WO2009030975A1

WO2009030975A1 - Medical device comprising a siliconized chamber and a coated closure means

Info

Publication number: WO2009030975A1
Application number: PCT/IB2007/003432
Authority: WO
Inventors: Laurence Boulange; Frédérique CROZET; Jean-Bernard Hamel; Florent Charlon
Original assignee: Becton Dickinson France
Priority date: 2007-09-03
Filing date: 2007-09-03
Publication date: 2009-03-12

Abstract

Medical device (1) comprising : - at least one chamber (9) having an inner surface (9a) delimiting an inner space (3) intended to receive a protein containing composition (4), - closure means (10) for tightly sealing said inner space, said closure means (10) having at least one face facing said inner space (3), said face being coated with a coating (8) consisting of at least one polymer material comprising polymer chains having the following repeat unit Formula (I); in which X represents a halogen, for example F, or a hydrogen, and in which Y1, Y2, Y3, Y4 each independently represent a halogen, for example Cl, or a hydrogen, characterized in that -said inner surface (9a) of said chamber (9) is coated with a layer (5) of a silicone, and - the mean thickness of the coating (8) of said face of said closure means (6; 10) ranges from 3 to 10 μm.

Description

Medical device comprising a siliconized chamber and a coated closure means

The present invention relates in general to a medical device, for example a container or a syringe, comprising a chamber intended to receive a protein containing composition and closure means. In the case the medical device of the invention is a syringe, the chamber and the closure means may be able to move one relative to the other, for example translationally and/or rotationally, when the medical device is operated. The chamber is intended to accommodate a protein containing composition in the liquid, gaseous, fluid, pasty or lyophilized phase. This protein containing composition may remain within said chamber for a certain period of time until the medical device is used. In order to be efficient at the time it is used, the protein containing composition should remain stable within said chamber.

It can happen that the proteins interact with the material the chamber is made of. In particular, it is known that some particles coming from glass chambers may cause aggregation of therapeutic proteins contained in the product stored in the chamber. For instance, glass nanoparticles generated during heating of glass chambers for depyrogenation may initiate the nucleation of protein aggregates.

Moreover, the closure means is preferably made at least partially from a viscoelastic material so as to ensure tightness in the region of contact between the chamber and the closure means. It can happen that the proteins interact with the material which the piston is made of, for example rubber. In particular, it is known that some particles coming from rubber pistons may cause aggregation of therapeutic proteins contained in the barrel of an injection device such as a syringe.

There is therefore a need for a medical device that would allow the storage of protein containing compositions, and in particular of liquid compositions comprising proteins, over time, for instance beyond 7 days, preferably beyond 15 days, without any undesirable modification of said proteins, for instance by aggregations.

In addition, in the case where the medical device is an injection device such as a syringe, the closure means is usually a piston which must be able to slide with respect to the internal surface of the chamber, for example the barrel of the syringe, in order to push the product such as the protein containing composition, towards the distal end of the barrel to realize the injection. It is therefore necessary that the piston shows good sliding properties with respect to the internal surface of the barrel.

In order to improve the slip between a barrel and a piston, it has been proposed to coat the piston with a coating consisting of at least one polymer material, whether this is a true polymer or a copolymer, comprising polymer chains including repeats of one or more chemical units:

in which X represents a halogen, for example F, or a hydrogen, and in which Yi, Y₂, Y₃, Y₄ each independently represent a halogen, for example Cl, or a hydrogen.

For example, the polymer material is chosen from the group consisting of poly(p-xylylene) polymers, which may or may not be substituted, and in particular, poly(p-xylylene), poly(p-meta-chloroxylylene), poly(p-ortho- chloro/meta-chloroxylylene) and poly(p-difluoroxylylene). The latter four polymer materials are manufactured and sold by UNION CARBIDE CORPORATION, or by SPECIALTY COATING SYSTEMS, under the names Parylene N, Parylene C, Parylene D and Parylene AF₄, respectively.

For information regarding the synthesis of these particular polymer materials, particularly using chemical vapour polymerization (CVP), on their various properties and on their main uses or applications, reference may usefully be made to the following documents, the respective contents of which are incorporated as required into this description: US 3,288,728, US 3,342,754, US 3,379,803, US 3,472,795, US 4,225,647, US 3,300,332 and US 6,270,872. These polymer materials have various properties, for example impervjousness to gases, for example oxygen, and to dry-lubricating liquids, for example water, which make them particularly attractive for use in numerous biomedical applications, particularly for certain medical devices.

