HOLLOW BODY HAVING A WALL OF GLASS WITH A SURFACE REGION HAVING CONTENTS OF SI AND N

Abstract

A hollow body includes a wall of glass which at least partially surrounds an interior volume of the hollow body. The wall of glass has a wall surface which has a surface region. At least in the surface region the wall surface has a content of N in a range from 0.3 to 10.0 at-%, and at least 5 at-% Si.

Claims

1. A hollow body, comprising: a wall of glass which at least partially surrounds an interior volume of the hollow body, the wall of glass having a wall surface which comprises a surface region, at least in the surface region the wall surface has a content of N in a range from 0.3 to 10.0 at-% and a content of at least 5 at-% Si, the contents of Ni and S being determinable by X-ray photoelectron spectroscopy.

2. The hollow body of claim 1, wherein in the surface region the wall surface further has a content of 0 in a range from 35 to 70 at-%, the content of 0 being determinable by X-ray photoelectron spectroscopy.

3. The hollow body of claim 1, wherein in the surface region the wall surface further has a content of less than 20 at-% of C, the content of C being determinable by X-ray photoelectron spectroscopy.

4. The hollow body of claim 1, wherein in the surface region the wall surface further has a content of alkali metal atoms and alkali metal ions in sum of at least 1 at-%, the content of alkali metal atoms and alkali metal ions being determinable by X-ray photoelectron spectroscopy.

5. The hollow body of claim 1, wherein in the surface region the wall surface further has a content of B of at least 0.5 at-%, the content of B being determinable by X-ray photoelectron spectroscopy.

6. The hollow body of claim 1, wherein X-ray photoelectron spectroscopy of the surface region shows an N1s-peak at a binding energy in a range from 397.5 to 405.0 eV.

7. The hollow body of claim 1, wherein the surface region of the wall surface has a coefficient of dry sliding friction of less than 0.4.

8. The hollow body of claim 1, wherein the hollow body lacks a coating applied to the wall of glass.

9. The hollow body of claim 8, wherein the hollow body is suitable for holding a pharmaceutical composition in accordance with Section 3.2.1 of the European Pharmacopoeia, 7th edition.

10. The hollow body of claim 1, wherein the wall of glass has a wall thickness and in the wall region the wall of glass has a content of chemically bound N throughout a functionalizing depth which extends from the wall surface along the wall thickness into the wall of glass.

11. The hollow body of claim 10, wherein the functionalizing depth is less than the wall thickness in the wall region.

12. The hollow body of claim 10, wherein the functionalizing depth is in a range from 5 nm to 10 m.

13. The hollow body of claim 1, wherein the hollow body has a transmission coefficient for a transmission of light of a wavelength in a range from 400 nm to 2300 nm through the hollow body via the surface region of more than 0.7.

14. The hollow body of claim 1, wherein the hollow body has a haze for a transmission of light through the hollow body via surface region in a range from 5% to 50%.

15. The hollow body of claim 1, wherein the hollow body is a container and further comprises a closure closing the container and a pharmaceutical composition placed in the interior volume.

16. The hollow body of claim 1, wherein the wall of glass comprises at least one of a borosilicate glass, an aluminosilicate glass, and fused silica.

17. The hollow body of claim 1, wherein the wall of glass comprises from top to bottom of the hollow body: a top region; a body region, which follows the top region via a shoulder; and a bottom region, which follows the body region via a heel.

18. The hollow body of claim 1, wherein, towards the interior volume, the wall of glass is at least partially super-imposed by at least one of an alkali metal barrier layer or a hydrophobic layer.

19. A process for making an item, comprising as process steps: a) providing a hollow body comprising a wall of glass, the wall of glass at least partially surrounding an interior volume of the hollow body, having a wall surface which comprises a surface region, and comprising a wall region which has the surface region; and b) introducing N at least into the wall region, thereby obtaining a content of N of the wall surface at least in the surface region in a range from 0.3 to 10.0 at-%, wherein the preceding content of N is determined by an X-ray photoelectron spectroscopy.

20. A process, comprising as process steps: A) providing a hollow body, the hollow body comprising a wall of glass which at least partially surrounds an interior volume of the hollow body, the wall of glass having a wall surface which comprises a surface region, at least in the surface region the wall surface has a content of N in a range from 0.3 to 10.0 at-% and a content of at least 5 at-% Si, the contents of Ni and S being determinable by X-ray photoelectron spectroscopy; B) inserting a pharmaceutical composition into the interior volume; and C) closing the hollow body.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0095] The above-mentioned and other features and advantages of this invention, and the manner of attaining them, will become more apparent and the invention will be better understood by reference to the following description of embodiments of the invention taken in conjunction with the accompanying drawings, wherein:

[0096] FIG. 1 illustrates a schematic depiction of an exemplary embodiment of a hollow body provided according to the present invention;

