CN118103340A

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

Info

Publication number: CN118103340A
Application number: CN202280069629.4A
Authority: CN
Inventors: 阿尔贝托·希隆; 法比奥·奇内拉托; 保罗·帕特里
Original assignee: Stevanato Group Co ltd
Current assignee: Stevanato Group Co ltd
Priority date: 2021-09-24
Filing date: 2022-09-26
Publication date: 2024-05-28
Also published as: IT202200003761A1

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 by same

Technical Field

The present invention relates to a method of manufacturing a medical injection device comprising a glass cylinder coated on an inner surface thereof, the cylinder being configured to receive a plunger in sliding engagement; the invention also relates to a medical injection device obtained by the above method and to a kit for assembling the above medical device.

Background

As is well known, injection devices, which typically include a sealed plunger slidingly engaged within a container for dispensing a medicament to a patient by injection, are widely used in the medical field.

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

In such devices, it is first desirable that the plunger exhibit optimal sliding properties (in terms of static and dynamic friction) within the syringe device barrel (e.g., barrel of a syringe). For this purpose, the inner surface of the syringe body and the plunger are applied using a generally silicone-based lubricating substance. In particular, the purpose of the lubricating substance is to optimize the sliding properties of the plunger, in particular to reduce the force required to overcome the static friction (release force) and the force required to overcome the dynamic friction when sliding the plunger (average sliding force).

Another challenge to be addressed is to keep the sliding properties of the plunger as constant as possible over a long period of time, especially in the case of injection devices such as pre-filled syringes.

In fact, on the one hand, if a prefilled injection device is used to ensure ease of administration and management, on the other hand, it means that the injection device must be stored for a considerable period of time, in the order of weeks or months, and sometimes even longer, for example in the case of protein drugs or vaccines, at very low temperatures, in order to ensure drug stability and to extend shelf life.

However, it is believed that the presence of silicon-based coatings is one of the factors for instability of biotechnological drugs, particularly recombinant proteins, which instability is associated with intrinsic structural sensitivity. In practice, silicone oil separates into solution to form particles, the meaning is classified as intrinsic particles, there may be proteins adsorbed to the particles at the interface of the silicone water, and structural denaturation and aggregation of the proteins may occur, resulting in agglomeration of the particles themselves. The reason why aggregation is critical is that it may lead to a loss of therapeutic effect and an increased risk of immunogenicity.

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

Disclosure of Invention

The inventors have noted that there are several methods of manufacturing medical injection devices that attempt to meet the above-mentioned needs, but these methods raise management or complexity issues and thus also create cost issues that have not heretofore been addressed.

In some cases a mixture of different types of silicone oils may be used, possibly with the addition of other substances. In this regard, the inventors have noted that the more pure silicon is discarded (i.e., without mixing or addition), the more difficult it is to maintain its properties and behavior over time.

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

In some cases it has been proposed to deposit several successive silicon layers, possibly also subjected to irradiation.

Such processes using additive-containing silicon or mixed silicon may also require irradiation treatment, see for example patent literature US20020012741A1、EP3378514A1、US7648487B2、US9662450B2、US10066182B2、EP2387502B1、US7553529B2、US20110276005A1、EP2081615B1、US5338312A、US4844986A、US4822632A、US20080071228A1.

Also described in WO2013045571A1 is a method aimed at obtaining a syringe that meets both the requirements of good sliding and low release, both of which have to be kept constant over a long period of time (and also have to keep the thickness constant over a long period of time). This document discloses spraying a silicone having a kinematic viscosity of 900cSt to 1200cSt onto the inner surface of a syringe, followed by a plasma treatment to cause the silicone to exhibit high stability and low release. This document indicates the reason for the low release in the plasma treatment of the silicone surface.

Similar technical solutions are provided in patent documents WO2009053947A2 and WO2015136037 A1.

All these documents show that the use of silicones with a rather low kinematic viscosity (about 1000 cSt) in combination with irradiation treatment, in particular plasma treatment, is an optimal combination for solving the above problems.

Patent document DE 10000505 also discloses a method for siliconizing the interior of hollow cylinders, in which silicone oil with a kinematic viscosity of preferably 350cSt to 20000cSt is deposited on the inner wall of the body cavity. The silicone oil is deposited by spraying, in particular by means of a spray head of the type used in ink jet printing, which may be heated in one embodiment.

However, the inventors have observed that the manufacturing method disclosed in the above prior art, in addition to implying an extended manufacturing time of the medical injection device and an increased complexity of the management of the method itself, may also cause problems not found in the prior art, namely the necessity of visual inspection of the medical injection device after filling the drug, the absence of defects and the optical detection of foreign contaminants in the form of particles.

Such examinations have previously had to be carried out manually, and can now be assigned to automation devices based on image analysis techniques of optical acquisition systems. The purity of the solution contained in the medical injection device is required to be increased continuously, so that the control device is required to not only highlight the ultra-small impurities in the liquid, but also distinguish the impurities from the defects that the appearance of the container does not form the impurities, and therefore, the medical injection device is scrapped due to misclassification.

In this regard, the inventors have observed that the partial cross-linking of the silicone oil layer applied to the inner surface of the barrel of a medical injection device, in particular the partial cross-linking obtained by plasma irradiation, produces a more irregular but more stable surface structure, which may mislead the automatic optical detection system to misclassify the surface irregularities as impurities, thus producing production waste that would otherwise be present, resulting in an economic loss.

In view of the above, the present inventors have recognized a need for developing a method of manufacturing a medical injection device that not only meets the above-described needs, but also allows the plunger to exhibit optimal sliding performance (in terms of static friction and dynamic friction) and optimal characteristics of low particulate release within the barrel of the injection device, both of which remain unchanged for a long period of time, and also reduces the problems associated with false defects that may be erroneously detected by visual inspection devices of the medical injection device.

The inventors have appreciated that all of these desirable features can be achieved by varying the rheological properties of the coating composition and the method of coating the coating composition for coating the interior surface of a medical injection device barrel, as compared to the prior art.

In particular, the inventors have experimentally confirmed that by coating the inner surface of the barrel of a medical injection device with a coating composition which is substantially composed almost entirely of a single type of silicone oil having a kinematic viscosity at room temperature which is much higher than that of silicone oils employed in the prior art, such silicone oil can be simultaneously obtained by thermally coating the inner surface of the barrel with a coating applied to the surface after cooling:

The desired optimum slip properties and low particulate release properties, both of which are substantially constant over a long period of time; and

The surface regularity of the coating is optimized so that visual inspection means of the medical injection device are not misled.

In particular, in the experiments, the surface regularity of the above-mentioned coating is comparable to that of the non-crosslinked coating obtained in the prior art using silicone oils of low kinematic viscosity but high release rate of particles. Although the kinematic viscosity at room temperature of the silicone oils used is much higher, although the average thickness of the applied coating is very thin, approximately only 100-250 nm,

However, in the experiments, the surface regularity of the above-mentioned coating is improved compared to the partially crosslinked coating obtained by using a silicone oil having a low kinematic viscosity in the prior art.

In addition, the present inventors have experimentally confirmed that by coating the inner surface of the barrel of a medical injection device with the above-mentioned coating composition, which is composed substantially almost entirely of a single type of silicone oil having a kinematic viscosity at room temperature far higher than that of silicone oils used in the prior art, the coating uniformity and high process reproducibility required for mass industrial production can be obtained after the coating applied to the inner surface of the barrel is cooled by thermally applying such silicone oil to the inner surface of the barrel.

Accordingly, a first aspect of the present invention relates to a method of manufacturing a medical injection device as defined in claims 1 and 2, the medical injection device comprising a glass cylinder with a coating on an inner surface, the cylinder being configured to receive a plunger in sliding engagement.

In particular, according to a first embodiment, the method of manufacturing a medical injection device of the present invention comprises 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) Applying the coating composition heated to said temperature to the inner surface of the cylinder to form a coating on said inner surface, having an average thickness S of 100nm to 250nm as measured by optical reflection;

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

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

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

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

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

Wherein the lot average standard deviation SD is obtained by:

(i) Measuring the coating thickness S _pi at least 6 points of each arbitrary portion ni of the lot where the planar-expanded axial length of the i-th cylinder is 1.0 mm;

(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 the batch, calculate the standard deviation SD _n for the batch average thickness S _nL for part 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.

The inventors have found through experiments that, as detailed below, by thermally coating the above-mentioned polydimethylsiloxane-based high-viscosity coating composition at room temperature, the coating layer formed on the inner surface of the cylinder can exhibit the same effect as the low-viscosity silicone oil in terms of application and distribution.

The inventors have also found through experimentation that after cooling of the coating and after restoration of the viscosity characteristics to room temperature viscosity characteristics, a favorable set of improved characteristics is achieved compared to the low viscosity coatings described in the prior art (whether or not subjected to a partial cross-linking treatment).

First, the inventors have experimentally observed that the coating formed by the method of the application advantageously is capable of not only having low thickness values required by the pharmaceutical and cosmetic industries, but also being very uniformly distributed along each length of the barrel on the inner surface of the barrel.

In particular, the inventors have experimentally observed that the thickness values of the coating applied on the inner surface of the cylinder according to the method of the application can advantageously be completely comparable to those obtained with the prior art with silicone oils of low viscosity.

The inventors have experimentally observed that the viscosity of the coating applied to the inner surface of the cylinder, once returned to its viscosity value at room temperature, imparts a stable character to the coating, allowing to overcome all the drawbacks of the formation of the coating from low viscosity (about 1000cSt, as previously mentioned) silicone oils which have not undergone partial crosslinking.

