Composite material for a pharmaceutical packaging, method for the production thereof, and use of the composite material

Abstract

A composite material for a pharmaceutical packaging is provided that includes a substrate and a protective layer. The substrate has a contact region in contact with the protective layer. The contact region includes a contact area between the substrate and the protective layer and a region of the substrate close to the surface. The substrate is made of glass or of a cyclic olefin polymer or a cyclic olefin copolymer, while the protective layer is made of ceramic material. The substrate in the contact region is different from the substrate outside the contact region.

Claims

1. A composite material for a pharmaceutical packaging, comprising: a substrate; and a protective layer comprising hydrogenated oxidized silicon carbide (SiC:OH) and/or nitrided oxidized hydrogenated silicon carbide (SiC:OHN), the substrate has a contact region in contact with the protective layer, the contact region comprising a contact area between the substrate and the protective layer and a region of the substrate, the region of the substrate being defined by a lateral extension along the contact area and a vertical extension in a depth direction perpendicular to the contact area, the substrate being made of a material selected from the group consisting of glass, cyclic olefin polymer, and cyclic olefin copolymer, the protective layer being made of a ceramic material, wherein the substrate in the contact region has a difference from the substrate outside the contact region.

2. The composite material as claimed in claim 1, wherein the material of the substrate is glass selected from the group consisting of hydrolytic class I to V and borosilicate glass of hydrolytic class I.

3. The composite material as claimed in claim 1, wherein the difference of the substrate in the contact region from the substrate outside the contact region is selected from the group consisting of a surface roughness, a chemical composition, a surface energy, and a chemical etching rate.

4. The composite material as claimed in claim 1, wherein the protective layer is attached to the contact area of the substrate by van der Waals forces and/or covalently.

5. The composite material as claimed in claim 1, wherein the protective layer has a structure selected from the group consisting of amorphous, partially crystalline, and crystalline.

6. The composite material as claimed in claim 1, wherein the protective layer is free of silicon dioxide (SiO2), at least in a portion thereof.

7. The composite material as claimed in claim 1, wherein the protective layer comprises a first sub-layer facing the substrate and a second sub-layer facing away from the substrate.

8. The composite material as claimed in claim 7, wherein the second sub-layer has a composition different from that of the first sub-layer.

9. The composite material as claimed in claim 7, further comprising a content of an element selected from the group consisting of nitrogen, oxygen, carbon and combinations thereof of the second sub-layer that is different from that of the first sub-layer.

10. The composite material as claimed in claim 7, wherein the first sub-layer has a carbon content c1(C) of c1(C)40% and/or a nitrogen content c1(N) of c1(N)0.01%, or c1(N)0.05%.

11. The composite material as claimed in claim 7, wherein the second sub-layer has a nitrogen content c2(N) of c2(N)0.1% and/or an oxygen content c2(O) of c2(O)5%.

12. The composite material as claimed in claim 7, wherein the second sub-layer has a density of an element selected from the group consisting of nitrogen, oxygen, carbon, and combinations thereof of >1.7 g/cm3 and/or has a thickness less than a thickness of the first sub-layer.

13. The composite material as claimed in claim 1, wherein the protective layer has a ratio alpha of carbon content to silicon content in a range of 0.8<alpha<7 and/or a ratio beta of nitrogen content to silicon content in a range of 0<beta<3.

14. The composite material as claimed in claim 1, wherein the composite material is configured for use as a device selected from the group consisting of a container for a medical product, a container for a pharmaceutical product, a hollow tube, a hollow container, a pharmaceutical packaging, a vial, a syringe, a cartridge, and an ampoule, and wherein the protective layer is sufficient to prevent delamination of glass from interaction with a liquid solution.

15. The composite material as claimed in claim 1, wherein the composite material is configured as a hollow body for use with a product selected from the group consisting of products including alkaline based drugs, products including protein-based drugs, products including surface active agents, non-buffered drug solutions, acidic formulations, neutral formulations, alkaline formulations, acidic formulations that include a surface active agent, acidic formulations that include a surfactant, neutral formulations that include a surface active agent, neutral formulations that include a surfactant, alkaline formulations that include a surface active agent, alkaline formulations that include a surfactant, solutions with polysorbate, solutions including sugar, and solutions including sugar alcohol.

