Hollow body having a wall with a layer of glass and at least one elevated region

Abstract

A hollow body includes a wall which at least partially surrounds an interior volume of the hollow body. The wall comprises a layer of glass comprising a first glass composition, comprises a base surface, and has a wall surface. The wall surface comprises at least one surface region, in which the base surface is at least partially superimposed by at least one elevated region, and at least one contact region, which extends along a contact range of a height of the hollow body. The at least one elevated region comprises a further glass composition. An exterior diameter of the hollow body has a maximum throughout the contact range. The at least one surface region is at least partially positioned in the at least one contact region.

Claims

1. A hollow body, comprising: a wall which at least partially surrounds an interior volume of the hollow body, the wall comprising a layer of glass comprising a first glass composition, the wall comprising an interior surface that faces the interior volume and an exterior surface opposite the interior surface that faces away from the interior volume, the wall defining a plurality of exterior diameters, the wall defining a maximum exterior diameter in at least one contact region, the maximum exterior diameter extending along at least a portion of a height of the hollow body, wherein at least one elevated region extends from the exterior surface of the wall in the at least one contact region and comprises a further glass composition, wherein the at least one elevated region covers 5% to 90% of the at least one contact region, wherein the at least one elevated region comprises a plurality of spaced apart elevated regions each extending from the exterior surface of the wall in the at least one contact region.

2. The hollow body according to claim 1, wherein at least one of the elevated regions is transparent.

3. The hollow body according to claim 1, wherein at least one of the elevated regions extends along at least 25% of a circumference of the hollow body.

4. The hollow body according claim 1, wherein the hollow body is a packaging container for at least one of a medical packaging good or a pharmaceutical packaging good.

5. The hollow body according to claim 1, wherein the plurality of elevated regions comprises a first elevated region and a further elevated region each extending from the exterior surface of the wall in the at least one contact region, the first elevated region and the further elevated region being spatially distanced by at least 10% of the height of the hollow body.

6. The hollow body according to claim 1, wherein the elevated regions of the plurality of elevated regions each have a diameter in a range from 5 μm to 2500 μm.

7. The hollow body according to claim 1, wherein the first glass composition is different from the further glass composition.

8. The hollow body according to claim 7, wherein the first glass composition has a first softening temperature, the further glass composition has a further softening temperature, and the further softening temperature is less than the first softening temperature.

9. A process for making an item, comprising as process steps: a) providing a hollow body comprising a wall which at least partially surrounds an interior volume of the hollow body, the wall comprising a layer of glass comprising a first glass composition, the wall comprising an interior surface that faces the interior volume and an exterior surface opposite the interior surface that faces away from the interior volume, the wall defining a plurality of exterior diameters, the wall defining a maximum exterior diameter in at least one contact region, the maximum exterior diameter extending along at least a portion of a height of the hollow body; b) contacting the exterior surface of the wall in the at least one contact region with a composition comprising a plurality of particles, the particles of the plurality of particles comprising a further glass composition; and c) forming a plurality of elevated regions each comprising the further glass composition on the exterior surface of the wall in the at least one contact region from the composition and joining the plurality of elevated regions to the exterior surface in the at least one contact region, wherein the plurality of elevated regions covers 5% to 90% of the at least one contact region and comprises spaced apart elevated regions each extending from the exterior surface of the wall in the at least one contact region.

10. A process, comprising: using a plurality of a plurality of glass particles for functionalizing an exterior surface of a wall of a glass container for packaging a pharmaceutical composition, the glass container comprising the wall which at least partially surrounds an interior volume of the hollow body, the wall comprising a layer of glass comprising a first glass composition, the wall comprising an interior surface that faces the interior volume and the exterior surface opposite the interior surface that faces away from the interior volume, the wall defining a plurality of exterior diameters, the wall defining a maximum exterior diameter in at least one contact region, the maximum exterior diameter extending along at least a portion of a height of the hollow body, the functionalizing comprising: A} contacting the exterior surface in the at least one contact region with the plurality of glass particles; and B} forming a plurality of elevated regions each comprising a further glass composition at least in part from the plurality of glass particles and joining the plurality of elevated regions to the exterior surface in the at least one contact region, wherein the plurality of elevated regions covers 5% to 90% of the at least one contact region and comprises spaced apart elevated regions each extending from the exterior surface of the wall in the at least one contact region.

11. The hollow body of claim 1, wherein the plurality of elevated regions is formed as a loop extending about at least a portion of a circumference of the hollow body.

12. A closed hollow body, comprising: a wall which at least partially surrounds an interior volume of the closed hollow body, the wall comprising a layer of glass comprising a first glass composition, the wall comprising an interior surface that faces the interior volume and an exterior surface opposite the interior surface that faces away from the interior volume, the wall defining a plurality of exterior diameters, the wall defining a maximum exterior diameter in at least one contact region, the maximum exterior diameter extending along at least a portion of a height of the closed hollow body, wherein at least one elevated region extends from the exterior surface of the wall in the at least one contact region and comprises a further glass composition, wherein the at least one elevated region covers 5% to 90% of the at least one contact region, wherein the at least one elevated region comprises a plurality of spaced apart elevated regions each extending from the exterior surface of the wall in the at least one contact region.

