WO1998017339A1

WO1998017339A1 - Syringe with a polyethylene stopper

Info

Publication number: WO1998017339A1
Application number: PCT/DE1997/002514
Authority: WO
Inventors: Reiner Kolberg; Ralf-Siegbert Hauck
Original assignee: Schering Aktiengesellschaft
Priority date: 1996-10-18
Filing date: 1997-10-17
Publication date: 1998-04-30
Also published as: CA2268655A1; KR100484458B1; EP0935476A1; KR20000049267A; WO1998017338A1; AU6810998A; AU5306198A; JP2001502568A

Abstract

The invention relates to a medical syringe with an inserted stopper (101). The syringe has the following features: a) the syringe comprises a cylinder with a proximal end and a distal end, and an outlet b) the syringe contains a medicament or a diagnostic agent c) the surfaces of the stopper (101) in contact with the inner wall (107) of the syringe cylinder are made of polytetrafluorethylene d) the surfaces of the stopper (101) in contact with the inner wall (107) of the syringe cylinder fit closely against the material of said wall e) the stopper has at least one sealing lip (108 and 109) and the resulting mass of the sealing lip forms a sharp angle with the syringe axis in distal direction. The syringe is intended to accommodate medicaments and diagnostic agents.

Description

Syringe with syringe stopper made of polyethylene

Introduction The invention relates to a medical syringe for receiving a medium or for use and a method for the terminal sterilization of these filled syringes. These syringes are preferably provided for the use of injectable diagnostics, in particular contrast media, which are injected, for example, into blood vessels, organs, organ parts, cavities and other vessels or which have an imaging effect there.

State of the art

Teflon stopper: German patent DE 3346 351, published on April 9, 1992, describes a stopper which is at least partially provided with a Teflon coating. Such a stopper touches the

Inner wall of the cylinder with beads which exert a specific pressure on the inner wall of the cylinder, which is to ensure the sealing effect. The beads are designed so that the perpendicular of the bead surface pointing away from the stopper points towards the wall of the syringe cylinder. The patent uses Teflon to create a protective surface between the medium and the rubber part of the plug. In this case it is only an insulating function, the excellent sliding properties of Teflon have not been taken into account. The term siliconizing was not mentioned in this publication. It can therefore be assumed that in this case the specialist will read this text in such a way that it is a syringe that otherwise corresponds to general technical knowledge (e.g. DIN standard 13 098, part 1, point 4.4), which is also on the inside of the Cylinder is siliconized.

Sealing lips:

DE-GM 19 73 042 dated November 23, 1967 describes a plastic syringe made of synthetic resin, which consists of a plastic cylinder with a needle opening and stopper opening, a stopper and a stamp. The essential feature of the syringe is a bowl-shaped or cup-shaped stopper, which consists of commercially available material. Such a sealing lip is only possible in combination with a lubricant, especially with silicone oil. If silicone is not present, the sealing lips would change due to the high friction and they would turn away from the force. The term siliconizing has not been mentioned in this publication either. It can therefore be assumed here that the specialist reads this text to the extent that it is a syringe that otherwise corresponds to general technical knowledge (eg DIN standard 13 098, part 1, item 4.4) and also siliconizes the inside of the cylinder is.

Siliconize:

A filled, terminal-sterilized syringe is described in the patent specification AT-E 68 979. The syringe is made of plastic. The syringe has a cylinder with a distal end with a syringe outlet. The syringe outlet piece is sealed by a closure. Before filling, the inner wall of the syringe is coated with silicone oil. After filling, the syringe is closed with a flexible rubber stopper, which is also slidable in the cylinder because of the silicone oil. The process of making a filled, terminally sterilized syringe begins with removing debris or other contaminants from the closure and plunger. Microbial contaminants on the cap and piston are destroyed. The cylinder is washed with a variety of water jets to remove pyrogens and waste particles. Then silicone oil is applied to the inner wall of the syringe. The closure is then placed on the syringe outlet piece. The contrast medium is filled into the syringe through the proximal end of the syringe. The syringe is then closed with the stopper. This assembled and filled syringe is sterilized in an autoclave. In addition to the usual autoclave pressure, an additional support pressure is generated in the autoclave.

From the publication by Venten and Hoppert (E. VENTEN and J. HOPPERT (1978) Pharm. Ind. Vol. 40, No. 6, pages 665 to 671), prefilled, terminally sterilized spray ampoules are known, which have a silicone oil layer on the inner wall are provided. The spray ampoules, which have a stopper at the proximal end, are filled distally through the rolled rim. The rolled edge is then sealed by a sealing washer, with a crimp cap fixing the sealing washer on the rolled edge. (M. JUNGA (1973) Pharm. Ind. Vol. 35, No. 11a, pages 824 to 829) The pre-filled Spray ampoules are then transferred to an autoclave. This autoclave can be regulated in terms of temperature and pressure.

European patent application EP 0 553 926 (January 26, 1993) describes a method for terminally sterilizing a prefilled plastic syringe or glass syringe, the syringe containing a contrast agent. The inside wall of the disposable syringes is coated with silicone oil. The syringe consists of a syringe barrel that has a syringe outlet at the distal end. Disposable injection ampoules in the form previously described by Venten and Hoppert are also listed. The disposable syringes have an open proximal end which can be closed by a stopper which can slide in the disposable syringe. The stopper is connected with a stamp.

WO 95/12482 describes a method for producing prefilled plastic syringes that are filled with a contrast agent. The inside wall of the syringe is coated with silicone oil. The syringes consist of a cylinder, a syringe outlet piece at the distal end, which is prepared for a cannula hub. The syringe further includes a stopper that can slide in the barrel. It seals the proximal end of the syringe. The syringe is made using a process that results in pyrogen-free objects. There are also no more particles. The syringe is filled through the proximal end, the syringe outlet piece being sealed with a closure. The filled syringe is closed with the stopper.