[0097] FIG. 2 illustrates a schematic depiction of an exemplary embodiment of a closed hollow body provided according to the present invention;

[0098] FIG. 3 illustrates a flow chart of an exemplary embodiment of a process provided according to the present invention for the preparation of a hollow body;

[0099] FIG. 4 illustrates a flow chart of an exemplary embodiment of a process provided according to the present invention for packaging a pharmaceutical composition;

[0100] FIG. 5 illustrates a flow chart of an exemplary embodiment of a process provided according to the present invention for treating a patient;

[0101] FIG. 6 illustrates results of measurements of the functionalizing depth of vials of the examples 1 to 3; and

[0102] FIG. 7 illustrates results of measurements of the transmission coefficient of vials according to the examples 1 to 4 and the comparative example 1.

[0103] Corresponding reference characters indicate corresponding parts throughout the several views. The exemplifications set out herein illustrate embodiments of the invention and such exemplifications are not to be construed as limiting the scope of the invention in any manner.

DETAILED DESCRIPTION OF THE INVENTION

[0104] Elemental Contents of the Wall of Glass

[0105] According to the present invention, the wall of glass is characterized at least in the surface region of the wall surface by contents of different chemical elements in at-%. The corresponding elemental analysis is conducted via an X-ray photoelectron spectroscopy as described herein. In other words, the contents of the different chemical elements in at-% are determinable by X-ray photoelectron spectroscopy (XPS). The chemical elements are referred to by their abbreviations as provided in the periodic table of elements. The elemental contents determined (or determinable) by XPS provided herein refer to the wall of glass itself, not to any optional coating or functionalization which may superimpose the wall of glass. Thus, the content of N is a content in the wall of glass at least in the wall region. This content is determined/determinable by conducting XPS at the surface region which is a region of the surface of the wall of glass itself, i.e. a glass surface. The N of the content of N may be chemically bound in the wall of glass via SiN-bonds.

[0106] Surface Region

[0107] Each surface region may be a coherent region. In other words, in some embodiments the surface regions is not a discontinuous region. Herein, a discontinuous region is a region which comprises multiple mutually spaced regions.

[0108] Hollow Body

[0109] The hollow body provided according to the present invention may have any size or shape which the skilled person deems appropriate in the context of the present invention. In some embodiments, the head region of the hollow body comprises an opening, which allows for inserting a pharmaceutical composition into the interior volume of the hollow body. In that case, the wall of glass surrounds the interior volume of the hollow body only partially. The hollow body may be a glass body or a glass container. The wall of glass may be of a one-piece design. The wall of glass of such a glass body or a glass container may be made by blow molding a glass melt; or by preparing a tube of a glass, such as in the form of a hollow cylinder, forming the bottom of the hollow body from one end of the tube, thereby closing the tube at this end, and forming the head region of the hollow body from the opposite end of the tube. The wall of glass may be transparent.

[0110] As used herein, the interior volume represents the full volume of the interior of the hollow body. This volume may be determined by filling the interior of the hollow body with water up to the brim and measuring the volume of the amount of water which the interior can take up to the brim. Hence, the interior volume as used herein is not a nominal volume as it is often referred to in the technical field of pharmacy. This nominal volume may, for example, be less than the interior volume by a factor of about 0.5.

[0111] Glass

[0112] The wall of glass comprises a glass, and may essentially consist of the glass. This glass may be any type of glass and may have any composition which the skilled person deems suitable in the context of the present invention. The glass may be, for example, suitable for pharmaceutical packaging. The glass may be, for example, of type I in accordance with the definitions of glass types in section 3.2.1 of the European Pharmacopoeia, 7.sup.th edition from 2011. Additionally or alternatively, the glass may be selected from the group consisting of a borosilicate glass, an aluminosilicate glass, and fused silica; or a combination of at least two thereof. As used herein, an aluminosilicate glass is a glass which has a content of Al.sub.2O.sub.3 of more than 8 wt.-%, such as more than 9 wt.-% or in a range from 9 to 20 wt.-%, in each case based on the total weight of the glass. An exemplary aluminosilicate glass has a content of B.sub.2O.sub.3 of less than 8 wt.-%, such as at maximum 7 wt.-% in a range from 0 to 7 wt.-%, in each case based on the total weight of the glass. As used herein, a borosilicate glass is a glass which has a content of B.sub.2O.sub.3 of at least 1 wt.-%, such as at least 2 wt.-%, at least 3 wt.-%, at least 4 wt.-%, at least 5 wt.-%, or in a range from 5 to 15 wt.-%, in each case based on the total weight of the glass. An exemplary borosilicate glass has a content of Al.sub.2O.sub.3 of less than 7.5 wt.-%, such as less than 6.5 wt.-% or in a range from 0 to 5.5 wt.-%, in each case based on the total weight of the glass. In some embodiments, the borosilicate glass has a content of Al.sub.2O.sub.3 in a range from 3 to 7.5 wt.-%, such as in a range from 4 to 6 wt.-%, in each case based on the total weight of the glass.

