CZ345697A3 - Apparatus for mixing pharmaceutical mixtures with liquid agents - Google Patents

Abstract

Device for mixing a pharmaceutical composition stored in a chamber (38) in said device with an agent to be added shortly before administration to form a preparation to be administered. The device should be capable of being shaken without leaking. It comprises a hollow body (2) having an outlet (4), sealed by a removably closure (12) and a plunger (6), which includes a flexible sealing member (20) having a circumferential edge in sealing contact with the inner wall (8) of the hollow body. The plunger (6), the hollow body (2) and the removable closure (12) define said chamber (38). A hollow rod (30) is connected to the plunger (6) for displacing the same in the hollow body (2) and includes at least one opening, which communicates with the interior of the rod (30) with the upper side of the flexible member (20). The flexible member (20) is supported on the plunger (6), so that it can only flex downwards. At a predetermined pressure differential over the upper side and the lower side of the flexible member (20) the flexible member will flex downwards to open a communication at the inner wall (8) of the hollow body into the chamber (38), so that said agent flows into the chamber (38).

Description

The invention relates to a device for mixing pharmaceutical, preferably dry and granular mixtures with other, preferably liquid, agents to form a preparation, preferably a gel, in accordance with the preamble of claim 1.

BACKGROUND OF THE INVENTION

The main problem which constitutes the basis of the present invention relates to the handling, storage and administration of pharmaceutical compositions which need to be mixed with other agents that may negatively affect the stability of the composition to form a formulation suitable for administration to living individuals, particularly animals.

In veterinary medicine, a method for administering pharmaceutical compositions in the form of paste preparations to horses using a syringe-like device is well known. This syringe is inserted into the horse's mouth and the specimen is pushed to the root of the tongue. The viscous nature of the preparation and its placement in the back of the mouth make it difficult for the horse to spit out the preparation.

These preparations, which are formed, for example, from a pharmaceutical composition and from a cohesive substance, have in some cases a short storage stability. Therefore, the components of these preparations must be stored in isolation until shortly before use, when they are mixed together to form the desired preparation.

There are many solutions to the problem of storing and mixing the two components of the preparation, which after mixing cannot be stored for a longer period of time. The most known prior art is a syringe as described in US-A-3 340 873 having a piston slidingly mounted in a cylindrical body. The two components to be mixed are located in two different parts which are insulated from each other by a thin partition. Shortly before the specimen is to be used, the septum is broken or pierced so that contact between the two parts is ensured. The mixture syringe is then shaken to give a homogeneous preparation. After this operation, the canal is opened by removing the cap, and the contents are pushed through the needle by pressing the plunger.

This kind of prior art has in most cases proved satisfactory and reliable and is also easy and inexpensive to carry out, for example by means of plastic moldings.

However, the aforementioned syringe is not suitable for the administration of a gel, mainly due to the presence of a needle. However, in general, it is not possible to use a device with two parts separated from each other by a thin septum of rubber or plastic for certain types of pharmaceutical compositions that are sensitive to moisture. An example of such a composition is a composition comprising a hydrogen ion pumping inhibitor such as omeprazole, which degrades during prolonged storage in the presence of moisture. The always present molecular migration through the rubber or plastic barrier will be sufficient to cause degradation of this sensitive composition during long-term storage.

Consequently, conventional mixing devices with two separate parts are not suitable for such mixtures.

DK Specification No. 112,893, filed July 25, 1996, discloses a syringe for injecting pharmaceutical compositions that cannot be stored for long periods in solutions without deleterious effects. The syringe essentially corresponds to a standard syringe, the main difference being that the opening in the needle flange is closed by a septum. The mixture is in dry form in the syringe. When the syringe is to be used, a two-needle injection needle is attached to the flange, one end piercing the septum. The solvent is drawn into the syringe with a needle. The syringe is then shaken and the resulting solution is injected with a needle.

• · • ·

The disadvantage of this type of syringe is that the filling operation is quite complicated, requiring the use of a double-ended injection needle to pierce the septum. In addition, after breaking the partition, the mixing chamber is opened to the atmosphere, so care must be taken during the shaking operation to prevent the mixture from escaping through the needle. Moreover, due to the high flow resistance of the syringe due to the narrow channel, especially in the needle, it cannot be used for viscous, pasty or gel-like preparations.