In particular, the coating formed by the method of the present invention advantageously overcomes the following drawbacks of the prior art non-crosslinked coatings:

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

use of medical injection devices (e.g., syringes) can result in uneven plunger sliding resistance;

the drug is more likely to interact directly with the material (glass) from which the barrel of the medical injection device (e.g., syringe) is made, and the partial coating is also more likely to come off the surface into solution;

Especially in combination with mechanical stresses such as stirring, or dispensing of the liquid contained in the cartridge by sliding the plunger, denaturation and protein aggregation may be triggered.

Thus, the method of the present invention advantageously enables the formation of a coating having thickness characteristics, uniformity characteristics and stability characteristics, allowing the plunger to achieve optimal sliding characteristics in the barrel, despite the fact that the viscosity of the silicone oil forming the coating is much higher than the silicone oils proposed in the prior art documents above.

Second, the inventors have experimentally observed that the inventive method is capable of advantageously forming a coating with high surface regularity and high coverage uniformity, such that visual inspection devices of medical injection devices, in particular automated visual inspection devices, are not misled.

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

Thus, the coating does not cause false defects, thereby solving the problems of the partially crosslinked silicon coating in the prior art.

Advantageously, the process according to the invention also allows to obtain a coating on the inner surface of the cylinder with an average thickness that is fully compatible with the requirements of the pharmaceutical and cosmetic industry, even though such a coating is made of a silicon material with high kinematic viscosity.

Thirdly, the inventors have experimentally observed that the coating formed by the method of the present application can advantageously exhibit low particulate release characteristics in a storage solution in a medical injection device cartridge due to the stable characteristics associated with the room temperature viscosity values of the coating.

According to the tests carried out by the inventors, these low particle release characteristics are completely comparable or improved with the characteristics of the prior art partially crosslinked silicon coatings, which, however, cause the above-mentioned false defect problems.

Fourth, the inventors have experimentally observed that the above-described optimal plunger sliding characteristics and low particle release characteristics in the stored solution in the cartridge remain substantially constant for long periods of time at or above room temperature storage, and that another important need in the pharmaceutical and cosmetic industries is met at low temperature storage.

Fifth, the inventors have experimentally observed that the above-mentioned average thickness uniformity characteristic of the coating can be obtained with high reproducibility in different production batches of medical devices, which is a very desirable characteristic in the pharmaceutical and cosmetic industries typical of mass production. Furthermore, although the coating is composed of a silicon material with high kinematic viscosity.

Another aspect of the invention relates to an apparatus for manufacturing a medical injection device as defined in claim 25, the medical injection device comprising a glass cylinder with a coated inner surface, the cylinder being configured to receive a plunger in sliding engagement.

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

a reservoir of coating composition, at least one heating element of the reservoir 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 respective heating elements of the dispensing heads being configured to heat the coating composition dispensed by the nozzle;

A circulation pump disposed upstream of the dispensing head;

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

wherein the at least one dispensing head and the support frame are movable relative to one another to insert/withdraw a nozzle of the at least one dispensing head into/from a respective one of the one or more cartridges.

A further aspect of the 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 coated on an inner surface thereof, the barrel being configured to receive a plunger in sliding engagement,

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

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

Wherein the lot average standard deviation SD is obtained by:

S_ni＝(Σ_p＝1,6S_pi)/6

S_nL＝(Σ_i＝1,10S_ni)/10

SD＝(Σ_i＝1,N SD_n)/N

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

Advantageously, the injection device described above achieves the advantageous technical features described above in relation to the method of manufacturing the same, as well as the advantageous technical features relating to the realisation of the coating on the inner surface of the cartridge.

A further aspect of the 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 cylinder coated on the inner surface, the cylinder configured to receive the plunger in sliding engagement,

A plunger configured to slidingly engage in the barrel,

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

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

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

A plunger configured to slidingly engage in the barrel,

Wherein the lot average standard deviation SD is obtained by:

S_ni＝(Σ_p＝1,6S_pi)/6

S_nL＝(Σ_i＝1,10S_ni)/10

SD＝(Σ_i＝1,N SD_n)/N

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

Advantageously, the kit of parts described above allows for storage, transportation and subsequent assembly of the injection device of the present disclosure in a sterile manner.

Definition of the definition

Within the scope of the present description and the claimed technical solutions, the term "Room Temperature (RT)" means a Temperature of 25 ℃ ± 2 ℃ measured at 60% relative humidity.

Within the scope of the present description and of the claims, all percentages specified are understood to be in weight percent.

Within the scope of the present description and of the claimed technical solutions, the term "Average Value" refers to the arithmetic mean of the values of the specific entities considered.

Within the scope of the present description and the claimed claims, all pressure values are understood to be relative pressure values. In other words, the pressure values noted herein do not include atmospheric pressure unless otherwise stated.

Within the scope of this specification and the claims, all numerical entities expressing quantities, parameters, percentages and the like are to be understood as being prefixed in any case by the term "about (about)", unless otherwise stated. In addition, unless 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 the present specification and the claimed technical solutions, the kinematic viscosity of polydimethylsiloxanes is measured by TGA and DSC thermogravimetric analysis techniques.

Thermogravimetric analysis (Thermogravimetry, TG) or thermogravimetric analysis (Thermogravimetric Analysis, TGA) is an experimental technique used to characterize a wider range of materials for thermal analysis. The technique involves continuously measuring the mass of a sample of material under controlled atmosphere conditions, either as a function of time (isothermal) or as a function of temperature (temperature rise/drop).

DSC techniques can determine what temperature or temperature range any transition (e.g., melting or crystallization process) occurs and quantitatively measure the energy associated therewith. DSC analysis actually determines the heat flow that occurs when a sample is heated/cooled under controlled (dynamic conditions) or kept at constant temperature (isothermal conditions).

By a combination of these two techniques, the thermal profile obtained can be correlated with a standard profile of silicone oils of known viscosity, thus determining the kinematic viscosity of the silicon material.

In this way, the kinematic viscosity of the silicon material can be determined using a calibration curve that can relate the viscosity value (related to the polymer chain length) to the thermal phenomena (weight loss) observed at different temperatures.

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

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

The thermal cycle followed by TGA analysis is: the temperature rise rate is 10 ℃/min from 30 ℃ to 500 ℃.

The DSC analysis followed the thermal cycle: the temperature rise rate is 10 ℃/min from-80 ℃ to 30 ℃.

Within the scope of the present description and the claimed technical solutions, the thickness of the coating applied to the inner surface of the barrel of the injection device is understood to be measured by an optical technique based on the impact analysis of the sample by the irradiation of emitted light (white light or laser light of a specific wavelength).

An optical reflectometer or the like detects the difference in reflected wavelengths of two beams, one beam being reflected from the barrel material (glass) of the injection device and the other beam being 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 630-680 nm collimated wavelength, the resolution can be increased to 20nm, in which case interferometric techniques can be used.

Within the scope of the present description and the claimed technical solutions, the average thickness S of the coating is in particular preferably obtained by:

(i) Measuring the coating thickness S _p at least 6 points of each arbitrary barrel portion n having a planar-spread axial length of 1.0 mm;

(ii) Calculating an average thickness S _n of each of the above n barrel portions, wherein S _n＝(Σ_p＝1,6S_p)/6;

(iii) The barrel coating average thickness S is calculated, where s= (Σ _n＝1,N S_n)/N, N is the total number of barrel portions N.

In general, within the scope of the present description and the claimed technical solutions, the term "standard deviation (Standard Deviation)" or "mean square error (Average Square Deviation)" for detecting an entity "x" (for example the thickness of a coating applied to the inner surface of a barrel of an injection device) in a population of N statistical units is defined as:

Wherein,

Is the arithmetic mean of the entity "x".

It is particularly preferred that 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) The standard deviation SD of the average thickness S _n of the n cylinder portions with respect to the average thickness S of the cylinder coating is calculated.

Within the scope of embodiments of the present invention, as described above, the average thickness of the coating applied to the inner surface of each of a predetermined number of cylinders (e.g., 10 cylinders) and the batch standard deviation of the coating may be obtained.

Within the scope of the examples of the present invention, "standard deviation SD of the batch average thickness of the coating" refers to the arithmetic mean of the standard deviation SD _n of the thickness obtained as above. As described above, this parameter indicates process reproducibility between different production batches.

Within the scope of the various embodiments of the present invention, the total number of N portions of the syringe barrel having a planar-deployment axial length of 1.0mm (denoted by N) varies with the size of the barrel itself.

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

Within the scope of the present specification and the claimed subject matter, a syringe is specified to have a nominal volume of 0.5mL, 1mL Long, or 3mL meeting standard ISO 11040-4 (2015).

Within the scope of the present description and of the claims, the term "axial" and the corresponding term "axial" (axially) are used to refer to the longitudinal direction of the medical injection device, corresponding to the longitudinal direction of its barrel, while the term "radial" and the corresponding term "radial" (radially) are used to refer to any direction perpendicular to the above-mentioned longitudinal direction.

Within the scope of the present description and the claims, the term "circumferential" and the corresponding term "circumferential" (circumferentially) are used to refer to the direction of extension of the inner surface of the barrel of a medical injection device in a plane perpendicular to the longitudinal direction of the barrel itself.

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

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

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

The manufacturing method thus provided can advantageously be carried out in a particularly simple and reproducible manner, minimizing or completely eliminating the problems associated with the difficulty of maintaining constant the rheological properties of the coating composition after mixing silicon materials of different densities and/or viscosities.

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

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

This advantageously always provides the amount of coating composition necessary for carrying out the process.

Preferably, the reservoir 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 ℃ to 150 ℃.

This advantageously optimizes the application of the heated coating composition to the interior surface of the barrel in subsequent step (c) to promote a very uniform coating on the interior surface.

In a preferred embodiment, step (b) heating the coating composition comprises heating the above-mentioned tank to bring the coating composition to said temperature of 100 ℃ to 150 ℃, preferably 120 ℃ to 150 ℃.

