EP0972504A1 - Universal container for medical purposes - Google Patents

Abstract

The universal container for liquid or solid medical preparations has a thin-wall container mantle (1), a shaped pouring opening (2) and a geometric inhomogenous base. The base has at least one rotational symmetrical recess or bulge, with a flat outer surface or with a slightly indented central recess. The container is of tubular or borosilicate glass, or an amorphous or partially crystalline plastics which can form a steam barrier which is better than 0.08 g/m<2> x d where d is a wall thickness of 500 mu m.

Description

The invention relates to a universal container for medical purposes for liquid and solid medical preparations.

It is particularly aimed at in-situ production and Storage of freeze-dried medical products. Based on Problems existing with this application are the following Background of the invention are presented without the invention being pointed out would be limited.

Special medical products, pharmaceuticals such as diagnostics, come especially for reasons of long-term pharmaceutical stability freeze-dried products in containers on the market. Freeze drying, lyophilization, typically takes place in such a way that the lyophilizing liquid in the container itself the freeze-drying process is subjected, the container being washed before filling and is sterilized. After freeze-drying, they are closed with Elastomer plug, and after further process steps Shipment. Immediately before application, the lyophilized medicinal substance dissolved by filling a liquid and typically taken into a disposable syringe with a needle.

A number of requirements are imposed on the aforementioned containers. There is first the material for the container.

Glass is given priority over plastic as a material for containers for freeze-drying or for the storage of freeze-dried medical products, because in contrast to plastics, glass has extraordinarily high barrier values against water vapor, CO ₂ and oxygen and can therefore be used universally for many medical products , while plastics have good barrier properties against either water vapor or oxygen and carbon dioxide, but not at the same time against water vapor and oxygen / carbon dioxide to a sufficient extent for numerous ingredients.

For special medical substances with low demands on the Protective effect of the container and / or short storage times are, however Plastic containers can be used in principle. So far, however, they are not widely used for parenteral preparations.

Glass containers for medical purposes are on the market both as tubular glass and as tubular glass containers. The manufacturing methods for tubular glass and metallurgical glass containers are well known. Tubular glass containers are then formed from prefabricated glass tubes by reshaping and separating. The tubular glass containers include in particular: ampoules, vials, syringe barrels and syringe bodies, the shapes and typical dimensions of which are standardized.
Metallurgical glass containers are then manufactured by molding a glass melt directly by blowing or press-blowing. The cottage glass containers include, for example, injection and infusion bottles, as have become known, for example, from DE 196 22 550 A1. Glass containers for the aforementioned purposes also have the advantage over plastic containers that they can be sterilized using recognized pharmaceutical methods, for example with hot air at temperatures of approximately 300 ° C. This is particularly the case if the containers are made of borosilicate glass because borosilicate glass has a high level Resistant to thermal shock, which is also important for the lyophilization process with temperatures between minus 45 ° C and plus 30 ° C.

The container should also be closable with standard closures and one have a high level of stability. On the other hand, it is for the Freeze-drying in the container is essential that it is a Lightweight container acts as possible for the freeze-drying process Small container masses (heat capacities) are desirable to this complex thermal processes as time and therefore cost-effectively to be able to execute.

Important for the freeze-drying process (synonym = lyophilization process) it is also a crystal structure of the lyophilizate that is as homogeneous as possible (= synonymous dry product) to achieve a uniform and ensure rapid dissolution by the user, and edge effects to keep it as low as possible: it is also very important for freeze drying avoid breaking containers during freeze drying. Both conditions must include through a suitable container dimensioning Be taken into account.

It has also been suggested to use additives such as potassium chloride and Lactose should be provided to at least reduce the breakage of vials. However, such an approach is very rarely acceptable because it does the pharmaceutical formulation of the product must be changed to to adapt to an unsuitable container.

Another problem with freeze drying is collapse; that is the Formation of an amorphous frozen product that occurs during freeze drying is not converted into the crystalline phase. This effect must also be used be considered when designing the glass container.

There is another circumstance to be taken into account.

Freeze-dried medical products are very expensive because of the Manufacturing technology very expensive products. That is why it is important that liquid content of a container with a dissolved lyophilisate if possible can be completely removed from the container. This is with the typically not used tubes or glass containers or requires cumbersome handling e.g. the shaking together of individuals Drip and pick up with a suction tube, a syringe cannula etc. This The process is due to the drop distribution determined by random laws practically not automatable, so that in the case of automatic removal e.g. through automatic analysis devices such as those used in blood analysis etc. full removal, if any, is used only very is possible to a limited extent. This complete removal does not just play a role with freeze-dried products, but of course generally an important one Role.