Moreover, the composition is not suitable for oral administration due to the needle. In addition, the manufacturing cost of a syringe would be relatively high.

Object of the invention

It is an object of the invention to avoid the disadvantages of the prior art method by providing a mixing device in which the pharmaceutical compositions can be stored for a long time and to which the desired agent can be added quickly and easily immediately before administration of the preparation. After addition of the reagent, the device should also be able to withstand vigorous shaking without leakage. In addition, the manufacturing cost of the invented device should be relatively low.

This object of the invention is a device according to the preamble of claim 1 comprising the features of the feature of claim 1.

Other independent claims define a method of using a pharmaceutical formulation mixing device and a method of administering a mixed formulation using the apparatus.

When the preparation is to be administered, it is first necessary to remove the package or closure that protects the filled chamber from moisture during storage, then adds the agent to be mixed with the substance contained in the chamber, the liquid agent being separated from the chamber by a resilient sealing element. Then the piston • · · • ·

Moves in a direction opposite to the outlet direction, causing the chamber defined by the piston, housing part and closure to enlarge, creating a vacuum in the chamber. The vacuum applied to the sealing element will initially be too small to bend, but as the piston continues to move, the vacuum in the chamber gradually increases so that the sealing element deforms and loses contact with the wall, thereby establishing a connection with the chamber. The reagent is then aspirated into the chamber. When the required amount of reagent is drawn into the chamber and the resilient sealing member returns to its rest position, the device is shaken until the formulation is ready for administration. Just before the preparation is administered, the chamber closure is removed and the device is inserted, for example, into the horse's mouth. Press the plunger to eject the contents.

Description of the proposed embodiments

The proposed embodiments of the invention will be described herein by way of example with reference to the drawings in which:

Fig. 1 is an axial section of a first embodiment of the invention; Fig. 2 shows the encircled portion in Fig. 1 on a larger scale; Fig. 3 is a cross-section along line III-III in Fig. 1; Fig. 5 shows the encircled portion in Fig. 4 on a larger scale, Fig. 6 is a section along the line IV-IV in Fig. 4, Fig. 7 shows a portion of a slight modification of the embodiment Fig. 4 is a larger-scale view, Fig. 8 is an axial section of another embodiment of the invention;

Fig. 9 is a cross-sectional view along the line IX-IX in Fig. 8, Fig. 10 shows the encircled portion in Fig. 8 on a larger scale, and Fig. 11 is a slight modification of the embodiment of Figs. 8-10.

As shown in FIG. 1, the syringe device of the first proposed embodiment of the invention consists of a tubular elongated cylindrical main portion 2 that is open at both ends. The lower end in FIG. 1 is the outlet end 4. The piston 6 is inserted by the open upper end 10. The flange 13 extends substantially perpendicular to the longitudinal axis of the hollow body 2 about its upper end. The outlet end 4 is closed by a removable lid 12 having a groove 14 with a diameter corresponding to the diameter of the side wall 8 of the hollow main part 2. The groove 14 has a depth such that together with the lower end of the hollow main part has a radially protruding eyelet 16 which facilitates removal of the cap 12 when the preparation is to be extruded.

As best seen in FIG. 2, the piston 6 is comprised of two parts 18, 20, i.e. a support member 18 in the form of a flat wall that is disposed along the entire diameter and perpendicular to the axis of the hollow body 2 and a sealing member 20 in the form a thin flexible disc having a load that is dimensionless enough to touch the inner wall 8 of the hollow body portion 2 and thereby insulate the spaces on both sides of the sealing member 20 from each other. The disc 20 has a pin 22 having a compressible convex portion 24 the wall 18 has in the center an opening 26 with a diameter smaller than the diameter of the convex portion 24. The shank 28 of the pin 22 is adapted to the thickness of the wall 18 so that the pin 22 can be engaged in the opening 26 so that the disc 20 abuts the wall 18.

The rod 30 is integrated with the piston 6. Its outer diameter is somewhat smaller than the inner diameter of the hollow body 2, so that the outer diameter of the hollow body 2 is so that ···· ·· ··

The 6 rod 30 is slidably guided therein. The rod 30 is tubular and its annular end portion 32 is made together with the wall 18 in one piece. The end face of said portion 32 is flush with the end face (bottom surface in FIG. 1) of the wall 18. A radially protruding handle 23 is disposed at the open end 40 of the rod 30.

