DE29702816U1 - Sterilizable glass container for medical purposes, in particular for storing pharmaceutical or diagnostic products - Google Patents

Description

18.02.1997

Sterilizable glass container for medical purposes, in particular for storing pharmaceutical or diagnostic products

The invention relates to sterilizable glass containers for medical purposes, in particular for storing pharmaceutical or diagnostic products, in particular solutions. Such containers are intended to come into direct contact with the contents. A wide variety of types of glass containers are used, for example vials (described in detail, for example, in ISO standard 8362, part 1), ampoules (described in detail, for example, in ISO standard 9187, part 1), syringe bodies (described in detail, for example, in ISO standard 11040, part 4), glass cylinders (described in detail, for example, in ISO standard 13926, part 1) and bottles (described in detail, for example, in ISO standard 8356, part 1). The filling volumes of these containers vary between 0.5 and 2000 ml.

For these purposes, for example for the packaging of injection solutions, glasses with high hydrolytic resistance (according to the pharmacopoeias, e.g. German Pharmacopoeia DAB 10, glasses of glass type I or II) are required. Glass containers that meet these requirements are known from the German utility model DE 296 09 958.9, which describes glass containers whose surfaces in contact with the solutions are coated with a layer of oxides and/or nitrides of the elements Si, Ti, Ta ₁ Al applied by means of a plasma CVD process.

For the majority of medical and pharmaceutical applications, it is necessary that empty containers are sterilized before they are filled. At present, suitable methods for sterilizing glass containers are only chemical processes that require complex equipment, such as gassing with ethylene oxide, autoclaving with superheated steam or heat sterilization at temperatures of around 250 to 300 ^° C. There is a great need for improvement here.

Another method, sterilization using high-energy radiation (e.g. ß-radiation, γ-radiation, strong UV radiation), cannot be used here, since the glasses used up to now, for example conventional borosilicate glasses or soda-lime glasses, discolor inhomogeneously yellow to brown, often spotty, after sterilization using high-energy radiation, depending on the radiation dose. The coloring changes depending on time, temperature and the influence of light. Such frequently inconsistent discoloration or the variability of the

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18.02.1997

Discoloration is unacceptable for pharmaceutical applications as it makes safe visual inspection of the contents almost impossible.

For example, the powdery contents of an inhomogeneously (spotted) colored container cannot be reliably checked for foreign particles. Since such checks are now mostly carried out using fully automated systems, any visible deviation from a specified norm (a colorless or homogeneously colored container) leads to the rejection of the affected container and possibly even to the shutdown of an entire production line.

The use of high-energy radiation for sterilization can also be advantageous for containers that are already filled. Here too, discoloration of the container is unacceptable, as this would severely limit the controllability of the drug manufacturer, the pharmacist and the user. For the end user, for example, it is important that two containers containing the same product are visually identical, as otherwise it cannot be decided which container may contain a spoiled product.

In glass chemistry, it is well known that the addition of stabilizers, particularly cerium oxide, can suppress the browning caused by high-energy rays. However, glasses containing cerium oxide have not yet been acceptable as materials for containers for storing pharmaceutical and diagnostic solutions, since Ce ions can be released into the solution during storage and other glass components such as SiO ₂ , Al ₂ O ₃ etc. are released to a greater extent after irradiation than in unirradiated containers. Since the interaction of the ingredient with the leached cerium ions can be critical, ie the effectiveness of the medication can be seriously affected, the impairment of the contents by Ce ions under different storage conditions and times would have to be examined in each individual case. This would mean an immense amount of testing.

The object of the invention is to find a glass container for storing pharmaceutical or diagnostic solutions which can be sterilized by high-energy radiation without any visible discoloration occurring and which is highly inert towards the solutions.

The problem is solved by the glass container described in the main claim.

The glass from which the container is made contains a stabilizer against high-energy radiation, i.e. a stabilizer that prevents discoloration in the glass caused by radiation. Such stabilizers are, for example, oxides of lanthanides, which can assume several valence states, in particular cerium oxide.

18.02.1997

The glasses commonly used for pharmaceutical applications can be used. Preference is given to using glasses that already have a high hydrolytic resistance, in particular the so-called neutral glasses (borosilicate glass) (DAB 10, glass type I). However, soda-lime glasses can also be used, which, when uncoated, correspond to glass type III (DAB 10).

The invention relates not only to colorless containers, but also to colored ones, since additional and uneven discoloration due to high-energy radiation is undesirable even for the brown glass used for light-sensitive substances.

The preferred stabilizer is cerium oxide, which is preferably present in the glass used at a content of 0.3 to 1.5% by weight. The minimum amount mentioned ensures sufficient effect. A content higher than 1.5% by weight is usually not advisable due to the inherent color of the cerium oxide, which then becomes disturbing, but is also not necessary due to the effectiveness of the cerium oxide. A content between 0.5 and 1.5% by weight is preferred.