13. The closed hollow body of claim 12, further comprising a pharmaceutical composition in the interior volume.

14. A process, comprising as process steps: A) providing a hollow body comprising: a wall which at least partially surrounds an interior volume of the hollow body, the wall comprising a layer of glass comprising a first glass composition, the wall comprising an interior surface that faces the interior volume and an exterior surface opposite the interior surface that faces away from the interior volume, the wall defining a plurality of exterior diameters, the wall defining a maximum exterior diameter in at least one contact region, the maximum exterior diameter extending along at least a portion of a height of the hollow body, wherein at least one elevated region extends from the exterior surface of the wall in the at least one contact region and comprises a further glass composition, wherein the at least one elevated region covers 5% to 90% of the at least one contact region, wherein the at least one elevated region comprises a plurality of spaced apart elevated regions each extending from the exterior surface of the wall in the at least one contact region; B) inserting a pharmaceutical composition into the interior volume; and C) closing the hollow body.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) 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:

(2) FIG. 1 illustrates a schematic depiction of an exemplary embodiment a hollow body provided according to the invention;

(3) FIG. 2 illustrates a schematic depiction of another exemplary embodiment of a hollow body provided according to the invention;

(4) FIG. 3 illustrates a schematic depiction of another exemplary embodiment of a hollow body provided according to the invention;

(5) FIG. 4 illustrates a schematic depiction of an exemplary embodiment of a closed hollow body provided according to the invention;

(6) FIG. 5 illustrates a flow chart of an exemplary embodiment of a process provided according to the invention for the preparation of a hollow body;

(7) FIG. 6 illustrates a flow chart of another exemplary embodiment of a process provided according to the invention for the preparation of a hollow body;

(8) FIG. 7 illustrates a flow chart of an exemplary embodiment of a process provided according to the invention for packaging a pharmaceutical composition;

(9) FIG. 8 illustrates a flow chart of an exemplary embodiment of a process provided according to the invention for treating a patient;

(10) FIG. 9A illustrates a microscope image of the result of a scratch test performed on a vial of example 1;

(11) FIG. 9B illustrates a microscope image of the result of a scratch test performed on a vial of comparative example 1.

(12) FIG. 9C illustrates a microscope image of the result of a scratch test performed on a vial of comparative example 2;

(13) FIG. 9D illustrates a microscope image of the result of a scratch test performed on a vial of comparative example 3; and

(14) FIG. 9E illustrates a microscope image of the result of a scratch test performed on a vial of comparative example 4.

(15) 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

(16) Hollow Body

(17) The hollow body provided according to the invention may have any size or shape which the skilled person deems appropriate in the context of the 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 surrounds the interior volume of the hollow body only partially. The hollow body may be a glass body or a glass container in that sense that the layer of glass extends over the full area of the wall surface. In that case, the layer of glass may determine a macroscopic shape of the wall. In some embodiments, the layer of glass is of a one-piece design. The layer 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 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. According to the nomenclature used herein, the wall of the hollow body comprises the layer of glass and every layer and every functionalization superimposed thereon. The wall surface is formed by the surface of the layer or functionalization, such as elevated regions, which is positioned at an outermost or innermost position of the wall.

(18) 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.

(19) As used herein, the exterior diameter of the hollow body at a position along the height of the hollow body is determined in a cross sectional plane through the height of the hollow body at this position, the cross-sectional plane being perpendicular to the height of the hollow body.

(20) Contact Region

(21) In some embodiments, the at least one contact region, i.e., each contact region, is a region of the exterior surface of the hollow body at which the hollow body contacts a further hollow body, the further hollow body being identical to the hollow body, both hollow bodies standing upright on a plane surface, a distance between both hollow bodies having been reduced until both hollow bodies have been brought into contact, the hollow body being positioned at a certain angle of rotation around an axis along the height of the hollow body with respect to the further hollow body. In some embodiments, the contact region is a cylindrically symmetric region of the exterior surface and thus, the preceding definition may be independent from the angle of rotation of the hollow body with respect to the further hollow body. In some embodiments, the at least one contact region extends along at least 50%, such as along at least 60%, along at least 70%, along at least 80%, along at least 90%, along at least 95%, or along a full length, of a circumference of the hollow body. In the case in which the at least one contact region extends along the full length of the circumference of the hollow body, the at least one contact region may form a closed loop. In some embodiments, the at least one contact region extends cylindrically symmetric around the interior volume of the hollow body. In some embodiments, the at least one contact region is a ring-shaped circumferential region. An exemplary maximum is a local maximum, or a global maximum, or both. Therein, a global maximum means that the hollow body does not have a larger exterior diameter in any cross-sectional plane which is perpendicular to the height of the hollow body and which is at a height which is not in the contact range. A local maximum means that the hollow body may have a larger exterior diameter in a cross-sectional plane which is perpendicular to the height of the hollow body and which is at a height which is not in the at least one contact range, but in any cross sectional plane which is perpendicular to the height of the hollow body and which is at a height which limits the at least one contact range the exterior diameter of the hollow body is smaller than in the at least one contact range.

(22) Base Surface and Elevated Regions

(23) For the use herein, the base surface defines a ground level on which the at least one elevated region is positioned. The base surface may be a lateral surface of a geometric body, such as of a cylinder. Further, the base surface may be a smooth curved surface on which the elevated regions form bumps or embossments. The base surface may be a surface of the layer of glass.