The resilient disc 20 is made of resilient material and, when subjected to a sufficiently large force, deflects and returns to its original position when this force is removed. When a cap 12 or other seal is provided at the outlet end 4, the cap 12 or other seal, the flexible disk 20 and the inner wall 8 of the hollow body define a closed chamber whose volume is variable due to the axially displaceable piston 6. The wall 18 and the annular end of the rod 32 prevent the peripheral edge 34 of the disc 20 from tilting upwards. The edge 34, on the other hand, may deflect downwards. When this occurs, the edge 34 releases its sealing contact with the inner wall 8 of the hollow body 2, thereby opening a connection around the wall 8 between the upper and lower sides of the flexible disc 20. The disc 20 thus functions as a check valve.

It should be noted that any method can be used to secure the flexible disk 20 to the rod 30. For example, the keyhole method can be used. At the lower end of the rod 30 is a keyhole opening and the pin 22 of the sealing disc 20 is then inserted into the wider keyhole opening and then pushed into the narrower keyhole slot. In another fastening method, the flexible disk 20 may be provided with a shaft in the middle, which is then inserted into an opening at the lower end of the rod 30. The shaft end is then heated to a softening temperature and then flattened to form a form of rivet joint.

As mentioned above and as can be seen in Figs. 1-3, the rod is tubular and has an open lower end, which is usually sealed by a flexible disc 20. The interior 36 of the rod 30 and the disc 20 form a filling compartment for the reagent to be. «

- 7 mixed with the substance in the chamber. - 7 · · ·> áno áno áno smích áno áno áno áno áno áno smích

The function of this first embodiment of the device will now be described by way of example. A suitable substance for this device is described in WO / SE94 / 25070. In the following example, the pharmaceutical composition comprises grains of the active ingredient, such as enteric coated layered pellets of omeprazole mixed with a gelling agent, such as xanthan gum, guar gum, carob gum, tragacanth, modified cellulose derivatives or the like, and to this mixture of dry components is a liquid agent such as water is later added to form a viscous gel. The use of the device defined by the present invention will not be limited to use in connection with the omeprazole formulation.

A suitable dose of a dry mixture of enteric-coated omeprazole pellets and a gelling agent is placed in chamber 38. To prevent premature dissolution of the enteric-coated beads when water is added, a buffer or pH adjusting agent such as citric acid may optionally be added. This operation can be accomplished in two ways, either by placing the piston 6 in a suitable position in the hollow body 2 with the cap 12 removed and filling occurs via the lower end 4, or the cap 12 is snapped onto the lower end 4 and the piston 6 is removed and The upper orifice 10. The amount or volume of the mixture is selectable within certain limits, since the volume of the chamber 38 is variable due to the axially displaceable piston. Upon completion of the filling, a cap 12 or other seal, respectively, is fitted to the end 4. the piston 6 is inserted into the hollow body 2.

It should be noted that the hollow rod 30 preferably serves as a gauge for the agent to be added to the chamber 38. It is transparent and preferably provided with a scale so that the added agent can be accurately measured by the device. Excess reagent can be poured from the rod 30 before the rod is displaced to open the joint into the chamber 38. Thanks to the built-in gauge created by the specific design of the rod 20, very accurate measurement of the reagent added can be performed without the need · · «• • • •» »» »» »» »» »

-8 any other means outside the syringe itself.

Due to the hygroscopic nature of the gelling agent and the desired shelf-life of the pharmaceutical preparation, the contents of the chamber must be protected from the penetrating moisture which would otherwise accumulate in the gelling agent during long-term storage and cause omeprazole degradation sooner or later. Therefore, after the filling operation, the device is enclosed in a moisture-tight package, preferably this barrier is made of aluminum, but of course other materials that fulfill the same purpose are also suitable. As a further protection against moisture it is advisable to add a desiccant to the package, preferably in small sachets. As an alternative to said package, it may be sufficient to provide an impermeable seal or lid or similar material to the upper end 40 of the rod 30.