[0113] A glass which is further exemplary according to the present invention is essentially free from B. Therein, the wording essentially free from B refers to glasses which are free from B which has been added to the glass composition by purpose. This means that B may still be present as an impurity, but at a proportion of, for example, not more than 0.1 wt.-%, such as not more than 0.05 wt.-%, in each case based on the weight of the glass.

[0114] Depyrogenization

[0115] In some embodiments of the process, after the process step b) the wall surface is heated at least partially to at least 200 C., such as at least 250 C., at least 300 C., or at least 320 C. This heating may be a measure of a depyrogenization step. In the technical field of pharmacy, depyrogenization is a step of decreasing an amount of pyrogenic germs on a surface, such as via a heat-treatment. Therein, the amount of pyrogenic germs on the surface may be decreased as much as possible, such as by at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, or by 100%, in each case based on an amount of the pyrogenic germs on the surface prior to the depyrogenization.

[0116] Pharmaceutical Composition

[0117] In the context of the present invention, every pharmaceutical composition which the skilled person deems suitable comes into consideration. A pharmaceutical composition is a composition comprising at least one active ingredient. An exemplary active ingredient is a vaccine. The pharmaceutical composition may be fluid or solid or both. An exemplary solid composition is granular such as a powder, a multitude of tablets or a multitude of capsules. A further exemplary pharmaceutical composition is a parenteral, i.e. a composition which is intended to be administered via the parenteral route, which may be any route which is not enteral. Parenteral administration can be performed by injection, e.g. using a needle (usually a hypodermic needle) and a syringe, or by the insertion of an indwelling catheter.

[0118] Wall

[0119] Herein, the hollow body comprises a wall of glass. The hollow body may comprise further layers of materials which superimpose the wall of glass fully or partially on one or both sides of the wall of glass. In any case, however, the wall surface with the surface region refers to the wall of glass, i.e. these are surfaces of the wall of glass itself, hence glass surfaces. If the hollow body comprises one or more layers which are superimposed to the wall of glass, these layers are joined to one another and to the wall of glass. Two layers are joined to one another when their adhesion to one another goes beyond Van-der-Waals attraction forces. Unless otherwise indicated, layers may follow one another in a direction of a thickness of the wall of glass indirectly, in other words with one or at least two intermediate components, or directly, in other words without any intermediate component. This is particularly the case with the formulation wherein one layer superimposes another. Further, if a component is superimposed onto a layer or a surface, this component may be contacted with that layer or surface or it may not be contacted with that layer or surface, but be indirectly overlaid onto that layer or surface with another component (e.g. a layer) in-between.

[0120] Alkali Metal Barrier Layer and Hydrophobic Layer

[0121] In some embodiments, the wall of glass of the hollow body is superimposed by an alkali metal barrier layer or by a hydrophobic layer or both, in each case towards the interior volume of the hollow body, such as across at least a part of the interior surface, or the full interior surface of the wall of glass. The alkali metal barrier layer may consist of any material or any combination of materials which the skilled person deems suitable for providing a barrier action against migration of an alkali metal ion, such as against any alkali metal ion. The alkali metal barrier layer may be of a multilayer structure. In some embodiments, the alkali metal barrier layer comprises SiO.sub.2, such as a layer of SiO.sub.2. Further, the hydrophobic layer may consist of any material or any combination of materials which provides a layer surface towards the interior volume which has a contact angle for wetting with water of more than 90. The hydrophobic layer may allow for the formation of a well-defined cake upon freeze-drying, in particular in terms of a shape of the cake. An exemplary hydrophobic layer comprises a compound of the general formula SiO.sub.xC.sub.yH.sub.z, such as a layer of this compound. Therein, x is a number which is less than 1, such as in a range from 0.6 to 0.9 or from 0.7 to 0.8; y is a number in a range from 1.2 to 3.3, such as from 1.5 to 2.5; and z is a number as well.

Measurement Methods

[0122] The following measurement methods are to be used in the context of the present invention. Unless otherwise specified, the measurements have to be carried out at an ambient temperature of 23 C., an ambient air pressure of 100 kPa (0.986 atm) and a relative atmospheric humidity of 50%.

[0123] Contact Angle for Wetting with Water

[0124] The contact angle of a surface for wetting with water is determined in accordance with the standard DIN 55660, parts 1 and 2. The contact angle is determined using the static method. Deviating from the standard, the measurement is conducted at curved surfaces as the wall of the hollow body is usually curved. Further, the measurements are conducted at 22 to 25 C. ambient temperature and 20 to 35% relative atmospheric humidity. A Drop Shape AnalyzerDSA30S from Krss GmbH is applied for the measurements. Uncertainty of the measurement increases for contact angles below 10.