(24) Elevated Regions

(25) The elevated regions can have any size or shape which the skilled person deems appropriate in the context of the invention. In a top view onto the at least one surface region, the at least one elevated region may be of a circular or elliptic shape. In case of a plurality of elevated regions, those may be of microscopic or macroscopic size and the elevated regions may form a pattern on the base surface. In case of a single elevated region per surface region, this elevated region may be of macroscopic size.

(26) In some embodiments, the at least one elevated region consists of the further glass composition. In some embodiments, the at least one elevated region further comprises at least one colorant, or at least one filler, or both. An exemplary colorant is a pigment, or a dye, or both. An exemplary filler, being used in the composition of the at least one elevated region, acts to modify a coefficient of thermal expansion (CTE) of the at least one elevated region to be closer to a coefficient of thermal expansion of the layer of glass, the filler may act to modify the coefficient of thermal expansion (CTE) of the at least one elevated region to be approximately equal to the coefficient of thermal expansion of the layer of glass. Hence, the filler may help to reduce mechanical stresses between the at least one elevated region and the layer of glass by bringing their coefficients of thermal expansion closer together. In some embodiments, the at least one elevated region comprises no colorant, such as the at least one elevated region is transparent for visible light. In some embodiments, the first glass composition and the further glass composition are identical.

(27) In some embodiments, the wall surface comprises a single surface region which represents at least 50%, such as at least 60%, at least 70%, or at least 80%, of a surface area of the exterior surface of the wall, throughout this surface region a plurality of elevated regions is superimposed on the base surface, and may form a pattern on the base surface. In some embodiments, the wall surface comprises at least two surface regions which each form a ring which extends circumferentially around the interior volume of the hollow body. In some embodiments, each of those rings comprises a single elevated region which convers the base surface in the respective ring fully. In some embodiments, each of those rings comprises a plurality of elevated regions which superimposes the base surface across the respective ring, each of those pluralities of elevated regions may form a pattern on the base surface across the respective ring. In some embodiments, one ring comprises a single elevated region which covers the base surface in the ring fully, and a further ring comprises a plurality of elevated regions which superimpose the base surface across the respective ring, and may form a pattern on the base surface across the respective ring.

(28) Surface Region

(29) In some embodiments, each surface region is a coherent region. In other words, in some embodiments none of the at least one surface regions is a discontinuous region. Herein, a discontinuous region is a region which comprises multiple mutually spaced regions.

(30) First Glass Composition

(31) The first glass composition of the layer of glass may be any type of glass and may consist of any material or combination of materials which the skilled person deems suitable in the context of the invention. In some embodiments, the first glass composition is suitable for pharmaceutical packaging. In some embodiments, the first glass composition is a glass of type I in accordance with the definitions of glass types in section 3.2.1 of the European Pharmacopoeia, 7th edition from 2011. Any references to a type I glass herein refer to the preceding definition. Additionally or alternatively to the preceding, the first glass composition is 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.-%, or 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.

(32) A glass which may also be used as the first glass composition according to the invention is essentially free from B (boron). 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 may be at a proportion of not more than 0.1 wt.-%, such as not more than 0.05 wt.-%, in each case based on the weight of the glass.

(33) Vehicle

(34) As the vehicle each vehicle which the skilled person knows and deems appropriate for being used in the context of the invention comes into consideration. Here, the vehicle is a, for example liquid, medium which allows for the at least partially application of the plurality of particles onto the wall surface in a convenient, uniform, manner. In some embodiments, the vehicle has a viscosity which is suitable for the preceding purpose. In some embodiments, the vehicle has a rather high vapour pressure which allows for decreasing the proportion of the vehicle in the composition through evaporation of the vehicle in the process step c). In some embodiments, in the process step c) the vehicle is evaporated completely. In a case in which the composition is a dispersion, the vehicle may be the continuous, for example liquid, phase of the dispersion. An exemplary vehicle is a screen printing oil. Suitable exemplary screen printing oils are commercially available under the tradenames H 948 Diluente 21 from Pemco, 650-63 IR-Medium Oil-based from Johnson Matthey, 80 3057-ME Siebdrucköl 670-315 (DSLA 80 3057-IME Screenprint DRM) from Ferro, and 80 3062-MS Siebdrucköl 670-687 from Ferro.

(35) In some embodiments, in the process step b) of the process provided according to the invention, the composition is a dispersion. An exemplary dispersion is a suspension, or a colloid, or both. The composition of the process provided according to the invention may be a dispersion. Generally, a dispersion is a system in which particles are dispersed in a continuous phase. There are three main types of dispersions: a coarse dispersion which is also referred to as suspension, a colloid, and a solution. A suspension is a heterogeneous mixture that contains solid particles sufficiently large for sedimentation. A suspension is a heterogeneous mixture in which the dispersed particles do not dissolve, but get suspended throughout the bulk of the continuous phase, left floating around freely in the medium. The particles may be dispersed throughout the continuous phase through mechanical agitation, with the use of certain excipients or suspending or dispersing agents. The suspended particles are visible under a microscope and will settle over time if left undisturbed. This distinguishes a suspension from a colloid, in which the dispersed particles are smaller and do not settle. Colloids and suspensions are different from a solution, in which the particles do not exist as a solid, but are dissolved. The composition of the invention may be a dispersion in which the particles of the plurality of particles are dispersed in a liquid phase, referred to herein as vehicle. In the context of the composition of the invention, an exemplary dispersion is a suspension or a colloid or both.

