CN118103340A - Method for manufacturing medical injection device and medical injection device manufactured by same - Google Patents

Abstract

A method of manufacturing a medical injection device (1) comprising a glass barrel (2) having an inner surface (3) coated with a coating (4), the barrel (2) being configured to receive a plunger (5) in sliding engagement, the method comprising the steps of: (a) Providing a coating composition comprising equal to or greater than 92wt.% polydimethylsiloxane having a kinematic viscosity at room temperature of 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s); (b) Heating the coating composition to a temperature of 100 ℃ to 150 ℃; (c) The coating composition heated to said temperature is applied to the inner surface (3) of the cylinder (2) to form a coating layer (4) on the inner surface (3), the average thickness S of which is 100nm to 250nm as measured by optical reflection, wherein the standard deviation of the thickness of the coating layer (4) of the inner surface (3) of the cylinder (2) is equal to or less than 90nm.

Description

Method for manufacturing medical injection device and medical injection device manufactured thereby

Technical Field

The present invention relates to a method for manufacturing a medical injection device, which comprises a glass barrel with a coating on the inner surface, and the barrel is configured to receive a plunger in a sliding engagement manner; the present invention also relates to a medical injection device obtained by the above method and a kit for assembling the above medical device.

Background technique

As is well known, injection devices generally include a sealed plunger slidably engaged within a container so as to dispense a drug to a patient by injection, and such injection devices are widely used in the medical field.

Such injection devices include injection needles, cartridges, and self-administered syringes or auto-injectors for subcutaneous and/or intravenous administration of drugs.

In such devices, it is first necessary that the plunger exhibits optimal sliding properties (in terms of static and dynamic friction) in the barrel of the injection device (e.g. the barrel of a syringe). For this purpose, a lubricating substance, usually based on silicone oil, is used to apply the inner surface of the syringe body and the plunger. In particular, the lubricating substance is used to optimize the sliding properties of the plunger, in particular to reduce the force required to overcome static friction (loosening force) and the force required to overcome dynamic friction when sliding the plunger (average sliding force).

Another problem that needs to be solved urgently is that, especially in the case of injection devices (such as pre-filled syringes), the sliding properties of the plunger should be kept unchanged for a long time as much as possible.

In fact, on the one hand, if a prefilled injection device is used to ensure convenient drug administration and flexible management, on the other hand, it means that the injection device must be stored for a considerable period of time after filling, about several weeks or months, and sometimes even longer. For example, in the case of protein drugs or vaccines, they also need to be stored at extremely low temperatures to ensure drug stability and extend the shelf life.

However, the presence of a silicon-based coating is believed to be a contributing factor to the instability of biotech drugs, especially recombinant proteins, which is related to intrinsic structural sensitivity. In fact, silicone oil separates into solution to form particles, which are literal classifications as intrinsic particles, and proteins may adsorb to the particles at the silicon-water interface, which may undergo structural denaturation and aggregation, resulting in agglomeration of the particles themselves. Aggregation is critical because it may lead to loss of therapeutic efficacy and increase the risk of immunogenicity.

Therefore, another important requirement that arises in prefilled injection devices is not only to maintain the optimal sliding properties of the coating over a long period of time, but also to maintain the low release of the silicon particles in the drug formulation over a long period of time.

Summary of the invention

The Applicant has noted that several methods of manufacturing medical injection devices have been proposed that attempt to meet the above needs, but these methods raise regulatory or complexity issues, and therefore cost issues, which have not been addressed to date.

In some cases, mixtures of different types of silicone oils are used, possibly with other substances added. In this regard, the Applicant has noted that the further one moves away from pure silicone (ie without admixture or addition), the more difficult it is to maintain its properties and behavior over the long term.

It has also been proposed to irradiate the silicone layer deposited on the inner surface of the syringe to at least partially crosslink the silicone, which has been shown to be beneficial in achieving reduced particle release values. This irradiation can be by UV, IR, gamma rays, ion bombardment or by plasma treatment of the torch type or corona effect type under vacuum or atmospheric pressure.

In some cases, it has been proposed to deposit several consecutive silicon layers, which may also be irradiated.

Such processes using silicon or mixed silicon containing additives may also require irradiation treatment, for example, refer to patent documents US20020012741A1, EP3378514A1, US7648487B2, US9662450B2, US10066182B2, EP2387502B1, US7553529B2, US20110276005A1, EP2081615B1, US5338312A, US4844986A, US4822632A, US20080071228A1.

Patent document WO2013045571A1 also describes a method for obtaining a syringe that meets the two requirements of good sliding and low release, both of which need to remain constant for a long time (and the thickness needs to remain constant for a long time). The document discloses spraying silicone with a kinematic viscosity of 900 cSt to 1200 cSt onto the inner surface of the syringe, followed by plasma treatment to make the silicone exhibit high stability and low release. The document points out the reason for the low release in the plasma treatment of the silicone surface.

Patent documents WO2009053947A2 and WO2015136037A1 provide similar technical solutions.

All these documents indicate the use of silicones with relatively low kinematic viscosity (about 1000 cSt) in combination with radiation treatment, in particular plasma treatment, as the best combination for solving the above problems.

Patent document DE 10000505 also discloses a method for siliconizing the interior of a hollow cylinder, wherein silicone oil having a kinematic viscosity of preferably 350 cSt to 20,000 cSt is deposited on the inner wall of the body cavity. The silicone oil is deposited by spraying a nozzle of the type used in inkjet printing, and in one embodiment, the nozzle can be heated.

However, the applicant has observed that the manufacturing method disclosed in the above-mentioned prior art, in addition to prolonging the manufacturing time of the medical injection device and increasing the management complexity of the method itself, may also cause problems that have not been discovered in the prior art, namely, after filling the drug, the medical injection device needs to be visually inspected to determine whether there are defects and foreign contaminants in the form of optically detectable particles.

This inspection, which previously had to be done manually, can now be assigned to automated equipment based on image analysis technology from optical acquisition systems. The purity requirements for the solutions contained in medical injection devices are constantly increasing, so the control device must not only highlight the presence of ultra-small impurities in the liquid, but also distinguish impurities from defects in the container appearance that do not constitute impurities. Therefore, incorrect classification will result in the scrapping of medical injection devices.

In this regard, the applicant has observed that the partial cross-linking of the silicone oil layer applied to the inner surface of the barrel of a medical injection device, especially the partial cross-linking obtained by plasma irradiation, produces a more irregular but more stable surface structure, which may mislead the automatic optical inspection system to mistakenly classify the surface irregularities as impurities, thereby generating production waste that should not exist and causing economic losses.

In view of the above, the applicant has recognized the need to develop a method for manufacturing medical injection devices that can not only meet the above requirements, so that the plunger exhibits optimal sliding performance (in terms of static and dynamic friction) in the injection device barrel and optimal characteristics of low particle release, both of which can remain unchanged for a long time, but also reduce the related problems of false defects that may be erroneously detected by visual inspection devices of medical injection devices.

The applicant has learned that all of these desired features can be achieved by modifying the rheological properties of the coating composition and the method by which the coating composition is used to coat the inner surface of the barrel of a medical injection device, as compared to the prior art.

In particular, the applicant has experimentally confirmed that by using a coating composition to coat the inner surface of the barrel of a medical injection device, the coating composition is substantially composed of a single type of silicone oil, the kinematic viscosity of which at room temperature is much higher than that of the silicone oil used in the prior art, and the silicone oil is hot-coated onto the inner surface of the barrel, and after the coating applied to the surface is cooled, it is possible to simultaneously obtain:

The desired optimum slip and low particle release, both of which are substantially constant over time; and

Optimal coating surface regularity so that visual inspection of medical injection devices is not misleading.

In particular, the surface regularity of the coatings described above is comparable to that of non-crosslinked coatings obtained in the prior art using silicone oils with low kinematic viscosity but high particle release rates. This is despite the fact that the kinematic viscosity of the silicone oils used at room temperature is much higher, and despite the fact that the average thickness of the applied coatings is very thin, approximately 100-250 nanometers.

However, in the experiment, compared with the partially cross-linked coating obtained by using low kinematic viscosity silicone oil in the prior art, the surface regularity of the above coating was improved.

In addition, the applicant has experimentally confirmed that by using the above-mentioned coating composition to coat the inner surface of the barrel of a medical injection device, the coating composition is basically almost entirely composed of a single type of silicone oil, and the kinematic viscosity of the silicone oil at room temperature is much higher than the silicone oil used in the prior art. This silicone oil is hot-coated onto the inner surface of the barrel, and after the coating applied to the surface is cooled, the coating uniformity and high process reproducibility required for large-scale industrial production can be obtained.

Thus, a first aspect of the present invention relates to a method for manufacturing a medical injection device as defined in claims 1 and 2, the medical injection device comprising a glass barrel having a coating on its inner surface, the barrel being configured to receive a plunger in sliding engagement.

In particular, according to the first embodiment, the method for manufacturing a medical injection device of the present invention comprises the following steps:

(a) providing a coating composition comprising equal to or greater than 92 wt.% of polydimethylsiloxane having a kinematic viscosity at room temperature of 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s);

(b) heating the coating composition to a temperature of 100° C. to 150° C.;

(c) applying the coating composition heated to the temperature to the inner surface of the cylinder to form a coating on the inner surface, the average thickness S of which is 100 nm to 250 nm as measured by optical reflection method;

Among them, the standard deviation of the thickness of the coating on the inner surface of the cylinder is equal to or less than 90nm.

In addition, in the second embodiment of the present invention, the method for manufacturing the medical injection device of the present invention comprises the following steps:

(a) providing a coating composition comprising equal to or greater than 92 wt.% of polydimethylsiloxane having a kinematic viscosity at room temperature of 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s);

(b) heating the coating composition to a temperature of 100° C. to 150° C.;

(c) applying the coating composition heated to the temperature to the inner surface of the cylinder to form a coating on the inner surface, the average thickness of which is 100 nm to 250 nm as measured by optical reflection method;

Wherein, for each batch of 10 cylinders, the batch average standard deviation SD of the coating thickness is equal to or less than 70 nm;

Among them, the batch mean standard deviation SD is obtained as follows:

(i) measuring the coating thickness _Spi at at least 6 points of each arbitrary portion ni of the i-th cylinder in the batch with a planar developed axial length of 1.0 mm;

(ii) for each of said parts ni of the ith cylinder in the batch and for each ith cylinder, the average thickness S _ni is calculated by the following formula:

S _ni =(Σ _{p = 1,6} S _pi )/6

(iii) For each barrel portion n, calculate the batch average thickness _SnL of the portion n by the following formula:

S _nL ＝(Σ _i＝1,10 S _ni )/10

(iv) calculating the standard deviation _SDn of the batch average thickness _SnL for portion n for the 10 syringes in the batch; and

(v) Calculate the batch average standard deviation SD from the value of thickness standard deviation _SDn by the following formula:

SD＝(Σ _i＝1,N SD _n )/N

Where N is the total number of parts n per cartridge in the batch.

The applicant has experimentally discovered that, as described in detail below, by hot coating the above-mentioned high-viscosity polydimethylsiloxane-based coating composition at room temperature, the coating formed on the inner surface of the cylinder can show the same effect as low-viscosity silicone oil in terms of application and distribution.

The applicant has also found through experiments that after the coating is cooled and the viscosity characteristics return to the room temperature viscosity characteristics, a series of favorable improved properties are achieved compared with the low viscosity coatings described in the prior art (regardless of whether they have undergone partial crosslinking treatment).

First, the applicant has experimentally observed that the coating formed by the method of the present invention can advantageously not only have low thickness values required by the pharmaceutical and cosmetic industries, but also be very uniformly distributed on the inner surface of the cylinder along each section of the cylinder.

In particular, the Applicant has experimentally observed that the thickness of the coating applied on the inner surface of the cylinder by the method of the invention can advantageously be completely comparable to the thickness values obtained in the prior art using low-viscosity silicone oils.

The Applicant has experimentally observed that once the viscosity of the coating applied to the inner surface of the cylinder returns to its viscosity value at room temperature, it confers stable properties to the coating, allowing all the drawbacks of coatings formed by low viscosity (as mentioned above, about 1000 cSt) silicone oils that have not undergone partial crosslinking to be overcome.

In particular, the coating formed by the method of the present invention can advantageously overcome the following defects of the non-crosslinked coating in the prior art:

When the barrel is in an upright position during storage, the silicon migrates toward the lower part of the barrel under the action of gravity, so the silicon layer tends to form an uneven distribution along the barrel axis of the medical injection device (e.g., syringe) over time;

When using a medical injection device (e.g., a syringe), it can cause uneven sliding resistance of the plunger;

The drug is more likely to interact directly with the material (glass) that the barrel of a medical injection device (e.g., a syringe) is made of, and parts of the coating are more likely to fall off the surface into the solution;

Especially when combined with mechanical stresses such as stirring, or when dispensing the liquid contained in the barrel by sliding a plunger, denaturation and protein aggregation phenomena may be triggered.

Therefore, the method of the present invention can advantageously form a coating having thickness characteristics, uniformity characteristics and stability characteristics, so that the plunger can achieve optimal sliding characteristics in the barrel, although the viscosity of the silicone oil forming the coating is much higher than the silicone oil proposed in the above prior art documents.

Second, the applicant has experimentally observed that the method of the present invention can advantageously form a coating with high surface regularity and high coverage uniformity, so that visual inspection devices for medical injection devices, especially automated visual inspection devices, will not be misled.

In particular, the method of the present invention can advantageously obtain a coating with a very uniform thickness on the inner surface of the cylinder, with the standard deviation of the coating thickness measured by optical reflection (or optical interference depending on the resolution) being equal to or less than 90 nm.

In this way, the coating will not cause false defects, thereby solving the problems existing in the partially cross-linked silicon coating in the prior art.

Advantageously, the method of the invention also makes it possible to obtain on the inner surface of the cylinder a coating whose average thickness fully complies with the requirements of the pharmaceutical and cosmetic industries, despite the fact that this coating is composed of a silicon material with a high kinematic viscosity.

Third, the applicant has experimentally observed that the coating formed by the method of the present invention can advantageously exhibit low particle release characteristics in the solution stored in the barrel of a medical injection device due to the stable characteristics related to the room temperature viscosity value of the coating.

According to tests performed by the applicant, these low particle release properties are completely comparable to or improved upon the properties of partially cross-linked silicone coatings in the prior art, which can cause the above-mentioned false defect problems.

Fourth, the applicant has experimentally observed that under storage conditions at room temperature or above room temperature, the above-mentioned optimal plunger sliding characteristics and low particle release characteristics in the solution stored in the barrel remain basically constant for a long time, and under low-temperature storage conditions, another important demand of the pharmaceutical and cosmetic industries is met.

Fifth, the applicant has experimentally observed that the above-mentioned coating has a uniform average thickness with high reproducibility in different production batches of medical devices, which is a very desirable characteristic in typical large-scale production in the pharmaceutical and cosmetic industries. Furthermore, although the coating is composed of a high kinematic viscosity silicon material.

Another aspect of the present invention relates to an apparatus for manufacturing a medical injection device as defined in claim 25, the medical injection device comprising a glass barrel having a coating on its inner surface, the barrel being configured to receive a plunger in sliding engagement.

In particular, the apparatus of the present invention for manufacturing a medical injection device comprises:

a storage tank for a coating composition, the storage tank having at least one heating element configured to heat the stored coating composition;

at least one dispensing head configured to dispense the heated coating composition and provided with at least one dispensing nozzle, the dispensing head having respective heating elements configured to heat the coating composition dispensed by the nozzle;

a circulation pump arranged upstream of the distribution head;

a support frame for one or more barrels of each medical injection device;

The at least one dispensing head and the support frame are movable relative to each other so as to insert/extract the nozzle of the at least one dispensing head into/from a corresponding barrel of the one or more barrels.

A further aspect of the present invention relates to a medical injection device as defined in claims 28 and 29.

In particular, according to a first embodiment, the medical injection device of the present invention comprises a glass barrel having an inner surface coated with a coating, the barrel being configured to receive a plunger in a sliding engagement,

Wherein, the inner surface coating of the cylinder is substantially made of polydimethylsiloxane, the kinematic viscosity of which at room temperature is 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s), and the average thickness is 100 nm to 250 nm;

Among them, the standard deviation of the thickness of the coating on the inner surface of the cylinder is equal to or less than 90nm.

In addition, according to a second embodiment, the medical injection device of the present invention comprises a glass barrel having an inner surface coated with a coating, the barrel being configured to receive a plunger in a sliding engagement manner,

Wherein, the inner surface coating of the cylinder is substantially made of polydimethylsiloxane, the kinematic viscosity of which at room temperature is 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s), and the average thickness is 100 nm to 250 nm;

Wherein, for each batch of 10 cylinders, the batch average standard deviation SD of the coating thickness is equal to or less than 70 nm;

Among them, the batch mean standard deviation SD is obtained as follows:

(i) measuring the coating thickness _Spi at at least 6 points of each arbitrary portion ni of the i-th cylinder in the batch with a planar developed axial length of 1.0 mm;

(ii) for each of said parts ni of the ith cylinder in the batch and for each ith cylinder, the average thickness S _ni is calculated by the following formula:

S _ni =(Σ _{p = 1,6} S _pi )/6

(iii) For each barrel portion n, calculate the batch average thickness _SnL of that portion n by the following formula:

_SnL ＝(Σi _{＝1,10Sni )} /10

(iv) calculating the standard deviation _SDn of the batch average thickness _SnL for portion n for the 10 syringes in the batch; and

(v) Calculate the batch average standard deviation SD from the value of thickness standard deviation _SDn by the following formula:

SD＝(Σ _i＝1,N SD _n )/N

Where N is the total number of parts n per cartridge in the batch.

Advantageously, the above-described injection device realizes the advantageous technical features described above with respect to its manufacturing method as well as the advantageous technical features concerning the properties achieved by the coating on the inner surface of the barrel.

A further aspect of the present invention relates to a kit of parts for assembling a medical injection device as defined in claims 46 and 47.

In particular, according to a first embodiment, the kit of parts of the invention comprises the following individual components in a sterile package:

a glass barrel having a coating on its inner surface, the barrel being configured to receive the plunger in sliding engagement,

a plunger configured to be slidably engaged in the barrel,

Wherein, the inner surface coating of the cylinder is substantially made of polydimethylsiloxane, the kinematic viscosity of which at room temperature is 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s), and the average thickness S is 100 nm to 250 nm;

The standard deviation of the thickness of the coating on the inner surface of the cylinder measured by the optical reflection method is equal to or less than 90nm.

Furthermore, according to a second embodiment, the kit of parts of the present invention comprises the following individual components in a sterile package:

a glass barrel having a coating on its inner surface, the barrel being configured to receive the plunger in sliding engagement,

a plunger configured to be slidably engaged in the barrel,

Wherein, the inner surface coating of the cylinder is substantially made of polydimethylsiloxane, the kinematic viscosity of which at room temperature is 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s), and the average thickness is 100 nm to 250 nm;

Wherein, for each batch of 10 cylinders, the batch average standard deviation SD of the coating thickness is equal to or less than 70 nm;

Among them, the batch mean standard deviation SD is obtained as follows:

(i) measuring the coating thickness _Spi at at least 6 points of each arbitrary portion ni of the i-th cylinder in the batch with a planar developed axial length of 1.0 mm;

(ii) for each of said parts ni of the ith cylinder in the batch and for each ith cylinder, the average thickness S _ni is calculated by the following formula:

S _ni =(Σ _{p = 1,6} S _pi )/6

(iii) For each barrel portion n, calculate the batch average thickness _SnL of that portion n by the following formula:

_SnL ＝(Σi _{＝1,10Sni )} /10

(iv) calculating the standard deviation _SDn of the batch average thickness _SnL for portion n for the 10 syringes in the batch; and

(v) Calculate the batch average standard deviation SD from the value of thickness standard deviation _SDn by the following formula:

SD＝(Σ _i＝1,N SD _n )/N

Where N is the total number of parts n per cartridge in the batch.

Advantageously, the above-described kit of parts allows for aseptic storage, transportation, and subsequent assembly of the disclosed injection device.

definition

In the scope of this specification and the claimed technical solution, the term "room temperature (RT)" means a temperature of 25°C ± 2°C measured at 60% relative humidity.

In the scope of this specification and the claimed technical solution, all percentages specifically indicated are understood to be percentages by weight.

Within the scope of this specification and the claimed technical solution, the term "average value" refers to the arithmetic mean of the specific entity values considered.

In the scope of this specification and the claimed technical solution, all pressure values should be understood as relative pressure values. In other words, the pressure values indicated in this article do not include atmospheric pressure unless otherwise stated.

In the scope of this specification and the claimed technical solution, all numerical entities representing quantities, parameters, percentages, etc. should be understood as being prefixed with the term "about" in any case, unless otherwise stated. In addition, except as specifically noted below, all numerical entity ranges also include all possible combinations of maximum and minimum values and all possible intermediate ranges.

Within the scope of this specification and the claimed technical solution, the kinematic viscosity of polydimethylsiloxane is measured by TGA and DSC thermogravimetric analysis techniques.

Thermogravimetry (TG) or Thermogravimetric Analysis (TGA) is an experimental technique used to characterize a wider range of materials in thermal analysis. The technique involves the continuous measurement of the mass of a material sample as a function of time (isothermal) or temperature (heating/cooling) under controlled atmosphere conditions.

The DSC technique can determine at what temperature or temperature range any transition occurs (such as melting or crystallization processes) and quantitatively measure the energy associated with it. DSC analysis actually measures the heat flow that occurs when a sample is heated/cooled in a controlled manner (dynamic conditions) or maintained at a constant temperature (isothermal conditions).

By combining these two techniques, the obtained thermal curve can be correlated with a standard curve of silicone oils of known viscosity to determine the kinematic viscosity of the silicone material.

This allows the kinematic viscosity of the silicon to be determined using a calibration curve that relates viscosity values (related to polymer chain length) to thermal phenomena (weight loss) observed at different temperatures.

