How to remove aldehydes from syringe adhesive

Abstract

The present invention relates to a method for depleting aldehydes from adhesives used to bond needles to syringes. The present invention also relates to a method for determining the releasable aldehydes from said syringes before or after such treatment. In particular, the present invention relates to a method for depleting residual aldehydes from a syringe, which method comprises a step of treating said syringe at a temperature of 50° C. or higher, preferably 90° C. or higher. Such a treatment step is preferably carried out in an autoclave at a temperature above 90° C. and at a pressure above atmospheric pressure.

Description

[Technical field]

[0001] (Technical field of the invention) The present invention relates to a method for extracting aldehydes from adhesives used for gluing needles to syringes, and also to a method for determining (or measuring) the releasable aldehydes from said syringes before or after such treatment. [Background technology]

[0002] (Background technology) The development of protein-based drugs has a major problem of contamination. Such problems are due to interactions with the primary container (e.g., a syringe) in which the drug is kept for storage and subsequent administration. Such problems are described, for example, in paragraphs 0001-0007 of US2016 / 0251261A1 and in the paper by Denfeng Liu et al. (“Interactions between Therapeutic Proteins and Acrylic Acid Leachable”, PDA, J. Pharm. Sci. And Tech. 2012, 66, 12-19.).

[0003] A particular class of substances that react negatively with such drugs and that may be released from the primary container are aldehydes, particularly formaldehyde and acrolein (including acetaldehyde and methacrolein). Aldehydes may be present in the cone of the syringe. Aldehydes may result from adhesives used to bond the needle to the syringe and may be released from such adhesives. Aldehydes may result from interactions with some drugs.

[0004] Various methods are known for reducing the release of substances from syringe-applied glues.

[0005] For example, it is known to appropriately vary the light emission parameters (or irradiation parameters or emission parameters) used during the process (or step) of curing the glue (or adhesive) (wavelength, type of light source, time profile and irradiation intensity).

[0006] However, such methods tend to be non-specific, i.e., they do not provide any special benefit in terms of aldehyde reduction, and further, such methods are not sufficiently robust when reducing such extractable classes to very low levels.

[0007] It is also known to use an autoclave process for the purpose of sterilizing (or disinfecting or disinfecting) the first container (or primary container). Such a process is described, for example, in EP 3 496 765 A2. Summary of the Invention [Problem to be solved by the invention]

[0008] However, such processes are generally not suitable for syringes because they may weaken the seal with the needle glue or may damage any rubber components (e.g., piston or needle shield cap) that are already preassembled to the syringe.

[0009] Therefore, EtO gas sterilization (or EtO gas sterilization or EtO gas disinfection) is preferred for these types of components.

[0010] In order to keep the syringe manufacturing process under control, it is also important to develop an aldehyde detection method that can determine the presence of aldehydes independently of the drug that is subsequently introduced into the syringe. Such a method must be highly precise and sensitive. As a detection method, it is known to use liquid chromatography. However, the results obtained depend on many factors. Such factors include the substances used for the so-called aldehyde derivatization.

[0011] In fact, aldehydes cannot be detected by themselves at low concentrations (ng / mL) unless they are first bound to a substance that allows their differentiation, which produces (or forms) a colored product (hydrazone) with it, which can be determined with a simple (or simple) UV-Vis detector. Such a chemical process (or method or step or treatment) is called derivatization. It allows the detection of aldehydes at picomolar levels, significantly improving the detection limit.

[0012] The choice of derivatization agent also influences the sensitivity of the method. For example, some substances cannot detect very small amounts of aldehydes (on the order of ng / ml) because the derivatization yield is insufficient to produce a certain amount of product, but the signal can be detected (determined or measured) using modern analytical techniques.

[0013] An example of a poor binder is pentafluorobenzylhydroxylamine (PFBHA). Its reactivity with carbonyl groups (to form oximes) is known, but the development of this reaction is analyte specific. The determination of the aldehydes reacting with PFBHA is generally possible by mass spectrometry detection. However, in this case the derivatization reaction is very sensitive to variables such as reaction time, temperature, pH, and reagent amounts for each specific aldehyde. The effect of each variable is specific for each aldehyde, thereby making the overall efficiency of the reaction favorable for some aldehydes, but at the same time unfavorable for others. Therefore, by using such derivatization reagents, it is not possible to simultaneously determine (or measure) the four aldehydes in a test at ng / mL concentration levels.

[0014] Furthermore, it was found that when the test is performed by filling a syringe with a sample liquid (e.g., water), the amount of aldehydes detected is not dependent on the amount and quality of adhesive present in the cone, but is also influenced by other factors (e.g., aldehydes present in the plunger or the water itself).