(36) Filler

(37) A filler may be a plurality of filler particles, the filler particles having a melting temperature which is above the further softening temperature of the further glass composition, such as by at least 10° C., by at least 20° C., or by at least 50° C. An exemplary filler, being used in the composition, acts to modify a coefficient of thermal expansion (CTE) of the at least one elevated region to be closer to a coefficient of thermal expansion of the layer of glass, such as the filler acts to modify the coefficient of thermal expansion (CTE) of the at least one elevated region to be approximately equal to the coefficient of thermal expansion of the layer of glass. Hence, the exemplary filler helps to reduce mechanical stresses between the at least one elevated region and the layer of glass by bringing their coefficients of thermal expansion closer together.

(38) Depyrogenation

(39) In some embodiments, the heating in the process step d) of the process or the heating prior the process step B) of the process or both is a measure of a depyrogenation step. In the technical field of pharmacy, depyrogenation 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 depyrogenation.

(40) Pharmaceutical Composition

(41) In the context of the 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 liquid or solid or both. An exemplary solid composition is granular such as a powder, a multitude of tablets or a multitude of capsules. An 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.

(42) Wall

(43) Herein, the wall of the hollow body comprises a layer of glass. The wall may comprise further layers on one or both sides of the layer of glass. The layer of glass may extend laterally throughout the wall. This means that, in some embodiments, each point on the wall surface lies on top of a point of the layer of glass. The hollow body may be a hollow body of glass. In any case, the layers of the wall are joined to one another. Two layers are joined to one another when their adhesion to one another goes beyond Van-der-Waals attraction forces.

(44) Unless otherwise indicated, the components of the wall, in particular layers and elevated regions, may follow one another in a direction of a thickness of the wall 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 component, for example an elevated region, superimposes another, for example the layer of glass. 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.

(45) Alkali Metal Barrier Layer and Hydrophobic Layer

(46) In some embodiments, the layer 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. In some embodiments, the alkali metal barrier layer or by the hydrophobic layer or both form at least a part of the interior surface, such as the full interior surface. 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

(47) The following measurement methods are to be used in the context of the 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%.

(48) Contact Angle for Wetting with Water

(49) 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 Analyzer—DSA30S from Krüss GmbH is applied for the measurements. Uncertainty of the measurement increases for contact angles below 10°.

(50) Wall Thickness and Tolerance of Wall Thickness

(51) 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:

(52) DIN ISO 8362-1 for vials,

(53) DIN ISO 9187-1 for ampoules,

(54) DIN ISO 110 4 0-4 for syringes,

(55) DIN ISO 13926-1 for cylindrical cartridges, and

(56) DIN ISO 11040-1 for dental cartridges.

(57) Scratch Test

(58) An MCT MikroCombiTester (MCT S/N 01-04488) from CSM Instruments is applied for the scratch test. As the scratch partner, a hollow body which is identical to the hollow body to be tested, including any coatings or functionalization, is used. Further, in the test same surfaces are scratched against each other. The scratch partner is hold in position by a special mount above the hollow body to be tested. Here, the scratch 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 scratch partner at a well-defined test force (normal force). For the test, the hollow body to be tested is moved forwards underneath the scratch partner at a velocity of 10 mm/min over a test length of 15 mm. 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.

(59) Coefficient of Linear Thermal Expansion

(60) Unless otherwise specified, the coefficients of linear thermal expansion mentioned herein refer to the temperature range from 20 to 300° C. The coefficient of linear thermal expansion is determined using a dilatometer. The dilatometer is used in accordance with the best practice which the skilled person knows and which is suitable here. In case of a glass sample which is not suitable for determining its coefficient of linear thermal expansion directly, the composition of the glass sample is determined using energy dispersive X-ray spectroscopy. Then a sample which is suitable for determining its coefficient of linear thermal expansion with the same composition is prepared and the coefficient of linear thermal expansion is determined for this sample.

(61) Softening Temperature

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

(63) Transformation Temperature T.sub.g

(64) The transformation temperature is determined in accordance with ISO 7884-8.

(65) Thickness of Elevated Regions

(66) A cross-sectional cut through the elevated regions to be studied is prepared in accordance with the best suitable practice which is known to the skilled person. Then, the thickness of the elevated regions is measured using either a scanning electron microscope or a white-light-microscope, whichever is suitable for the size of the elevated regions to the studied. 5 single thicknesses are measured, in case of a plurality of elevated regions each on another elevated region, and the arithmetic mean of the 5 values is calculated.

(67) Diameter of Elevated Regions

(68) The diameter of an elevated region of a plurality of elevated regions is determined by measuring the length of the longest straight line which lies completely in the elevated region, which is perpendicular to the thickness of the elevated region, and which connects two points on the rim of the elevated region. If appropriate, depending on the size of the elevated regions to be studied, the measurement is conducted using a scanning electron microscope or a white-light-microscope.

