WO2012168268A1

WO2012168268A1 - Plunger stopper for a lyophilization unit

Info

Publication number: WO2012168268A1
Application number: PCT/EP2012/060640
Authority: WO
Inventors: Mark VAN ESSCHE; Ronny Prosper Elisabeth Vrijens
Original assignee: Helvoet Pharma Belgium N. V.
Priority date: 2011-06-10
Filing date: 2012-06-06
Publication date: 2012-12-13
Also published as: DE202011050413U1

Abstract

The invention relates to a plunger stopper (1, 101) for a lyophilization unit, with an upper side (2), and with an underside (3) lying opposite the upper side (2) in an axial direction. In order to further improve a plunger stopper in an advantageous manner, it is proposed that the plunger stopper (1) has, in the area of the underside (3), at least one recess (4) which is open to the outside and permits gas exchange during the lyophilization, which recess (4) is open at the bottom in the axial direction and is open in the radial direction.

Description

Piston stopper for a lyophilization unit

The invention relates to a piston stopper for a lyophilization unit. Lyophilization or lyophilization is used in the pharmaceutical sector to dry drugs that are not stable in dissolved form for a long time and thus to be able to store them until application. In a typical method, the solution of the drug is first placed in a container, e.g. a cartridge, and then freeze-dried, after which the container is sealed. Here, the typically cylindrical cartridge can be either closed by an end plug, or it is a piston plug - typically made of elastic material - used, which not only hermetically seals the cartridge, but is also displaceable within this.

For this purpose, a method is known in the prior art, in which the piston stopper is placed on the end of the cartridge, wherein during the lyophilization between the wall of the cartridge and plunger stopper remains a gap through which the solvent (typically water) can escape in a gaseous form. After drying is completed, the piston stopper is pressed into the cartridge so that it closes it.

In the context of the present application, a system comprising a container, such as a cartridge, within which a lyophilization is carried out, and at least one piston stopper, which is intended to close the container and be inserted into it after the lyophilization has been carried out, are used as lyophilization Unit designates. The object of the present invention is to propose measures with which a lyophilization can be carried out simply and safely and a subsequent closure of the container is made possible. The object is achieved by a piston stopper for a lyophilization unit according to claim 1. The stopper has an upper side and a lower side opposite to the upper side in an axial direction. The axial direction is in this case the direction in which the piston can be displaced within the container, this direction corresponds in many cases, for example when the container is a cylindrical cartridge, an axis of symmetry of Kolbenstop- fens. The underside is in this case the one side which faces the lyophilizate when the solution to be dried is placed on the stopper or after the drying has ended. These are also used in the following terms such as "below" and "above". According to the invention, the piston stopper in the region of the underside at least one outwardly continuously open recess for gas exchange during lyophilization, which is open in the axial direction downwards and in the radial direction. Such an outwardly continuously open recess may in particular represent a depression or depression. It always has a single, continuous opening. In the case of an approximately cylindrical plug, such an opening is accordingly open from the bottom of the cylinder to the cylinder jacket to the outside. The recess is used for gas exchange during lyophilization, ie when the piston stopper is placed in a drying position on the container, a gas exchange between the interior of the container and an outdoor area is possible through the recess. The embodiment according to the invention thus makes it possible to place the piston stopper on the container so that it is partially closed, at least one passage of defined size for gaseous solvent being formed by the at least one recess. According to one embodiment of the invention, the piston stopper on a plurality, preferably two to ten, more preferably four recesses for gas exchange. Such a plurality of recesses may preferably be arranged symmetrically with respect to an axis extending in the axial direction. In the case of a cylindrical container, the entire piston plug can be constructed rotationally symmetrical, whereby a corresponding symmetrical distribution of the recesses is predetermined. The dimension of the at least one recess allows the rate of sublimation to be controlled during lyophilization. Qualitatively, the sublimation speed is greater, the larger the recesses are. Advantageously, the proportion of the at least one recess on the cross-sectional area of the piston plug is altogether between 5% and 80%, preferably between 10% and 60%, particularly preferably between 15% and 30%. Said ratio can be determined by comparing the cross-sectional area perpendicular to the axial direction on the one hand directly above the recesses and on the other hand in the lowermost region of the recesses. Also advantageously, the at least one recess extends by 5% to 80%, preferably 10% to 60%, particularly preferably 30% to 50% of a maximum radius of the piston plug in the radial direction inwards. In cases where the piston plug does not have a circular cross section, this statement refers to half of the largest transverse dimension of the piston stopper instead of a maximum radius. The height of the at least one recess in the axial direction can be varied within a wide range. It is advantageously 5% to 80%, preferably 10% to 50%, particularly preferably 15% to 30% of the height of the piston stopper. In the following, the term "height" always refers to a dimension in the axial direction. In a particularly preferred embodiment, the piston stopper on four recesses, wherein the tangential extent of each recess between 5 ° and 80 °, preferably between 30 ° and 70 °, more preferably between 50 ° and 60 °.