[0015] Based on the above, there is therefore a need to develop a method of manufacturing a syringe that minimizes the release of aldehydes without compromising the release of other substances, and that is independent of the type of drug that the syringe is filled with.

[0016] There is also a need to develop an analytical method to determine the residual aldehyde that may be released by a syringe, particularly a syringe that is subjected to a method for extracting aldehyde from a glue. [Means for solving the problem]

[0017] Summary of the Invention The first technical problem set forth above is substantially solved by a method for extracting residual aldehyde from a syringe, the syringe comprising the technical features as set forth in one or more of the appended claims, the definitions of which form an integral part of the present specification for the purposes of a full description.

[0018] The present invention therefore relates to a method for extracting residual aldehyde from a syringe, the method comprising a step of treating said syringe at a temperature of at least 50° C., preferably at a temperature of at least 90° C.

[0019] Furthermore, the present invention relates to an analytical method (or analytical method) for detecting (or measuring) residual aldehyde (or residual aldehyde) releasable (or releasable residual aldehyde (or residual aldehyde)) from a syringe, the method comprising the following steps (or processes) (i) to (iii):

[0020] Step (i) is a step of preparing a sample that can be analyzed by isolating a cone (2) of a syringe (1), the cone (2) including a part (or a portion) of a needle (3) and a glue (4), the part (or a portion) of the needle (3) being inserted into the cone (2). Step (ii) A compound of the formula: Ar-NH-NH2, wherein Ar is one or more electron withdrawing groups (or a step of derivatizing the sample of step (i) with a compound represented by the formula (I) (phenyl substituted with an electron-withdrawing group) (or derivatization treatment); Step (iii) Analyzing the solution obtained from step (ii) by reversed-phase HPLC coupled to a UV detector.

[0021] Further characteristics and advantages of the invention will become apparent from the following description of preferred embodiments, given as non-limiting examples. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows a cross section of a cone (or cone-shaped portion or cone section) of a syringe with a needle (or needle) attached (or connected or coupled). [Figure 2A] FIG. 2A is a graph showing the reduction in releasable aldehyde (or releasable aldehyde) from a syringe (invention, after treatment). [Figure 2B] FIG. 2B is a graph showing the reduction in releasable aldehyde (or releasable aldehyde) from a syringe (invention, post-treatment). [Figure 2C] FIG. 2C is a graph showing the reduction in releasable aldehyde (or releasable aldehyde) from a syringe (invention, post-treatment). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description of the Invention In a first aspect, the present invention relates to a method for extracting residual aldehyde from a syringe, the method comprising a step of treating said syringe at a temperature of at least 50° C., preferably at a temperature of at least 90° C.

[0024] Within the meaning of the present invention, the term "syringe" or "syringes" refers to a syringe-needle assembly, in which the needle is connected to the cone of the syringe by means of an adhesive or glue, which contains residual aldehyde. In this assembly, the syringe does not contain any rubber parts. Such glue is typically of the type that can be crosslinked by UV radiation.

[0025] Referring to Figure 1, Figure 1 shows a partial view of a syringe 1. In particular, it shows only a cross section of a cone 2. A conventional method for coupling (or connecting or joining) a needle 3 to a syringe 1 includes the following steps (or steps) (a) to (d).

[0026] Step (a) A step of pre-assembling the needle 3 on the cone 2 (pre-assembly) Step (b) applying (or applying or administering or dosing) glue 4 to cone 2 Step (c) pulling (or drawing) the glue 4 from the base of the flange 5. Step (d) Crosslinking the glue with, for example, a UV lamp (LED or mercury lamp)

[0027] In a particular embodiment, after the provisional assembly step (a), the needles 3 to be bonded are plasma treated under oxygen atmosphere. Such treatment increases the wettability and surface energy of the needles 3, which leads to better cleaning of the surface. Thus, during bonding, the needles 3 are more likely to release less contaminants. Such contaminants are possibly due to reactions between the glue and the material of the needles.

[0028] According to the present invention, the method for extracting (or drawing out or extracting or removing or extracting or extracting) residual aldehyde (or residual aldehyde) from a syringe (or an injector) comprises a process (or step) of treating the syringe (or a process of treatment or a treatment step or a treatment) at a temperature of 50°C or higher, preferably 90°C or higher, as described above.

[0029] Such treating steps (or steps of treating or treatment) may be carried out under reduced pressure, or under atmospheric pressure in a liquid or gaseous fluid, or under vapour pressure.