(69) Cover Ratio

(70) Here, a topographical measurement of the surface to be studied is conducted with a white-light-spectrometer of the type Coherence Scanning Interferometry/Phase Shift Interferometry (CSI/PSI) from Zygo Corporation. The cover ratio is calculated from the obtained topographical image. The sum of the elevated areas is divided by the total area of measurement.

(71) Particle Size Distribution

(72) The particle size distribution of the plurality of particles in the composition is determined by static light scattering. A particle size analyser named CILAS 920 from CILAS is applied for the measurement. For measurement the particles are dispersed in water. The concentration is defined by the obscuration value of the dispersion. A value of 14 to 16% has proven to be a good value for a reliable measurement. The dispersion is pumped continuously through a measuring cell where the laser beam can illuminate the particle ensemble. During the pumping in the measuring circuit, ultrasound is applied for 120 s to the system enabling destruction of agglomerates.

(73) The aspect ratio of the particles is determined using an optical microscope or a scanning electron microscope. In each case, lengths and thicknesses of 10 arbitrarily chosen particles of the plurality of particles to be studied are measured and the arithmetic mean value is determined.

(74) Particles

(75) A cross-sectional cut through the elevated regions to be studied is prepared in accordance with the best suitable practice which is known to the skilled person. Then, the cut is inspected for the presence of particles, such as pigments and fillers, using a scanning electron microscope and a white-light-microscope.

(76) Exemplary embodiments of the invention are set out in more detail below by examples and drawings, with the examples and drawings not denoting any restriction on the invention. Furthermore, unless otherwise indicated, the drawings are not to scale.

Example 1 (According to the Invention)

(77) Preparation of the Composition:

(78) Glass frits are prepared from a glass melt of the composition:

(79) 62 mol-% of SiO.sub.2,

(80) 3.5 mol-% of Al.sub.2O.sub.3,

(81) 1.4 mol-% of Bi.sub.2O.sub.3,

(82) 23 mol-% of B.sub.2O.sub.3,

(83) 9.8 mol-% of Li.sub.2O, and

(84) 0.3 mol-% of Na.sub.2O.

(85) The glass has a coefficient of linear thermal expansion for the temperature range from 20 to 300° C. of 4.8 ppm/K, a transformation temperature of 470° C., and a softening temperature of 860° C. The glass frits are ground until a particle size distribution with a D.sub.50 in a range from 1 to 10 μm is obtained. Then, 45 g of the ground glass frits are mixed with 55 g of the solvent H948 Diluent 21 from Pemco in a dissolver of the type DISPERMAT from Getzmann. Subsequently, the glass frits in the obtained mixture are homogenised by feeding the mixture two times through a 3-roll-mill. The gaps between the rolls of the mill are adjusted to get successively narrower from each pair of rolls to the next. A suspension for functionalizing containers as set forth below is obtained.

(86) Functionalization with the Composition:

(87) 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, is provided. The glass of the vial has a transformation temperature of 560° C. The surface of this vial does not have any coating or functionalization. The vial has a body region which is of the shape of a hollow cylinder. Hence, the vial has a global maximum of its exterior diameter throughout the body region. The vial is washed as described below. The suspension which is obtained as explained above is applied to the exterior surface of the vial by screen printing and lithography, thereby forming a regular pattern of a plurality of ellipses across the full exterior surface of the vial in its body region. The screen which is used for the screen printing has a mesh 120 T of polyester. The pattern consists of ellipses which have a length in the x-direction of 930 μm and in the y-direction of 1,100 μm. The distance between the ellipses in the x-direction is 740 μm and in the y-direction 930 μm. The thickness of the applied suspension is about 10 μm. The applied suspension is cured for 10 min at 600° C. in an oven.

Example 2 (According to the Invention)

(88) Preparation of the Composition: The composition is prepared as provided above for the example 1.

(89) Functionalization with the Composition:

(90) 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, is provided. The glass of the vial has a transformation temperature of 560° C. The surface of this vial does not have any coating or functionalization. This vial is washed as described below. The suspension which is obtained as explained above is applied to the exterior surface of the vial by screen printing and lithography, thereby forming two rings which extend circumferentially around the interior of the container (see FIG. 2) in the body region of the vial. This body region is of the shape of a hollow cylinder. Hence, the vial has a global maximum of its exterior diameter throughout the body region. Each ring has a width of 1 mm. The two rings are spaced by 1 cm in a direction of the height of the vial. The screen used for screen printing has the same characteristics as provided above for the example 1. Thus, a regular pattern of ellipses is formed across the full exterior surface of the vial within each ring. The thickness of the applied suspension is about 10 μm. Then the applied suspension is cured by heating in an oven. Therein, the temperature is increased within 10 min to 250° C. This temperature is kept constant for 1 min. Subsequently, the temperature is increased further within 1 h to 650° C. Again, the temperature is kept constant for 1 min. The subsequent cooling is conducted in accordance with the characteristic curve of the oven.

Example 3 (According to the Invention)

(91) Preparation of the Composition:

(92) The composition is prepared as provided above for the example 1.