The use of silicone oil for surface modification is also prohibited freeze-drying containers as this can lead to undesirable Contamination of the lyophilisates after freeze-drying can result. Furthermore, the use of silicone for parenteral products should only be used in absolute exceptional cases are used, as this is the only way to exclude can cause silicone droplets to enter the body by injection. This also applies not only to freeze-dried products, but to everyone Injection / infusion preparations in liquid or solid form.

In addition, for reasons of rational Processing / use of the containers generally also for liquid and not only for freeze-dried medical preparations should be able to be used to keep the storage of different containers to a minimum limit.

The known vials, be they made of glass or plastic, do however meet the aforementioned claims not to the full extent.

The invention is based, based on the task designated container for medical purposes to design this that he is very light-weight and yet stable, lyophilization allows, which leads to a homogeneous dry product, low risk of breakage during freeze-drying and almost complete emptying of the liquefied lyophilisate, and the universal for liquid and solid medical preparations can be used.

• einem relativ zum Boden dünnwandigen Behältermantel,
• einem daran angeformten Ausflußteil, das mit einem üblichen Verschluß verschließbar ist, und
• einem geometrisch inhomogen ausgeformten Bodenteil, das jeweils mindestens eine rotationssymmetrische Vertiefung sowie Materialanhäufung aufweist, und dessen äußere Fläche eben oder nur mit mit einer sehr geringen zentrischen Einziehung ausgebildet ist.

This object is achieved according to the invention with the container described at the outset

• a thin-walled container casing relative to the bottom,
• an integrally formed discharge part, which can be closed with a conventional closure, and
• a geometrically inhomogeneously shaped bottom part, each of which has at least one rotationally symmetrical depression and material accumulation, and the outer surface of which is flat or has only a very slight central indentation.

The configuration of this container enables a lightweight container with great stability and ensures a lyophilization, which leads to a homogeneous dry product leads. The container has only one small breakage rate and can be almost completely emptied. It is also universal usable for liquid and solid contents.

In further embodiments of the invention, various configurations of the Bottom part possible, which are the subject of subclaims.

The Japanese abstract JP 08322908 A is an ampoule made of plastic with a specially configured bottom part.

The contents of ampoules are typically used in syringes transferred. For this purpose, the outflow part of the known ampoule is designed so that a needleless syringe can be placed on the ampoule. To the content to transfer the ampoule, this "overhead" must be emptied so that the Content liquid gets into the syringe body. To transfer this into the To facilitate syringe, the bottom of the ampoule is tapered with a central recess designed so that it can be squeezed together. The well-known The central depression therefore has no purpose of completely removing the liquid contained in the ampoule by accumulating the liquid to ensure at the deepest point of the container. That would only make sense make, if an injection needle would be provided that to the bottom of the Ampoule was enough. However, this is not the case. The well-known design of the Soil should not let it become too massive, so that the ampoule at their "Over-head" emptying is easier to crumple.

This function would not be the case if the ampoule were made of glass possible.

Furthermore, the known ampoule has a pronounced indentation. she is not very suitable for in-situ lyophilization, since the bottom does not have the necessary flat contact with the cooling plate of the lyophilizer guaranteed.

Further design features and advantages of the invention result based on the description of shown in the drawings Embodiments.

Fig. 1

eine Vorderansicht eines erfindungsgemäßen Fläschchens, teilweise im Schnitt,

Fig. 2

in einer Schnittdarstellung einen vergrößerten Ausschnitt des Bodenteils des Fläschchens nach Fig. 1,

Fig. 2 A bis 2 E

verschiedene Ausgestaltungen des Fläschenbodens, und

Fig. 3

verschiedene Varianten A - D der Querschnittsflächen des Mantels der Behälter, und zwar
in der Variante A mit dreieckiger Ausführungsform,
in der Variante B mit viereckiger, speziell rechteckiger Ausführungsform,
in der Variante C mit bevorzugter sechseckiger Ausführungsform, wobei das Sechseck jeweils zwei einander gegenüberliegende gleichlange und parallel zueinander ausgerichtete Seiten aufweist, und
in der Variante D mit der am meisten bevorzugten Ausführungsform mit regelmäßigen Sechsecken.