Unlike a conventional polymer material, a polymer material of the poly(p-xylylene) type is not employed by injection, dissolving or suspending in a solvent, but is used by depositing it onto the part by a direct dry vacuum deposition process using the following protocol:

(a) use is made of a polymerization intermediate of the polymer material, in this instance of a cyclic dimer form of the aforementioned chemical unit, in solid and divided form, (b) the dimer is vaporized under vacuum (1 mm of mercury for example) and at approximately 150⁰C for example,

(c) the vaporized dimer is then pyrolized, still under vacuum but at a higher temperature, for example at 650⁰C, in order to obtain the reactive monomer form corresponding to the aforementioned dimer and to the afore- mentioned chemical unit, and

(d) the reactive monomer is deposited directly on the entire accessible developed surface of the part, both internal and external, and polymerized at ambient temperature under a low vacuum, in a method akin to the vacuum deposition of a thin metal layer, so as to obtain a continuous coating of (substituted or unsubstituted) poly(p-xylylene) of relatively uniform thickness, completely (with no discontinuity) covering the part of the medical device.

Various equipment and corresponding operating procedures are nowadays available on the market for the purposes of obtaining a poly(p- xylylene) coating and, by way of example, reference may be made to the equipment sold by COMELEC SA, CH-2301 La Chaux de Fonds, Switzerland, or alternatively to the PDS 2010 Labcoter 2 equipment sold by SPECIALTY COATING SYSTEMS.

The coating thus obtained, made of relatively crystalline polymer, adheres to the piston directly or indirectly. Because of its slip characteristics, the coating facilitates the relative movement between the two parts of the medical device. In addition, the elastic behaviour of the coating allows it in a resilient manner to accommodate the deformations and stresses imposed on the part provided with it, for example the piston, as it slides in the container. Thus, tightness in the region of contact between the piston and the container can be guaranteed to be maintained. Adhesion between the coating and the part may be direct, particularly by means of chemical bonds formed at the time of deposition and polymerization of the reactive monomer, between the said part and the polymer material, or indirect, by way of a tie layer or primer layer applied beforehand to the surface that is to be coated, if appropriate after that surface has been cleaned or prepared.

According to document US-A-2005/0 010 175, it has been proposed that the polymer material coating of the poly(p-xylylene) type has a thickness ranging from 0.25 μm to 1 μm, it being possible for a coating thickness of 0.10 to 76 μm to be obtained in a single stage.

In the experience of the Applicant, this thickness range seems inappropriate for most medical devices, particularly of the syringe type. This is because with this range of thicknesses, when the two parts of the medical device move relative to one another, the coating breaks, tears or breaks up. This permanently worsens the surface finish of the coated part, at the region of contact between the two moving parts, thus increasing resistance to movement, or friction, between the said two parts.

There is therefore a need for an improved medical device allowing the preservation of a protein containing composition over time. Moreover, there is a need for such a medical device capable of injecting such a protein containing composition with good sliding properties between a barrel and a piston movable within said barrel.

It is therefore an object of the present invention to provide a medical device that preserves the stability of a protein containing composition stored within said medical device. Moreover, it is an object of the present invention to provide such a medical device allowing a good tightness together with good sliping functions between a barrel and a piston when said medical device is an injection device comprising such a barrel and a piston movable within said barrel. The present invention meets this need by providing a medical device comprising a chamber intended to receive a protein containing composition, said chamber being provided with a first specific coating on its internal wall, and a closure means, optionally capable of sliding within said chamber, said closure means being provided with a second specific coating, said medical device allowing protein compositions to remain stable over time when said compositions are stored within said medical device. A first aspect of the invention is a medical device comprising :

- at least one chamber having an inner surface delimiting an inner space intended to receive a protein containing composition,

- closure means for tightly sealing said inner space, said closure means having at least one face facing said inner space, said face being coated with a coating (8) consisting of at least one polymer material comprising polymer chains having the following repeat unit:

in which X represents a halogen, for example F, or a hydrogen, and in which Y-i, Y₂, Y₃, Y₄ each independently represent a halogen, for example Cl, or a hydrogen, characterized in that -said inner surface of said chamber is coated with a layer of silicone, and

- the mean thickness of the coating of said face of said closure means ranges from 3 to 10 μm.