The polydimethylsiloxane present in the coating was extracted with multiple portions of dichloromethane, which was evaporated prior to analysis.

TGA analysis was performed using a TGA 4000 thermogravimetric analyzer (PerkinElmer), while DSC analysis was performed using a DSC 204F1 differential scanning calorimeter (Netzsch).

The thermal cycle followed by TGA analysis was from 30°C to 500°C with a heating rate of 10°C/min.

The DSC analysis followed a thermal cycle from -80 °C to 30 °C with a heating rate of 10 °C/min.

Within the scope of this specification and the claimed technical solution, the thickness of the coating applied to the inner surface of the barrel of the injection device is understood to be measured by optical techniques based on emitting light radiation (white light or laser light of a specific wavelength) impinging on the analysis sample.

Instruments such as optical reflectometers detect the difference in reflected wavelengths of two beams of light, one reflected from the barrel material (glass) of the injection device and the other reflected from the coating. This difference allows the layer thickness to be determined by knowing the refractive index and geometry of the sample being analyzed. If white light is used as the light source during the analysis, the instrument can detect a minimum thickness of 80nm. By using a specific collimated wavelength (laser), for example 630-680nm collimated wavelength, the resolution can be increased to 20nm, in which case interferometry can be used.

Within the scope of this specification and the claimed technical solution, the average thickness S of the coating is preferably obtained by the following method:

(i) measuring the coating thickness S _p at at least 6 points of each arbitrary cylindrical portion n with a planar developed axial length of 1.0 mm;

(ii) calculating the average thickness _Sn of each of the n barrel portions, where _Sn = (Σp _{= 1,6Sp )} /6;

(iii) Calculate the average thickness S of the cylinder coating, where S = (Σ _{n = 1, N} S _n )/N, and N is the total number of cylinder parts n.

Generally speaking, within the scope of this specification and the claimed technical solution, the term "Standard Deviation" or "Average Square Deviation" of an entity "x" (e.g., the thickness of a coating applied to the inner surface of the barrel of an injection device) detected in a population consisting of N statistical units is defined as:

in,

is the arithmetic mean of entity "x".

Particularly preferably, the standard deviation of the thickness of the coating applied to the inner surface of the barrel of the injection device is obtained by determining the average thickness S of the coating according to the above three points (i)-(iii), and

(iv) Calculate the standard deviation SD of the average thickness _Sn of the n barrel parts relative to the average thickness S of the barrel coating.

Within the scope of the embodiment of the present invention, as described above, the average thickness of the inner surface coating applied to each cylinder in a batch of a predetermined number of cylinders (eg, 10 cylinders) and the batch standard deviation of the coating can be obtained.

In the context of the embodiments of the present invention, "batch average thickness standard deviation SD of the coating" refers to the arithmetic mean of the thickness standard deviations _SDn obtained as above. As mentioned above, this parameter indicates the process reproducibility between different production batches.

Within the scope of various embodiments of the present invention, the total number of n portions (denoted by N) of the injection device barrel having a mid-plane developed axial length of 1.0 mm varies with the size of the barrel itself.

Thus, for example, the total number N of n parts of the injection device is equal to 40 in the case of a syringe with a nominal volume of 0.5 mL, the total number N is equal to 45 in the case of a syringe with a nominal volume of 1.0 mL Long, and the total number N is equal to 90 in the case of a syringe with a nominal volume of 3.0 mL.

Within the scope of this specification and the claimed technical solution, the specified nominal volume of the syringe is 0.5mL, 1mL Long or 3mL in accordance with standard ISO 11040-4 (2015).

Within the scope of this specification and the claimed technical solution, the term "axial" and the corresponding term "axially" are used to refer to the longitudinal direction of the medical injection device, corresponding to the longitudinal direction of its barrel, and the term "radial" and the corresponding term "radially" are used to refer to any direction perpendicular to the above-mentioned longitudinal direction.

In the scope of this specification and the claimed technical solution, the term "circumferential" and the corresponding term "circumferentially" are used to refer to the extension direction of the inner surface of the barrel of the medical injection device in a vertical plane in the longitudinal direction of the barrel itself.

One or more of the above aspects of the present invention may have one or more of the following preferred features, which may be combined with each other according to application requirements.

In a preferred embodiment, step (a) comprises providing a coating composition having a polydimethylsiloxane content of 95 wt.% or more, preferably 98 wt.% or more, and a kinematic viscosity of 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s) at room temperature.

More preferably, step (a) comprises providing a coating composition having a polydimethylsiloxane content of about 100 wt.%, and a kinematic viscosity of 11500 cSt (115 cm ² /s) to 13500 cSt (135 cm ² /s) at room temperature.

This provides a manufacturing method that can advantageously be implemented in a particularly simple and reproducible manner, minimizing or completely eliminating the problems associated with maintaining constant rheological properties of the coating composition after mixing silicone materials of different densities and/or viscosities.

Advantageously, the manufacturing method can also be implemented without adding any additives to the silicon material.

In a preferred embodiment, providing the coating composition in step (a) comprises storing the coating composition in a storage tank.

In this way, advantageously, the required amount of coating composition is always available for carrying out the method.

Preferably, the storage tank is made of a material suitable for containing the silicone coating composition, such as stainless steel.

Preferably, step (b) heats the coating composition to a temperature of 120°C to 150°C.

This advantageously optimizes the subsequent step (c) of applying the heated coating composition to the inner surface of the cylinder, thereby promoting the formation of a very uniform coating on the inner surface.

In a preferred embodiment, step (b) of heating the coating composition comprises heating the storage tank to make the coating composition reach the temperature of 100°C to 150°C, preferably 120°C to 150°C.

To this end, the coating composition storage tank is provided with at least one heating element configured to heat the stored coating composition.

For purposes of the present invention, a heating element of a storage tank may be any element configured to release thermal energy and selectively placed in heat exchange relationship with the coating composition stored in the storage tank.

By way of example only, the heating element may be a heating coil placed inside the tank (and e.g. a resistor or a pipe circulating a suitable heating fluid inside) or a sheath placed outside the tank with one or more resistors mounted therein or a suitable heating fluid circulating therein.

In a preferred embodiment, the method may further include the step (d) maintaining the pressure of the heated coating composition stored in the storage tank at 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably 10 psi (0.69 bar) to 30 psi (2.07 bar), more preferably 10 psi (0.69 bar) to 15 psi (1.03 bar).

This advantageously optimizes the subsequent step (c) of applying the heated coating composition to the inner surface of the cylinder, thereby promoting the formation of a very uniform coating on the inner surface.

In a preferred embodiment, the method further comprises the step of (e) feeding the heated coating composition to a dispensing head provided with at least one dispensing nozzle.

This advantageously allows the heated coating composition to be applied to the inner surface of the cylinder, thereby forming a very uniform coating on the inner surface.

Preferably, the heated coating composition dispensing head is provided with a corresponding heating element configured to heat the coating composition dispensed by the nozzle.

For purposes of the present invention, a heating element of a nozzle may be any element configured to release thermal energy and selectively placed in heat exchange relationship with the coating composition dispensed by the nozzle itself.

By way of example only, the heating element may be a resistor in heat exchange relationship with the dispensing nozzle, such as integrated into a housing (eg, a cylindrical housing) associated with the dispensing nozzle.

Preferably, step (e) of feeding the heated coating composition to the dispensing head is performed by means of a circulation pump arranged upstream of the dispensing head.

This advantageously allows the coating composition to be fed appropriately to the dispensing head according to production needs.

In a preferred embodiment, the corresponding heating element of the circulation pump is configured to heat the delivery head of the pump.

For purposes of the present invention, an element of a pump delivery head may be any element configured to release thermal energy and selectively placed in heat exchange relationship with the coating composition dispensed by the delivery head itself.

By way of example only, the heating element may comprise one or more resistors in heat exchange relationship with the pump delivery head, such as being integrated into a corresponding housing (eg, a cylindrical housing) associated with the delivery head.

In a preferred embodiment, step (c) of applying the heated coating composition onto the inner surface of the barrel is performed by dispensing the coating composition through a dispensing head.

This advantageously allows the heated coating composition to be applied very evenly to the inner surface of the cylinder.

In a preferred embodiment, step (b) heating the coating composition comprises heating a dispensing head and/or a pump, preferably heating a pump delivery head, so that the coating composition reaches or maintains the temperature of 100° C. to 150° C.

This advantageously reduces the power absorption and wear of the pump, thereby benefiting the operating and maintenance costs of the pump.

In a preferred embodiment, the dispensing head and pump may be heated as described above.

In a preferred embodiment, the manufacturing method provides for heating the pump delivery head to a temperature of 50°C to 60°C.

In a preferred embodiment, the storage tank of the coating composition, the circulation pump and the dispensing head are in fluid communication with each other via a pipeline.

Preferably, the conduits are in heat exchange relationship with a corresponding heating element (eg a resistor) or conduit jacket (in which a suitable heating fluid circulates).

Preferably, the pipeline is made of heat-resistant materials such as stainless steel and is heat-insulated, or is made of heat-insulating metal or plastic.

The applicant has observed through experiments that by heating one or more of the storage tank, circulation pump, distribution head and corresponding connecting pipes of the coating composition, the viscosity of the coating composition can be advantageously balanced before distributing the coating composition onto the inner surface of the cylinder, thereby advantageously shortening the distribution time and making the distribution of the coating composition on the inner surface of the cylinder more uniform.

In the context of this preferred embodiment, step (b) of heating the coating composition preferably comprises heating the above-mentioned pipe to make the coating composition at or maintain the above-mentioned temperature of 100°C to 150°C.

The applicant has experimentally observed that heating the coating composition to temperatures exceeding 150°C may result in changes in the properties of the silicon material, which may result in increased release of undesirable particles and/or release of materials that are normally retained at low temperatures.

In a preferred embodiment, step (c) of applying the heated coating composition onto the inner surface of the cylinder is carried out by dispensing the heated coating composition at a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably 6 psi (0.41 bar) to 10 psi (0.69 bar).

This advantageously allows the heated coating composition to be applied very evenly to the inner surface of the cylinder.

In a preferred embodiment, step (c) applying the heated coating composition onto the inner surface of the barrel includes: feeding a distribution gas (e.g., air) at a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably 6 psi (0.41 bar) to 10 psi (0.69 bar), to the dispensing head.

This advantageously distributes the heated coating composition in a very uniform manner so as to apply an equally uniform coating to the inner surface of the cylinder.

In a preferred embodiment, the method includes maintaining a pressure in the coating composition storage tank that is higher than a pressure in the dispensing nozzle of the dispensing head.

This advantageously distributes the heated coating composition in a very uniform manner so as to apply an equally uniform coating to the inner surface of the cylinder.

In a preferred embodiment, step (c) of applying the heated coating composition onto the inner surface of the barrel comprises imparting relative motion between the dispensing head and the barrel while dispensing the heated coating composition.

In a preferred embodiment, step (c) of applying the heated coating composition onto the inner surface of the barrel comprises dispensing the heated coating composition onto the inner surface of the barrel during the relative movement of the dispensing head inserted into the barrel.

In a preferred embodiment, one or more barrels of a corresponding medical injection device may be supported by a support frame that is movable relative to one or more corresponding dispensing heads of the heated coating composition.

This allows the nozzle of the dispensing head to be inserted into/extracted from a corresponding one of the one or more cartridges.

Preferably, the dispensing head is fixed and the support frame of the one or more cartridges is moveable towards and away from the dispensing head to enable relative movement between the dispensing head and the cartridges.

In alternative preferred embodiments, the dispensing head may be movable and the support frame of the one or more cartridges may be fixed, or similarly both the dispensing head and the support frame may be movable.

Preferably, step (c) of applying the heated coating composition onto the inner surface of the barrel comprises dispensing the coating composition through a nozzle of the dispensing head while moving the barrel toward the corresponding dispensing head.

This advantageously allows a very uniform coating to be applied to the inner surface of the barrel.

In a preferred embodiment, the time for dispensing the heated coating composition onto the inner surface of the cylinder is 0.3 seconds to 1 second, preferably 0.4 seconds to 0.7 seconds.

This advantageously limits the so-called "total cycle time" or "spraying time", given by the sum of the time for inserting and withdrawing the dispensing head from the cartridge, to less than about 3 seconds, which is considered compatible with normal cycle times of industrial production lines.

In this regard, the applicant has experimentally observed that by implementing one or more of the above steps to heat the tank, heat the dispensing head, heat the circulation pump upstream of the dispensing head or a component of the pump (for example, preferably a pump delivery head), and heat the connecting pipe that ensures fluid communication between the tank, the pump and the dispensing head, it is possible to advantageously facilitate the above-mentioned dispensing time of the heated coating composition.

In a particularly preferred embodiment, the above-mentioned dispensing time of the heated coating composition is advantageously facilitated by carrying out the step of heating the storage tank, pump, dispensing head and associated connecting pipes.

As mentioned above, the applicant has actually observed experimentally that operating in this manner allows the coating composition to be dispensed onto the inner surface of the barrel after the viscosity of the coating composition has been equalized, thereby advantageously shortening the dispensing time and making the coating composition more evenly distributed on the inner surface of the barrel.

In a preferred embodiment, step (c) of applying the heated coating composition onto the inner surface of the barrel comprises dispensing the heated coating composition at a flow rate of 0.1 μL/s to 5 μL/s, preferably about 0.5 μL/s.

This advantageously allows very thin coatings to be applied to the inner surface of the barrel.

In a preferred embodiment, step (c) of applying the heated coating composition onto the inner surface of the cylinder comprises applying the heated coating composition onto the inner surface of the cylinder at an amount of 0.2 μg/mm ² to 0.4 μg/mm ² per unit area.

Likewise, in this case it is advantageously possible to apply very thin coatings to the inner surface of the cylinder.

In a preferred embodiment, in step (c), the heated coating composition is applied onto the inner surface of the cylinder, so that the coating formed on the inner surface of the cylinder has an average thickness of 100 nm to 200 nm as measured by an optical reflection method.

Advantageously, as mentioned above, this average thickness of the coating formed on the inner surface of the cylinder fully complies with the requirements of the pharmaceutical and cosmetic industries, despite the fact that the coating is composed of a silicon material with a high kinematic viscosity.

In a preferred embodiment, the method of the present invention can obtain a coating with very uniform thickness on the inner surface of the cylinder, and its thickness standard deviation measured by optical reflection method (or optical interference method depending on the resolution) is equal to or less than 70nm, preferably equal to or less than 50nm.

This advantageously makes it possible to achieve a coating with optimal surface texture properties, so that visual inspection means, in particular automated visual inspection means, of the medical injection device are not misled.

In a preferred embodiment, the method of the present invention can form a coating with very uniform thickness on the inner surface of the cylinder for each batch of 10 cylinders, and the value of the batch average thickness standard deviation SD of the coating defined above is equal to or less than 60nm, preferably equal to or less than 50nm.

This advantageously makes it possible to obtain a coating with optimal surface regularity properties on a batch of multiple cylinders in a highly reproducible manner, as required in large-scale industrial production.

In a preferred embodiment, the method for manufacturing a medical injection device of the present invention may further include: after applying the heated coating composition to the inner surface of the barrel in step (c), step (f) partially cross-linking the coating formed on the inner surface of the barrel with polydimethylsiloxane.

Preferably, the partial cross-linking treatment is carried out by irradiation.

Preferably, the coating is irradiated by plasma irradiation, preferably by means of a plasma torch at atmospheric pressure through a flow of argon gas, preferably with a purity exceeding 99% (eg 99.999%).

This may be advantageous in that, if necessary, depending on the specific application, the low particle release properties of the coating may be further improved.

Advantageously, the applicant has experimentally discovered that a partial crosslinking treatment can be performed without affecting the lubricating properties of the coating.

To this end, in a preferred embodiment, the irradiation treatment time is 0.2 seconds to 1 second, preferably 0.2 to 0.6 seconds, more preferably 0.2 to 0.5 seconds (including end values), and even more preferably about 0.3 seconds.

The applicant has experimentally found, as detailed below, that by limiting the irradiation time to this range of values, the coating obtained can advantageously have optimal sliding properties of the plunger in the barrel of the injection device (in terms of static and dynamic friction) and optimal low particle release properties, both of which remain constant over a long period of time.

Advantageously, the partially cross-linked coating obtained according to this preferred embodiment can still significantly reduce the problem of false defects that may be misdetected by visual inspection devices (especially automated visual inspection devices) for medical injection devices due to its surface regularity.

Without being bound by any explanatory theory, the applicant believes that the irradiation time within the above-mentioned range is beneficial to the consolidation of the coating and further reduces the release of particles, but will not significantly affect the regularity of the coating surface, nor cause a significant change in the average values of the static friction and dynamic sliding friction of the plunger in the cylinder.

In particular, the applicant has experimentally observed that the particle release value obtained by irradiation according to the preferred embodiment of the present invention is much lower than that of coatings using non-crosslinked low-viscosity silicone materials in the prior art, which is equivalent to a coating treated with irradiation.

Advantageously, as detailed below with reference to experiments conducted by the applicant, this low particle release characteristic also remains substantially unchanged over a long period of time, whether at room temperature or above, or at low temperature, for example at a temperature in the range of -5°C to -40°C.

This feature is particularly important when medical injection devices (such as syringes) are subject to long-term storage and/or are filled with drugs that need to be kept at low temperatures.

In addition, the applicant has found through experiments that, as described in detail below, the irradiation time within the above range will not adversely affect the coating coverage percentage on the inner surface of the cylinder, which is maintained at least around 90% on average.

In a preferred embodiment, after applying the heated coating composition onto the inner surface of the cylinder in step (c), the time interval for irradiating the coating formed on the inner surface of the cylinder in step (f) is at least 15 minutes, preferably 15 to 20 minutes.

This advantageously allows the silicon droplets dispensed onto the inner surface of the cylinder to coalesce to achieve at least 90% coverage of the surface.

In this regard, the applicant has observed that if the waiting time is less than 15 minutes, the coverage percentage of the inner surface of the barrel will lead to more unnecessary interactions between the injection liquid pharmaceutical composition stored in the barrel and its glass inner surface.

The applicant also pointed out that, in the case of a significant increase in production time, waiting time exceeding 20 minutes will not bring about significant improvement.

In a preferred embodiment, the manufacturing method of the present invention may further include: before applying the heated coating composition to the inner surface of the cylinder in step (c), step (g) pretreating the inner surface of the cylinder to improve the adhesion of the coating to the inner surface.

In a particularly preferred embodiment, the pretreatment includes forming an adhesion promoter layer on the inner surface of the cylinder, preferably an adhesion promoter layer comprising [(bicycloheptyl)ethyl]trimethoxysilane.

Preferably, the above pretreatment is implemented by the following steps:

(g1) atomizing a solution of [(bicycloheptyl)ethyl]trimethoxysilane in isopropanol, preferably a 2.2 wt.% solution, onto the inner surface of the cylinder, preferably by means of an ultrasonic static nozzle;

(g2) The treated cylinder is preferably heated in an oven until the isopropyl alcohol present on the glass surface evaporates and provides thermal energy for forming a chemical bond between the glass and the adhesion promoter layer.

In an alternative preferred embodiment, the above pre-processing can be implemented by the following steps:

(g1') preferably heating the cylinder to a predetermined temperature in an oven;

(g2′) atomizing a solution of [(bicycloheptyl)ethyl]trimethoxysilane in isopropanol, preferably a 2.2 wt.% solution, onto the inner surface of the heated cylinder, preferably by means of an ultrasonic static nozzle;

In this case, the barrel is heated to a temperature suitable for subsequently evaporating the isopropyl alcohol in the atomized solution and providing sufficient thermal energy to form a chemical bond between the glass and the adhesion promoter layer.

Preferably, the heating of the cylinder in steps (g2) and (g1') is carried out in an oven heated to a temperature preferably between 120°C and 145°C, more preferably approximately equal to 140°C, for 14 to 25 minutes, preferably approximately equal to 20 minutes.

Preferably, the amount of the [(bicycloheptyl)ethyl]trimethoxysilane isopropanol solution sprayed onto the inner surface of the cylinder is 7 μL to 50 μL, preferably 7 μL to 22 μL.

In a preferred embodiment of the present invention, according to the U.S. USP 787 standard specified in the United States Pharmacopoeia 2021 edition 44-NF39, after storage at -40°C for 3 months, the average particle size of the microparticles released by the inner surface coating of the cylinder in the test solution is equal to or greater than 10 μm or equal to or greater than 25 μm, and the average value of the normalized microparticle concentration measured by the light obscuration method is equal to or less than 60% of the limit value specified in the above standard.

In particular, for particles having an average particle size equal to or greater than 25 μm, the average value is equal to or less than 5% of the limit value specified in the above standard.

In a preferred embodiment, according to the U.S. USP 787 standard specified in the United States Pharmacopoeia 2021 edition 44-NF39, after storage at -40°C for 3 months, for example by irradiation treatment, preferably by plasma irradiation treatment, the partially cross-linked coating on the inner surface of the cylinder releases microparticles with an average particle size equal to or greater than 10 μm or equal to or greater than 25 μm in the test solution, and the average value of the normalized microparticle concentration determined by the photoresistance method is equal to or less than 10% of the limit value specified in the above standard.

In particular, for particles having an average particle size equal to or greater than 25 μm, the average value is equal to or less than 1% of the limit value specified in the above standard.

These two preferred embodiments are particularly advantageous in the case of injectable pharmaceutical compositions containing temperature-sensitive active ingredients, such as so-called biotech drugs containing recombinant proteins or mRNA vaccines. In fact, these preferred embodiments achieve a significant reduction in the amount of microparticles released into the pharmaceutical composition stored in the barrel of a medical injection device, even after such pharmaceutical compositions have been stored at low temperatures for a long period of time as required.