Show it:

Fig. 1

2 shows a front view of a vial according to the invention, partly in section,

Fig. 2

1 shows a sectional view of an enlarged section of the bottom part of the vial according to FIG. 1,

2A to 2E

different designs of the bottle bottom, and

Fig. 3

different variants A - D of the cross-sectional areas of the jacket of the container, namely
in variant A with a triangular design,
in variant B with a square, especially rectangular embodiment,
in variant C with a preferred hexagonal embodiment, the hexagon each having two opposite sides of equal length and aligned parallel to one another, and
in variant D with the most preferred embodiment with regular hexagons.

1 is a front view of a trained according to the invention Container, in the example in the form of a glass vial, with an exemplary Filling volume of 4 ml shown, which is cut in the right part. The Fig. 1 A shows the bottom of this in an enlarged section Vial with the crucial features of the invention in one Sectional view.

The glass vial is preferably made of tubular glass with borosilicate glass known techniques.

The production from tubular glass has compared to the production from cottage glass just in the present case the advantage of being relatively simple let diverse floor configurations be shaped.

The vial consists of a cylindrical section 1, the wall of which in terms of meeting the need for a Light weight container is uniformly relatively thin. It is in present example of the 4 ml bottle is only 1 mm. On the cylindrical Section 1 is followed by a tapered neck section 2, in which a standard thread is formed so that a commercially available closure in Form of a standard screw cap can be used. The amount of Neck part 2 in this example is approximately 9 mm, the length of the cylindrical Part 1 approx. 23 mm with a total length of the vial of approx. 35 mm. For the transition from the cylindrical part 1 into the neck part 2 therefore remain approx. 2 mm. The inner diameter of the neck part 2 is approximately 9 mm Outside diameter of the cylindrical part 1 about 18 mm.

The solid base 3 is characteristic of the vial according to the invention, which is significantly thicker than the wall of the cylindrical section 1 is formed, as well as the geometrically inhomogeneous shape of the Bottom of the container itself. In the embodiment according to FIG. 1A, the edge of the container a glass accumulation 3 a formed, the average wall thickness of which Three times the wall thickness in the cylindrical part 1 is.

The container bottom 3 also has a central recess 3 b and one minimum indentation 3 c in the middle, i.e. one if possible small distance from the center of the container bottom 3 of the Footprint. In the example, the confiscation is max. 0.7 mm.

The mass of the container is only slightly larger than that of one comparable known container with the same filling volume, since only the soil mass was increased.

Through this lowering of the center of gravity and the largest possible footprint achieved the required stability.

The recess 3 b in the container bottom leads to the possibility of the container almost completely empty, since the liquid in the container is in this deepening, i.e. the glass container according to the invention has only a residual volume of less than 1% of the container content Filling volume, and is also automatically emptied.

Freeze drying tests have another surprising effect described inhomogeneous soil formation: there was always a very uniform formation of the crystalline freeze-drying product (Lyophilisate), without collapsed amorphous areas, one rotationally symmetrical lyophilisate structure could be obtained. The Freeze-drying process was compared despite the average Standard containers with increased soil mass not measurably slowed down. Further the result was also due to the special floor design Effect that the number of vials broken during lyophilization declines considerably. When freeze-drying 3% Manitole solutions with a filling height of 24 mm (filling volume approx. 10 ml) the number was broken vials only 10% of the number of standard broken vials with the same test conditions. The test conditions corresponded to the relevant known parameters.

Basically, there are different embodiments of the bottle bottom alternatively possible to that shown in Fig. 1A, the limiting factor always the ratio of the glass diameter of the original tubular glass to Wall thickness is. In Fig. 2, five representations A - E are five different embodiments shown.

In version A, the glass accumulations are 3a compared to the version 1A formed more towards the center than an annular bead, in Connection with a trough-shaped central recess 3 b in comparison to the more angular corresponding depression in Fig. 1 A. Furthermore, the Bottom 3 completely flat at the bottom, also for version B.

Version B differs from version A by one less pronounced ring bead 3 a or a shallower depression 3 b.

2 C are a central glass accumulation 3 a and a concentric annular bead 3 a and one concentric at the edge circumferential recess 3 b in connection with a slight retraction of the Bottom center provided in accordance with FIG. 1A.

The embodiment D with a flat underbody has a single one central platform-like expanded glass cluster 3 a and a groove-like circumferential recess 3 b on the edge.

The embodiment according to the sub-figure E is in principle similar to that according to FIG. 2 D, but the central glass accumulation 3 a is less pronounced in connection with a glass accumulation at the lower outer edge of the floor due to the one circumferential bead 3 a ₁ .

In the embodiments described so far, the invention is Round cross-sectional shape made of glass. However, he can can also be made of plastic.