After the syringe parts come out of the mold, they are blown off with gas to remove particles. The syringe is then washed and lubricated. The syringe is then sterilized so that the syringe can optionally be processed, stored or transported.

disadvantage

A disadvantage of the known syringes is that silicone oil must be used to reduce the friction between the stopper and the inner wall of the syringe. As useful as rubber stoppers are with regard to elastic forces, behavior with regard to sliding friction is problematic. Especially the static friction is even worse. When the syringe is stored for a long time with the plug inserted, static friction plays a very important role. Furthermore, the cold flow behavior of rubber stoppers must always be taken into account. Since this is a not negligible size, rubber plugs with a considerable preload must be used. The friction is so great in all cases that the syringes cannot be handled without silicone oil.

Even if rubber sealing lips are used, these are not sufficiently tight in the static state or suffer from the cold flow behavior. In this case too, considerable preload must be used, so that silicone oil is also indispensable in this case. A solid plug made of Teflon has a considerable disadvantage with syringes that are exposed to thermal stress. Here, temperature fluctuations from -10 ° C to + 40 ° C are sufficient to allow the plastic of the syringe wall to expand compared to the very strong Teflon material. These are usual temperature fluctuations. In this case too, the cold flow behavior has a negative impact. In order to make the stopper tight, a high preload is necessary due to the low elastic behavior of the solid Teflon stopper, which results in high friction. Such a Teflon stopper should not be used with plastic syringes because the cold flow behavior of the plastic syringe wall increases the inside diameter of the syringe at the level of the stopper. This creates gaps through which liquid can escape from the syringe in an uncontrolled manner. Air can also be sucked in in an uncontrolled manner. Glass syringes that do not show such a cold flow behavior must nevertheless be coated with silicone oil on the inner wall in order to reduce friction, which is caused by the very high preload.

task

It is therefore the task of offering a medical syringe in which the addition of a lubricant in the form of, for example, silicone oil is dispensed with, without the sliding capacity of the stopper, which is to be made of plastic, being impaired in the syringe and at the same time sufficient sealing of the contents of the syringe is ensured by the stopper in relation to the outer area of the syringe. Solution of the task

The object is achieved by a medical syringe with an inserted stopper, the syringe comprising the following features: a) the syringe

(i) a cylinder with an inner cylinder wall, (ii) a proximal end, (iii) a distal end, and (iv) an outlet, b) the syringe is prepared for receiving a medium, c) at least the surfaces of the stopper, which contact the inner wall of the syringe are made of polytetrafluoroethylene or of substituted polyethylene or polypropylene, the hydrogen atoms of the polyethylene or

Polypropylene are at least partially substituted by fluorine atoms, d) the surface of the stopper, which contacts the inner wall of the syringe, is in direct contact with the material of the inner wall of the cylinder, e) the stopper has at least one sealing lip, which lies tightly against the inner wall of the syringe, f) at least the distal or proximal surface or mass resultant of the sealing lip forms an angle with the axis of the syringe that is smaller than a right angle, or f) the elastic forces that press the sealing lip against the inner wall of the cylinder are caused by a region of the sealing lip which area lies outside the perpendicular to the inner wall of the cylinder, the vertical running through the contact area between the sealing lip and the inner wall of the cylinder, or f ") the elastic forces which the sealing lip bears against

Press inner cylinder wall, in the static state of the Plug caused by a range of elasticity, which has a tensile zone next to a compression zone.

The points _> f); f); and f ^" ) are alternative descriptions of one and the same technical solution principle. The description of f) is more preferred, the description by the point f ^" ) is most preferred.

More specific embodiment:

Preferred is a more specific embodiment of a medical syringe made of glass and / or plastic with an inserted stopper, with the following features: a) the syringe comprises

(i) a cylinder with a cylinder inner wall, (ii) a proximal end which can be closed by the stopper, (iii) a distal end which is closed by a cylinder cover, and (iv) an outlet which connects the cylinder cover or the cylinder inner wall penetrates, b) the syringe is prepared for receiving a medium or for use, c) at least the surfaces of the stopper which contact the inner wall of the syringe are made of polytetrafluoroethylene or of substituted polyethylene or

Polypropylene, the hydrogen atoms of the polyethylene or polypropylene being at least partially substituted by fluorine atoms, d) the area of the stopper which covers the inner wall of the cylinder

Contact the syringe, the material of the inner wall of the cylinder lies directly in the area of the cylinder jacket, e) the stopper has at least one annular sealing lip, which lies tightly against the inner wall of the syringe, so that when the stopper moves in the distal direction, none

Medium can slide past the sealing lip, unless the inner wall has a bulge to the outside, f) at least the distal or proximal surface or mass resultant of the sealing lip forms an angle with the axis of the syringe, which is smaller than a right angle, or f) the elastic forces that press the sealing lip against the inner wall of the cylinder become through an area caused by the sealing lip, which area lies outside the perpendicular to the inner wall of the cylinder, the perpendicular running through the contact area between the sealing lip and the inner wall of the cylinder, or f ^" ) the elastic forces which the sealing lip acts against

Pressing the inner wall of the cylinder, in the static state of the plug, is caused by an elastic region which has a tensile zone next to a compression zone. .

Minimize the lubricant

The delivery is also achieved by a medical syringe with an inserted stopper, the syringe comprising the following features: a) the syringe comprises (i) a cylinder with a cylinder inner wall,

(ii) a proximal end, (iii) a distal end, and (iv) an outlet, b) the syringe is prepared to receive a medium, c) at least the surfaces of the stopper that the

Contact the inner wall of the syringe is off

Polytetrafluoroethylene or from substituted polyethylene or polypropylene, the hydrogen atoms of the polyethylene or polypropylene being at least partially substituted by fluorine atoms, d) there is no lubricant between the surface of the stopper which contacts the inner wall of the syringe and the inner wall of the cylinder, or

- a lubricant of at most a thickness which, when the stopper in the syringe is moved in practice, no longer permits satisfactory sliding friction and static friction which would occur if rubber stoppers were used, or