In a preferred embodiment, according to the U.S. USP 789 standard specified in the United States Pharmacopoeia 2021 edition 44-NF39, after storage at +5°C or +25°C or +40°C for 3 months, for example by irradiation treatment, preferably by plasma irradiation treatment, the partially cross-linked coating on the inner surface of the cylinder releases microparticles with an average particle size equal to or greater than 10 μm or equal to or greater than 25 μm in the test solution, and the average value of the normalized microparticle concentration measured by the photoresistance method is equal to or lower than the limit specified in the above standard.

The above preferred embodiments are particularly advantageous for use of injectable pharmaceutical compositions in the ophthalmic field, for which the U.S. standard USP 789 provides very strict limits on the maximum tolerable amount of particles in a pharmaceutical composition stored in the barrel of a medical injection device even after such pharmaceutical composition has been stored for a long period of time at the required storage temperature.

In relation to the above, within the scope of the present specification and the claimed technical solution, the term "normalised" refers to a normalized value relative to the limit value of the considered standard or the maximum value of the particle count.

In a preferred embodiment, the method of the present invention further comprises step (h) of filling the barrel of the medical injection device with the injection liquid pharmaceutical composition, wherein step (h) is performed after the coating formed on the inner surface of the barrel is cooled to room temperature.

This advantageously enables a medical device, such as a syringe, to be pre-filled with a certain dose of the injection pharmaceutical composition for use.

In a preferred embodiment of the medical injection device of the present invention, the coverage rate corresponding to the total area of each arbitrary barrel portion with a planar developed axial length of 1.0 mm is equal to at least 90%, and the coverage rate is defined as the ratio of the coating coverage area to the total measured area.

This can advantageously achieve:

Reducing the risk of undesirable contact between the injectable drug composition stored in the barrel of the injection device and the glass inner surface of the barrel;

Optimal sliding properties of the plunger in the barrel of the injection device (in terms of static and dynamic friction);

The coating's optimal surface regularity properties significantly reduce problems associated with visual inspection of medical injection devices that may falsely detect defects.

In a preferred embodiment of the medical injection device of the present invention, an empty barrel with a nominal volume of 1 mL is used to measure the static sliding friction force of the plunger in the barrel at room temperature, and the average value of at least 30 measurements is 2N to 3N.

In a preferred embodiment of the medical injection device of the present invention, an empty barrel with a nominal volume of 0.5 mL is stored at room temperature for 3 months and then used to measure the static sliding friction of the plunger in the barrel at room temperature. The average value of at least 30 measurements is 1N to 3N.

In a preferred embodiment of the medical injection device of the present invention, an empty barrel with a nominal volume of 1 mL is stored at -40°C for 7 days and used to measure the static sliding friction of the plunger in the barrel. The average value of at least 30 measurements is 1.5N to 3N.

In a preferred embodiment of the medical injection device of the present invention, an empty barrel with a nominal volume of 1 mL is used to measure the dynamic sliding friction of the plunger in the barrel at room temperature, and the average value of at least 30 measurements is 1.5N to 2.5N.

In a preferred embodiment of the medical injection device of the present invention, an empty barrel with a nominal volume of 0.5 mL is stored at room temperature for 3 months and then used to measure the dynamic sliding friction of the plunger in the barrel at room temperature. The average value of at least 30 measurements is 1N to 2N.

In a preferred embodiment of the medical injection device of the present invention, an empty barrel with a nominal volume of 1 mL is stored at -40°C for 7 days and used to measure the dynamic sliding friction of the plunger in the barrel. The average value of at least 30 measurements is 1.5N to 2.5N.

Advantageously, the average values of the static sliding friction and the dynamic sliding friction of the plunger in the barrel fully meet the requirements of the pharmaceutical and cosmetic industries, with the static sliding friction generally being 2N to 6N and the dynamic sliding friction generally being 1N to 3N.

Preferably, the average values of static sliding friction and dynamic sliding friction of the plunger in the barrel are measured by the following test method.

The plunger is installed in an empty cylinder with a nominal volume of 1 mL Long or 0.5 mL. Within 24 hours after its positioning, starting from zero preload, for the cylinder with a nominal volume of 1 mL Long, a constant sliding speed equal to 240 mm/min is applied to the plunger, and for the cylinder with a nominal volume of 0.5 mL, a constant sliding speed equal to 100 mm/min is applied to the plunger, suitable for maintaining the movement of the plunger, and the static friction force is first measured by the dynamometer, and then the dynamic friction force during this plunger sliding period is measured.

See the examples below for more details on this test method.

In a preferred embodiment, as described above with respect to the manufacturing method, the medical injection device of the present invention comprises a partially crosslinked coating on the inner surface of the barrel, preferably partially crosslinked by irradiation treatment, more preferably by plasma irradiation treatment, as described above.

In a preferred embodiment, as described above with respect to the manufacturing method, the medical injection device of the present invention may further include an adhesion promoter layer applied to the inner surface of the barrel, preferably an adhesion promoter layer containing [(bicycloheptene)ethyl]trimethoxysilane.

In a preferred embodiment, as described above with respect to the manufacturing method, the medical injection device of the present invention further comprises a plunger installed in the barrel and slidably engaged with the barrel.

In a preferred embodiment, as described above with respect to the manufacturing method, the medical injection device of the present invention may further include an injection liquid pharmaceutical composition in the barrel and in contact with the inner surface thereof.

In a preferred embodiment, the injection pharmaceutical composition comprises one or more drugs and/or active ingredients in a form suitable for injection selected from the following: allergen-specific immunotherapy compositions, oligonucleotides, especially antisense oligonucleotides and RNAi antisense oligonucleotides, biological response modifiers, blood derivatives, enzymes, monoclonal antibodies, especially conjugated monoclonal antibodies and bispecific monoclonal antibodies, oncolytic viruses, peptides, especially recombinant peptides and synthetic peptides, polysaccharides, proteins, especially recombinant proteins and fusion proteins, vaccines, especially conjugate vaccines, DNA vaccines, inactivated vaccines, mRNA vaccines, recombinant vector vaccines, subunit vaccines or combinations thereof, as long as they are compatible.

More preferably, the drug and/or active ingredient suitable for injection form is selected from: GEN-3009, human pancreatic analog A21G+Pramlintide, AZD-5069+Durvalumab, Futuximab+Modotuximab, [225Ac]-FPI-1434, 111In-CP04, 14-F7, 212Pb-TCMC-Trastuzumab, 2141V-11, 3BNC-117LS, 3K3A-APC, 8H-9, 9MW-0211, A-166, A-319, AADvac-1, AB-002, AB-011, AB-022, AB-023, AB-154, AB-16B5, AB-729, ABB V-011, ABBV-0805, ABBV-085, ABBV-151, ABBV-154, ABBV-155, ABBV-184, ABBV-3373, ABBV-368, ABBV-927, Abelacimab, AbGn-107, AbGn-168H, ABL-001, ABvac-40, ABY-035, acetylcysteine + bromelain, ACI-24, ACI-35, ACP-014, ACP-015, ACT-101, Actimab-A, Actimab-M, AD-214, Adavosertib + Durvalumab, ADCT-602, ADG-106, ADG-116, ADM -03820, Advince, AEX-6003, Aflibercept biosimilars, AFM-13, AGEN-1181, AGEN-2373, AGLE-177, AGT-181, AIC-649, AIMab-7195, AK-101, AK-102, AK-104, AK-109, AK-111, AK-112, AK-119, AK-120, AL-002, AL-003, AL-101, Aldafermin, Aldesleukin, ALG-010133, ALM-201, ALMB-0168, ALNAAT-02, ALNAGT-01, ALN-HSD, ALPN-101, ALT -801, ALTP-1, ALTP-7, ALX-0141, ALX-148, ALXN-1720, AM-101, Amatuximab, AMC-303, Amelimumab, AMG-160, AMG-199, AMG-224, AMG-256, AMG-301, AMG-330, AMG-404, AMG-420, AMG-427, AMG-509, AMG-673, AMG-701, AMG-714, AMG-757, AMG-820, AMRS-001, AMV-564, AMY-109, AMZ-002, Analgecine, Ancrome, Andecaliximab, Anetumab, Corixetin Ravtansine, ANK-700, snake venom antibodies, anthrax antibodies, COVID-19 antibodies, tetanus antibodies, type I diabetes antibodies, solid tumor OX40 agonist antibodies, (recombinant) anti-hemophilic factor, solid tumor and ovarian cancer inhibition of EPHA2 antisense oligonucleotide RNAi, ANX-007, ANX-009, AP-101, Apitegromab, APL-501, APL-501, APN-01, APS-001 + flucytosine, APSA-01, APT-102, APVAC-1, APVAC-2, APVO-436, APX-003, APX-005M, ARCT-810, ARGX-109, AR GX-117, AROANG-3, AROAPOC-3, AROHIF-2, ARO-HSD, Ascrinvacumab, ASLAN-004, ASP-1235, ASP-1650, ASP-9801, AST-008, Astegolimab, Asunercept, AT-1501, Atacicept, ATI-355, ATL-101, ATOR-1015, ATOR-1017, ATP-128, ATRC-101, Atrosab, ATX-101, ATXGD-59, ATXMS-1467, ATYR-1923, AU-011, (conjugated) Rituximab AV-1, AVB-500, Avdoralimab, AVE-1642, AVI-3207, AVID-100, AVID-200, Aviscumine, Avizakimab, Axatilimab, B-001, B-002, Barusiban, BAT-1306, BAT-4306, BAT-4406F, BAT-5906, BAT-8003, Batroxobin, BAY-1905254, BAY-2315497, BAY-2701439, BB-1701, BBT-015, BCD-096, BCD-131, BCD-217, BCT-100, Bemarituzumab, Bepranemab, Bermekimab, Bertilimumab, Betalu tin, Bevacizumab, Bexmarilimab, BG-00010, BGBA-445, BHQ-880, BI-1206, BI-1361849, BI-456906, BI-655064, BI-655088, BI-754091, BI-754111, BI-836858, BI-836880, BI-905677, BI-905711, BIIB-059, BIIB-076, BIIB-101, BIL-06v, Bimagrumab, BIO89-100, Coronavirus disease 2019 (COVID-19), Urinary tract infection, Prosthetic joint and Acinetobacter infection Biological response modifier, Unknown indication Biological response modifier, Diabetic macular edema and wet macular degeneration bispecific monoclonal antibody I, HIV infection inhibits HIV 1Env bispecific monoclonal antibody, detection of tumor GD2 and CD3 bispecific monoclonal antibody, detection of pancreatic ductal adenocarcinoma PD-L1 and CTLA4 bispecific monoclonal antibody, BIVV-020, Bleselumab, BM-32, BMS-986012, BMS-986148, BMS-986156, BMS-986178, BMS-986179, BMS-986207, BMS-986218, BMS-986226, BMS-986253, BMS-986258, BMS-986258, BMS-986263, BNC-101, BNT-111, BNT-112, BNT-113, BNT-114, BNT-121, BOS-580, botulinum toxin, BP-1002, BPI-3016, BrevaRex MAb-AR20.5, Brivoligide, Bromelain, BT-063, BT-1718, BT-200, BT-5528, BT-588, BT-8009, BTI-322, BTRC-4017A, Budigalimab, BXQ-350, (human) C1 esterase inhibitor, Cabiralizumab, Camidanlumab Tesirine, Canerpaturev, Cavatak, CBA-1205, CBP-201, CBP-501, CC-1, CC-90002, CC-90006, CC-93269, CC-99712, CCW-702, CDX-0159, CDX-301, CDX-527, Celyvir, Cemdisiran, Cendakimab, CERC-002, CERC-007, Cevostamab, Cibisatamab, CIGB-128, CIGB-258, CI GB-300, CIGB-500, CIGB-552, CIGB-814, CIGB-845, Cinpanemab, Cinrebafuspα, CIS-43, CiVi-007, CJM-112, CKD-702, Clustoid D. Pteronyssinus, CM-310, CMK-389, CMP-001, CNTO-6785, CNTO-6785, CNV-NT, (recombinant) coagulation factor VIII, Cobomarsen, Codrituzumab, Cofetuzumab Pelidotin, COR-001, Cosibelimab, Cosibelimab, Cotadutide, CPI-006, CRX-100, CSJ-137, CSL-311, CSL-324, CSL-346, CSL-730, CSL-889, CTB-006, CTI-1601, CTP-27, CTX-471, CUE-101, Cusatuzumab, CV-301, CVBT-141, CX-2009, CX-2029, CYN-102, CyPep-1, CYT-107, CYT-6091, (Human) Anti-Cytomegalovirus Immune Globulin, Dabrafenib Mesylate + Panitumumab + Trametinib Dimethyl Sulfoxide, DAC-002, Dalcinonacogα, Dalotuzumab, Danvatirsen + Durvalumab, Da piglutide, Daxdilimab, DB-001, DCRA-1AT, Decavil, Depatuxizumab, Desmopressin, DF-1001, DF-6002, Diamyd, Dilpacimab, Diridavumab, DK-001, DKN-01, DM-101, DM-199, DMX-101, DNL-310, DNP-001, DNX-2440, Domagrozumab, Donanemab, Donidalorsen sodium salt, DP-303c, DS-1055a, DS-2741, DS-6157, DS-7300, DS-8273, Durvalumab+Monalizumab, Durvalumab+Oleclumab, Durvalumab+Oportuzumab Monatox, Durvalumab + Selumetinib sulfate, DX-126262, DXP-593, DXP-604, DZIF-10c, E-2814, E-3112, EBI-031, EBI-031, Yttrium 90 labeled Efavaleukinα, Efpegsomatropin, EG-Mirotin, Elezanumab, Elipovimab, Emactuzumab, Enadeno tucirev, Engedi-1000, Ensituximab, EO-2401, Epcoritamab, ERY-974, Etigilimab, Etokimab, Evitar, EVX-02, Exenatide, F-0002ADC, F-520, F-598, F-652, Faricimab, FAZ-053, FB-704A, FB-825, FF-21101, (human) fibrinogen concentrate, Ficla tuzumab, Flotetuzumab, FLYSYN, FmAb-2, FNS-007, FOL-005, FOR-46, Foralumab, Foxy-5, FPP-003, FR-104, Fresolimumab, FS-102, FS-118, FS-120, FS-1502, FSH-GEX, allergic asthma fusion protein, idiopathic thrombocytopenic purpura antagonist thrombopoietin receptor fusion protein, glioblastoma multiforme and malignant glioma Tumor antagonist epidermal growth factor receptor fusion protein, tumor suppressor CD25 fusion protein, tumor targeting mesothelin fusion protein, colitis, hypertension and ulcerative colitis fusion protein, FX-06, G-035201, G-207, G-3215, Garetosmab, Gatipotuzumab, GB-223, GBB-101, GC-1118A, GC-5131A, GEM-103, GEM-333, GEM-3PSCA, Gemibotulinumtoxin A, GEN-0101, GEN-1046, Gensci-048, Gentuximab, Gevokizumab, Glenzocimab, Glofitamab, Glucagon, GM-101, GMA-102, GMA-301, GNR-051, GNR-055, GNR-084, GNX-102, Goserelin acetate, Gosuranemab, gp-ASIT, GR-007, GR-1401, GR-1405, GR-1501, GRF-6019, GRF-6021, GS-1423, GS-2872, GS-5423, GSK-10 70806, GSK-2241658A, GSK-2330811, GSK-2831781, GSK-3174998, GSK-3511294, GSK-3537142, GT-02037-, GT-103, GTX-102, GW-003, GWN-323, GX-301, GXG-3, GXP-1, H-11B6, HAB-21, HALMPE-1, HB-0021, HBM-4003, HDIT-101, HER-902, HFB-30132A, HH-003, HL-06, HLX-06, HLX-07, HLX-20, HLX-22, HM-15211, HM-15912, HM-3, HPN-217, HPN-328, HPN-424, HPN-536, HPV-19, hRESCAP, HS-214, HS-628, HS-630, HS-636, HSV-1716, HTD-4010, HTI-1066, Hu8F4, HUB-1023, hVEGF-26104, HX-009, (recombinant) hyaluronidase, IBI-101, IBI-110, IBI-112, IBI-188, IBI-302, IBI-318, IBI-322, IBI-939, IC-14, ICON-1, I CT-01, Ieramilimab, Ifabotuzumab, IGEM-F, IGM-2323, IGM-8444, IGN-002, IMA-950, IMA-970A, IMC-002, IMCF-106C, IMCY-0098, IMGN-632, IMGN-005, IMM-01, IMM-201, (human) immunoglobulin, Imsidolimab, INA-03, INBRX-101, INBRX-105, INCAGN-1876, INCAGN-1949, INCAGN-2385, Inclacumab, Indatuximab Ravtansine, Interferon α-2b, INVAC-1, IO-102, IO-103, IO-112, IO-202, ION-224, ION-251, ION-464, ION-537, ION-541, ION-859, IONIS-AGTLRx, IONISAR-2.5Rx, IONIS-C9Rx, IONIS-FB-LRx, IONIS-FXILRx, IONIS-FXIRx, IONIS-GCGRRx, IONIS-HBVLRx, IONIS-HBVRx, IONIS-MAPTRx, IONIS-PKKRx, IONISMPRSS-6LRx, IPN-59011, IPP-204106, Ir-CPI, IRL-201104, IRL -201805, ISA-101, ISB-1302, ISB-1342, ISB-830, Iscalimab, ISU-104, IT-1208, ITF-2984, IXTM-200, JBH-492, JK-07, JMT-101, JMT-103, JNJ-0839, JNJ-3657, JNJ-3989, JNJ-4500, JN J-67571244, JNJ-75348780, JNJ-9178, JS-003, JS-004, JS-005, JSP-191, JTX-4014, JY-025, JZB-30, JZB-34, K-170, K-193, KAN-101, KD-033, KER-050, KH-903, KHK-4083, KHK-6640, EDV Paediatric, KLA-167, KLA-167, KLT-1101, KMRC-011, KN-026, KPL-404, KSI-301, KTN-0216, KTP-001, KUR-113, KY-1005, KY-1044, Labetuzumab Govitecan, Lacnotuzumab, Lacutamab, Ladiratuzumab Vedotin, Laronidase, LBL-007, LDOS-47, Letolizumab, Leuprorelin acetate, LEVI-04, LH-021, Liatermine, Lirilumab, LIS-1, LKA-651, LLF-580, LMB-100, LNA-043, LOAd-703, Lodapolimab, Lorucafuspα, LP-002, LT-1001, LT-1001, LT-1001, LT-3001, LT-3001, LTI-01, LTX-315, LuAF-82422, LuAF-87908, Lulizumab Pegol, LVGN-6051, LY-3016859, LY-3022855, LY-3041658, LY-3305677, LY-3372993, LY-3375880, LY-3434172, LY-3454738, LY-3561774, LZM-009, M-032, M-1095, M-254, M-6495, M-701, M-802 、M-9241、MAG-Tn3、MAU-868、MB-108、MBS-301、MCLA-117、MCLA-145、MCLA-158、MDNA-55、MDX-1097、MEDI-0457、MEDI-0618、MEDI-1191、MEDI-1341、MEDI-1814、MEDI-3506、MEDI-3617+Tremelim umab, MEDI-5117, MEDI-5395, MEDI-570, MEDI-5752, MEDI-5884, MEDI-6012, MEDI-6570, MEDI-7352, MEDI-9090, MEN-1112, Meplazumab, Mezagitamab, MG-021, MG-1113A, MGC-018, MIL-62, MIL-77, MIL-86, Mitazalimab, MK-1654, MK-3655, MK-4166, MK-4280, MK-4621, MK-5890, Molgramostim, tumor identification CD276 conjugated monoclonal antibody, tumor identification CD45 conjugated monoclonal antibody, non-small cell lung cancer and metastatic colorectal cancer identification CEACAM5 conjugated monoclonal antibody, metastatic colorectal cancer identification Mucin 1 conjugated monoclonal antibody, PSMA-targeted conjugated monoclonal antibody for prostate cancer, dengue fever monoclonal antibody, celiac disease, tumors and tropical spastic paraplegia antagonizing IL-2Rβ monoclonal antibody, rheumatoid arthritis antagonizing interleukin 6 receptor monoclonal antibody, tumor antagonizing PD1 monoclonal antibody, solid tumor antagonizing PD1 monoclonal antibody, HIV-1 inhibiting CD4 monoclonal antibody, tumor inhibiting GD2 monoclonal antibody, rabies inhibiting glycoprotein monoclonal antibody, autoimmune diseases and musculoskeletal diseases inhibiting IL17 monoclonal antibody, asthma and chronic obstructive pulmonary disease (COPD) inhibiting IL5 monoclonal antibody, solid tumor inhibiting PD-L1 monoclonal antibody, ankylosing spondylitis, psoriasis and rheumatoid arthritis inhibiting TNF-α monoclonal antibody, Dupuytren's contracture inhibiting TNF-α monoclonal antibody, diabetic macular edema and wet age-related macular degeneration inhibiting VEGF monoclonal antibody, tumor and ophthalmology inhibiting VEG Monoclonal antibody targeting F, monoclonal antibody inhibiting VEGFA for metastatic colorectal cancer and non-small cell lung cancer, monoclonal antibody targeting CD66b for blood cancer and metabolic disorders, monoclonal antibody targeting GP41 for HIV infection, MORAb-202, Motrem, MP-0250, MP-0274, MP-0310, MP-0420, MRG-001, MRG-002, MRG-003, MRG-110, mRNA-241 6. mRNA-2752, mRNA-3927, MSB-0254, MSB-2311, MSC-1, MT-1001, MT-1002, MT-2990, MT-3724, MT-3921, MTX-102, Murlentamab, MVT-5873, MVXONCO-1, MW-11, MW-33, NA-704, Namilumab, Naratuximab Emtansine, Navicixizumab, NBE-002, NBF-006, NC-318, NC-410, Nemvaleukinα, NEOPV-01, NG-348, NG-350a, NG-641, NGM-120, NGM-395, NGM-621, NI-006, NI-0801, Nidanilimab, Nimacimab, NIS-79 3. NIZ-985, NJA-730, NJH-395, NKTR-255, NKTR-358, NMIL-121, NN-9215, NN-9499, NN-9775, NN-9838, NN-9931, NNC-03850434, NP-024, NP-025, NP-137, NPC-21, NPT-088, NPT-189, NRP-2945, NStride APS, NVG-111, NXT-007, NZV-930, OBI-888, OBI-999, OBT-076, OC-001, Octreotide Acetate, Octreotide Acetate CR, Octreotide Acetate Microspheres, Odronextamab, Odronextamab, OH-2, Olamkicept, Oleclumab, Olinvacimab, Olpasiran, Olvimulogene Nanivacirepvec, OMS-906, OnabotulinumtoxinA, ONC-392, ONCase-PEG, Human papillomavirus-related cancer, Human papillomavirus infection and COVID-19 oncolytic virus, Metastatic breast cancer oncolytic virus, Tumor oncolytic virus, Solid tumor oncolytic virus, Recurrent prostate cancer and metastatic pancreatic cancer IL-12-activating oncolytic virus, Tumor-activating thymidine kinase oncolytic virus, Solid tumor antagonistic PD1 oncolytic virus, Solid tumor targeting CD155/NECL5 oncolytic virus, Tumor targeting CD46 and SLC5A5 oncolytic virus, Human papillomavirus (HPV)-related solid tumors targeting E6 and E7 oncolytic virus, Solid tumor targeting MAGE-A3 oncolytic virus, ONCOS-102 、ONCR-177、Ongericimab、ONO-4685、Onvatilimab、OPK-88005、OPT-302、ORCA-010、OrienX-010、Orilanolimab、Oricumab、OS-2966、OSE-127、Osocimab、Otelixizumab、OTO-413、OTSA-101、OXS-1550、OXS-3550、P-28R、P-2G12、Pacmilimab、Panobacumab、Parvoryx、Pasireotide、Pasotuxizumab、PC-mAb、PD-01、PD-0360324、PD-1+Antagonist Ropeginterferon α-2b, Pegbelfermin, Peginterferon λ-1a, Pelareorep, Pelareorep, Pemziviptadil, PEN-221, Sodium Pentothiosulfate, Pepinemab, COVID-19 Peptide, Solid Tumor Peptide, Pertuzumab Biomodifier, Pexastimogene Devacirepvec, PF-04518600, PF-06480605, PF-06730512, PF-06755347, PF-06804103, PF-06817024, PF-06823859, PF-06835375, PF-06863135, PF-06940434, PF-07209326, PF-655, PHN-013, PHN-014, PHN-015, Pidilizumab, PIN-2, Plamotamab, (human) Plasminogen 1, Plexaris, PM-8001, PNT-001, Pollinex Quattro Tree, PolyCAb, Poly-ICLC, PolyPEPI-1018, Ponsegromab, PP-1420, PR-15, PR-200, Prasinezumab, Prexigebersen, PRL3-ZUMAB, diabetic foot ulcer and cerebral hemorrhage protein, osteoarthritis and asthma protein, infectious disease and tumor activated IL12 protein, PRS-060, PRTX-100, PRV-300, PRV-3279, PRX-004, PSB-205, PT-101, PT-320, PTR-01, PTX-35, PTX-9908, PTX-9908, PTZ-329, PTZ-522, PVX- 108, QBECO-SSI, QBKPN-SSI, QL-1105, QL-1203, QL-1207, QL-1604, QPI-1007, QPI-1007, Quavonlimab, Quetmolimab, QX-002N, QX-005N, Radspherin, Ranibizumab, Ranpirnase, Ravagalimab, New Generation Ravulizumab, RC-28, RC-402, RC-88, RD-001, REC-0438, Methotrexate Toxicity Recombinant Carboxypeptidase G2, Organophosphorus Nerve Agent Poisoning Recombinant Enzyme, Cardiovascular, Central Nervous System, Musculoskeletal and Metabolic Diseases Arousal of GHRH Recombinant peptides, recombinant plasma gelatinase substitutes for infectious diseases, recombinant proteins for inflammatory bowel disease, multiple sclerosis and psoriasis, recombinant tumor proteins, tumor-stimulating IFNAR1 and IFNAR2 recombinant proteins; chemotherapy-induced gastrointestinal mucositis and oral mucositis stimulating KGFR recombinant proteins, idiopathic thrombocytopenic purpura stimulating thrombopoietin receptor recombinant proteins, lymphoma and solid tumor inhibition CD13 recombinant proteins, hemophilia A and hemophilia B inhibiting coagulation factor XIV recombinant proteins, acute hyperuricemia recombinant urate oxidase substitutes, trifluoroacetate red enzyme peptides, REGN-19081909, REGN-3048, REGN-3051, REGN-3500, REGN-4018, REGN-4461, REGN-5093, REGN-5458, REGN-5459, REGN-5678, REGN-5713, REGN-5714, REGN-5715, REGN-6569, REGN-7075, REGN-7257, Remlarsen, Renaparin, REP-2139, REP-2165, Reteplase, RG-6139, RG-6147, RG-6173, RG-6290, RG-6292, RG-6346, RG-70240, RG-7826, RG-7835, RG-7861, RG-7880, RG-7992, RGLS-4326, Rigvir, Rilimogene Galvacirepvec, Risuteganib, Rituximab, RMC-035, RO-7121661, RO-7227166, RO-7284755, RO-7293583, RO-7297089, Romilkimab, Ropocamptide, Rosibafuspα, RPH-203, RPV-001, rQNestin-34.5v.2, RSLV-132, RV-001, RXI-109, RZ-358, SAB-176, SAB-185, SAB-301, SAIT-301, SAL-003 、SAL-015、SAL-016、Sanguinate、SAR-439459、SAR-440234、SAR-440894、SAR-441236、SAR-441344、SAR-442085、SAR-442257、SB-11285、SBT-6050、SCB-313、SCIB-1、SCO-094、SCT-200、SCTA-01、SD-101、SEA-BCMA、SEA-CD40、SelectAte、Selicrelumab、SelK-2、Semorinemab、Serclutamab Talirine, Seribantumab, Setrusumab, Sevuparin sodium salt, SFR-1882, SFR-9213, SFR-9216, SFR-9314, SG-001, SGNB-6A, SGNCD-228A, SGN-TGT, SHR-1209, SHR-1222, SHR-1501, SHR-1603, SHR-1701, SHR-1702, SHR-1802, SHRA-1201, SHRA-1811, SIB-001, SIB-003, Simlukafuspα, Siplizumab, Sirukumab, SKB-264, SL-172154, SL-279252, SL-701, SOC-101, SOJB, Somatropin SR, Sotatercept, Sprifermin, SRF-617, SRP-5051, SSS-06, SSS-07, ST-266, STA-551, STI-1499, STI-6129, STK-001, STP-705, STR-324, STRO-001, STRO-002, STT-5058, SubQ-8, Sulituzumab, Suvratoxumab, SVV-001, SY-005, SYD-1875, Sym-015, Sym-021, Sym-022, Sym-023 , SYN-004, SYN-125, SLC10A1 synthetic peptides inhibiting hepatitis B and type II diabetes, GHSR synthetic peptides regulating chronic kidney disease, CCKBR synthetic peptides targeting medullary thyroid cancer, somatostatin receptor synthetic peptides targeting neuroendocrine gastrointestinal pancreatic tumors, T-3011, T-3011, TA-46, TAB-014, TAB-014, Tafoxiparin sodium salt, TAK-101, TAK-169, TAK-573, TAK-611, TAK-671, Talquetamab, Tasadenoturev, TBio-6517, TBX.OncV NSC, Tebotelimab, Teclistamab, Telisotuzumab Vedotin, Telomelysin, Temelimab, Tenecteplase, Tesidolumab, Teverelix, TF-2, TG-1801, TG-4050, TG-6002, TG-6002, T-Guard, Thor-707, THR-149, THR-317, Thrombosomes, Thymalfasin, Tilavonemab, TILT-123, Tilvestamab, Tinurilimab, Tipapkinogene Sovacivec, Tiprelestat, TM-123, TMB-365, TNB-383B, TNM-002, TNX-1300, Tomaralimab, Tomuzotuximab, Tonabacase, Tralesinidase α, Trebananib, Trevogrumab, TRK-950, TRPH-222, TRS-005, TST-001, TTHX-1114, TTI-621, TTI-622, TTX-030, TVT-058, TX-250, TY-101, Tyzivumab, U-31402, UB-221, UB-311, UB-421, UB-621, U BP-1213, UC-961, UCB-6114, UCHT-1, UCPVax, Ulocuplumab, UNEX-42, UNI-EPO-Fc, Urelumab, UV-1, V-938, Acute Lymphocytic Leukemia Vaccine, B-cell Non-Hodgkin's Lymphoma Vaccine, Chronic Lymphocytic Leukemia Vaccine, Glioma Vaccine, Hormone-sensitive Prostate Cancer Vaccine, Melanoma Vaccine, Non-muscle Invasive Bladder Cancer Vaccine, Ovarian Cancer Vaccine, Tumor-targeted Brachyury and HER2 Vaccine, Tumor-targeted Brachyury Vaccine, B-cell Non-Hodgkin's Lymphoma Targeted CCL20 Vaccine, Colorectal Cancer Targeted CEA Vaccine, Metabolic Disorders, Immunity, Infectious Diseases and Musculoskeletal Diseases Targeted IFN-α Vaccine, VAL-201, V antictumab, Vanucizumab, Varlilumab, Vas-01, VAX-014, VB-10NEO, VCN-01, Vibecotamab, Vibostolimab, VIR-2218, VIR-2482, VIR-3434, VIS-410, VIS-649, Vixarelimab, VLS-101, Vofatamab, Volagidemab, Vopratelimab, Voyager-V1, VRC-01, VRC-01LS, VRC-07523LS, VTP-800, Vunakizumab, Vupanorsen sodium salt, Vx-001, Vx-006, W -0101, WBP-3425, XAV-19, Xentuzumab, XmAb-20717, XmAb-22841, XmAb-23104, XmAb-24306, XMT-1536, XoGlo, XOMA-213, XW-003, Y-14, Y-242, YH-003, YH-14618, YS-110, YYB-101, Zagotenemab, Zaliferelimab, Zampilimab, Zanidatamab, Zanidatamab, Zansecimab, Zenocutuzumab, ZG-001, ZK-001, ZL-1201, Zofin, or a combination thereof, as long as they are compatible.