The medical device of the invention allows to store protein containing compositions for a certain period of time, for example over 7 days or over 15 days, while maintaining the stability of the proteins.

Moreover, in the case the medical device of the invention is an injection device provided with a syringe barrel and a piston movable within said barrel, the invention allows to have decreased activation, sustainable and final forces for moving the piston within the barrel in which it is lodged, without having to add a lubricant on the piston and while preserving the tightness at the contact region between the piston and the internal surface of the barrel. For example, in a medical device such as a syringe, the piston must be able to be moved relative to the barrel, through a gliding movement, while at the same time ensuring the tightness with said barrel, so that all of the product to be administered escapes only via the distal end of the barrel and does not leak out of said barrel via the piston at the proximal end of the barrel. The medical device of the invention, thanks to a first specific coating on the internal surface of the barrel and to a second coating having a specific thickness range on the piston, allows the successful completion of these two relatively incompatible requirements and the preservation of the stability of the proteins contained in the product to be administered.

In this application, the distal end of a component or of a device means the end furthest away from the hand of the user and the proximal end means the end closest to the hand of the user. Similarly, in this application, the terms "in the distal direction" and "distally" mean in the direction of the injection, and the terms "in the proximal direction" and "proximally" mean in the direction opposite to the direction of injection.

Moreover, with the medical device of the invention, it is possible to decrease the total amount of lubricant, for example silicone oil, that is necessary in such a medical device, by eliminating the need to have such a silicone oil on the piston.

In an embodiment of the invention, the mean thickness of the said coating of said face of said closure means ranges from 3 to 5 μm.

In an embodiment of the invention said closure means consists of a viscoelastic material. Preferably, the said coating of said face of said closure means is continuous and elastic.

Preferably, the said polymer material is chosen from the group consisting of poly(p-xylylene), poly(p-meta-chloroxylylene), poly(p-ortho- chloro/meta-chloroxylylene) and poly(p-difluoroxylylene). More preferably, the said polymer material consists of poly(p-meta-chloroxylene).

In an embodiment of the invention, the outer surface of said coating of said face of said closure means has a mean roughness Ra of less than 2.5 μm, preferably less than 2 μm and, for example, of the order of 1.0 μm.

In an embodiment of the invention, said layer of a silicone has a mean thickness ranging from 0.05 to 2 μm.

Preferably, the mean thickness of the layer of silicone is about 0.5 to 1.5 μm.

In an embodiment of the invention, the silicone is selected from the class of polydimethylsiloxanes of general structure :

wherein R and R¹ are alkyl groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and n is an integer ranging from 1 to 2000, preferably about 1 to 800.

Preferably, the silicone has a viscosity ranging from 10 to 100,000 centistokes, more preferably from 50 to 1000 centistokes.

In a preferred embodiment of the invention, the silicone has a molecular weight ranging from 100 to 200,000 g/mol, and preferably from 1,000 to 100,000 g/mol.

In an embodiment of the invention, said chamber is the barrel of an injection device and said closure means is a piston movable within said barrel when said injection device is operated. The present invention is now described with reference to the attached drawings in which:

- Figure 1 depicts, schematically and in cross section, a medical device considered by the present invention and according to a first embodiment thereof, - Figure 2 depicts, again schematically and in cross section, a portion of a medical device according to a second embodiment of the invention,

- Figure 3 is a graphic showing the necessary forces to move a piston within a barrel for a medical device according to the invention and for prior art devices. With reference to Figure 1 , a medical device 1 of the invention, under the form of a closed container or a vial is shown. The medical device 1 of figure 1 comprises a chamber under the form of a container 2, having an inner surface 2a delimiting an inner space 3 receiving a protein containing composition 4, under form of a liquid in the example shown. The container 2 may be in plastic or in glass. The inner surface 2a of the container 2 is coated with a layer 5 of silicone oil or a mixture of silicone oils. The silicone may be selected in the class of poiydimethylsiloxanes of general structure:

wherein R and R' are alkyl groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and n is an integer ranging from 1 to 2000, preferably about 1 to 800.

The silicone has preferably a viscosity ranging from 10 to 100,000 centistokes, more preferably from 50 to 1000 centistokes. In addition, the silicone has preferably a molecular weight ranging from 100 to 200,000 g/mol, and preferably from 1,000 to 100,000 g/mol.