(93) Functionalization with the Composition:

(94) 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, is provided. The surface of this vial does not have any coating or functionalization. The vial has a body region which is of the shape of a hollow cylinder. Hence, the vial has a global maximum of its exterior diameter throughout the body region. The vial is washed as described below. The suspension which is obtained as explained above is applied to the exterior surface of the vial by screen printing and lithography, thereby forming two rings which extend circumferentially around the interior of the container (see FIG. 3) in its body region. Each ring has a width of 1 mm. The two rings are spaced by 1 cm in a direction of the height of the vial. The suspension forms a continuous layer which covers the full exterior surface of the vial in each of the rings and which has a thickness of 10 μm. Then the suspension is cured by heating it in an oven. Therein, the temperature is increased within 10 min to 250° C. This temperature is kept constant for 1 min. Subsequently, the temperature is increased further within 1 h to 650° C. Again, the temperature is kept constant for 1 min. The subsequent cooling is conducted in accordance with the characteristic curve of the oven.

Comparative Example 1 (not According to the Invention)

(95) 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 Invention)

(96) 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 washed and then coated on its exterior surface throughout its body region with MED10-6670 from NuSiL.

Comparative Example 3 (not According to the Invention)

(97) 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, is provided. The surface of this vial does not have any coating or functionalization. This vial is washed as described below. Then the vial is placed inside a SCS Labcoater®, Model PDS 2010. Via a vacuum process, the vial is first functionalized with 3-methacrylaoxypropyltrimethoxysilane by evaporation without further heat treatment and then coated with Parylen C by evaporation at 100° C. The final coating has a film thickness of 250 nm.

Comparative Example 4 (not According to the Invention)

(98) Preparation of the Composition:

(99) 99.8 ml of high purity water are provided in a beaker. 0.2 ml of Levasil CS50-34P (50% SiO.sub.2, average particle size less than 100 nm) from Akzo Nobel N.V. are added to the beaker and the obtained composition is stirred for 30 s with a magnetic stirrer at ambient temperature of 20° C. Subsequently, 0.5 ml g of Tween20 from Sigma Aldrich are added. Then, the composition is stirred for another 10 min. The thus obtained composition is ready for use.

(100) Functionalization with the Composition:

(101) 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, is provided. The surface of this vial does not have any coating or functionalization. The vial has a body region which is of the shape of a hollow cylinder. Hence, the vial has a global maximum of its exterior diameter throughout the body region. The vial is washed as described below. The washed vial is immersed with its bottom first into the composition, which has been prepared as set out above, at a velocity of 30 cm/min. Therein, the head region of the vial, including the vial opening, is not immersed into the composition in order to prevent contacting the interior surface of the vial with the composition. The vial is kept in the composition for 2 s. Afterwards, the vial is retracted from the composition at a velocity of 20 cm/min. Subsequently, the vial is kept as it is for 10 s at ambient temperature of 20° C. Then the vial is placed with its bottom onto an absorbent substrate such as a paper towel. Then the composition which has been applied to the vial is dried by keeping the vial for 30 min at a temperature of 600° C. in an oven.

(102) Evaluation

(103) For each of the examples 1 to 3 and the comparative examples 1 to 4, the contact angle for wetting with water is determined in the respective functionalized region on the exterior surface of the vial body in accordance with the above measurement method. The results are shown in Table 1.

(104) TABLE-US-00001 TABLE 1 Characterization of the exterior surfaces of the glass vials of the examples and comparative examples by their contact angles for wetting with water, in each case prior to any post treatment Example Contact angle for water [°] Example 1 <10 Example 2 <10 Example 3 <10 Comparative example 1 <10 Comparative example 2 70 Comparative example 3 93 Comparative example 4 <10

(105) 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 2 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 −.

(106) TABLE-US-00002 TABLE 2 Comparison of the tendency of the glass vials to be damaged on the filling line for the examples and comparative examples Example Low tendency to damages on filling line Example 1 ++ Example 2 ++ Example 3 + Comparative example 1 −− Comparative example 2 − Comparative example 3 − Comparative example 4 −−

(107) 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. Here, vials of the examples 2 and 3 turn out to be advantageous as the optical inspection can easily be conducted on the vials between the functionalized rings of the exterior surface of the vials. Between those rings, no functionalization which could disturb the inspection is present on the vial surface.

(108) For further studies, functionalized surfaces of vials according to the examples 1 to 3 and the comparative examples 1 to 4 have been subjected to a scratch test which is described in detail in the above measurement methods section. Typical results of these tests are shown in FIGS. 9A to 9E. Therein, FIG. 9A shows a functionalized vial surface according to example 1, FIG. 9B an unfunctionalized surface of a reference vial according to comparative example 1, FIG. 9C a functionalized vial surface according to comparative example 2, FIG. 9D a functionalized vial surface according to comparative example 3, and FIG. 9E a functionalized vial surface according to comparative example 2, in each case after having been subjected to the scratch test. It can be seen that the vial surface of example 1 has been protected from scratches by the functionalization better than the surfaces of the vials of the comparative examples. In the FIGS. 9A to 9E, the force with which the scratch partner is pushed against the vial surface is increased linearly from 0.1 N (at the left margins of the figures) up to 30 N (at the right margins of the figures). As the FIGS. 9A to 9E show typical results of the scratch test studies, it can be concluded that the protection of the vial surfaces from scratches has been improved for vials which have been functionalized according to the invention with respect to the unfunctionalized reference vial and also with respect to the vials which have been functionalized according to the comparative examples 2 to 4. Further, the emission of particles from the scratched surfaces is observed. During scratching glass particles or particles of the functionalization may detach from the vial surface. The detachment of particles is to be avoided as far as possible on a pharmaceutical filling line as such particles may contaminate the containers in a pharmaceutically relevant manner. Table 3 below summarizes the results of the scratch test studies regarding protection of the glass surface of the vials and the detachment of particles during scratching. Therein, ++ means a more favourable result than +, + means a more favourable result than −, and − means a more favourable result than −−.