In a preferred embodiment, the parts kit for assembling the medical injection device of the present invention includes any applicable preferred features of the above-mentioned medical device.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the present invention will become apparent from the following description of certain preferred embodiments of the present invention by way of non-limiting examples in conjunction with the accompanying drawings.

In the figure:

FIG1 shows a partial longitudinal sectional view of a medical injection device, in particular a syringe, according to a preferred embodiment of the present invention;

FIG2 shows a schematic block diagram of a medical injection device manufacturing apparatus according to a preferred embodiment of the present invention;

3 and 4 show a plurality of graphs according to a preferred embodiment of the present invention, respectively indicating the thickness curves of an exemplary coating applied to the inner surface of the barrel when the barrel of a medical injection device with a nominal volume of 1 mL and 3 mL is expanded axially;

5 to 10 show a plurality of graphs according to a preferred embodiment of the present invention and according to the prior art, indicating the thickness curves of an exemplary coating applied to the inner surface of the barrel when the barrel of a medical injection device with a nominal volume of 0.5 mL is expanded axially, measured at room temperature immediately after the coating is applied and cooled (t0) and measured after storage at room temperature for 3 months (t3);

FIG11 shows the average static sliding friction force of the plunger installed in an empty cylinder with a nominal volume of 1 mL at different time points in some examples of medical injection devices according to the present invention and the prior art;

FIG12 shows the average values of dynamic sliding friction force of plungers installed in an empty cylinder with a nominal volume of 1 mL at different time points in certain examples of medical injection devices according to the present invention and the prior art;

FIG13 shows the average static sliding friction force of a plunger installed in a barrel with a nominal volume of 1 mL and filled with a test solution with a dynamic viscosity of 1 mPa·s at different time points in certain examples of medical injection devices according to the present invention and the prior art;

FIG14 shows the average values of dynamic sliding friction of a plunger installed in a barrel with a nominal volume of 1 mL and filled with a test solution with a dynamic viscosity of 1 mPa·s at different time points in certain examples of medical injection devices according to the present invention and the prior art;

FIG15 shows the average static sliding friction of the plunger installed in the barrel with a nominal volume of 1 mL and filled with the test solution after being stored at different temperatures for 7 days in some examples of medical injection devices according to the present invention and the prior art;

FIG16 shows the average value of the dynamic sliding friction of the plunger installed in the barrel with a nominal volume of 1 mL and filled with the test solution after being stored at different temperatures for 7 days in some examples of medical injection devices according to the present invention and the prior art;

FIG17 shows the average static sliding friction of the plunger installed in the barrel with a nominal volume of 1 mL and filled with the test solution after being stored at -40°C for 2 days and 7 days in some examples of medical injection devices according to the present invention and the prior art;

FIG18 shows the average value of the dynamic sliding friction of the plunger installed in the barrel with a nominal volume of 1 mL and filled with the test solution after being stored at -40°C for 2 days and 7 days in some examples of medical injection devices according to the present invention and the prior art;

FIG19 shows the average values of static sliding friction force of a plunger installed in an empty barrel with a nominal volume of 0.5 mL measured at different time points at room temperature in certain examples of medical injection devices according to the present invention and the prior art;

FIG20 shows the average values of dynamic sliding friction force of a plunger installed in an empty barrel with a nominal volume of 0.5 mL measured at different time points at room temperature in certain examples of medical injection devices according to the present invention and the prior art;

FIG21 shows the average static sliding friction force of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of -40°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG22 shows the average values of dynamic sliding friction of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of -40°C and a nominal volume of 0.5 mL according to certain examples of medical injection devices of the present invention and the prior art;

FIG23 shows the average static sliding friction force of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of +5°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG24 shows the average values of dynamic sliding friction of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of +5°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG25 shows the average static sliding friction force of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of +25°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG26 shows the average values of dynamic sliding friction of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of +25°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG27 shows the average static sliding friction force of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of +40°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG28 shows the average values of dynamic sliding friction of the plunger installed in the barrel filled with the test solution at different time points using a storage temperature of +40°C and a nominal volume of 0.5 mL according to some examples of medical injection devices of the present invention and the prior art;

FIG29 summarizes the average static sliding friction of the plunger installed in the barrel with a nominal volume of 0.5 mL and filled with the test solution as shown in FIGS. 21 to 28 after being stored at different temperatures for three months in some examples of medical injection devices according to the present invention and the prior art;

FIG30 summarizes the average values of dynamic sliding friction of the plunger installed in the barrel with a nominal volume of 0.5 mL and filled with the test solution as shown in FIGS. 21 to 28 after being stored at different temperatures for three months in some examples of medical injection devices according to the present invention and the prior art;

FIG31 shows the normalized concentration values of particles with a particle size equal to or greater than 10 μm measured at room temperature for a cylinder with a nominal filling capacity of 3.0 mL, filled with 3.3 mL of a test aqueous solution, and subjected to automatic stirring (the sample rotates at 360° C.) in certain examples of medical injection devices according to the present invention and the prior art;

FIG32 shows the normalized concentration values of particles with a particle size equal to or greater than 25 μm measured at room temperature for a cylinder with a nominal filling capacity of 3.0 mL, filled with 3.3 mL of a test aqueous solution, and subjected to automatic stirring (the sample rotates at 360° C.) in certain examples of medical injection devices according to the present invention and the prior art;

33 to 35 show the normalized concentration values of particles with a particle size equal to or greater than 10 μm measured at three different temperature conditions at time 0 for a cylinder with a nominal filling capacity of 0.5 mL and filled with 0.25 mL of a test aqueous solution after storage for 6 months according to some examples of medical injection devices of the present invention and the prior art;

FIG36 shows the normalized concentration values of particles measured by the MFI test at different storage times at -40°C for a barrel with a nominal filling capacity of 1.0 mL and filled with 0.55 mL of a test aqueous solution in certain examples of injection devices for medical use according to the present invention and the prior art;

37 and 38 show the normalized concentration values of particles with a particle size equal to or greater than 10 μm and equal to or greater than 25 μm measured at a temperature of -40°C for a cylinder with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art;

39 and 40 show the particle release values of a barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in certain examples of medical injection devices according to the present invention and the prior art, measured at different storage times at a temperature of -40°C by an MFI test;

41 and 42 show the normalized concentration values of particles with a particle size equal to or greater than 10 μm and equal to or greater than 25 μm measured at a temperature of +5°C for a cylinder with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art;

43 and 44 show the normalized concentration values of particles with a particle size of 10 μm or more and 25 μm or more measured at a temperature of +5°C after the coating of the barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art is subjected to plasma irradiation treatment;

45 and 46 show the particle release values of a barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art measured at different storage times at a temperature of +5°C through an MFI test;

47 and 48 show the normalized concentration values of particles with a particle size equal to or greater than 10 μm and equal to or greater than 25 μm measured at a temperature of +25°C for a cylinder with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art;

49 and 50 show the normalized concentration values of particles with a particle size of 10 μm or more and 25 μm or more measured at a temperature of +25°C after the coating of the barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art is subjected to plasma irradiation treatment;

51 and 52 show the particle release values of a barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in certain examples of medical injection devices according to the present invention and the prior art measured at different storage times at a temperature of +25°C through an MFI test;

53 and 54 show the normalized concentration values of particles with a particle size equal to or greater than 10 μm and equal to or greater than 25 μm measured at a temperature of +40° C. for a cylinder with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art;

FIG55 and FIG56 show the normalized concentration values of particles with a particle size of 10 μm or more and 25 μm or more measured at a temperature of +40°C after the coating of the barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution in some examples of medical injection devices according to the present invention and the prior art is subjected to plasma irradiation treatment;

57 and 58 show the particle release values of the barrel with a nominal filling capacity of 0.5 mL and filled with 500 μL of the test aqueous solution in some examples of medical injection devices according to the present invention and the prior art measured at different storage times at a temperature of +40° C. through the MFI test;

FIG59 and FIG60 summarize the normalized concentration values of particles with a particle size of 10 μm or more and 25 μm or more for a cylinder with a nominal filling capacity of 0.5 mL and filled with 500 μL of a test aqueous solution after being stored at different temperatures for three months in some examples of medical injection devices according to the present invention and the prior art after the coating thereof is treated with plasma irradiation;

61 to 67 show a plurality of pictures taken through an optical microscope after the silicon coating according to the present invention and the prior art was partially cross-linked by plasma irradiation in different regions of the barrel of a medical injection device at different irradiation times.

Detailed ways

In FIG. 1 , a medical injection device, in particular a syringe, according to a preferred embodiment of the present invention is generally marked with reference numeral 1 .

The term "syringe" is used herein in a broad sense to include cartridges, "pens," and other types of tubes or reservoirs suitable for assembly with one or more other components to provide a functional syringe.

The term "syringe" also includes related items, such as self-administered injectors, that provide a mechanism for dispensing the contents.

The syringe 1 comprises a glass syringe barrel 2 having a substantially cylindrical body 2a provided with a substantially conical end 2b.

The inner surface 3 of the cylinder 2 is coated with a coating 4 .

The barrel 2 is also configured to receive a plunger 5 in sliding engagement.

In a manner conventional per se, the plunger 5 is associated with one end of a drive rod 6 .

In the preferred embodiment shown in FIG. 1 , the syringe 1 further comprises an injection liquid 7 in the barrel 2 and in contact with the inner surface 3 thereof, such as a liquid drug composition.

The syringe 1 is also provided with a closure cap 8 of the end 2b of the barrel 2 so as to allow the delivery of the injection liquid 7 under safe conditions.

In a preferred embodiment, the coating 4 comprises about 100 wt. % of polydimethylsiloxane, whose kinematic viscosity at room temperature is about 12500 cSt (125 cm ² /s), such as polydimethylsiloxane (PDMS) medical fluid with the product name Liveo ^™ 360 (DuPont).

The coating 4 of the syringe 1 shown in FIG. 1 comprises one or more of the features described in the above summary of the invention and cited herein.

In a preferred embodiment, the syringe 1 can be manufactured by an apparatus 10 schematically shown in FIG. 2 .

The apparatus 10 comprises a tank 11 for storing the coating composition, preferably a stainless steel tank, having at least one heating element configured to heat the stored coating composition.

For example, the heating element of the tank 11 may be a resistor or a pipe through which a suitable heating fluid circulates (placed inside the tank 11 itself) or may be a jacket of the tank 11 through which a suitable heating fluid circulates.

The storage tank 11 is in fluid communication with a circulation pump 12 for the coating composition via a conduit 13, preferably made of stainless steel, suitably thermally insulated in a manner known per se.

In a preferred embodiment, a corresponding heating element of the pump 12 (not explicitly shown in FIG. 2 ) is configured to heat a delivery head (also not shown) of the pump 12 .

By way of example only, the heating element of the delivery head of pump 12 may include one or more resistors in heat exchange relationship with the delivery head of pump 12, such as integrated into a corresponding housing (eg, a cylindrical housing) associated with the delivery head.

The pump 12 is in fluid communication with a dispensing head 14 configured to dispense the coating composition via a conduit 15, preferably made of stainless steel, suitably thermally insulated in a manner known per se.

At least one dispensing nozzle (not explicitly shown in FIG. 2 ) provided in the dispensing head 14 is configured to spray the coating composition onto the inner surface 3 of the barrel 2 of the syringe 1 .

A corresponding heating element (also not explicitly shown in FIG. 2 ) provided with the dispensing head 14 is configured to heat the coating composition dispensed by the nozzle.

By way of example only, the heating element may be a resistor in heat exchange relationship with the dispensing nozzle, such as integrated into a housing (eg, a cylindrical housing) associated with the dispensing nozzle.

In this preferred embodiment of the device 10 , the tank 11 , the pump 12 and the dispensing head 14 are in fluid communication with each other via conduits 13 , 15 .