16. A composite material for a pharmaceutical packaging, comprising: a substrate; and a protective layer, the substrate has a contact region in contact with the protective layer, the contact region comprising a contact area between the substrate and the protective layer and a region of the substrate, the region of the substrate being defined by a lateral extension along the contact area and a vertical extension in a depth direction perpendicular to the contact area, the substrate being made of a material selected from the group consisting of glass, cyclic olefin polymer, and cyclic olefin copolymer, the protective layer being made of a ceramic material, wherein the substrate in the contact region has a difference from the substrate outside the contact region, wherein the protective layer comprises a first sub-layer facing the substrate and a second sub-layer facing away from the substrate, and wherein the second sub-layer has a content that varies continuously as a function of a distance from the first sub-layer.

17. The composite material as claimed in claim 16, wherein the content of the second sub-layer that is in contact with the first sub-layer is the same as a content of the first sub-layer.

18. A composite material for a pharmaceutical packaging, comprising: a substrate; and a protective layer, the substrate has a contact region in contact with the protective layer, the contact region comprising a contact area between the substrate and the protective layer and a region of the substrate, the region of the substrate being defined by a lateral extension along the contact area and a vertical extension in a depth direction perpendicular to the contact area, the substrate being made of a material selected from the group consisting of glass, cyclic olefin polymer, and cyclic olefin copolymer, the protective layer being a ceramic crystalline coating, wherein the substrate in the contact region comprises, but the substrate outside the contact region does not comprise, a chemical element of glass selected from a group consisting of Na, B, Al, K, Ca, Mg, Ba, Cl, a combination of Si and O, and any combinations thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 is a sectional view of a first embodiment of the composite material;

(2) FIG. 2 is a sectional view of a second embodiment of the composite material;

(3) FIG. 3 is an intensity/sputter time profile of a composite material obtained in a first embodiment of the production method, acquired using TOF-SIMS;

(4) FIG. 4 is an intensity/sputter time profile of a composite material obtained in a second embodiment of the production method, acquired using TOF-SIMS; and

(5) FIG. 5 is a profile of refractive index and extinction coefficient, acquired using ellipsometry.

DETAILED DESCRIPTION

(6) When storing liquid drug formulations in pharmaceutical packaging made of glass, glass delamination, i.e. a partial release of glass flakes, may occur during storage in conjunction with buffers, such as phosphate and citrate buffers, or salt-containing solutions and other formulation components. Such delamination is a current issue in the pharmaceutical industry, and new cases of glass delamination constantly become known.

(7) Glass delamination can be avoided or at least reduced in a surprisingly simple way, by a coating. On the one hand, the coating prevents a corrosive attack on the glass substrate, and on the other the coating is intrinsically corrosion resistant, thereby preventing a dissolution of the layer even under a chemical attack, for example a hydrolytic attack. In this manner, improved stability of the product in the pharmaceutical packaging is achieved.

(8) Moreover, the coating also provides for a longer shelflife of the container in combination with improved product safety.

(9) In particular, the intension is a reduction of risk for the pharmaceutical industry, and to provide a solution which is effective on various inhomogeneous glass surfaces of glasses of hydrolytic class I, but also glasses of hydrolytic class II to V, and which is applicable for a largest possible variety of buffer solutions and formulation variants.

(10) The composite material 1 can be employed for a large variety of process variations during sterilization or depyrogenation and cleaning of the vials.

(11) FIG. 1 shows a composite material 1 for pharmaceutical packaging according to a first embodiment. Composite material 1 comprises a substrate 2 and a protective layer 4.

(12) The substrate 2 includes a contact region 6 in contact with the protective layer 4. Contact region 6 comprises the contact area between substrate 2 and protective layer 4, and a region of the substrate 2 close to the surface.

(13) Substrate 2 is made of glass. In the present example, substrate 2 is provided in form of a flat substrate or a glass sheet.

(14) Protective layer 4 is made of ceramic material.

(15) When storing a liquid product in a glass container, glass delamination may occur during storage, i.e. a partial release of glass flakes.

(16) The protective layer advantageously enables to achieve an anti-delamination effect and improved layer resistance, if the container for storing the product is made of the composite material.

(17) Advantageously, the protective layer 4 is covalently attached to the surface of contact region 6.

(18) The protective layer 4 and its covalent attachment to the surface of contact region 6 is advantageously capable to inhibit a diffusion of ions. In this way, a release of substrate components due to a chemical interaction between the product and the substrate 2 can be prevented.

(19) Thus, the composite material 1 has improved corrosion resistance as compared to a conventional glass substrate.

(20) FIG. 2 shows a composite material 1 for pharmaceutical packaging according to a second embodiment. The composite material 1 comprises a substrate 2 and a protective layer 4a, 4b.