In an advantageous development of the invention, the piston stopper has a preferably concave groove which is arranged above the at least one recess and rotates in the tangential direction. The lower edge of the groove is preferably between 20% and 60%, more preferably between 30% and 50%, particularly preferably between 40% and 50% of the total height of the piston stopper and its upper boundary is preferably between 50% and 90 ° %, more preferably between 70% and 90%, more preferably between 80% and 90% of the height of the piston stopper.

In order to ensure in a simple manner that the piston stopper is arranged in a defined position on the container during the drying process, the piston stopper advantageously has a tangential in the circumferential direction taper, through the upper edge of a bearing for the edge of a container of a lyophilization -Systems is defined. The upper edge preferably forms a shoulder here. In order to ensure optimum passage of gas through the recess, the taper extends starting from the bottom up to 5% to 95%, preferably 20% to 80%, particularly preferably 40% to 60% of the height of the at least one recess. In this case, the effective size of the opening for the passage of gas is preferably defined by the part of the recess which lies above the upper edge of the taper.

If the plunger stopper is pressed onto or into the container, there is a risk due to the lyophilization that it freezes on the tool provided for this purpose. This risk can be minimized if the piston at the top has an upper end surface, which has at least one rib member, wherein the total surface area of the rib members preferably between 0.5% and 20%, more preferably between 1% and 10%, particularly preferably between 1.5% and 5% of Face is. As rib elements, in this context, raised structures on the upper end face are referred to, which, for example, may be rounded or pointed upwards, and which may be elongate straight or curved, but also point-like. In a further development of the invention, the piston stopper is designed to receive a piston rod. For this purpose, it has an outgoing from the bottom, extending in the axial direction recess for a piston rod whose height is 20% to 90%, preferably 40% to 85%, particularly preferably 60% to 80% of the height of the piston stopper.

With regard to the disclosure, the ranges and ranges of values given above and below also include all intermediate values, in particular in 1/10 increments of the respective dimension, if appropriate also without dimension, that is to say, for example, 1/10 μιτι, mm, kg or m ³ on the one hand to delineate the abovementioned area boundaries from below and / or above, alternatively or additionally, but also with regard to the disclosure of one or more singular values from a respectively specified area.

Details of the invention are explained below with reference to Ausführungsbeispie- len with reference to the figures. Hereby shows:

1 is a perspective view of a first embodiment of a piston plug according to the invention obliquely from above. FIG. 2 is a side view of the piston plug of FIG. 1; FIG. Fig. 3 is a plan view of the piston stopper of Fig. 1;

Fig. 4 is a side sectional view taken along the line IV - IV in Fig. 3;

Fig. 5 is a side sectional view taken along the line V - V in Fig. 3;

Fig. 6 is a bottom view of the piston stopper of Figures 1 to 5.

7 is a perspective view of a second embodiment of a piston plug according to the invention obliquely from above;

Fig. 8 is a plan view of the piston plug of Fig. 7;

9 is a side sectional view along the line IX - IX in Fig. 8 and

10 is a perspective view of the piston stopper of FIGS. 7 to 9 obliquely from below.

Furthermore show:

FIGS. 11-17 are photorealistic representations of the piston stopper from FIG. 1

Fig. 18 - 24 line drawings of the piston stopper of Fig. 1;

25 - 31 photo-realistic representations of the piston stopper from FIG. 7

32-38 line drawings of the piston stopper of Fig. 7. The figures 11-38 will not be referred to hereinafter.

FIGS. 1 to 6 show a first embodiment of a piston stopper 1 according to the invention. In order to ensure a sufficient elasticity of the stopper 1, this stopper is made of rubber or a thermoplastic elastomer, in particular halobutyl elastomers being suitable. The piston plug 1 is intended for use with a cylindrical cartridge (not shown) and therefore has a roughly cylindrical shape. In this case, it is symmetrical with respect to an axis of symmetry Z extending along an axial direction along which the piston stopper 1 is displaceable within the cartridge.