In a particularly preferred embodiment, the conduits 13, 15 are in heat exchange relationship with respective heating elements (eg resistors) or conduits housing a suitable heating fluid circulated therein.

In a manner known per se, the nozzle of the dispensing head 14 is in fluid communication with a suitable dispensing gas source 16 , for example a compressed air source, via a conduit 17 .

Preferably, the air distribution source 16 distributes compressed air at a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably approximately equal to 30 psi (2.07 bar).

In a manner known per se (not explicitly shown in FIG. 2 ), the device 10 comprises a movable support frame for a plurality of barrels 2 of respective syringes 1 , one of which is schematically shown in FIG. 2 .

The coating composition dispensing head 14 and the supporting frames of the barrel 2 of the syringe 1 are movable relative to each other to insert/extract each nozzle of the dispensing head 14 into/from a corresponding barrel 2 of the plurality of barrels 2 .

In a preferred embodiment, the relative movement between the dispensing head 14 and the support frame of the cartridge 2 is achieved by moving the support frame of the cartridge 2 relative to the fixed dispensing head 14 .

A preferred embodiment of a method for manufacturing a medical injection device (eg, the above-mentioned syringe 1 ) includes the following steps, preferably performed by the apparatus 10 shown in FIG. 2 .

In the first step, a coating composition containing polydimethylsiloxane is provided, for example, Liveo ^™ 360 medical fluid (DuPont) containing approximately 100 wt.% polydimethylsiloxane, and the nominal kinematic viscosity thereof at room temperature is approximately 12500 cSt (125 cm ² /s).

Preferably, the step of providing the coating composition comprises storing the coating composition in a storage tank 11 .

Preferably, the coating composition stored in the tank 11 is heated to a temperature of 100° C. to 150° C., for example to a temperature approximately equal to 120° C., by a heating element associated with the tank 11 .

Preferably, the heated coating composition stored in the storage tank 11 is maintained at a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably 10 psi (0.69 bar) to 30 psi (2.07 bar), more preferably 10 psi (0.69 bar) to 15 psi (1.03 bar).

Next, the heated coating composition is sent to a dispensing head 14 provided with at least one nozzle, preferably a plurality of dispensing nozzles, via a pump 12 . The dispensing head 14 is used to dispense the heated coating composition onto the inner surface 3 of the cylinder 2 to form a coating 4 on the inner surface 3 .

As mentioned above, the time for dispensing the heated coating composition onto the inner surface 3 of the cylinder 2 is 0.3 seconds to 1 second, preferably 0.4 seconds to 0.7 seconds.

The method comprises heating the dispensing head 14, preferably also heating the delivery head of the pump 12 and the pipes 13 and 15, so that the coating composition maintains a temperature of, for example, 100° C. to 150° C., for example approximately equal to 120° C., during its passage from the tank 11 to the nozzle of the dispensing head 14, and the dispensing head 14 dispenses the coating composition at the above temperature.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the barrel 2 at the above temperature is carried out by dispensing the heated coating composition at a pressure of 5psi (0.34 bar) to 150psi (10.34 bar), preferably 6psi (0.41 bar) to 10psi (0.69 bar).

Preferably, such dispensing of the heated coating composition includes feeding distribution air from distribution air source 16 to distribution head 14 at a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably 6 psi (0.41 bar) to 10 psi (0.69 bar).

Preferably, the pressure of the coating composition reservoir 11 is maintained above the pressure of the nozzle of the dispensing head 14 in order to optimize the dispensing of the heated coating composition.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the barrel 2 comprises imparting relative motion between the dispensing head 14 and the barrel 2 while dispensing the heated coating composition.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the barrel 2 comprises dispensing the heated coating composition to the inner surface 3 of the barrel 2 during the relative movement of the dispensing head 14 inserted into the barrel 2 .

Preferably, the step of applying the heated coating composition onto the inner surface 3 of the barrel 2 comprises dispensing the heated coating composition at a flow rate of 0.1 μL/s to 5 μL/s, such as about 0.5 μL/s.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the cylinder 2 comprises applying the heated coating composition to the inner surface 3 at an amount of 0.2 μg/mm ² to 0.4 μg/mm ² per unit area.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the cylinder 2 is performed so that the coating 4 formed on the inner surface 3 has an average thickness of 100 nm to 250 nm, preferably 100 nm to 200 nm, as measured by an optical reflection method.

In a preferred embodiment, the thickness standard deviation of the coating 4 formed on the inner surface of the cylinder (measured by optical reflection method) is equal to or less than 90 nm, preferably equal to or less than 70 nm, more preferably equal to or less than 50 nm.

In a preferred embodiment, for each batch of 10 cylinders 2, the batch average standard deviation SD of the coating 4 thickness (obtained as above) has a value equal to or less than 70 nm, preferably equal to or less than 60 nm, more preferably equal to or less than 50 nm.

If necessary, after the step of applying the heated coating composition to the inner surface 3 of the cylinder 2, a further step of partially cross-linking the coating 4 formed on the inner surface 3 of the cylinder 2 with polydimethylsiloxane can be implemented, for example, by irradiating the coating 4 with an argon gas flow at atmospheric pressure using a plasma torch for partial cross-linking.

Preferably, the irradiation treatment time is 0.2 seconds to 1 second, more preferably 0.2 seconds to 0.6 seconds, and even more preferably 0.2 seconds to 0.5 seconds, both inclusive.

Preferably, after the step of applying the heated coating composition to the inner surface 3 of the cylinder 2, the irradiation treatment is carried out at a time interval of at least 15 minutes, preferably 15 to 20 minutes.

If necessary, before the step of applying the heated coating composition to the inner surface 3 of the cylinder 2 , another step of pre-treating the inner surface 3 of the cylinder 2 may be performed to improve the adhesion of the coating 4 to the inner surface 2 .

In a particularly preferred embodiment, the pretreatment comprises forming an adhesion promoter layer on the inner surface 3 of the cylinder 2, preferably an adhesion promoter layer comprising [(bicycloheptyl)ethyl]trimethoxysilane.

If it is desired to manufacture a prefilled syringe, such as the syringe illustrated in FIG. 1 , another step of filling the barrel 2 with the injection liquid 7 may be performed after the coating 4 formed on the inner surface 3 of the barrel 2 has cooled to room temperature.

Finally, if one wishes to manufacture the prefilled syringe 1 shown in FIG. 1 , a further step may be performed of associating the closure cap 8 to the end 2 b of the barrel 2 , so as to seal the contents of the syringe 1 .

The exemplary and non-limiting technical objectives of the present invention are described below through certain embodiments of the present invention.

Similarly, in an illustrative and non-limiting sense, in the following examples, the medical injection device (syringe) manufactured according to the method of the present invention has a nominal filling capacity of 0.5 mL, 1 mL Long or 3 mL in accordance with the ISO 11040-4 standard (2015), and is manufactured by applying the heated coating composition to the inner surface 3 of the barrel 2 under the following application conditions.

Syringe with nominal filling volume of 0.5mL

Total travel of each dispensing head 14 in each cylinder 2: maximum 75 mm

Speed of dispensing head 14: 35 mm/s

Total cycle time (insertion/dispensing time + pumping time of dispense head 14): 2.1 seconds

Dispensing flow rate of heated coating composition: 0.30 μL/s

Volume of dispensed coating composition: 0.30 μL

Dispensing time of heated coating composition: 1 second.

Syringe with nominal filling volume of 1mL

Total travel of each dispensing head 14 in each cylinder 2: maximum 80 mm

Speed of the dispensing head 14: 52 mm/s

Total cycle time (insertion/dispensing time + pumping time of dispenser head 14): 1.5 seconds

Dispensing flow rate of heated coating composition: 0.63 μL/s

Volume of dispensed coating composition: 0.63 μl

Dispensing time of the heated coating composition: 1 second.

Example 1 to Example 2 (the present invention)

Manufacturing of medical injection device barrels and evaluation of the thickness and uniformity of the coating formed on the inner surface of the barrel - Syringe standard The filling volume is 1mL or 3mL

By the above method and apparatus, a coating composition composed of PDMS Liveo ^™ 360 medical fluid (DuPont) heated to about 120°C and having a nominal kinematic viscosity of about 12500 cSt (125 cm ² /s) at room temperature was applied to the inner surface of a syringe barrel with a nominal filling capacity of 1 mL (Example 1) or 3 mL (Example 2).

The storage tank is maintained at 120°C, the pump delivery head is maintained at about 50°C, and the nozzle of the dispensing head is maintained at about 120°C.

The amount of silicone oil deposited was approximately 0.2 μg/mm ² .

Thus, a coating is formed on the inner surface of the barrel, characterized by an extremely thin thickness, measured by optical reflectometry, which is constant over the entire axial extension of the main body of the syringe barrel.

In particular, the coating thickness remains constant, less than 200 nm on average, preferably less than 150 nm on average, and in the range of 120 nm to 160 nm over the entire axial length of the cylinder.

Figures 3 and 4 report measured graphs illustrating the coating thickness distribution applied onto the inner surface of a syringe barrel with a nominal filling volume of 1 mL and 3 mL, respectively.

As can be seen from the above figure, the inner surface coating of the barrel exhibits obvious surface regularity. In the syringe with a nominal capacity of 3mL, the standard deviation of its thickness is low, less than 30nm (Figure 4), and in the syringe with a nominal volume of 1mL, the standard deviation of its thickness is less than 20nm (Figure 3).

Neither syringe caused any evaluation error when tested by visual (and possibly automated) inspection.

Example A to Example G

Manufacturing process of the syringe of the present invention and the control syringe

By the above method and apparatus, a heating coating composition consisting of PDMSLiveo ^™ 360 medical fluid (DuPont) with a nominal kinematic viscosity of about 12500 cSt (125 cm ² /s) at room temperature was applied to the inner surface of a syringe barrel with a nominal filling capacity of 1 mL (Examples A, B, C, D) and 3 mL (Examples E, F, G).

A coating composition consisting of PDMS Liveo ^™ 360 medical fluid (DuPont) was applied to the inner surface of the barrel of the same type of syringe by conventional methods and conventional equipment. The coating composition had a nominal kinematic viscosity of about 1000 cSt (10 cm ² /s) at room temperature.

Table 1 below reports the temperatures of the reservoir, pump delivery head and dispense head nozzle as well as the amount of silicone oil deposited.

Thus, a coating is formed on the inner surface of the barrel, characterized by an extremely thin thickness, measured by optical reflectometry, which is constant over the entire axial extension of the main body of the syringe barrel.

In some cases, the resulting coating is partially crosslinked by irradiation at atmospheric pressure using a plasma torch with variable irradiation times and under the following conditions:

Maximum power output: 100W

Gas used: Argon purity exceeds 99%

Argon flow rate 7SLM

Table 1 below reports the syringe barrel manufacturing parameters.

Table 1

* = Control

RT = Room temperature

Silicon material with a nominal kinematic viscosity of 12500 cSt (125 cm ² /s) of the present invention: PDMS Liveo ^TM medical fluid (DuPont)

Comparative Example Silicon material with a nominal kinematic viscosity of 1000 cSt (10 cm ² /s): PDMS Liveo ^™ 360 medical fluid 1000 cSt.

The following parameters were determined:

- the average thickness S of the applied coating and the corresponding standard deviation (t0) measured after deposition and after cooling of the coating;

- Standard deviation SD of the coating batch mean thickness for a batch of 10 syringes.

The results obtained are reported in Table 2 below:

Table 2

* = Control

The pretreatment of the inner surface of the syringe barrel (if any) is implemented as follows:

(g1) atomizing a 2.2 wt.% [(bicycloheptene)ethyl]trimethoxysilane isopropanol solution onto the inner surface of the cylinder through an ultrasonic static nozzle, with the amount of solution ranging from 5 μL to 80 μL, depending on the size of the cylinder;

(g2) The cylinder thus treated was heated in an oven at 140°C for 20 minutes.

It can be seen from the data in Table 2 above that in the syringe of the present invention, the average thickness S of the coating is always maintained below 180 nm, and the thickness standard deviation is equal to or less than 70 nm, confirming that the deposition regularity is extremely high.

The data that the standard deviation SD of the average coating batch thickness calculated for a batch of 10 syringes is less than 60 nm also confirms the high reproducibility of the syringe manufacturing method of the present invention.

The syringes thus manufactured were subjected to several tests to evaluate the static and dynamic friction, particle release and morphological characteristics of the resulting coatings. The results of these tests are reported below.

Example H～Example O

Manufacturing process of the syringe of the present invention and the control syringe

By the above method and apparatus, a coating composition composed of PDMS Liveo ^™ 360 medical fluid (DuPont) heated to about 120°C and having a nominal kinematic viscosity of about 12500 cSt (125 cm ² /s) at room temperature was applied to the inner surface of a syringe barrel with a nominal filling capacity of 0.5 mL.

A control coating composition consisting of PDMS Liveo ^™ 360 medical fluid (DuPont) having a nominal kinematic viscosity of about 1000 cSt (10 cm ² /s) at room temperature was applied to the inner surface of the same type of syringe barrel by conventional methods and conventional equipment.

Table 3 below reports the temperatures of the reservoir, pump delivery head and dispense head nozzle as well as the amount of silicone oil deposited.

Thus, a coating is formed on the inner surface of the barrel, characterized by an extremely thin thickness, measured by optical reflectometry, which is constant over the entire axial extension of the main body of the syringe body.

In some cases, the resulting coatings were partially crosslinked by irradiation at atmospheric pressure using a plasma torch for variable irradiation times and under the conditions mentioned in Examples A to G.

Table 3 below reports the syringe barrel manufacturing parameters.

table 3

* = Control

RT = Room temperature

Silicon material with a nominal kinematic viscosity of 12500 cSt (125 cm ² /s) of the present invention: PDMS Liveo ^TM medical fluid (DuPont)

Comparative Example Silicon material with a nominal kinematic viscosity of 1000 cSt (10 cm ² /s): PDMS Liveo ^™ 360 medical fluid 1000 cSt.

After the deposition and cooling of the layers (t0) and after 3 months storage at room temperature (t3), the following parameters were determined for Examples H, I, K (invention) and M, N, O (control):

- the average thickness S of the applied coating and the corresponding standard deviation of the thickness;

- Standard deviation SD of the coating batch mean thickness for a batch of 10 syringes.

The results obtained are reported in Table 4 below:

Table 4

* = Control

Furthermore, it was experimentally observed that the maximum batch thickness standard deviation of the coatings applied in Examples H, I, and K (the present invention) always remained less than 70 nm.

The method for pretreatment of the inner surface of the syringe barrel (if any) is the same as the method described above for Examples A to G.

The syringes thus manufactured were subjected to several tests to evaluate the static and dynamic friction, particle release and morphological characteristics of the resulting coatings. The results of these tests are reported below.

Coating thickness evaluation

Figures 5 to 10 report measured graphs illustrating the thickness distribution of the coating applied to the inner surface of a syringe barrel with a nominal filling volume of 0.5 mL after deposition and cooling to room temperature (t0) and after storage at room temperature for 3 months (t3).

It can be seen from the data in Table 4 and the above figure that in the syringe of the present invention, the coating on the inner surface of the barrel has a low average thickness and exhibits obvious surface regularity.

In fact, the average thickness of the coatings always remained below 230 nm, with a thickness standard deviation of less than 50 nm, confirming the high regularity of the coating thickness.

In particular, as shown in Table 4, by comparing the syringes of the present invention with syringes of the prior art that have not been plasma treated (Example H and Example M), it was experimentally found that the thickness standard deviation confirmed that the coating deposition regularity was significantly improved despite the much higher kinematic viscosity of the silicon material used.

The standard deviation SD of the average coating batch thickness calculated for a batch of 10 syringes is less than 50 nm, which also confirms the high reproducibility of the method for manufacturing the medical injection device of the present invention.

When tested by automated visual inspection, the syringe according to the invention did not cause any evaluation errors.

Evaluation of the average static and dynamic sliding friction of empty syringes stored at room temperature

A series of comparative tests were conducted on the syringes of Examples A and B (invention) and Examples C and D (control) to evaluate the average values of static and dynamic sliding friction on the empty barrel.

All syringes had a nominal filling volume of 1.0 mL, and the friction force was measured at time zero at room temperature and after 6 months of storage at room temperature.

The friction force was measured using a ZwickiLine Z2.5 (Zwick Roell) dynamometer according to the following method.

Place the syringe on the appropriate dynamometer stand

Reset load cell side force (not compressed)

Set the constant speed deformation to 240mm/min, preload to 0.5N, and the end point preset force to 30N

Start testing (30 samples/case) and perform force measurement

By analyzing the curve generated by the dynamometer, the static friction force is determined as the force corresponding to the first initial peak, and the dynamic friction force is determined as the average value of the interval between the first initial peak and the terminal peak.

Figures 11 and 12 report the average values of static and dynamic friction, respectively, measured for batches of 30 syringes.

As can be seen from the above figure, the average values of static friction and dynamic friction of the barrel coating of the syringe of the present invention (Example A and Example B) subjected to different irradiation times are completely acceptable and are within the limit values required by the pharmaceutical and cosmetic industries previously indicated (static sliding friction is 6N, dynamic sliding friction is 3N).

It should also be noted that the maximum acceptable irradiation time for barrel coating is approximately 1 second.

Evaluation of the average static and dynamic sliding friction of prefilled syringes stored at room temperature - nominal filling of empty syringes The amount is 1mL Long

Another series of control tests were conducted on the syringes of Examples A and B (the present invention) and Examples C and D (control) to evaluate the average static and dynamic sliding friction on the barrel of a test aqueous solution (injection solution) with a nominal filling capacity of 1.0 mL and filled with water and glycerol (glycerol volume fraction of 0.02% vol to 0.04% vol), simulating a dynamic viscosity of 1 mPas (1 cP) of the drug property.

The tests were performed under the same conditions as for the empty syringes, giving the average values of the static and dynamic frictions measured for batches of 30 syringes reported in Figures 13 and 14, respectively.

Likewise, in this case, the average values of static and dynamic friction of the barrel coating of the syringe of the present invention (Examples A and B) after various irradiation times are still acceptable (static sliding friction is 6N, dynamic sliding friction is 3N).

Again, the maximum acceptable irradiation time for the barrel coating was found to be approximately 1 second in this case.

Evaluation of the average static and dynamic sliding friction of prefilled syringes after 7 days of storage at different temperatures - Nominal Filling volume is 1mLong

A series of comparative tests were conducted on the syringes of Examples E and F (the present invention) and D (control) to evaluate the average static and dynamic sliding friction forces on the barrel with a nominal filling capacity of 1.0 mL and filled with 0.55 mL of a test aqueous solution (injection solution) containing the following ingredients:

Tromethamine 0.34 mg

Tromethamine hydrochloride 1.30 mg

Acetic acid 0.047 mg

·Sodium acetate 0.132 mg

Sucrose 47.85 mg

Water for injection, balanced to 0.55 mL

After a storage time of 7 days, the friction force was measured as described above at room temperature (RT) and at temperatures of -20°C and -40°C.

Figures 15 and 16 report the average values of static and dynamic friction, respectively, measured for batches of 30 syringes.

As can be seen from the above figure, the average values of static friction and dynamic friction of the syringes of the present invention (Examples E and F) are comparable to the average values of static friction and dynamic friction of a control syringe (Example D) provided with a known type of coating (silicon material with a nominal kinematic viscosity of about 1000 cSt), wherein the barrel coating was not irradiated (Example E) or was irradiated for 0.3 seconds (Example F).

Furthermore, the mean values of the static and dynamic friction of the syringes according to the invention (Examples E and F) are well within the previously indicated limit values required by the pharmaceutical and cosmetics industries (6 N for static sliding friction and 3 N for dynamic sliding friction).

Evaluation of the average static and dynamic sliding friction of prefilled syringes after storage at -40°C for 2 and 7 days - Injection The nominal filling volume of the device is 1mL Long

Another series of comparative tests were conducted on the syringes of Examples E and F (the present invention) and D (control) to evaluate the average static and dynamic sliding friction forces on the barrel with a nominal filling capacity of 1.0 mL and filled with 0.55 mL of a test aqueous solution (injection solution) containing the following ingredients:

Tromethamine 0.34 mg

Tromethamine hydrochloride 1.30 mg

Acetic acid 0.047 mg

·Sodium acetate 0.132 mg

Sucrose 47.85 mg

Water for injection, balanced to 0.55 mL

After storage at -40°C for 2 and 7 days, the friction force was measured as described above.

Figures 17 and 18 report the average values of static and dynamic friction, respectively, measured for batches of 30 syringes.

As can be seen from the above figure, the average values of static friction and dynamic friction of the syringes of the present invention (Examples E and F) are comparable to the average values of static friction and dynamic friction of a control syringe (Example D) provided with a known type of coating (silicon material with a nominal kinematic viscosity of about 1000 cSt), wherein the barrel coating was not irradiated (Example E) or was irradiated for 0.3 seconds (Example F).

Furthermore, the average values of the static and dynamic friction of the syringes of the present invention (Examples E and F) are substantially stable and fall well within the previously indicated limit values required by the pharmaceutical and cosmetic industries (6 N for static sliding friction and 3 N for dynamic sliding friction).

Evaluation of the average static and dynamic sliding friction of empty syringes stored at room temperature - the nominal filling volume of the empty syringe is 0.5mLLong

A series of comparative tests were conducted on the syringes of Examples H, I, J, K, L (invention) and M, N, O (control) to evaluate the average values of static and dynamic sliding friction on the empty barrel.

All syringes had a nominal filling volume of 0.5 mL, and the friction force was measured at time zero and after 1 and 3 months of storage at room temperature.

The friction force was measured using a ZwickiLine Z2.5 (Zwick Roell) dynamometer in the following manner.

Place the syringe on the appropriate dynamometer stand

Reset load cell side force (not compressed)

Set the constant speed deformation to 100mm/min, no preload, and set the end point preset force to 30N

Start testing (30 samples/case) and perform force measurement

By analyzing the curve generated by the dynamometer, the static friction force is determined as the force corresponding to the first initial peak, and the dynamic friction force is determined as the average value of the interval between the first initial peak and the terminal peak.

