METHOD FOR PRODUCING A MEDICAL INJECTION DEVICE AND MEDICAL INJECTION DEVICE SO OBTAINED - Patent application

Abstract

A method for manufacturing a medical injection device (1) comprising a glass cylinder (2) having an inner surface (3) coated with a coating layer (4), the cylinder (2) configured to receive a plunger (5) by sliding engagement, the method comprising: a) administering to the patient a glass cylinder having a viscosity of 11,500 cSt (115 cm3) at room temperature; 2 / s) ~ 13500cSt (135cm 2 % or more by weight, and the coating composition has a kinematic viscosity of 100-150°C; b) heating the coating composition to a temperature of 100°C to 150°C; and c) applying the coating composition heated to said temperature onto an inner surface (3) of a cylinder (2) to form a coating layer (4) on the inner surface (3) having an average thickness S of 100-250 nm as measured by optical reflectance measurement, wherein the coating layer (4) on the inner surface (3) of the cylinder (2) has a thickness standard deviation of 90 nm or less.

Description

[Technical field]

[0001] The present invention relates to a method for manufacturing a medical injection device comprising a glass cylinder having an inner surface coated with a coating layer and configured to receive a plunger by sliding engagement, to the medical injection device obtained by said method, and to a kit for assembling said medical device. [Background technology]

[0002] As is known, injection devices are widely used in the medical field, generally comprising a sealed plunger that slidingly engages within a container for expelling a medication by injection into a patient.

[0003] Such injection devices include syringes, cartridges, as well as self-injectors or auto-injectors used for subcutaneous and / or intravenous administration of drugs.

[0004] In this type of device, the first requirement to be met is to have optimal sliding properties (in terms of static and dynamic friction) of the plunger in the cylinder of the injection device, for example in the cylinder of a syringe.For this purpose, a lubricating substance, typically based on silicone oil, is used to coat the inner surface of both the body of the syringe and the plunger.In particular, the purpose of the lubricating substance used is to optimize the sliding properties of the plunger, in particular to obtain low values ​​of the force required to overcome static friction (sliding yield stress) and the force required to slide the plunger overcoming dynamic friction (average sliding stress).

[0005] Particularly in the case of injection devices pre-filled with a drug, such as syringes, the need to keep the sliding characteristics of the plunger as constant as possible over time is particularly felt.

[0006] Indeed, if on the one hand the use of prefilled injection devices guarantees greater ease of administration of the drug and flexibility of administration, on the other hand it requires that the injection device must in some cases be stored after filling for rather long times, of the order of weeks or months, even at very low temperatures in order to guarantee stability and a longer shelf life of the drug, as for example in the case of protein-type drugs or vaccines.

[0007] However, the presence of silicone-based coatings has been identified as one of the causes of instability of biotechnological drugs, especially recombinant proteins, an instability that is believed to be related to inherent structure sensitivity. Silicone oils, in fact, can separate into solutions and form particles, which in the literature are classified as intrinsic particles, onto which proteins can be adsorbed at the silicone-water interface level, and these proteins can undergo structural denaturation and aggregation, leading to the aggregation of the particles themselves. The phenomenon of aggregation is important, since it leads to a possible loss of efficacy of the therapeutic treatment and an increased risk of immunogenicity.

[0008] Therefore, in the case of prefilled injection devices, a further important need arises, namely the need to maintain over time not only the optimal sliding properties of the coating but also the low release properties of the silicone particles within the pharmaceutical formulation. Summary of the Invention

[0009] The Applicant has noted that several methods of manufacturing medical injection devices have been proposed to meet these needs, but that these methods pose management or complexity, and therefore cost, problems that have not heretofore been solved.

[0010] In some cases, mixtures of different types of silicone oils, possibly with other substances added, are used. In this regard, the applicant has noted that the further one moves away from pure silicone (i.e. unmixed or unadded), the more difficult it becomes to keep its properties and behavior constant over time.

[0011] It has also been proposed to irradiate the silicone layer deposited on the inner surface of the syringe in order to at least partially crosslink the silicone, which has proven to be beneficial in achieving low values ​​of particle emission. Such irradiation may be by UV, IR, gamma radiation, ion bombardment, or by plasma treatment under vacuum or at atmospheric pressure of the torch or corona effect type.

[0012] In some cases, it has been proposed to deposit several successive layers of silicone which may be subjected to irradiation.

[0013] Examples of such processes using silicone-mixed silicones with additives, which may include irradiation treatment, are described in US Patent Application Publication No. 20020012741 A1, EP Patent No. 3378514 A1, US Patent No. 7648487 B2, US Patent No. 9662450 B2, US Patent No. 10066182 B2, EP Patent No. 2387502 B1, US Patent No. 7553529 B2, US Patent Application Publication No. 20110276005 A1, EP Patent No. 2081615 B1, US Patent No. 5338312 A, US Patent No. 4844986 A, US Patent No. 4822632 A and US Patent Application Publication No. 20080071228 A1.

[0014] A method aimed at obtaining a syringe that meets the two requirements of good sliding and low emission, both of which are constant over time (and also maintains a constant thickness over time) is also described in WO2013045571A1. This document discloses spraying silicone with a kinematic viscosity of 900-1200 cSt onto the inner surface of the syringe, followed by plasma treatment to make the silicone stable and low emission. This document shows the reason for low emission in plasma treatment of the silicone surface.

[0015] Similar disclosures are provided by documents WO2009053947A2 and WO2015136037A1.

[0016] All these documents point to the use of silicones with fairly low kinematic viscosity (around 1000 cSt) in combination with irradiation treatments, especially plasma treatments, as the best combination for solving the above problems.

[0017] A method for the internal siliconization of hollow cylinders is also known from German Patent No. 100 00 505, in which a silicone oil, preferably having a kinematic viscosity of 350 to 20,000 cSt, is deposited on the inner wall of the cavity. The silicone oil is deposited by spraying, in particular by means of a head of the type used in inkjet printing, which in one embodiment can be heated.

[0018] However, the Applicant has observed that the manufacturing methods disclosed by the above mentioned prior art, in addition to implying an undesirable extension of the manufacturing time of the medical injection device and an increased complexity of the management of the method itself, give rise to further problems related to the need to carry out a visual inspection of the medical injection device once filled with the drug, not identified by the prior art, to determine the absence of defects in the form of optically detectable particles and exogenous contaminants.

[0019] This inspection, previously performed manually, is now delegated to automated equipment based on the analysis techniques of images obtained from optical acquisition systems. The constantly increasing purity required of the solutions contained in medical injection devices requires controls that are not only able to highlight even the smallest impurities present in the liquid, but also to distinguish them from surface defects of the container that do not constitute impurities and therefore would lead to the rejection of the medical injection device if incorrectly classified as such.

[0020] In this regard, the Applicant has observed that partial cross-linking of the layer of silicone oil applied to the inner surface of the cylinder of a medical injection device, in particular obtained by plasma irradiation, generates a more irregular but more stable surface structure that can mislead automatic optical inspection systems, causing them to erroneously classify the surface irregularities as impurities and thus generating production waste that has no reason to exist and resulting in economic losses.

[0021] The Applicant has therefore realised the need to develop a method for manufacturing a medical injection device which not only makes it possible to meet the aforementioned needs of having optimal sliding properties (in terms of static and dynamic friction) of the plunger in the cylinder of the injection device and optimal properties of low particle emission, but also reduces problems associated with false defects that may be erroneously detected by visual inspection devices for medical injection devices.

[0022] Applicant has realised that all of these desirable characteristics may be achieved by affecting the rheological properties of the coating composition and the application method of the coating composition used to coat the inner surface of the cylinder of a medical injection device, as compared to those suggested by the prior art.

[0023] In particular, the applicant has discovered that by using a coating composition substantially entirely composed of a single type of silicone oil having a kinematic viscosity at room temperature much higher than that of the silicone oils proposed by the prior art to coat the inner surface of the cylinder of a medical injection device, and by applying this silicone oil to the inner surface of the cylinder under heating, after cooling of the coating layer applied to this surface, - the desired optimum sliding properties and low particle emission properties, both of which are substantially constant over time, and It has been experimentally verified that it is possible to simultaneously obtain optimal properties of surface regularity of the coating layer, such that the visual inspection device of the medical injection device is not misled.

[0024] In particular, the aforementioned characteristics of the surface regularity of the coating layer were experimentally comparable to those of the non-crosslinked coating layer obtained by using a silicone oil of the prior art, which has a low kinetic viscosity but a high particle release. This is despite the use of a silicone oil with a significantly higher kinetic viscosity at room temperature and despite the fact that the applied coating layer has a very low average thickness of the order of 100-250 nm.

[0025] However, the aforementioned features of surface regularity of the coating layer were experimentally improved compared to the partially crosslinked coating layers of the prior art obtained by using low kinematic viscosity silicone oils.

[0026] Furthermore, the applicant has experimentally verified that by using the above-mentioned coating composition, which is substantially composed almost entirely of a single type of silicone oil having a kinematic viscosity at room temperature much higher than that of the silicone oils proposed by the prior art, to coat the inner surface of the cylinder of a medical injection device, and by applying this silicone oil to the inner surface of the cylinder by heating, it is possible to obtain the coating uniformity characteristics with high process reproducibility required for large-scale industrial production.

[0027] The present invention therefore relates in a first aspect to a method for manufacturing a medical injection device comprising a glass cylinder having an inner surface coated with a coating layer and adapted to receive a plunger having sliding engagement, as defined in claims 1 and 2.

[0028] In particular, in its first embodiment, the method for producing a medical injection device according to the invention comprises the steps of: a) At room temperature, 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 providing a coating composition comprising a polydimethylsiloxane in an amount of 92 weight percent or greater having a kinematic viscosity of 1.0 g / s; b) heating the coating composition to a temperature of 100°C to 150°C; c) applying the coating composition heated to said temperature onto said inner surface of the cylinder to form a coating layer on the inner surface having an average thickness S of 100 to 250 nm as measured by optical reflectance measurement; Including, The coating layer on the inner surface of the cylinder has a thickness standard deviation of less than 90 nm.

[0029] Moreover, in a second embodiment thereof, a method for producing a medical injection device according to the invention comprises the steps of: a) At room temperature, 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 providing a coating composition comprising a polydimethylsiloxane in an amount of 92 weight percent or greater having a kinematic viscosity of 1.0 g / s; b) heating the coating composition to a temperature of 100°C to 150°C; c) applying the coating composition heated to the temperature onto the inner surface of the cylinder to form a coating layer on the inner surface having an average thickness of 100 to 250 nm as measured by optical reflectance measurement; Including, For each batch of 10 cylinders, the batch mean standard deviation SD of the coating layer thickness has a value of 70 nm or less; The batch mean standard deviation SD is i) The thickness S of the coating layer (4) at least 6 points of each arbitrary portion ni of the i-th cylinder of the batch having an axial length of 1.0 mm and spread out on a plane pi To measure, ii) for each of said portions ni of the i-th cylinder of the batch, and for each i-th cylinder, the formula S ni =(Σ p=1,6 S pi ) / 6 By the average thickness S ni Calculating iii) For each cylinder section n, the formula S nL =(Σi=1,10 S ni ) / 10 The batch average thickness S of part n by nL Calculating iv) For the 10 syringes in the batch, what is the batch average thickness S of part n? nL Regarding standard deviation SD n Calculating v) formula SD=(Σ i=1,N SD n ) / N where N is the total number of cylinder parts in the batch. By, thickness standard deviation SD n Calculate the batch mean standard deviation SD from the values ​​of is obtained by

[0030] The applicant has experimentally found that by hot-applying the aforementioned coating composition based on high viscosity polydimethylsiloxane at room temperature, as will be explained in more detail below, it is possible to form a coating layer on the inner surface of a cylinder that has the same effect in terms of application and distribution of lower viscosity oils.

[0031] The applicant has also experimentally found that the coating layer after cooling and after its viscosity characteristics have returned to those present at room temperature, whether or not it has been subjected to partial crosslinking as described by the prior art, achieves a series of advantageous improved properties compared to a coating layer having a lower viscosity.

[0032] Firstly, the Applicant has experimentally observed that the method of the invention advantageously makes it possible to form a coating layer that has not only the low thickness values ​​required by the pharmaceutical and cosmetic industries, but also a very uniform distribution along the inner surface and each part of the cylinder.

[0033] In particular, the Applicant has experimentally observed that the method of the invention advantageously makes it possible to apply a coating layer to the inner surface of a cylinder having thickness values ​​that are fully comparable to those obtained using the low-viscosity silicone oils proposed by the prior art.

[0034] The Applicant has experimentally observed that the viscosity of the coating layer applied to the inner surface of the cylinder, when it returns to its value at room temperature, has a lower viscosity (as stated, of the order of about 1000 cSt), endowing the layer with stability properties such as to overcome all the disadvantages of a coating layer formed by a silicone oil that has not undergone partial crosslinking.

[0035] In particular, the method of the present invention advantageously makes it possible to form a coating layer that overcomes the following disadvantages of non-crosslinked coating layers of the prior art: the tendency of the silicone layer to develop over time a non-uniform distribution along the axis of the cylinder of a medical injection device, e.g. a syringe, due to the gravity-induced migration of the silicone towards the bottom of the cylinder body during storage in an upright position, - non-uniformity as a result of the sliding resistance of the plunger when a medical injection device, e.g. a syringe, is used, as a result, there is a higher probability of direct interaction of the drug with the material (glass) of which the cylinder of the medical injection device, for example a syringe, is made, and of separation of parts of the coating layer from the surface into the solution, and - the possibility of causing denaturation and protein aggregation phenomena, especially when combined with mechanical stresses such as stirring or while ejecting the liquid present in the cylinder caused by sliding the plunger.

[0036] The method of the invention therefore advantageously makes it possible to form a coating layer having thickness, uniformity and stability properties which make it possible to achieve optimal sliding properties of the plunger in the cylinder, this layer being formed by a silicone oil having a much higher viscosity than that suggested by the prior art documents mentioned above.

[0037] Secondly, the applicant has experimentally observed that the method of the present invention advantageously makes it possible to form a coating layer having high surface regularity and high coverage uniformity so as not to mislead visual inspection devices of medical injection devices, in particular visual inspection devices of the automated type.

[0038] In particular, the method of the invention advantageously makes it possible to obtain a coating layer on the inner surface of a cylinder having a very uniform thickness with a thickness standard deviation measured by optical reflectance measurements (or optical interferometry depending on the resolution) of less than 90 nm.

[0039] In this way, the coating layer does not cause spurious defect problems, thus solving the problems observed with prior art partially crosslinked silicone coatings.

[0040] Advantageously, the method of the invention also makes it possible to obtain a coating layer on the inner surface of the cylinder having an average thickness that is fully in line with the requirements of the pharmaceutical and cosmetic industry, despite the fact that such coating layer is constituted by a silicone material with a high kinematic viscosity.

[0041] Thirdly, the Applicant has experimentally observed that the method of the invention advantageously makes it possible to form a coating layer having properties of low particle release in solution stored in the cylinder of a medical injection device, due to its stability properties related to the viscosity value at room temperature of the coating layer.

[0042] According to tests carried out by the applicant, these properties of low particle emission are fully comparable or improved compared to the properties of prior art partially crosslinked silicone coating layers which nevertheless give rise to the above-mentioned false defect problems.

[0043] Fourth, Applicant has experimentally observed that the aforementioned properties of optimal sliding of the plunger and low particle release in the solution stored in the cylinder remain substantially constant over time, both when stored at or above room temperature, and when stored at low temperatures, thus satisfying another important requirement of the pharmaceutical and cosmetic industries.

[0044] Fifth, the Applicant has experimentally observed that the aforementioned property of uniformity of the average thickness of the coating layer can be obtained in a highly reproducible manner within different production batches of medical devices, a highly desirable property within large-scale production typical of the pharmaceutical and cosmetic industries, and this despite the fact that this coating layer is constituted by a silicone material with a high kinematic viscosity.

[0045] In a further aspect thereof, the present invention relates to an apparatus for manufacturing a medical injection device comprising a glass cylinder having an inner surface coated with a coating layer and configured to receive a plunger having a sliding engagement according to claim 25.

[0046] In particular, an apparatus for manufacturing a medical injection device according to the invention comprises: a storage tank for the coating composition comprising at least one heating element configured to heat the stored coating composition; at least one discharge head configured for discharging a heated coating composition and provided with at least one discharge nozzle, the discharge head being provided with a respective heating element configured for heating the coating composition dispensed by the nozzle, a circulation pump arranged upstream of the discharge head; - a support frame for one or more cylinders of a respective medical injection device; Equipped with The at least one dispensing head and support frame are movable relative to one another to insert / retract nozzles of the at least one dispensing head into / from respective ones of the one or more cylinders.

[0047] In a further aspect, the present invention relates to a medical injection device as defined in the accompanying claims 28 and 29.

[0048] In particular, according to a first embodiment, the medical injection device according to the invention comprises a glass cylinder having an inner surface coated with a coating layer, the cylinder being configured to receive a plunger having a sliding engagement, The coating layer on the inner surface of the cylinder has a thermal conductivity of 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 / s) and has an average thickness of 100 to 250 nm; The coating layer on the inner surface of the cylinder has a thickness standard deviation of less than 90 nm.