[0125] Wall Thickness and Tolerance of Wall Thickness

[0126] The wall thickness and deviations from the mean value of the wall thickness (tolerance) are determined in accordance with the following standards for the respective type of hollow body:

DIN ISO 8362-1 for vials,
DIN ISO 9187-1 for ampoules,
DIN ISO 11040-4 for syringes,
DIN ISO 13926-1 for cylindrical cartridges, and
DIN ISO 11040-1 for dental cartridges.

[0127] Transmission Coefficient

[0128] Herein, the transmission coefficients are defined as T=I.sub.trans/I.sub.0, wherein I.sub.0 is the intensity of the light which is incident at a right angle on an incidence region of the surface region and I.sub.trans is the intensity of the light which leaves the hollow body on a side of the hollow body which is opposite to the incidence region. Hence, T refers to light which transmits the empty hollow body completely, i.e. one time through the wall into the empty interior volume and from there a second time through the wall out of the interior volume. Hence, the light transmits through two curved sections of the wall of the hollow body. The transmission coefficient is determined in accordance with the standard ISO 15368:2001(E), wherein an area of measurement of the dimensions 3 mm4 mm is used. Further, the light is incident on the hollow body at a right angle to the vertical extension of the exterior surface of the hollow body. In some embodiments, the transmission coefficients herein refer to a hollow body of the type 2R according to DIN/ISO 8362 and to a transmission of the light through a part of the hollow body which is of the shape of a hollow cylinder. In case the transmission coefficient for a transmission of light via an unfunctionalized surface of a hollow body (herein also referred to as first transmission coefficient) is to be determined and the hollow body does not have any unfunctionalized surface which is suitable for the measurement, the functionalization (e.g. particles) is removed first and then the transmission coefficient via the surface from which the functionalization has been removed is determined.

[0129] Haze

[0130] The haze is a measure for the light scattering properties of a transparent sample, such as a glass sample. The value of the haze represents the fraction of light which has been transmitted through the sample, here the empty container, and which is scattered out of a certain spatial angle around the optical axis. Thus, the haze quantifies material defects in the sample which negatively affect transparency. Herein, the haze is determined according to the standard ASTM D 1033. In accordance with this standard, 4 spectra are measured and for each of them the transmission coefficient is calculated. The haze value in % is calculated from these coefficients of transmission. A Thermo Scientific Evolution 600 spectrometer with integrating sphere and the software OptLab-SPX are applied for the measurements. In order to allow for measuring the diffusive transmission, the sample is positioned in front of the entrance of the integrating sphere. The reflection opening is left empty such that only the transmitted and scattered fraction of the incident light is detected. The fraction of the transmitted light which is not sufficiently scattered is not detected. Further measurements pertain to detection of the scattered light in the sphere (without sample) and to the overall transmission of the sample (reflection opening closed). All the measurement results are normalized to the overall transmission of the sphere without sample which is implemented as obligatory baseline correction in the software. Herein, the haze refers to light which transmits the hollow body completely, i.e. one time through the wall into the interior volume and from there a second time through the wall out of the interior volume. Hence, the light transmits through two curved sections of the wall of the hollow body. Further, the light is incident on the hollow body at a right angle to the vertical extension of the exterior surface of the hollow body. The hollow body may be a vial of the type 2R according to DIN/ISO 8362 and the transmission is conducted through a part of the hollow body which is of the shape of a hollow cylinder. In case the haze for a transmission of light via an unfunctionalized surface of a hollow body (herein also referred to as first haze) is to be determined and the hollow body does not have any unfunctionalized surface which is suitable for the measurement, the functionalization (e.g. particles) is removed first and then the haze via the surface from which the functionalization has been removed is determined.

[0131] Scratch Test and Coefficient of Dry Sliding Friction

[0132] An MCT MikroCombiTester (MCT S/N 01-04488) from CSM Instruments is applied for the scratch test and for measuring the coefficient of dry friction. As the friction partner, a hollow body which is identical to the hollow body to be tested, including any coatings or functionalizations, is used. Further, in the test same surfaces are scratched/slide against each other. The friction partner is hold in position by a special mount above the hollow body to be tested. Here, the friction partner and the hollow body to be tested incline an angle of 90 in a top view. For both measurements, the hollow body to be tested is moved forwards, thereby scratching over the surface of the friction partner at a well-defined normal force (test force). For both tests, the hollow body to be measured is moved forwards underneath the friction partner at a velocity of 10 mm/min over a test length of 15 mm. In case of the scratch test, the test force is progressively increased from 0 to 30 N (load rate 19.99 N/min) across the test length. Afterwards, the scratched surface is checked with a microscope at a magnification of 5 times. In case of measuring the coefficient of dry sliding friction, a constant normal force of 0.5 N is applied. The lateral friction force is measured using the friction measuring table. The coefficient of dry friction is determined from the measured curves as the ratio of friction force to normal force (test force), wherein only values after the initial 0.2 mm up to the full test length of 15 mm are considered, in order to minimize the influence of the static friction.