Figures 19 and 20 report the average values of static and dynamic friction, respectively, measured for batches of 30 syringes.

As can be seen from the above figures, the average values of static and dynamic friction of the syringes of the present invention (Examples H, I, J, K, and L) are completely acceptable and within the previously specified limit value range for the pharmaceutical and cosmetic industries (static sliding friction is 6N and dynamic sliding friction is 3N), wherein the barrel coating is not irradiated (Example H) or subjected to different irradiation times (Examples I, J, K, and L).

Average static and dynamic sliding friction of prefilled syringes stored at -40℃, +5℃, +25℃ and +40℃ Value evaluation-syringe nominal filling capacity is 0.5mL

Another series of control tests were conducted on the syringes of Examples H, I, J, K, L (the present invention) and M, N, and O (control) to evaluate the average static and dynamic sliding friction forces on the barrel with a nominal filling capacity of 0.5 mL and 500 μL of a test aqueous solution (injection solution) having the following composition:

Sodium phosphate 10mM

·Sodium chloride 40mM

Polysorbate 20 0.03% (v/v)

Sucrose 5% (w/v)

Water for injection (MilliQ aqueous solution filtered with a diameter of 0.22 μm), balanced to 0.5 mL, pH 6.2.

As described above, the friction force was measured after the coating was deposited and cooled (t0) and after storage at -40°C, +5°C, +25°C, +40°C for 1 month (t1) and 3 months (t3).

Figures 21 to 28 report the average values of static and dynamic friction measured for 30 syringe batches.

As can be seen from the above figure, the average values of static friction and dynamic friction of the syringes of the present invention (Examples H, I, J, K, and L) are comparable to the average values of static friction and dynamic friction of control syringes (Examples M, N, and O) provided with a known type of coating (silicon material with a nominal kinematic viscosity of approximately 1000 cSt), wherein the barrel coating was not irradiated (Example H) or was irradiated for 0.3 seconds or 0.5 seconds (Examples K, I, J, and L).

In addition, the average values of the static friction and dynamic friction of the syringes of the present invention (Examples H, I, J, K, and L) are basically stable and fall completely within the limit values required by pharmaceutical and cosmetic companies previously noted (static sliding friction is 6N and dynamic sliding friction is 3N).

The comparison in Figures 29 and 30 further reports the average values of static friction and dynamic friction of the plungers of the syringes according to the present invention and according to the prior art after being stored at the above-mentioned temperatures of -40°C, +5°C, +25°C, and +40°C for three months.

As can be seen from the above figure, the average values of static friction and dynamic friction of the syringes of the present invention (Examples H, I, J, K, and L) after storage for three months at different temperatures are comparable to the average values of static friction and dynamic friction of the control syringes (Examples M, N, and O) provided with known types of coatings, and are completely within the previously indicated limit values for the pharmaceutical and cosmetic industries (static sliding friction of 6N and dynamic sliding friction of 3N).

Evaluation of Particle Release from Prefilled Syringes at Room Temperature

The syringes of Example E (invention) and Examples C and G (control) were subjected to a series of comparative tests to evaluate microparticle release in aqueous test solutions (injections).

All syringes have a nominal filling capacity of 3.0 mL and are filled with 3.3 mL of a test aqueous solution (injection) containing the following ingredients:

Sodium phosphate 10 mM (adjust to pH 7.0 with phosphoric acid)

Sodium chloride 0.9% (w/v)

Polysorbate 80 0.02% (w/v)

Water for injection, balanced to 3.3 mL

Particle Analysis Test Sample Preparation

Fill the syringe barrel with the test solution and seal the barrel with the plunger

Storage (if testing is required)

The syringe was turned over (i.e. rotated about an axis perpendicular to the longitudinal axis of the barrel) by a multi-tooth stirrer at 30 rpm for 3 hours

Dispensing of test aqueous solution from syringe barrel: Automatic operation via dynamometer

The test liquid is collected in a special container.

The aliquot volume of the sample solution (pool) is at least 6 mL for the particle analysis (eg, 2 syringes filled with 3.30 mL, then 1 pool = 1 particle analysis sample for).

The concentration of released microparticles in the test solution was measured by the following method.

Analysis of Particle Release from Test Solution - Examples A to G

Light Obscuration (LO)

The test solution pool obtained above was analyzed by a light blocking device (KL04A, RION) to determine the particle size and count of sub-visible particles.

The instrument counts particles in the analytical solution according to USP standards (787-788-789) specified in United States Pharmacopeia 44-NF39 (2021).

Specifically, a solution is drawn from the instrument through a special needle and passed over a laser light source. Particles in the solution cause the laser beam to be blocked, generating a signal that is sent to a sensor; the amount of light blocked determines the particle size.

The instrument can measure particle sizes ranging from 1.3 μm to 100 μm.

Figures 31 and 32 list the normalized concentration values of particles with a size equal to or greater than 10 μm and equal to or greater than 25 μm, respectively, measured immediately after rotating the syringe at room temperature, both values being obtained from 15 measurement cells starting with 30 syringes.

As can be seen from the above figure, the syringe of the present invention whose barrel coating was not irradiated (Example E) showed improved particle release behavior relative to the control syringes (Examples C and G) whose barrel coating was irradiated for 0.3 seconds (Control Example C) or not irradiated (Control Example G), respectively.

Evaluation of particle release from prefilled syringes at different temperatures (with and without storage)

A series of comparative tests were performed on the syringes of Example A (invention) and Example C (control) to evaluate the release of microparticles from the test aqueous solution (injection).

All syringes have a nominal filling capacity of 0.5 mL and are filled with 0.25 mL of a test aqueous solution (injection) containing the following ingredients:

Sodium phosphate 10mM

·Sodium chloride 40mM

Polysorbate 20 0.03% (w/v)

Sucrose 5% (w/v)

Water for injection (MilliQ aqueous solution filtered with a diameter of 0.22 μm), balanced to 0.5 mL, pH 6.2.

Particle analysis sample preparation

Fill the syringe barrel with the test solution and seal the barrel with the plunger

·store

The syringe was tumbled (i.e. rotated about an axis perpendicular to the longitudinal axis of the barrel) by a multi-tooth stirrer at 30 rpm for 3 hours

Dispensing of test aqueous solution from syringe barrel: Manual operation under laminar flow hood

The concentration of released microparticles in the test solution was measured by the following method.

Analysis of particle release from test solution

Light Obscuration (LO)

Figures 33, 34 and 35 report the normalized values of the concentration of particles with a size equal to or greater than 10 μm measured at time zero after storage for 6 months at 5°C ± 3°C, 25°C/60% RH and 40°C/75% RH from 12 pools prepared (the solutions manually dispensed from a total of 24 syringes were grouped in pairs during the preparation).

As can be seen from the above figure, the syringe of the present invention whose barrel coating is irradiated for 0.3 seconds (Example A) shows significantly improved particle release behavior compared with the control syringe whose barrel coating is also irradiated for 0.3 seconds (Control Example C).

The microparticle release values shown in Figures 33 to 35 also show that the syringes of the present invention exhibit improved release stability over long periods of time after storage at different temperatures compared to the control syringes.

Evaluation of particle release from prefilled syringes stored at low temperatures

The syringes of Example E (invention) and Example D (control) were subjected to a series of comparative tests to evaluate microparticle release in aqueous test solutions (injections).

All syringes have a nominal filling capacity of 1.0 mL and are filled with 0.55 mL of an aqueous solution (test injection) containing the following ingredients:

Tromethamine 0.34 mg

Tromethamine hydrochloride 1.30 mg

Acetic acid 0.047 mg

·Sodium acetate 0.132 mg

Sucrose 47.85 mg

Water for injection, balanced to 0.55 mL

Particle analysis sample preparation

Fill the syringe barrel with the test solution and seal the barrel with the plunger

·store

Dispensing of test aqueous solution from syringe barrel: Automatic operation via dynamometer

The released microparticles in the test solution were measured by the following method.

Analysis of particle release from test solution

Micro Flow Imaging (MFI)

The obtained 1 mL per pool was analyzed using a flow imaging analyzer (MFI ^™ Micro-Flow Imaging, MFI 5200, ProteinSimple) to evaluate the morphology of the particles in the solution, thanks to the instrument's optical system that can distinguish different types of particles (silicon particles and non-silicon particles) based on certain parameters such as circularity and light intensity.

The specific parameters used to distinguish silicon particles are as follows:

Aspect ratio ≥ 0.83 (i.e. the ratio of the minor axis length to the major axis length of the particle ellipse with the same second-order moment);

Intensity STD ≥ 185 (i.e., the standard intensity difference of all pixels representing the particle);

ECD 10-25μm and 25-100μm (i.e. the diameter of the circle of equal area of the particles).

The instrument can measure particle sizes ranging from 2μm to 70μm, and has good resolution for images of particles larger than 10μm.

Figure 36 reports the normalized concentration values of microparticles ranging from 5 μm to 70 μm measured from 15 measuring cells after 2 and 7 days of storage at -40°C (the solutions dispensed by the dynamometer from a total of 30 syringes were grouped in pairs during preparation).

As can be seen from the above figure, the syringe of the present invention whose barrel coating is not irradiated (Example E) shows considerable improvement (after 2 days of storage) or significant improvement (after 7 days of storage) in the particle release behavior compared with the control syringe (Example D) whose barrel coating is also not irradiated.

The microparticle release values shown in FIG. 36 also demonstrate that the syringes of the present invention exhibit improved release stability over long periods of time after cryogenic storage compared to the control syringes.

Evaluation of particle release from prefilled syringes stored at different temperatures - the nominal filling volume of the syringe is 0.5mL - Example H to Example O

A series of control tests were performed on the syringes of Examples H, I, J, K, L (invention) and M, N, O (control) to evaluate microparticle release in aqueous test solutions (injections).

All syringes have a nominal filling capacity of 0.5 mL and are filled with 500 μL of a test aqueous solution (injection) containing the following ingredients:

Sodium phosphate 10mM

·Sodium chloride 40mM

Polysorbate 20 0.03% (v/v)

Sucrose 5% (w/v)

Water for injection (MilliQ aqueous solution filtered with a diameter of 0.22 μm), balanced to 0.5 mL, pH 6.2.

Particle analysis sample preparation

Fill the syringe barrel with the test solution and seal the barrel with a plunger (the plunger is 4023/50GrayFlurotec, Westar)

Storage at different temperatures

ο5℃±3℃

ο25℃/60％RH

ο40℃/75％RH

-40℃

For syringes stored at -40°C, thaw at room temperature for one hour without inversion before dispensing the solution. This is done to simulate the real-life use of products that are typically stored at this temperature, i.e., extremely temperature-sensitive biotech drugs.

The syringe was tumbled (ie rotated about an axis perpendicular to the longitudinal axis of the barrel) by means of a multi-tooth stirrer at a rotation speed equal to 30 rpm for 3 hours.

Dispense the test aqueous solution from the syringe barrel: manually under a laminar flow hood, group the solution into 12 syringes in total

The concentration of released microparticles in the test solution was measured by the following method.

Analysis of particle release from test solution

Light Obscuration (LO)

Ten pools of 5 mL each (manually dispensed solutions of a total of 12 syringes were pooled in preparation) were analyzed by a particle counting analysis apparatus (Light Obscuration Particle Counter KL-04A, manufactured by Rion Co., LTD.).

The device allows operation according to USP <787>, <788>, <789> as specified in USP 44-NF39 (2021) and Ph.Eur.2.9.19 (10th edition, 2021) for subvisible particle count analysis of parenteral solutions.

The size of the analyzed particle depends on the amount of light from the source blocked by the particle itself as it passes through the laser beam, thereby generating a voltage change that is detected by the sensor.

The device can analyze particles with a size range of 1.3μm to 100μm.

Figures 37, 38, 41 to 44, 47 to 50, 53 to 56 and 59 to 60 report the normalized concentration values of particles with a particle size equal to or greater than 10 μm and equal to or greater than 25 μm measured at time zero after storage for 1 month and 3 months at -40°C, 5°C±3°C, 25°C/60%RH, and 40°C/75%RH after preparation from 10 pools.

As can be seen from the above figure, at all test times (t0, t1 and t3) and all storage temperatures, the syringes of the present invention (Example H, Example I, Example J, Example K, Example L) show significantly improved performance in the particle release behavior relative to the control syringes (Example M, Example N, Example O), especially when the storage temperature is -40°C, as clearly shown in Figures 37 and 38.

In particular, as shown in the above figure, by comparing the syringe of the present invention with the syringe of the prior art under the same process conditions, that is, with or without plasma treatment and with or without pretreatment to improve the adhesion between the coating and the inner surface of the syringe barrel, it was found through experiments that:

- In the case where the coating was not plasma treated and the syringe was not subjected to adhesion pretreatment, particle release was reduced by about 70% (Example H vs. Example M);

- In the case where the coating was plasma treated for 0.3 seconds and the syringe was not pre-treated for adhesion, particle release was reduced by about 86% (Examples I and N);

- In case the coating was plasma treated for 0.3 seconds and the syringe was adhesive pre-treated, particle release was reduced by about 90% (Example K vs. Example O).

In addition, as clearly shown in Figures 41 to 44, Figures 47 to 50, and Figures 53 to 56, by comparing syringes with plasma treatment (with or without pretreatment) of the coating of the present invention (Examples I, J, K, L) with syringes of the prior art (Examples N, O) subjected to the same treatment, it was found experimentally that all syringes of the present invention fully met the strict particle release requirements of the USP 789 standard for ophthalmic applications at all test temperatures and storage times, while in the prior art syringes, such results would not occur as long as the particle size of the particles was equal to or greater than 10 μm (see Figures 41, 43, 47, 49, 53, 55, and 59).

On the contrary, for particles with a particle size of equal to or greater than 25 μm, all syringes with the coating of the present invention subjected to plasma treatment, whether or not pre-treated (Examples I, J, K, L), meet the particle release requirements of the USP 789 standard at all tested temperatures and storage times, while the prior art syringes only show such results in some cases (Examples N, O). In particular, after a storage time of 3 months, the syringe of Control Example N meets the particle release requirements of the standard USP 789 only at storage temperatures of 5° C. and 40° C., while the syringe of Control Example O does not meet the particle release requirements of the standard USP 789 at any storage temperature (see Figures 42, 44, 48, 50, 54, 56, and 60).

Micro Flow Imaging (MFI)

The morphology of the microparticles in solution was assessed using a flow imaging device (MFI ^™ Micro-Flow Imaging, MFI 5200, ProteinSimple) analyzing 1 mL per well obtained for a 0.5 mL syringe as described above.

Figures 45 to 46, Figures 51 to 52 and Figures 57 to 58 report the percentage concentration of particles with a particle size of 10 μm to 25 μm (calculated as in the example) measured at time zero after storage for 1 month and 3 months at -40°C, +5°C±3°C, +25°C/60%RH and +40°C/75%RH from 10 samples (1 mL of solution was taken from each sample pool prepared according to the above method).

As can be seen from the above figure, compared with the control syringes (Example M, Example N, Example O), the syringes of the present invention (Example H, Example I, Example J, Example K, Example L) can significantly reduce the release of silicon particles at all temperatures and all test detection times (t0, t1 and t3).

Evaluation of the morphological characteristics of the coating on the inner surface of an empty syringe barrel

In order to evaluate the possible influence of different irradiation times on the coating morphology of the coatings obtained according to the invention and according to the prior art, some images were collected by optical microscopy.

Generally speaking, the more uniform the coating surface or the finer the particle size, the better it performs from a morphological perspective, and therefore the less likely the surface is to mislead the automatic optical inspection system and cause false alarms due to irregular coating surfaces.

In this regard, as mentioned above, the Applicant has observed that the degree of partial crosslinking related to the irradiation time, for example in plasma treatment, is critical because it produces streaks and detachments which can be falsely "read" by automated optical inspection systems as impurities present in the storage solution of medical injection device barrels.

The applicant has observed that these striations and detachments tend to appear first in the region of the tapered portion of the syringe barrel (closest to the rear end where the needle is located) and then propagate towards the cylindrical portion.

Figure 61 reports images showing the effect of irradiating the coating obtained in Example B of the present invention for a time exceeding a threshold of 1 second.

As can be seen in the figure above, the inhomogeneity extends for several millimeters, which is equivalent to grooves or lifting of the coating itself. Obviously, using extremely thin coatings (related to the limited amount of silicon material used) is more likely to produce this effect.

Figure 62 reports images showing the effect of irradiation equal to 0.3 seconds on the coating obtained in Example A according to the invention.

As can be seen from the above figure, the coating surface is characterized by a finer coating distribution unevenness, with micron-scale peaks and valleys, and no defects detectable in Figure 61.

Figure 63 reports an image showing the area near the tapered rear end of the barrel of the same syringe as Figure 62.

As can be seen from Figure 63, the coating surface is substantially uniform and substantially defect-free.

Figures 64 and 65 report images showing the effect of irradiation equal to 0.3 seconds on the coating obtained according to comparative example C.

As can be seen from the above figures, observing the cylindrical part of the barrel and the adjacent conical tail end part respectively, the coating surface is characterized by a particle size that is larger than the surface particle size of the syringe of the present invention (Example A), as shown in Figures 62 and 63 above.

Figures 66 and 67 report images showing the effect of irradiation close to 1 second limit in the connection area between the cylindrical part and the conical part of the syringe barrel of the coating obtained in Example A of the present invention and the comparative example C.

As can be seen from Figures 66 and 67, by plasma irradiating the coating obtained in Example A of the present invention (Figure 66), the presence of stripes can be observed in the right area of the image (the tapered part of the cylinder), even if it is not very obvious.

However, in the coating obtained in Control Example C, under the same irradiation conditions, the streaks appeared more obvious, as shown in FIG. 67 .

Claims (59)

1. A method of manufacturing a medical injection device (1) comprising a glass cylinder with an inner surface (3) coated with a coating (4), the cylinder (2) being configured to receive a plunger (5) in sliding engagement, the method comprising the steps of:

(a) Providing a coating composition comprising equal to or greater than 92wt.%, preferably greater than 95wt.%, more preferably greater than 98wt.%, even more preferably about equal to 100wt.% of a polydimethylsiloxane having a kinematic viscosity at room temperature of from 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s);

(b) Heating the coating composition to a temperature of 100 ℃ to 150 ℃, preferably 120 ℃ to 150 ℃;

(c) Applying a coating composition heated to said temperature to the inner surface (3) of said cylinder (2) to form a coating (4) on said inner surface (3), having an average thickness S, measured by optical reflection, of 100nm to 250nm, preferably 100nm to 200nm,

Wherein the standard deviation of the thickness of the coating (4) of the inner surface (3) of the cylinder (2) is equal to or less than 90nm, preferably equal to or less than 70nm, more preferably equal to or less than 50nm.

2. A method of manufacturing a medical injection device (1) comprising a glass cylinder with an inner surface (3) coated with a coating (4), the cylinder (2) being configured to receive a plunger (5) in sliding engagement, the method comprising the steps of:

(a) Providing a coating composition comprising equal to or greater than 92wt.%, preferably greater than 95wt.%, more preferably greater than 98wt.%, even more preferably about equal to 100wt.% of a polydimethylsiloxane having a kinematic viscosity at room temperature of from 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s);

(b) Heating the coating composition to a temperature of 100 ℃ to 150 ℃, preferably 120 ℃ to 150 ℃;

(c) Applying a coating composition heated to said temperature to the inner surface (3) of said cylinder (2) to form a coating (4) on said inner surface (3) having an average thickness of 100nm to 250nm, preferably 100nm to 200nm, measured by optical reflection,

Wherein for each batch of 10 cylinders (2), the coating (4) thickness has a value of the batch average standard deviation SD equal to or less than 70nm, preferably equal to or less than 60nm, more preferably equal to or less than 50nm;

Wherein the lot average standard deviation SD is obtained by:

(i) Measuring the thickness S _pi of the coating (4) at least 6 points of each arbitrary portion ni of 1.0mm in the batch of the planar development axial length of the ith cylinder;

(ii) For each of the portions ni of the ith barrel in the batch and for each ith barrel, the average thickness Sni was calculated by:

S_ni＝(Σ_p＝1,6S_pi)/6

(iii) For each barrel portion n, the batch average thickness S _nL for that portion n is calculated by:

S_nL＝(Σ_i＝1,10S_ni)/10

(iv) For 10 injectors in a batch, calculate the standard deviation SD _n of the batch average thickness S _nL for the portion n; and

(V) The batch average standard deviation SD is calculated from the value of the thickness standard deviation SDn by:

SD＝(Σ_i＝1,N SD_n)/N

Where N is the total number of portions N of each barrel in the batch.

3. The method of claim 1 or 2, wherein the step (a) of providing a coating composition comprises: the coating composition is stored in a storage tank (11).

4. A method according to claim 3, wherein said step (b) of heating the coating composition comprises: heating the tank (11) to bring the coating composition to said temperature of 100 ℃ to 150 ℃.

5. The method according to claim 3 or 4, further comprising the step of (d) maintaining the heated coating composition stored in the tank (11) at a pressure of 5psi (0.34 bar) to 150psi (10.34 bar), preferably 10psi (0.69 bar) to 30psi (2.07 bar), more preferably 10psi (0.69 bar) to 15psi (1.03 bar).

6. The method according to any of the preceding claims, further comprising the step (e) of feeding the heated coating composition to a dispensing head (14), the dispensing head (14) being provided with at least one dispensing nozzle.

7. The method of claim 6, wherein the feeding of the heated coating composition to the dispensing head (14) of step (e) is performed by a circulation pump (12) arranged upstream of the dispensing head (14).

8. A method according to claim 6 or 7, wherein said step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2) is performed by dispensing the coating composition via the dispensing head (14).

9. The method of claim 7 or 8, wherein the step (b) of heating the coating composition comprises: -heating the dispensing head (14) and/or the circulation pump (12) to bring or maintain the coating composition to the temperature of 100 ℃ to 150 ℃.