To this end, at least one heating element provided in the coating composition reservoir is configured to heat the stored coating composition.

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

By way of example only, the heating element may be a heating coil (and, for example, a resistor or conduit for internally circulating a suitable heating fluid) disposed within the tank or a sheath disposed outside the tank with one or more resistors or circulated with a suitable heating fluid.

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

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 interior surface of the cylinder to form a very uniform coating on the interior surface.

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

For the purposes of the present invention, the heating element of the 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 being integrated into a housing (e.g., a cylindrical housing) associated with the dispensing nozzle.

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

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

In a preferred embodiment, the respective heating element of the circulation pump is configured as a delivery head of the heating pump.

For the purposes of the present invention, the element of the 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.

For example only, the heating element may include one or more resistors in heat exchange relationship with the pump delivery head, such as integrated into a respective housing (e.g., a cylindrical housing) associated with the delivery head.

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

This advantageously allows for a very uniform application of the heated coating composition to the interior surface of the cylinder.

In a preferred embodiment, step (b) heating the coating composition comprises heating the dispensing head and/or the pump, preferably the pump delivery head, to bring or maintain the coating composition to said temperature of 100 ℃ to 150 ℃.

This advantageously reduces the power absorption and wear of the pump, thereby facilitating the operation 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 method of manufacture provides for heating the pump delivery head to a temperature of 50 ℃ to 60 ℃.

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

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

Preferably, the pipe is made of a temperature resistant material such as stainless steel to insulate or made of a heat-insulating metal or plastic.

The inventors have experimentally observed that by heating one or more of the reservoir, circulation pump, dispensing head and corresponding connecting tubing of the coating composition, the viscosity of the coating composition can be advantageously equalized before dispensing the coating composition onto the interior surface of the barrel, thereby advantageously reducing the dispensing time and making the distribution of the coating composition more uniform on the interior surface of the barrel.

In the context of the present preferred embodiment, step (b) heating the coating composition preferably comprises heating the above-described pipe so that the coating composition is at or maintains the above-described temperature of 100 ℃ to 150 ℃.

The inventors have experimentally observed that heating the coating composition to a temperature exceeding 150 ℃ may result in a change in the properties of the silicon material, which may lead to an increased undesirable release of particulates and/or release of substances that are normally retained at low temperatures.

In a preferred embodiment, step (c) of applying the heated coating composition to the interior surface of the barrel is performed by dispensing the heated coating composition at a pressure of from 5psi (0.34 bar) to 150psi (10.34 bar), preferably from 6psi (0.41 bar) to 10psi (0.69 bar).

In a preferred embodiment, step (c) of applying the heated coating composition to the interior surface of the can comprises: the dispensing head is fed with a gas (e.g., air) at a pressure of 5psi (0.34 bar) to 150psi (10.34 bar), preferably 6psi (0.41 bar) to 10psi (0.69 bar).

This advantageously allows the heated coating composition to be dispensed in a very uniform manner to apply Tu Tongdeng a uniform coating on the interior surface of the barrel.

In a preferred embodiment, the method includes maintaining the pressure of the coating composition reservoir above the pressure of the dispensing nozzle of the dispensing head.

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

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

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

This allows the nozzle of the dispensing head to be inserted into/removed from the 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 movable towards and away from the dispensing head so as to effect relative movement between the dispensing head and the cartridges.

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

Preferably, step (c) applying the heated coating composition to the interior surface of the cartridge comprises dispensing the coating composition through the nozzle of the dispensing head while moving the cartridge toward the corresponding dispensing head.

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

In a preferred embodiment, the heated coating composition is dispensed onto the interior surface of the barrel for a period of time ranging from 0.3 seconds to 1 second, preferably from 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 times of insertion and extraction of the dispensing head into the cartridge to less than about 3 seconds, which is considered to be compatible with the normal cycle time of an industrial line.

In this regard, the inventors have experimentally observed that the above-described dispensing times of the heated coating composition can be advantageously facilitated by performing one or more of the above-described steps to heat the reservoir, heat the dispensing head, heat the circulation pump upstream of the dispensing head or a component of the pump (e.g., preferably the pump delivery head), and heat the connecting tubing that ensures fluid communication between the reservoir, pump and dispensing head.

In a particularly preferred embodiment, the above-described dispensing time of the heated coating composition is advantageously facilitated by the step of performing the steps of heating the reservoir, pump, dispensing head and associated connecting piping.

As noted above, the inventors have in fact experimentally observed that this manner of operation allows for the coating composition to be dispensed onto the interior surface of the barrel after the viscosity of the coating composition has been equalized, thereby advantageously reducing the dispensing time and allowing for a more uniform distribution of the coating composition on the interior surface of the barrel.

In a preferred embodiment, step (c) applying the heated coating composition to the interior surface of the barrel comprises dispensing the heated coating composition at a flow rate of from 0.1. Mu.L/s to 5. Mu.L/s, preferably about equal to 0.5. Mu.L/s.

This advantageously allows a very thin coating to be applied to the inner surface of the cylinder.

In a preferred embodiment, step (c) applying the heated coating composition to the interior surface of the can comprises applying the heated coating composition to the interior surface of the can in an amount of from 0.2 μg/mm ² to 0.4 μg/mm ² per unit area.

Also in this case it is advantageously possible to apply a very thin coating on the inner surface of the cylinder.

In a preferred embodiment, step (c) applies the heated coating composition to the interior surface of the barrel such that the coating formed on the interior surface of the barrel has an average thickness of 100nm to 200nm as measured by optical reflection.

Advantageously, as mentioned above, this average thickness of the coating formed on the inner surface of the cylinder is fully satisfactory for the pharmaceutical and cosmetic industry, despite the fact that the coating is made of a silicon material of high kinematic viscosity.

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

In this way, a coating with optimal surface regularity can advantageously be obtained, so that visual inspection means of the medical injection device, in particular automated visual inspection means, are not misled.

In a preferred embodiment, the method of the invention enables the formation of a coating of very uniform thickness on the inner surface of the cylinder for each batch of 10 cylinders, the value of the batch average thickness standard deviation SD of the coating being equal to or less than 60nm, preferably equal to or less than 50nm, as defined above.

This advantageously allows to obtain a coating with optimal surface regularity on a batch of multiple cylinders in a highly reproducible manner, according to the requirements of large-scale industrial production.

In a preferred embodiment, the method for manufacturing a medical injection device of the present invention may further comprise: after step (c) applying the heated coating composition to the interior surface of the cylinder, step (f) subjecting the coating formed on the interior surface of the cylinder to a partial cross-linking treatment of the polydimethylsiloxane.

Preferably, the partial crosslinking treatment is performed by irradiation.

Preferably, the coating is irradiated by plasma irradiation, preferably by a stream of argon with a plasma torch at atmospheric pressure, preferably with an argon purity of more than 99% (e.g. 99.999%).

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

Advantageously, the inventors have found experimentally that a partial cross-linking treatment can be performed so that the lubricating properties of the coating are not affected.

For this purpose, in a preferred embodiment, the irradiation treatment time is from 0.2 seconds to 1 second, preferably from 0.2 to 0.6 seconds, more preferably from 0.2 to 0.5 seconds (inclusive), and even more preferably about equal to 0.3 seconds.

The inventors have found through experiments that, as detailed below, by limiting the irradiation time to this range of values, the resulting coating can advantageously possess optimal sliding properties (in terms of static friction and dynamic friction) of the plunger within the barrel of the injection device, while possessing optimal low particle release characteristics, both of which remain constant over a long period of time.

Advantageously, the partially crosslinked coating obtained according to this preferred embodiment still significantly reduces the problems associated with the possibility of false defects being false detected by visual inspection devices (particularly automated visual inspection devices) of medical injection devices due to its surface regularity.

Without being bound by any explanation theory, the inventors believe that the irradiation time in the above-mentioned value interval is favorable for coating consolidation, further reduces particle release, but does not significantly affect the surface regularity of the coating, nor cause significant changes in the average value of static friction and sliding friction of the plunger in the barrel.

In particular, the inventors have experimentally observed that according to a preferred embodiment of the present application, the release value of particles obtained by irradiation treatment is much lower than that of the coating using the non-crosslinked low-viscosity silicon material of the prior art, corresponding to the coating subjected to irradiation treatment.

Advantageously, as described in more detail below with reference to experiments made by the inventors, such low particle release characteristics remain substantially unchanged for a long period of time, either at room temperature or above, or at low temperature conditions, e.g. at temperatures in the range of-5 ℃ to-40 ℃.

This feature is particularly important in cases where medical injection devices (e.g., syringes) are subject to long-term storage and/or are filled with medicaments that require cryogenic storage.

Further, the inventors have found through experimentation that the irradiation time in the above-mentioned interval of values does not adversely affect the percentage of coating coverage of the inner surface of the cylinder, which on average remains at least about 90%, as described in more detail below.

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

This advantageously allows the silicon material droplets dispensed onto the inner surface of the barrel to coalesce with one another, achieving a percentage coverage of that surface of at least 90%.

In this regard, the inventors have observed that if the waiting time is less than 15 minutes, the percentage of coverage of the interior surface of the cartridge results in more unwanted interactions between the injectable pharmaceutical composition stored in the cartridge and the glass interior surface thereof.

The inventors have also shown that in the case of a substantial increase in production time, waiting times exceeding 20 minutes do not lead to a significant improvement.

In a preferred embodiment, the method of manufacturing of the present invention may further comprise: step (g) pretreats the interior surface of the barrel to improve adhesion of the coating to the interior surface prior to step (c) applying the heated coating composition to the interior surface of the barrel.

