WO2003075822A1

WO2003075822A1 - Discharge container with an automatically following sliding element for liquid, suspension-type viscous or pasty filling items

Info

Publication number: WO2003075822A1
Application number: PCT/EP2003/001840
Authority: WO
Inventors: Werner Müller; Karl Karch; Hermann Koch; Hans-Joachim Ploss
Original assignee: Aventis Pharma Deutschland Gmbh
Priority date: 2002-03-08
Filing date: 2003-02-24
Publication date: 2003-09-18
Also published as: TW200400915A; DE10210095A1; AR038745A1; AU2003210339A1

Abstract

The invention relates to a discharge container which can remove liquid, suspension-type, viscous or pasty filling items such that no excess air remains or contact with the atmosphere is kept to a minimum during storage and removal. Said discharge container containing the filling items is made of a hollow body which is closed on one end by means of a sliding element and on the other end by means of a membrane secured to the hollow body. Said sliding element is displaced through the membrane during the removal of the filling items exclusively by means of air pressure acting upon the sliding element. The invention also relates to a method for removing filling items.

Description

description

Withdrawal container with automatically sliding element for liquid, suspension-like, viscous or pasty filling goods

The invention relates to a removal container which allows liquid, suspension-like, viscous or pasty filling goods, in particular protein-containing injection preparations or pharmaceutical preparations of biotechnologically produced pharmaceutical substances, to be filled and removed in such a way that there is no air supernatant or the contact during storage and removal to the surrounding atmosphere is minimized.

As packaging for liquid pharmaceutical preparations, e.g. Sterile insulin solutions or suspensions are used, on the one hand, for multiple collection bottles which contain an air space above the solution for injection. When taking the solution for injection, e.g. "Non-sterile" air is also injected into the bottle by means of a syringe. The use of cartridges which allow application by means of application aids, for example a pen, is also known , pushed towards the outlet of the cartridge after an injection needle has been installed.

In the case of the multiple collection bottles containing a considerable amount of air, changes in the filled injection solutions can be observed during transport, storage or during or after the removal of the injection solutions, e.g. Particle formation, cloudiness, discoloration etc., which represent a loss of stability of these injection solutions. According to the package leaflet of the drug, e.g. for insulin preparations, such an altered e.g. cloudy solution for injection can no longer be applied, so should be disposed of.

It is known that the stability of protein solutions is drastically reduced by interaction with hydrophobic surfaces such as liquid / air interfaces can be. Using the example of insulin preparations, it could be shown that shaking solutions which were brought into contact with hydrophobic surfaces leads to denaturation / aggregation in a few hours, which led to a drastic reduction in the insulin content. (Sluzky et al .; Proc.Natl. Acad. Sci. USA; Vol.88; pp.9377-9381, Nov. 1991, Applied Biological Sciences). In the absence of hydrophobic surfaces, the solutions were stable for several days even after shaking.

The aim of the invention was now to develop a removal container which does not have the disadvantages mentioned above, i.e. a removal container, the z. B. actually contains no airspace, the injection preparation is drastically stabilized against physical stress, and in which, despite partial removal of the contents, the stability is maintained in the same way.

The object is achieved by a removal container containing a filling material consisting of a) a hollow body, which b) is closed at one end by a sliding element and c) at the other end by a membrane attached to the hollow body, characterized in that the sliding element during the removal of the filling material through the membrane only by the air pressure acting on the sliding element.

The hollow body must be shaped in such a way that the sliding element can move in the container according to the amount removed. The hollow body can take various cross-sectional shapes, such as. B. round or angular with rounded corners, preferably round. The cross-sectional shape must be so constant over the entire useful length of the hollow body that the sliding element closes the hollow body securely. However, the cross-sectional area may twist over the usable length. The line of movement of the sliding element in the hollow body does not necessarily have to be a straight line. Furthermore, the hollow body can be formed from a wide variety of materials, e.g. As glass, aluminum, etc., glass is preferred. If necessary, the hollow body can also be tapered at the “membrane end”.

The sliding element can consist of various materials, such as. B. rubber, ceramic or plastic, preferably rubber. It must be shaped in such a way that it simultaneously slides freely in the hollow body, if appropriate after appropriate treatment of the hollow body and / or sealing element, and also tightly closes the hollow body. For this purpose, the sliding element has a circumferential sealing element on its contact surface with the hollow body, which sealingly seals both elements. This sealing element can be an integral part of the sliding element or additionally applied to it. As an additional sealing element, O-rings made of elastic, sealing material can be used, e.g. Rubber or teflon. Piston plugs or ceramic pistons provided with a sealing element may be mentioned as examples of sliding elements; the piston plug is particularly preferably made of rubber.

The filling material is removed by piercing the membrane with a removal system. As removal systems for removal of the filling z. B. syringes such. B. disposable syringes with needles, unfilled pre-filled syringes, insulin syringes, etc. are suitable.

The membrane must be able to seal itself again during and after removal. As materials, elastic materials come into question such as. B. rubber or plastic, rubber is preferred.

The membrane can be positively connected to the hollow body by various fastening systems, such as. B. by means of a crimp cap, a union nut, by gluing, etc .; the crimp cap is preferred.