On an upper side 2 of the piston stopper 1, this has a substantially flat, circular end face 8, on which four elongated rib elements 9 are formed, which are each offset with respect to. The symmetry axis Z offset by 90 °. While the diameter of the piston stopper 1 shown in the region of the end face 8 is 10 mm and its height from the top 2 to the opposite bottom 3 is 11 mm, the rib elements only have a length of 3 mm and a width of 0.5 mm and a height of 0.25 mm. Therefore, when the plunger stopper 1 is pressed onto the cartridge by means of a tool during the lyophilization process, the rib members 9 provide only a very small contact surface, thereby minimizing the risk of freezing. In the region of the underside 3, the piston stopper 1 four recesses 4, which, as is apparent in particular from the bottom view in Fig. 6, symmetrically with respect. The symmetry axis Z are arranged. The shape of the recesses 4 is substantially concave and their lower boundary is circular arc-like, as shown in FIG. 6 can be seen. The recesses extend in the radial direction from the outside 2 mm inwards and their height is in axial Direction 2.5 mm. In the lower region of the recesses 4, the piston stopper 1 also has a taper 6. In this area, its wall is tapered by 0.2 mm. The upper edge 7 of the taper 6 is when placing the piston stopper 1 on the cartridge at its upper edge, which is why a further slipping of the piston stopper 1 without further effort is not possible. In this way, the piston stopper 1 is held in a defined position. As a result, the portion of the recesses 4 located below the edge 7 is shielded by the wall of the cartridge to the outside and only the part above it allows a passage of gas to the outside. Here, the number, shape and size of the recesses 4 and the position of the edge 7 are selected such that there is a specific passage for gases, which in turn results in a certain desired sublimation. Above the recesses 4 closes, as can be seen, for example, from Fig. 2, an approximately cylindrical, slightly tapering down to the area. Above this in turn, the piston stopper 1 has a circumferential groove 5, at the narrowest region of which a diameter of 9.2 mm is present.

In Fig. 7 to 10, another embodiment of a fiction, contemporary piston stopper is shown. This piston plug 101 is substantially similar to the just described plug 1, but also has a recess 10 for a piston rod. This recess 10 is arranged centrally and extends in the axial direction. It extends from an opening at the bottom 3 to a height of 8 mm, wherein it is approximately cylindrical, but tapers from bottom to top of 3.5 mm to 3 mm in diameter.

All disclosed features are essential to the invention. The disclosure of the associated / attached priority documents (copy of the prior application) is hereby also incorporated in full in the disclosure of the application, also for the purpose of defining features of these documents in US Pat Claims of the present application to include. The subclaims characterize in their optional sibling version independent inventive development of the prior art, in particular to make on the basis of these claims divisional applications.

Claims

A piston stopper (1, 101) for a lyophilization unit, having an upper side (2) and a lower side (3) facing the upper side (2) in an axial direction, characterized in that the piston stopper (1) in Area of the bottom (3) has at least one outwardly continuously open recess (4) for gas exchange during lyophilization, which is open in the axial direction downwards and in the radial direction.

2. Piston stopper according to claim 1, characterized by a plurality, preferably two to ten, particularly preferably four recesses (4) according to claim 1.

3. Piston stopper according to claim 2, characterized in that the recesses (4) are arranged symmetrically with respect to an axis extending in the axial direction (Z).

4. Piston stopper according to claim 1, characterized in that the proportion of at least one recess (4) on the cross-sectional area of the piston stopper (1, 101) in total between 5% and 80%, preferably between 10% and 60%, particularly preferably between 15 % and 30%.

5. Piston stopper according to claim 1, characterized in that the at least one recess (4) by 5% to 80%, preferably 10% to 60%, particularly preferably 30% to 50% of a maximum radius of the piston stopper (1, 101) in extends radially inward.

6. Piston stopper according to claim 1, characterized in that the height of the at least one recess (4) in the axial direction 5% to 80%, Preferably 10% to 50%, more preferably 15% to 30% of the height of the piston stopper (1, 101).

Piston stopper according to claim 2, characterized by four recesses (4), wherein the tangential extent of each recess (4) between 5 ° and 80 °, preferably between 30 ° and 70 °, more preferably between 50 ° and 60 °.

Piston stopper according to claim 1, characterized by a preferably concave groove (5), which is arranged above the at least one recess (4) and rotates in a tangential direction, the lower boundary of which is preferably between 20% and 60%, more preferably between 30% and 50%. , more preferably between 40% and 50% of the total height of the piston plug (1), and whose upper boundary is preferably between 50% and 90%, more preferably between 70% and 90%, most preferably between 80% and 90% of the height of the piston stopper (1, 101) is located.

Piston stopper according to claim 1, characterized by a tapering in tangential direction taper (6), through the upper edge (7) a bearing for the edge of a container of a lyophilization system is defined, and extending from the bottom (3) up to 5% to 95%, preferably 20% to 80%, particularly preferably 40% to 60% of the height of the at least one recess (4).

Piston stopper according to claim 1, characterized by an upper end face (8) located on the upper side (2) and comprising at least one rib element (9), wherein the total area of the rib elements (9) is preferably between 0.5% and 20%, more preferably between 1% and 10%, more preferably between 1.5% and 5% of the end face (8). Piston stopper according to claim 1, characterized by an opening (10) extending from the underside (3) and extending in the axial direction for a piston rod whose height is 20% to 90%, preferably 40% to 85%, particularly preferably 60% to 80 % of the height of the piston stopper (101).