[0030] Autoclave (under steam pressure) · Ultrasonic heat bath (or ultrasonic heating bath or ultrasonic hot bath) Storage (or preservation) (50℃, 24 hours) Vacuum storage (T>50°C, balancing the vacuum by continuous extraction to prevent the vacuum bell from becoming saturated with volatile compounds) Washing with water (T=90℃ or boiling point)

[0031] A particularly preferred method comprises a process (or step) of treating the syringe with a water vapor pressure of 1.2 to 3 bar at a temperature of 110° C. to 130° C. More preferably, the temperature is 118° C. to 123° C. and the pressure is 1.8 to 2.3 bar.

[0032] The duration of the treatment is an important parameter (e.g., more than 60 minutes, or more than 90 minutes). It does not bring about a significant improvement, but tends to reduce the tensile strength of the needle, or even to cause separation without load. Thus, the duration of the treatment is 5-50 minutes, or 15-40 minutes, or 15-25 minutes, or 20-35 minutes, or 25-30 minutes.

[0033] 2A, 2B and 2C are graphs showing the reduction of formaldehyde, acetaldehyde and acrolein released from the syringes, respectively. In 2A, 2B and 2C, three different glues (Glue A, Glue B and Glue C) were used (with different initial aldehyde contents). The glues used were commercial photopolymerizable acrylic glues. The measurements were carried out immediately after the syringes were produced. A substantial reduction was achieved in all cases with respect to the content of aldehydes releasable from the syringes. This allows the syringes treated according to the method of the invention to be used with any biological fluid, including fluids containing protein materials. Glue A was subjected to an autoclave process. In this case, additional (or extra) curing (or cure) (or extra-curing (EC)) may or may not be present ("Glue A (with EC)" on the graph). That is, a process (or method or step or treatment) of further exposure to UV light may or may not be present (standard times or times). This shows how this parameter does not affect the final result.

[0034] Thus, a syringe obtainable by the method of the invention and having a content of releasable aldehyde (or releasable aldehyde) such that: Formaldehyde < 60ng / syringe Acetaldehyde <300ng / syringe, preferably <200ng / syringe Acrolein < 20ng / syringe, preferably less than 10ng / syringe

[0035] An evaluation of the aldehyde content released from the syringe has been carried out, such evaluation being carried out by a method developed by the inventors and forming (or achieving) a further object of the present invention.

[0036] Such methods are described below.

[0037] The analytical method (or analytical method) of the present invention comprises the following steps (or steps) (iv) to (vi).

[0038] Step (iv) is a step of preparing a sample that can be analyzed by isolating a cone 2 of a syringe 1, the cone 2 including a part of a needle 3 and a glue 4, the part of the needle 3 being inserted into the cone 2. Step (v) Derivatization treatment of the sample of step (i) with a compound of formula Ar-NH-NH2, where Ar is phenyl substituted with one or more electron-withdrawing groups. Step (vi) Analyzing the solution obtained from step (ii) by reversed-phase HPLC coupled to a UV detector.

[0039] Step (i) of preparing the sample comprises detaching the cone 2 from the cylindrical body of the syringe 1 and removing the protruding part of the needle 3. The cone 2 is removed, for example, by a shearing tool or other suitable tool. The part of the syringe 1 thus obtained, consisting of the cone 2, the part of the needle 3 inside the cone 2 and the glue 4 contained in the cone 2, is further subjected to a process of breaking the part of the syringe to provide the sample.

[0040] The step (ii) of derivatizing the sample comprises the following steps:

[0041] -Suspending the sample in a solution of water / acetonitrile / derivatization liquid (or derivatization liquid or derivatization solution) heating the suspension thus obtained to a temperature of 40-55°C, preferably to a temperature of about 50°C, for a period of 1.5-2.5 hours, preferably about 2 hours;

[0042] The derivatization treatment makes it possible to transform the aldehydes released by the glue into hydrazones by reaction with compounds of the formula Ar-NH-NH2, which can be easily detected by UV spectroscopy.

[0043] Preferably, the water / acetonitrile / derivatization liquid (or derivatization liquid or derivatization solution) solution comprises 16-17 parts by volume water, 1.5-2.5 parts by volume acetonitrile, and 0.8-1.2 parts by volume derivatization liquid.

[0044] The derivatization solution comprises a compound of the above formula: Ar-NH-NH2, where Ar is phenyl substituted with one or more electron-withdrawing (or electron-withdrawing) groups. The derivatization solution preferably comprises: 120-130 parts by weight of a compound of the formula Ar-NH-NH2 in 13-17 parts by volume of acetonitrile; 18 to 22 parts by volume of a strong acid, preferably 37% hydrochloric acid; Water to make up to 100 parts by volume It consists of:

[0045] It is important that the pH of this solution is between 1 and 1.2, and more preferably about 1.1.