The size of the withdrawal container can vary widely. It depends on the desired amount of the filling and can, for. B. Volume ranges from 1 to 250 ml, such as 1, 5 ml, 1, 7 ml, 3 ml, 5 ml, 10 ml, 20 ml, 50 ml. Also larger or smaller volumes are conceivable. Withdrawal containers of size 5 to 20 ml are preferred, very particularly preferably 10 ml.

All liquid, suspension-like, viscous or pasty filling materials are considered as filling material, such as, for. B. solutions or suspensions, preferably protein preparations or pharmaceutical preparations of biotechnologically produced drugs. Insulins and their analogs, growth hormones or antithrombotics are particularly preferred, insulins and their analogs are very particularly preferred.

The invention also relates to a method for removal from a removal container as described above, which is characterized in that the membrane is pierced with a removal system and the filling material is transferred into the removal system, the sliding element automatically moving upwards in accordance with the amount of filling material removed.

An embodiment of the invention is described below, but without restricting it thereto.

In Fig. 1 a removal container (1) is shown in section. The hollow body (2) is closed at one end (3a) with the sliding element (3) and at the other end (4a) with a membrane (4). The sliding element (3) is freely movable in the hollow body (2) in the direction of the end (4a). The end (4a) is closed with a membrane (4) by means of a fastening system (5). The filling material fills the removal container without any significant air overhang. When removing by means of the removal system, the membrane (4) is pierced. The sliding element (3) moves in the direction of the end (4a) in accordance with the amount of filling material that is currently being removed. No or no significant amount of "non-sterile" air penetrates into the removal container.

Fig. 2 shows a partially emptied state of the removal container on average. The reference numbers correspond to those in Fig. 1. The physical stabilization was checked, for example, using an insulin preparation with an acidic pH. For this purpose, a vibration test was used, an established method for the investigation of insulin aggregations after influence by physical stress (V. Feingold et.al., Diabetologia (1984), 27, 373-378).

In the test system used, the insulin preparation to be investigated is filled into a glass vessel with a volume of 2 ml (HPLC vial) once without and once with an air supernatant of 100 μl, in order to fill a full container with no air supernatant and the other time the air volume in a normal one Simulate multiple sampling bottle. The bottles are placed in a bottle holder and fixed to a specially designed vibration system and loaded at 37 ° C (thermal load), a frequency of 40Hz and a deflection of 20G (mechanical load). The vibration is generated by a kind of loudspeaker membrane, coupled to an amplifier with frequency and deflection controller. The period of time until which the preparation remains clear can be regarded as a measure of the physical stability of insulin preparations. B. by aggregation (V. Feingold et.al.). To measure turbidity, the vials are removed from the test system at different times and examined for the degree of turbidity.

Trial 1:

3 batches of an insulin preparation with an acidic pH were filled with 3 vials without air space and one with 100 μl air space and examined by means of a vibration test. While all vials in the 3 batches with air supernatant showed a clear turbidity after 24 hours, all vials in the 3 batches without air supernatant showed no turbidity even after 168 hours (after which the test was stopped) and were therefore stable.

In order to be able to better assess the temporal course of the turbidity of the batches, the time intervals of the measurements were shortened in a second experiment. Trial 2:

In experiment 2, 6 batches were examined. 5 of them were incubated with 100 μl of air supernatant and one batch without air supernatant. While the batches with an air supernatant showed an increasing turbidity within 3 hours, the preparation without an air supernatant is stable for at least 209 hours and showed no turbidity at all (the test was then stopped).

Both experiments prove that a multiple-use bottle without airspace has a stabilizing effect on protein, especially insulin preparations.

Trial 3

A further experiment was carried out to demonstrate the stability of the preparation with and without airspace during removal. It was shown that the simulated removal using a syringe from a multiple collection container can result in slight cloudiness if an air space is contained. The removal was simulated by daily piercing with a needle, without the filling material being removed. A comparative experiment with an insulin preparation of acidic pH with a 10 ml multiple sampling bottle with and without air space showed that a fine cloudiness was recognizable after approx. 23 days for the bottle with air space, while the bottle without air space showed no cloudiness even after 50 days showed (the test was then canceled).

These results clearly demonstrate that by using the removal container according to the invention, the stability of the preparation contained therein - in contrast to the known removal containers with air space - could be increased considerably.

Claims

claims:

1. Removal container containing a filling consisting of a) a hollow body, which b) is closed at one end by a sliding element and c) at the opposite end by a membrane attached to the hollow body, characterized in that the sliding element during the removal of the Filled material is displaced through the membrane solely by the air pressure acting on the sliding element.

2. Withdrawal container according to claim 1, wherein the hollow body has a round cross-sectional shape.

3. Removal container according to claim 1 or "2, wherein the hollow body consists of glass.

4. Removal container according to claims 1 to 3, wherein the hollow body is tapered at the membrane end.

5. Removal container according to claims 1 to 4, wherein the sliding element is a piston plug made of rubber.

6. Withdrawal container according to claims 1 to 5, wherein the membrane is made of rubber.

7. Removal container according to claims 1 to 6, wherein the membrane is attached to the hollow body by means of a crimp cap.

8. Withdrawal container according to claims 1 to 7 containing insulin and its analogs as filling.

9. A method for removing the filling material from a removal container according to claims 1 to 8, characterized in that the membrane with a removal system. punctures and transfers the contents into the removal system, with the sliding element automatically moving up according to the amount of contents removed.

10. The method according to claim 9, characterized in that the removal system is a syringe.