(109) TABLE-US-00003 TABLE 3 Comparison of scratch test results regarding protection of the glass surface of the vial and avoidance of particle detachment from the vial or the functionalization upon scratching Glass surface of vial protected Avoidance of from scratches particle detachment Example 1 + + Example 2 + + Example 3 ++ + Comparative example 1 −− − Comparative example 2 − − Comparative example 3 − − Comparative example 4 −− −

(110) Post-Treatment

(111) For further studies, the vials of the examples 1 to 3 and of the comparative example 1 as reference are subjected to three different kinds of post-treatment, i.e. a washing procedure, a depyrogenation procedure and a freeze drying. These kinds of post-treatment are described below. The washing procedure is the same as used prior to functionalizing/coating the vials in the examples 1 to 3 and of the comparative examples 2 to 4. Also the reference vial of comparative example 1 has been washed as described below.

(112) Washing:

(113) 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.

(114) cage 1: 144 with 4 mm nozzles

(115) cage 2: 252 with 4 mm nozzles

(116) drying cabinet from Heraeus (adjustable up to 300° C.)

(117) 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:

(118) pre-washing without heating for 2 min

(119) washing at 40° C. for 6 min

(120) pre-rinsing without heating for 5 min

(121) rinsing without heating for 10 min

(122) end-rinsing at without heating for 10 min

(123) drying without heating for 5 min

(124) 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.

(125) Depyrogenation:

(126) The vials are depyrogenized by placing them in an oven which is heated to 350° C. This temperature is kept constant for 1 h. Subsequently, the vials are taken out of the oven and left to cool down.

(127) Freeze Drying:

(128) The vials are freeze dried by storing them for 4 hours at −70° C.

(129) Evaluation after Post-Treatment

(130) Vials of the examples 1 to 3 have been subjected to various combinations of the above types of post-treatment. It has been found that the functionalizations of examples 1 to 3 withstand the washing procedure as well as the depyrogenation procedure and the freeze drying. In particular, tests have been conducted, in that vials according to the examples 1 to 3 have been freeze dried. Prior to and after this procedure the functionalized surfaces have been checked for damages and defects under the microscope at a magnification of 5 to 20 times. It has been observed that no defects or damages have been caused by the freeze-drying procedure.

(131) FIG. 1 shows a schematic depiction of a hollow body 100 according to the invention. The hollow body 100 comprises a wall 102 which partially surrounds an interior volume 101 of the hollow body 100. The wall 102 surrounds the interior volume 101 only partially in that the hollow body 100 comprises an opening 110 which allows for filling the hollow body 100 with a pharmaceutical composition 401 (not shown). The wall 102 forms from top to bottom in FIG. 1: a top region of the hollow body 100, which consists of a flange 111 and a neck 112; a body region 114, which follows the top region via a shoulder 113; and a bottom region 116, which follows the body region 114 via a heel 115. Here, the body region 114 is a lateral region of the hollow body 100 in form of a hollow cylinder. Thus, a contact range 118 of a height 117 of the hollow body 100 extends throughout the body region 114. Throughout that contact range 118 an exterior diameter 119 of the hollow body 100 has a global maximum. This means, nowhere outside of the body region 114 the hollow body 100 has an exterior diameter 119 which is larger than in the body region 114. The wall 102 comprises a layer of glass 104 and a wall surface 103, wherein the layer of glass 104 extends across the full area of the wall surface 103. The layer of glass 104 consists of a first glass composition. The wall surface 103 consists of an interior surface 108 which faces the interior volume 101, and an exterior surface 109 which faces away from the interior volume 101. Here, the part of the exterior surface 109 which lies in the body region 114 of the hollow body 100 forms a contact region 120 which thus, extends throughout the contact range 118 of the height 117 of the hollow body 100. Further, the contact region 120 is a region of the exterior surface 109 of the hollow body 100 at which the hollow body 100 contacts a further hollow body (not shown), wherein the further hollow body is identical to the hollow body 100, wherein both hollow bodies stand upright on a plane surface, wherein a distance between both hollow bodies has been reduced until both hollow bodies have been brought into contact. Here, the contact region 120 is a cylindrically symmetric region of the exterior surface 109 and thus, the preceding definition is independent from the angle of rotation of the hollow body 100 around an axis along the height 117 of the hollow body 100 with respect to the further hollow body. In case of the hollow body 100 of FIG. 1, the contact region 120 is identical to a surface region 105 of the wall surface 103. The layer of glass 104 forms a base surface 106 which is partially superimposed by a plurality of elevated regions 107 throughout that surface region 105. The elevated regions 107 adjoin the base surface 106 which is a surface of the layer of glass 104. Further, the elevated regions 107 are joined to the base surface 106. Moreover, the elevated regions 107 form a regular pattern of ellipses across the full surface region 105. The elevated regions 107 consist of a further glass composition. The hollow body 100 of FIG. 1 is a vial according to the example 1 above.