The plastic container according to the invention can be manufactured in a simpler manner Way according to known methods of plastics molding, such as Injection blowing, injection molding, immersion blowing, etc. are done. The manufacture of the desired geometrically inhomogeneous inner floor contour is made by Introducing a press ram that has a corresponding counter contour.

The containers are preferably made of a plastic material, which is translucent or transparent so that e.g. the freeze-dried substance when dissolving immediately before its intended use Assessment, e.g. is accessible by medical personnel. The translucent plastic material used should preferably be used in a Wall thickness of 2 mm a light transmittance according to ASTM 1003 of> Have 90%. If the plastics used are not inherently are sufficiently translucent, the person skilled in the art by adding in the prior art Technically known additives increase transparency.

The plastic material for containers for lyophilization and storage of less oxygen-sensitive substances is selected from the group with a density <1.1 g / cm ³ , a water vapor permeability according to DIN 53122 with a layer thickness of 1 mm of <0.1 g / m ² · d and a water absorption according to ASTM D 570 of <0.05%. Plastic material with such a specification can be found in particular among the cycloolefin polymers or cycloolefin copolymers, such as those under the trade names TOPAS ^® (all types) from Ticona, ZEONEX ^® from Nippon Zeon (all types, preferably ZEONEX ^® 250 and ZEONEX ^® 280) or APEL ^® from Misui are commercially available. Cycloolefin polymers or cycloolefin copolymers with a water vapor permeability according to DIN 53122 of <0.03 g / m ² · d and a heat distortion temperature (HDTB / B (0.45 N / nm ² ) according to ISO 75 part 1 and 2 in the range between 50 ° C and 90 ° C, such as TOPAS ^® 8007 with a glass transition temperature in the range of 60 ° C to 100 ° C.

The plastic material for containers for lyophilization and storage of more oxygen-sensitive substances is selected from the group with a density ≤ 1.4 g / cm ³ and an oxygen permeability according to DIN 53380 with a layer thickness of 100 µm of <50 cm ³ / m ² · d ·bar. Plastic material with such a specification is composed, for example, of polymers based on polyethylene terephthalate (PET), glycol-modified PET (PETG), oriented PET (O-PET) or polyethylene naphthalate (PEN).

The use of plastic for the manufacture of the invention Container also enables the production of Containers with a cross-sectional shape that differs from the circular shape. To improve the thermal conditions in the lyophilization process it is advantageous if the container according to the invention is level Has side surfaces that are able to make contact with the plan Side surfaces of each adjacent container body to kick. The A cross-sectional shape of such a container body can preferably be Triangle, a square or a hexagon. Typical examples are in the Fig. 3 shown in variants A, B, C and D. Is the cross-sectional shape a triangle, then at least two of the three sides are preferably from same size. The preferred triangular cross-sectional shape is one isosceles triangle (variant A). With a square as Cross-sectional shape are advantageously at least two each other opposite sides formed parallel to each other. Such Cross-sectional shape can be a trapezoid, a parallelogram, a rhombus Rectangle (variant B) and in particular a square.

However, the preferred cross-sectional shape is a hexagon, each of which two opposite sides are of equal length and parallel to each other (Variant C). A regular hexagon after is most preferred Variant D.

The flat shape of the side surfaces of the container body and its Cross-sectional geometry make it possible to use a batch process lyophilizing batch of containers so in the lyophilization chamber to arrange that the available space is used optimally can be. The flat design of the side surfaces of the container casing together with the triangular, quadrangular or hexagonal Cross-sectional shape allow any container in a batch, provided it not exactly occupying a position on the outer areas of the footprint, so can be arranged so that it is in planar contact with each of its sides with the side surfaces of the container adjacent to it. In addition to the optimal use of the footprint, this means that despite the generally lower thermal conductivity of plastics in comparison with glass, between the side surfaces of the container during the Heat transfer or compensation can take place during the lyophilization process, so that there is a more or less homogeneous in all containers of a batch Temperature distribution. The inevitable with round glass vials Dead volumes occurring between the containers, which act as heat insulators act between the walls of the individual containers, occur at the angular ones Containers. In addition to the homogeneous heat exchange among the Individual containers can have a higher one than glass vials Heat exchange between the base plate of the lyophilizer (cooling plate) and occur in the containers to be lyophilized, because the flat Bottom shape with a bottom indentation of less than 0.5 mm Heat exchange in comparison with the more or less drawn Favored bottoms of known containers made of glass.