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

Preferably, the pretreatment is carried out by the following steps:

(g1) Atomizing a [ (bicycloheptene) ethyl ] trimethoxysilane isopropyl alcohol solution, preferably a 2.2wt.% solution, onto the inner surface of the cylinder, preferably by means of an ultrasonic static nozzle;

(g2) The treated barrel 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 pretreatment may be performed by:

(g 1') heating the cylinder to a predetermined temperature, preferably in an oven;

(g 2') atomizing a [ (bicycloheptene) ethyl ] trimethoxysilane isopropyl alcohol solution, preferably a 2.2wt.% 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 subsequent evaporation of the isopropanol in the atomized solution and providing sufficient thermal energy to form a chemical bond between the glass and the adhesion promoter layer.

Preferably, steps (g 2) and (g 1') heating the cylinder are carried out in an oven heated to a temperature preferably between 120 ℃ and 145 ℃, more preferably equal to about 140 ℃ for 14 to 25 minutes, preferably equal to about 20 minutes.

Preferably, the amount of [ (bicycloheptene) ethyl ] trimethoxysilane isopropyl alcohol solution sprayed onto the inner surface of the cylinder is 7 to 50. Mu.L, preferably 7 to 22. Mu.L.

In a preferred embodiment of the present invention, the average particle size of the particles released from the inner surface coating of the cartridge in the test solution after 3 months of storage at-40℃according to the USP 787 standard prescribed in the United states Pharmacopeia 2021 edition 44-NF39 is 10 μm or more or 25 μm or more, and the average value of the normalized particle concentration measured by the photo-resist method is 60% or less of the limit prescribed in the above standard.

In particular, for fine particles having an average particle diameter of 25 μm or more, the average value is 5% or less of the above standard specification limit.

In a preferred embodiment, the partially crosslinked coating on the inner surface of the cylinder releases particles having an average particle size of 10 μm or more or 25 μm or more in the test solution after storage for 3 months at a temperature of-40 ℃ according to the USP 787 standard specified in the USP 2021 edition 44-NF39, for example by irradiation treatment, preferably by plasma irradiation treatment, and the average value of the normalized particle concentration as determined by the photoresist method is 10% or less of the limit specified in the above standard.

In particular, for fine particles having an average particle diameter of 25 μm or more, the average value is 1% or less of the above standard specification limit.

These two preferred embodiments are particularly advantageous in the case of injectable pharmaceutical compositions comprising temperature sensitive active ingredients, for example so-called biotechnological drugs comprising recombinant protein or mRNA vaccines. In fact, these preferred embodiments enable a significant reduction in the amount of particulates released into the pharmaceutical composition stored in the barrel of a medical injection device even after such pharmaceutical composition has been stored for a desired low temperature and long period of time.

In a preferred embodiment, the partially crosslinked coating on the inner surface of the cylinder releases particles in the test solution having an average particle size of 10 μm or greater or 25 μm or greater after storage for 3 months at a temperature of +5 ℃, or +25 ℃, or +40 ℃ according to the U.S. USP 789 standard as specified in U.S. pharmacopoeia 2021 edition 44-NF39, for example by irradiation treatment, preferably by plasma irradiation treatment, and the average value of the normalized particle concentration determined by the photoresist method is equal to or lower than the limit specified by the standard.

The preferred embodiment described above is particularly advantageous in the case of injectable pharmaceutical compositions used in the ophthalmic field, where the U.S. standard USP 789 specifies very stringent limits, namely the maximum amount of tolerable microparticles in the pharmaceutical composition stored in the barrel of a medical injection device even after prolonged storage of such pharmaceutical composition at the required storage temperature.

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

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

In this way, a medical device, such as a syringe, is advantageously obtained ready for use, prefilled with a dose of an injectable pharmaceutical composition.

In a preferred embodiment of the medical injection device according to the invention, the coverage in each arbitrary barrel portion having a planar deployment axial length of 1.0mm, which corresponds to the total area of that portion, is equal to at least 90%, which coverage is defined as the ratio of the coating coverage area to the total measured area.

This can be advantageously achieved:

reducing the risk of undesirable contact between the stored injectate pharmaceutical composition in the barrel of the injection device and the glass inner surface of the barrel;

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

the optimal surface finish characteristics of the coating, such as significantly reducing problems associated with false defects that may be misdetected by visual inspection devices of medical injection devices.

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

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

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

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

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

In a preferred embodiment of the medical injection device of the present invention, an empty barrel of nominal volume 1mL is stored at-40 ℃ for 7 days for measuring the sliding friction of the plunger in the barrel, at least 30 measurements having an average value of 1.5N to 2.5N.

Advantageously, the average value of the static sliding friction force and the dynamic sliding friction force of the plunger in the barrel completely meets the requirements of pharmaceutical and cosmetic industries, and the static sliding friction force is generally 2N to 6N and the dynamic sliding friction force is generally 1N to 3N.

Preferably, the static sliding friction and the average value of the sliding friction of the plunger in the cylinder are measured by the following test method.

The plunger was mounted in an empty cylinder of nominal volume 1mL Long or 0.5mL, starting from zero pre-compression within 24 hours after its positioning, a constant sliding speed of 240mm/min was applied to the plunger for a cylinder of nominal volume 1mL Long, and a constant sliding speed of 100mm/min was applied to the plunger for a cylinder of nominal volume 0.5mL, suitable for maintaining the plunger in motion, and the static friction was measured first by a load cell, and then the dynamic friction during sliding of this plunger was measured.

For more details on this test method see the examples below.

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

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

In a preferred embodiment, the medical injection device of the present invention further comprises a plunger mounted in the barrel in sliding engagement with the barrel as described above with respect to the method of manufacture.

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

In a preferred embodiment, the injectable pharmaceutical composition comprises a drug and/or 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.

More preferably, the pharmaceutical 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.

In a preferred embodiment, the kit of parts for assembling the medical injection device of the present invention comprises any suitable preferred features of the medical device described above.

Drawings

Further features and advantages of the invention will become apparent from the following description of certain preferred embodiments of the invention, given by way of non-limiting example, with reference to the accompanying drawings.

In the figure:

fig. 1 shows a partial longitudinal section of a medical injection device, in particular a syringe, according to a preferred embodiment of the invention;

Fig. 2 shows a schematic block diagram of a medical injection device manufacturing apparatus according to a preferred embodiment of the present invention;

FIGS. 3 and 4 illustrate various graphs showing thickness curves of exemplary coatings applied to the interior surface of a barrel of a medical injection device having nominal volumes of 1mL and 3mL, respectively, when the barrel is axially deployed, in accordance with a preferred embodiment of the present invention;

FIGS. 5-10 illustrate various graphs showing that the thickness profile of an exemplary coating applied to the interior surface of a barrel of a medical injection device having a nominal volume of 0.5mL when the barrel is axially deployed, measured at room temperature (t 0) immediately after the coating is applied and cooled, and measured after 3 months of storage at room temperature (t 3), according to a preferred embodiment of the present invention and according to the prior art;

FIG. 11 shows the average value of static sliding friction of a plunger contained in an empty cylinder of nominal volume 1mL at various points in time according to some medical injection device examples according to the present invention;

FIG. 12 shows the average value of the sliding friction of a plunger contained in an empty cylinder of nominal volume 1mL at various points in time according to some medical injection device embodiments of the present invention according to the prior art;

FIG. 13 shows the average value of static sliding friction at various points in time for a plunger contained in a barrel filled with a test solution of dynamic viscosity 1 mPa.s, of nominal volume of 1mL, according to the invention and according to some examples of medical injection devices of the prior art;

FIG. 14 shows the average values of the sliding friction of a plunger contained in a barrel filled with a test solution of dynamic viscosity 1 mPa.s at various points in time, according to the invention and according to some examples of medical injection devices of the prior art, nominal volume 1 mL;

FIG. 15 shows the average value of static sliding friction force for a plunger contained in a cartridge filled with test solution, having a nominal volume of 1mL after 7 days of storage at different temperatures, in some examples of medical injection devices according to the present invention;

FIG. 16 shows the average value of the sliding friction of a plunger contained in a cartridge filled with a test solution, having a nominal volume of 1mL after 7 days of storage at different temperatures, in accordance with certain examples of medical injection devices according to the present invention and in accordance with the prior art;

FIG. 17 shows the average value of static sliding friction force for a plunger contained in a cartridge filled with test solution having a nominal volume of 1mL after storage at-40℃for 2 days and 7 days in some examples of medical injection devices according to the present invention and according to the prior art;

FIG. 18 shows the average value of the sliding friction of a plunger contained in a cartridge filled with a test solution, having a nominal volume of 1mL after storage at-40℃for 2 days and 7 days, in accordance with certain medical injection device examples according to the present invention and in accordance with the prior art;

FIG. 19 shows the average value of static sliding friction measured at various points in time at room temperature for a plunger mounted in an empty cylinder having a nominal volume of 0.5mL in certain medical injection device examples according to the present invention and according to the prior art;

FIG. 20 shows the average values of sliding friction measured at various points in time at room temperature for a plunger mounted in an empty cylinder having a nominal volume of 0.5mL in certain medical injection device examples according to the present invention and according to the prior art;

FIG. 21 shows the average value of static sliding friction at various points in time for a plunger contained in a cartridge filled with test solution using a storage temperature of-40℃, a nominal volume of 0.5mL, in some examples of medical injection devices according to the present invention;

FIG. 22 shows the average values of the sliding friction of a plunger contained in a cartridge filled with a test solution at various points in time using a storage temperature of-40℃, a nominal volume of 0.5mL, in some examples of medical injection devices according to the present invention;

FIG. 23 shows the average value of static sliding friction at various points in time for a plunger contained in a cartridge filled with test solution using a storage temperature of +5℃, a nominal volume of 0.5mL, in some examples of medical injection devices according to the present invention, according to the prior art;