[0049] Furthermore, according to a second embodiment, the medical injection device according to the invention comprises a glass cylinder having an inner surface coated with a coating layer, the cylinder being configured to receive a plunger having a sliding engagement, The coating layer on the inner surface of the cylinder has a thermal conductivity of 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 / s) and has an average thickness of 100 to 250 nm; For each batch of 10 cylinders, the batch mean standard deviation SD of the coating layer thickness has a value of 70 nm or less; The batch mean standard deviation SD is i) The thickness S of the coating layer (4) at least 6 points of each arbitrary portion ni of the i-th cylinder of the batch having an axial length of 1.0 mm and spread out on a plane pi To measure, ii) for each of said portions ni of the i-th cylinder of the batch, and for each i-th cylinder, the formula S ni =(Σ p=1,6 S pi ) / 6 By the average thickness S ni Calculating iii) For each n section of the cylinder, the equation S nL =(Σ i=1,10 S ni ) / 10 The batch average thickness S of part n by nL Calculating iv) For the 10 syringes in the batch, what is the batch average thickness S of part n? nL Regarding standard deviation SD n Calculating v) formula SD=(Σ i=1,N SD n ) / N where N is the total number of cylinder parts in the batch. By, thickness standard deviation SD n Calculate the batch mean standard deviation SD from the values ​​of is obtained by

[0050] Advantageously, the aforementioned injection device achieves, in relation to its manufacturing method, the advantageous technical properties mentioned above in relation to the properties achieved by the coating layer on the inner surface of the cylinder.

[0051] In a further aspect, the present invention relates to a kit of parts for assembling a medical injection device as defined in the accompanying claims 46 and 47.

[0052] In particular, according to a first embodiment, the kit of parts according to the invention comprises in a sterile package the following separate components: - a glass cylinder having an inner surface coated with a coating layer, the glass cylinder being configured to receive a plunger by sliding engagement; a plunger configured for sliding engagement within said cylinder; Equipped with The coating layer on the inner surface of the cylinder has a thermal conductivity of 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 / s) and has an average thickness of 100 to 250 nm; The coating layer on the inner surface of the cylinder has a thickness standard deviation of less than 90 nm as measured by optical reflectance measurements.

[0053] Furthermore, according to a second embodiment, the kit of parts according to the invention comprises in a sterile package the following separate components: - a glass cylinder having an inner surface coated with a coating layer, the glass cylinder being configured to receive a plunger by sliding engagement; a plunger configured for sliding engagement within said cylinder; Equipped with The coating layer on the inner surface of the cylinder has a thermal conductivity of 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 / s) and has an average thickness of 100 to 250 nm; For each batch of 10 cylinders, the batch mean standard deviation SD of the coating layer thickness has a value of 70 nm or less; The batch mean standard deviation SD is i) The thickness S of the coating layer (4) at least 6 points of each arbitrary portion ni of the i-th cylinder of the batch having an axial length of 1.0 mm and spread out on a plane pi To measure, ii) for each of said portions ni of the i-th cylinder of the batch, and for each i-th cylinder, the formula S ni =(Σ p=1,6 S pi ) / 6 By the average thickness S ni Calculating iii) For each cylinder section n, the formula S nL =(Σ i=1,10 S ni ) / 10 The batch average thickness S of part n by nL Calculating iv) For the 10 syringes in the batch, what is the batch average thickness S of part n? nL Regarding standard deviation SD n Calculating v) formula SD=(Σ i=1,N SD n ) / N where N is the total number of cylinder parts in the batch. By, thickness standard deviation SD n Calculate the batch mean standard deviation SD from the values ​​of is obtained by

[0054] Advantageously, the aforementioned kit of parts allows for the storage and transport in a sterile manner and for the subsequent assembly of the injection device disclosed herein.

[0055] definition Within the framework of this specification and the subsequent claims, the term "room temperature" (RT) denotes a temperature of 25°C ± 2°C measured at a relative humidity of 60%.

[0056] Within the framework of this specification and the subsequent claims, all percentages, if specifically indicated, are to be understood as percentages by weight.

[0057] In the context of the specification and the claims that follow, the term "average" refers to the arithmetic mean of the values ​​of the particular entities under consideration.

[0058] Within the framework of this specification and the following claims, all pressure values ​​are to be understood as relative pressure values, in other words, the pressure values ​​given in this specification do not include the pressure of the weight of atmosphere, unless otherwise specified.

[0059] Within the framework of this specification and the claims that follow, all numerical entities indicating quantities, parameters, percentages, and the like, unless otherwise indicated, are to be understood in all circumstances to be preceded by the term "about." Also, all ranges of numerical entities include all possible combinations of maximum and minimum numerical values, as well as all possible intermediate ranges, in addition to those specifically set forth below.

[0060] Within the framework of this specification and the subsequent claims, the kinematic viscosity of the polydimethylsiloxanes was measured by TGA and DSC thermogravimetric analysis techniques.

[0061] Thermogravimetric analysis (TG) or thermogravimetric analysis (TGA) is an experimental technique for characterizing materials that is included in the broader family of thermal analyses. The technique consists of the continuous measurement over time of the change in mass of a material sample as a function of time (isotherms) or temperature (heating / cooling ramps) under controlled atmospheric conditions.

[0062] The DSC technique makes it possible to determine at what temperature or temperature range any transition occurs (for example, melting or crystallization processes) and to quantitatively measure the energy associated with it. DSC analysis actually measures the heat flow that occurs in a sample when it is heated / cooled in a controlled way (dynamic conditions) or maintained at a constant temperature (isothermal conditions).

[0063] By combining these two techniques, it is possible to determine the kinematic viscosity of a silicone material by correlating the thermal curves obtained with standard silicone oils with known viscosities.

[0064] In this way, it is possible to determine the kinematic viscosity of a silicone material using a calibration curve that allows correlating the viscosity value (related to the length of the polymer chain) with the thermal phenomenon (weight loss) observed at different temperatures.

[0065] The polydimethylsiloxane present in the coating layer was extracted with aliquots of dichloromethane, which was evaporated before analysis.

[0066] TGA analyses were performed using a TGA 4000 thermogravimetric analyzer (PerkinElmer) and DSC analyses were performed using a DSC 204 F1 differential scanning calorimeter (Netzsch).

[0067] The thermal cycle followed by TGA analysis was from 30 °C to 500 °C with a heating gradient of 10 °C / min.

[0068] The thermal cycle according to the DSC analysis was from −80° C. to 30° C. with a heating gradient of 10° C. / min.

[0069] Within the framework of this specification and the subsequent claims, it shall be understood that the thickness of the coating layer applied to the inner surface of the cylinder of the injection device is measured by optical techniques based on the emission of optical radiation (white light or light of a specific wavelength by a laser) impinging on the analysis sample.

[0070] Instruments, for example optical reflectometers, detect the difference in the reflected wavelengths of two light beams, one reflected by the material of the cylinder of the injection device (glass) and one reflected by the coating layer. This difference makes it possible to determine the thickness of the layer by knowing the refractive index and the geometric shape of the sample to be analyzed. If white light is used as the light source during the analysis, the instrument may detect a minimum thickness of 80 nm. By using a specific collimated wavelength (laser), for example a collimated wavelength of 630-680 nm, the resolution can be increased to 20 nm, in this case interference techniques can be used.

[0071] Within the framework of this specification and the subsequent claims, the average thickness S of the coating layer is particularly preferably i) The thickness S of the coating layer is measured at at least six points of each arbitrary portion n of a cylinder having an axial length of 1.0 mm and developed on a plane. p To measure, ii) the average thickness S of each of the aforementioned n portions of the cylinder n Calculate S n =(Σ p=1,6 S p ) / 6, the average thickness S n Calculating iii) Calculating the average thickness S of the coating layer (4) of the cylinder, where S=(Σ n=1,N S n Calculate the average thickness S, which is 1 / N, where N is the total number of cylinder segments, n; is obtained by

[0072] In general, within the framework of this specification and the subsequent claims, the term "standard deviation" or "mean square deviation" of an entity "x", e.g. the thickness of a coating layer applied to the inner surface of a cylinder of an injection device, detected in a population of N statistical units, is defined as follows:

number

number

[0073] Particularly preferably, the thickness standard deviation of the coating layer applied to the inner surface of the cylinder of the injection device is within the above mentioned points i) to iii) and iv) The average thickness S of the coating layer on the cylinder versus the average thickness S of the aforementioned n portions of the cylinder n The average thickness S of the coating layer is obtained by calculating the standard deviation SD of the

[0074] Within the framework of an embodiment of the present invention, the average thickness of the coating layer applied to the inner surface of each cylinder of a given number of cylinders, for example a batch of 10, and the batch standard deviation of the coating layer are obtained as described above.

[0075] Within the framework of the embodiment of the present invention, the "batch average standard deviation SD of the coating layer thickness" refers to the thickness standard deviation SD obtained as described above. n As mentioned above, this parameter indicates the process reproducibility between different manufacturing batches.

[0076] Within the framework of all embodiments of the present invention, the total number of n portions having an axial length of 1.0 mm and deployed in the plane of the injection device cylinder, denoted N, varies as a function of the size of the cylinder itself.

[0077] Thus, for example, the total number N of n parts of an injection device is equal to 40 for a syringe with a nominal capacity of 0.5 mL, 45 for a syringe with a nominal capacity of 1.0 mL, and 90 for a syringe with a nominal capacity of 3.0 mL.

[0078] Within the framework of this disclosure and in the claims that follow, the designation of syringes having a nominal volume of 0.5 mL, 1 mL length or 3 mL is intended in accordance with standard ISO 11040-4 (2015).

[0079] Within the framework of this specification and the subsequent claims, the term "axial" and the corresponding term "axially" are used to refer to a longitudinal direction of the medical injection device corresponding to the longitudinal direction of its cylinder, and the term "radial" and the corresponding term "radially" are used to refer to any direction perpendicular to said longitudinal direction.

[0080] Within the framework of this specification and the subsequent claims, the term "circumferential" and the corresponding term "circumferentially" are used to refer to the direction of deployment of the inner surface of the cylinder of a medical injection device in a plane perpendicular to the longitudinal direction of the cylinder itself.

[0081] The present invention, in one or more of the aforementioned aspects, may have one or more of the preferred features described below, which may be combined with one another as desired depending on the requirements of the application.

[0082] In a preferred embodiment, step a) is carried out at 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 The present invention includes providing a coating composition comprising a polydimethylsiloxane in an amount of 95% by weight or greater, more preferably 98% by weight or greater, having a kinematic viscosity of 100 / s.

[0083] Even more preferably, step a) is carried out at 11500 cSt (115 cm 2 / s) ~ 13500cSt (135cm 2 The method includes providing a coating composition comprising a polydimethylsiloxane in an amount equal to about 100% by weight having a kinematic viscosity of 100 g / s.

[0084] In this way it is advantageously possible to have a manufacturing process that can be carried out in a particularly simple and repeatable manner by minimizing or completely eliminating the problems associated with the difficulties of maintaining constant the rheological properties of the coating composition after mixing silicone materials with different densities and / or viscosities.

[0085] Advantageously, the manufacturing process can also be carried out without adding additives to the silicone material.

[0086] In a preferred embodiment, step a) of providing a coating composition comprises storing the coating composition in a storage tank.

[0087] In this way, it is advantageously possible to always have the desired amount of coating composition available for carrying out the method.

[0088] Preferably, the tank is made of a material suitable for containing the silicone coating composition, such as stainless steel.

[0089] Preferably, step b) provides for heating the coating composition to a temperature between 120°C and 150°C.

[0090] In this way it is advantageously possible to optimise the subsequent step c) of applying the heated coating composition onto the inner surface of the cylinder, thereby facilitating the formation of a very uniform coating layer on the inner surface.

[0091] In a preferred embodiment, step b) of heating the coating composition comprises heating said storage tank so as to bring the coating composition to a temperature in the range 100°C to 150°C, more preferably in the range 120°C to 150°C.

[0092] For this purpose, the storage tank of the coating composition is provided with at least one heating element configured to heat the stored coating composition.

[0093] For purposes of the present invention, a tank heating element can be any element configured to emit thermal energy and selectively positioned in heat exchange relationship with the coating composition stored in the storage tank.

[0094] By way of example only, the heating element may be a heating coil (e.g., an electrical resistor or tube through which a suitable heating fluid is circulated) disposed inside the tank, or a jacket on the outside of the tank through which one or more electrical resistors are disposed or a suitable heating fluid is circulated.

[0095] In a preferred embodiment, the method may further comprise step d) maintaining the heated coating composition stored in the storage tank at a pressure of from 5 psi (0.34 bar) to 150 psi (10.34 bar), preferably from 10 psi (0.69 bar) to 30 psi (2.07 bar), even more preferably from 10 psi (0.69 bar) to 15 psi (1.03 bar).

[0096] In this way it is advantageously possible to optimise the subsequent step c) of applying the heated coating composition onto the inner surface of the cylinder, thereby facilitating the formation of a very uniform coating layer on the inner surface.

[0097] In a preferred embodiment, the method further comprises the step e) of supplying the heated coating composition to a discharge head provided with at least one discharge nozzle.

[0098] In this way it is advantageously possible to apply the heated coating composition to the inner surface of the cylinder to form a very uniform coating layer on the inner surface.

[0099] Preferably, the heated coating composition dispensing head is provided with respective heating elements configured to heat the coating composition dispensed by the nozzles.

[0100] For purposes of the present invention, a nozzle heating element may be any element configured to emit thermal energy selectively placed in heat exchange relationship with the coating composition dispensed by the nozzle itself.

[0101] By way of example only, the heating element may be an electrical resistor in heat exchange relationship with the discharge nozzle, and may for example be incorporated in a cylindrical casing, for example, associated with the discharge nozzle.

[0102] Preferably, step e) of supplying the heated coating composition to the discharge head is performed by means of a circulation pump arranged upstream of the discharge head.

[0103] In this way, it is advantageously possible to provide an appropriate supply of coating composition discharge heads according to production needs.

[0104] In a preferred embodiment, the circulation pump comprises a respective heating element configured to heat the delivery head of the pump.

[0105] For purposes of the present invention, a heating element of a pump delivery head may be any element configured to emit thermal energy selectively placed in heat exchange relationship with the coating composition dispensed by the delivery head itself.

[0106] By way of example only, the heating element may comprise one or more electrical resistors in heat exchange relationship with the delivery head of the pump, for example integrated into a respective, for example cylindrical, casing associated with the delivery head.

[0107] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder is performed by dispensing the coating composition through a dispensing head.

[0108] In this way it is advantageously possible to apply the heated coating composition very uniformly to the inner surface of the cylinder.

[0109] In a preferred embodiment, step b) of heating the coating composition comprises heating the discharge head and / or the pump, more preferably the delivery head of the pump, to bring or maintain the coating composition at a temperature of 100°C to 150°C.

[0110] In this way it is advantageously possible to reduce the power absorption and wear of the pump, to the benefit of pump operation and maintenance costs.

[0111] In a preferred embodiment, the dispensing head and pump may be heated as described above.

[0112] In a preferred embodiment, the method provides for heating the pump's delivery head to a temperature of 50°C to 60°C.

[0113] In a preferred embodiment, the coating composition storage tank, the circulating pump and the dispensing head are in fluid communication with each other via piping.

[0114] Preferably, the tubes are in heat exchange relationship with a respective heating element, such as an electrical resistor or an outer jacket of the tube through which a suitable heating fluid is circulated.

[0115] Preferably, the aforementioned tubes are made of a heat resistant material, such as stainless steel, and are insulated or made of an insulating, metal or plastic material.

[0116] The applicant has experimentally observed that by heating one or more of the coating composition storage tank, the circulation pump, the discharge head and the respective connecting pipes, it is advantageously possible to equalize the viscosity of the coating composition before it is discharged onto the inner surface of the cylinder, resulting in an advantageous reduction in the discharge time and a greater distribution uniformity of the coating composition on the inner surface of the cylinder.

[0117] In connection with this preferred embodiment, step b) of heating the coating composition preferably comprises heating said tube so as to bring or maintain the coating composition at the aforementioned temperature of between 100°C and 150°C.

[0118] Applicant has experimentally observed that heating the coating composition to temperatures above 150°C can change the properties of the silicone material, which can result in undesirable particulate release and / or increased release of substances that are normally retained at lower temperatures.

[0119] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder is carried out by dispensing the heated coating composition at a pressure of from 5 psi (0.34 bar) to 150 psi (10.34 bar), more preferably from 6 psi (0.41 bar) to 10 psi (0.69 bar).

[0120] In this way it is advantageously possible to apply the heated coating composition very uniformly to the inner surface of the cylinder.

[0121] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder comprises supplying a discharge gas (e.g., air) to the discharge head having a pressure of between 5 psi (0.34 bar) and 150 psi (10.34 bar), preferably between 6 psi (0.41 bar) and 10 psi (0.69 bar).

[0122] In this manner, it is advantageously possible to dispense the heated coating composition very uniformly to apply a uniform coating layer to the inner surface of the cylinder.

[0123] In a preferred embodiment, the method includes maintaining a storage tank of the coating composition at a pressure greater than the pressure of the discharge nozzle of the discharge head.

[0124] In this manner, it is advantageously possible to dispense the heated coating composition very uniformly to apply a uniform coating layer to the inner surface of the cylinder.

[0125] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder comprises imparting relative motion between a dispensing head and the cylinder while dispensing the heated coating composition.

[0126] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder comprises dispensing the heated coating composition onto the inner surface of the cylinder during relative insertion movement of the dispensing head into the cylinder.

[0127] In a preferred embodiment, one or more cylinders of each medical injection device may be supported by a movable support frame relative to one or more respective discharge heads of the heated coating composition.