- A lubricant of a thickness which does not allow the stopper to move in the syringe under normal conditions of use if the stopper were made of rubber, e) the stopper has at least one sealing lip which lies tightly against the inner wall of the syringe, f) at least that towards the distal or proximal surface or mass resultant of the sealing lip forms an angle with the axis of the syringe that is smaller than a right angle, or f) the elastic forces that press the sealing lip against the inner wall of the cylinder are caused by a region of the sealing lip, which area lies outside the perpendicular to the inner wall of the cylinder, the perpendicular running through the contact area between the sealing lip and the inner wall of the cylinder, or f ") the elastic forces which press the sealing lip against the inner wall of the cylinder are caused in the static state of the stopper by an elastic region which is a Has tension zone next to a compression zone. , benefits

No lubricant:

The direct contact of the stopper on the inner wall of the syringe means that lubricants can be dispensed with. Lubricants can be greases, silicone oil or fine granules. A disadvantage of all these lubricants is that they can interact with the medium in the syringe. This is particularly important if the medium is in direct contact with the lubricant for a long period of time. It is customary here, based on the prior art, to apply the lubricant to the inner wall of the syringe, which results in a large area which is in contact with the medium.

Improvement of the solid stopper without sealing lip: The stoppers in DE 33 46 351 are not to be used if the syringe is autoclaved in a pre-filled form or is subjected to a thermal load. In such a situation, the material always expands because the plastics of the syringe barrel or stopper have flow properties at elevated temperatures. As a result, the plastic material is permanently and permanently deformed, at least on the stopper, sometimes also on the syringe. Teflon in the form of the coating is also one of the substances that are changed as a result of the thermal effect during autoclaving. Because of the excess that the stopper must have, expansion occurs during the autoclaving cycle or the thermal load, which leads to permanent damage to the stopper due to the flow behavior of the stopper. This leads to leaks in many cases, be it that material escapes from the prefilled syringe or that air may penetrate into the syringe from the outside. In both cases it is a question of contamination, which is not desirable. In the latter case, the ingress of air is possible. This can result in contamination of the syringe contents, which is extremely dangerous for the patient. Based on tests that we have carried out in-house, it has been found that solid plugs, which either consist of Teflon or are coated with Teflon, cannot be used for syringes that are autoclaved in the pre-filled state or exposed to thermal loads. Tests have also shown that syringes which are not prefilled as disposable syringes are also Problems arise.

Material polytetrafluoroethylene and fluorine-substituted polyethylene or polypropylene: The choice of the material of the stopper is restricted. Polytetrafluoroethylene and its modifications are particularly suitable because the temperature resistance is very high. Autoclaving the stoppers according to the invention is possible without any problems. The plugs are stable, they have a cold flow behavior, which is practically negligible in the requirements. This means that the plugs have a long shelf life even when they come into direct contact with the syringe body. The sealing function of the plug is not affected. The plugs are compatible with humans, polytetrafluoroethylene has an approval with the US health authority (FDA). The resilience of polytetrafluoroethylene is respectable, which also has a positive effect on the shelf life. Polytetrafluoroethylene shows good sliding properties, which means that the forces acting on the syringe inner wall can be relatively large without negatively influencing the movement of the stopper in the distal or proximal direction. The cold flow behavior of the material is desirably small, so that this aspect also has a beneficial effect on the shelf life.

The forces which are exerted on the inner wall of the cylinder by the stopper according to the invention are significantly lower than the forces which occur with other conventional elastomers. This is possible due to the material used and the design of the sealing lips. However, shaping the sealing lips according to the prior art alone is not sufficient to achieve such an effect. Only when lubricants are added to the inside wall of the syringe or on the outside of the stopper can such good proportions arise between the forces in the longitudinal direction of the cylinder and the forces in the direction of the inner wall of the cylinder. A syringe according to the invention is advantageous in which the sealing lip points in the direction of the distal end and has a surface facing the axis of the syringe, which transmits the force which is generated by the internal pressure of the syringe (when using or during autoclaving) in the direction of the inner wall.

Unsatisfactory sealing lips made of rubber:

A syringe according to DE-GM 19 73 042 dated November 23, 1967 is not autoclaved in pre-filled form. It is possible during the heating and sterilization phase that the cup-shaped stopper is displaced in the proximal direction due to the internal pressure. The sealing function is guaranteed at this moment. In the course of cooling, the liquid and above all the residual gas in the syringe contract again, which creates a negative pressure in relation to the surrounding atmosphere. This causes suction to be applied to the stopper. Even with a siliconized inner wall, it leads to such a syringe drawing air laterally at the sealing lips. Such an effect is even more unavoidable if silicone oil is not used. If no lubricant is used, the protuberances of the cup-shaped stopper fold over during distal movement, since the friction between the stopper and the inner wall of the cylinder is so great that the protuberances evade due to the elasticity.

Even small amounts of lubricants have the effect according to the invention:

A simple circumvention of the invention, if the wording of the claims is limited to the omission of a lubricant, would be to reduce the amount of the lubricant so that it would no longer be sufficient for a rubber stopper. Since no lubricant is required for the teflon stopper or stopper made from derivatives of teflon, a small amount of lubricant would be one way of offering a deteriorating embodiment. Since the harmfulness of all substances depends on the concentration, an amount of lubricant can be conveniently selected which is no longer physiologically noteworthy and which is at the same time not sufficient for a rubber stopper, but which would of course be usable in connection with a Teflon stopper. Synergism of Teflon and sealing lips:

The combination of the material and the specifically shaped sealing lips ensures that otherwise problematic syringes, which are autoclaved, for example, in the pre-filled state, can be manufactured and stored without failures.

We have the interplay of three different parameters. Firstly, there is the material. Here, Teflon or its derivatives is particularly advantageous due to its inert behavior towards medication. Teflon also has a low coefficient of friction. However, if you follow the technical teachings from the state of the art and you manufacture plugs with a conventional shape from Teflon, a satisfactory result cannot be achieved. Leaks and unwanted liquid or air intake can be observed as a disadvantage.