10. A method according to claims 3 or 4 and 7, wherein the reservoir (11), the circulation pump (12) and the dispensing head (14) are in fluid communication via pipes (13, 15), and wherein the step (b) of heating the coating composition comprises: heating the pipe (13, 15) to bring or maintain the coating composition to the temperature of 100 ℃ to 150 ℃.

11. The method according to any one of claims 6 to 10, wherein the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2) is performed by dispensing the heated coating composition at a pressure of 5psi (0.34 bar) to 150psi (10.34 bar), preferably 6psi (0.41 bar) to 10psi (0.69 bar).

12. The method according to any one of claims 6 to 11, wherein the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2) comprises: the dispensing head (14) is fed with a gas distribution at a pressure of 5psi (0.34 bar) to 150psi (10.34 bar), preferably 6psi (0.41 bar) to 10psi (0.69 bar).

13. The method according to any one of claims 8 to 12, wherein the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2) comprises: simultaneously with dispensing the heated coating composition, a relative movement is transferred between the dispensing head (14) and the cartridge (2).

14. The method of claim 13, wherein the step (c) of applying the heated coating composition to the inner surface (3) of the barrel (2) comprises: -dispensing the heated coating composition onto the inner surface (3) of the cartridge (2) during a relative movement of the dispensing head (14) inserted into the cartridge (2).

15. A method according to claim 13 or 14, wherein the heated coating composition is dispensed onto the inner surface (3) of the cylinder (2) for a time of 0.3 to 1 second, preferably 0.4 to 0.7 seconds.

16. The method according to any of the preceding claims, wherein the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2) comprises: the heated coating composition is dispensed at a flow rate of 0.1 to 5. Mu.L/s, preferably equal to about 0.5. Mu.L/s.

17. The method according to any of the preceding claims, wherein the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2) comprises: the heated coating composition is applied to the inner surface (3) of the cylinder (2) in an amount of 0.2 μg/mm ² to 0.4 μg/mm ² per unit area.

18. A method according to any of the preceding claims, further comprising the step (f) of subjecting the coating (4) formed on the inner surface (3) of the cylinder (2) to a partial cross-linking treatment of polydimethylsiloxane, preferably by irradiation, after the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2).

19. The method according to claim 18, wherein the irradiation treatment is a plasma irradiation treatment, preferably an atmospheric argon flow plasma torch irradiation treatment.

20. The method of any one of claims 18 to 19, wherein the irradiation treatment is for a time of 0.2 seconds to 1 second, preferably 0.2 to 0.6 seconds, more preferably 0.2 to 0.5 seconds, inclusive.

21. A method according to any one of claims 18 to 20, wherein after the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2), the step (f) of irradiating the coating (4) formed on the inner surface (3) of the cylinder (2) is performed for a time interval of at least 15 minutes, preferably 15 to 20 minutes.

22. A method according to any of the preceding claims, further comprising the step (g) of pre-treating the inner surface (3) of the cylinder (2) to improve the adhesion of the coating (4) to the inner surface (3) before the step (c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2).

23. The method of claim 22, wherein the preprocessing comprises: an adhesion promoter layer, preferably comprising [ (bicycloheptene) ethyl ] trimethoxysilane, is formed on the inner surface (3) of the cylinder (2).

24. The method according to any of the preceding claims, further comprising a step (h) of filling the cartridge (2) with an injection pharmaceutical composition, said step (h) being performed after cooling the coating (4) formed on the inner surface (3) of the cartridge (2) to room temperature.

25. An apparatus (10) for manufacturing a medical injection device comprising a glass barrel (2) having an inner surface (3) coated with a coating (4), the barrel (2) being configured to receive a plunger (5) in sliding engagement, the apparatus comprising:

A reservoir (11) of a coating composition, at least one heating element of the reservoir (11) being configured to heat the stored coating composition;

at least one dispensing head (14) configured to dispense a heated coating composition and provided with at least one dispensing nozzle, the respective heating elements of the dispensing heads (14) being configured to heat the coating composition dispensed by the dispensing nozzle;

-a circulation pump (12) arranged upstream of the dispensing head (14);

a support frame for one or more barrels (2) of each medical injection device (1),

Wherein the at least one dispensing head (14) and the support frame are movable relative to each other to insert/withdraw a nozzle of the at least one dispensing head (14) into/from a respective cartridge (2) of the one or more cartridges.

26. The apparatus (10) of claim 25, wherein the respective heating elements of the circulation pump (12) are configured to heat a delivery head of the circulation pump (12).

27. The apparatus (10) according to claim 25 or 26, wherein the reservoir (11), the circulation pump (12) and the dispensing head (14) are in fluid communication with each other through a conduit (13, 15), and wherein the conduit (13, 15) is in heat exchange relationship with a respective heating element.

28. A medical injection device (1) comprising a glass barrel (2) having an inner surface (3) coated with a coating (4), the barrel (2) being configured to receive a plunger (5) in sliding engagement,

Wherein the coating (4) of the inner surface (3) of the cylinder (2) is substantially made of polydimethylsiloxane having a kinematic viscosity at room temperature ranging from 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s), an average thickness ranging from 100nm to 250nm, preferably from 100nm to 200nm; and is also provided with

Wherein the standard deviation of the thickness of the coating (4) of the inner surface (3) of the cylinder (2) is equal to or less than 90nm, preferably equal to or less than 70nm, more preferably equal to or less than 50nm.

29. A medical injection device (1) comprising a glass barrel (2) with an inner surface (3) coated with a coating (4), the barrel (2) being configured to receive a plunger (5) in sliding engagement,

Wherein the coating (4) of the inner surface (3) of the cylinder (2) is substantially made of polydimethylsiloxane having a kinematic viscosity at room temperature of 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s), a batch average thickness of 100nm to 250nm, preferably 100nm to 200nm;

Wherein for each batch of 10 cylinders (2), the coating (4) thickness has a value of the batch average standard deviation SD equal to or less than 70nm, preferably equal to or less than 60nm, more preferably equal to or less than 50nm;

Wherein the lot average standard deviation SD is obtained by:

(i) Measuring the thickness S _pi of the coating (4) at least 6 points of each arbitrary portion ni of 1.0mm in the batch of the planar development axial length of the ith cylinder;

(ii) For each of the portions ni of the ith barrel in the batch and for each of the ith barrels, an average thickness S _ni is calculated by:

S_ni＝(Σ_p＝1,6S_pi)/6

(iii) For each barrel portion n, the batch average thickness S _nL for that portion n is calculated by:

S_nL＝(Σ_i＝1,10S_ni)/10

(iv) For 10 injectors in a batch, calculate the standard deviation SD _n of the batch average thickness S _nL for the portion n; and

(V) The batch average standard deviation SD is calculated from the value of the thickness standard deviation SDn by:

SD＝(Σ_i＝1,N SD_n)/N

Where N is the total number of portions N of each barrel in the batch.

30. The medical injection device (1) according to any one of claims 28 or 29, wherein the coverage in each arbitrary portion of the barrel (2) having a planar unfolded axial length of 1.0mm, corresponding to the total area of said portions, is equal to at least 90%, said coverage being defined as the ratio of the coverage area of the coating (4) to the total measured area.

31. The medical injection device (1) according to any one of claims 28 to 30, wherein an empty barrel (2) of nominal volume 1mL is used to measure the static sliding friction of the plunger (5) in the barrel (2) at room temperature, at least 30 measurements having an average value of 2N to 3N.

32. The medical injection device (1) according to any one of claims 28 to 31, wherein an empty cylinder (2) of nominal volume 0.5mL is stored for 3 months at room temperature for measuring the static sliding friction of the plunger (5) in the cylinder (2) at room temperature, at least 30 measurements having an average value of 1 to 3N.

33. The medical injection device (1) according to any of claims 28 to 32, wherein an empty cylinder (2) of nominal volume 1mL is stored at 40 ℃ for 7 days for measuring the static sliding friction of the plunger (5) in the cylinder (2), at least 30 measurements having an average value of 1.5N to 3N.

34. The medical injection device (1) according to any one of claims 28 to 33, wherein an empty barrel (2) of nominal volume 1mL is used to measure the sliding friction of the plunger (5) in the barrel (2) at room temperature, at least 30 measurements having an average value of 1.5N to 2.5N.

35. The medical injection device (1) according to any one of claims 28 to 34, wherein an empty cylinder (2) of nominal volume 0.5mL is stored at room temperature for 3 months for measuring the sliding friction of the plunger (5) in the cylinder (2) at room temperature, at least 30 measurements having an average value of 1 to 2N.

36. The medical injection device (1) according to any one of claims 28 to 33, wherein an empty cylinder (2) of nominal volume 1mL is used to measure the sliding friction of the plunger (5) in the cylinder (2) at room temperature after 7 days of storage at 40 ℃ with an average value of 1.5N to 2.5N for at least 30 measurements.

37. Medical injection device (1) according to any one of claims 28 to 36, wherein the coating (4) of the inner surface (3) of the barrel (2) is partially crosslinked, preferably by irradiation treatment, more preferably by plasma irradiation treatment.

38. The medical injection device (1) according to any one of claims 28 to 37, further comprising: an adhesion promoter layer applied to the inner surface (3) of the cylinder (2), preferably an adhesion promoter layer comprising [ (bicycloheptene) ethyl ] trimethoxysilane.

39. The medical injection device (1) according to any one of claims 28 to 38, wherein the coating (4) of the inner surface (3) of the cartridge (2) releases particles in the test solution having an average particle size of 10 μm or more or 25 μm or more after 3 months of storage at a temperature of-40 ℃ according to the USP 787 standard specified in the USP 2021 edition 44-NF39, the average value of the normalized particle concentration determined by the photoresist method being 60% or less of the standard specified limit.

40. The medical injection device (1) according to any one of claims 37 to 39, wherein the average particle size of the release particles in the test solution of the partially crosslinked coating (4) on the inner surface (3) of the cartridge (2) after 3 months of storage at a temperature of-40 ℃ according to the USP 787 standard specified in the USP 2021 edition 44-NF39 is equal to or greater than 10 μm or equal to or greater than 25 μm, the average normalized particle concentration determined by the photoresist method being equal to or less than 10% of the standard specified limit.

41. The medical injection device (1) according to any one of claims 37 to 40, wherein the average particle size of the release particles in the test solution of the partially crosslinked coating (4) on the inner surface (3) of the cartridge (2) is equal to or greater than 10 μm or equal to or greater than 25 μm after 3 months of storage at a temperature of +5 ℃ or +25 ℃ or +40 ℃ according to USP 787 standard as specified in USP 2021 edition 44-NF39, the average value of the normalized particle concentration determined by the photoresist method being equal to or less than the limit specified by the standard.

42. The medical injection device (1) according to any one of claims 28 to 41, further comprising: a plunger (5) in sliding engagement with the barrel (2).

43. The medical injection device (1) according to any one of claims 28 to 42, further comprising: an injection drug composition (7) in contact with the inner surface (3) of the cylinder (2).

44. Medical injection device (1) according to claim 43, wherein the injectable pharmaceutical composition (7) comprises a drug and/or an active ingredient suitable for injection form selected from one or more of the following: allergen-specific immunotherapeutic compositions, oligonucleotides, in particular antisense oligonucleotides and RNAi antisense oligonucleotides, biological response modifiers, blood derivatives, enzymes, monoclonal antibodies, in particular conjugated monoclonal antibodies and bispecific monoclonal antibodies, oncolytic viruses, peptides, in particular recombinant peptides and synthetic peptides, polysaccharides, proteins, in particular recombinant proteins and fusion proteins, vaccines, in particular conjugate vaccines, DNA vaccines, inactivated vaccines, mRNA vaccines, recombinant vector vaccines, subunit vaccines or combinations thereof, provided that they are compatible.