A desiccant could then be incorporated in the seal or cap to absorb any penetrating vapor. The device can now be stored for several years before use.

Prior to use, the device is removed from the moisture-tight package, or the seal is removed from the end of the tubular rod 30.

A suitable amount of water to be added to the mixture in the chamber 38 is then filled into the tubular section of the rod 30 to the desired height (indicated by a scale or line). The piston 6 is then moved upwards to create a vacuum in the chamber 38. After sufficient displacement there will be such a vacuum inside that the flexible disk 20 swings downward, the peripheral edge 34 of the flexible disk loses its sealing contact with the inner wall 8 so as to form a connection between the compartment 36 into the chamber 38 and the water in the compartment 36 of the draw bar 30 is sucked into the chamber 38. When the water is moved, the disc 20 returns to its rest position and the device is then shaken until a viscous gel is formed containing pellets of omeprazole. The flexible disc 20 prevents leakage of the composition into the compartment 36 during shaking. The composition may be stored in the device for a short period of time before being administered. Immediately before administration, the cap 12 is removed and the device is placed where the preparation is to be administered. The specimen is then extruded by pressing the bar 30.

• • • •

Advantageously, the rod 30 is of such an axial length that, when fully compressed, all the preparation is forced out of the device. The flexible disk 20 preferably has a flat surface to expel the mixture completely, thereby avoiding the risk of any residues, pellets or gel remaining in the holes and slots, which could occur with the notch disks.

Instead of the plastic cap 12, a tear or break seal may be used to seal the chamber 38.

Giant. 4 demonstrates a slight modification of the embodiment of FIGS. 1-3. Instead of opening the tubular rod 30a at the lower end, it has two opposing longitudinal slots 42 that extend from the lower portion of the rod 30a to about half the height of the rod 30a, thereby providing a connection between the interior 36a of the rod 30a and the upper side of the disc 20a. The lower portion has an opening 26a in the middle that functions similar to the opening 26 in the embodiment of FIG.

1. The lower portion of the rod 30 is circular and supports the middle portion of the flexible disk 20a.

In a further modification of the embodiment of Fig. 4, the sealing member 20a is integrated with the rod 30a and consists of a circular flexible disk, see Fig. 7. The advantage of this embodiment is that it requires only one operation to manufacture the rod 30a and the sealing member 20a.

In another modification (Figs. 8-10) of the previously described embodiments, the upper portion of the rod 30b is tubular, while the lower portion 46 has a cross-sectional cross-section as is clearly seen in Fig. 9. perpendicular walls 48, 50 that extend from the lower portion of the rod 30b to about half the height of the rod 30b. The cross-section portion 46 that extends downwardly from the tubular portion 40 has a first portion of constant cross section that provides sufficient rigidity and guidance to the inner wall 8. The other portion 56 converges towards the bottom portion, which in turn has a circular flange 60 supporting the flexible disc 20b and prevents it from deflecting downwards. The lower part also has an opening 62.

into which the bulge 24b of the flexible disk 20b is engaged (see FIG. 10).

Fig. 11 shows a modification of the embodiment of Figs. 8-10. Similar to FIG. 7, the resilient sealing member 34'b is an integral part of a rod 30b having a radially protruding annular rim 60 that is elongated by a thinner resilient edge 34'b and forms a sealing contact with the inner wall 8 of the hollow body 2.

In the embodiment of Figs. 8-11, water is added as before through the open end 40 of the rod 30b, but unlike the above-described embodiment, water will not be present in the lower tubular portion of the rod but will flow along the cross portion up to the desired height. In this case, the cross section could be provided with colored lines to indicate the volume level.

In these embodiments, the rod may not be transparent, but may be made in a suitable color.

As can be understood, all embodiments function in a similar manner. The liquid agent, preferably water, is filled into the upper portion 40 of the rod 30, and this water then flows through the hole in the rod and subsequently reaches the upper side of the resilient sealing member. The sealing element prevents the water from entering the chamber 38. The rod is then moved backwards, creating a vacuum in the chamber 38. The combined effect of the weight of water and vacuum will deflect the sealing member downwardly so that water is sucked into the chamber 38. When water disappears from the space above the sealing member into the chamber, this element returns to its original rest position and closes the chamber 38.