The glass container is coated on its inside, i.e. on its surface in contact with the solution, with a layer of oxides and/or nitrides of the elements Si, Ti, Ta, Ai or mixtures thereof.

Preferably, the layer has been produced using a plasma CVD process (PCVD process), in particular using the plasma pulse process (PICVD process). In these processes, a layer is deposited from the gas phase (CVD = chemical vapor deposition), whereby the energy required to split the precursor gases is introduced into the system by means of an electrical high-frequency plasma. These processes are well known per se. Layers produced using these processes have a particularly high resistance to leaching by the solution and to high-energy radiation.

Particularly suitable are oxide layers, in particular those made of SiO ₂ and/or TiO ₂ , with SiO ₂ being preferred.

The layer must have a thickness of less than 400 nm, since it does not contain cerium oxide and can be discolored by the high-energy radiation, but at this thinness - less than the wavelength of visible light - it is not visible to the naked eye. Layer thicknesses between 10 and 200 nm are preferred. Several layers of different compositions can also be deposited as a layer package, whereby the layer package should then have the above-mentioned layer thickness.

G1108
18.02.1997

Such a layer has an excellent barrier effect against the leaching of ions from the glass by the solution, in particular and essential for the invention against the leaching of cerium ions.

The following glass containers are preferably used: injection vials, syringe bodies, glass cylinders or injection bottles.

The special properties of the glass container according to the invention are shown in the following examples of coated glass vials:

Vials according to ISO 8362, Part I with a bottle size of 6R were used.

Table 1 gives an overview of the glass compositions investigated.
Glasses 1 - 6 are soda-lime glasses; glasses 7-14 are borosilicate glasses. Glasses 1 and 7 do not contain a stabilizer against high-energy radiation and serve as comparison examples.

Table 1:

Glass compositions used *) (content in wt.%):

Glass _{SiO2 B2O3 ​ Al2O3 ​ Na2O} K ₂ O MgO CaO BaO _{Ce2O3 ​} 1 69 1.0 4 12.5 3.5 2.5 5 2 0 2 68.7 1.0 4 12.5 3.5 2.5 5 2 0.3 3 68.5 1.0 4 12.5 3.5 2.5 5 2 0.5 4 68.2 1.0 4 12.5 3.5 2.5 5 2 0.8 5 68 1.0 4 12.5 3.5 2.5 5 2 1.0 6 67.5 1.0 4 12.5 3.5 2.5 5 2 1.5 7 75 11 5 7 1.5 0.5 0 8th 74.2 11 5 7 1.5 0.5 0.8 9 79.5 13 2.5 3.5 0.5 0.5 10 70.5 8th 5.5 7 1.5 1 2 0.3 11 70 8th 5.5 7 1.5 0.5 2 0.8 12 72 11 7 7 1 1 0.8 13 72.5 10 6 6 3 0.5 0.8 14 73.5 10 6 8th 1 0.8

*) Remainder 100 % other elements (for Nos. 10 and 11 Fe ₂ O ₃ and TiO ₂ together 3.5 %).

18.02.1997

Glass vials with the listed compositions, which have a 100 nm - 150 nm thick SiO ₂ layer applied to their inside using the PICVD process, were irradiated with different energy doses and examined for color changes. This was done by visual inspection in transmitted light; the color change was checked approximately 3 weeks after irradiation.

The results are summarized in Table 2:

They show that the coated and irradiated containers do not change color visibly or change color very slightly at concentrations of 0.3% by weight and more of cerium oxide in the glass, so that the above-mentioned controls are not affected. The transmission values of the coated and irradiated vials differ only slightly from the coated and unirradiated vials.

G1108 18.02.1997

Table 2:

Color change of coated glass vials depending on the glass composition (see Table 1) and the irradiation dose

l· ·
I % I
P * Glass No.
* 1 2 3 4 4 5 6 7 8th 9 10 11 12 13 14 t *
* 4
*·
• * Üe-Oxide-
Salary
Jwt.%] 0 0.3 0.5 0.8 0.8 1 1.5 0 0.8 0.5 0.3 0.8 0.8 0.8 0.8 *
4 · · Irradiation
aosis [kGy] 25 25 25 25 35 35 35 25 25-35 25 35 35 35 35 25 * ··
* Color before
Irradiation colorless colorless colorless colorless colorless colorless colorless colorless colorless colorless brown brown colorless colorless colorless * * Color change
"roof irradiation
lation Yes
strong Yes
weak no no weak no no Yes
strong no no Yes
weak no no no no

G1108

18.02.1997

Both uncoated and coated glass vials of selected compositions according to Table 1 were irradiated with different energy doses. They were then filled with double distilled water and then autoclaved for 60 minutes at 121 ⁰ C. The amount of silicon and Ce ions released was then determined in pg/ml. The results are shown in Table 3. The ion concentrations were determined using atomic absorption spectroscopy. The measured values given are averages of 5-7 individual determinations. All concentrations are converted to the respective oxides and are given in μg/ml (ppm).

