, the kit may further include injection needles of varying lengths and / or thicknesses depending on the location where the drug is to be administered.

[0060] These kits may additionally include instructions for use. In one embodiment, the present invention provides a carton containing a pre-filled syringe according to the present invention, a needle, and optionally administration instructions contained in a blister pack.

[0061]

[0062] Examples

[0063] Example 1: MPC coating of a magnetoabsorbent surface using UV irradiation

[0064] In the present invention, the possibility of surface coating with MPC by UV irradiation was explored on the rubber pristine rubber, which is an internal accessory of a pre-filled syringe (Seogyeong Techcal, Korea). For surface coating, a method was used to modify the surface using UV energy by sequentially applying an initiator and a coating agent. BPO (benzoyl peroxide, Sigma-Adrich, USA) and DPHA (dipentaerythritol hexaacrylate, Sigma-Adrich, USA) were used as reaction initiators, and MPC (2-methacryroyloxyethyl phosphorylcholine, NOF corp, Japan) and EGDMA (ethylene glycol dimethacrylate, Sigma-Adrich, USA) were used as coating agents.

[0065] To determine the optimal MPC coating concentration for application to rubber squirts, 50 mM of BPO and 2.5 mM of DPHA, which are initiators, were dissolved in acetone, and the squirts were immersed in the solution and dried at room temperature under light-blocked conditions for 1 hour. After drying, the rubber squirts were immersed in a solution of EGDMA and MPC at various concentrations (50 mM to 250 mM) dissolved in triple-distilled water, as shown in Figure 2, and then the MPC was coated on the surface of the rubber squirts by UV irradiation using a UV irradiator (0.5 W / cm2, HBTX-1, Alpha Global, Korea). In addition, to determine the optimal UV irradiation time, the surface coating of MPC was checked while increasing the irradiation time from 5 minutes to 120 minutes.

[0066] The evaluation results confirmed the presence of MPC coating by verifying the injection operability of the syringe, which involves fixing a rubber suction device to the syringe plunger and pushing it into the inner cylinder. As shown in Figure 2, the optimal coating conditions for the rubber suction device were found to be an MPC concentration of 200–250 mM and a UV irradiation time of approximately 60 minutes. The amount of UV energy irradiated during this time was approximately 1020 J / cm². 2 It was measured using a UV illuminance meter (IEI-Fastcure 250, Awellcure Shanghai UV Group, China).

[0067]

[0068] Example 2: Characterization of MPC-coated rubber absorbers

[0069] 2-1. Analysis of Surface Characteristics of Rubber Suckers

[0070] Infrared spectroscopy was used to analyze the surface composition of the MPC-coated rubber absorbers produced in this invention. Rubber absorbers prepared in Fig. 2 with various concentrations of MPC and UV irradiation times were analyzed using an infrared spectrometer (FTIR-4600, Jasco, Japan) to confirm the presence of MPC coating on the surface of the absorbers, as shown in Figs. 3a and 3b. As can be seen in Fig. 3a, the untreated rubber absorber exhibits a characteristic peak of bromeratyl rubber at 2952 cm⁻¹. -1 (CH), 1472 cm -1 (C=C), 1366 cm -1 (CH2), 1007 cm -1 (CS), 667 cm -1 (C-Br) cm -1 Although expression occurred in all groups, the surface-coated groups with increasing MPC concentration showed a decrease in the intensity of the characteristic peak of bromerbutyl rubber, and the characteristic peak of MPC at 1730 cm⁻¹ -1 (C=O), 1080 cm -1 It was confirmed that the peak intensity (P=O) increased as the reaction concentration of MPC increased. In addition, the results of analyzing the surface characteristics of the rubber absorber according to the increase in UV irradiation time showed that, as can be seen in Figure 3b, the characteristic peak of MPC was strongly expressed on the surface as the UV irradiation time increased from 5 minutes to 60 minutes, but the characteristic peak did not show an increasing trend at UV irradiation times longer than that, confirming that the optimal UV irradiation time for coating MPC on the surface of the rubber absorber is 60 minutes.

[0071] Next, to confirm the surface characteristics of a rubber absorber coated with MPC having extreme hydrophilicity, hydrophilicity was analyzed using a water contact angle measuring instrument (goniometer, SEO, Korea). As shown in Figure 4a, the water contact angle of the pristine rubber was approximately 80 degrees, indicating a non-aqueous surface. It was confirmed that this non-aqueous surface tendency was maintained even when 50 and 100 mM of MPC were coated on the surface while keeping the UV irradiation time fixed at 60 minutes. However, when the concentration of MPC was increased to 150 mM, the water contact angle decreased by approximately 60 degrees, and when the coating concentration of MPC was increased to 200 mM, the water contact angle was found to be less than 30 degrees, indicating a change to an extremely hydrophilic surface. In addition, as shown in Figure 4b, when the concentration of MPC was fixed at 200 mM and the water contact angle was measured while increasing the UV irradiation time, it was observed that an extremely hydrophilic surface with a water contact angle of 30 degrees or less was produced when the UV irradiation time was 60 minutes or more. This confirms that the optimal concentration of MPC and UV irradiation time for coating rubber absorbent surfaces are 200 mM and 60 minutes, respectively, through this experiment.