The solutions described offer various advantages. If the sealing element is a separate component, it offers great freedom of choice of material. The material of the sealing member can be selected to have optimal sealing and elastic properties, while the rod material can be selected to provide sufficient rigidity and support for the sealing member. If the rod and the sealing element are integrated, the selected material must be a compromise between • · · · · · *

- 11 ········ · · necessary stiffness of the rod and necessary elasticity of the sealing element. However, this second solution offers advantages in terms of production costs.

It should further be noted that in these two embodiments, all elements can be made of polymeric materials such as polyethylene, polypropylene, polyester, elastomer, polycarbonate, rubber or silicone, and can be made by conventional and inexpensive methods such as injection molding. In addition, all components have a simple design and are easy to install. As a result, these devices can be manufactured at low cost.

In the above-described embodiments of the invention, the cap 12 is provided with a radially protruding projection 16 that extends around a portion of the periphery of the cap 12 to form a handle to facilitate removal of said elements. It will be appreciated that this handle may have any suitable arrangement. For example, it may be oval, or may be formed by a protruding flange extending around the entire periphery of the cap.

The devices are particularly suitable for oral administration to animals, especially horses, especially aqueous gels containing a proton pump inhibitor composition. eg omeprazole or the like. However, it will be appreciated by those skilled in the art that the use of this device is not limited to this field, since it can be used to mix different kinds of pharmaceutical agents with other agents and for oral, rectal or any other suitable administration of many different animal species, including humans.

It should also be noted that a pharmaceutical composition within the meaning of this application does not only mean a drug, but also includes other kinds of beneficial agents, such as the main nutrients.

Claims (30)