[0133] Softening Temperature

[0134] The softening temperature of a glass is defined as the temperature of the glass at which the glass has a viscosity in dPa.Math.s (=Poise) such that log.sub.10()=7.6. The softening temperature is determined in accordance with ISO 7884-3.

[0135] Washing Process

[0136] A HAMO LS 2000 washing machine is applied for the washing procedure. The HAMO LS 2000 is connected to the purified water supply. Further, the following devices are used.

cage 1: 144 with 4 mm nozzles
cage 2: 252 with 4 mm nozzles
drying cabinet from Heraeus (adjustable up to 300 C.)

[0137] The tap is opened. Then the machine is started via the main switch. After conducting an internal check, the washing machine shows to be ready on the display. Program 47 is a standard cleaning-program which operates with the following parameters:

pre-washing without heating for 2 min
washing at 40 C. for 6 min
pre-rinsing without heating for 5 min
rinsing without heating for 10 min
end-rinsing at without heating for 10 min
drying without heating for 5 min

[0138] The holder for the vials in the cages 1 and 2 have to be adjusted considering the size of the vials in order to obtain a distance of the nozzle of about 1.5 cm. The vials to be washed are placed on the nozzles with the head first. Subsequently, the stainless steel mesh is fixed on the cage. The cage is oriented to the left and pushed into the machine. Then the machine is closed. Program 47 (GLAS040102) is selected and then the HAMO is started via START. After the program has finished (1 h), the cages are taken out and the vials are placed with their opening facing downwards in drying cages. A convection drying cabinet with ambient air filter is applied for the drying. The drying cabinet is adjusted to 300 C. The vials are placed into the drying cabinet for 20 min. After the vials have cooled down, they are sorted into appropriate boxes.

[0139] X-Ray Photoelectron Spectroscopy (XPS)

[0140] Prior to the XPS-measurement, the hollow body to be studied is washed. In case of a vial as the hollow body, the above washing process is applied, otherwise a suitable analogue washing process is applied. The XPS-studies are conducted on the washed hollow body. Any contamination of the hollow body after the washing process is to be avoided. The X-ray photoelectron spectroscopy measurements are performed using a PHI Quantera SM system. For data acquisition, the software SmartSoft-XPS V3.6.2.7 is used. For the XPS-measurement, the excitation is carried out with a monochromatic Al-k source (1486.6 eV/15 kV) with 200 m spot size. The electrons are detected under an angle to the normal of 45. The built-in charge compensation system is employed during analysis, using electrons and low-energy argon ions to prevent charging of the sample. The pressure inside the measurement chamber is 1.5.Math.10.sup.6 Pa during measurement, and pass energies of 55 eV (high resolution spectra) and 140 eV (survey spectra) are used. For data processing the software MultiPak V9.5.0.8 is used. A so-called Shirley background is applied to fit the background of all spectra. For quantification the sensitivity factors as implemented in the software MultiPak (based on C. D. Wagner et al. in Surface and Interfaces Analysis, 3 (1981) 211) and the analyzer transmission function are applied. All spectra are referenced to the C is-peak of hydrocarbon at 285.0 eV binding energy and controlled by means of the well-known photoelectron peaks of metallic Cu, Ag, and Au.

[0141] Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS)

[0142] Prior to the ToF-SIMS-measurement, the hollow body to be studied is washed. In case of a vial as the hollow body, the above washing process is applied, otherwise a suitable analogue washing process is applied. The ToF-SIMS-studies are conducted on the washed hollow body. Any contamination of the hollow body after the washing process is to be avoided. ToF-SIMS depth profiles are performed using a TOF-SIMS IV-100, company ION-TOF GmbH equipped with 25 keV Ga+ primary ions. The analysis is performed on an area of 5050 m.sup.2 with a primary ion current of approximately 1.0 pA. The sputter treatment is performed in alternating mode by a Cs+ sputter ion gun on an area of 300300 m.sup.2 with an energy of 0.5 keV and a sputter current of approximately 40 nA. For charge compensation an electron flood gun is used. Negatively charged ions are analyzed andfor better standardisationthe detected intensities are normalised to the Si ion intensities. For data processing the software SurfaceLab 6.7 is used.

[0143] Exemplary embodiments provided according to the present invention are set out in more detail below, with the examples and drawings not denoting any restriction on the present invention. Furthermore, unless otherwise indicated, the drawings are not to scale.