Therefore the second aspect is also important. The shape of the sealing lip must be designed so that due to the cold flow behavior and the resulting elasticity, the sealing lips are pressed sufficiently against the inner wall of the syringe. Here, especially with prefilled, sterilized syringes, the static tightness is of particular importance. Long storage and thermal treatment must not lead to leaks. Due to the special shape of the sealing lips in the special selection of the material, it is ensured that the stopper is sufficiently sealed. This is not just a one-way seal that occurs when the syringe is squeezed out, for example, but it also ensures tightness when it is sucked up. This is particularly important if the stopper moves during autoclaving or when absorbing liquid. When autoclaving, the stopper follows a force parallelogram, which is composed of the internal pressure of the syringe and the external pressure in the autoclave. In order to avoid excessive pressures in the syringe, the stopper migrates to the outside during the heating and sterilization phase. However, the opposite direction of migration can be observed during the cooling phase. A comparable behavior occurs when suctioning liquids. The third further essential aspect is the lack of coating with silicone oil. The use of lubricants is generally customary in previously known plastic syringes. This is evident from the DIN standards (for example DIN standard 13 098). Only the old glass syringes with a metal stopper were not siliconized. Definitions

Direction of the sealing lips: The sealing lips usually have an essentially triangular cross section. The base points to the center of the stopper, the two legs meet in the tip of the sealing lip. The surfaces of the sealing lips can be curved in a straight line or angled. It is preferred if the sealing lips are designed to be significantly wider in the base than in their tips. This leads to the fact that the seal is particularly successful without having to make a large expenditure of material. This basis is called the sealing lip attachment point.

It is also possible to arrange a reinforcement instead of the tapered sealing lip at its end, which has the effect that the tip of the sealing lip is also pressed against the inner wall of the cylinder. This reinforcement thus has the function of creating a further range of elasticity. It is also possible to produce the reinforcement from another elastic material, such as a highly elastic rubber, which can be supported at the center of the stopper and on the inside of the sealing lip presses the sealing lip against the inner wall of the cylinder.

It is desirable to have a sealing lip which is relatively long and which has a relatively flat angle with respect to the axis of the stopper. This fulfills two functions. On the one hand, dynamic behavior means that the sealing lip is pressed against the inner wall of the cylinder because of the pressure in the syringe. Furthermore, a sensible compromise between elasticity and plasticity has been made in the static system. This is particularly important when additional loads such as autoclaving, thermal stress (temperature during normal storage), pressure and solar radiation stress the material with regard to plasticity.

Another characterization of the direction of the sealing lips can be given with the help of the mass results. If the cross section of the sealing lip is considered, a line can be drawn from the base of the sealing lip, which is inserted on the stopper (sealing lip attachment point) and the tip of the sealing lip, which lies in the center of the two sides. With respect to a triangle, one would speak of the bisector in such a case. The angle that lies in the tip of the sealing lip is halved. The line described above has an acute angle with the axis of the Syringe on, the function of the sealing lip is guaranteed. An integral behavior of the "bisector" or "bisector" is also conceivable. For example, the surfaces of the sealing lip can be curved or indented, they can have protuberances or notches, and they can be hammer-shaped or ax-shaped at the tip. It is essential to compare the resultants of the forces that occur on the sealing lip when pressure is applied in the distal direction. These resulting forces are easy to determine, regardless of the shape of the sealing lip. The distal direction is the preferred direction of the sealing lips, but proximal alignment is also possible. Such a proximally oriented sealing lip will certainly fulfill the sealing function to a certain extent.

Range of elasticity:

It is essential that the sealing lip presses onto the inner wall of the cylinder with a force that is perpendicular to it. Unlike the beads of the prior art, this force is obtained from elastic forces which are caused by a deformable area which is not perpendicular to the inner wall of the cylinder, which lies through the contact area between the sealing lip and the inner wall of the cylinder.

Tensile zone and compression zone:

The sealing lips are pressed against the inner wall of the syringe under a prestress. This requires a force that is caused by an elastic zone of the sealing lip. This zone of elasticity absorbs both tensile and shear forces. Relative to the length of the sealing lip, a laterally acting force is applied to the inner wall of the cylinder. It is essential that the

Plug behaves statically. In such a case, only a compression of beads or thickenings that press against the inner wall of the cylinder is known from the prior art. Only when the stopper is moved in the prior art will a shear force continue to be exerted on the beads, which also creates a pull zone with these stoppers. It is therefore important that the tensile and shear forces run approximately parallel to the axis of the syringe. When the stopper moves, whether new or old, the shear force continues to exert tensile and shear forces that are approximately perpendicular to the axis of the syringe. Plug materials:

The substance polytetrafluoroethylene is the substance known as Teflon. Teflon has remarkable properties, so there is only a slight weight loss above 300 ° C, only above 400 ° C does Teflon decompose. The Teflon has a low coefficient of friction of 0.3 on average, the coefficient of static friction is 0.05 to 0.1 higher. The pressure and the sliding speed are irrelevant. It is particularly advantageous that even after a long period of storage there are no high "breakaway and starting torques" compared to other elastomers. Parts made from Teflon are physiologically harmless. In animal feeding trials, no harmful effects have been observed when taking Teflon. Teflon complies with the FDA regulations on food contact. Teflon is, the term syringe comprises the terms cartridge (large-volume syringe with at least 100 ml volume), ampoule syringes, disposable syringes, disposable injection ampoules, disposable injection ampoules, disposable syringes, injection ampoules, disposable injection ampoules, RTS ampoule, cartridge, dual-chamber injection cartridge, two-chamber syringe, dual-chamber injection cartridge, Two-chamber syringe and immediate syringe.

Lubricant:

Lubricants are used so that the plug can be moved within the cylinder without great effort. Preferred is silicone oil, which has the following properties: viscosity at least 1000 cSt for plastic syringes and 300 - 400 cSt for glass (baked-on siliconization); Quality: medical grade.

The step of siliconizing is not explicitly mentioned in property rights and technical, scientific publications. However, it is wrong to conclude that this step has been dispensed with. Rather, siliconizing is an obligatory step without which the syringe application and therefore the syringe production cannot exist.