FIG. 24 shows the average values of the sliding friction of a plunger contained in a cartridge filled with a test solution at various points in time using a storage temperature of +5℃, a nominal volume of 0.5mL, according to the present invention, in some examples of medical injection devices according to the prior art;

FIG. 25 shows the average value of static sliding friction at various points in time for a plunger contained in a cartridge filled with test solution using a storage temperature of +25℃, a nominal volume of 0.5mL, according to the present invention, in some examples of medical injection devices according to the prior art;

FIG. 26 shows the average values of the sliding friction of a plunger contained in a cartridge filled with a test solution at various points in time using a storage temperature of +25℃, a nominal volume of 0.5mL, according to the present invention, in some examples of medical injection devices according to the prior art;

FIG. 27 shows the average value of static sliding friction at various points in time for a plunger contained in a cartridge filled with test solution using a storage temperature of +40℃, a nominal volume of 0.5mL, in some examples of medical injection devices according to the present invention, according to the prior art;

FIG. 28 shows the average values of the sliding friction of a plunger contained in a cartridge filled with a test solution at various points in time using a storage temperature of +40℃, a nominal volume of 0.5mL, according to the present invention and in some examples of medical injection devices according to the prior art;

FIG. 29 summarizes the average value of static sliding friction of a plunger contained in a cartridge filled with a test solution, as shown in FIGS. 21-28, having a nominal volume of 0.5mL after three months of storage at different temperatures in certain medical injection device examples according to the present invention and according to the prior art;

FIG. 30 summarizes the average values of the sliding friction of a plunger contained in a cartridge filled with a test solution, as shown in FIGS. 21-28, having a nominal volume of 0.5mL after three months of storage at different temperatures in certain medical injection device examples according to the present invention and according to the prior art;

FIG. 31 shows normalized concentration values of microparticles having a particle size of 10 μm or greater measured at room temperature for a cartridge according to the present invention and according to the present invention in some examples of medical injection devices having a nominal fill volume of 3.0mL, filled with 3.3mL of test aqueous solution, subjected to automatic stirring (360℃rotation of the sample);

FIG. 32 shows normalized concentration values of microparticles having a particle size of 25 μm or greater measured at room temperature for a cartridge according to the present invention and according to the prior art with a nominal fill volume of 3.0mL, filled with 3.3mL of test aqueous solution, subjected to automatic stirring (360℃rotation of the sample);

FIGS. 33-35 show normalized concentration values of microparticles having a particle size of 10 μm or greater measured at three different temperatures at time 0 for a cartridge filled with 0.25mL of test aqueous solution having a nominal fill volume of 0.5mL after 6 months of storage in certain medical injection device examples according to the present invention and according to the prior art;

FIG. 36 shows normalized concentration values of microparticles measured by MFI test at different storage times at-40℃for a cartridge filled with 0.55mL of test aqueous solution and having a nominal fill volume of 1.0mL in certain examples of injection devices for medical use according to the present invention and according to the prior art;

FIGS. 37 and 38 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at a temperature of-40℃for a cartridge filled with 500. Mu.L of a test aqueous solution having a nominal filling capacity of 0.5mL according to the present invention and according to some examples of medical injection devices of the prior art;

FIGS. 39 and 40 show the particle release values measured by the MFI test for different storage times at-40℃for a cartridge filled with 500. Mu.L of test aqueous solution, according to the present invention, with a nominal filling capacity of 0.5mL in some examples of medical injection devices according to the prior art;

FIGS. 41 and 42 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at a temperature of +5℃fora cartridge filled with 500. Mu.L of a test aqueous solution having a nominal filling capacity of 0.5mL according to the present invention and according to some examples of medical injection devices of the prior art;

FIGS. 43 and 44 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at +5℃ temperature after plasma irradiation treatment of a coating layer in accordance with the present invention and in accordance with the prior art for a cylinder having a nominal fill volume of 0.5mL and filled with 500. Mu.L of test aqueous solution in some examples of medical injection devices;

FIGS. 45 and 46 show the particle release values measured by the MFI test for different storage times at +5℃, for a cartridge filled with 500. Mu.L of test aqueous solution, according to the present invention, with a nominal filling capacity of 0.5mL in some examples of medical injection devices according to the prior art;

FIGS. 47 and 48 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at a temperature of +25℃fora cartridge filled with 500. Mu.L of test aqueous solution having a nominal filling capacity of 0.5mL according to the present invention and according to some examples of medical injection devices of the prior art;

FIGS. 49 and 50 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at +25℃afterplasma irradiation treatment of a coating layer in accordance with the present invention and in accordance with the prior art for a cylinder having a nominal fill volume of 0.5mL and filled with 500. Mu.L of test aqueous solution in some examples of medical injection devices;

FIGS. 51 and 52 show the particle release values measured by the MFI test for different storage times at +25℃for a cartridge filled with 500. Mu.L of test aqueous solution, according to the present invention, with a nominal filling capacity of 0.5mL in some examples of medical injection devices according to the prior art;

FIGS. 53 and 54 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at a temperature of +40℃fora cartridge filled with 500. Mu.L of test aqueous solution having a nominal filling capacity of 0.5mL according to the present invention and according to some examples of medical injection devices of the prior art;

FIGS. 55 and 56 show normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more measured at a temperature of +40℃afterplasma irradiation treatment of a coating layer of a cylinder filled with 500. Mu.L of a test aqueous solution having a nominal filling capacity of 0.5mL according to the present invention and some examples of medical injection devices according to the prior art;

FIGS. 57 and 58 show the particle release values measured by the MFI test for different storage times at +40℃for a cartridge filled with 500. Mu.L of test aqueous solution, according to the present invention and according to the prior art, with a nominal filling capacity of 0.5mL in some examples of medical injection devices;

FIGS. 59 and 60 summarize normalized concentration values of microparticles having a nominal fill volume of 0.5mL, a 500. Mu.L test aqueous solution filled cylinder having a particle size of 10 μm or more and 25 μm or more after plasma irradiation treatment of the coating layer, according to the present invention and in some examples of medical injection devices according to the prior art, after three months of storage at different temperatures;

Fig. 61 to 67 show a plurality of pictures taken by means of an optical microscope after partial crosslinking of a silicon material coating according to the invention by means of plasma irradiation in different irradiation times and different areas of a medical injector cylinder.

Detailed Description

In fig. 1, a medical injection device, in particular a syringe, according to a preferred embodiment of the invention is generally indicated by reference numeral 1.

The term "Syringe" as used herein is used in a broad sense to include cartridges, "injection 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-contained injectors, which provide a mechanism for dispensing the contents.

The syringe 1 comprises a glass syringe barrel 2 having a substantially cylindrical body 2a, the body 2a being 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 further configured to receive a plunger 5 in sliding engagement.

The plunger 5 is associated with one end of a drive rod 6 in a manner conventional per se.

In the preferred embodiment shown in fig. 1, the syringe 1 further comprises an injection liquid 7, such as a liquid pharmaceutical composition, in the barrel 2 in contact with its inner surface 3.

The syringe 1 is also provided with a cap 8 at the end 2b of the barrel 2 to allow the delivery of the injection liquid 7 in a safe condition.

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

The coating 4 of the syringe 1 shown in fig. 1 includes one or more features described in the above summary and referenced herein.

In a preferred embodiment, the syringe 1 may be manufactured by means of a device 10 schematically shown in fig. 2.

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

For example, the heating element of the tank 11 may be a resistor or a pipe (placed inside the tank 11 itself) circulating a suitable heating fluid or may also be an outer jacket of the tank 11 circulating a suitable heating fluid.

The reservoir 11 is in fluid communication with a circulation pump 12 of the coating composition through a conduit 13, the conduit 13 preferably being made of stainless steel, suitably insulated in a manner known per se.

In a preferred embodiment, the respective heating elements (not explicitly shown in fig. 2) of the pump 12 are configured as delivery heads (also not shown) of the heat pump 12.

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

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

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

The respective heating elements (also not explicitly shown in fig. 2) provided by the dispensing head 14 are configured to heat the coating composition dispensed by the nozzle.

In the preferred embodiment of the apparatus 10, the reservoir 11, pump 12 and 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 a corresponding heating element (e.g. resistor) or conduit (in which a suitable heating fluid is circulated) jacket.

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

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

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

The dispensing head 14 of the coating composition and the support frame of the barrel 2 of the syringe 1 are movable relative to each other to insert/withdraw each nozzle of the dispensing head 14 into/from a respective 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 of manufacturing a medical injection device, such as the injector 1 described above, comprises performing the following steps, preferably by means of the apparatus 10 shown in fig. 2.

In a first step, a polydimethylsiloxane-containing coating composition, such as a medical fluid (DuPont) containing about 100wt.% polydimethylsiloxane Liveo ^TM, is provided having a nominal kinematic viscosity at room temperature of about 12500cSt (125 cm ²/s).

Preferably, this 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 ℃ to 150 ℃, for example a temperature approximately equal to 120 ℃, by a heating element associated with the tank 11.

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

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

As described above, the heated coating composition is dispensed onto the inner surface 3 of the barrel 2 for a time of from 0.3 seconds to 1 second, preferably from 0.4 seconds to 0.7 seconds.

The above method comprises heating the dispensing head 14, preferably also the delivery head of the heat pump 12 and the pipes 13 and 15, so that the coating composition is maintained at a temperature of, for example, 100 ℃ to 150 ℃ as described above, for example, about 120 ℃ during the nozzle from the reservoir 11 to the dispensing head 14, at which temperature the dispensing head 14 dispenses the coating composition.

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

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

Preferably, the pressure of the reservoir 11 of the coating composition 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 transmitting relative movement 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 onto the inner surface 3 of the barrel 2 during relative movement of the dispensing head 14 into the barrel 2.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the barrel 2 comprises dispensing the heated coating composition at a flow rate of from 0.1 to 5. Mu.L/s, for example about 0.5. Mu.L/s.