(21) In contrast to the first embodiment shown in FIG. 1, the protective layer comprises two sub-layers 4a, 4b. Here, a first layer 4a is formed as a base layer, and a second layer 4b is formed as a near-surface layer.

(22) The second layer 4b has a composition different from that of first layer 4a in that the second layer 4b has a content of nitrogen and/or oxygen and/or carbide different from that of the first layer 4a.

(23) The composite material of the invention may also be used for plastic containers comprising a substrate of cyclic olefin polymer (COP) or cyclic olefin copolymer (COC), such as for vials made of COP or COC, and for COP or COC syringe bodies or cartridge bodies, in order to create a corrosion resistant barrier layer. The inventive coating adheres well to these plastics, with very little or no delamination tendency.

(24) In this case, a layer is deposited on the cyclic olefin polymers, which includes one or more of the following substances or bonds: silicon carbide SiC; hydrogenated oxidized silicon carbide SiC:OH; nitrided oxidized hydrogenated silicon carbide SiC:OHN; nitrogen; and NH bonds, or CN bonds.

(25) First Embodiment of the Production Method

(26) Two vials made of borosilicate glass (SCHOTT's Fiolax) with filling volume of 10 ml and brimful volume of 14 ml are fed into a dual chamber plasma coating reactor and are each placed on a sealing surface at the bottom of the reactor. Then, the reactor chambers are closed, and the interior of the vials is evacuated to a base pressure of <0.1 mbar. The exterior remains at atmospheric pressure throughout the treatment process. While at the lower side in the region of the opening of the vials the connection to the vacuum is maintained, the gas inlet valve is opened and argon is introduced via the gas supply as a first process gas.

(27) Subsequently, using a microwave source, pulsed microwave energy is supplied at a frequency of 2.45 GHz and a plasma is ignited. Through the plasma, the substrate is heated to a temperature above 200 C. Subsequently, during a gas exchange period, a mixture of hexamethyldisilane and argon is introduced, with a concentration of hexamethyldisilane of 5% based on a total flow of 50 sccm, and a process pressure of 0.3 mbar is adjusted, and using the pulsed microwave plasma (average microwave power of 340 W) and a pulse interval of 30 ms, a hydrogenated oxidized nitrided silicon carbide layer of 25 nm thickness is deposited in a coating time of 3 s.

(28) After the coating process, the vials are separated from the vacuum source by a valve, and are purged with nitrogen gas at atmospheric pressure, and are removed from the coating apparatus.

(29) Second Embodiment of the Production Method

(30) Similar to the first embodiment of the production method, two vials of the same size are heated at the beginning of the process, but then, during the gas exchange period, a mixture of hexamethyldisilane, oxygen, and argon is introduced, with a concentration of 35% of hexamethyldisilane, 60% of oxygen, and 5% of argon, based on the total flow, and with the same plasma parameters as in the first embodiment of the production method a hydrogenated oxidized nitrided silicon carbide layer of 50 nm thickness is produced.

(31) Analyzes

(32) After preparation of further coated vials with the same method according to the first and second embodiments of the production method, respectively, function tests were performed on the coated samples and on non-coated references as follows:

(33) 1. Determination of sodium leaching after autoclaving for a period of 6 hours at 121 C. with different buffer systems (sealed vials of 12.4 ml filling volume)

(34) 2. Determination of silicon leaching after autoclaving for a period of 6 hours at 121 C. with different buffer systems (sealed vials of 12.4 ml filling volume).

(35) The determination of the sodium and silicon release from the inner surface of the coated containers was performed based on ISO 4802-2. For the filling for autoclaving, the following buffer systems were used: pH 1: HCl c=0.1 mol/L pH 7: Tris(hydroxymethyl)aminomethane/maleic acid buffer, adjusted to pH 7 using KOH pH 9: Tris(hydroxymethyl)aminomethane buffer, adjusted to pH 9 using HCl.

(36) This results in the values for different samples given in Table 1 below.

(37) TABLE-US-00001 TABLE 1 Leaching levels of sodium and silicon after autoclaving (AC; 6 hours at 121 C.) with different buffer systems and pH values Function test AC 6 h AC 6 h 121 C. AC 6 h AC 6 h AC 6 h 121 C. 121 C. TRIS pH 7 121 C. 121 C. AC 6 h 121 C. 0.1M HCl 0.1M HCl Na TRIS pH 7 TRIS pH 9 TRIS pH 9 Embodiment Na [mg/L] Si [mg/L] [mg/L] Si [mg/L] Na [mg/L] Si [mg/L] Example 1 0.04 0.16 0.00 0.07 0.01 0.06 Example 2 0.05 0.08 0.03 0.05 Reference 10 ml 2.64 6.27 0.42 1.52 0.70 2.34 vial

(38) The test results show that:

(39) 1. The layers have a high barrier effect or protective effect against an ion exchange of sodium ions between the Fiolax glass matrix and the aqueous solutions.