[0128] In this way it is therefore possible to insert / remove the nozzle of the ejection head(s) into / from each of said one or more cylinders.

[0129] Preferably, the ejection head(s) are fixed and the support frame of the one or more cylinders is movable towards and away from the ejection head(s) to facilitate effecting relative movement between the ejection head(s) and the cylinder(s).

[0130] In alternative preferred embodiments, the dispensing head(s) may be movable and the support frame of the one or more cylinders may be fixed, or similarly, the dispensing head(s) and the support frame may both be movable.

[0131] Preferably, step c) of applying the heated coating composition to the inner surface of the cylinder comprises discharging the coating composition by nozzles of the discharging heads while moving the cylinder(s) towards the respective discharging head(s).

[0132] In this way it is advantageously possible to apply a very uniform coating layer to the inner surface of the cylinder.

[0133] In a preferred embodiment, the time for discharging the heated coating composition onto the inner surface of the cylinder is 0.3 seconds to 1 second, more preferably 0.4 seconds to 0.7 seconds.

[0134] In this way it is advantageously possible to limit the so-called "total cycle time" or "spray time", given by the sum of the times for inserting the discharge head into the cylinder and for withdrawing it from the cylinder, to a value of less than about 3 seconds, which is believed to be compatible with the normal cycle times of industrial production lines.

[0135] In this regard, the applicant has experimentally observed that the aforementioned discharge times of the heated coating composition can be advantageously and conveniently achieved by carrying out one or more of the following steps: heating the storage tank, heating the discharge head, heating a circulation pump arranged upstream of the discharge head or a part of the pump in question (e.g., preferably the delivery head of the pump), and heating a connecting pipe ensuring fluid communication between the storage tank, the pump and the discharge head.

[0136] In particularly preferred embodiments, the above-mentioned dispense times of the heated coating composition are advantageously and conveniently achieved by implementing steps of heating the storage tank, pump, dispense head and associated connecting tubing.

[0137] As explained above, the Applicant has indeed experimentally observed that by operating in this manner it is possible to equalize the viscosity of the coating composition before it is dispensed onto the inner surface of the cylinder, resulting in an advantageous reduction in the dispensing time and a greater distribution uniformity of the coating composition on the inner surface of the cylinder.

[0138] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder comprises expelling the heated coating composition at a flow rate between 0.1 μL / s and 5 μL / s, more preferably equal to about 0.5 μL / s.

[0139] In this way it is advantageously possible to apply a very thin coating layer to the inner surface of the cylinder.

[0140] In a preferred embodiment, the step c) of applying the heated coating composition to the inner surface of the cylinder has a coating density of 0.2 to 0.4 μg / mm 2 of the heated coating composition to the inner surface of the cylinder.

[0141] Again, it is advantageously possible to apply a very thin coating layer to the inner surface of the cylinder.

[0142] In a preferred embodiment, step c) of applying the heated coating composition to the inner surface of the cylinder is carried out such that the coating layer formed on the inner surface of the cylinder has an average thickness, as measured by optical reflectance measurement, of 100 to 200 nm.

[0143] Advantageously, as explained above, this average thickness of the coating layer formed on the inner surface of the cylinder is fully in line with the requirements of the pharmaceutical and cosmetic industries, despite the fact that the coating layer is composed of a silicone material having a high kinetic viscosity.

[0144] In a preferred embodiment, the method of the invention makes it possible to obtain a coating layer formed on the inner surface of a cylinder having a very uniform thickness with a thickness standard deviation measured by optical reflectance measurements (or optical interferometry depending on the resolution) of less than or equal to 70 nm, even more preferably less than or equal to 50 nm.

[0145] In this way it is advantageously possible to obtain a coating layer which has optimal properties of surface regularity and which is not misleading to visual inspection devices of medical injection devices, in particular visual inspection devices of the automated type.

[0146] In a preferred embodiment, the method of the invention makes it possible to obtain, for each batch of 10 cylinders, a coating layer formed on the internal surface of the cylinders having a very uniform thickness, the batch mean standard deviation SD of the thickness of the coating layer as defined above having a value of less than or equal to 60 nm, and even more preferably less than or equal to 50 nm.

[0147] In this way it is advantageously possible to obtain a coating layer with optimal properties of surface regularity in a highly reproducible manner on several cylinders of a batch, as is required in large-scale industrial production.

[0148] In a preferred embodiment, the method for producing a medical injection device according to the present invention may further comprise, after step c) of applying the heated coating composition to the inner surface of the cylinder, step f) of subjecting the coating layer formed on the inner surface of the cylinder to a partial crosslinking treatment of polydimethylsiloxane.

[0149] The partial crosslinking treatment is preferably carried out by irradiation.

[0150] Preferably, the irradiation treatment of the coating layer is a plasma irradiation treatment, preferably with a plasma torch at atmospheric pressure using a flow of argon having a purity of more than 99% (eg 99.999%).

[0151] In this way it is advantageously possible to further improve the low particle emission properties of the coating layer, as desired by the particular application.

[0152] Advantageously, the applicant has found experimentally that the partial cross-linking treatment can be carried out in such a way that the lubricating properties of the coating layer are not adversely affected.

[0153] To this end, in a preferred embodiment, the irradiation treatment is carried out for a period between 0.2 seconds and 1 second, preferably between 0.2 seconds and 0.6 seconds, more preferably between 0.2 seconds and 0.5 seconds inclusive, and even more preferably equal to about 0.3 seconds.

[0154] The Applicant has experimentally found that by limiting the irradiation time to this range of values, as will be explained in more detail below, it is advantageously possible to obtain a coating layer having optimal sliding properties of the plunger in the cylinder of the injection device (in terms of static and dynamic friction) and at the same time optimal properties of low particle emission, both of which are constant over time.

[0155] Advantageously, the partially cross-linked coating layer obtained according to this preferred embodiment, due to its surface regularity, is still able to substantially reduce problems associated with false defects that may be erroneously detected by visual inspection devices of medical injection devices, in particular visual inspection devices of the automated type.

[0156] Without wishing to be bound by any theory of interpretation, the Applicant believes that an exposure time within the aforementioned values ​​favors compaction of the coating layer, further reducing particle shedding, without significantly affecting the surface regularity of the coating layer or causing significant changes in the average values ​​of static and dynamic sliding friction of the plunger in the cylinder.

[0157] In particular, Applicant has experimentally observed that particle emission values ​​obtained with irradiation treatment according to this preferred embodiment of the present invention are significantly lower when compared to coatings using prior art non-crosslinked low viscosity silicone materials, and are comparable to the values ​​of coatings that have been subjected to irradiation treatment.

[0158] Advantageously, as described in more detail below with reference to experiments carried out by the applicant, this property of low particle emission is also substantially constant over time by both storing the cylinders at or above room temperature, and by storing the cylinders at low temperatures, for example at temperatures in the range of -5°C to -40°C.

[0159] This feature is particularly appreciated in the case of medical injection devices, such as syringes, which are filled with pharmaceutical agents that have a long shelf life and / or need to be stored at low temperatures.

[0160] Additionally, applicants have experimentally found that exposure times within the aforementioned range of values ​​do not adversely affect the coating rate of the inner surface of the cylinder, which remains at least about 90% on average, as shown in more detail below.

[0161] In a preferred embodiment, step f) of subjecting the coating layer formed on the inner surface of the cylinder to an irradiation treatment is carried out at a time distance of at least 15 minutes, preferably 15 to 20 minutes, after step c) of applying the heated coating composition onto the inner surface of the cylinder.

[0162] In this way it is advantageously possible for the droplets of silicone material dispensed on the inner surface of the cylinder to fuse together, achieving a coverage of at least 90% of this surface.

[0163] In this regard, the Applicant has observed that waiting times of less than 15 minutes create a coverage of the inner surface of the cylinder that causes greater undesirable interactions between the injectable liquid pharmaceutical composition stored within the cylinder and its inner glass surface.

[0164] Applicant also noted that waiting times in excess of 20 minutes did not result in significant improvements in significantly increasing production times.

[0165] In a preferred embodiment, the manufacturing method of the present invention may further comprise a step g) prior to step c) of applying the heated coating composition to the inner surface of the cylinder, of subjecting the inner surface of the cylinder to a pre-treatment to improve adhesion of the coating layer to the inner surface.

[0166] In a particularly preferred embodiment, this pretreatment involves forming a layer of an adhesion promoter on the interior surface of the cylinder, preferably a layer of an adhesion promoter comprising [(bicycloheptenyl)ethyl]trimethoxysilane.

[0167] Preferably, the pretreatment comprises: g1) spraying the inner surface of the cylinder with a solution of [(bicycloheptenyl)ethyl]trimethoxysilane in isopropyl alcohol, preferably a 2.2 wt.% solution, preferably with an ultrasonic static nozzle; and g2) heating the cylinder thus treated, preferably in an oven, until the isopropyl alcohol present on the surface of the glass has evaporated and thermal energy has been provided for the formation of chemical bonds between the glass and the adhesion promoter layer; It is performed by.

[0168] In an alternative preferred embodiment, the pretreatment comprises: g1') heating the cylinder, preferably in an oven, to a predetermined temperature; and g2') spraying, preferably by means of an ultrasonic static nozzle, a solution of [(bicycloheptenyl)ethyl]trimethoxysilane in isopropyl alcohol, preferably a 2.2% by weight solution, onto the inner surface of the heated cylinder; It can be executed by:

[0169] In this case, the cylinder is then heated to a temperature suitable to evaporate the isopropyl alcohol of the spray solution and provide sufficient thermal energy for the formation of a chemical bond between the glass and the layer of adhesion promoter.

[0170] Preferably, steps g2) and g1') of heating the cylinder are carried out in an oven preferably heated to a temperature between 120°C and 145°C, more preferably equal to approximately 140°C, for a time between 14 and 25 minutes, more preferably equal to approximately 20 minutes.

[0171] Preferably, the amount of the solution of [(bicycloheptenyl)ethyl]trimethoxysilane in isopropyl alcohol sprayed onto the inner surface of the cylinder is 7-50 μL, more preferably 7-22 μL.

[0172] In a preferred embodiment of the present invention, after storage for 3 months at a temperature of -40°C, the average normalized concentration of particles released from the coating layer on the inner surface of the cylinder into the test solution and having an average diameter of 10 μm or more or 25 μm or more, as determined by the LO (light obscuration) method according to the US standard USP787 described in the United States Pharmacopeia 44-NF39 (2021), is less than or equal to 60% of the limit value according to the standard.

[0173] In particular, for particles having a mean diameter of 25 μm or more, this mean value is not more than 5% of the limit value according to the standard.

[0174] In a preferred embodiment, after storage for 3 months at a temperature of -40°C, the average value of the normalized concentration of particles having an average diameter of 10 μm or more or 25 μm or more, released from the partially crosslinked coating layer into the test solution, for example by irradiation treatment, preferably plasma irradiation treatment, of the inner surface of the cylinder, and determined by the LO (light obscuration) method according to the US standard USP787 described in the United States Pharmacopeia 44-NF39 (2021), is less than or equal to 10% of the limit value according to said standard.

[0175] In particular, for particles having a mean diameter of 25 μm or more, this mean value is not more than 1% of the limit value according to the standard.

[0176] Both of these preferred embodiments are particularly advantageous in the case of injectable pharmaceutical compositions containing temperature-sensitive active ingredients, such as so-called biotechnological drugs containing recombinant proteins or mRNA vaccines. These preferred embodiments make it possible to achieve a significant reduction in the amount of particles released in pharmaceutical compositions stored in the cylinder of a medical injection device, even after long storage periods at the low temperatures required for this type of pharmaceutical composition.

[0177] In a preferred embodiment, after storage for 3 months at a temperature of +5°C or +25°C or +40°C, the average value of the normalized concentration of particles having an average diameter of 10 μm or more or 25 μm or more, released from the partially crosslinked coating layer into the test solution, for example by irradiation treatment, preferably plasma irradiation treatment, of the inner surface of the cylinder, and determined by the LO (light obscuration) method according to the US standard USP789 described in the United States Pharmacopeia 44-NF39 (2021), is below the limit value according to the standard.

[0178] This preferred embodiment is particularly advantageous in the case of injectable pharmaceutical compositions used in the ophthalmic field, where the American standard USP 789 provides very strict limitations regarding the maximum amount of particles acceptable in pharmaceutical compositions stored in the cylinder of a medical injection device, even after long periods of storage at the storage temperatures required for this type of pharmaceutical composition.

[0179] In connection with what has been indicated above, within the framework of the description and the subsequent claims, the term "normalized" refers to values ​​normalized with respect to the limit value of the standard or maximum value of the particle count considered.

[0180] In a preferred embodiment, the method of the present invention further comprises step h) of filling the cylinder of the medical injection device with the injectable liquid pharmaceutical composition, which step h) is carried out after cooling the coating layer formed on the inner surface of the cylinder to room temperature.

[0181] In this way it is advantageously possible to obtain a medical device, such as a syringe, pre-filled with a predetermined amount of an injectable liquid pharmaceutical composition and ready to use.

[0182] In a preferred embodiment of the medical injection device according to the invention, in each arbitrary part of a cylinder having an axial length of 1.0 mm and unfolded in a plane, the coverage, defined as the ratio between the area covered by the coating layer and the total measured area, corresponding to the total area of ​​said part, is at least equal to 90%.

[0183] In this way, advantageously - reducing the risk of unwanted contact between the injectable liquid pharmaceutical composition stored in the cylinder of the injection device and the inner glass surface of the cylinder, - optimal sliding properties (in terms of static and dynamic friction) of the plunger in the cylinder of the injection device, and - optimal properties of surface regularity of the coating layer, such as substantially reducing the problems associated with false defects that may be erroneously detected by visual inspection devices of medical injection devices, It is possible to have:

[0184] In a preferred embodiment of the medical injection device according to the invention, the average value of at least 30 measurements of the static sliding friction force of the plunger in the cylinder, measured on an empty cylinder of nominal volume of 1 mL at room temperature, is between 2 N and 3 N.

[0185] In a preferred embodiment of the medical injection device according to the invention, after storage at room temperature for 3 months, the average value of at least 30 measurements of the static sliding friction force of the plunger in the cylinder, measured at room temperature on an empty cylinder of nominal volume 0.5 mL, is between 1 N and 3 N.

[0186] In a preferred embodiment of the medical injection device according to the invention, after storage at -40°C for 7 days, the average value of at least 30 measurements of the static sliding friction force of the plunger in the cylinder, measured on an empty cylinder of nominal volume of 1 mL, is between 1.5 N and 3 N.

[0187] In a preferred embodiment of the medical injection device according to the invention, the average value of at least 30 measurements of the dynamic sliding friction force of the plunger in the cylinder, measured on an empty cylinder of nominal volume of 1 mL at room temperature, is between 1.5 N and 2.5 N.

[0188] In a preferred embodiment of the medical injection device according to the invention, after storage at room temperature for 3 months, the average value of at least 30 measurements of the dynamic sliding friction force of the plunger in the cylinder, measured at room temperature on an empty cylinder of nominal volume 0.5 mL, is between 1 N and 2 N.

[0189] In a preferred embodiment of the medical injection device according to the invention, after storage at -40°C for 7 days, the average value of at least 30 measurements of the dynamic sliding friction force of the plunger in the cylinder, measured on an empty cylinder of nominal volume of 1 mL, is between 1.5 N and 2.5 N.

[0190] Advantageously, the above-mentioned average values ​​of the static and dynamic sliding frictional forces of the plunger in the cylinder fully correspond to those required by the pharmaceutical and cosmetic industries, which are generally 2-6 N for the static sliding frictional force and 1-3 N for the dynamic sliding frictional force.

[0191] Preferably, the average values ​​of the static sliding friction force and the dynamic sliding friction force of the plunger in the cylinder are measured by the following test method.

[0192] The plunger is mounted in an empty cylinder of nominal capacity 1 mL long or 0.5 mL and within 24 hours of its positioning, starting from zero preload, a constant sliding speed is applied to the plunger equal to 240 mm / min for a cylinder of nominal capacity 1 mL long and equal to 100 mm / min for a cylinder of nominal capacity 0.5 mL, which is adapted to keep the plunger in motion and to measure, by a dynamometer, first the static friction force and then the kinetic friction force of the same plunger during sliding.

[0193] Further details of this test method are provided below in the Examples.

[0194] In a preferred embodiment, as explained above in relation to the manufacturing method, the medical injection device according to the invention comprises a partially cross-linked coating layer on the inner surface of the cylinder, preferably by irradiation treatment, even more preferably by plasma irradiation treatment as described above.

[0195] In a preferred embodiment, as described above in relation to the manufacturing method, the medical injection device according to the invention may further comprise a layer of adhesion promoter applied to the inner surface of the cylinder, preferably a layer of adhesion promoter comprising [(bicycloheptenyl)ethyl]trimethoxysilane.

[0196] In a preferred embodiment, as described above in relation to the method of manufacture, the medical injection device according to the invention further comprises a plunger mounted within and in sliding engagement with the cylinder.

[0197] In a preferred embodiment, as described above in connection with the method of manufacture, the medical injection device according to the invention may further comprise an injectable liquid pharmaceutical composition within the cylinder in contact with its inner surface.