The silicone layer may be applied on the inner surface 2a of the container 2 via spraying. Alternatively, the silicone may be deposited on the inner surface 2a of the container 2 and then baked. Methods of applying a silicone layer on the inner surface of a container are well known from the man skilled in the art.

Preferably, the silicone layer 5 has a mean thickness ranging from 0.05 to 2 μm. More preferably, said thickness is about 0.5 to 1.5 μm.

The medical device 1 of figure 1 further comprises closure means for tightly sealing said inner space 3, under the form of a plug 6 in the example shown. The plug 6 is preferably made out of a viscoelastic material, for example an elastomer or a rubber, in order to ensure tightness at the contact region 7 defined between the coated inner surface 2a of the container 2 and the plug 6.

The plug 6 is provided, at least on its face facing the inner space 3 and in contact with the container 2 with a coating 8. On figure 1 , the plug 6 is provided with the coating 8 on its entire outer surface. The coating 8 is preferably continuous, intrinsically elastic and firmly secured to the plug 6.

Before use of the medical device 1 , for example during storage, the coating 8 ensures the tightness between the plug 6 and the container 2 by preventing the leakage of the product 4 at the contact region 7 between the plug 6 and the container 2.

According to the invention, the coating 8 consists of at least one polymer material comprising polymer chains consisting of the following repeat unit:

in which X represents a halogen, for example F, or a hydrogen, and in which Y-i, Y2. Y3 and Y₄ each independently represent a halogen, for example Cl, or a hydrogen. This coating 8 according to the invention is obtained by dry vacuum deposition/polymerization at ambient temperature, as described above.

The coating 8 according to the invention has a thickness ranging from 3 to 10 μm.

Starting with the appropriate dimer, and using equipment as identified hereinabove, the person skilled in the art will know how to deposit and control a predetermined thickness of the polymer material adopted, particularly by varying the time for which the plug that is to be coated is exposed to the reactive monomer form of the poly(p-xylylene) chosen. Furthermore, a person skilled in the art knows that the rate of deposition/ polymerization is directly proportional to the square of the reactive monomer concentration, and inversely proportional to the absolute temperature of the part exposed to the monomer, this information allowing him to modify and control the thickness of the coating deposited on the plug.

The present invention considers various substrates or viscoelastic materials to be appropriate to the deposition of a coating 8 as previously defined, these being various natural or synthetic elastomers: silicones, nitrile- based elastomers, natural or synthetic rubber, fluorocarbon elastomers, polyurethanes. As a preference, the invention will devote itself to bromobutyl and chlorobutyl synthetic elastomers. By way of example, the mean thickness of the coating 8 ranges from 3 to 10 μm and preferably from 3 to 10 μm and, more preferably still, from 3 to 5 μm.

Such a specific thickness range allows the protein containing composition 4 to be preserved for contamination from particles coming from the plug 6.

As stated above, the polymer material is preferably chosen from the group consisting of poly(p-xylylene), poly(p-meta-chloroxylylene), poly(p-ortho- chloro/meta-chloroxylylene) and poly(p-difluoroxylylene). As a preference, the polymer material consists of poly(p-meta-chioroxylylene).

With reference to figure 2 is partially shown a variant of a medical device 1 according to the invention, wherein the chamber is the barrel 9 of an injection device and the closure means is a piston 10 movable within said barrel 9. The barrel 9 and the piston 10 are in contact with one another via a contact surface 11. The piston 10 and the barrel 9 are able to move one with respect to the other in a predetermined gliding movement, for example translationally and/or rotationally. Such a translational movement is represented on figure 2 by the arrow F. The inner surface 9a of the barrel 9 delimits an inner space 3 which receives a protein containing product 4 in the liquid, gaseous or fluid phase, the volume of said product varying according to the movement of the piston 10 with respect to the barrel 9.

The inner surface 9a of the barrel 9 is coated with a silicone layer 5 applied on said inner surface 9a by any classical method known in the art. Preferably, the silicone layer 5 has a mean thickness ranging from 0.05 to 2 μm. More preferably, said thickness ranges from 0.5 to 1.5 μm.