Preferably, the step of applying the heated coating composition to the inner surface 3 of the barrel 2 comprises applying the heated coating composition to the inner surface 3 in an amount of from 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 such that the coating 4 formed on the inner surface 3 has an average thickness of 100nm to 250nm, preferably 100nm to 200nm, as measured by optical reflection.

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

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

If necessary, after the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2, a further step of subjecting the coating layer 4 formed on the inner surface 3 of the cylinder 2 to a polydimethylsiloxane partial crosslinking treatment, for example, a partial crosslinking treatment by irradiation of argon gas stream at atmospheric pressure by a plasma torch, may be carried out.

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

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

If desired, a further step of pre-treating the inner surface 3 of the cylinder 2 to improve the adhesion of the coating 4 to the inner surface 2 may be performed prior to the step of applying the heated coating composition to the inner surface 3 of the cylinder 2.

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

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 it is desired to manufacture the prefilled syringe 1 shown in fig. 1, a further step of associating a cap 8 to the end 2b of the barrel 2 may be performed in order to seal the contents of the syringe 1.

Exemplary and non-limiting technical objects of the present invention are described below by way of certain embodiments of the present invention.

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

Syringe with nominal filling level of 0.5mL

Total travel of each dispensing head 14 within each cartridge 2: maximum 75 mm

Speed of the dispensing head 14: 35mm/s

Total cycle time (insertion/dispensing time + withdrawal time of the dispensing head 14): 2.1 seconds

Dispensing flow rate of heated coating composition: 0.30 mu L/s

Volume of the dispensed coating composition: 0.30 mu L

Dispensing time of heated coating composition: 1 second.

1ML syringe with nominal filling quantity

Total travel of each dispensing head 14 within each cartridge 2: maximum 80mm

Speed of the dispensing head 14: 52mm/s

Total cycle time (insertion/dispensing time + withdrawal time of the dispensing head 14): 1.5 seconds

Dispensing flow rate of heated coating composition: 0.63 mu L/s

Volume of the dispensed coating composition: 0.63 mu L

Dispensing duration of heated coating composition: 1 second.

Examples 1 to 2 (invention)

Medical injector cartridge manufacture and thickness and uniformity evaluation of the coating formed on the inner surface of the cartridge-nominal filling capacity of the syringe is 1mL or 3mL

By the above method and apparatus, a coating composition consisting of PDMS Liveo ^TM medical fluid (DuPont) heated to about 120deg.C and having a nominal kinematic viscosity of about 12500cSt (125 cm ²/s) at room temperature is applied to the interior surface of a syringe barrel having a nominal fill volume of 1mL (example 1) or 3mL (example 2).

The reservoir was maintained at 120 c and the pump delivery head was maintained at about 50c and the nozzle of the dispensing head was maintained at about 120 c.

The amount of silicone oil deposited was about 0.2. Mu.g/mm ².

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

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

Figures 3 and 4 report graphs of measurements illustrating the thickness distribution of the coating applied to the inner surface of syringe barrels having nominal fill capacities of 1mL and 3mL, respectively.

From the above figures, it can be seen that the surface coating on the inside of the cylinder exhibits a pronounced surface regularity, with a standard deviation of thickness of less than 30nm in a syringe having a nominal volume of 3mL (fig. 4), and a standard deviation of thickness of less than 20nm in a syringe having a nominal volume of 1mL (fig. 3).

Both syringes did not cause any evaluation errors when visual (possibly automated) inspection tests were performed.

Examples A to G

The invention injector and control injector manufacturing process

By the above method and apparatus, a heated coating composition consisting of PDMS Liveo ^TM medical liquid (dupont) having a nominal kinematic viscosity of about 12500cSt (125 cm ²/s) at room temperature was applied to the interior surface of syringe barrels having nominal fill volumes of 1mL (example a, example B, example C, example D) and 3mL (example E, example F, example G).

A coating composition consisting of PDMS Liveo ^TM medical fluid (dupont) having a nominal kinematic viscosity of about 1000cSt (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 1 below reports the temperatures of the reservoir, pump delivery head and dispense head nozzles and the amount of silicone oil deposited.

In some cases, the resulting coating is irradiated by a plasma torch at atmospheric pressure for a variable irradiation time and under the following conditions to accomplish partial crosslinking:

Maximum power output: 100W

The gas is used: argon purity is over 99%

Argon flow rate 7SLM

The syringe barrel manufacturing parameters are reported in table 1 below.

TABLE 1

* Comparative example =

Rt=room temperature

Silicon materials with nominal kinematic viscosity of 12500cSt (125 cm ²/s): PDMS Liveo ^TM medical fluid (DuPont)

Control nominal kinematic viscosity of 1000cSt (10 cm ²/s) silicon: PDMS Liveo ^TM 360 medical fluid 1000cSt.

The following parameters were determined:

-the average thickness S of the applied coating and the corresponding standard deviation (t 0) measured after deposition and after cooling of the coating;

coating batch average thickness standard deviation SD for a batch of 10 syringes.

The results obtained are reported in table 2 below:

TABLE 2

* Comparative example =

The pretreatment of the inner surface of the syringe barrel, if any, is carried out as follows:

(g1) Atomizing a 2.2wt.% [ (bicycloheptene) ethyl ] trimethoxysilane isopropyl alcohol solution onto the inner surface of the cylinder by means of an ultrasonic static nozzle in an amount of 5 to 80 μl depending on the cylinder size;

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

As can be seen from the data in table 2 above, in the injector of the present invention, the average thickness S of the coating remained always below the value of 180nm, with standard deviation of thickness equal to or less than 70nm, confirming extremely high deposition regularity.

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

The syringes so fabricated 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.

Examples H to O

The invention injector and control injector manufacturing process

By the above method and apparatus, a coating composition consisting of PDMS Liveo ^TM medical fluid (DuPont) heated to about 120deg.C and having a nominal kinematic viscosity of about 12500cSt (125 cm ²/s) at room temperature is applied to the interior surface of a syringe barrel having a nominal fill volume of 0.5 mL.

A control coating composition consisting of PDMS Liveo ^TM medical liquid (dupont) having a nominal kinematic viscosity of about 1000cSt (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 nozzles and the amount of silicone oil deposited.

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

In some cases, the resulting coating is partially crosslinked by irradiation with a plasma torch at atmospheric pressure under variable irradiation times and conditions as mentioned in examples a to G.

The syringe barrel manufacturing parameters are reported in table 3 below.

TABLE 3 Table 3

* Comparative example =

Rt=room temperature

After deposition and cooling of the layers (t 0) and after 3 months of storage at room temperature (t 3), the following parameters of examples H, I, K (invention) and M, N, O (control) were determined:

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

The results obtained are reported in table 4 below:

TABLE 4 Table 4

* Comparative example =

Furthermore, it was experimentally observed that the standard deviation of the maximum batch thickness of the applied coatings of examples H, I, K (invention) remained always at a value of less than 70 nm.

The pretreatment of the inner surface of the syringe barrel, if any, was carried out in the same manner as described above for examples a to G.

Evaluation of coating thickness

Fig. 5-10 report graphs of measurements illustrating the thickness profile of a coating applied to the inner surface of a syringe barrel having a nominal fill volume of 0.5mL (t 0) after deposition and cooling to room temperature and the thickness profile after 3 months of storage at room temperature (t 3).

As can be seen from the data in table 4 above and the figures above, in the injector of the present invention, the coating on the inner surface of the barrel has a low average thickness and exhibits significant surface regularity.

In fact, the average thickness of the coating remains always below the value of 230nm, the standard deviation of the thickness is less than 50nm, confirming that the regularity of the thickness of the coating is extremely high.

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

The high reproducibility of the manufacturing method of the medical injection device of the invention was also demonstrated for values of the standard deviation SD of the coating batch average thickness calculated for a batch of 10 syringes less than 50 nm.

The injector of the present invention does not cause any evaluation errors during the automatic visual inspection test.

Average value evaluation of static and dynamic sliding friction force of room temperature storage air injector

A series of control tests were performed on the syringes of examples a and B (invention) and examples C and D (control) to evaluate the average static and dynamic sliding friction on the empty cartridge.

The nominal fill volume of all syringes was 1.0mL and friction was measured at zero time at room temperature and after 6 months of storage at room temperature.

The friction was measured using a ZwickiLine Z2.5.2 (Zwick Roell) load cell as follows.

Placing the syringe on the appropriate dynamometer support

Reset load cell side force (not pressed)

Setting constant-speed deformation at 240mm/min, pre-pressing at 0.5N and final preset force at 30N

Start test (30 samples/use case) and perform force measurement

By analyzing the curve generated by the load cell, the static friction force is determined as the force corresponding to the first initial peak value, and the dynamic friction force is determined as the average value of the interval values between the first initial peak value and the end point peak value.

The average of static and dynamic friction measured for 30 syringe batches is reported in fig. 11 and 12, respectively.

From the above figures, it can be seen that the barrel coating of the injector of the present invention (examples a and B) was subjected to the mean values of static and dynamic friction at different irradiation times was perfectly acceptable and within the previously indicated limits required by the pharmaceutical and cosmetic industries (static sliding friction 6N, dynamic sliding friction 3N).

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

Static and dynamic sliding friction force average value evaluation of prefilled syringe stored at room temperature-nominal filling amount of empty syringe is 1mLLong

A further series of control tests were performed on the syringes of examples a and B (invention) and examples C and D (control) to evaluate the average static and dynamic sliding friction on the cylinder of a nominal fill volume of 1.0mL, filled with test aqueous solutions (injectables) containing water and glycerol (glycerol volume fraction of 0.02% vol to 0.04% vol), simulating a dynamic viscosity of 1mPas (1 cP).