(132) FIG. 2 shows a schematic depiction of a further hollow body 100 provided according to the invention. The hollow body 100 of FIG. 2 is designed as the hollow body 100 of FIG. 1, except that the hollow body of FIG. 2 has exactly a first and a further surface region 105. Each of these surface regions 105 forms a ring that extends circumferentially around the interior volume 101 of the hollow body 100. Hence, the surface regions 105 are cylindrically symmetric. Both rings lie in the contact region 120 of the exterior surface 109 of the wall 102. Just as the surface region 105 of FIG. 1, the first and the further surface regions 105 of FIG. 2 each comprise a regular pattern of elevated regions 107. The hollow body 100 of FIG. 1 is a vial according to the example 2 above.

(133) FIG. 3 shows a schematic depiction of a further hollow body 100 provided according to the invention. The hollow body 100 of FIG. 3 is designed as the hollow body 100 of FIG. 2, except that in both of the surface regions 105 the base surface 106 is fully covered by a single elevated region 107, respectively. The hollow body 100 of FIG. 3 is a vial according to the example 3 above.

(134) FIG. 4 shows a schematic depiction of a closed hollow body 400 provided according to the invention. This closed hollow body 400 is a vial which has been obtained by filling the hollow body 100 of FIG. 1 with a pharmaceutical composition 401 and closing the opening 110 with a lid 402 via a crimping step. Here, the pharmaceutical composition 401 is a vaccine.

(135) FIG. 5 shows a flow chart of a process 500 provided according to the invention for the preparation of a hollow body 100. The process 500 comprises a process step a) 501 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) 502, a composition is applied to the exterior surface 109 of the vial by screen printing and lithography as described in detail above in the context of the example 1 according to the invention. A process step c) 503 of forming a plurality of elevated regions 107 and joining those to the vial surface is as well conducted as described in the context of the example 1 according to the invention. The hollow body 100 of FIG. 1 is obtained through the process 500.

(136) FIG. 6 shows a flow chart of a further process 600 provided according to the invention for the preparation of a hollow body 100. The process 600 of FIG. 6 comprises the process steps a) 501 to c) 503 of the process 500 according to FIG. 5 and further, a process step d) 601 of depyrogenising the hollow body 100 in accordance with the above described depyrogenation process.

(137) FIG. 7 shows a flow chart of a process 700 provided according to the invention for packaging a pharmaceutical composition 401. In a process step A) 701, the hollow body 100 according to FIG. 1 is provided. In a process step B) 702, a pharmaceutical composition 401 is filled into the interior volume 101 of the hollow body 100, and in a process step C) 703 the opening 110 of the hollow body 100 is closed, thereby obtaining the closed hollow body 400 of FIG. 4.

(138) FIG. 8 shows a flow chart of a process 800 provided according to the invention for treating a patient. This process 800 comprises the process steps of: A. 801 providing the closed hollow body 400 of FIG. 4, opening the closed hollow body 400 by penetrating the lid 402 with a needle of a syringe, filling the syringe with the vaccine; and B. 802 administering the vaccine subcutaneously to a patient using the syringe.

(139) FIG. 9A shows a microscope image of the result of a scratch test performed on a part of the exterior surface 109 in the body region 114 of a vial of example 1. In the figure, the applied force increases linearly from 0.1 N on the left margin to 30 N on the right margin. The image shows that the elevated regions 107 on the base surface 106 protect the base surface 106, which is a surface of the layer of glass 104, from scratches.

(140) FIG. 9B shows a microscope image of the result of a scratch test performed on the exterior surface of a vial of comparative example 1. In the figure, the applied force increases linearly from 0.1 N on the left margin to 30 N on the right margin.

(141) FIG. 9C shows a microscope image of the result of a scratch test performed on the exterior surface of a vial of comparative example 2. In the figure, the applied force increases linearly from 0.1 N on the left margin to 30 N on the right margin.

(142) FIG. 9D shows a microscope image of the result of a scratch test performed on the exterior surface of a vial of comparative example 3. In the figure, the applied force increases linearly from 0.1 N on the left margin to 30 N on the right margin.

(143) FIG. 9E shows a microscope image of the result of a scratch test performed on the exterior surface of a vial of comparative example 4. In the figure, the applied force increases linearly from 0.1 N on the left margin to 30 N on the right margin.

(144) 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

(145) 100 hollow body according to the invention 101 interior volume 102 wall 103 wall surface 104 layer of glass 105 surface region 106 base surface 107 elevated region 108 interior surface 109 exterior surface 110 opening 111 flange 112 neck 113 shoulder 114 body region 115 heel 116 bottom region 117 height 118 contact range 119 exterior diameter 120 contact region 400 closed hollow body according to the invention 401 pharmaceutical composition 402 lid 500 process according to the invention for the preparation of a hollow body 501 process step a) 502 process step b) 503 process step c) 600 process according to the invention for the preparation of a hollow body 601 process step d) 700 process according to the invention for packaging a pharmaceutical composition 701 process step A) 702 process step B) 703 process step C) 800 process according to the invention for treating a patient 801 process step A. 802 process step B.