[0198] In a preferred embodiment, the injectable liquid pharmaceutical composition comprises a drug and / or active ingredient in a form suitable for injection selected from one or more of the following, as far as compatible: allergen-specific immunotherapy compositions, oligonucleotides, particularly antisense oligonucleotides and RNAi antisense oligonucleotides, biological response modifiers, blood derivatives, enzymes, monoclonal antibodies, particularly conjugated and bispecific monoclonal antibodies, oncolytic viruses, peptides, particularly recombinant and synthetic peptides, polysaccharides, proteins, particularly recombinant and fusion proteins, vaccines, particularly conjugate vaccines, DNA vaccines, inactivated vaccines, mRNA vaccines, recombinant vector vaccines, subunit vaccines, or combinations thereof.

[0199] More preferably, the drug and / or active ingredient in a form suitable for injection is selected, where compatible, from the following: GEN-3009, (human insulin analog A21G + pramlintide), (AZD-5069 + durvalumab), (futuximab + modotuximab), [225Ac]-FPI-1434, 111In-CP04, 14-F7, 212 Pb-TCMC-trastuzumab, 2141 V-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 biosimilar, 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, Ancrod, Andecaliximab, Anetumab corixetan, Anetumab ravtansine, ANK-700, Antibodies against snake venom,, Antibodies against anthrax, antibodies against coronavirus disease 2019 (COVID-19), antibodies against tetanus, antibodies against type 1 diabetes, antibodies against OX40 agonist against solid tumors, antihemophilic factor (recombinant), antisense oligonucleotide RNAi inhibiting EPHA2 in case of solid tumors and ovarian cancer, ANX-007, ANX-009, AP-101, apitegromab, APL-501, APL-501, APN-01, APS-001+flucytosine, APSA-01, APT-102, APVAC-1, APVAC-2, APVO-436, APX-003, APX-005M, ARCT-810, ARGX-109, ARGX-117, AROANG-3, AROAPOC-3, AROHIF-2, ARO-HSD, asclinbacumab, ASLAN-004, ASP-1235, ASP-1650, ASP-9801, AST-008, Astegolimab, Asnercept, 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, Rituximab (conjugated) (Aurixim®), AV-1, AVB-500, Avdoralimab, AVE- 1642, AVI-3207, AVID-100, AVID-200, Aviscumin, Avizaximab, Axatilimab, B-001, B-002, Barsiban, 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, Bepraneumab, Bermekimab, Bertilimumab, Betalutin, bevacizumab, becmarilimab, 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-0 76, BIIB-101, BIL-06v, bimagrumab, BIO89-100, coronavirus disease 2019 (COVID-19), biological response modifiers for urinary tract infections, prosthetic joints and Acinetobacter infections, biological response modifiers for unspecified indications, bispecific monoclonal antibody 1 for diabetic macular edema and wet macular degeneration, HIV for HIV infection Bispecific monoclonal antibodies inhibiting 1 Env, Bispecific monoclonal antibodies detecting GD2 and CD3 for oncology, Bispecific monoclonal antibodies detecting PD-L1 and CTLA4 for pancreatic ductal adenocarcinoma, 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-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, Brivolizide, Bromelain, BT-063, BT-1718, BT-200, BT-5528, BT-588, BT-8009, BTI-322, BTRC-4017A, Budicalimab, BXQ-350, C1 esterase inhibitor (human), Caviralizumab, Kamidanlumab Tecillin, Canalpatuleb, Cavatak, CBA-1205, CBP-201, CBP-501, CC-1, CC-90002, CC-90006, CC-93269, CC-9 9712, CCW-702, CDX-0159, CDX-301, CDX-527, Celyvir, semdisiran, sendakimab, CERC-002, CERC-007, cebostamab, civisatamab, CIGB-128, CIGB-258, CIGB-300, CIGB-500, CIGB-552, CIGB-814, CIGB-845, simpanemab, cinrebafusp alpha, CIS-43, CiVi-007, CJM-112, CKD-702, Clustoid Dermatophagoides pteronyssinus, CM-310, CMK-389, CMP-001, CNTO-6785, CNTO-6785, CNV-NT, coagulation factor VIII (recombinant), cobomersen, codrituzumab, cofetuzumabperidotin, 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, Cy Pep-1, CYT-107, CYT-6091 Anti-cytomegalovirus immunoglobulin (human), Dabrafenib mesylate + panitumumab + trametinib dimethyl sulfoxide, DAC-002, Darcinonacog alfa, Dalotuzumab, Dambatirsen + durvalumab, Dapiglutide, Daxzilimab, DB-001, DCRA-1AT, Decavi le, depatuxizumab, desmopressin, DF-1001, DF-6002, diamide, zilpacimab, ziridabuumab, DK-001, DKN-01, DM-101, DM-199, DMX-101, DNL-310, DNP-001, DNX-2440, domaglozumab, donanemab, donidarolsen sodium, DP-303c, DS-1055 a, DS-2741, DS-6157, DS-7300, DS-8273, durvalumab + monalizumab, durvalumab + oleculab, durvalumab + oportuzumab monatox, durvalumab + selumetinib sulfate, DX-126262, DXP-593, DXP-604, DZIF-10c, E-2814, E-3112, EBI-031, Yttrium-90 labeled etreotide, efabaleukin alfa, efpegsotropine, effluxifermin, eftiragimod alfa, eftozanermin alfa, EG-milotin, elezanumab, elipovimab, emaactuzumab, enadenotsileb, Engedi-1000, ensituximab, EO-2401, epcolitamab, ERY-974, etiglimab, etokimab, Evitar, EVX-02, exenatide, F-0002ADC, F-520, F-598, F-652, faricimab, FAZ-053, FB-704A, FB-825, FF-21101, fibrinogen concentrate (human), 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, fusion proteins for allergic asthma, fusion proteins antagonizing the thrombopoietin receptor for idiopathic thrombocytopenic purpura, fusion proteins antagonizing the EGFR for glioblastoma multiforme and malignant glioma, fusion proteins inhibiting CD25 for oncology Fusion proteins, Fusion proteins targeting mesothelin for oncology, Fusion proteins for colitis, hypertension and ulcerative colitis, FX-06, G-035201, G-207, G-3215, Galetusumab, Gatipotuzumab, GB-223, GBB-101, GC-1118A, GC-5131A, GEM-103, GEM-333, GEM-3PSCA, GemibotulinumtoxinA, GEN-0101, GEN-1046, Gensci-048, Gentuximab, Gevokizumab, Glezocimab, Glofitamab, Glucagon, GM-101, GMA-102, GMA-301, GNR-051, GNR-055, GNR-084, GNX-102, goserelin acetate, goslanemab, 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-31749 98, 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-1 9, hRESCAP, HS-214, HS-628, HS-630, HS-636, HSV-1716, HTD-4010, HTI-1066, Hu8F4, HUB-1023, hVEGF -26104, HX-009, Hyaluronidase (recombinant), IBI-101, IBI-110, IBI-112, IBI-188, IBI-302, IBI-318, IBI-322, IBI-939, IC-14, ICON-1, ICT-01, Ielamirimab, Ifavotuzumab, IGEM-F, IGM-2323, IGM-8444, IGN-002, IMA-950, IMA-970A, IMC-002, IMCF-106C, IMCY-0098, IMGN-632, IMM-005, IMM-01, IMM-201, Immunoglobulin (human), Imsidolimab, INA-03, INBRX-101, INBRX-105, INBRX-105, INCAGN-1876, INCAGN-1949, INCAGN-2385, Incacumab, Indatuximab ravtansine, Interferon alfa-2b, Interferon alfa-2b, INV AC-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, IO NIS-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-19 1, JTX-4014, JY-025, JZB-30, JZB-34, K-170, K-193, KAN-101, KD-033, KER-050, KH-903, KHK-4083, KHK-664 0, EDV pediatric, 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, lanotuzumab, lactomab, radilatuzumab vedotin, laronidase, LBL-007, LDOS-47, letolizumab, leuproreductase acetate Lido, LEVI-04, LH-021, riathermin, lirilumab, LIS-1, LKA-651, LLF-580, LMB-100, LNA-043, LOAd-703, rodapolimab, lorcafusp alfa, LP-002, LT-1001, LT-1001, LT-1001, LT-3001, LT-3001, LTI-01, LTX-315, LuAF-82422, LuAF-87908, ルリズマブペゴール、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, meplasmab, mezagitamab, MG-021, MG-1113A, MGC-018, MIL-62, MIL-77, MIL-86, mitazarimab, MK-1654, MK-3655, MK-4166, MK-4280, MK -4621, MK-5890, molgramostim, conjugated monoclonal antibodies identifying CD276 for oncology, conjugated monoclonal antibodies identifying CD45 for oncology, conjugated monoclonal antibodies identifying CEACAM5 for non-small cell lung cancer and metastatic colorectal cancer, conjugated monoclonal antibodies identifying mucin 1 for metastatic colorectal cancer, conjugated monoclonal antibodies targeting PSMA for prostate cancer, conjugated monoclonal antibodies targeting dengue fever Monoclonal antibodies, monoclonal antibodies antagonizing IL-2Rβ for celiac disease, monoclonal antibodies antagonizing interleukin-6 receptor for oncology and tropical spastic paraparesis, rheumatoid arthritis, monoclonal antibodies antagonizing PD1 for oncology, monoclonal antibodies antagonizing PD1 for solid tumors, monoclonal antibodies inhibiting CD4 for HIV-1, monoclonal antibodies inhibiting GD2 for oncology, monoclonal antibodies inhibiting glycoproteins for rabies, monoclonal antibodies inhibiting IL17 for autoimmune and musculoskeletal disorders, monoclonal antibodies inhibiting IL5 for asthma and chronic obstructive pulmonary disease (COPD), monoclonal antibodies inhibiting PD-L1 for solid tumors, monoclonal antibodies inhibiting TNF-α for ankylosing spondylitis, psoriasis and rheumatoid arthritis, monoclonal antibodies inhibiting TNF-α for Dupuytren's contracture, monoclonal antibodies inhibiting VEGF for diabetic macular edema and wet age-related macular degeneration, Monoclonal antibodies to inhibit VEGF for oncology and ophthalmology, monoclonal antibodies to inhibit VEGFA for metastatic colorectal cancer and non-small cell lung cancer, monoclonal antibodies targeting CD66b for hematological cancers and metabolic disorders, monoclonal antibodies targeting GP41 for HIV infection, MORAb-202, Motrem, MP-0250, MP-0274, MP-0310, MP-0420, MRG-001, MRG-002, MRG-003, MRG-110, mRNA-2416, mRNA-2752, mRNA-3927, MSB-0254, MSB-2311, MSC-1, MT-1001, MT-1002, MT- 2990, MT-3724, MT-3921, MTX-102, murentamab, MVT-5873, MVXONCO-1, MW-11, MW-33, NA-704, namilumab, naratuximab emtansine, navacizumab, NBE-002, NBF-006, NC-318, NC-410, nembulkin alfa, NEOPV-01 , NG-348, NG-350a, NG-641, NGM-120, NGM-395, NGM-621, NI-006, NI-0801, Nidanilimab, Nimasimab, 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, Octreotide acetate CR, Octreotide acetate microspheres, Odronextamab, Odronextamab, OH-2, Olamuxept, Olecurumab, Olinbasimab, Olpaciran, Olvimulogene nanobasilepvec nanivacirepvec), OMS-906, onabotulinumtoxinA, ONC-392, ONCase-PEG, human papillomavirus-associated cancers, oncolytic viruses for human papillomavirus infection and coronavirus disease 2019 (COVID-19), oncolytic viruses for metastatic breast cancer, oncolytic viruses for oncology, oncolytic viruses for solid tumors, oncolytic viruses that activate IL-12 for recurrent prostate and metastatic pancreatic cancer, oncolytic viruses that activate thymidine kinase for oncology, oncolytic viruses that antagonize PD1 for solid tumors, oncolytic viruses that target CD155 / NECL5 for solid tumors, oncolytic viruses that target CD46 and SLC5A5 for oncology, human papillomavirus Oncolytic viruses targeting E6 and E7 for human papilloma virus (HPV)-associated solid tumors, oncolytic viruses targeting MAGE-A3 for solid tumors, ONCOS-102, ONCR-177, ongelicimab, ONO-4685, ombatilimab, OPK-88005, OPT-302, ORCA-010, OrienX-010, orilanolimab, olutismab, OS-29 66, OSE-127, osocimab, otelixizumab, OTO-413, OTSA-101, OXS-1550, OXS-3550, P-28R, P-2G12, pakmilimab, panobakumab, palvorix, pasireotide, pasotuxizumab, PC-mAb, PD-01, PD-0360324, PD-1+antagonist pegylated interferon alfa-2b, pegbelfermin,Peginterferon lambda-1a, Peralep, Peralep, Pemziviptadil, PEN-221, Pentosan polysulfate sodium, Pepinemab, Pepinemab, Peptides against coronavirus disease 2019 (COVID-19), Peptides against solid tumors, Pertuzumab biobetter, Pexastimodine devasilepvec, PF-04518600, PF-06480605, PF-06730512, PF-0 6755347, 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, Pramotamab, Plasminogen (human) 1, Plexalis, PM-8001, PNT-001, Pollinex Quattro Tree, PolyCAb, Poly-ICLC, PolyPEPI-1018, Poncegromab, PP-1420, PR-15, PR-200, Prasinezumab, Plexigeversen, PRL3-ZUMAB, Proteins for diabetic foot ulcers and cerebral hemorrhage, Proteins for osteoarthritis and asthma, Proteins that activate IL12 for infectious diseases and oncology, PRS-06 0, PRTX-100, PRV-300, PRV-3279, PRX-004, PSB-205, PT-101, PT-320, PTR-01, PTX-35, PTX-9908, PTX-99 08, PTZ-329, PTZ-522, PVX-108, QBECO-SSI, QBKPN-SSI, QL-1105, QL-1203, QL-1207, QL-1604, QPI-1007, QPI-1007, quavonlimab, ketomolimab, QX-002N, QX-005N, radosferlin, ranibizumab, ranpirnase, ravagalimab, next generation ravulizumab, RC-28, RC-402, RC-88, RD-001, REC-0438, recombinant carboxypeptidase G2 for methotrexate toxicity, recombinant enzymes for organophosphate nerve agent poisoning, recombinant peptides stimulating GHRH for cardiovascular, central nervous system, musculoskeletal and metabolic disorders, recombinant plasma gelsolin substitutes for infectious diseases, recombinant proteins for inflammatory bowel disease, multiple sclerosis and psoriasis. recombinant proteins for oncology; recombinant proteins stimulating IFNAR1 and IFNAR2 for oncology; recombinant proteins stimulating KGFR for chemotherapy-induced gastrointestinal and oral mucositis; recombinant proteins stimulating thrombopoietin receptor for idiopathic thrombocytopenic purpura; recombinant proteins inhibiting CD13 for lymphomas and solid tumors; recombinant proteins inhibiting coagulation factor XIV for hemophilia A and hemophilia B; recombinant urate oxidase substitutes for acute hyperuricemia; resemtide trifluoroacetate, REGN-1908 1909, 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, Lenaparin, REP-2139, REP-2165, Reteplase, RG-6139, RG-6147, RG-6173, RG-6290, RG-6292, RG-6346, RG-70240, RG-70240, RG-7826, RG-7835, RG-7861, RG-7880, RG-7992, RGLS-4326 rigvir, rilimogene galvacirepvec, ristenigini, rituximab, RMC-035, RO-7121661, RO-7227166, RO-7284755, RO-7293583, RO-7297089, romilkimab, lopocampid, rozivafusp alfa, RPH-203, RPV-001, rQNestin-34.5v.2, RSLV-132, RV-001, RXI-109, R Z-358, SAB-176, SAB-185, SAB-301, SAIT-301, SAL-003, SAL-015, SAL-016, Sanguinate, SAR-4 39459, SAR-440234, SAR-440894, SAR-441236, SAR-441344, SAR-442085, SAR-442257, SB-11285, SBT-605 0, SCB-313, SCIB-1, SCO-094, SCT-200, SCTA-01, SD-101, SEA-BCMA, SEA-CD40, SelectAte, celecrelumab, SelK-2, semolinemab, cercultamabbutariline, seribantomab, setrusumab, sebparin sodium, SFR-1882, SFR-9213, SFR-9216, SFR-9314, SG-0 01, 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, simlukafusp alpha, siplizumab, sirukumab, SKB-264, SL-172154, SL-279252, SL-701, SOC-101, SOJB, somatropin SR, sotatercept, spifermin, 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, slituzumab, subratoxumab, SVV-001, SY-005, SYD-1875, Sym-015, Sym-021, Sym-022, Sym-023, SYN-004, S YN-125, synthetic peptides inhibiting SLC10A1 for hepatitis B and type 2 diabetes, synthetic peptides modulating GHSR for chronic kidney disease, synthetic peptides targeting CCKBR for medullary thyroid carcinoma, synthetic peptides targeting somatostatin receptors for neuroendocrine gastroenteropancreatic ductal tumors, T-3011, T-3011, TA-46, TAB-014, TAB-014, tafoxiparin sodium, TAK-101, TAK-169, TAK-573, TAK-611, TAK-671, talquetamab, tasadenotulev, TBX-6517, TBV. NSC, tebotelimab, teclistamab, teisotuzumab vedotin, telomelysin, temelimab, tenecteplase, tesidormab, teverelix, TF-2, TG-1801, TG-4050, TG-6002, TG-6002, T-Guard, THOR-707, THR-149, THR-317, thrombosome, thymalfasin, tirabonemab, TILT-123, tilvestamab, tinurimab, tipakinogensovatine, tiplerestat, TM-123, TMB-365, TNB-383B, TNM-002, TNX-1300, tomalalimab, tomzotuximab, tonabacase, tralesinidase alfa, Trebananib, trevoglumab, TRK-950, TRPH-222, TRS-005, TST-001, TTHX-1114, TTI-621, TTI-622, TTX-030, TVT-058, TX-250, TY-101, tidivumab, U-31402, UB-221, UB-311, UB-421, UB-621, UBP-1213, UC-961, UCB-6114, UCHT-1, UCPVax, urocupulumab, UNEX-42, UNI-EPO-Fc, urelumab, UV-1, V-938, vaccine against acute lymphoblastic leukemia, vaccine against B-cell non-Hodgkin's lymphoma, vaccine against chronic lymphocytic leukemia, vaccine against glioma, vaccine against hormone-sensitive prostate cancer, Vaccines for laminoma, Vaccines for non-muscle invasive bladder cancer, Vaccines for ovarian cancer, Vaccines targeting Brachyury and HER2 for oncology, Vaccines targeting Brachyury for oncology, Vaccines targeting CCL20 for B-cell non-Hodgkin's lymphoma, Vaccines targeting CEA for colorectal cancer, Vaccines targeting IFN-alpha for metabolic, immunological, infectious and musculoskeletal disorders, VAL-201, vanticumab, vanucizumab, varlilumab, Vas-01, VAX-014, VB-10NEO, VCN-01, bibecotamab, vibostolimab, VIR-2218, VIR-2482, VIR-3434, VIS-410, VIS-649, Bixarelimab, VLS-101, bofatamab, boragidemab, bopratelimab, Voyager-V1, VRC-01, VRC-01LS, VRC-07523LS, VTP-800, bunakizumab, bupanorthene sodium, Vx-001, Vx-006, W-0101, WBP-3425, XAV-19, xentuzumab, XmAb-20717, XmAb-22841, XmAb-23 104, 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, zantecimab, zenoctuzumab, ZG-001, ZK-001, ZL-1201, Zofin, or combinations thereof.