[0072] Next, an electron microscope (JSM-7800F Prime, JEOL, Japan) was used to observe the microsurface morphology depending on whether or not MPC was surface coated. For this purpose, pristine rubber and 200MPC60 (a sample coated with 200 mM MPC by irradiating the rubber absorber with UV light for 60 minutes) were surface-coated with platinum for 1 minute using a metal deposition system (IB-2, Eiko, Japan), and the absorber surfaces were photographed. As shown in Figure 5a, smooth surface morphologies were observed in both groups regardless of whether or not MPC was coated. However, to qualitatively analyze whether the surface of the MPC was coated, the surface elements were measured using an energy dispersive spectroscopy (EDS, Energy dispersive spectroscopy, JEOL, Japan) attached to an electron microscope, and the basic elements of the rubber absorber, C, O, Si, and Br, were detected. In particular, as shown in Figure 5b, 0.33 wt% of P, a constituent element of MPC, was detected on the surface, it was qualitatively confirmed that the MPC was stably introduced onto the surface of the rubber absorber.

[0073]

[0074] 2-2. Analysis of microcontamination particles generated by silicone oil inside the syringe

[0075] It has been reported that microcontamination particles formed by proteins and salts inside the syringe are generated in all commercially available syringes using silicone oil-coated suction pads. Although the harmfulness of these generated microcontamination particles has not been established, they are classified as items that must be discarded during visual quality inspections, and it is known that there are currently no preventive measures in place. Therefore, in this experiment, microparticles induced by silicone oil and MPC, which are coated on rubber suction pads to ensure the airtightness and lubricity of the syringe, were compared and analyzed. To this end, 1 ml each of phosphate buffer solution (PBS) and immunoglobulin G (0.1 mg / ml, IgG, from human serum, Sigma-Aldrich, USA) solution were filled into syringes coated with silicone oil and MPC, respectively, on rubber suction pads. After vortexing at 250 rpm for 5 minutes, the microparticles formed inside the solution were analyzed using a particle size analyzer (Nano ZS, Malvern Panalytical Ltd, UK) as shown in Figure 5. As shown in Fig. 6a, the results confirmed that in the group coated with silicone oil on the rubber aspirator, particles of approximately 400 nm were formed by elution into the phosphate buffer solution, and microparticles of approximately 10 nm and 1100 nm were detected in the solution containing immunoglobulin G (Fig. 6b). However, it was confirmed that no microparticles were formed inside the syringe combined with the MPC-coated rubber aspirator, and these results demonstrate that the introduction of MPC onto the surface of the rubber aspirator is an excellent combination that can ensure the stability and efficacy of protein-based drugs filled in the syringe.

[0076]

[0077] 2-3. Analysis of Syringe Airtightness

[0078] In this experiment, to evaluate the airtightness of the filled drug, which is an essential requirement for syringes used for intravascular drug infusion, fluorescent substance-protein (BSA-FITC, bovine serum albumin conjugated FITC, Sigma-Aldrich, USA) was injected into syringes coated with silicone oil and MPC, respectively, on rubber aspirators, and the leaked fluorescent substance was detected. To this end, BSA-FITC was dissolved in distilled water at a concentration of 0.5 mg / ml and injected into the upper part of a syringe with a double rubber aspirator inserted. Then, a pressure of 2 atm was applied to the syringe, and the fluorescent substance-protein leaking into the lower part of the syringe was detected using an absorbance analyzer (Spectra Max M2, molecular device, USA). As a control group, a pinhole was formed on the wall of the rubber aspirator, and the leakage of fluorescent substance-protein from the upper part to the lower part under a pressure of 2 atm was analyzed to compare airtightness.

[0079] As shown in Figure 7 below, the analysis results indicate that while the control group showed leakage of approximately 40% (about 193.8 ug / ml) of the fluorescent protein, the group using a suction device coated with silicone oil and MPC showed only about 0.2% (about 0.9–1.2 ug / ml), confirming that there was no leakage of the fluorescent protein. These results indicate that the syringe with a rubber suction device surface-coated with MPC has no difference in airtightness compared to the commercially available product coated with silicone oil, which means that the basic performance as a syringe is identical.