An apparatus for mixing pharmaceuticals, preferably dry and granular substances, with preferably liquid agents for the manufacture of a preparation, preferably a gel or gel-like preparation, and subsequently administering the preparation to a living individual, eg an animal or a human; ) having an outlet (4) closed by a removable closure (12), a piston (6, 6a, 6'a, 6b, 6'b) which is slidably mounted in this hollow body (2) and closely touches the inner wall said hollow body (8), a drive element (30, 30a, 30b) connected to and moving said piston (6, 6a, 6'a, 6b, 6'b) in the hollow body (2), the piston which, with the hollow body and the removable closure defines a chamber for said substance, characterized in that it comprises a sealing element (20, 20a, 20'a, 20b, 20'b) having a resilient edge (34, 34a, 34'a, 34b, 34'b) in close contact with the MV the inner wall (8) of the hollow body (2) and one side of this edge is directed into said chamber (38) thereby separating the chamber from the opposite side of the resilient edge, the edge being supported so that when the piston is moved in the direction away from the chamber (38), it could deflect sufficiently in one direction to break its close contact with the inner wall (8) of the hollow body (2) to form a connection between the chamber (38) and the opposite side of this edge. Device according to claim 1, characterized in that in said driving part a tubular rod (30, 30a, 30b) is provided with at least one opening in its lower part. Device according to claim 2, characterized in that said rod (30, 30a, 30b) has a wall (18) along its entire diameter and openings are defined between the side edges of the wall (18) and the inner wall of the tubular rod (30). . Device according to claim 3, characterized in that said wall (18) has a central opening (26) adapted - 13 for detachably attaching the flexible sealing element (20) to the rod (30), the sealing element being circular and extending at least to the outer wall of said tubular rod. The device of claim 2, wherein said tubular rod (30a) has a closed bottom portion and axial slots (42) extending from said bottom portion. A device according to claim 5, characterized in that the resilient sealing element is a circular disc (20a) releasably fastened to the bottom. A device according to claim 6, characterized in that the resilient sealing element is an integral part of the tubular rod (30) and consists of a resilient annular ring (34'a) which projects radially from the bottom to the inner wall (8) of the hollow barrel parts (2). Device according to any one of claims 2-7, characterized in that the tubular rod (30, 30a, 30'a) comprises means for measuring the volume of the substance to be added. Device according to claim 8, characterized in that the tubular rod (30, 30a, 30'a) has a scale for the level of the substance to be added. Device according to claim 8 or 9, characterized in that the tubular rod (30, 30a, 30'a) is transparent. The apparatus of claim 2, wherein the rod (30b) comprises a tubular first portion (44) connected to a second portion (46) having a cross-sectional cross section. Device according to claim 11, characterized in that the second part (46) tapers towards the lower part of the rod (30b). Apparatus according to claim 11 or 12, characterized in that the rod has a flat bottom with a central opening (26) adapted for detachably attaching the flexible sealing. - 14 · »» * * 14 14 14 14 14 14 9 9 · 9 4 · 8 · 9999 9 9 «9 ··· 99 99 of the element (20b) to the rod (30b), the sealing element being circular and extending to the inner wall of the hollow body (2). Apparatus according to claims 11 or 12, characterized in that the resilient sealing element is an integral part of the rod (30b) and consists of a resilient annular ring (34'b) that extends radially from the bottom to the inner wall (8) of the hollow the main parts (2). Apparatus according to claims 11-14, characterized in that the second cross-sectional portion (46) comprises means for measuring the volume of the substance to be added. Apparatus according to claim 15, characterized in that the second portion (46) has a level of level of added substance. Device according to claim 16, characterized in that there are colored lines on this scale. A device according to any one of claims 11-17, characterized in that the second part (46) is colored. Device according to any one of claims 2-18, characterized in that the tubular rod (30, 30a, 30b) has an open end (40) spaced from the piston (6) which is closed by a moisture seal. Device according to any one of claims 1-19, characterized in that the closure is a removable lid (12). Apparatus according to any one of claims 1-19, characterized in that the removable closure (12) is a break-through or tear. Apparatus according to any one of the preceding claims, characterized in that the chamber (38) is pre-filled with a pharmaceutical substance and the apparatus is enclosed in a moisture-tight package comprising at least one moisture barrier. · A I t t t t t t t t t t t t t t t t t t t t t t t - 15 Device according to claim 22, characterized in that the at least one moisture barrier consists of an aluminum layer. Device according to claims 22 or 23, characterized in that a desiccant is present in the package. Apparatus according to any one of the preceding claims, characterized in that the pharmaceutical composition consists of enteric coated pellets containing a proton pump inhibitor, eg omeprazole pellets, mixed with a dry gelling agent. A process for preparing a pharmaceutical preparation by mixing a pharmaceutical, preferably dry, and granular mixture with a preferably liquid agent shortly before its administration to an individual, comprising the following steps: a) filling said mixture into a chamber 38 of a device comprising a hollow body (2) and a piston (6) displaceable therein and in close contact with the inner wall of said hollow body (2), thereby defining a movable wall of said chamber (38); the piston (6) has a sealing member (20) having a resilient lip (34) in sealing contact with the inner wall (8) of the hollow body (2) thereby separating the chamber (38) from the opposite side of the lip, and this edge (34) ) can deflect and allow the connection between the chamber (38) and the opposite side of the edge (34), b) closing the chamber with a closure (12), c) ensuring the sealing of the filled chamber (38) against moisture, d) storage of the equipment until use, e) removing said moisture seal from the chamber (38), f) enlarging the chamber (38) by repositioning the piston (6) and thereby establishing a connection between (38) by opening the rim (34) thereby moving the liquid agent into the chamber (38), g) shaking the device, if necessary, to form a preparation. h) opening the chamber (38) by removing the closure (12) when the preparation is to be administered, allowing said preparation to be - 16 «4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 c 4 4 4 c 4 4444 44 4 · pushed out of the machine by moving the piston (6) towards the bore. Method according to claim 26, characterized in that the sealing of the moisture chamber (38) in step c) is carried out by enclosing the device in a moisture-tight package comprising at least one moisture barrier. 28. The method of claim 27, wherein the at least one moisture barrier is an aluminum layer. Process according to any one of claims 26-28, characterized in that the pharmaceutical agent consists of enteric coated hydrogen ion transfer inhibitor pellets, eg omeprazole pellets, mixed with a dry gelling agent, and wherein said preferably liquid agent is water. The method of oral administration of a pharmaceutical preparation to an individual is achieved by mixing the preferably dry and granular material with the preferably liquid agent using a device according to any of claims 1-25. The method of claim 10 is an animal, The method of claim 1 is inserted into the horse's mouth just prior to the straight muzzle, said preparation being extruded onto the root of the tongue. 30> which is characterized by the fact that