In particular, for administering the product 4, the piston 10 is caused to move distally along arrow F of figure 2 in order to push the product 4 out of the barrel 9. The piston 10 is designed to deform in order to tighten the contact region 11. For example on figure 2, the face of the piston 10 which faces the product 4 and the contact region 11 is provided with a coating 8 which is continuous, intrinsically elastic and firmly secured to the piston 10.

The piston 10 may be made in its entirety of a viscoelastic material, for example an elastomer. According to the embodiment of figure 2, the contact surface 11 between the barrel 9 and the piston 10 determines a region of gliding contact between the piston 10 and the barrel 9.

The coating 8 of the piston 10 of the medical device 1 of the invention encourages the gliding of the piston 10 relative to the barrel 9 at the time of administration of the product 4. Moreover, the coating 8 also ensures static and dynamic tightness at the contact surface 11 of the piston 10 and the barrel 9. In particular, before use of the medical device 1 , for example during storage, the coating 8 ensures the static tightness between the piston 10 and the barrel 9 by preventing the leakage of the product 4 at the contact surface 11 between the piston 10 and the barrel 9. When the medical device 1 is in use, the coating 8 ensures the dynamic tightness between the piston 10 and the barrel 9 by preventing the leakage of the product 4 at the contact surface 11 between the piston 10 and the barrel 9 while the piston 10 is moving relative to the barrel 9.

in which X represents a halogen, for example F, or a hydrogen, and in which Yiι Y2, Y3 and Y₄ each independently represent a halogen, for example Cl, or a hydrogen. This coating 8 according to the invention is obtained by dry vacuum deposition/polymerization at ambient temperature, as described above.

The coating 8 according to the invention has a thickness ranging from 2 to 10 μm.

The deposition of the coating 8 is completed as described above for the embodiment of figure 1. The present invention considers various substrates or viscoelastic materials to be appropriate to the deposition of a coating 8 as previously defined, these being various natural or synthetic elastomers: silicones, nitrile-based elastomers, natural or synthetic rubber, fluorocarbon elastomers, polyurethanes. As a preference, the invention will devote itself to bromobutyl and chlorobutyl synthetic elastomers.

By way of example, the mean thickness of the coating 8 ranges from

3 to 10 μm and preferably from 3 to 10 μm and, more preferably still, from 3 to 5 μm.

Such a specific thickness range allows a smooth gliding of the piston

10 and the barrel 9 relative to each other while ensuring tightness at the contact region between the piston 10 and the barrel 9.

As stated above, the polymer material is preferably chosen from the group consisting of poly(p-xylylene), poly(p-meta-chloroxylylene), poiy(p-ortho- chloro/meta-chloroxylylene) and poly(p-difluoroxylylene). As a preference, the polymer material consists of poly(p-meta-chloroxylylene).

By implementing the invention, it is possible, to a significant extent, to limit or even eliminate the amount of lubricant other than the aforementioned polymer material, for example silicone oil, customarily added on the pistons of devices of the prior art at the contact region of sliding contact between the piston and the barrel.

According to the present invention, it has also been discovered that the roughness, and therefore the surface finish, of the coating 8 of the piston 10 of the medical device 1 in the contact surface 11 of sliding contact with the barrel 9, is important in giving the coating 8 the desired performance and function, and this, independently of the thickness of the coating 8, provided said thickness ranges from 3 to 10 μm as defined in the present invention.

According to an embodiment of the invention, the surface finish of the coating 8, in the contact surface 11 of sliding contact, has a mean roughness R_a of less than 2.5 μm and preferably less than 2 μm and, more preferably still, less than 1.5 μm, for example of the order of 1.0 μm.

In the present application, the roughness is measured according the following method : roughness measurements done in triplicate are performed by using a profiler Wyko NT 1100 (Veeco Instruments Inc. Tucson USA) on scans 370 μm x 240 μm with a VSI mode (Vertical Scanning Interferometry).

The calibration of the apparatus is performed following the procedure Wl 7.6-20 using measuring instruments traceable to the National Institute of Standards and Technology (NIST). A roughness of less than 2.5 μm, measured as described hereinabove, for the coating 8 of the piston 10 of a medical device 1 of the invention allows a smooth gliding of such a coated piston 10, relative to the barrel 9.

The present invention will now be illustrated with the following examples.

EXAMPLES 1-4 :

Tests were performed in order to compare the ability of medical devices 1 according to the invention to preserve the stability of a product 4 containing proteins with respect to medical devices of the prior art.