45. Medical injection device (1) according to claim 43 or 44, wherein the drug and/or active ingredient suitable for injection form is selected from: GEN-3009, human pancreatic analog A21G+Pramlintide、AZD-5069+Durvalumab、Futuximab+Modotuximab、[225Ac]-FPI-1434、111In-CP04、14-F7、212Pb-TCMC-Trastuzumab、2141V-11、3BNC-117LS、3K3a-aPC、8H-9、9MW-0211、A-166、A-319、AADvac-1、AB-002、AB-011、AB-022、AB-023、AB-154、AB-16B5、AB-729、ABBV-011、ABBV-0805、ABBV-085、ABBV-151、ABBV-154、ABBV-155、ABBV-184、ABBV-3373、ABBV-368、ABBV-927、Abelacimab、AbGn-107、AbGn-168H、ABL-001、ABvac-40、ABY-035、 acetylcysteine+bromelain 、ACI-24、ACI-35、ACP-014、ACP-015、ACT-101、Actimab-A、Actimab-M、AD-214、Adavosertib+Durvalumab、ADCT-602、ADG-106、ADG-116、ADM-03820、AdVince、AEX-6003、Aflibercept biological analog 、AFM-13、AGEN-1181、AGEN-2373、AGLE-177、AGT-181、AIC-649、AIMab-7195、AK-101、AK-102、AK-104、AK-109、AK-111、AK-112、AK-119、AK-120、AL-002、AL-003、AL-101、Aldafermin、Aldesleukin、ALG-010133、ALM-201、ALMB-0168、ALNAAT-02、ALNAGT-01、ALN-HSD、ALPN-101、ALT-801、ALTP-1、ALTP-7、ALX-0141、ALX-148、ALXN-1720、AM-101、Amatuximab、AMC-303、Amelimumab、AMG-160、AMG-199、AMG-224、AMG-256、AMG-301、AMG-330、AMG-404、AMG-420、AMG-427、AMG-509、AMG-673、AMG-701、AMG-714、AMG-757、AMG-820、AMRS-001、AMV-564、AMY-109、AMZ-002、Analgecine、 A-clerosins, andecaliximab, anetumab Corixetan, anetumab Ravtansine, ANK-700, snake venom antibody, anthrax antibody, 2019 coronavirus disease (COVID-19) antibody, tetanus antibody, type I diabetes antibody, solid tumor OX40 agonist antibody, (recombinant) anti-hemophil, solid tumor and ovarian cancer inhibition EPHA2 antisense oligonucleotide RNAi, ANX-007, ANX-009, AP-101, apitegromab, APL-501, APL-501, APN-01, APS-001+fluorocytosine 、APSA-01、APT-102、APVAC-1、APVAC-2、APVO-436、APX-003、APX-005M、ARCT-810、ARGX-109、ARGX-117、AROANG-3、AROAPOC-3、AROHIF-2、ARO-HSD、Ascrinvacumab、ASLAN-004、ASP-1235、ASP-1650、ASP-9801、AST-008、Astegolimab、Asunercept、AT-1501、Atacicept、ATI-355、ATL-101、ATOR-1015、ATOR-1017、ATP-128、ATRC-101、Atrosab、ATX-101、ATXGD-59、ATXMS-1467、ATYR-1923、AU-011、( conjugated) RituximabAV-1、AVB-500、Avdoralimab、AVE-1642、AVI-3207、AVID-100、AVID-200、Aviscumine、Avizakimab、Axatilimab、B-001、B-002、Barusiban、BAT-1306、BAT-4306、BAT-4406F、BAT-5906、BAT-8003、Batroxobin、BAY-1905254、BAY-2315497、BAY-2701439、BB-1701、BBT-015、BCD-096、BCD-131、BCD-217、BCT-100、Bemarituzumab、Bepranemab、Bermekimab、Bertilimumab、Betalutin、Bevacizumab、Bexmarilimab、BG-00010、BGBA-445、BHQ-880、BI-1206、BI-1361849、BI-456906、BI-655064、BI-655088、BI-754091、BI-754111、BI-836858、BI-836880、BI-905677、BI-905711、BIIB-059、BIIB-076、BIIB-101、BIL-06v、Bimagrumab、BIO89-100、2019 Coronavirus disease (COVID-19), urinary tract infection, artificial joint and Acinetobacter infection biological response modifier, unknown indication biological response modifier, diabetic macular edema and wet macular degeneration bispecific monoclonal antibody I, HIV infection inhibition HIV 1Env bispecific monoclonal antibody, detection of tumor GD2 and CD3 bispecific monoclonal antibody, detection of pancreatic duct adenocarcinoma PD-L1 and CTLA4 bispecific monoclonal antibody 、BIVV-020、Bleselumab、BM-32、BMS-986012、BMS-986148、BMS-986156、BMS-986178、BMS-986179、BMS-986207、BMS-986218、BMS-986226、BMS-986253、BMS-986258、BMS-986258、BMS-986263、BNC-101、BNT-111、BNT-112、BNT-113、BNT-114、BNT-121、BOS-580、 botulinum toxin 、BP-1002、BPI-3016、BrevaRex MAb-AR20.5、Brivoligide、Bromelain、BT-063、BT-1718、BT-200、BT-5528、BT-588、BT-8009、BTI-322、BTRC-4017A、Budigalimab、BXQ-350、( human) C1 esterase inhibitor 、Cabiralizumab、Camidanlumab Tesirine、Canerpaturev、Cavatak、CBA-1205、CBP-201、CBP-501、CC-1、CC-90002、CC-90006、CC-93269、CC-99712、CCW-702、CDX-0159、CDX-301、CDX-527、Celyvir、Cemdisiran、Cendakimab、CERC-002、CERC-007、Cevostamab、Cibisatamab、CIGB-128、CIGB-258、CIGB-300、CIGB-500、CIGB-552、CIGB-814、CIGB-845、Cinpanemab、Cinrebafuspα、CIS-43、CiVi-007、CJM-112、CKD-702、Clustoid D.pteronyssinus、CM-310、CMK-389、CMP-001、CNTO-6785、CNTO-6785、CNV-NT、( recombinant) coagulation factor VIII、Cobomarsen、Codrituzumab、Cofetuzumab Pelidotin、COR-001、Cosibelimab、Cosibelimab、Cotadutide、CPI-006、CRX-100、CSJ-137、CSL-311、CSL-324、CSL-346、CSL-730、CSL-889、CTB-006、CTI-1601、CTP-27、CTX-471、CUE-101、Cusatuzumab、CV-301、CVBT-141、CX-2009、CX-2029、CYN-102、CyPep-1、CYT-107、CYT-6091、( human) anti-cytomegalovirus immunoglobulin, Darafenib mesylate+panitumumab+trimetinib dimethyl sulfoxide 、DAC-002、Dalcinonacogα、Dalotuzumab、Danvatirsen+Durvalumab、Dapiglutide、Daxdilimab、DB-001、DCRA-1AT、Decavil、Depatuxizumab、Desmopressin、DF-1001、DF-6002、Diamyd、Dilpacimab、Diridavumab、DK-001、DKN-01、DM-101、DM-199、DMX-101、DNL-310、DNP-001、DNX-2440、Domagrozumab、Donanemab、Donidalorsen sodium 、DP-303c、DS-1055a、DS-2741、DS-6157、DS-7300、DS-8273、Durvalumab+Monalizumab、Durvalumab+Oleclumab、Durvalumab+Oportuzumab Monatox、Durvalumab+Selumetinib sulfate, DX-126262, DXP-593, DXP-604, DZIF-10c, E-2814, E-3112, EBI-031, yttrium 90 labeled ertapeptide Efavaleukinα、Efpegsomatropin、EG-Mirotin、Elezanumab、Elipovimab、Emactuzumab、Enadenotucirev、Engedi-1000、Ensituximab、EO-2401、Epcoritamab、ERY-974、Etigilimab、Etokimab、Evitar、EVX-02、Exenatide、F-0002ADC、F-520、F-598、F-652、Faricimab、FAZ-053、FB-704A、FB-825、FF-21101、( human) concentrated fibrinogen 、Ficlatuzumab、Flotetuzumab、FLYSYN、FmAb-2、FNS-007、FOL-005、FOR-46、Foralumab、Foxy-5、FPP-003、FR-104、Fresolimumab、FS-102、FS-118、FS-120、FS-1502、FSH-GEX、 allergic asthma fusion protein, idiopathic thrombocytopenic purpura antagonistic thrombopoietin receptor fusion protein, glioblastoma multiforme and glioblastoma malignant tumor antagonistic epidermal growth factor receptor fusion protein, Tumor suppressor CD25 fusion protein, tumor targeting mesothelin fusion protein, colitis, hypertension and ulcerative colitis fusion protein 、FX-06、G-035201、G-207、G-3215、Garetosmab、Gatipotuzumab、GB-223、GBB-101、GC-1118A、GC-5131A、GEM-103、GEM-333、GEM-3PSCA、Gemibotulinumtoxin A、GEN-0101、GEN-1046、Gensci-048、Gentuximab、Gevokizumab、Glenzocimab、Glofitamab、Glucagon、GM-101、GMA-102、GMA-301、GNR-051、GNR-055、GNR-084、GNX-102、 goserelin acetate 、Gosuranemab、gp-ASIT、GR-007、GR-1401、GR-1405、GR-1501、GRF-6019、GRF-6021、GS-1423、GS-2872、GS-5423、GSK-1070806、GSK-2241658A、GSK-2330811、GSK-2831781、GSK-3174998、GSK-3511294、GSK-3537142、GT-02037-、GT-103、GTX-102、GW-003、GWN-323、GX-301、GXG-3、GXP-1、H-11B6、HAB-21、HALMPE-1、HB-0021、HBM-4003、HDIT-101、HER-902、HFB-30132A、HH-003、HL-06、HLX-06、HLX-07、HLX-20、HLX-22、HM-15211、HM-15912、HM-3、HPN-217、HPN-328、HPN-424、HPN-536、HPV-19、hRESCAP、HS-214、HS-628、HS-630、HS-636、HSV-1716、HTD-4010、HTI-1066、Hu8F4、HUB-1023、hVEGF-26104、HX-009、( recombinant) hyaluronidase 、IBI-101、IBI-110、IBI-112、IBI-188、IBI-302、IBI-318、IBI-322、IBI-939、IC-14、ICON-1、ICT-01、Ieramilimab、Ifabotuzumab、IGEM-F、IGM-2323、IGM-8444、IGN-002、IMA-950、IMA-970A、IMC-002、IMCF-106C、IMCY-0098、IMGN-632、IMGN-005、IMM-01、IMM-201、( human) immunoglobulin 、Imsidolimab、INA-03、INBRX-101、INBRX-105、INCAGN-1876、INCAGN-1949、INCAGN-2385、Inclacumab、Indatuximab Ravtansine、Interferonα-2b、INVAC-1、IO-102、IO-103、IO-112、IO-202、ION-224、ION-251、ION-464、ION-537、ION-541、ION-859、IONIS-AGTLRx、IONISAR-2.5Rx、IONIS-C9Rx、IONIS-FB-LRx、IONIS-FXILRx、IONIS-FXIRx、IONIS-GCGRRx、IONIS-HBVLRx、IONIS-HBVRx、IONIS-MAPTRx、IONIS-PKKRx、IONISTMPRSS-6LRx、IPN-59011、IPP-204106、Ir-CPI、IRL-201104、IRL-201805、ISA-101、ISB-1302、ISB-1342、ISB-830、Iscalimab、ISU-104、IT-1208、ITF-2984、IXTM-200、JBH-492、JK-07、JMT-101、JMT-103、JNJ-0839、JNJ-3657、JNJ-3989、JNJ-4500、JNJ-67571244、JNJ-75348780、JNJ-9178、JS-003、JS-004、JS-005、JSP-191、JTX-4014、JY-025、JZB-30、JZB-34、K-170、K-193、KAN-101、KD-033、KER-050、KH-903、KHK-4083、KHK-6640、EDV Paediatric、KLA-167、KLA-167、KLT-1101、KMRC-011、KN-026、KPL-404、KSI-301、KTN-0216、KTP-001、KUR-113、KY-1005、KY-1044、Labetuzumab Govitecan、Lacnotuzumab、Lacutamab、Ladiratuzumab Vedotin、Laronidase、LBL-007、LDOS-47、Letolizumab、 leuprorelin acetate 、LEVI-04、LH-021、Liatermine、Lirilumab、LIS-1、LKA-651、LLF-580、LMB-100、LNA-043、LOAd-703、Lodapolimab、Lorucafuspα、LP-002、LT-1001、LT-1001、LT-1001、LT-3001、LT-3001、LTI-01、LTX-315、LuAF-82422、LuAF-87908、Lulizumab Pegol、LVGN-6051、LY-3016859、LY-3022855、LY-3041658、LY-3305677、LY-3372993、LY-3375880、LY-3434172、LY-3454738、LY-3561774、LZM-009、M-032、M-1095、M-254、M-6495、M-701、M-802、M-9241、MAG-Tn3、MAU-868、MB-108、MBS-301、MCLA-117、MCLA-145、MCLA-158、MDNA-55、MDX-1097、MEDI-0457、MEDI-0618、MEDI-1191、MEDI-1341、MEDI-1814、MEDI-3506、MEDI-3617+Tremelimumab、MEDI-5117、MEDI-5395、MEDI-570、MEDI-5752、MEDI-5884、MEDI-6012、MEDI-6570、MEDI-7352、MEDI-9090、MEN-1112、Meplazumab、Mezagitamab、MG-021、MG-1113A、MGC-018、MIL-62、MIL-77、MIL-86、Mitazalimab、MK-1654、MK-3655、MK-4166、MK-4280、MK-4621、MK-5890、Molgramostim、 tumor identification CD276 conjugated monoclonal antibody, tumor identification CD45 conjugated monoclonal antibody, non-small cell lung cancer and metastatic colorectal cancer identification CEACAM5 conjugated monoclonal antibody, metastatic colorectal cancer identification Mucin 1 conjugated monoclonal antibody, Prostate cancer targeting PSMA conjugated monoclonal antibodies, dengue monoclonal antibodies, celiac disease, tumor and tropical spastic paraplegia antagonistic IL-2 Rbeta monoclonal antibodies, rheumatoid arthritis antagonistic interleukin 6 receptor monoclonal antibodies, tumor antagonistic PD1 monoclonal antibodies, solid tumor antagonistic PD1 monoclonal antibodies, HIV-1 CD4 inhibitory monoclonal antibodies, tumor GD2 monoclonal antibodies, rabies glycoprotein inhibiting monoclonal antibodies, autoimmune and musculoskeletal disease inhibiting IL17 monoclonal antibodies, asthma and Chronic Obstructive Pulmonary Disease (COPD) IL5 inhibiting monoclonal antibodies, HIV-1 CD4 inhibiting monoclonal antibodies, autoimmune diseases and musculoskeletal disease inhibiting monoclonal antibodies, Monoclonal antibodies to solid tumor suppressor PD-L1, ankylosing spondylitis, psoriasis and rheumatoid arthritis, TNF-alpha, dupuytren's contracture, diabetic macular edema and wet age macular degeneration, VEGF, metastatic colorectal cancer and non-small cell lung cancer, VEGFA, CD66b targeting for blood cancer and metabolic disorders, GP41 targeting HIV infection, octreotide acetate 、MORAb-202、Motrem、MP-0250、MP-0274、MP-0310、MP-0420、MRG-001、MRG-002、MRG-003、MRG-110、mRNA-2416、mRNA-2752、mRNA-3927、MSB-0254、MSB-2311、MSC-1、MT-1001、MT-1002、MT-2990、MT-3724、MT-3921、MTX-102、Murlentamab、MVT-5873、MVXONCO-1、MW-11、MW-33、NA-704、Namilumab、Naratuximab Emtansine、Navicixizumab、NBE-002、NBF-006、NC-318、NC-410、Nemvaleukinα、NEOPV-01、NG-348、NG-350a、NG-641、NGM-120、NGM-395、NGM-621、NI-006、NI-0801、Nidanilimab、Nimacimab、NIS-793、NIZ-985、NJA-730、NJH-395、NKTR-255、NKTR-358、NMIL-121、NN-9215、NN-9499、NN-9775、NN-9838、NN-9931、NNC-03850434、NP-024、NP-025、NP-137、NPC-21、NPT-088、NPT-189、NRP-2945、NStride APS、NVG-111、NXT-007、NZV-930、OBI-888、OBI-999、OBT-076、OC-001、, octreotide acetate CR, octreotide acetate microsphere 、Odronextamab、Odronextamab、OH-2、Olamkicept、Oleclumab、Olinvacimab、Olpasiran、Olvimulogene Nanivacirepvec、OMS-906、Onabotulinumtoxin A、ONC-392、ONCase-PEG、 human papillomavirus related cancers, human papillomavirus infections and 2019 coronavirus diseases (COVID-19) oncolytic viruses, metastatic breast cancer oncolytic viruses, solid tumor oncolytic viruses, oncolytic viruses of recurrent prostate cancer and metastatic pancreatic cancer activating IL-12, oncolytic viruses of tumor activating thymidine kinase, oncolytic viruses of solid tumor antagonizing PD1, oncolytic viruses of solid tumor targeting CD155/NECL5, oncolytic viruses of tumor targeting CD46 and SLC5A5, oncolytic viruses of Human Papillomavirus (HPV) related solid tumors targeting E6 and E7, Oncolytic viruses 、ONCOS-102、ONCR-177、Ongericimab、ONO-4685、Onvatilimab、OPK-88005、OPT-302、ORCA-010、OrienX-010、Orilanolimab、Oricumab、OS-2966、OSE-127、Osocimab、Otelixizumab、OTO-413、OTSA-101、OXS-1550、OXS-3550、P-28R、P-2G12、Pacmilimab、Panobacumab、Parvoryx、Pasireotide、Pasotuxizumab、PC-mAb、PD-01、PD-0360324、PD-1+Antagonist Ropeginterferonα-2b、Pegbelfermin、Peginterferonλ-1a、Pelareorep、Pelareorep、Pemziviptadil、PEN-221、 to MAGE-A3 for solid tumor targeting sodium pentylphulfide, pepinemab, 2019 coronavirus disease (COVID-19) polypeptides, solid tumor polypeptides, pertuzumab biological modifiers 、Pexastimogene Devacirepvec、PF-04518600、PF-06480605、PF-06730512、PF-06755347、PF-06804103、PF-06817024、PF-06823859、PF-06835375、PF-06863135、PF-06940434、PF-07209326、PF-655、PHN-013、PHN-014、PHN-015、Pidilizumab、PIN-2、Plamotamab、( human )Plasminogen 1、Plexaris、PM-8001、PNT-001、Pollinex Quattro Tree、PolyCAb、Poly-ICLC、PolyPEPI-1018、Ponsegromab、PP-1420、PR-15、PR-200、Prasinezumab、Prexigebersen、PRL3-ZUMAB、 diabetic foot ulcers and cerebral hemorrhage proteins, osteoarthritis and asthma proteins, infectious diseases and tumor activating IL12 protein 、PRS-060、PRTX-100、PRV-300、PRV-3279、PRX-004、PSB-205、PT-101、PT-320、PTR-01、PTX-35、PTX-9908、PTX-9908、PTZ-329、PTZ-522、PVX-108、QBECO-SSI、QBKPN-SSI、QL-1105、QL-1203、QL-1207、QL-1604、QPI-1007、QPI-1007、Quavonlimab、Quetmolimab、QX-002N、QX-005N、Radspherin、Ranibizumab、Ranpirnase、Ravagalimab、 new generations Ravulizumab, RC-28, RC-402, RC-88, RD-001, REC-0438, methotrexate toxic recombinant carboxypeptidase G2, Organophosphorus nerve agent poisoning recombinant enzyme, cardiovascular, central nervous system, musculoskeletal and metabolic diseases agonizing GHRH recombinant peptide, infectious disease recombinant plasma gel zymogen substitute, enteritis, multiple sclerosis and psoriasis recombinant protein, tumor agonizing IFNAR1 and IFNAR2 recombinant protein; chemotherapy-induced gastrointestinal and oral mucositis agonizing KGFR recombinant proteins, idiopathic thrombocytopenic purpura agonizing thrombopoietin receptor recombinant proteins, lymphoma and solid tumor inhibiting CD13 recombinant proteins, hemophilia A and hemophilia B inhibiting factor XIV recombinant proteins, acute hyperuricemia recombinant urate oxidase substitutes, trifluoroacetic acid erythrose peptide 、REGN-19081909、REGN-3048、REGN-3051、REGN-3500、REGN-4018、REGN-4461、REGN-5093、REGN-5458、REGN-5459、REGN-5678、REGN-5713、REGN-5714、REGN-5715、REGN-6569、REGN-7075、REGN-7257、Remlarsen、Renaparin、REP-2139、REP-2165、Reteplase、RG-6139、RG-6147、RG-6173、RG-6290、RG-6292、RG-6346、RG-70240、RG-7826、RG-7835、RG-7861、RG-7880、RG-7992、RGLS-4326、Rigvir、Rilimogene Galvacirepvec、Risuteganib、Rituximab、RMC-035、RO-7121661、RO-7227166、RO-7284755、RO-7293583、RO-7297089、Romilkimab、Ropocamptide、Rosibafuspα、RPH-203、RPV-001、rQNestin-34.5v.2、RSLV-132、RV-001、RXI-109、RZ-358、SAB-176、SAB-185、SAB-301、SAIT-301、SAL-003、SAL-015、SAL-016、Sanguinate、SAR-439459、SAR-440234、SAR-440894、SAR-441236、SAR-441344、SAR-442085、SAR-442257、SB-11285、SBT-6050、SCB-313、SCIB-1、SCO-094、SCT-200、SCTA-01、SD-101、SEA-BCMA、SEA-CD40、SelectAte、Selicrelumab、SelK-2、Semorinemab、Serclutamab Talirine、Seribantumab、Setrusumab、Sevuparin sodium salt 、SFR-1882、SFR-9213、SFR-9216、SFR-9314、SG-001、SGNB-6A、SGNCD-228A、SGN-TGT、SHR-1209、SHR-1222、SHR-1501、SHR-1603、SHR-1701、SHR-1702、SHR-1802、SHRA-1201、SHRA-1811、SIB-001、SIB-003、Simlukafuspα、Siplizumab、Sirukumab、SKB-264、SL-172154、SL-279252、SL-701、SOC-101、SOJB、Somatropin SR、Sotatercept、Sprifermin、SRF-617、SRP-5051、SSS-06、SSS-07、ST-266、STA-551、STI-1499、STI-6129、STK-001、STP-705、STR-324、STRO-001、STRO-002、STT-5058、SubQ-8、Sulituzumab、Suvratoxumab、SVV-001、SY-005、SYD-1875、Sym-015、Sym-021、Sym-022、Sym-023、SYN-004、SYN-125、 hepatitis B and type II diabetes inhibiting SLC10A1 synthetic peptides, chronic kidney disease regulating GHSR synthetic peptides, thyroid medullary carcinoma targeting CCKBR synthetic peptides, neuroendocrine gastrointestinal pancreatic tumor targeting somatostatin receptor synthetic peptides, t-3011, TA-46, TAB-014, tafoxiparin sodium salt 、TAK-101、TAK-169、TAK-573、TAK-611、TAK-671、Talquetamab、Tasadenoturev、TBio-6517、TBX.OncV NSC、Tebotelimab、Teclistamab、Telisotuzumab Vedotin、Telomelysin、Temelimab、Tenecteplase、Tesidolumab、Teverelix、TF-2、TG-1801、TG-4050、TG-6002、TG-6002、T-Guard、Thor-707、THR-149、THR-317、Thrombosomes、Thymalfasin、Tilavonemab、TILT-123、Tilvestamab、Tinurilimab、Tipapkinogene Sovacivec、Tiprelestat、TM-123、TMB-365、TNB-383B、TNM-002、TNX-1300、Tomaralimab、Tomuzotuximab、Tonabacase、Tralesinidaseα、Trebananib、Trevogrumab、TRK-950、TRPH-222、TRS-005、TST-001、TTHX-1114、TTI-621、TTI-622、TTX-030、TVT-058、TX-250、TY-101、Tyzivumab、U-31402、UB-221、UB-311、UB-421、UB-621、UBP-1213、UC-961、UCB-6114、UCHT-1、UCPVax、Ulocuplumab、UNEX-42、UNI-EPO-Fc、Urelumab、UV-1、V-938、 acute lymphoblastic leukemia vaccine, B-cell non-Hodgkin's lymphoma vaccine, chronic lymphoblastic leukemia vaccine, glioma vaccine, hormone sensitive prostate cancer vaccine, melanoma vaccine, non-myoinvasive bladder cancer vaccine, ovarian cancer vaccine, tumor-targeted Brachyury and HER2 vaccine, tumor-targeted Brachyury vaccine, B-cell non-Hodgkin's lymphoma-targeted CCL20 vaccine, colorectal cancer-targeted CEA vaccine, Metabolic disorders, immune, infectious and musculoskeletal diseases targeting IFN-alpha vaccine 、VAL-201、Vantictumab、Vanucizumab、Varlilumab、Vas-01、VAX-014、VB-10NEO、VCN-01、Vibecotamab、Vibostolimab、VIR-2218、VIR-2482、VIR-3434、VIS-410、VIS-649、Vixarelimab、VLS-101、Vofatamab、Volagidemab、Vopratelimab、Voyager-V1、VRC-01、VRC-01LS、VRC-07523LS、VTP-800、Vunakizumab、Vupanorsen sodium salt 、Vx-001、Vx-006、W-0101、WBP-3425、XAV-19、Xentuzumab、XmAb-20717、XmAb-22841、XmAb-23104、XmAb-24306、XMT-1536、XoGlo、XOMA-213、XW-003、Y-14、Y-242、YH-003、YH-14618、YS-110、YYB-101、Zagotenemab、Zalifrelimab、Zampilimab、Zanidatamab、Zanidatamab、Zansecimab、Zenocutuzumab、ZG-001、ZK-001、ZL-1201、Zofin or a combination thereof, provided that they are compatible.

46. A kit of parts for assembling a medical injection device (1), comprising the following individual components in a sterile package:

A glass cylinder (2) with an inner surface (3) coated with a coating (4), the cylinder (2) being configured to receive a plunger (5) in sliding engagement,

A plunger (5) configured to be slidingly engaged in the cylinder (2),

Wherein the coating (4) of the inner surface (3) of the cylinder (2) is substantially made of polydimethylsiloxane having a kinematic viscosity at room temperature ranging from 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s), an average thickness ranging from 100nm to 250nm, preferably from 100nm to 200nm;

Wherein the standard deviation of the thickness of the coating (4) of the inner surface (3) of the cylinder (2) is equal to or less than 90nm, preferably equal to or less than 70nm, more preferably equal to or less than 50nm.

47. A kit of parts for assembling a medical injection device (1), comprising the following individual components in a sterile package:

A glass cylinder (2) with an inner surface (3) coated with a coating (4), the cylinder (2) being configured to receive a plunger (5) in sliding engagement,

A plunger (5) configured to be slidingly engaged in the cylinder (2),

Wherein the coating (4) of the inner surface (3) of the cylinder (2) is substantially made of polydimethylsiloxane having a kinematic viscosity at room temperature of 11500cSt (115 cm ²/s) to 13500cSt (135 cm ²/s), a batch average thickness of 100nm to 250nm, preferably 100nm to 200nm;

Wherein for each batch of 10 cylinders (2), the coating (4) thickness has a value of the batch average standard deviation SD equal to or less than 70nm, preferably equal to or less than 60nm, more preferably equal to or less than 50nm;

Wherein the lot average standard deviation SD is obtained by:

(i) Measuring the thickness S _pi of the coating (4) at least 6 points of each arbitrary portion ni of 1.0mm in the batch of the planar development axial length of the ith cylinder;

(ii) For each of the portions ni of the ith barrel in the batch and for each of the ith barrels, an average thickness S _ni is calculated by:

S_ni＝(Σ_p＝1,6S_pi)/6

(iii) For each barrel portion n, the batch average thickness S _nL for that portion n is calculated by:

S_nL＝(Σ_i＝1,10S_ni)/10

(iv) For 10 injectors in a batch, calculate the standard deviation SD _n of the batch average thickness S _nL for the portion n; and

(V) The batch average standard deviation SD is calculated from the value of the thickness standard deviation SD _n by:

SD＝(Σ_i＝1,N SD_n)/N

Where N is the total number of portions N of each barrel in the batch.

48. The kit of parts according to any one of claims 46 or 47, wherein the coverage, defined as the ratio of the silicon coverage area to the total measured area, in each arbitrary portion of the cylinder (2) having a planar development axial length of 1.0mm corresponds to at least 90%.

49. Kit of parts according to any of claims 46 to 48, wherein an empty cylinder (2) of nominal volume 1mL is used to measure the static sliding friction of the plunger (5) in the cylinder (2) at room temperature, at least 30 measurements having an average value of 2N to 3N.

50. Kit of parts according to any of claims 46 to 49, wherein an empty cylinder (2) of nominal volume 0.5mL is stored at room temperature for 3 months for measuring the static sliding friction of the plunger (5) in the cylinder (2) at room temperature, at least 30 measurements having an average value of 1 to 3N.

51. Kit of parts according to any of claims 46 to 50, wherein an empty cylinder (2) of nominal volume 1mL is used to measure the static sliding friction of the plunger (5) in the cylinder (2) after 7 days of storage at 40 ℃ with an average value of 1.5N to 3N for at least 30 measurements.

52. Kit of parts according to any one of claims 46 to 51, wherein an empty cylinder (2) of nominal volume 1mL is used to measure the sliding friction of the plunger (5) in the cylinder (2) at room temperature, at least 30 measurements having an average value of 1.5N to 2.5N.

53. Kit of parts according to any one of claims 46 to 52, wherein an empty cylinder (2) of nominal volume 0.5mL is stored at room temperature for 3 months for measuring the sliding friction of the plunger (5) in the cylinder (2) at room temperature, at least 30 measurements having an average value of 1N to 2N.

54. Kit of parts according to any of claims 46 to 53, wherein an empty cylinder (2) of nominal volume 1mL is used to measure the sliding friction of the plunger (5) in the cylinder (2) after 7 days of storage at 40 ℃ with an average value of at least 30 measurements of 1.5N to 2.5N.

55. Kit of parts according to any one of claims 46 to 54, wherein the coating (4) of the inner surface (3) of the cylinder (2) is partially crosslinked, preferably by irradiation treatment, more preferably by plasma irradiation treatment.

56. Kit of parts according to any one of claims 46 to 55, wherein the cartridge (2) further comprises an adhesion promoter layer applied to its inner surface (3), preferably an adhesion promoter layer comprising [ (bicycloheptene) ethyl ] trimethoxysilane.

57. The kit of parts according to any one of claims 46 to 56, wherein the coating (4) of the inner surface (3) of the cylinder (2) releases particles in the test solution having an average particle size of 10 μm or more or 25 μm or more after 3 months of storage at a temperature of-40 ℃ according to the USP 787 standard specified in the USP 2021 edition 44-NF39, the average value of the normalized particle concentration determined by the photoresist method being 60% or less of the standard specified limit.

58. The kit of parts according to any one of claims 55 to 57, wherein the partially crosslinked coating (4) on the inner surface (3) of the cylinder (2) releases particles in the test solution having an average particle size of 10 μm or more or 25 μm or more after 3 months of storage at a temperature of-40 ℃ according to the USP 787 standard specified in the USP 2021 edition 44-NF39, the average normalized particle concentration value measured by the photoresist method being 10% or less of the standard specified limit.

59. The kit of parts according to any one of claims 55 to 58, wherein the average particle size of the release particles in the test solution of the partially crosslinked coating (4) on the inner surface (3) of the cylinder (2) is equal to or greater than 10 μm or equal to or greater than 25 μm after 3 months of storage at a temperature of +5 ℃ or +25 ℃ or +40 ℃ according to USP 787 standard as specified in USP 2021 edition 44-NF39, the average value of the normalized particle concentration determined by the photoresist method being equal to or less than the limit specified by said standard.