Tests were performed under the same conditions as for the empty syringes, giving the average of static and dynamic friction for the 30 syringe batches reported in fig. 13 and 14, respectively.

Also in this case, the barrel coating of the injector of the present invention (examples a and B) was still acceptable in terms of the average value of static friction and dynamic friction over various irradiation times (static sliding friction was 6N and dynamic sliding friction was 3N).

Also in this case it was found that the maximum acceptable irradiation time of the barrel coating was about 1 second.

Static and dynamic sliding friction force average value evaluation of prefilled syringe after 7 days of storage at different temperatures, namely 1mLLong of nominal filling quantity of the syringe

The syringes of examples E and F (invention) and example D (control) were subjected to a series of control tests to evaluate the average static and dynamic sliding friction on a cylinder with a nominal fill volume of 1.0mL and filled with 0.55mL of an aqueous test solution (injectate) containing the following components:

Tromethamine 0.34mg

Tromethamine hydrochloride 1.30mg

Acetic acid 0.047mg

Sodium acetate 0.132mg

Sucrose 47.85mg

Water for injection formulation equilibrated to 0.55mL

After a storage time of 7 days, the friction is measured as described above at Room Temperature (RT) and at temperatures of-20℃and-40 ℃.

The average of static and dynamic friction measured for 30 syringe batches is reported in fig. 15 and 16, respectively.

From the above figures, it can be seen that the average values of the static and dynamic friction of the syringes of the present invention (examples E and F) were comparable to those of the control syringe provided with a known type of coating (example D) with a nominal kinematic viscosity of about 1000cSt, with the barrel coating either not irradiated (example E) or irradiated for 0.3 seconds (example F).

Furthermore, the average value of the static friction and the dynamic friction of the syringes of the present invention (examples E and F) falls well within the previously indicated limits required by the pharmaceutical and cosmetic industries (static sliding friction 6N, dynamic sliding friction 3N).

Average static and dynamic sliding friction force evaluation of prefilled syringe after storage at-40 ℃ for 2 days and 7 days-nominal filling amount of syringe of 1mLLong

A further series of control tests were performed on the syringes of examples E and F (invention) and example D (control) to evaluate the average of static and dynamic sliding friction on a cylinder with a nominal fill volume of 1.0mL and filled with 0.55mL of an aqueous test solution (injectate) containing the following components:

Tromethamine 0.34mg

Tromethamine hydrochloride 1.30mg

Acetic acid 0.047mg

Sodium acetate 0.132mg

Sucrose 47.85mg

Water for injection formulation equilibrated to 0.55mL

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

The average of static and dynamic friction measured for 30 syringe batches is reported in fig. 17 and 18, respectively.

Furthermore, the average value of the static friction and the dynamic friction of the syringes of the present invention (examples E and F) was substantially stable, falling entirely within the previously indicated limits required by the pharmaceutical and cosmetic industries (static sliding friction of 6N and dynamic sliding friction of 3N).

Average static and dynamic sliding friction force evaluation of empty syringe stored at room temperature-nominal filling amount of empty syringe is 0.5mLLong

A series of control tests were performed on the syringes of examples H, I, J, K, L (invention) and examples M, N, O (control) to evaluate the average static and dynamic sliding friction on the empty cylinder.

All syringes were rated for 0.5mL and friction was measured at zero time at room temperature and after 1 and 3 months of storage at room temperature.

The friction was measured using ZwickiLine Z2.5.2 (Zwick Roell) load cell as follows.

Placing the syringe on the appropriate dynamometer support

Reset load cell side force (not pressed)

Setting a constant-speed deformation of 100mm/min, setting an end-point preset force of 30N without pre-pressing

Start test (30 samples/use case) and perform force measurement

The average of static and dynamic friction measured for 30 syringe batches is reported in fig. 19 and 20, respectively.

As can be seen from the above figures, the mean values of static and dynamic friction of the inventive syringes (example H, example I, example J, example K, example L) are fully acceptable and within the previously specified limits of the pharmaceutical and cosmetic industry (static sliding friction of 6N, dynamic sliding friction of 3N), wherein the barrel coating was not irradiated (example H) or subjected to different irradiation times (example I, example J, example K, example L).

Static and dynamic sliding friction force average value evaluation of prefilled syringe stored at-40 ℃, +5 ℃, +25 ℃ and +40 ℃ temperature-syringe nominal filling capacity of 0.5mL

A further series of control tests were performed on the syringes of examples H, I, J, K, L (invention) and M, N, O (control) to evaluate the average static and dynamic sliding friction on a cylinder with a nominal fill volume of 0.5mL and filled with 500 μl of test aqueous solution (injectate) having the following composition:

Sodium phosphate 10mM

Sodium chloride 40mM

Polysorbate 200.03% (v/v)

Sucrose 5% (w/v)

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

As described above, after the coating was deposited and cooled (t 0) and after storage for 1 month (t 1) and 3 months (t 3) at temperatures of-40 ℃, +5 ℃, +25 ℃, +40 ℃.

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

From the above figures, it can be seen that the mean values of the static and dynamic friction of the inventive syringes (example H, example I, example J, example K, example L) are comparable to those of the control syringes (example M, example N, example O) provided with a coating of known type (silicon material with nominal kinematic viscosity of about 1000 cSt), in which the barrel coating was not irradiated (example H) or was subjected to irradiation for a period of 0.3 seconds or 0.5 seconds (example K, example I, example J, example L).

Furthermore, the average value of the static friction force and the dynamic friction force of the syringe of the present invention (example H, example I, example J, example K, example L) was substantially stable, and falls completely within the limit values required by the pharmaceutical and cosmetic industry company as indicated previously (static sliding friction force is 6N, dynamic sliding friction force is 3N).

The average values of static and dynamic friction after the plungers of the syringes according to the present invention and according to the prior art were stored at the above-described temperatures of-40 ℃, +5 ℃, +25 ℃, +40 ℃ for three months are further reported by the controls in fig. 29 and 30.

As can be seen from the above figures, the average values of the static and dynamic friction of the syringes according to the invention (examples H, I, J, K, L) after three months of storage at different temperatures are comparable to those of the control syringes provided with the known type of coating (examples M, N, O), falling completely within the limits indicated previously for the pharmaceutical and cosmetic industry (static and dynamic friction of 6N, dynamic and sliding friction of 3N).

Pre-filled syringe particle release evaluation at room temperature

A series of control tests were performed on the syringes of example E (invention) and examples C and G (control) to evaluate the release of particulates in the aqueous test solutions (injectables).

All syringes were rated for 3.0mL and filled with 3.3mL of test aqueous solution (injectate) containing the following ingredients:

Sodium phosphate 10mM (adjusted to pH 7.0 using phosphoric acid)

Sodium chloride 0.9% (w/v)

Polysorbate 800.02% (w/v)

Water for injection formulation equilibrated to 3.3mL

Microparticle analysis test sample preparation

Filling the syringe barrel with the test solution and closing the barrel with the plunger

Store (if testing is envisaged)

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

Dispense test aqueous solution from syringe barrel: operated automatically by dynamometers

The test liquid is collected in a special container.

The aliquot of sample solution (pool) is at least 6 milliliters in volume for performing the microparticle analysis (e.g., 2 syringes filled with 3.30mL, then 1 pool = 1 microparticle analysis sample for use).

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

Test solution release microparticle analysis-examples A-G

Photoresist method (Light Obscuration, LO)

The test solution pool obtained above was analyzed by a light blocking device (KL 04A, RION) to determine the particle size and count of sub-visible particles.

The apparatus counts particles in an analytical solution according to USP standards (787-788-789) specified in United states Pharmacopeia 44-NF39 (2021).

In particular, the solution is aspirated from the instrument through a special needle and passed through a laser light source. Particles in the solution cause blocking of the laser beam, thereby generating a signal to be sent to the sensor; the amount of light that is blocked determines the particle size of the particles.

The particle size range measurable by the instrument is 1.3 μm to 100 μm.

Fig. 31 and 32 list normalized concentration values of microparticles having a particle size of 10 μm or more and 25 μm or more, respectively, measured immediately after rotating the syringe at room temperature, both values being obtained from 15 measuring cells starting from 30 syringes.

As can be seen from the above figures, the inventive syringes (example E) with the barrel coating not irradiated exhibited improved particle release behavior relative to the control syringes (examples C and G) with the barrel coating not irradiated for 0.3 seconds (control example C) or not irradiated (control example G), respectively.

Prefilled syringes were evaluated for release of particulates (stored and not stored) at different temperatures

A series of control tests were performed on the syringes of example a (invention) and example C (control) to evaluate the release of particulates in the aqueous test solutions (injectate).

All syringes were nominally 0.5mL filled with 0.25mL of test aqueous solution (injectate) containing the following ingredients:

Sodium phosphate 10mM

Sodium chloride 40mM

Polysorbate 200.03% (w/v)

Sucrose 5% (w/v)

Preparation of microparticle analysis samples

Store. Store

Tumbling the syringe by a multi-rack stirrer at 30rpm (i.e., rotating about an axis perpendicular to the longitudinal axis of the barrel) for 3 hours

Dispense test aqueous solution from syringe barrel: manual operation under laminar flow hood

Test solution release microparticle analysis

Photoresist (LightObscuration, LO)

Fig. 33, 34 and 35 report the normalized values of the particle concentration of 10 μm or more measured at time zero after 6 months of storage at 5±3 ℃, 25 ℃/60%rh and 40 ℃/75%rh temperatures after preparation from 12 pools (two by two solutions manually dispensed from 24 syringes in total in preparation).

From the above figures, it can be seen that the inventive syringe (example a) having a barrel coating subjected to irradiation for 0.3 seconds exhibited significantly improved particle release behavior relative to the control syringe (control example C) having a barrel coating also subjected to irradiation for 0.3 seconds.