The tested chambers were glass barrels of prefilled syringes commercially available under the trade name "Hypak 1 mlL" from the company Becton and Dickinson, Company. The syringe barrels were provided with bromobutyl pistons from the Company West. Various systems piston-barrel were tested : the characteristics of the tested systems are collected in the following table 1 :

Table 1. Tested Systems piston-barrel.

For system S2, the piston was coated with 150 μg of silicone according to the following method : the uncoated piston was cleaned for 10 min in distilled water at a temperature of 8O⁰C and then spray siliconized with 150 μg of a silicone oil of viscosity 1000 Cst (available at company Dow Corning).

For systems S4 and S5, the piston was coated with poly(p-meta- chloroxylylene) (Parylene C) according to the dry vacuum deposition/polymerization method previously described hereinabove. The mean thickness of the Parylene C coating on each piston was about 3 μm. For systems S1 , S2 and S4, the inner surface of each barrel was coated with a silicone layer of 0.05-1 μm by spraying a silicone oil of viscosity 1000 Cst (available at company Dow Corning) on said surface by means of nozzles. For system S5, the inner surface of the barrel was coated with a silicone layer of 0.5-1.5 μm, by first spraying onto said surface an emulsion of water and silicone oil of viscosity 360 Cst (available at company Dow Corning) stabilized with a surfactant ("Triton X100" commercially available at company Union carbide Chemicals and Plastic), and then heating said coated barrel in an oven at a temperature of 300⁰C in order to evaporate the water phase.

Various compositions containing different proteins were tested. Prior to the contact with the protein containing composition, all the barrels to be tested were cleaned by a sequence of soda (1N) during 10 min, wter rinsing during 10 min, chlorhydric acid (1N) during 10 min, water rinsing during 10 min and then sterilized during 20 min at a temperature of 121⁰C.

In examples 1-4 below, the protein stability was studied at 37⁰C and the hydrodynamic diameter of the protein (nm) was measured by dynamic light scattering (DLS). The measurements were made with a He Ne laser 633 nm at 173° in order to verify the presence of aggregates and to minimize the effects of dust contamination. Each native protein has a specific hydrodynamic diameter that is typically less than 20 nm. A study of the kinetics was performed at 37°C and the hydrodynamic diameter was measured after 7, 15 and 30 days. When proteins formed aggregates, large hydrodynamic diameters were measured. All the experiments were done in isotonic conditions (300 mOsm). The percentage of intensity was recorded as a function of the hydrodynamic diameter. Several peaks can be observed.

Peak 1 corresponds to the hydrodynamic diameter of the native protein,

Peaks 2 and 3 correspond to the protein aggregates.

Values in brackets correspond to the percentage of light intensity for each peak.

In consequence, the higher the percentage of light intensity is for Peak 1 , the more stable is the protein.

Example 1 : study of stability of Bovine Serum Albumine Bovine Serum Albumin (BSA) is a serum albumin that is used to stabilize some enzymes. It plays a role in transport of low hydrosoluble proteins. It is a negative protein, i.e. it has an isoelectric point less than 7 at pH 7.

The stabilization of BSA was studied for one month in a buffer (sodium phosphate 10 mM, NaCI 130 mM pH 7.2). the results are collected in the following Table 2 :.

Table 2. Percentage of native protein (BSA) after stabilization (days) at 37°C with systems S1, S2, S4, S5 obtained by DLS. Peak 1 corresponds to the hydrodynamic diameter of the native protein and peaks 2 and 3 to the protein aggregates. Values in brackets correspond to the percentage of light intensity for each peak.

The most stable system was obtained with system S5 according to the invention. Indeed, for S5, the percentage of native protein is more than 70% after 7, 14 and 30 days of stabilization (72% at 7 days, 77% at 15 days and 80% at 30 days) at 37°C. With comparative systems S1 and S2, the stable protein is only 30% after 15 days of stabilization.

Example 2 : study of stability of lyzozyme

Lyzozyme is an enzyme, commonly referred to as the 'body's own antibiotic' since it disintegrates the bacteria walls. It is abundantly present in secretions such as tears or saliva. It is a positive protein, i.e. it has an isoelectric point more than 7 at pH 7.