[0200] In a preferred embodiment, the kit of parts for assembling a medical injection device according to the invention includes, wherever applicable, the preferred features of the medical device described above.

[0201] Further features and advantages of the present invention will become more readily apparent from the following description of some of its preferred embodiments, given below as non-limiting examples, with reference to the accompanying drawings, in which:

[0202] In the figure: [Brief description of the drawings]

[0203] [Figure 1] FIG. 1 shows in partial longitudinal section a medical injection device, in particular a syringe, according to a preferred embodiment of the invention. [Diagram 2] FIG. 2 shows a block diagram that illustrates generally an apparatus for manufacturing a medical injection device according to a preferred embodiment of the present invention. [Diagram 3] FIG. 3 shows a number of graphs illustrating the profile along the axial development of the cylinder of a medical injection device with a nominal capacity of 1 mL and, respectively, 3 mL of exemplary coating layer thicknesses applied to the inner surface of the cylinder according to a preferred embodiment of the present invention. [Figure 4] FIG. 4 shows a number of graphs illustrating the profile along the axial development of the cylinder of a medical injection device with a nominal capacity of 1 mL and, respectively, 3 mL of exemplary coating layer thicknesses applied to the inner surface of the cylinder according to a preferred embodiment of the present invention. [Diagram 5] FIG. 5 shows an equal number of graphs illustrating the profiles of exemplary coating layers applied to the inner surface of the cylinder of a medical injection device with a nominal volume of 0.5 mL along its axial development, with thicknesses measured at room temperature immediately after application and cooling of the coating layer (t0) and after storage at room temperature for 3 months (t3), according to a preferred embodiment of the present invention and according to the prior art. [Figure 6] FIG. 6 shows an equal number of graphs illustrating the profiles of exemplary coating layers applied to the inner surface of the cylinder of a medical injection device with a nominal volume of 0.5 mL along the axial development of the cylinder, with thicknesses measured at room temperature immediately after application and cooling of the coating layer (t0) and after storage at room temperature for 3 months (t3), according to a preferred embodiment of the present invention and according to the prior art. [Figure 7] FIG. 7 shows an equal number of graphs illustrating the profiles of exemplary coating layers applied to the inner surface of the cylinder of a medical injection device with a nominal volume of 0.5 mL along the axial development of the cylinder, with thicknesses measured at room temperature immediately after application and cooling of the coating layer (t0) and after storage at room temperature for 3 months (t3), according to a preferred embodiment of the present invention and according to the prior art. [Figure 8] FIG. 8 shows an equal number of graphs illustrating the profiles of exemplary coating layers applied to the inner surface of the cylinder of a medical injection device with a nominal volume of 0.5 mL along its axial development, with thicknesses measured at room temperature immediately after application and cooling of the coating layer (t0) and after storage at room temperature for 3 months (t3), according to a preferred embodiment of the present invention and according to the prior art. [Figure 9]FIG. 9 shows an equal number of graphs illustrating the profiles of exemplary coating layers applied to the inner surface of the cylinder of a medical injection device with a nominal volume of 0.5 mL along the axial development of the cylinder, with thicknesses measured at room temperature immediately after application and cooling of the coating layer (t0) and after storage at room temperature for 3 months (t3), according to a preferred embodiment of the present invention and according to the prior art. [Figure 10] FIG. 10 shows an equal number of graphs illustrating the profiles of exemplary coating layers applied to the inner surface of the cylinder of a medical injection device with a nominal volume of 0.5 mL along its axial development, with thicknesses measured at room temperature immediately after application and cooling of the coating layer (t0) and after storage at room temperature for 3 months (t3), according to a preferred embodiment of the present invention and according to the prior art. [Figure 11] FIG. 11 shows the average values ​​of the static sliding friction force of the plunger attached to an empty cylinder with a nominal volume of 1 mL for several examples of medical injection devices according to the present invention and the prior art at different times. [Figure 12] FIG. 12 shows average values ​​of dynamic sliding friction forces of plungers attached to empty cylinders with a nominal volume of 1 mL for several examples of medical injection devices according to the present invention and according to the prior art at different times. [Figure 13] FIG. 13 shows the average values ​​of the static sliding friction forces of plungers attached to cylinders with a nominal volume of 1 mL filled with a test solution having a dynamic viscosity of 1 mPa s for several examples of medical injection devices according to the present invention and according to the prior art at different times. [Figure 14] FIG. 14 shows the average values ​​of the dynamic sliding friction forces of plungers attached to cylinders having a nominal volume of 1 mL filled with a test solution having a dynamic viscosity of 1 mPa s for several examples of medical injection devices according to the present invention and according to the prior art at different times. [Figure 15]FIG. 15 shows the average values ​​of static sliding friction forces of plungers attached to cylinders of nominal volume 1 mL filled with test solutions for several examples of medical injection devices according to the present invention and according to the prior art after storage times of 7 days at different temperatures. [Figure 16] FIG. 16 shows the average values ​​of the dynamic sliding friction forces of the plungers attached to cylinders with a nominal volume of 1 mL filled with the test solution for several examples of medical injection devices according to the present invention and according to the prior art after a storage time of 7 days at different temperatures. [Figure 17] FIG. 17 shows the average values ​​of the static sliding friction forces of the plungers attached to cylinders with a nominal volume of 1 mL filled with the test solution after storage times of 2 and 7 days at a temperature of −40° C. for several examples of medical injection devices according to the invention and according to the prior art. [Figure 18] FIG. 18 shows the average values ​​of the dynamic sliding friction forces of the plungers attached to cylinders with a nominal volume of 1 mL filled with the test solution after storage times of 2 and 7 days at a temperature of −40° C. for several examples of medical injection devices according to the invention and according to the prior art. [Figure 19] FIG. 19 shows the average values ​​of the static sliding friction forces of the plungers attached to an empty cylinder with a nominal volume of 0.5 mL at room temperature for several examples of medical injection devices according to the present invention and according to the prior art at different times. [Figure 20] FIG. 20 shows average values ​​of dynamic sliding friction forces of plungers attached to an empty cylinder with a nominal volume of 0.5 mL at room temperature for several examples of medical injection devices according to the present invention and according to the prior art at different times. [Figure 21] FIG. 21 shows the average static sliding friction forces of plungers attached to cylinders of nominal volume 0.5 mL filled with test solutions for several examples of medical injection devices according to the present invention and the prior art at different time points using a storage temperature of −40° C. [Figure 22]FIG. 22 shows the average values ​​of the dynamic sliding friction forces of the plungers attached to cylinders of nominal volume 0.5 mL filled with test solutions for several examples of medical injection devices according to the present invention and the prior art, using a storage temperature of −40° C., at different time points. [Figure 23] FIG. 23 shows the average static sliding friction force of the plunger attached to a cylinder of nominal volume 0.5 mL filled with the test solution for several examples of medical injection devices according to the present invention and according to the prior art, using a storage temperature of +5° C., at different time points. [Figure 24] FIG. 24 shows the average values ​​of the dynamic sliding friction forces of the plungers attached to cylinders of nominal volume 0.5 mL filled with test solutions for several examples of medical injection devices according to the present invention and according to the prior art, using a storage temperature of +5° C., at different time points. [Diagram 25] FIG. 25 shows the average static sliding friction force of the plunger attached to a cylinder of nominal volume 0.5 mL filled with the test solution for several examples of medical injection devices according to the present invention and according to the prior art, using a storage temperature of +25° C., at different time points. [Figure 26] FIG. 26 shows the average values ​​of the dynamic sliding friction forces of the plungers attached to cylinders of nominal volume 0.5 mL filled with test solutions for several examples of medical injection devices according to the present invention and according to the prior art, using a storage temperature of +25° C., at different time points. [Figure 27] FIG. 27 shows the average static sliding friction force of the plunger attached to a cylinder of nominal volume 0.5 mL filled with the test solution for several examples of medical injection devices according to the present invention and according to the prior art, using a storage temperature of +40° C., at different time points. [Figure 28] FIG. 28 shows the average values ​​of the dynamic sliding friction forces of the plungers attached to cylinders of nominal volume 0.5 mL filled with test solutions for several examples of medical injection devices according to the present invention and according to the prior art, using a storage temperature of +40° C., at different time points. [Figure 29]FIG. 29 summarizes the average values ​​of static sliding friction forces of plungers attached to cylinders having a nominal volume of 0.5 mL filled with the test solutions shown in FIGS. 21 to 28 for examples of medical injection devices according to the present invention and the prior art after three months of storage at different temperatures. [Diagram 30] FIG. 30 summarizes the average values ​​of the dynamic sliding friction forces of plungers attached to cylinders having a nominal volume of 0.5 mL filled with the test solutions shown in FIGS. 21 to 28 for examples of medical injection devices according to the present invention and the prior art after three months of storage at different temperatures. [Diagram 31] FIG. 31 shows normalized values ​​of concentration of particles having a size of 10 μm or more for example medical injection devices having a cylinder with a nominal fill volume of 3.0 mL, filled with 3.3 mL of aqueous test solution, and subjected to automatic agitation (360° rotation of the sample), measured at room temperature according to the present invention and according to the prior art. [Diagram 32] FIG. 32 shows normalized values ​​of concentration of particles having a size of 25 μm or greater for example medical injection devices having a cylinder with a nominal fill volume of 3.0 mL, filled with 3.3 mL of aqueous test solution, and subjected to automatic agitation (360° rotation of the sample), measured at room temperature according to the present invention and according to the prior art. [Diagram 33] FIG. 33 shows normalized values ​​of the concentration of particles having a size of 10 μm or more measured at time 0 and after 6 months of storage at three different temperature conditions for example medical injection devices according to the present invention and according to the prior art, having a cylinder with a nominal fill volume of 0.5 mL filled with 0.25 mL of aqueous test solution. [Diagram 34] FIG. 34 shows normalized values ​​of the concentration of particles having a size of 10 μm or more measured at time 0 and after 6 months of storage at three different temperature conditions for example medical injection devices according to the present invention and according to the prior art, having a cylinder with a nominal fill volume of 0.5 mL filled with 0.25 mL of aqueous test solution. [Diagram 35]FIG. 35 shows normalized values ​​of the concentration of particles having a size of 10 μm or more measured at time 0 and after 6 months of storage at three different temperature conditions for example medical injection devices according to the present invention and according to the prior art, having a cylinder with a nominal fill volume of 0.5 mL filled with 0.25 mL of aqueous test solution. [Diagram 36] FIG. 36 shows normalized values ​​of particle concentration of examples of medical injection devices according to the present invention and according to the prior art, having a cylinder with a nominal filling volume of 1.0 mL and filled with 0.55 mL of aqueous test solution, determined by MFI test measured at different storage times at a temperature of -40°C. [Figure 37] FIG. 37 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of −40° C. and filled with 500 μL of an aqueous test solution. [Figure 38] FIG. 38 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of −40° C. and filled with 500 μL of an aqueous test solution. [Figure 39] FIG. 39 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by MFI test at different storage times at a temperature of −40° C. [Diagram 40] FIG. 40 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by MFI test at different storage times at a temperature of −40° C. [Diagram 41]FIG. 41 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of +5° C. and filled with 500 μL of an aqueous test solution. [Diagram 42] FIG. 42 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of +5° C. and filled with 500 μL of an aqueous test solution. [Diagram 43] FIG. 43 shows normalized values ​​of the concentration of particles having a size of 10 μm and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, filled with 500 μL of an aqueous test solution, whose coating has been treated by plasma irradiation, measured at a temperature of +5° C. [Diagram 44] FIG. 44 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for example medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, filled with 500 μL of an aqueous test solution, whose coating has been treated by plasma irradiation, measured at a temperature of +5° C. [Diagram 45] FIG. 45 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by the MFI test at different storage times at a temperature of +5° C. [Diagram 46] FIG. 46 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by the MFI test at different storage times at a temperature of +5° C. [Figure 47]FIG. 47 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of +25° C. and filled with 500 μL of an aqueous test solution. [Figure 48] FIG. 48 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of +25° C. and filled with 500 μL of an aqueous test solution. [Figure 49] FIG. 49 shows normalized values ​​of the concentration of particles having a size of 10 μm and 25 μm or more, respectively, for example medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, filled with 500 μL of an aqueous test solution and whose coating has been treated by plasma irradiation, measured at a temperature of +25° C. [Figure 50] FIG. 50 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for example medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, filled with 500 μL of an aqueous test solution and having a coating treated by plasma irradiation, measured at a temperature of +25° C. [Figure 51] FIG. 51 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by the MFI test at different storage times at a temperature of +25° C. [Figure 52] FIG. 52 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by the MFI test at different storage times at a temperature of +25° C. [Diagram 53]FIG. 53 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of +40° C. and filled with 500 μL of an aqueous test solution. [Figure 54] FIG. 54 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, measured at a temperature of +40° C. and filled with 500 μL of an aqueous test solution. [Figure 55] FIG. 55 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for example medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, filled with 500 μL of an aqueous test solution, whose coating has been treated by plasma irradiation, measured at a temperature of +40° C. [Figure 56] FIG. 56 shows normalized values ​​of the concentration of particles having a size of 10 μm or more and 25 μm or more, respectively, for examples of medical injection devices according to the present invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL, filled with 500 μL of an aqueous test solution, whose coating has been treated by plasma irradiation, measured at a temperature of +40° C. [Figure 57] FIG. 57 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by the MFI test at different storage times at a temperature of +40° C. [Figure 58] FIG. 58 shows particle release values ​​of examples of medical injection devices according to the invention and according to the prior art having a cylinder with a nominal filling volume of 0.5 mL filled with 500 μL of aqueous test solution, measured by the MFI test at different storage times at a temperature of +40° C. [Figure 59]FIG. 59 summarizes the normalized values ​​of the concentration of particles having a size of 10 μm and 25 μm and above, respectively, for example medical injection devices according to the present invention and according to the prior art, having a nominal filling volume of 0.5 mL and having a cylinder filled with 500 μL of aqueous test solution, whose coating was subjected to plasma irradiation treatment after storage for 3 months at different temperatures. [Figure 60] Figure 60 summarizes the normalized values ​​of the concentration of particles having a size of 10 μm and 25 μm and above, respectively, for example medical injection devices according to the present invention and according to the prior art, having a nominal filling volume of 0.5 mL and having a cylinder filled with 500 μL of aqueous test solution, whose coating was subjected to plasma irradiation treatment after storage for 3 months at different temperatures. [Figure 61] FIG. 61 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. [Figure 62] FIG. 62 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. [Figure 63] FIG. 63 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. [Figure 64] FIG. 64 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. [Figure 65]FIG. 65 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. [Figure 66] FIG. 66 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. [Figure 67] FIG. 67 shows an equal number of photographs made by optical microscopy of coating layers of silicone materials according to the present invention and according to the prior art that have been subjected to partial cross-linking by plasma irradiation at various irradiation times in various regions of the cylinder of a medical injection device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0204] A medical injection device, in particular a syringe, according to a preferred embodiment of the present invention is generally indicated by the reference numeral 1 in FIG.

[0205] As used herein, the term "syringe" is broadly defined to include cartridges, injection "pens" and other types of barrels or reservoirs adapted for assembly with one or more other components to provide a functional syringe.

[0206] The term "syringe" also includes related articles, such as autoinjectors, that provide a mechanism for expelling the contents.

[0207] The syringe 1 comprises a glass syringe cylinder 2 having a substantially cylindrical body 2a provided with a substantially conical end 2b.

[0208] The cylinder 2 has an inner surface 3 that is coated with a coating layer 4 .

[0209] The cylinder 2 is also configured to receive a plunger 5 through sliding engagement.