[0080]

[0081] 2-4. Comparative Evaluation of Syringe Injection Power

[0082] In this experiment, 1.5 ml of distilled water was filled into syringes coated with silicone oil and MPC, respectively, on rubber absorbers, and the change in injection force over time was compared using a tensile-compression tester (JSV-H1000, JISC, Japan). The analysis conditions were an injection speed of 200 mm / min, an injection distance of 300.0 mm, and a 26G needle. As shown in Figure 8a, the evaluation results showed that the group coated with MPC on the surface of the rubber absorber exhibited a constant injection force of approximately 4–6 N over 4 weeks, whereas the group coated with silicone on the absorber all showed a change in injection force in which the initial injection force increased sharply and then decreased sharply. Although the trend of change in injection force (8.5 N → 1.5 N) was similar until the second week, at the fourth week, a phenomenon was observed where the initial injection force increased sharply compared to the second week. For a more intuitive comparison of this trend, Figure 8b, which compares only the experimental group at the 4th week of sample production, shows that the group coated with silicone oil on the rubber absorber had an initial injection force up to about 3 times greater than the group coated with MPC. This injection force dropped to about 3.8 N after an injection distance of 30.0 mm, showing a trend of rapid decline in injection force to about 75%. As previously mentioned, this rapid change in injection force of silicone oil-based syringes is a major problem with existing syringe products, but it is judged that the MPC coating on the rubber absorber proposed through the present invention can be an alternative to solve this injection force problem.

Claims

1. A pre-filled syringe capable of filling with a drug, wherein the pre-filled syringe is a pre-filled syringe coated with an amphoteric material of the acrylate series containing a phosphorylcholine group.

2. In Paragraph 1, The amphoteric acrylate-based material containing the above phosphorylcholine group is selected from MPC (2-Methacryloyloxyethyl phosphorylcholine), APC (Acryloyloxyethyl phosphorylcholine), or a combination thereof, in a pre-filled syringe.

3. In Paragraph 1, A pre-filled syringe in which the amphoteric acrylate-based substance containing the above phosphorylcholine group is MPC (2-Methacryloyloxyethyl phosphorylcholine).

4. In Paragraph 2, A pre-filled syringe coated with an acrylate-based amphoteric material containing the above-mentioned phosphorylcholine group, polymerized by UV treatment together with a crosslinking agent.

5. In Paragraph 4, A pre-filled syringe having a concentration of 180 to 300 mM of an acrylate-based amphoteric substance containing the above phosphorylcholine group.

6. In Paragraph 4, A pre-filled syringe in which the above-mentioned crosslinking agent is 1 to 2% based on the molar concentration of an amphoteric substance of the acrylate series containing a phosphorylcholine group.

7. In any one of paragraphs 1 through 6, The above-mentioned pre-filled syringe is a pre-filled syringe filled with at least one therapeutic drug or tissue repair agent.

8. In Paragraph 7, The above therapeutic agent or tissue repair agent is a pre-filled syringe selected from stem cells and stem cell-derived active ingredients, microbial or plant-derived natural polysaccharides, heterologous or homologous collagen and / or hyaluronic acid preparations, fish-derived gene extracts, blood coagulation factors, cytokines, growth factors, hormones, signaling molecules, vaccines, antibody therapeutic agents, antibody-drug conjugates, and combinations thereof. 9.a) A step of applying a photoinitiator to the rubber absorber of a pre-filled syringe and drying it; b) a step of further adding a polymerization solution containing an acrylate-based amphoteric monomer material containing a phosphorylcholine group and a crosslinking agent to the above rubber absorbent and drying it; and c) a step of polymerizing and coating a rubber absorber to which the above polymerization solution has been added by applying UV light; comprising, Method for manufacturing a pre-filled syringe.

10. In Paragraph 9, A method for manufacturing a pre-filled syringe, wherein the amphoteric monomer material is selected from MPC (2-Methacryloyloxyethyl phosphorylcholine), APC (Acryloyloxyethyl phosphorylcholine), or a combination thereof.

11. In Paragraph 9, A method for manufacturing a pre-filled syringe, wherein the concentration of the amphoteric monomer material is 180 to 300 mM.

12. In Paragraph 9, A method for manufacturing a pre-filled syringe, wherein the crosslinking agent is one or more selected from the group consisting of dipentaerythritol hexaacrylate (DPHA), ethylene glycol diacrylate (EGDA), ethylene glycol dimethacrylate (EGDMA), allyl methacrylate (AMA), acetoacetoxyethyl methacrylate (AAEM), isocyanatoethyl methacrylate (IEM), isobutyl methacrylate (IBMA), normal butyl methacrylate (BMA), and combinations thereof.

13. In Paragraph 9, A method for manufacturing a pre-filled syringe, wherein the ratio of the crosslinking agent is 1 to 2% based on the molar concentration of the amphoteric monomer material.

14. A composition for coating pre-filled syringes comprising an amphoteric monomer of the acrylate series containing a phosphorylcholine group.

15. In Paragraph 14, The above-mentioned amphoteric monomer material is selected from MPC (2-Methacryloyloxyethyl phosphorylcholine), APC (Acryloyloxyethyl phosphorylcholine), or a combination thereof, for a composition for coating pre-filled syringes.

16. In Paragraph 15, A composition for coating a pre-filled syringe, wherein the concentration of the amphoteric monomer material is 180 to 300 mM.

17. In Paragraph 14, A pre-filled syringe coating composition comprising, wherein the coating composition further comprises a crosslinking agent, and the crosslinking agent is 1 to 2% based on the molar concentration of the amphoteric monomer material.

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