The results shown in Table 3 show that the coating has a very good barrier effect against the leaching of the ions mentioned and that this effect is not impaired by irradiation, while in uncoated containers the already strong leaching of cerium ions and silicon ions is further increased by irradiation.

18.02.1997

Table 3

Eluate concentrations for coated and uncoated, irradiated and unirradiated glasses of selected compositions (see Table 1)

Glass No. Ce ₂ O ₃ -
Salary
[Wt.%] Coating
100-150nm S1O2
with PICVD Irradiation
dose [kGy] Eluate concentrations
[mg/ml] _{Ce2O3 ​ SiO2} - 1 0 Yes 0 <0.3 - 1 0 Yes 25 <0.3 - 1 0 no 0 9.4 - 1 0 no 25 10.8 < 0.05 4 0.8 Yes 0 <0.3 <0.05 4 0.8 Yes 35 <0.3 2.6 4 0.8 no 0 9.6 3.0 4 0.8 no 35 11.8 - 7 0 Yes 0 <0.3 - 7 0 Yes 25 <0.3 - 7 0 no 0 4.6 - 7 0 no 25 5.8 <0.05 8th 0.8 Yes 0 <0.3 <0.05 8th 0.8 Yes 35 <0.3 2.1 8th 0.8 no 0 4.4 2.4 8th 0.8 no 35 5.6 <0.05 12 0.8 Yes 0 <0.3 <0.05 12 0.8 Yes 35 <0.3 2.9 12 0.8 no 0 6.1 3.1 12 .0.8 no 35 7.6 <0.05 13 0.8 Yes 0 <0.3 <0.05 13 0.8 Yes 35 <0.3 1.8 13 0.8 no 0 3.7 2.3 13 0.8 no 35 5.0 <0.05 14 0.8 Yes 0 <0.3 <0.05 14 0.8 Yes 0.25 <0.3 2.5 14 0.8 no 0 5.1 3.4 14 0.8 no 0.25 5.2

The detection limits were:

_SiO2 :

_{Ce2O3 :}

not investigated

0.3 pg/ml 0.05 pg/ml

18.02.1997

The coated containers made of soda-lime glasses 2-6 therefore correspond to the specifications for glass containers of type II according to the German Pharmacopoeia (DAB 10).

Radiation treatment without discoloration or color change is also possible in borosilicate glasses, without leaching (elution) of Ce ions after autoclaving. The coated containers made of glasses 7-14 correspond to the specifications for type I glass containers according to the German Pharmacopoeia (DAB 10).

The illustration in Figure 1 shows an example of a 10 ml injection vial. The vial consists of the cerium oxide-containing glass body 1 and the SiO ₂ layer 2 on the inside. The thickness of the SiO ₂ layer is not shown to scale.

The glass container according to the invention can be sterilized with the usual doses (25 to 35 kGy) without visibly discoloring and meets or exceeds the requirements of the DAB and the European Pharmacopoeia for containers of glass type il.

The novel combination of known individual features according to the invention makes it possible to obtain, in a strikingly simple way, a glass container that can be sterilized by radiation, has no disturbing coloring and is sufficiently inert, particularly for storing pharmaceutical or diagnostic products.

Claims (8)

1) Sterilizable glass container for medical purposes, in particular for storing pharmaceutical or diagnostic products, in particular solutions, the surface of which in contact with the solution is coated with a layer of oxides and/or nitrides of the elements Si, Ti, Ta, Al or mixtures thereof, characterized, that it consists of a glass containing a stabilizer against high-energy radiation and that the layer is less than 400 nm thick. 2) Glass container according to claim 1, characterized in that the stabilizer is cerium oxide. 3) Glass container according to claim 2, characterized in that the cerium oxide is present in the glass in a proportion of 0.3 to 1.5 wt.%. 4) Glass container according to at least one of claims 1 to 3, characterized in that said layer is 10 to 200 nm thick. 5) Glass container according to at least one of claims 1 to 4, characterized in that the layer consists of SiO ₂ . 6) Glass container according to at least one of claims 1 to 5, characterized in that the layer is applied by means of a plasma CVD process. 7) Glass container according to at least one of claims 1 to 6, characterized in that the layer is applied by means of a plasma pulse CVD process. 8) Glass container according to at least one of claims 1 to 7, characterized in that the glass container contains an injection vial, a syringe body,
a glass cylinder or an injection vial.