[0210] As such, in a conventional manner, a plunger 5 is associated with one end of a drive stem 6 .

[0211] In a preferred embodiment, shown in FIG. 1, the syringe 1 further comprises within the barrel 2 in contact with its inner surface 3 an injectable liquid 7, such as a liquid pharmaceutical composition.

[0212] The syringe 1 is also provided with a closure cap 8 at the end 2b of the cylinder 2 to allow the transport of the injectable liquid 7 in safe conditions.

[0213] In a preferred embodiment, the coating layer 4 has a viscosity of about 12500 cSt (125 cm 2 The composition may comprise about 100% by weight of a polydimethylsiloxane having a dynamic viscosity equal to about 100 g / s, for example, polydimethylsiloxane (PDMS) commercially available under the name Liveo™ 360 Medical Fluid (DuPont).

[0214] The coating layer 4 of the syringe 1 shown in FIG. 1 includes one or more of the features set forth in the description above and referenced herein.

[0215] In a preferred embodiment, the syringe 1 may be manufactured by an apparatus 10 shown diagrammatically in FIG.

[0216] The apparatus 10 comprises a storage tank 11, preferably made of stainless steel, for storing the coating composition provided with at least one heating element configured to heat the stored coating composition.

[0217] For example, the heating element for tank 11 may be an electrical resistor or tube through which a suitable heating fluid is circulated, and may be located within tank 11 itself, or may be an outer jacket of tank 11 through which a suitable heating fluid is circulated.

[0218] The tank 11 is in fluid communication with a coating composition circulation pump 12 by means of a tube 13, suitably insulated in a manner known per se, preferably made of stainless steel.

[0219] In a preferred embodiment, pump 12 includes a respective heating element, not well shown in FIG. 2, configured to heat a delivery head of pump 12, also not shown.

[0220] By way of example only, the heating element of the delivery head of the pump 12 may comprise one or more electrical resistors in a heat exchange relationship with the delivery head 12 of the pump, for example integrated into a respective casing, e.g., cylindrical, associated with the delivery head.

[0221] The pump 12 is in fluid communication with a dispensing head 14 configured to dispense the coating composition through a suitably insulated, preferably stainless steel, tube 15 in a manner known per se.

[0222] The dispensing head 14 is provided with at least one dispensing nozzle (not well shown in FIG. 2) configured to spray the coating composition onto the inner surface 3 of the barrel 2 of the syringe 1 .

[0223] Dispensing head 14 is provided with respective heating elements (also not clearly shown in FIG. 2) configured to heat the coating composition dispensed by the nozzles.

[0224] By way of example only, the heating element may be an electrical resistor in heat exchange relationship with the discharge nozzle, and may for example be incorporated in a cylindrical casing, for example, associated with the discharge nozzle.

[0225] Thus, in this preferred embodiment of the apparatus 10, the storage tank 11, the pump 12 and the dispensing head 14 are in fluid communication with each other via the tubes 13,15.

[0226] In a particularly preferred embodiment, the tubes 13, 15 are in heat exchange relationship with respective heating elements, such as electrical resistors or outer jackets of the tubes through which a suitable heating fluid is circulated.

[0227] In a manner known per se, the nozzle(s) of the dispensing head 14 are in fluid communication with a source 16 of a suitable dispensing gas, for example compressed air, via a tube 17 .

[0228] Preferably, the source 16 delivers compressed air at a pressure between 5 psi (0.34 bar) and 150 psi (10.34 bar), more preferably equal to about 30 psi (2.07 bar).

[0229] In a manner known per se, not clearly shown in FIG. 2, the device 10 comprises a movable support frame for a number of cylinders 2 of respective syringes 1, one of which is shown diagrammatically in FIG.

[0230] The coating composition dispensing head 14 and the support frame for the cylinder 2 of the syringe 1 are movable relative to one another to insert / retract each nozzle of the dispensing head 14 into / from each of the cylinders 2 of the plurality of cylinders 2 .

[0231] In a preferred embodiment, the relative movement between the dispensing head 14 and the support frame of the cylinder 2 is achieved by moving the latter relative to the dispensing head 14 which is fixed.

[0232] A preferred embodiment of a method for manufacturing a medical injection device, such as the syringe 1 described above, comprises the following steps, preferably performed by an apparatus 10 shown in FIG.

[0233] The first step is, for example, about 12500 cSt (125 cm 2 The method includes providing a coating composition comprising polydimethylsiloxane, the coating composition comprising polydimethylsiloxane Liveo™ 360 Medical Fluid (DuPont) in an amount of about 100% by weight having a nominal kinematic viscosity at room temperature equal to 100 g / s.

[0234] Preferably, this step of providing the coating composition includes storing the coating composition in a storage tank 11 .

[0235] Preferably, the coating composition stored in the storage tank 11 is heated by a heating element associated with the tank 11 to a temperature between 100°C and 150°C, for example equal to about 120°C.

[0236] Preferably, the heated coating composition stored in storage tank 11 is maintained at a pressure between 5 psi (0.34 bar) and 150 psi (10.34 bar), preferably between 10 psi (0.69 bar) and 30 psi (2.07 bar), and even more preferably between 10 psi (0.69 bar) and 15 psi (1.03 bar).

[0237] In a next step, the heated coating composition is delivered via pump 12 to a discharge head 14 equipped with at least one nozzle, preferably a plurality of discharge nozzles, which discharge the heated coating composition onto the inner surface 3 of the cylinder 2 so as to form a coating layer 4 on said inner surface 3.

[0238] As explained above, the time for discharging the heated coating composition onto the inner surface 3 of the cylinder 2 is 0.3 seconds to 1 second, preferably 0.4 seconds to 0.7 seconds.

[0239] The method includes heating the discharge head 14, more preferably also the delivery head of the pump 12 and the pipes 13 and 15, so as to maintain the coating composition at the aforementioned temperature between 100°C and 150°C, for example equal to about 120°C, during its movement from the storage tank 11 to the nozzle of the discharge head 14 which discharges the coating composition at the aforementioned temperature.

[0240] Preferably, the step of applying the coating composition heated at the aforementioned temperature onto the inner surface 3 of the cylinder 2 is carried out by expelling the heated coating composition at a pressure of between 5 psi (0.34 bar) and 150 psi (10.34 bar), more preferably between 6 psi (0.41 bar) and 10 psi (0.69 bar).

[0241] Preferably, this discharge of the heated coating composition involves supplying discharge air (gas) from source 16 to discharge head 14 having a pressure of between 5 psi (0.34 bar) and 150 psi (10.34 bar), preferably between 6 psi (0.41 bar) and 10 psi (0.69 bar).

[0242] Preferably, the coating composition storage tank 11 is maintained at a pressure greater than the pressure at the nozzle(s) of the dispensing head 14 to optimize dispensing of the heated coating composition.

[0243] Preferably, the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2 includes imparting relative motion between the dispensing head 14 and the cylinder 2 while dispensing the heated coating composition.

[0244] Preferably, the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2 includes discharging the heated coating composition onto the inner surface 3 of the cylinder 2 during relative insertion movement of the discharge head 14 into the cylinder 2.

[0245] Preferably, the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2 includes expelling the heated coating composition at a flow rate of 0.1 μL / s to 5 μL / s, for example at a flow rate of about 0.5 μL / s.

[0246] Preferably, the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2 has a coating density of 0.2 to 0.4 μg / mm 2 the amount per unit area of ​​the heated coating composition on said inner surface 3.

[0247] Preferably, the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2 is carried out such that the coating layer 4 formed on the inner surface 3 has an average thickness, as measured by optical reflectance measurement, of 100 to 250 nm, more preferably 100 to 200 nm.

[0248] In a preferred embodiment, the coating layer 4 formed on the inner surface of the cylinder has a thickness standard deviation of 90 nm or less, preferably 70 nm or less, and even more preferably 50 nm or less, as measured by optical reflectance measurements.

[0249] In a preferred embodiment, for each batch of 10 cylinders 2, the batch mean standard deviation SD of the thickness of the coating layer 4 obtained as described above has a value of 70 nm or less, preferably 60 nm or less, and more preferably 50 nm or less.

[0250] If desired, after the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2, a further step can be carried out in which the coating layer 4 formed on the inner surface 3 of the cylinder 2 is subjected to a partial crosslinking treatment of the polydimethylsiloxane, for example by irradiation with a plasma torch at atmospheric pressure accompanied by a flow of argon.

[0251] Preferably, the irradiation treatment is carried out for a period of 0.2 seconds to 1 second inclusive, more preferably 0.2 seconds to 0.6 seconds, and even more preferably 0.2 seconds to 0.5 seconds inclusive.

[0252] Preferably, the irradiation treatment is carried out at a time distance of at least 15 minutes, preferably 15 to 20 minutes, after the step of applying the heated coating composition onto the inner surface 3 of the cylinder 2 .

[0253] If desired, prior to the step of applying the heated coating composition to the inner surface 3 of the cylinder 2, a further step can be carried out to pre-treat the inner surface 3 of the cylinder 2 to improve adhesion of the coating layer 4 to the inner surface 2.

[0254] In a particularly preferred embodiment, this pretreatment comprises forming a layer of an adhesion promoter on the inner surface 3 of the cylinder 2, preferably a layer of an adhesion promoter comprising [(bicycloheptenyl)ethyl]trimethoxysilane.

[0255] If it is desired to produce a pre-filled syringe such as the one shown by way of example in FIG. 1, the coating layer 4 formed on the inner surface 3 of the cylinder 2 can be cooled to room temperature before a further step of filling the cylinder 2 with an injectable liquid 7.

[0256] Finally, if it is desired to manufacture the pre-filled syringe 1 shown in FIG. 1, a further step can be performed in which a cap 8 is associated with the end 2b of the cylinder 2 to seal the contents of the syringe 1.

[0257] The present invention will now be described by way of some examples thereof, to be understood for illustrative and non-limiting purposes.

[0258] In the following examples, again by way of illustration and not limitation, medical injection devices (syringes) manufactured according to the method according to the present invention and having a nominal filling volume of 0.5 mL, 1 mL length or 3 mL according to the ISO 11040-4 standard (2015) were manufactured by providing the following application conditions of a heated coating composition on the inner surface 3 of the cylinder 2:

[0259] Syringe with a nominal filling volume of 0.5 mL Total stroke of each discharge head 14 in each cylinder 2: Maximum 75 mm Discharge head 14 speed: 35 mm / s Total cycle time (insertion / discharge time of dispense head 14 + withdrawal time): 2.1 seconds Heated coating composition discharge flow rate: 0.30 μL / s Amount of coating composition dispensed: 0.30 μL Dispensing time of heated coating composition: 1 second.

[0260] Syringe with a nominal filling volume of 1 mL Total stroke of each discharge head 14 in each cylinder 2: Maximum 80 mm Discharge head 14 speed: 52 mm / s Total cycle time (insertion / discharge time of dispense head 14 + withdrawal time): 1.5 seconds Heated coating composition discharge flow rate: 0.63 μL / s Volume of dispensed coating composition: 0.63 μL Dispensing time of heated coating composition: 1 second.

[0261] Examples 1-2 (present invention) Manufacturing of medical injection device cylinders and evaluation of the thickness and uniformity of the coating layer formed on the inner surface of the cylinders - Syringes with nominal filling volume of 1 mL or 3 mL The above method and apparatus heats the liquid to approximately 120° C. and produces a liquid of approximately 12,500 cSt (125 cm 2 A coating composition consisting of PDMS Liveo™ 360 Medical Fluid (DuPont) having a nominal kinematic viscosity of 1000 µg / s was applied to the inner surface of the barrel of a syringe with a nominal fill volume of 1 mL (Example 1) or 3 mL (Example 2).

[0262] The storage tank was maintained at 120°C, the pump delivery head at approximately 50°C and the nozzle of the discharge head at approximately 120°C.

[0263] The amount of silicone oil deposited is approximately 0.2μg / mm 2 It was.

[0264] In this way, a coating layer was formed on the inner surface of the syringe cylinder, characterized by a very thin thickness that was constant over the entire axial extension of the body of the cylinder, as measured by optical reflectometry.

[0265] In particular, the thickness of the coating layer remained constant and was less than 200 nm on average, preferably less than 150 nm on average, with the average value of the total axial length of the cylinder being between 120 and 160 nm.

[0266] Figures 3 and 4 report graphs obtained from the measurements carried out, showing the thickness profile of the coating layer applied to the inner surface of the cylinder of syringes with nominal filling volumes of 1 mL and 3 mL, respectively.

[0267] As can be seen from the aforementioned figures, the coating layer on the inner surface of the cylinder has a remarkable surface regularity indicated by low values ​​of thickness standard deviation, which is less than 30 nm for the syringe with a nominal capacity of 3 mL (Figure 4) and less than 20 nm for the syringe with a nominal capacity of 1 mL (Figure 3).

[0268] When subjected to visual and, in some cases, automated inspection tests, both syringes did not induce any evaluation errors.

[0269] Examples A-G Manufacturing of Syringes According to the Invention and Comparative Syringes The above method and apparatus allows for a temperature of approximately 12,500 cSt (125 cm 2 A heated coating composition consisting of PDMS Liveo™ 360 Medical Fluid (DuPont) having a nominal kinematic viscosity of 100 µg / s was applied to the inner surface of the barrels of syringes with nominal fill volumes of 1 mL (ABCD) and 3 mL (EFG).

[0270] Conventional methods and conventional equipment produce a temperature of about 1000 cSt (10 cm 2 A coating composition consisting of PDMS Liveo™ 360 Medical Fluid (DuPont) having a nominal kinematic viscosity of 1000 µg / s was applied to the inner surface of the barrel of the same type of syringe.

[0271] The temperatures of the storage tank, the pump delivery head and the nozzle of the ejection head, as well as the amount of silicone oil deposited are reported in Table 1 below.

[0272] In this way, a coating layer was formed on the inner surface of the syringe cylinder, characterized by a very thin thickness that was constant over the entire axial extension of the body of the cylinder, as measured by optical reflectometry.

[0273] The resulting coating layer was optionally subjected to partial crosslinking by irradiation with a plasma torch at atmospheric pressure carried out for variable irradiation times and under the following conditions: Maximum output: 100W Gas used: argon with purity over 99% Argon flow rate: 7SLM

[0274] The manufacturing parameters of the syringe cylinder are reported in Table 1 below. [Table 1] Nominal kinematic viscosity 12500cSt (125cm 2 Silicone material according to the invention having a thickness of 100 μm / s: PDMS Liveo™ Medical Fluid (DuPont) Nominal kinematic viscosity 1000cSt (10cm 2 / s): PDMS Liveo™ 360 Medical Fluid 1000 cSt.

[0275] The following parameters were determined: - the average thickness S of the applied coating layer and its respective standard deviation measured after deposition of the layer and after cooling (t0); - Batch mean standard deviation SD of coating layer thickness for a batch of 10 syringes.

[0276] The results obtained are reported in Table 2 below. [Table 2]

[0277] If present, pretreatment of the inner surface of the syringe barrel g1) spraying the inner surface of the cylinder with a 2.2 wt. % solution of [(bicycloheptenyl)ethyl]trimethoxysilane in isopropyl alcohol by means of an ultrasonic static nozzle, with a solution volume of 5-80 μL depending on the size of the cylinder; g2) heating the cylinder thus treated in an oven at a temperature of 140° C. for 20 minutes. was carried out by.

[0278] As can be seen from the data in Table 2 above, in the case of the syringe according to the invention, the average thickness S of the coating layer was always maintained at a value less than 180 nm, with a thickness standard deviation of less than 70 nm, confirming a very high regularity of deposition.

[0279] The data for the batch mean standard deviation SD of the coating layer thickness calculated for a batch of 10 syringes was less than 60 nm, also confirming the high reproducibility of the method for manufacturing syringes according to the invention.

[0280] The syringes thus produced were subjected to several tests to evaluate the static and dynamic friction, particle release and morphological properties of the resulting coating. The results of these tests are reported below.

[0281] Example H~O Manufacturing of Syringes According to the Invention and Comparative Syringes The above method and apparatus heats the liquid to approximately 120° C. and produces a liquid of approximately 12,500 cSt (125 cm 2 A coating composition consisting of PDMS Liveo™ 360 Medical Fluid (DuPont) having a nominal kinematic viscosity of 1000 µg / s was applied to the inner surface of the barrel of a syringe with a nominal fill volume of 0.5 mL.

[0282] Conventional methods and conventional equipment produce a temperature of about 1000 cSt (10 cm 2A comparative coating composition consisting of PDMS Liveo™ 360 Medical Fluid (DuPont) having a nominal kinematic viscosity of 1.0 g / s was applied to the inner surface of the barrel of the same type of syringe.

[0283] The temperatures of the storage tank, the pump delivery head and the nozzle of the ejection head, as well as the amount of silicone oil deposited are reported in Table 3 below.

[0284] In this way, a coating layer was formed on the inner surface of the cylinder, characterized by a constant and very thin thickness, as measured by optical reflectometry, over the entire axial extension of the body of the syringe cylinder.

[0285] The resulting coating layers were optionally subjected to partial crosslinking by irradiation with a plasma torch at atmospheric pressure carried out under the conditions mentioned in Examples A-G and with variable irradiation times.

[0286] The manufacturing parameters of the syringe cylinders are reported in Table 3 below. [Table 3] Nominal kinematic viscosity 12500cSt (125cm 2 Silicone material according to the invention having a thickness of 100 μm / s: PDMS Liveo™ Medical Fluid (DuPont) Nominal kinematic viscosity 1000cSt (10cm 2 / s): PDMS Liveo™ 360 Medical Fluid 1000 cSt.