[0046] The compound of formula Ar-NH-NH2 is more preferably 2,4-dinitrophenylhydrazine.

[0047] In certain embodiments, it may be necessary or advisable to crystallize 2,4-dinitrophenylhydrazine prior to use, for example by crystallizing 2,4-dinitrophenylhydrazine in acetonitrile by heating (or hot solubilization) followed by reprecipitation (or reprecipitation).

[0048] Step (iii) is a step of analyzing the sample solution obtained from step (ii), and includes the following steps (1) to (4): The sample solution obtained from step (ii) contains hydrazone of aldehyde released from the glue.

[0049] Step (1) is a step of calibrating an HPLC column, preferably a C18 column, connected to a UV detector, with standard calibration samples of hydrazones of the compound of formula Ar-NH-NH2 as above, together with formaldehyde, acetaldehyde, acrolein and methacrolein, using a suitable eluent; Step (2) injecting (or injecting, or ejecting, or spraying) the sample solution into the HPLC column after the calibration; step (3) calculating the area under the UV absorption peak of the sample solution; Step (4) Calculating the remaining amount (or residual amount) of aldehyde

[0050] The eluent (or eluent or eluent) preferably consists of a mixture of varying compositions of eluent A (H2O / THF (71-74% / 26-29% (V / V))) and eluent B (acetonitrile).

[0051] Preferably, the operating (or working or running or operation) conditions of the column are as follows:

[0052] Column temperature: 38 to 42°C, preferably 40°C Autosampler temperature: 2-8℃, preferably 5℃ Injection volume (or injection volume or injection volume or jet volume): 100 μl Wavelength of UV detector: 367nm Flow: 1mL / min ·Eluate A / Eluate B: 65 / 35~30 / 70~65 / 35

[0053] The calculation of the remaining amount (or residual amount) of aldehyde is carried out by applying the following equation:

[0054] C サンプル =(A サンプル ×C スタンダード ×F×D×R) / A スタンダード [In the equation, C = concentration A = area (or surface area) D = dilution factor (or dilution factor or dilution factor) = 1 F = conversion factor of the derivatized aldehyde to the free aldehyde R = correction factor (or correction factor or correction factor) for the derivatization rate (or derivatization rate or derivatization yield)

[0055] The R-factor (or Factor R) and the F-factor (or Factor F) are as shown in the table below.

[0056]

number

[0057] The choice of 2,4-dinitro-phenyl-hydrazine for derivatization has been shown to give very satisfactory results.

[0058] A method thus defined has the specificity, i.e. the ability to distinguish the required substances with respect to noise, according to the validation standards required by the main pharmacopoeias.

[0059] The quantification limit of the published method is very low and therefore applicable to the detection of even the smallest amounts of aldehydes present in the analyzed samples. The lowest quantifiable signal over background noise was about 1-2 ng / ml per syringe.

[0060] The coefficient of variation (or coefficient of variation) of the measurements according to the method of the invention (RSD×100, obtained by RSD=relative standard deviation (SD / mean)) is less than or equal to 3%.

[0061] The method is also stable to within 10% over a sample storage time of 2 hours at room temperature (T) or 6 hours at 5°C. EXAMPLES

[0062] Aldehyde Content Reduction Test Table I below summarizes the tests carried out on syringes (uncapped) using the various aldehyde reduction methods described above. The determination of the amount of residual aldehyde was carried out as described above. In all cases, Loctite® AA3345 (Henkel, Duesseldorf) was used as glue. For each type of treatment, five syringes were tested and the mean value ± SD (standard deviation) of the residual aldehyde was calculated.

[0063] NT: No treatment Treatment 1: Autoclave (P = 2 bar, T = 121 °C, t = 20 min) Treatment 2: Autoclave (P = 2 bar, T = 121 °C, t = 60 min) Process 3: Dry vacuum heating (T=60℃, t=60min) Treatment 4: Storage (T = 50°C, P = atm, t = 1 month) Process 5: Vacuum (T = ambient temperature, t = 24 hours) Treatment 6: Ultrasonic bath (P = atm, T = 75°C, t = 3 hours)

[0064] Treatment 1 was also repeated with a capped syringe (which had a rubber part present) (treatment 7).

[0065] [Table 1]

[0066] The above data show that 3 hours of ultrasonic bath (75°C) and autoclave (121°C) resulted in the greatest reduction in aldehyde content, especially by shortening the time from 60 to 20 minutes.