All publications are therefore to be read under the aspect of general specialist knowledge. It should be noted that the siliconization step is always read as a mandatory procedure. That it goes without saying is specified in DIN standard 13 098, part 1 under point 4.4. clear. Attention is drawn to the inevitable siliconization of disposable syringes. The standard is not mandatory for prefilled single-use syringes, but it can also can be used because there is no other standard opposing this DIN standard 13 098.

Material of the stopper and syringe: plastics are described in detail in Römpps - Chemie - Lexikon, editors Jürgen FALBE and Manfred REGITZ, 9th edition, Stuttgart, 1990 on pages 2398 ff. COC, PP and polymethylpentene are preferred. [COC = cycloolefin copolymer with the brand names CZ (manufacturer: Nihon Zeon) and TOPAS (manufacturer: Mitsui Chemicals and Hoechst)]. These plastics are particularly suitable for use with pre-filled, terminally sterilized syringes because their high melting point (at least 130 ° C) allows steam sterilization (standard procedure 121 ° C). In addition, the optical properties are sufficient for a 100% visual inspection in accordance with the medicinal product.

Shape of the plug:

A syringe is advantageous in which the stopper is guided so that the axis of the stopper substantially coincides with the axis of the syringe. A guide can be achieved by guide ribs or guide sliding surfaces on the stopper. The purpose of these parts is to prevent the stopper from tilting and to ensure that the stopper is oriented in such a way that the axis of the stopper and the axis of the syringe can differ only slightly. It is also possible for the stopper to be fastened with a stamp which is itself guided or which has a guide in which the stamp is movable. However, both axis (piston and

Syringe barrel) up to 10 °, preferably 5 °, more preferably 3 °, without problems

Syringes:

Glass syringes and plastic syringes are described in detail in the publication by Junga (M. JUNGA (1973) Pharm. Ind. Vol. 35, No. 11a, pages 824 to 829). A mixture of glass and plastic is shown in WO 96/00098 (filing date June 23, 1995). extremely hydrophobic and almost completely repels water. This ensures that there is no interaction between the medium and the stopper. Due to the thickness of the plug, the diffusion of Gases from outside to inside and from the medium from inside to outside negligible.

As a variant, the polyethylene is at least partially substituted. The hydrogen atoms are at least partially replaced by fluorine atoms. It can be polytetrafluoroethylene or a derivative thereof, in which not all hydrogen atoms are substituted.

Shape of the syringes:

The syringes are usually rotationally symmetrical, only the finger holders and device holders and sometimes also the syringe outlet piece deviate from the symmetry. So the syringe outlet piece can be arranged eccentrically. The Luer lock is particularly preferred since it is only used when contrast agents are applied when mechanical pumping devices are used. Even with manual application, the Luer Lock and the tubing connected to it prevent unintentional movements of the doctor from being transmitted directly to the cannula. The simple Luer approach and the record approach are also known.

It is also possible to weld the syringe outlet piece and thereby seal it. It is then advantageous that a syringe outlet piece has a predetermined breaking point, which allows the syringe outlet piece to be opened easily before use.

Syringe outlet: The proximal and distal ends of the syringe must be closable. The distal end is sealed by a closure which can be placed on the syringe outlet piece. In this protective right, the syringe outlet piece covers the ceiling of the syringe barrel. The syringe outlet piece further comprises a tube leading to the needle or the hose, an end piece which is in contact with the needle or the hose and a threaded cylinder on the inside, the cylinder surrounding the end piece and a thread for for example wearing a Luer lock. The syringe outlet piece can be in one piece or in several pieces. The ceiling can be arched, flat or pyramid-shaped. Mixed forms are also conceivable. The stopper closes the proximal end of the syringe. It must be slidable in the cylinder and must safely keep the medium out of the environment. It should be as little permeable to gases and liquids as possible. Temperature fluctuations must also be absorbed without malfunction his. The stopper is usually not provided with its own stamp when the syringes are mechanically emptied. Rather, a stamp, which is part of the pumping device, engages in a closure inside the stopper, so that movement of the stopper is possible without any problems. (see EP 0 584 531)

Proximal and distal:

The terms proximal and distal are defined from the point of view of the patient

Doctor. At the distal end is the syringe outlet piece, to which, for example, the cannula or a hose leading to a cannula is connected. At the proximal end is the stopper that pushes the medium through the distal end during application. The plug can be moved manually or mechanically. The term stopper also includes pistons. For the manual actuation of the syringe, it is helpful for the operating personnel if the syringe has finger holders at the proximal end. The finger holders usually have at least one surface as an abutment for the index finger and middle finger, the surface of the finger holder being essentially perpendicular to the axis of the syringe barrel. Various models are known for mechanical pumping devices. A syringe then preferably carries one or more device holders at the preferably proximal end. Such a mechanical pump is described particularly well in EP 0 584 531 (Reilly et al. Filing date July 21, 1993). Mixed forms of finger holder and device holder are also possible.

Medium:

The medium in the filled syringe is a mixture of a fluid medium and at least one gas. The gas volume should be as small as possible, a gas volume that has the value zero is desirable. The medium can be a liquid, a solution, a suspension or an emulsion. These manifestations are in W. SCHRÖTER et al., (1987) Chemie; Facts and Laws, 14th edition, Leipzig on pages 23 and following.

A fluid medium which is a contrast medium is preferred. These are the following contrast agents with the generic names: amidotrizoic acid, gadopentetic acid, gadobutrol, gadolinium EOB-DTPA, lopamidide, lopromide, lotrolan and lotroxinic acid. Dynamic pressure boosting

The syringe according to the invention is very preferred, in which at least one surface or the mass resultant of the sealing lip points distally. In this way, corresponding pressures can be built up, since when the sealing lips behave dynamically, the contact pressure is increased by the pressure increase in the lumen of the syringe.

The sealing lip is preferably ring-shaped.

A medical syringe according to the invention is preferred in which the sealing lip is pressed against the inner wall of the syringe in a sealing manner under pressure in the distal direction.

A medical syringe is more preferred, in which the sealing lip is pressed sealingly against the inner wall of the syringe during movement and pressure in the distal direction, the pressure inside the syringe being greater in the volume prepared for receiving the flowable medium than in the compartment, which α) is formed either by the inner wall of the cylinder and the stopper wall or ß) by the inner wall of the cylinder and the open proximal end.