[0287] For examples H, I, K (invention) and M, N and O (comparison), the following parameters were determined after deposition and cooling of the layer (t0) and after storage at room temperature for 3 months (t3): - the average thickness S of the applied coating layer and the respective thickness standard deviation; - Batch mean standard deviation SD of coating layer thickness for a batch of 10 syringes

[0288] The results obtained are reported in Table 4 below. [Table 4]

[0289] Furthermore, it was experimentally observed that the maximum batch standard deviation of the applied coating layer thickness for Examples H, I, K (invention) was always maintained at a value below 70 nm.

[0290] Pretreatment of the inner surface of the syringe barrel, if present, was performed by the same methods described above with reference to Examples AG.

[0291] The syringes thus produced were subjected to several tests to evaluate the static and dynamic friction, particle release and morphological properties of the resulting coating. The results of these tests are reported below.

[0292] Coating layer thickness evaluation Figures 5 to 10 report graphs obtained from the measurements carried out and showing the thickness profile of the coating layer applied to the inner surface of the cylinder of a syringe with a nominal filling volume of 0.5 mL after deposition and cooling to room temperature (t0) and after 3 months of storage at room temperature (t3).

[0293] As can be seen from the data in Table 4 above and the figures above, in the case of the syringe according to the present invention, the coating layer on the inner surface of the cylinder has a low average thickness with remarkable surface regularity.

[0294] Indeed, the average thickness of the coating layer was always maintained at a value less than 230 nm, with a thickness standard deviation of less than 50 nm, confirming a very high regularity of the coating layer thickness.

[0295] In particular, as shown in Table 4, by comparing the syringe according to the present invention with a syringe according to the prior art without plasma treatment (Example H vs. Example M), it was experimentally found that the thickness standard deviation was reduced by more than 50%, confirming a significant improvement in the regularity of deposition of the coating layer, despite the much higher kinetic viscosity of the silicone material used.

[0296] The values ​​of the batch mean standard deviation SD of the coating layer thickness calculated for a batch of 10 syringes were less than 50 nm, also confirming the high reproducibility of the method for manufacturing the medical injection device according to the invention.

[0297] When subjected to automated visual inspection tests, the syringes according to the invention did not induce any rating errors.

[0298] Evaluation of the average static and dynamic sliding friction forces for empty syringes stored at room temperature The syringes of Examples A and B (invention), and C and D (comparison) were subjected to a series of comparative tests to evaluate the average static and dynamic sliding friction forces performed on an empty cylinder.

[0299] All syringes had a nominal fill volume of 1.0 mL and frictional forces were measured at room temperature at time zero as well as after 6 months storage time at room temperature.

[0300] Friction force measurements were performed using a ZwickiLine Z2.5 (Zwick Roell) dynamometer in the following manner. Place the syringe on a suitable support in the dynamometer Reset the load cell force (not under pressure) Set a constant speed deformation of 240mm / min, a preload of 0.5N, and an end stop with a preset force of 30N. Start the test (30 samples / example) and measure the resulting force.

[0301] By analyzing the curves obtained from the dynamometer, the static friction force was identified as the force corresponding to the first initial peak, and the kinetic friction force was identified as the average of the values ​​in the zone between the first initial peak and the end-stop peak.

[0302] The average values ​​of static and kinetic friction forces measured on a batch of 30 syringes are reported in Figures 11 and 12, respectively.

[0303] As can be seen from the above figures, the average values ​​of static and dynamic frictional forces of the syringes according to the invention (Examples A and B) having coating layers on the cylinders subjected to various irradiation times are completely acceptable and fall within the previously indicated limits required by the pharmaceutical and cosmetic industries (6N for static sliding frictional force and 3N for dynamic sliding frictional force).

[0304] It should also be noted that the maximum allowable exposure time of the coating layer on the cylinder is on the order of 1 second.

[0305] Evaluation of the average static and dynamic sliding frictional forces of syringes filled and stored at room temperature - Empty syringes with a nominal filled volume of 1 mL The syringes of Examples A and B (invention) and Examples C and D (comparison) were subjected to a further series of comparative tests to evaluate the average values ​​of the static and dynamic sliding friction forces performed against a cylinder having a nominal fill volume of 1.0 mL filled with an aqueous test solution (injectable liquid) containing water and glycerol (volume fraction of 0.02% to 0.04% vol of glycerol) to achieve a dynamic viscosity of 1 mPa s (1 cP) simulating the behavior of a pharmaceutical product.

[0306] The tests were performed under the same conditions with blank syringes, giving the average values ​​of static and kinetic friction measured on a batch of 30 syringes reported in Figures 13 and 14, respectively.

[0307] In this case too, the average values ​​of the static and dynamic friction forces of the syringes according to the invention (Examples A and B) having coating layers on the cylinders subjected to various irradiation times were still acceptable (6 N for the static sliding friction force and 3 N for the dynamic sliding friction force).

[0308] In this case too, it was found that the maximum allowable irradiation time for the cylinder coating layer was about 1 second.

[0309] Evaluation of the average static and dynamic sliding friction of filled syringes after 7 days of storage at different temperatures - Syringes with a nominal filled volume of 1 mL The syringes of Examples E and F (invention) and Example D (comparison) were subjected to a series of comparative tests to evaluate the average static and dynamic sliding friction forces against a cylinder of nominal 1.0 mL fill filled with 0.55 mL of an aqueous test solution (injectable liquid) having the following composition: Tromethamine 0.34 mg Tromethamine hydrochloride 1.30 mg Acetic acid 0.047 mg Sodium acetate 0.132 mg Sucrose 47.85mg - Water for injections, balanced up to 0.55mL.

[0310] Frictional forces were measured as described above at room temperature (RT) and at temperatures of -20°C and -40°C after a storage time of 7 days.

[0311] The average values ​​of static and kinetic friction forces measured on a batch of 30 syringes are reported in Figures 15 and 16, respectively.

[0312] As can be seen from the above figures, the average values ​​of the static and kinetic frictional forces of the syringes according to the invention (Examples E and F) having a coating layer on the cylinder that is not irradiated (Example E) or is irradiated for 0.3 seconds (Example F) are comparable to those of a comparative syringe (Example D) provided with a coating layer of known type (a silicone material having a nominal kinetic viscosity of about 1000 cSt).

[0313] Furthermore, the average values ​​of the static and dynamic friction of the syringes according to the invention (Examples E and F) are entirely within the specified limits previously required by the pharmaceutical and cosmetic industries (6 N for the static sliding friction and 3 N for the dynamic sliding friction).

[0314] Evaluation of the average values ​​of static and dynamic sliding friction of filled syringes after storage for 2 and 7 days at a temperature of -40°C - Syringes with a nominal filling volume of 1 mL The syringes of Examples E and F (invention) and Example D (comparison) were subjected to a further series of comparative tests to evaluate the average static and dynamic sliding friction forces against a cylinder having a nominal fill of 1.0 mL filled with 0.55 mL of an aqueous test solution (injectable liquid) having the following composition: Tromethamine 0.34 mg Tromethamine hydrochloride 1.30 mg Acetic acid 0.047 mg Sodium acetate 0.132 mg Sucrose 47.85mg - Water for injections, balanced up to 0.55mL.

[0315] Frictional forces were measured as above after storage times of 2 and 7 days at -40°C.

[0316] The average values ​​of static and kinetic friction forces measured on a batch of 30 syringes are reported in Figures 17 and 18, respectively.

[0317] As can be seen from the above figures, the average values ​​of the static and kinetic frictional forces of the syringes according to the invention (Examples E and F) having a coating layer on the cylinder that is not irradiated (Example E) or is irradiated for 0.3 seconds (Example F) are comparable to those of a comparative syringe (Example D) provided with a coating layer of known type (a silicone material having a nominal kinetic viscosity of about 1000 cSt).

[0318] Furthermore, the average static and dynamic frictional forces of the syringes according to the invention (Examples E and F) were substantially stable and were entirely within the specified limits previously required by the pharmaceutical and cosmetic industries (6 N for static sliding frictional force and 3 N for dynamic sliding frictional force).

[0319] Evaluation of the average static and dynamic sliding frictional forces of empty syringes stored at room temperature - Empty syringes with a nominal filled volume of 0.5 mL The syringes of Examples H, I, J, K and L (invention), and M, N and O (comparison) were subjected to a series of comparative tests to evaluate the average static and dynamic sliding friction forces performed on an empty cylinder.

[0320] All syringes had a nominal fill volume of 0.5 mL and frictional forces were measured at room temperature at time zero and after 1 month and 3 months storage times at room temperature.

[0321] Friction force measurements were performed using a ZwickiLine Z2.5 (Zwick Roell) dynamometer in the following manner. Place the syringe on a suitable support in the dynamometer Reset the load cell force (not under pressure) · Set the deformation at a constant speed of 100mm / min without preload and stop end set to a preset force of 30N Start the test (30 samples / example) and measure the resulting force.

[0322] By analyzing the curves obtained from the dynamometer, the static friction force was identified as the force corresponding to the first initial peak, and the kinetic friction force was identified as the average of the values ​​in the zone between the first initial peak and the end-stop peak.

[0323] The average static and kinetic friction forces measured on a batch of 30 syringes are reported in Figures 19 and 20, respectively.

[0324] As can be seen from the aforementioned figures, the average values ​​of the static and dynamic friction forces of syringes according to the invention (examples H, I, J, K and L) having a coating layer on the cylinder that has not been irradiated (example H) or has been subjected to various irradiation times (examples I, J, K and L) are completely acceptable and are within the limits previously required by the pharmaceutical and cosmetic industries (6 N for the static sliding friction force and 3 N for the dynamic sliding friction force).

[0325] Evaluation of the average static and dynamic sliding frictional forces of filled syringes stored at temperatures of -40°C, +5°C, +25°C and +40°C - Syringes with a nominal filled volume of 0.5 mL The syringes of Examples H, I, J, K and L (invention) and Examples M, N and O (comparison) were subjected to a further series of comparative tests to evaluate the average values ​​of static and dynamic sliding friction forces performed against a cylinder of nominal fill volume of 0.5 mL filled with 500 μL of an aqueous test solution (injectable liquid) having the following composition: 10mM Sodium Phosphate 40mM Sodium Chloride 0.03% (v / v) Polysorbate 20 5% (w / v) sucrose For injection preparations, balance with water (0.22 μm filtered MilliQ water solution) to 0.5 mL and pH 6.2.

[0326] The frictional forces were measured as described above after deposition and cooling of the coating layer (t0) and after storage times of 1 month (t1) and 3 months (t3) at the following temperatures: -40°C, +5°C, +25°C and +40°C.

[0327] The average values ​​of static and kinetic friction forces measured on a batch of 30 syringes are reported in Figures 21 to 28.

[0328] As can be seen from the above figures, the average values ​​of the static and kinetic frictional forces of the syringes according to the invention (examples H, I, J, K and L) having a coating layer on the cylinder that has not been subjected to irradiation (example H) or has been subjected to irradiation for a time period of 0.3 seconds or 0.5 seconds (examples K, I, J and L) are comparable to those of the comparative syringes (examples M, N and O) provided with a coating layer of known type (silicone material having a nominal kinetic viscosity of about 1000 cSt).

[0329] Furthermore, the average values ​​of the static and dynamic frictional forces of the syringes according to the invention (Examples H, I, J, K and L) were substantially stable and were, for example, entirely within the specified limits previously required by the pharmaceutical and cosmetic industries (6 N for the static sliding frictional force and 3 N for the dynamic sliding frictional force).

[0330] The average static and kinetic frictional forces of the plungers of syringes according to the invention and the prior art after storage for three months at the aforementioned temperatures of -40°C, +5°C, +25°C and +40°C are further reported as a comparison in Figures 29 and 30.

[0331] As can be seen from the aforementioned figures, after 3 months of storage at various temperatures, the average values ​​of static and dynamic friction of the syringes according to the invention (examples H, I, J, K and L) are comparable to those of comparative syringes (examples M, N and O) provided with coating layers of known type and which are entirely within the previously indicated limits required by the pharmaceutical and cosmetic industry (6 N for static sliding friction and 3 N for dynamic sliding friction).

[0332] Evaluation of particle release for filled syringes at room temperature The syringes of Example E (invention) and Examples C and G (comparison) were subjected to a series of comparative tests to evaluate particle release in aqueous test solutions (injectable liquids).

[0333] Each syringe had a nominal fill volume of 3.0 mL and was filled with 3.3 mL of an aqueous test solution (injectable liquid) having the following composition: 10 mM sodium phosphate (adjusted to pH 7.0 with phosphoric acid) 0.9% (w / v) sodium chloride 0.02% (w / v) Polysorbate 80 Balance up to 3.3mL with water for injectable preparations.

[0334] Preparation of samples for particle analysis testing Fill the syringe cylinder with the test solution and close the cylinder with the plunger. Storage (if anticipated by the test) End-over-end rotation (i.e., rotation about an axis perpendicular to the longitudinal axis of the cylinder) of the syringe in a multi-rack agitator at a rotation speed of 30 rpm for 3 hours Dispensing of aqueous test solutions from the syringe barrel: automated via dynamometer

[0335] The test liquid is collected in a special container.

[0336] Obtain an aliquot (pool) of sample solution with a volume of at least 6 mL of liquid for performing particle analysis (e.g., two syringes filled with 3.30 mL will result in one pool = one sample for particle analysis).

[0337] The concentration of particles released into the test solution was measured in the following manner.

[0338] Analysis of particles released into test solutions - Examples A to G Light occlusion (LO) method The test solution pool obtained above was analyzed by a light obscuration instrument (KL 04A, RION) to determine the sub-visible particle size and count.

[0339] The instrument performs particle counting in the analytical solution according to US standards (787-788-789) as described in the United States Pharmacopeia 44-NF39 (2021).

[0340] In particular, the solution is aspirated from the instrument by a special needle and passed through a laser light source: any particles in the solution induce an obstruction of the beam of laser light and thus a signal that is sent to the sensor, the size of the particle being given by the amount of obscured light.

[0341] The size range that can be determined by the instrument is in the range of 1.3 to 100 μm.

[0342] The normalized values ​​of the concentrations of particles with sizes above 10 μm and above 25 μm obtained in 15 measurement pools starting from 30 syringes, measured immediately after rotation of the syringe at room temperature, are reported in Figures 31 and 32, respectively.

[0343] As can be seen from the above figures, the syringe according to the present invention having a non-irradiated cylinder coating layer (Example E) exhibited improved particle release behavior compared to the comparative syringes (Examples C and G) having a cylinder coating layer that was irradiated for 0.3 seconds (Comparative Example C) or not irradiated (Comparative Example G), respectively.

[0344] Evaluation of particle release at different temperatures in filled syringes with and without storage The syringes of Example A (invention) and Example C (comparison) were subjected to a series of comparative tests to evaluate particle release in aqueous test solutions (injectable liquids).

[0345] Each syringe had a nominal fill volume of 0.5 mL and was filled with 0.25 mL of an aqueous test solution (injectable liquid) having the following composition: 10mM Sodium Phosphate 40mM Sodium Chloride 0.03% (w / v) Polysorbate 20 Sucrose 5% (w / v) For injection preparations, balance with water (filtered MilliQ aqueous solution with a filter size of 0.22 μm) to 0.5 mL and pH 6.2.

[0346] Preparation of samples for particle analysis testing Fill the syringe cylinder with the test solution and close the cylinder with the plunger. ·storage End-over-end rotation (i.e., rotation about an axis perpendicular to the longitudinal axis of the cylinder) of the syringe in a multi-rack agitator at a rotation speed of 30 rpm for 3 hours Discharge of the test solution from the syringe barrel: Manually under a laminar flow hood

[0347] Measurement of the particle concentration released into the test solution was performed in the following manner.

[0348] Analysis of particles released into the test solution LO (light shielding) The normalized concentrations of particles having a size of 10 μm or more obtained in 12 pools (prepared by grouping two of the manually expelled solutions from a total of 24 syringes) measured at time 0 after preparation and after 6 months of storage at temperatures of 5° C.±3° C., 25° C. / 60% RH and 40° C. / 75% RH are reported in Figures 33, 34 and 35, respectively.

[0349] As can be seen from the above figures, the syringe according to the present invention (Example A) having a coating layer on the cylinder irradiated for 0.3 seconds showed a clearly improved particle release behavior compared to the comparative syringe (Comparative Example C) having a coating layer on the cylinder irradiated for 0.3 seconds.

[0350] The particle release values ​​shown in Figures 33-35 also demonstrate that syringes according to the present invention exhibit improved release stability over time after storage at various temperatures relative to the comparative syringes.

[0351] Evaluation of particle release for filled syringes with low temperature storage The syringes of Example E (invention) and Example D (comparison) were subjected to a series of comparative tests to evaluate particle release in aqueous test solutions (injectable liquids).

[0352] All syringes had a nominal fill volume of 1.0 mL and were filled with 0.55 mL of an aqueous solution (injectable test fluid) having the following composition: The composition of the test aqueous solutions (injectable liquids) was as follows: Tromethamine 0.34 mg Tromethamine hydrochloride 1.30 mg Acetic acid 0.047 mg Sodium acetate 0.132 mg Sucrose 47.85mg - Water for injections, balanced up to 0.55mL.

[0353] Preparation of samples for particle analysis testing Fill the syringe cylinder with the test solution and close the cylinder with the plunger. ·storage Dispensing aqueous test solutions from a syringe barrel: automated via dynamometer

[0354] Measurement of particles released into the test solution was performed in the following manner.