[0067] Processes 4 and 6 do not sufficiently reduce acrolein (particularly important component) (although compared to processes 1 and 2 in the autoclave), while providing good reductions of formaldehyde and acetaldehyde. Furthermore, these processes require very long processing times for industrial implementation.

[0068] This information pertains to the comparison of data from autoclaving (121°C, 20 min), capped (treatment 1) and uncapped (treatment 7), which deserves special discussion.

[0069] These data indicate that caps with rubber parts contribute significantly to aldehyde release, thus improving sterilization in autoclaves where rubber parts are absent.

[0070] It should be noted that removing the rubber parts is not necessary per se. The purpose of the rubber parts is to prevent the rubber from softening and thus being able to adhere the cap to the needle at high temperatures, because the materials used for the caps (including rubber) are manufactured to withstand the sterilization temperatures of an autoclave without "stitching", a process often used by many manufacturers.

[0071] However, the inventors have demonstrated that autoclaving with a cap results in contamination of the cones with higher concentrations of aldehydes because the cap material contains more aldehydes and tends to release aldehydes both in the cones and in the autoclaving environment (where the aldehydes are removed).

[0072] This results in syringes with higher residual aldehyde content even downstream of the autoclave.

[0073] By autoclaving the syringe alone, the aldehydes in the syringe are then removed in a more effective way. On the other hand, when assembled after autoclaving, the cap does not contribute to the contamination of the syringe with aldehydes, because the contact surface between the cap and the drug is limited to a circular area (the area related to the needle cannula), and there is an air blast between the rubber and the drug.

[0074] It is obvious that only some specific embodiments of the invention have been described, to which those skilled in the art can make all the modifications necessary to adapt it to their particular applications, without departing from the scope of protection of the invention.

Claims

1. 1. A method for removing residual aldehyde from a syringe, the method comprising treating the syringe at a temperature of 50° C. or higher, the syringe being a syringe (1)-needle (3) assembly, the needle (3) being attached to a cone (2) of the syringe (1) by an adhesive or glue (4), the adhesive or glue (4) containing residual aldehyde, and the syringe (1) not containing any rubber parts.

2. 10. The method of claim 1, wherein the treating step is carried out under reduced pressure, or under atmospheric pressure in a liquid or gaseous fluid, or under vapor pressure.

3. The processing step may be carried out by the following method: Autoclave (under steam pressure), Ultrasonic Heat Bath, Storage (50°C, 24 hours), Vacuum storage (T>50°C, continuous withdrawal balances the vacuum to prevent the vacuum bell from becoming saturated with volatile compounds); Wash with water (T=90° C. or boiling point) The method of claim 2, wherein the method is performed by one of the following:

4. 4. The method of claim 3, wherein the treating step is carried out at a temperature of 110° C. to 130° C. and a water vapor pressure of 1.2 to 3 bar.

5. 5. The method of claim 4, wherein the temperature is between 118°C and 123°C and the pressure is between 1.8 and 2.3 bar.

6. The method according to claim 4 or 5, wherein the treatment time is from 5 to 50 minutes, or from 15 to 40 minutes, or from 15 to 25 minutes, or from 20 to 35 minutes, or from 25 to 30 minutes.

7. A method for manufacturing a syringe (1), the syringe (1) consisting of a syringe (1)-needle (3) assembly, the needle (3) being bonded to a cone (2) of the syringe (1) by means of an adhesive or glue (4), the adhesive or glue (4) containing residual aldehyde, the syringe (1) being free of rubber parts, the cone (2) having a flange (5), the method comprising the following steps (a) to (d): Step (a) temporarily assembling the needle (3) in the cone (2); Step (b) applying said glue (4) to said cone (2); Step (c) pulling the glue (4) from the base of the flange (5); Step (d) Crosslinking the glue, for example with UV, LED or mercury lamps. and comprising a final processing step according to any one of claims 1 to 7.

8. The method according to claim 7, wherein after the provisional assembly step (a), the needle (3) to be bonded is subjected to a plasma treatment in an oxygen atmosphere.

9. A syringe (1), consisting of a syringe (1)-needle (3) assembly, the needle (3) being joined to the cone (2) of said syringe (1) by means of an adhesive or glue (4), said adhesive or glue (4) containing residual aldehydes, said syringe (1) being free of rubber parts, obtainable by the method according to any one of claims 1 to 6 or the method according to claims 7 or 8, Formaldehyde <60ng / syringe, Acetaldehyde < 200ng / syringe, Acrolein <20 ng / syringe, preferably <10 ng / syringe; having a releasable aldehyde content of Syringe (1).

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