Examples 1 to 3 (Provided According to the Present Invention)

[0144] For each of the examples 1 to 3, commercially available glass vials of the type Vial 2.00 ml Fiolax clear from Schott AG, which are further of the type 2R according to DIN/ISO 8362, are provided. These vials are washed as described above in the measurement methods section. In each example, the vials are treated with a plasma which is created from a gas of NH.sub.3 (100 vol-%). The vials are placed in a reactor of the type Diener Nano (PlasmaCoat Express) which is commercially available from Diener Electronics. The reactor has a volume of 17 dm.sup.3 and consists of a quartz glass tube. The plasma precursor gas is introduced into the reactor at the flow rate provided in table 1 below. In the reactor, a plasma is created from the gas via radio frequency (RF) at 13.56 MHz at a power of 600 W. The created plasma contains nitrogen atoms and ions and contacts the vials in the reactor across their full glass surface. For each of the examples, the plasma treatment is conducted for the duration of treatment provided in the Table 1 below. Thereby, N is implanted into the glass walls of the vials. The depth, measured from the outer surface of the vial, up to which N is implanted into the glass wall is shown for vials of the examples 1 to 3 in FIG. 6. After the plasma treatment, the RF-generator is shut off and the vials are taken from the reactor.

TABLE-US-00001 TABLE 1 Parameters of the plasma treatment according to the examples 1 to 3 Flow rate of the plasma precursor gas Duration of plasma [sccm per m.sup.3 reaction volume] treatment [h] Example 1 300 6 Example 2 300 8 Example 3 30 8

Comparative Example 1 (not According to the Present Invention)

[0145] A commercially available glass vial of the type Vial 2.00 ml Fiolax clear from Schott AG, which of the type 2R according to DIN/ISO 8362, is provided as a reference. The surface of this vial does not have any coating or functionalization. Prior to any measurement, the vial is washed.

Comparative Example 2 (not According to the Present Invention)

[0146] A commercially available glass vial of the type Vial 2.00 ml Fiolax clear from Schott AG, which is further of the type 2R according to DIN/ISO 8362, and which has been washed as described below is coated on its exterior surface with MED10-6670 from NuSiL. The coated vial is dried for 10 min at 350 C. in an oven. No plasma treatment is applied.

[0147] Evaluation

[0148] XPS-measurements are conducted as described above on the exterior surfaces of the vials of the examples 1 to 3 and the comparative example 1. The vials of the comparative example 2 have glass bodies which are identical to the reference vials of the comparative example 1, however, with a coating on top. Therefore, the elemental contents of the glass bodies of the vials of comparative example 2 can be assumed to be identical to those of the comparative example 1. The elemental contents as determined are presented in the Table 2 below.

TABLE-US-00002 TABLE 2 Elemental contents as determined by the XPS-measurements conducted on the vials of the examples 1 to 3 and the reference vial of the comparative example 1 Content of [at-%] alkali N Si O C metals B Example 1 0.4 22.1 53.4 12.5 3.3 1.9 Example 2 0.6 21.1 53.7 3.9 6.3 1.8 Example 3 1.45 14.4 55.6 8.4 0 0.6 Comparative 0.25 24.0 61.8 7.4 2.85 1.8 Example 1

[0149] The detection threshold of the XPS-measurements for N is at about 0.2 at-%. Accordingly, essentially no N is measured in case of the comparative example 1. This finding is in line with scientific reports (G. Iucci et al., Solid State Sciences 12, 1861-1865 (2010); G. Kaklamani et al., Materials Letters, 111, 225-229 (2013); D. Ditter et al., European Journal of Pharmaceutics and Biopharmaceutics 125 (2018) 58-67) according to which essentially no N is measured via XPS at uncontaminated glass surfaces of the prior art, in particular at the outer glass surfaces of pharmaceutical containers of the prior art.

[0150] XPS is a surface sensitive measurement technique, which makes it a good fit for characterizing a low friction layer on the exterior surface of the vial body. Other measurement techniques are more directed to the depth of the sample and analyze multiple layers, which makes it difficult to characterize the low friction layer that is the exposed and may be thin.

[0151] Further, the binding energies reported in Table 3 below are determined via XPS as described in the measurement methods section.

TABLE-US-00003 TABLE 3 Binding energies as determined by the XPS-measurements conducted on the vials of the examples 1 to 3 and the reference vial of the comparative example 1 Si2p binding N1s binding energy [eV] energy [eV] Example 1 103.3 402.5 Example 2 103.1 402.5 Example 3 102.9 403.0 Comparative 103.2 402.0 example 1

[0152] Further, for each of the examples 1 to 3 and the comparative examples 1 and 2, the coefficient of dry sliding friction is determined on the exterior surface of the vial body in accordance with the above measurement method. The results are shown in Table 4.