Lyzozyme stabilization was studied for one month in a buffer (sodium phosphate 10 mM, NaC1 130 mM pH 7.2) . The results are collected in the following Table 3 :

Table 3. Percentage of native protein (lyzozyme) after stabilization

(days) at 37°C with systems S2, S5. Peak 1 corresponds to the hydrodynamic diameter of the native protein and peaks 2 and 3 to the protein aggregates. Values in brackets correspond to the percentage of light intensity for each peak.

As shown in Table 3, after stabilization for 7, 25 or 30 days, the percentage of native protein is higher with system S5 according to the invention (100%) than with comparative system S2.

Example 3: study of stability of Ribonuclease

Ribonuclease, abbreviated commonly as RNase, is a nuclease that catalyzes the breakdown of RNA into smaller components.

RNase stabilization was studied for one month of contact in a buffer

(sodium phosphate 10 mlvl, NaC1 130 mM pH=7.2) . The results are collected in the following Table 4 :

Table 4. Percentage of native protein (RNase) after stabilization (days) at 37°C with systems S2, S4, S5. Peak 1 corresponds to the hydrodynamic diameter of the native protein and peaks 2 and 3 to the protein aggregates. Values in brackets correspond to the percentage of light intensity for each peak

As shown in this table, systems S4 and S5 according to the invention insure at least 90%, and even 100%, of RNAse stability after 15 and 30 days at 37°C. On the contrary, with comparative system S2, this stability is less than 63% after 30 days.

Example 4 : study of stability of insulin

Insulin is a polypeptide hormone that regulates glucose metabolism.

Human insulin stabilization was studied for one month of contact in a buffer (sodium phosphate 10 mM, NaCI 130 mM pH=7.2) The results are collected in the following Table 5:

Table 5. Percentage of native protein (human insulin) after stabilization (days) at 37⁰C with systems S1, S2, S4, S5. Peak 1 corresponds to the hydrodynamic diameter of the native protein and peaks 2 and 3 to the protein aggregates. Values in brackets correspond to the percentage of light intensity for each peak

The initial solution (at day 0) remains constant in systems S4 and S5 according to the invention after 15 and/or 30 days of stabilization in comparison with comparative systems S1 and S2 over the same period (15 and 30 days).

EXAMPLE 5:

The barrier properties of chlorobutyl pistons available from the Company West, coated with different thicknesses of a coating of poly(p-meta- chloroxylylene) (Parylene C) were evaluated.

The characteristics of the various tested pistons are reproduced in the following Table 6 :

Table 6

Pistons C2 and C3 were coated with poly(p-meta-chloroxylylene) (Parylene C) according to the dry vacuum deposition/polymerization method previously described hereinabove.

Each piston was tested as follows : the piston was inserted in a glass barrel initially filled with a composition of distilled water and ethanol (80/20 V/V). The system was heated at 121⁰C for 20 min and the composition was then analyzed by HPLC (High Performance Liquid Chromatography). A chromatogram with different peaks as a function of time was obtained, in which each peak corresponds to a chemical species coming either from the coating of the piston or from the piston itself.

For each piston type, the measure was completed twice.

The following Table 7 summarizes the main peaks obtained for each piston type.

Table 7. Main organic components analyzed from Pistons C1 , C2 and C3 by

HPLC

Absence of peak on the chromatogram ='-' Presence of peak on the chromatogram = V Six peaks were obtained for the comparative uncoated piston C1 i .e. at retention times of 2.2, 2.8, 3.2, 3.7, 3.8 and 5.2 min. This means that at least 6 chemical species have transferred from the piston into the composition contained in the barrel. On comparative piston C2, 6 peaks are also observable, some corresponding to species coming from the piston itself (retention times of 3.2, 3.7 and 5.2 min) and others coming from the coating (retention times of 2.1 , 2.4 and 2.9 min). With the piston C3 of the invention, only 4 peaks are observable. The coated piston of the invention allows the elimination of the transfer into the stored composition of most of the chemical species coming from the piston (namely the species corresponding to the retention times of 2.2, 2.8, 3.2, 3.7 and 3.8 min).

EXAMPLE 6 :

The sliding properties of a medical device of the invention comprising a piston and a barrel in sliding relationship was evaluated in comparison to medical devices of the prior art.