The contact pressure of the sealing lips against the inner wall of the syringe increases when the stopper is pressed in the distal direction. This increase in the contact pressure is preferably linear, possibly large at low pressures and later lower. The sealing lip has a function like a lip valve or sail valve.

A syringe according to the invention is preferred in which the sealing lip points in the direction of the distal end and has a surface facing the axis of the syringe, which has the force which is caused by the internal pressure of the syringe (at Use or during autoclaving) arises, forwards towards the inner wall.

Minimization of the residual volume Medical syringes according to the invention are advantageous, the stopper being designed complementary to the shape of the distal end of the syringe in order to minimize a residual volume which cannot be removed from the syringe despite the stopper being fully pressed in.

A medical syringe according to the invention is preferred, the stopper having convex, plane or concave design or also having pyramid-shaped, conical, truncated pyramid-shaped, truncated-cone-shaped or hemispherical configurations, the protuberance pointing distally or proximally, depending on the design of the end of the syringe.

Disposable syringes are preferred.

Pressure intensification

A syringe according to the invention is preferred in which the sealing lip, which runs at least partially axially parallel to the inner wall of the cylinder, has a reinforcement or material thickening which is connected to the sealing lip attachment point on the stopper via a plastic area and / or elastic area.

Preferred material

Syringes according to the invention are preferred in which the polytetrafluoroethylene is a TFM which has the following properties:

Elongation at break greater than 500%,

Deformation under load less than 10%; SVI value less than 250,

Permeability of sulfur dioxide less than 310 with a film thickness of 1 mm,

Permeability of hydrochloric acid less than 600 with a film thickness of 1 mm, permeability of chlorine less than 300 with a film thickness of 1 mm. The values are measured according to the following standards: elongation at break according to ISO 12086, deformation bacg ASTM D 621; SVI value ISO 12086, permeability according to DIN 53380 with a film thickness of 1mm.

A syringe according to the invention in which the stopper is made of one substance is more preferred.

A syringe according to the invention in which the stopper has a modulus of elasticity of 550 ± 100 N / mm ² at 25 ° C. is even more preferred.

A syringe according to the invention is most preferred in which the stopper has a static friction coefficient of μ _τ = 0.35 ± 0.05 and a sliding friction coefficient of μ 0.3 ± 0.05.

Filled, sterilized syringe

A syringe according to the invention is preferred in which the syringe is filled with a medium and is autoclavable.

A syringe according to the invention is more preferred in which the syringe can be autoclaved at a support pressure.

It makes sense that at least the syringe body is poured or sprayed in a sterile room at at least 250 ° C.

A syringe according to the invention is advantageous in which the sterile syringe can be packaged in a sterile container which has at least one gas-permeable but not germ-permeable wall.

Explanations of sterilization

A syringe must be cleaned of foreign objects. Foreign bodies are all the particles that are not made of the material of the syringe and the medium and the detached fragments of the syringe. Pyrogens are substances that, as fragments of bacteria, provoke an immune response in humans. In particular, they are lipopolysaccharides, ie cell wall components of gram-negative bacteria.

Treatment with ethylene oxide, propan-3-olide and diethyl dicarbonate, hydrogen peroxide and an ozone / steam mixture are known as chemical sterilization processes.

Sterilization with high-energy radiation is also possible. Gamma rays and X-rays are known here.

The syringe or cartridge is thermally sterilized in an autoclave or sterilizer with hot air or using a microwave.

So that the stopper does not move within the cylinder, it is advantageous if the stopper is fixed during sterilization.

If necessary, it is possible to build up a support pressure in the sterilization space of the autoclave or the sterile chamber by a gas in the sterilization space, the pressure on the outer surface of the syringe being greater than, equal to or less than the pressure on the inner surface of the syringe. The support pressure is to be defined as the pressure which corresponds to the sum of the partial pressures in the sterilization room minus the partial pressure of the steam.

It is also advantageous that the filled and terminally filled syringe is packaged in sterile plastic film and / or aluminum film under possibly aseptic conditions. It is advantageous here that the syringe is packed in possibly sterile blisters, where aseptic conditions may prevail.

Method of making a prefilled sterile syringe The invention also includes a method of making a prefilled sterile syringe which comprises the following features: a) sterile making the syringe parts or cleaning and sterilizing the made syringe parts, b) assembling the parts, (i) thereby the distal end is closed during proximal filling or

(ii) the proximal end is closed by the stopper during distal filling, c) optionally sterilizing the assembled syringe, d) proximal or distal filling, depending on the remaining opening, e) proximal closure by the stopper or distal closure by an outlet closure or a welding of the

Outlets, f) sterilizing the filled and closed syringe, g) optionally sterile packaging of the syringe in a container with at least one surface that is gas-permeable but not germ-resistant.

Such methods are described in detail in EP 0 227 401, EP 0 553 926 and US Pat. No. 5,207,983. Reference is also made to the references E. Venten and J. Hoppert, Pharm. Ind. Vol. 40, No. 6 (1978). This publication, including the literature cited therein, deals extensively with sterilization methods. The publication by Venten and Hoppert becomes part of the registration by quotation. It is particularly advantageous if a combination of the syringes according to the invention and an application device consists of an injector and connections, the injector being a pump system and the connections connecting the outlet of the syringe to the patient. Such an injector is z. B. described in EP 0 192 786.

Combination of syringe and injector The invention further comprises a combination of a prefilled, terminally sterilized syringe according to the invention, and an application device made of injector and connections, the injector being a pump system and the connections connecting the outlet of the syringe to the patient. Such a pump system is described in the publication EP 0 584 531.

51464AWOM2XX00 + P 10/15/1997 wide Specific embodiments

The preferred embodiments of a syringe according to the invention can be seen in the figures. The invention is not limited to these statements.

Figure 1 shows a cross section through a Teflon stopper. Figure 2 shows in cross section the balance of forces on the sealing lip. Figure 3 shows a cross section through a stopper part with two sealing lips. Figure 4 shows a cross section through a biconcave sealing lip.