The microparticle release values shown in fig. 33-35 also demonstrate that the inventive syringes exhibit improved release stability over time after storage at different temperatures compared to the control syringes.

Particle release evaluation on prefilled syringe for cryogenic storage

A series of control tests were performed on the syringes of example E (invention) and example D (control) to evaluate the release of particulates in the aqueous test solutions (injectate).

All syringes were rated for 1.0mL and filled with 0.55mL of an aqueous solution containing the following ingredients (test injectate):

Tromethamine 0.34mg

Tromethamine hydrochloride 1.30mg

Acetic acid 0.047mg

Sodium acetate 0.132mg

Sucrose 47.85mg

Water for injection formulation equilibrated to 0.55mL

Preparation of microparticle analysis samples

Store. Store

The release of particulates from the test solutions was measured by the following method.

Test solution release microparticle analysis

Microfluidic imaging (Micro Flow Imaging, MFI)

The morphology of the particles in the solution was evaluated by analyzing 1mL per cell obtained as described above using a Flow Imaging analyzer (MFI ^TM Micro-Flow Imaging, MFI 5200, proteinSimple), thanks to the fact that the optical system of the instrument is able to distinguish between different types of particles (silicon particles and non-silicon particles) based on certain parameters like circularity and light intensity.

The specific parameters for distinguishing the silicon particles are as follows:

aspect ratio > 0.83 (i.e. ratio of small to large axial length of the same second moment particle ellipse);

intensity STD+.185 (i.e., standard intensity difference for all pixels representing particles);

ECDs 10-25 μm and 25-100 μm (i.e. diameter of equal area circles of particles).

The instrument can measure particle sizes ranging from 2 μm to 70 μm, and exhibits good resolution for particle images with particle sizes greater than 10 μm.

FIG. 36 reports normalized concentration values of microparticles of 5 μm to 70 μm in particle size obtained from 15 cells (two-by-two groups of solutions dispensed from a total of 30 syringe load cells in preparation) measured after 2 days and 7 days of storage at-40 ℃.

From the above figures, it can be seen that the inventive syringe with a non-irradiated barrel coating (example E) exhibited a comparable improvement (after 2 days of storage) or a significant improvement (after 7 days of storage) in particle release behavior relative to the control syringe with the same barrel coating not irradiated (example D).

The microparticle release values shown in fig. 36 also demonstrate that the inventive syringes exhibit improved release stability over time after low temperature storage compared to the control syringes.

Evaluation of particle release on prefilled syringes stored at different temperatures-nominal fill volume of syringe was 0.5 mL-examples H to O

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

All syringes were nominally 0.5mL filled with 500 μl of test aqueous solutions (injectables) containing the following ingredients:

Sodium phosphate 10mM

Sodium chloride 40mM

Polysorbate 200.03% (v/v)

Sucrose 5% (w/v)

Preparation of microparticle analysis samples

Filling the syringe barrel with the test solution and closing the barrel with a plunger (plunger 4023/50Gray Flurotec, westar)

Storage at different temperatures

ο5℃±3℃

ο25℃/60％RH

ο40℃/75％RH

ο-40℃

For syringes stored at-40 ℃, the solution was redistributed after thawing one hour at room temperature without inversion. The purpose of this is to simulate the actual use of the product that is normally stored at that temperature, i.e. an extremely temperature sensitive biotechnological drug.

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

Dispense test aqueous solution from syringe barrel: manual operation under laminar flow hood, solutions of a total of 12 syringes were grouped

Test solution release microparticle analysis

Photoresist (LightObscuration, LO)

Each of the 10 pools was analyzed for 5mL (12 syringes in preparation for manual dispensing solutions) by a particle count analysis apparatus (Light Obscuration particle counter KL-04A, produced by rionco, ltd.).

The apparatus allows operation according to USP <787>, <788>, <789> as specified in the united states pharmacopeia 44-NF39 (2021) and ph.eur.2.9.19 (10 th edition, 2021), for sub-visible particle count analysis of parenteral solutions.

The particle size of the particles analyzed depends on the amount of laser light from the light source that is blocked by the particles themselves as they pass through the laser beam, thereby creating a voltage change that is detected by the sensor.

The apparatus can analyze particles ranging in size from 1.3 μm to 100 μm.

The normalized concentration values of particles having a particle size of 10 μm or more and 25 μm or more measured at zero time after storage for 1 month and 3 months at-40 ℃,5±3 ℃, 25 ℃/60%rh, 40 ℃/75%rh temperature after preparation from 10 cells are reported in fig. 37, 38, 41 to 44, 47 to 50, 53 to 56, and 59 to 60.

From the above figures, it can be seen that the inventive syringes (examples H, I, J, K, L) exhibited significantly improved performance in terms of particle release behavior relative to the control syringes (examples M, N, O) at all times of detection (t 0, t1 and t 3) and at all storage temperatures, particularly with storage temperatures of-40 ℃, as clearly shown in fig. 37 and 38.

In particular, as shown in the above figures, by comparing the inventive syringe with prior art syringes under the same process conditions, i.e., with or without plasma treatment and with or without pretreatment to improve the adhesion of the coating to the inner surface of the syringe barrel, it was found experimentally that:

In the case of a coating which has not been plasma treated and a syringe which has not been subjected to an adhesion pretreatment, the particle release is reduced by about 70% (examples H and M);

In the case of a coating with plasma treatment for 0.3 seconds and a syringe without adhesive pretreatment, the particle release is reduced by about 86% (examples I and N);

In the case of a plasma treatment of the coating for 0.3 seconds and an adhesion pretreatment of the syringe, the particle release was reduced by approximately 90% (example K and example O).

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

In contrast, for particles having a particle size of 25 μm or greater, all of the inventive coated syringes subjected to plasma treatment, with or without pretreatment (example I, example J, example K, example L), met the particle release requirements of USP 789 standard at all test temperatures and storage times, whereas prior art syringes only exhibited such results in some cases (example N, example O). In particular, after 3 months of storage time, the syringe of control N met the particulate release requirements of standard USP 789 only at storage temperatures of 5 ℃ and 40 ℃, while the syringe of control O did not meet the particulate release requirements of standard USP 789 at any storage temperature (see fig. 42, 44, 48, 50, 54, 56 and 60).

Microfluidic imaging (Micro Flow Imaging, MFI)

The particle morphology in the solution was evaluated using a Flow Imaging device (MFI ^TM Micro-Flow Imaging, MFI 5200, protein simple) analysis of 1mL per cell obtained for a 0.5mL syringe as described above.

Figures 45 to 46, 51 to 52 and 57 to 58 report the percentage concentration of particles of particle size 10 μm to 25 μm measured at time zero (calculated as in the examples) after storage for 1 month and 3 months at-40 ℃, +5±3 ℃, +25 ℃/60%rh, +40 ℃/75%rh temperatures from 10 samples (1 mL of solution from each cell prepared as described above).

From the above figures, it can be seen that the syringes of the present invention (examples H, I, J, K, L) significantly reduced the release of silicon particles at all temperatures and all test times (t 0, t1, and t 3) compared to the control syringes (examples M, N, O).

Evaluation of morphology characteristics of coating on inner surface of hollow syringe barrel

In order to evaluate the possible effect of the coating obtained according to the invention and according to the prior art on the morphology of the coating at different irradiation times, several images were acquired by means of an optical microscope.

Generally, the more uniform the coating surface or finer the particle size, the better the appearance from a morphology perspective, so the less misleading the automatic optical detection system to the surface, the less misinformation problem due to the irregular coating surface.

In this regard, as noted above, the inventors have observed that the extent of irradiation time-dependent partial crosslinking in, for example, plasma processing is critical in that streaks and detachment thereof can be erroneously "read" by an automated optical detection system as impurities present in the medical injector cartridge storage solution.

The inventors have observed that these fringes and breaks tend to first appear in the region of the tapered portion of the syringe barrel (closest to the tail end of the needle) and then propagate towards the cylindrical portion.

FIG. 61 reports images showing the effect of irradiation of the coating obtained in inventive example B for a threshold time exceeding 1 second.

From the above figures, it can be seen that the non-uniformities extend a few millimeters, corresponding to grooves or reliefs of the coating itself. Obviously, this effect is more easily produced by using extremely thin coatings (associated with a limited amount of silicon material).

FIG. 62 reports images showing the effect of irradiation for 0.3 seconds on the coating obtained in example A of the present invention.

From the above figures, it can be seen that the coating surface is characterized by finer coating distribution non-uniformity, with micron-sized peaks and valleys, without the defects detectable in fig. 61.

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

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

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

From the above figures it can be seen that the cylindrical portion and the adjacent conical tail portion of the barrel, respectively, are observed, and that the coated surface is characterized by a larger particle size than the surface of the injector (example a) of the present invention, as shown in figures 62 and 63 above.

Fig. 66 and 67 report images showing the effect of irradiation of the coating obtained in inventive example a and comparative example C near the limit of 1 second in the junction area between the cylindrical portion and the conical portion of the syringe barrel.

As can be seen from fig. 66 and 67, by subjecting the coating obtained in the invention example a to plasma irradiation (fig. 66), the presence of streaks in the right-hand region of the image (the cylindrical cone portion) can be observed, if not clearly.

However, in the coating obtained in comparative example C, the streaks appeared more pronounced under the same irradiation conditions, as shown in FIG. 67.

Claims

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:

(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

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

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 the lot average standard deviation SD is obtained by:

S_ni＝(Σ_p＝1,6S_pi)/6

S_nL＝(Σ_i＝1,10S_ni)/10

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;

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

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

Wherein the lot average standard deviation SD is obtained by:

S_ni＝(Σ_p＝1,6S_pi)/6

S_nL＝(Σ_i＝1,10S_ni)/10

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.