TABLE-US-00004 TABLE 4 Coefficients of dry sliding friction of the exterior surfaces of the vials of the examples 1 to 3 and the comparative examples Coefficient of dry sliding friction Example 1 0.36 Example 2 0.37 Example 3 0.18 Comparative example 1 0.5 Comparative example 2 0.28

[0153] Further, 10,000 of the vials of each example and comparative example, respectively, are processed on a standard pharmaceutical filling line and thus, filled with an influenza vaccine. Table 5 below shows an evaluation of the vials regarding their tendency to be damaged or even break on the filling line. Here, ++ means that no or only very few vials are being damaged or broken, + means that few vials are being damaged or broken, means that damages to vials and broken vials occur more often than for +, means that damages to vials and broken vials occur more often than for .

TABLE-US-00005 TABLE 5 Comparison of the tendency of the glass vials to be damaged on the filling line and the maximum temperature of the vials during the above described treatment for the examples 1 to 3 and the comparative examples 1 and 2 Low tendency to damages on filling line Example 1 + Example 2 + Example 3 ++ Comparative example 1 Comparative example 2 +

[0154] It can be seen from the results presented in the above Tables 4 and 5 that vials of the examples 1 to 3 are superior to the untreated reference vials of comparative example 1. Further, the inventive examples 1 to 3 include no coating of the glass vials, whereas the vials of comparative example 2 are provided with a silicone coating. Silicone, however, is often not completely and securely bonded to the glass surface of the vial. Therefore, the silicone tends to creep across the glass surface. This bears a risk of contamination of the inner surface of the vial. Such contamination is inacceptable for pharmaceutical containers. Even more, contamination with an organic composition such as the silicone coating of the comparative example 2 is particularly undesirable. Further, vials having a silicone coating cannot be labelled as easy as vials without such a coating. If a standard adhesive is used, the label often does not sufficiently adhere to the coated vial. If, however, a special adhesive is used which provides better adhesion of the label to the coated vial, the special adhesive partly softens the silicone coating which then tends to creep even more. In consequence, the risk of contamination is increased even more. It follows that a silicone coating such as the one applied in the comparative example 2 is particularly undesirable to be applied to pharmaceutical containers.

[0155] Further, vials which have been filled with a pharmaceutical composition and closed typically have to be inspected, in particular for pharmaceutically relevant particles. This is usually done by optical methods which call for a high transparency and low haze of the vials. Here, prior to filling them, vials of the examples and comparative examples are studied for their optical characteristics which may influence an optical inspection of the vials. The increase of the haze by the above described treatments and the transmission coefficient of the vials are determined in accordance with the above measurement methods. The results of the haze measurements are provided in the Table 6 below. The increase of the haze by the treatment of vial with respect to the untreated vial which corresponds to comparative example 1 is shown.

TABLE-US-00006 TABLE 6 Increase of the haze of the vials of the examples and the comparative examples Increase of haze [%] Example 1 <0.3 Example 2 <0.3 Example 3 <0.3 Comparative example 1 / Comparative example 2 6

[0156] Results of the transmission coefficient measurements on vials of the examples 1 to 3 and the reference vial of the comparative example 1 are shown in FIG. 7. From this, it can be seen that the plasma treatment according to the examples 1 to 3 does not significantly deteriorate the transmission coefficient in the studied spectral range. Therefore, the vials of the inventive examples are very well suited for being optically inspected.

[0157] FIG. 1 shows a schematic depiction of a hollow body 100 provided according to the present invention. The hollow body 100 comprises a wall of glass 101 which partially surrounds an interior volume 102 of the hollow body 100. The wall of glass 101 surrounds the interior volume 102 only partially in that the hollow body 100 comprises an opening 108 which allows for filling the hollow body 100 with a pharmaceutical composition 201 (not shown). Further, the wall of glass 101 has a wall surface 103, which consists of an interior surface 107 which faces the interior volume 102, and an exterior surface 106 which faces away from the interior volume 102. The wall of glass 101 forms from top to bottom in the FIG. 1: a top region of the hollow body 100, which consists of a flange 109 and a neck 110; a body region 112, which follows the top region via a shoulder 111; and a bottom region 114, which follows the body region 112 via a heel 113. Here, the body region 112 is a lateral region of the hollow body 100 in form of a hollow cylinder. The hollow body 100 of FIG. 1 is a vial which has been treated according to the example 1 above. The exterior surface 106 forms a surface region 104 of the wall surface 103 according to the nomenclature used herein. Thus, the exterior surface 106 has the contents of N, Si, 0 and C measured/measurable by XPS as reported above. Here, the N has been implanted into the wall of glass 101 by the process described above for example 1 from the exterior surface 106 up to a functionalizing depth 115 into the wall of glass 101. It can be seen from FIG. 6 that the functionalizing depth 115 is 10 nm.

[0158] FIG. 2 shows a schematic depiction of a closed hollow body 200 provided according to the present invention. This closed hollow body 200 is a vial which has been obtained by filling the hollow body 100 of FIG. 1 with a pharmaceutical composition 201 and closing the opening 108 with a lid 202 via a crimping step. Here, the pharmaceutical composition 201 is a vaccine.