FIG. 5 shows a cross section through two sealing lips pointing in different directions. Figure 6 shows a cross section through two sealing thickenings and the associated pressure / area diagram. Figure 7 shows a cross section through a sealing lip and the associated pressure / area diagram. Figure 8 shows a cross section through a sealing lip with reinforcement.

FIG. 1, which is the preferred embodiment, shows a cross section through a stopper 101 which is arranged in a syringe barrel 102. The stopper 101 consists of a core 103, which has three notches 105 on the stopper cylinder edge 104, which are part-circular. The notches 105 do not abut one another directly, but are connected by webs 106 which bear directly against the inner wall 107 of the cylinder.

Then, at the bottom, that is to say toward the medium and pointing away from the stamp, there are two sealing lips 108 and 109 which are arranged one behind the other. The proximal sealing lip 108 forms a right-angled triangle, the angled part 111 at the more acute angle, which lies proximally, being formed by the cylinder wall 110 of the stopper 101, the opposite part 112 by a radially projecting side and the hypotenuse 113 by an oblique part to the stopper axis 114 pointing side. The hypotenuse 113 only bears against the inner wall 107 of the cylinder in a small area that abuts the counter-catheter 112.

The distal sealing lip 109 has a triangular shape, the base 115 being arranged obliquely to the plug axis 114. Two legs 116 and 117 extend approximately from the base 115, only that of the Plug axis 114 pointing leg touches the cylinder inner wall 107. Due to the material, the two sealing lips 108 and 109 are elastic, they also press lightly against the inner wall 107 of the cylinder even in the idle state.

FIG. 2 shows the basic balance of forces in a stopper 201 according to the invention. It represents a cross section through the stopper 201, which is arranged in a syringe cylinder 202. The plug 201 consists of a core 203, which has two notches 205 on the plug cylinder edge 204, which are rectangular. The notches 205 do not abut one another directly, but are connected by a web 206 which lies directly against the inner wall 207 of the cylinder.

The sealing lip 209 has an almost triangular shape, the base 215 being arranged obliquely to the plug axis 214. Two legs 216 and 217 extend approximately the same from the base 215, only the leg pointing away from the plug axis 214 touching the cylinder inner wall 207. Due to the material, the sealing lip 209 is elastic; it presses lightly against the inner wall 207 of the cylinder even in the idle state.

The forces on the sealing lip 209 are designed differently in the dynamic and static state. The dynamic state is when pressure is exerted on the plunger so that the plug 201 is pressed in the distal direction. The internal syringe pressure of the medium is increased. In the static state, neither the medium nor the stamp exert pressure on the stopper, which is in equilibrium. If the coefficient of friction were infinitely small, the stamp would be in this position voluntarily if no forces acted on it.

The sealing lip 209 is slightly pretensioned and is therefore slightly in contact with the inner wall 207 of the cylinder. Since the pressure area is very small, the surface pressure is still relatively high. In the static state, the stopper 201 thus sufficiently seals the interior of the syringe barrel 202. Low forces are applied. Low forces also mean that the cold flow behavior of the polytetrafluoroethylene is not stressed. Such a syringe can be stored for a long time without the material of the stopper 201 being significantly deformed by the cold flow. In the dynamic state, the plug 201 is pressed in the distal direction, a pressure is built up in the medium. This presses on the leg 216 pointing inwards, as a result of which the mass of the sealing lip 209 is pressed outwards. The force is absorbed on the one hand by the base 215 and on the other hand by the front part of the outer leg 217. The last-mentioned part causes the pressure of the lip 209 on the inner cylinder wall 207 per unit area to be very high. The area is large enough to successfully prevent the medium from passing from the lumen of the syringe into the surrounding area. Since the webs 206 are not essentially sealing, atmospheric pressure is exerted on the outwardly pointing leg 217, which opposes the internal syringe pressure.

FIG. 3 shows a cross section through a stopper 301 which is arranged in a syringe cylinder 302. The plug 301 consists of a core 303, which has three notches 305 on the plug cylinder edge 304, which are rectangular. The notches 305 do not abut one another directly, but are connected by webs 306 which bear directly against the inner wall 307 of the cylinder.

Then, distally, that is to say toward the medium and pointing away from the stamp, there are two sealing lips 308 and 309, which are arranged one behind the other. These two sealing lips 308 and 309 form a right-angled triangle, the ankathetes 311 at the more acute angle, which points proximally, being formed by the cylinder wall 310 of the plug 301, the opposing cathets 312 by a radially projecting side and the hypotenuses 313 by an oblique side facing plug axis 314. The hypotenuses 313 lie against the inner wall 307 of the cylinder only in a small area which abuts the counter-catheter 312.

4 shows a sealing lip 409, which has a convex shape both in the outer leg 417 and in the inner leg 416.

FIG. 5 shows three sealing lips, one that points distally with both legs 516 and 517 and one that points proximally with the two legs 516 ^' and 517 ^' . There is a dovetail-shaped web between the two, which is also sealing when the plug 501 is moved dynamically, since it rests slightly against the direction of movement due to the elastic base 515 ^" bends and is pressed against the cylinder inner wall 507 by its contact area pointing in the direction of movement.

Figure 6 shows a seal according to the prior art. The spatial division of the webs in relation to the punctiform surface pressure of the webs on the inner wall of the cylinder was shown. It is obvious that the surface pressure is distributed over a larger area and has a point pressure that is relatively low.

FIG. 7 shows a sealing lip 709 according to the invention, which due to its shape has only a small contact area with the inner wall 707 of the cylinder. Here, relatively large pressures are exerted at certain points, but the total area that lies against the inner wall 707 of the cylinder is smaller.

The dashed areas in FIGS. 6 and 7 should be of the same size with respect to the integral. The main difference is that the surface pressure in FIG. 7 is greater than in FIG. 6. Furthermore, and this is the most important point, this pressure-area diagram only shows the static state. In the dynamic state, with the medium being compressed in the syringe, significantly higher values occur in FIG. 7, whereas the values in FIG. 6 remain the same in terms of quantity, the highest being shifted proximally in their position.