(40) 2. The layers also have a high barrier effect against a release of silicon from the glass.

(41) 3. The layers are intrinsically resistant to chemical attack. For, if the layers were not stable, elevated amounts of silicon would be released from the silicon carbide containing layer system during an attack on the layer.

(42) 4. All statements apply to a wide pH range from pH 1 to pH 9, i.e. the layers both prevent an ion exchange in the acidic pH range and an attack on the glass network in the alkaline pH range.

(43) 5. Furthermore, the layers intrinsically have an excellent chemical and in particular hydrolytic resistance in this wide pH range. Especially in the alkaline pH range, the layers are highly resistant against an attack on the network of the layer itself.

(44) Additional samples prepared in accordance with embodiments 1 and 2 of the production method were analyzed using time of flight secondary ion mass spectrometry (TOF-SIMS) analysis (negative ions) and XPS (under 2 tilt angles).

(45) The second embodiment of the production method, with the intensity/sputter time profile of FIG. 4 and the XPS analysis of Table 2 under Example 2, reveals a higher oxygen content than embodiment 1, with the intensity/sputter time profile of FIG. 3 and the XPS analysis according to Table 2 under Example 1, which is caused by the oxygen supplied as an additional process gas. The lateral curve shape of the intensity/sputter time profiles of FIG. 4 and FIG. 3 prove that the layers of embodiments 1 and 2 of the production method have different thicknesses, which can be seen, inter alia, from the different sputtering durations until the C signal drops, which indicates the transition from the layer to the substrate.

(46) FIG. 3 shows an intensity/sputter time profile according to the first embodiment of the production method, acquired by TOF-SIMS.

(47) FIG. 4 shows an intensity/sputter time profile according to the second embodiment of the production method, acquired by TOF-SIMS.

(48) TABLE-US-00002 TABLE 2 XPS analyses of the first and second embodiments of the production method Angle embodiment () C [at %] N [at %] O [at %] Si [at %] C/Si O/Si N/Si Example 1 0 63.2 0.6 18.1 18.1 3.5 1.0 0.03 50 63 0.4 19.5 17 3.7 1.1 0.02 Example 2 0 54.8 0 26.6 18.7 2.9 1.4 0.00 50 56.2 0.1 26.5 17.3 3.2 1.5 0.01

(49) Furthermore, the curve shape and jump of the NH, SiN, and C2 N signals of the intensity/sputter time profiles and, in good agreement therewith, the XPS analyses indicate that small amounts of nitrogen are incorporated into the layers. The nitrogen content is found in the entire range of the intensity/sputter time depth profile that corresponds to the layer. Only when the C signal for carbon drops, these signals simultaneously drop, in the area of the interface to the substrate.

(50) Third Embodiment of the Production Method

(51) Vials are coated similarly to the embodiments 1 and 2 of the manufacturing process, but previously the vials are preheated to a process temperature using a nitrogen-containing plasma. The coated vials have a good barrier effect against leaching of sodium ions and silicon from the glass, and high layer resistance similar to that of embodiments 1 and 2.

(52) Fourth Embodiment of the Production Method

(53) Glass syringe bodies are coated with a hydrogenated oxidized nitrided silicon carbide layer in a production method similar to that of embodiments 1 and 2, but in a single seat chamber. The coated syringes have a good barrier effect against leaching of sodium ions and silicon from the glass, and a high layer resistance similar to that of embodiments 1 and 2 of the production method.

(54) Layers that were similarly prepared according to the above embodiments were measured with respect to their refractive index and extinction coefficient as a function of wavelength, using ellipsometry.

(55) The determined curve is shown in FIG. 5. The wavelength is plotted on the abscissa axis, the refractive index n is plotted on the left ordinate axis, and the extinction coefficient k is plotted on the right ordinate axis.

(56) As can be seen here, the protective layer has a wavelength-dependent absorptivity, with the extinction coefficient increasing as the wavelength decreases from a wavelength of 500 nm to a wavelength of 250 nm with a slope that is considerably steeper than a linear increase.

REFERENCE NUMERALS

(57) 1 Composite material 2 Substrate 4 Protective layer 4a First sub-layer of protective layer 4b Second sub-layer of protective layer 6 Contact region