[0159] FIG. 3 shows a flow chart of a process 300 provided according to the present invention for the preparation of a hollow body 100. The process 300 comprises a process step a) 301 in which a commercially available glass vial of the type Vial 2.00 ml Fiolax clear from Schott AG which of the type 2R according to DIN/ISO 8362 is provided. In a process step b) 302, N is introduced into the wall of glass 101 by a plasma treatment of the exterior surface 106 as described in detail above in the context of the example 1 according to the present invention. The hollow body 100 of FIG. 1 is obtained through the process 300.

[0160] FIG. 4 shows a flow chart of a process 400 provided according to the present invention for packaging a pharmaceutical composition 201. In a process step A) 401, the hollow body 100 according to FIG. 1 is provided. In a process step B) 402, a pharmaceutical composition 201 is filled into the interior volume 102 of the hollow body 100, and in a process step C) 403 the opening 108 of the hollow body 100 is closed, thereby obtaining the closed hollow body 200 of FIG. 2.

[0161] FIG. 5 shows a flow chart of a process 500 provided according to the present invention for treating a patient. This process 500 comprises the process steps of: A. 501 providing the closed hollow body 200 of FIG. 2, opening the closed hollow body 200 by penetrating the lid 202 with a needle of a syringe, filling the syringe with the vaccine; and B. 502 administering the vaccine subcutaneously to a patient using the syringe.

[0162] FIG. 6 shows results of measurements of the functionalizing depth 115 in nm of vials of the examples 1 to 3. The bar 601 denotes the results for the example 1, 602 the results for example 2, and 603 the results for example 3. The results presented in FIG. 6 have been determined by ToF-SIMS as described above in the measurement methods section.

[0163] FIG. 7 shows results of measurements of the transmission coefficient 702 of vials according to the examples 1 to 4 and the comparative example 1 over the wavelength in nm 701. In the diagram, 703 denotes the measurement results for the examples 1 to 4 and 704 the results for the comparative example 1. All these results are so close to each other that the corresponding graphs appear essentially as one in the diagram. The dip at 865 nm is a measurement artefact.

[0164] Exemplary embodiments provided according to the present invention provide a glass container for pharmaceutical packaging which allows for an increase of a production rate of a filling line. Also provided is a glass container for pharmaceutical packaging which allows for an increase of a processing speed of a filling line, or for a reduction of disruptions of a filling line, or both. Also provided is a glass container for pharmaceutical packaging which shows a reduced tendency to being damaged or even broken while being processed on a filling line. Also provided is a container that is further suitable for an easy and reliable optical inspection after having been filled. Also provided is a container that does not show an increased tendency to being contaminated, for example in a pharmaceutically relevant manner. The preceding contamination refers, in particular, to the presence of a contaminating organic composition in the container interior. In this context, the container may comprise no multilayer coating, or no coating at all, which could be a potential source of contamination. Also provided is a glass container for pharmaceutical packaging that can be labelled easily. Also provided is a container that is further suitable for a post-treatment, for example a sterilization treatment, which may be effected as a high-temperature-treatmentin particular a depyrogenisation; or a washing process; or a low-temperature-treatmentin particular a freeze drying. Also provided is a process for producing one of the above advantageous glass containers for pharmaceutical packaging, the process being less complex than known processes.

[0165] While this invention has been described with respect to at least one embodiment, the present invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.

LIST OF REFERENCE NUMERALS

[0166] 100 hollow body provided according to the present invention [0167] 101 wall of glass [0168] 102 interior volume [0169] 103 wall surface [0170] 104 surface region [0171] 105 wall region [0172] 106 exterior surface [0173] 107 interior surface [0174] 108 opening [0175] 109 flange [0176] 110 neck [0177] 111 shoulder [0178] 112 body region [0179] 113 heel [0180] 114 bottom region [0181] 115 functionalizing depth [0182] 200 closed container provided according to the present invention/closed hollow body provided according to the present invention [0183] 201 pharmaceutical composition [0184] 202 lid [0185] 300 process provided according to the present invention for the preparation of a hollow body [0186] 301 process step a) [0187] 302 process step b) [0188] 400 process provided according to the present invention for packaging a pharmaceutical composition [0189] 401 process step A) [0190] 402 process step B) [0191] 403 process step C) [0192] 500 process provided according to the present invention for treating a patient [0193] 501 process step A. [0194] 502 process step B. [0195] 601 measurement results for comparative example 1 [0196] 602 measurement results for example 1 [0197] 603 measurement results for example 3 [0198] 701 wavelength in nm [0199] 702 transmission coefficient [0200] 703 measurement results for examples 1 to 4 [0201] 704 measurement results for comparative example 1