The tested chambers were glass barrels of prefilled syringes commercially available under the trade name "Hypak 1 mlL" from the company Becton and Dickinson, Company. The syringe barrels were provided with chlorobutyl pistons available from the Company West.

Various systems piston-barrel were tested : the characteristics of the tested systems are collected in the following table 8 :

Table 8. Tested Systems piston-barrel. For all systems S6-S9, the inner surfaces of the barrels were coated with 0.04 mg of silicone corresponding to a layer of silicone of 0.05-0.1 μm. Pistons of systems S7-S9 were coated with poly(p-meta- chloroxylylene) (Parylene C) according to the dry vacuum deposition/polymerization method previously described hereinabove.

Tests (Activation Gliding Force tests) were performed to determine the necessary forces for moving each piston with respect to the barrel in which it is housed. These tests were performed using a LLOYD-CB190 tensile testing machine dynamometer using NEXYGEN operating software, according to the test protocol outlined briefly below.

Activation Gliding Force (AGF) tests were applied on barrels filled with 1 mL of demineralised water and each plugged with one piston to be tested (coated or uncoated). Each barrel-piston system was tested 32 times in order to ensure the reproducibility and to validate the results. To prepare the 32 syringes for a system, and particularly to insert the piston in the barrel, a Groninger machine was used.

The necessary forces measured are shown on graphic of figure 3.

As appears from this graphic, the system S9 according to the. invention necessitates lower values to move the piston within the barrel compared to comparative systems S6-S8. The system S9 according to the invention has improved sliding properties compared to the systems of the prior art S6-S8.

Claims

1. Medical device (1) comprising :

- at least one chamber (2; 9) having an inner surface (2a; 9a) delimiting an inner space (3) intended to receive a protein containing composition (4),

- closure means (6: 10) for tightly sealing said inner space, said closure means having at least one face facing said inner space (3), said face being coated with a coating (8) consisting of at least one polymer material comprising polymer chains having the following repeat unit:

in which X represents a halogen, for example F, or a hydrogen, and in which Y₁, Y₂, Y₃, Y₄ each independently represent a halogen, for example Cl, or a hydrogen, characterized in that

-said inner surface (2a; 9a) of said chamber (2; 9) is coated with a layer (5) of silicone, and - the mean thickness of the coating (8) of said face of said closure means (6; 10) ranges from 3 to 10 μm.

2. Medical device (1) according to Claim 1 , characterized in that the mean thickness of the said coating (8) of said face of said closure means (6;

10) ranges from 3 to 5 μm.

3. Medical device (1) according to Claim 1 , characterized in that said closure means (6; 10) consists of a viscoelastic material.

4. Medical device (1) according to one of claims 1 to 3, characterized in that the said coating (8) of said face of said closure means (6; 10) is continuous and elastic.

5. Medical device (1) according to one of claims 1 to 4, characterized in that the said polymer material is chosen from the group consisting of poly(p- xylylene), poly(p-meta-chloroxylylene), poly(p-ortho-chloro/meta- chloroxylylene) and poly(p-difluoroxylylene).

6. Medical device (1) according to the preceding claim, characterized in that the said polymer material consists of poly(p-meta-chloroxylene).

7. Medical device (1) according to any of claims 1 to 6, characterized in that the outer surface of said coating (8) of said face of said closure means (6; 10) has a mean roughness Ra of less than 2.5 μm, preferably less than 2 μm and, for example, of the order of 1.0 μm.

8. Medical device (1) according to one of claims 1 to 7, characterized in that said layer (5) of silicone has a mean thickness ranging from 0.05 to 2 μm.

9. Medical device (1) according to the preceding claim, characterized in that the mean thickness of said layer (5) of silicone ranges from 0.5 to 1.5 μm.

10. Medical device (1) according to any of claims 1 to 9, characterized in that said silicone is selected from the class of polydimethylsiloxanes of general structure :

11. Medical device (1) according to claim 10, characterized in that said silicone has a viscosity ranging from 10 to 100,000 centistokes, more preferably from 50 to 1000 centistokes.

12. Medical device (1) according to claim 10, characterized in that said silicone has a molecular weight ranging from 100 to 200,000 g/mol, and preferably from 1 ,000 to 100,000 g/mol.

13. Medical device (1) according to any of claims 1 to 12, characterized in that said chamber is the barrel (9) of an injection device and said closure means is a piston (10) movable within said barrel when said injection device is operated.