[0355] Analysis of particles released into the test solution MFI (Micro Flow Imaging) 1 mL of each of the pools obtained above was analyzed by a flow imaging analyzer (MFI™ Microflow Imaging, MFI 5200, ProteinSimple) to assess the morphology of the particles in the solution, with the optics of the instrument being able to distinguish different types of particles (particles of silicone material and non-phase particles) based on certain parameters such as circularity and light intensity.

[0356] The specific parameters used to identify the particles of silicone material were as follows: Aspect ratio ≥ 0.83 (i.e. the ratio of the length of the minor axis to the length of the major axis of an ellipse having the same second moment of the particle); · Intensity STD ≥ 185 (i.e. the standard deviation of the intensities of all pixels representing particles); ·ECD 10-25μm and 25-100μm (i.e. the diameter of a circle occupying the same area as the particle).

[0357] The size range that can be determined by the instrument is 2-70 µm with good resolution for images of particles with sizes above 10 µm.

[0358] Normalized values ​​of the concentration of particles with sizes between 5 and 70 μm obtained in 15 measurement pools (prepared by grouping two by two the solutions ejected by the dynamometer for a total of 30 syringes) measured after 2 and 7 days of storage at -40 °C are reported in Figure 36.

[0359] As can be seen from the above figures, the syringe according to the present invention having a non-irradiated cylinder coating layer (Example E) showed comparable (after 2 days of storage) or significantly improved (after 7 days of storage) particle release behavior compared to the comparative syringe having a non-irradiated cylinder coating layer (Example D).

[0360] The particle release values ​​shown in FIG. 36 also demonstrate that syringes according to the present invention exhibit improved release stability over time after low temperature storage versus the comparative syringes.

[0361] Evaluation of particle release for filled syringes stored at various temperatures - Syringes with a nominal filled volume of 0.5 mL - Example H to Example O The syringes of Examples H, I, J, K and L (invention) and Examples M, N and O (comparison) were subjected to a series of comparative tests to evaluate particle release in aqueous test solutions (injectable liquids).

[0362] Each syringe had a nominal fill volume of 0.5 mL and was filled with 500 μL of an aqueous test solution (injectable liquid) having the following composition: 10mM Sodium Phosphate 40mM Sodium Chloride 0.03% (v / v) Polysorbate 20 5% (w / v) sucrose For injection preparations, balance with water (filtered MilliQ aqueous solution with a filter size of 0.22 μm) to 0.5 mL and pH 6.2.

[0363] Preparation of samples for particle analysis testing Filling the syringe cylinder with the test solution and closing the cylinder with the plunger (plunger 4023 / 50 Grey Flurotec, Westar) Storage at different temperatures o 5℃±3℃ 25℃ / 60% RH 40℃ / 75% RH -40℃ Syringes stored at -40°C were thawed at room temperature for 1 hour without end-over-end rotation before dispensing the solution. This was done to simulate the real-life usage of products that are typically stored at this temperature, i.e. biotech drugs that are very temperature sensitive. End-over-end rotation (i.e., rotation about an axis perpendicular to the longitudinal axis of the cylinder) for 3 hours at a rotation speed equal to 30 rpm of the syringe using a Multirack agitator Dispensing of test solutions from the syringe cylinders: manually under a laminar flow hood, grouping a total of 12 syringes of solution.

[0364] The concentration of particles released into the test solution was measured in the following manner.

[0365] Analysis of particles released into the test solution LO (light shielding) 5 mL of each of the 10 pools (prepared by pooling the manually ejected solutions of a total of 12 syringes) was analyzed by a particle counting analyzer (light-obscuring particle counter KL-04 A, Rion Co., LTD.).

[0366] The device meets USP 44-NF39(2021) and Ph.Eur.2.9.19 (10th Edition, 2021) for subvisible particle count analysis of parenteral solutions. <787> , <788> , <789> This enables the device to operate in accordance with the

[0367] The size of the analyzed particle is determined by the amount of the source laser light that is obscured by the particle itself as it passes through the laser beam, thus producing a voltage variation that is detected by the sensor.

[0368] The size range of particles that can be analyzed by the instrument is 1.3-100 μm.

[0369] The normalized values ​​of the concentration of particles with sizes ≥ 10 μm and ≥ 25 μm obtained in 10 pools after storage at temperatures of -40°C, 5°C ± 3°C, 25°C / 60% RH, 40°C / 75% RH for time 0 and for 1 and 3 months after preparation are reported in Figures 37, 38, 41-44, 47-50, 53-56 and 59-60.

[0370] As can be seen from the above figures, at all detection times (t0, t1 and t3) and all storage temperatures, the syringes according to the present invention (examples H, I, J, K and L) showed clearly improved particle release behavior with respect to the comparative syringes (examples M, N and O), especially using a storage temperature of -40°C, as better shown in Figures 37 and 38.

[0371] In particular, as shown in the above figures, by comparing the syringe according to the present invention with the syringe according to the prior art under the same process conditions, i.e. with and without plasma treatment and with and without pretreatment to improve the adhesion of the coating layer to the inner surface of the syringe barrel, - in the case of a coating layer not treated with plasma and a syringe not subjected to a pre-adhesion treatment, particle release was reduced by approximately 70% (example H vs. example M); - when the coating layer was treated with plasma for 0.3 seconds and the syringe was not subjected to any pre-adhesion treatment, particle emission was reduced by approximately 86% (example I vs. example N); When the coating layer was treated with plasma for 0.3 seconds and the syringe was subjected to a pre-adhesion treatment, particle release was reduced by approximately 90% (example K vs. example O).

[0372] Furthermore, as better shown in Figures 41 to 44, 47 to 50 and 53 to 56, by comparing syringes according to the present invention with coating layers subjected to plasma treatment with or without pretreatment (Examples I, J, K and L) and with coating layers according to the prior art subjected to the same treatment (Examples N and O), it was experimentally found that all syringes according to the present invention meet the stringent particle release requirements of the USP789 standard for ophthalmic applications at all temperatures and storage times tested, a result which does not occur in the case of conventional syringes as far as particles of a size of 10 μm or more are concerned (see Figures 41, 43, 47, 49, 53, 55 and 59).

[0373] Conversely, for particles with a size of 25 μm or more, all syringes according to the invention with a plasma treatment on the coating layer, with or without pretreatment (examples I, J, K and L), meet the particle release requirements of the USP789 standard at all temperatures and storage times tested, a result that occurs only in some cases with syringes according to the prior art (examples N and O). In particular, after a storage time of 3 months, the syringe of comparative example N meets the particle release requirements of the standard USP789 only at storage temperatures of 5° C. and 40° C., while the syringe of comparative example O does not meet the particle release requirements of the standard USP789 at any storage temperature (see Figures 42, 44, 48, 50, 54, 56 and 60).

[0374] MFI (Micro Flow Imaging) 1 mL of each pool obtained above for the 0.5 mL syringe was analyzed by a flow imaging device (MFI™ Microflow Imaging, MFI 5200, ProteinSimple) to assess the morphology of particles in solution as described above.

[0375] The percentage values ​​(calculated in the examples) of the concentration of particles with sizes between 10 and 25 μm obtained for 10 samples (obtained by taking 1 mL of solution from each pool prepared as described above) measured at time 0 after preparation and after storage for 1 month and 3 months at temperatures of -40°C, +5°C±3°C, +25°C / 60%RH and +40°C / 75%RH are reported in Figures 45-46, 51-52 and 57-58.

[0376] As can be seen from the above figures, the syringes according to the present invention (Examples H, I, J, K and L) were able to dramatically reduce the release of silicone particles compared to the comparative syringes (Examples M, N and O) at all temperatures and all test detection times (t0, t1 and t3).

[0377] Evaluation of the morphological characteristics of coating layers applied to the inner surface of empty syringe barrels To evaluate the possible effect on the morphology of the coating layer of different irradiation times obtained according to the present invention and the prior art, several images were taken by optical microscopy.

[0378] In general, the more homogeneous the surface of the coating layer, or the finer the grain size, the better it will look from a morphological point of view and therefore the less prone it will be to mislead automated optical inspection systems into generating false positive problems due to surface irregularities in the coating layer.

[0379] In this regard, as explained above, the applicant has observed that the degree of partial cross-linking, e.g. related to the exposure time in the plasma treatment, is important insofar as it produces streaks and peeling that may be erroneously "read" by automated optical inspection systems as impurities present in the solution stored in the cylinder of the medical injection device.

[0380] Applicant has observed that these streaks and peeling tend to occur first in the area of ​​the conical portion of the syringe cylinder (closest to the end where the needle is located) and then propagate toward the cylindrical portion.

[0381] FIG. 61 reports images illustrating the effect of irradiation carried out for a time exceeding a threshold of 1 second on a coating layer obtained according to Example B according to the invention.

[0382] As can be seen from the aforementioned figures, non-uniformities are seen that extend up to several millimeters, comparable to grooves or lifting of the coating itself. Obviously, the use of very thin coating layers (related to the limited amount of silicone material applied) accentuates the occurrence of this effect.

[0383] FIG. 62 reports images illustrating the effect of an irradiation equal to 0.3 seconds carried out on a coating layer obtained according to Example A according to the invention.

[0384] As can be seen from the aforementioned figures, the surface of the coating layer is characterized by much finer non-uniformities in the distribution of the coating with micrometer-sized peaks and valleys and has no detectable defects in FIG.

[0385] FIG. 63 reports an image showing a zone near the conical end of the cylinder of the same syringe according to FIG.

[0386] As can be seen from FIG. 63, the surface of the coating layer is substantially uniform and substantially free of defects.

[0387] 64 and 65 report images showing the effect of an irradiation equal to 0.3 seconds carried out on a coating layer obtained according to Comparative Example C.

[0388] As can be seen from the aforementioned figures, taken at the cylindrical part and at the adjacent conical end of the cylinder, respectively, the surface of the coating layer is characterized by a larger grain size than in the syringe according to the invention (Example A) according to the previous Figures 62 and 63.

[0389] Figures 66 and 67 report images showing the effect of a 1 second near-limit irradiation carried out on the coating layers obtained according to Example A according to the invention and Comparative Example C, in the connection zone between the cylindrical and conical parts of the syringe cylinder.

[0390] As can be seen from Figures 66 and 67, by carrying out plasma irradiation of the coating layer obtained according to Example A according to the present invention (Figure 66), the presence of streaks can be observed, although less pronounced, in the right-hand zone of the image (the conical part of the cylinder).

[0391] However, as shown in FIG. 67, by carrying out the case of the coating layer obtained according to Comparative Example C, under the same radiation conditions, the streaks appear much more prominently.

Claims

1. A method for manufacturing a medical injection device (1) comprising a glass cylinder having an inner surface (3) coated with a coating layer (4), the cylinder (2) being configured to receive a plunger (5) by sliding engagement, the method comprising: a) 11500 cSt (115 cm) at room temperature ２ / s) ~ 13500cSt (135cm ２ providing a coating composition comprising a polydimethylsiloxane in an amount of 92 wt. % or greater having a kinematic viscosity of 1 / s; b) heating the coating composition to a temperature of 100°C to 150°C; c) applying the coating composition heated to the temperature onto the inner surface (3) of the cylinder (2) to form a coating layer (4) on the inner surface (3) having an average thickness S of 100 to 250 nm as measured by optical reflectance measurement; Including, The method, wherein the coating layer (4) on the inner surface (3) of the cylinder (2) has a thickness standard deviation of 90 nm or less.

2. 2. The method of claim 1, wherein said step a) of providing said coating composition comprises storing said coating composition in a storage tank (11).

3. 3. The method of claim 2, wherein said step b) of heating said coating composition comprises heating said storage tank (11) to bring said coating composition to said temperature of 100°C to 150°C.

4. 3. The method of claim 2, further comprising step d) maintaining the heated coating composition stored in the storage tank (11) at a pressure of between 5 psi (0.34 bar) and 150 psi (10.34 bar).

5. 10. The method of claim 1, further comprising step e) of supplying the heated coating composition to a discharge head (14) provided with at least one discharge nozzle, wherein step e) of supplying the heated coating composition to the discharge head (14) is performed by a circulation pump (12) arranged upstream of the discharge head (14).

6. 6. The method according to claim 5, wherein step c) of applying the heated coating composition to the inner surface (3) of the cylinder (2) is carried out by discharging the coating composition through the dispensing head (14).

7. 6. The method of claim 5, wherein step b) of heating the coating composition comprises heating the dispensing head (14) and / or the pump (12) to bring or maintain the coating composition at the temperature of 100°C to 150°C.

8. 6. The method of claim 5, wherein the storage tank (11), the pump (12) and the discharge head (14) are in fluid communication by pipes (13, 15), and wherein step b) of heating the coating composition comprises heating the pipes (13, 15) to bring or maintain the coating composition at the temperature of 100°C to 150°C.

9. 6. The method of claim 5, wherein step c) of applying the heated coating composition to the inner surface (3) of the cylinder (2) is carried out by discharging the heated coating composition at a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar), and includes supplying a discharge gas having a pressure of 5 psi (0.34 bar) to 150 psi (10.34 bar) to the discharge head (14).

10. 7. The method of claim 6, wherein step c) of applying the heated coating composition to the inner surface (3) of the cylinder (2) comprises imparting relative motion between the dispensing head (14) and the cylinder (2) while dispensing the heated coating composition, and dispensing the heated coating composition onto the inner surface (3) of the cylinder (2) during relative insertion motion of the dispensing head (14) into the cylinder (2).

11. The method according to claim 10, wherein the dispensing time of the heated coating composition onto the inner surface (3) of the cylinder (2) is between 0.3 seconds and 1 second.

12. 2. The method of claim 1, wherein the step c) of applying the heated coating composition to the inner surface (3) of the cylinder (2) comprises ejecting the heated coating composition at a flow rate equal to 0.1 μL / s to 5 μL / s.

13. The step c) of applying the heated coating composition to the inner surface (3) of the cylinder (2) has a coating concentration of 0.2 to 0.4 μg / mm ２ 2. The method of claim 1, comprising applying to the inner surface (3) of the cylinder (2) an amount per unit area of ​​the heated coating composition of

14. 2. The method according to claim 1, further comprising, after step c) of applying the heated coating composition onto the inner surface (3) of the cylinder (2), step f) of subjecting the coating layer (4) formed on the inner surface (3) of the cylinder (2) to a partial crosslinking treatment of the polydimethylsiloxane, wherein the partial crosslinking treatment is carried out by irradiation.

15. The method of claim 14 , wherein the irradiation treatment is a plasma irradiation treatment.

16. 15. The method of claim 14, wherein the irradiation treatment is carried out for a time period between 0.2 seconds and 1 second inclusive.

17. A medical injection device (1) comprising a glass cylinder (2) having an inner surface (3) coated with a coating layer (4), said cylinder (2) configured to receive a plunger (5) by sliding engagement; The coating layer (4) on the inner surface (3) of the cylinder (2) has a viscosity of 11500 cSt (115 cm ２ / s) ~ 13500cSt (135cm ２ / s) and has an average thickness of 100 to 250 nm; A medical injection device (1), wherein the coating layer (4) on the inner surface (3) of the cylinder (2) has a thickness standard deviation of 90 nm or less.

18. 18. The medical injection device (1) according to claim 17, wherein the coating layer (4) on the inner surface (3) of the cylinder (2) is partially cross-linked by irradiation treatment.

19. 18. The medical injection device (1) according to claim 17, wherein after 3 months of storage at a temperature of -40°C, the average normalized concentration of particles released from the coating layer (4) on the inner surface (3) of the cylinder (2) into a test solution and having an average diameter of 10 μm or more or 25 μm or more, as determined by the LO (light obscuration) method according to USP 787 as described in the United States Pharmacopeia 44-NF39 (2021), is 60% or less of the limit value according to said standard.

20. 19. The medical injection device (1) according to claim 18, wherein after 3 months of storage at a temperature of -40°C, the average normalized concentration of particles released into a test solution from the partially crosslinked coating layer (4) on the inner surface (3) of the cylinder (2) and having an average diameter of 10 μm or more or 25 μm or more, as determined by the LO (light obscuration) method according to USP 787 as described in United States Pharmacopeia 44-NF39 (2021), is 10% or less of the limit value according to said standard.

21. 19. The medical injection device (1) according to claim 18, wherein after storage for 3 months at a temperature of +5°C, +25°C or +40°C, the average normalized concentration of particles released into a test solution from the partially crosslinked coating layer (4) on the inner surface (3) of the cylinder (2) and having an average diameter of 10 μm or more or 25 μm or more, as determined by the LO (light obscuration) method according to US Standard USP 789 described in United States Pharmacopeia 44-NF39 (2021), is below the limit value according to said standard.

22. A kit of parts for assembling the medical injection device (1) of claim 17, comprising the following separate components in a sterile package: a glass cylinder (2) having an inner surface (3) coated with a coating layer (4), the glass cylinder (2) being adapted to receive a plunger (5) by means of sliding engagement; a plunger (5) adapted to slidingly engage within said cylinder (2); Equipped with The coating layer (4) on the inner surface (3) of the cylinder (2) has a viscosity of 11500 cSt (115 cm ２ / s) ~ 13500cSt (135cm ２ / s) and has an average thickness of 100 to 250 nm; A kit of parts, wherein the coating layer (4) on the inner surface (3) of the cylinder (2) has a thickness standard deviation of 90 nm or less.

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