FIG. 8 shows a cross section through a stopper 801 with a sealing lip 809 which bears against the inner wall 807 of the cylinder. The sealing lip 809 does not end in a point, but has a thickening 820. Furthermore, FIG. 8 clearly shows the elastic zone and plastic zone 821, which lies between the sealing lip attachment point 822 and the contact surface 823 between the sealing lip 809 and the inner wall 807 of the cylinder. Furthermore, the elasticity zone and plasticity zone 821 are arranged between the sealing lip attachment point 822 and the thickening 820. In the area of the elasticity zone there is a compression zone 824 and a tension zone 825, both of which run approximately parallel to the plug axis 814. Furthermore, it can be seen that the elastic zone 821 does not lie on the perpendicular to the inner wall 807 of the cylinder, which perpendiculars simultaneously pass through the contact surface 823. The plasticity zone 821 comes into play when there is permanent pressure or thermal stress on the Sealing lip 809 acts, as occurs especially during autoclaving. This area has a flow behavior without at the same time losing all of the elasticity of the sealing lip. The balanced ratio between plasticity and elasticity in this area 821 is essential for successful sealing of the stopper. The forces and changes that occur can easily be checked by a specialist by means of tests.

Claims

claims

1. Medical syringe with inserted stopper, the syringe comprising the following features: a) the syringe

Polypropylene are at least partially substituted by fluorine atoms, d) the surface of the stopper, which contacts the inner wall of the syringe, is in direct contact with the material of the inner wall of the cylinder, e) the stopper has at least one sealing lip, which fits tightly against the inner wall of the syringe, f ^" ) in the static state of the stopper, the elastic forces that press the sealing lip against the inner wall of the cylinder are caused by a range of elasticity, the one

Has tension zone next to a compression zone.

2. Medical syringe made of glass and / or plastic with inserted stopper, with the following features: a) the syringe includes

(i) a cylinder with a cylinder inner wall,

(ii) a proximal end which can be closed by the stopper, (iii) a distal end which is closed by a cylinder ceiling, and

(iv) an outlet which penetrates the cylinder ceiling or the inner wall of the cylinder, b) the syringe is prepared for receiving a medium or for use, c) at least the surfaces of the stopper which contact the inner wall of the syringe are made of polytetrafluoroethylene or of substituted polyethylene or

Medium can slide past the sealing lip, unless the inner wall has a bulge to the outside, f ^" ) the elastic forces that press the sealing lip against the inner wall of the cylinder are in the static state of the

Plug caused by a range of elasticity, the one

Has tension zone next to a compression zone.

3. Medical syringe with inserted stopper, the syringe comprising the following features: a) the syringe

(i) a cylinder with an inner cylinder wall, (ii) a proximal end, (iii) a distal end, and (iv) an outlet, b) the syringe is prepared for receiving a medium, c) at least the surfaces of the stopper, which contact the inner wall of the syringe are made of polytetrafluoroethylene or of substituted polyethylene or polypropylene, the hydrogen atoms of the polyethylene or polypropylene being at least partially substituted by fluorine atoms, d) there is no lubricant between the surface of the stopper which contacts the inner wall of the syringe and the inner wall of the cylinder, or

a lubricant of such a thickness that does not permit movement of the stopper in the syringe under normal conditions of use if the stopper were made of rubber, e) the stopper has at least one sealing lip which lies sealingly against the inner wall of the syringe, f ^" ) which Elastic forces that press the sealing lip against the inner wall of the cylinder are caused in the static state of the stopper by a range of elasticity, the one

Has tension zone next to a compression zone.

4. Medical syringe according to one of the preceding claims, wherein the sealing lip is pressed sealingly against distal direction against the inner wall of the syringe.

5. Medical syringe according to one of the preceding claims, wherein the sealing lip is pressed in the movement and pressure in the distal direction sealingly against the inner wall of the syringe, the pressure inside the syringe being greater in the volume prepared for receiving the flowable medium than in that Compartment, which is formed either by the inner wall of the cylinder and the stopper or by the inner wall of the cylinder and the open proximal end.

6. Medical syringe according to one of the preceding claims, wherein the sealing lip, which runs at least partially axially parallel to the inner wall of the cylinder, has a reinforcement or material thickening which is connected to the sealing lip attachment point on the stopper via a plastic region and / or elastic region.

7. Syringe according to one of the preceding claims, wherein the polytetrafluoroethylene has the following properties:

Elongation at break greater than 500%, deformation under load less than 10%;

SVI value less than 250,

Permeability of sulfur dioxide less than 310 with a film thickness of 1 mm,

Permeability of hydrochloric acid less than 600 with a film thickness of 1 mm, permeability of chlorine less than 300 with a film thickness of

1 mm.

8. Syringe according to one of the preceding claims, wherein the stopper is made of one material.

9. Syringe according to one of the preceding claims, wherein the stopper has a modulus of elasticity of 550 ± 100 N / mm ² at 25 ° C.

10. Syringe according to one of the preceding claims, wherein the stopper has a static friction coefficient of μ _τ = 0.35 ± 0.05 and a sliding friction coefficient of μ 0.3 ± 0.05.

11. A method for producing a prefilled sterile syringe according to one of the preceding claims, which comprises the following features: a) sterile production of the syringe parts or cleaning and sterilization of the manufactured syringe parts, b) assembly of the parts,

(i) the distal end is closed during proximal filling, or (ii) the proximal end is closed by the plug on the distal

Filling closed, c) if necessary, sterilizing the assembled syringe, d) proximal or distal filling, depending on the remaining opening, e) proximal closure by the stopper or distal closure by an outlet closure or a welding of the outlet, f) sterilization of the filled and closed syringe, g) if necessary, sterile packaging of the syringe in a container with at least one surface that is gas-permeable but not germ-permeable.

12. Combination of a prefilled, terminal-sterilized syringe according to one of the preceding claims, and an application device made of injecting machines and of connections, the injecting machine being a pump system, and the connections connecting the outlet of the syringe to the patient.