Given a predetermined amount of good to be lyophilized and predetermined Space in a lyophilizer is therefore required when using the square container less time for lyophilization than when using conventional round vial. Then the good to be lyophilized can be distributed over a larger area at a given volume (plus the area for the dead volumes for round vials), can therefore a smaller fill level can be set than for round container bodies for the same volume, which then means the ratio of "active surface" to fill level in a container and therefore the efficiency of sublimation of the Ice from the active surface is enlarged. Conversely, one needed then a smaller footprint with the same filling level in the square container and thus smaller freeze drying systems than when using round ones Glass vials.

The containers with the angular jacket cross section according to 3 have a geometrically inhomogeneous shape Base part analogous to the representations in FIG. 2, but preferably with the modification that the material accumulations and depressions are not rotationally symmetrical, but all round according to the geometric Shape of the cross-sectional circumference are formed.

Claims (21)

Universal glass container for medical purposes for liquid and solid medical preparations, with a container wall (1) which is thin-walled relative to the bottom, an integrally molded discharge part (2) which can be closed with a conventional closure, and a geometrically inhomogeneously shaped bottom part (3), each having at least one circumferential, preferably rotationally symmetrical depression (3 b) and material accumulation (3 a), and the outer surface of which is flat or has only a very slight central indentation. Container according to claim 1, characterized in that it is made of tubular glass. Container according to claim 1 or 2, characterized in that it consists of borosilicate glass. Container according to claim 1, characterized in that it consists of an amorphous or partially crystalline plastic. Container according to claim 4, characterized in that a plastic is used which has a water vapor barrier better than 0.08 g / m ² xd, based on a wall thickness d of 500 µm. A container according to claim 5, characterized gekennzeichne t, that the plastic PEN, PET / PEN copolymer, cycloolefin polymer or a cycloolefin copolymer is. Container according to one of claims 1 to 6, characterized in that the bottom part (3) has a peripheral material accumulation a) (3 a) and a central recess (3 b) on the edge (FIG. 1A). Container according to one of claims 1 to 6, characterized in that the base part (3) has an inner, circumferential, wall-shaped material accumulation (3a) with a central trough-like recess (3b) and a circumferential recess (Figures 2A, B). Container according to one of claims 1 to 6, characterized in that the base part (3) has a central material accumulation (3 a) and concentrically with it forming a circumferential recess (3 b) a further circumferential, wall-shaped material accumulation with a circumferential recess to the edge has (Fig. 2 C). Container according to one of claims 1 to 6, characterized in that the base part (3) has a platform-like central material accumulation (3 a) and a recess (3b) running around the edge (Fig. 2 D). Container according to claim 10, characterized in that a peripheral bead (3a1) is formed on the outside of the base (Fig. 2 E). A container according to claim 4 or one of the following, characterized in that the container shell has flat side surfaces which are capable of planar contact with the side surfaces of an adjacent container shell. A container according to claim 12, characterized in that the container shell has the cross-sectional area of a hexagon, each with two mutually opposite sides of equal length, aligned parallel to one another. A container according to claim 13, characterized in that the container shell has the cross-sectional area of a regular hexagon. A container according to claim 12, characterized in that the container casing has the cross-sectional area of a square with at least two mutually opposite parallel sides. Container according to claim 12, characterized in that the container casing has the cross-sectional area of a triangle with at least two sides of equal length. Container according to one of Claims 4 to 16, characterized in that the plastic material is used to store medical products which are less sensitive to oxygen a density <1.1 g / cm ³ a water vapor permeability according to DIN 53122 with a layer thickness of 1 mm of <0.1 g / m ² · d and has a water absorption according to ASTM D 570 of <0.05%. Container according to one of claims 4 to 16, characterized in that the plastic material is used to store medical products sensitive to oxygen a density ≤ 1.4 g / ccm ³ and has an oxygen permeability according to DIN 53380 with a layer thickness of 100 µm of <50 cm ³ / m ² · d · bar. Container according to claim 6 or one of the following, characterized in that the cycloolefin polymer or cycloolefin copolymer has a water vapor permeability according to DIN 53122 of less than 0.03 g / m ² · d and a heat distortion temperature (HDTB / B (0.45 N / mm ² ) according to ISO 75 part 1 and 2 in the range between 50 ° C and 90 ° C. Container according to claim 19, characterized in that the cycloolefin polymer or cycloolefin copolymer has a glass transition temperature in the range from 60 ° C to 100 ° C. Use of the container according to one of claims 1 to 20 for the in situ freeze drying of a liquid medical preparation in the container.

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