SK142897A3 - Device and process for mixing a pharmaceutical composition with another agent and method for oral administration of the pharmaceutical preparation - 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

Technical field

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

BACKGROUND OF THE INVENTION

The main problem which constitutes the starting point for 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, especially animals.

In veterinary medicine, a method for administering pharmaceutical compositions in the form of paste formulations for horses using a syringe-like device is well known. This syringe is inserted into the mouth of the horse and the preparation is pressed onto the root of the tongue. The viscous nature of the product and its placement in the back of the mouth will make it difficult for the horse to set sail.

These formulations, which are formed, for example, from a pharmaceutical composition and a cohesive agent, have in some cases a short storage stability. The components of these preparations must therefore be stored in isolation for a short time before use, when mixed together to form the desired preparation.

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

This kind of prior art has in most cases proved satisfactory and reliable and is, moreover, 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, especially because of the presence of a needle. However, in general, it is generally 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 which 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 long-term 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 mixture during long-term storage.

Conventional mixing devices with two separate portions are also not suitable for such mixtures.

Specification of DK patent no. No. 112,893, filed on July 25, 1996, discloses a syringe for injecting pharmaceutical compositions that cannot be stored in solutions for a long period without harmful 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 double-ended 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.

A drawback 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 septum, the mixing chamber is open to the atmosphere, so care must be taken during the shaking operation to prevent leakage of the mixture by the needle. Moreover, due to the high flow resistance of the syringe with respect to the narrow channel, especially in the needle, it cannot be used in viscous, pasty or gel-like formulations. In addition, the composition is not suitable for oral administration due to the needle. Moreover, the manufacturing cost of the syringe would be relatively high.

SUMMARY OF THE INVENTION

The object of the invention is to avoid the disadvantages of the prior art by providing a mixing device in which the pharmaceutical compositions can be stored for a longer period of time and to which the desired agent can be added quickly and easily immediately before administration of the formulation. After addition of the reagent, the device should also be able to withstand vigorous shaking without leakage. Furthermore, the manufacturing costs of the device according to the invention should be relatively low.

The invention provides a device according to the preamble of claim 1, comprising the features of the claim feature

First

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

When the composition is to be administered, it is first necessary to remove the container or cap 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. Thereafter, the piston is moved in a direction opposite to the outlet direction, causing the chamber defined by the piston, a portion of the housing and the closure to enlarge, thereby creating a vacuum in the chamber. The vacuum applied to the sealing element will initially be too low to deflect it, 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 forming 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, in the horse's mouth. Press the plunger to print the contents of the device.

BRIEF DESCRIPTION OF THE DRAWINGS

The proposed embodiments of the invention will be described by way of example with reference to the drawings, in which Fig. 1 shows an axial section of a first proposed embodiment of the invention; 1 on a larger scale, FIG. 3 is a cross-section along line III-III in FIG. 1, FIG. 4 shows an axial section of another embodiment, which is compared to FIG. 1 to 3 slightly modified, FIG. 5 shows the encircled portion in FIG. 4 is a cross-section along line IV-IV in FIG. 4 shows a portion of the slight modification of the embodiment of FIG. Figure 4 is a cross-sectional view along line IX-IX of Figure 4; 8, FIG. 10 shows the encircled portion of FIG. 8 on a larger scale and FIG. 11 is a slight modification of the embodiment of FIG. 8 to 10.

DETAILED DESCRIPTION OF THE INVENTION

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

As can be clearly seen in FIG. 2, the piston 6 consists of two parts 18, 20, i. a flat wall support element 18 which is located all over and perpendicular to the axis of the hollow main body 2, and a sealing element 20 in the form of a thin flexible disc that is dimensioned so as to be in close contact with the inner wall of the hollow main body The disc 20 is provided in the middle with a pin 22 having a compressible convex portion 24, while the wall 18 has in the center an opening 26 with a diameter smaller than the diameter of the convex portion 24. 28 of the pin 22 is adapted to the thickness of the wall 18 so that the pin 22 can be engaged in the bore 26 so that the disc 20 is snugly against the wall 18.

The rod 30 is integrated with the piston 6. Its outer diameter is slightly smaller than the inner diameter of the hollow body 2 so that the rod 30 is guided therein. The rod 30 is tubular and its annular end portion 32 is made in one piece with the wall 18. 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 flexible disk 20 is made of a resilient material and, if subjected to a sufficiently large force, will deflect and return to its original position when the force is removed. When a cap 12 or other seal is placed on the outlet end 4, the cap 12 or other seal, the flexible disc 20 and the inner wall 8 of the hollow body are defined as a closed chamber whose volume is variable due to the axially movable piston 6. in the opening 26, the unloaded disc 20 lies opposite the wall 18 and the annular end of the rod 30. The wall 18 and the annular end of the rod 32 prevent the circumferential edge 34 of the disc 20 from tilting upwards. The edge 34, on the other hand, can deflect downwards. When this happens, 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 may be used. At the lower end of the rod 30, a keyhole opening is provided, 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 in the middle of the shank, which is then inserted into an opening at the lower end of the rod 30. The shank end is then heated to the softening temperature and then flattened to form a form of yarn joint.

As mentioned above and as can be seen in FIG. 1 to

3, the rod 30 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 agent to be mixed with the substance contained in the chamber.

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, a pharmaceutical composition consisting of grains of the active ingredient, such as enteric coated layered pellets of omeprazole, is mixed with a gelling agent such as xanthan gum, guar gum, carob gum, tragacanth, modified cellulose derivatives, and the like, if 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, optionally a buffer or pH adjusting agent such as citric acid may be added. This operation can be carried out 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 through the lower end

4, or the cap 12 is fitted to the lower end 4 and the piston 6 is removed and filled through the upper aperture 10. The amount or volume of the mixture is optional 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. a piston 6 is inserted into the hollow body 2.

It should be noted that the hollow rod 30 advantageously serves as a measure 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 means of the device. Excess reagent can be poured out of the rod 30 before the rod is moved to open the joint into the chamber 38. Thanks to the built-in gauge created by the specific design of the rod 30, it is possible to perform very accurate measurement of the reagent added without any means other than the syringe.

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 penetrating moisture that 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 sealed 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 pockets. As an alternative to said package, it may be sufficient to provide an impermeable seal or cap or similar material to the upper end 40 of the rod 30.

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

Before 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 compartment of the rod 30 up to the desired height (marked ). 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 the connection between compartment 36 into chamber 38 and water in compartment 36 of draw bar 30 is sucked into compartment 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 disk 20 prevents leakage of the mixture into the compartment 36 during shaking. The mixture may be stored in the device for a short time before administration. Immediately before administration, the cap 12 is removed and the device is placed where the formulation is to be administered. The formulation is then printed out by pressing the .30 bar. Preferably, the rod 30 is of such an axial length that all of the device is pushed out of the device when fully pressed. The flexible disk 20 preferably has a flat surface to extrude the mixture completely, avoiding the risk of any residues, pellets or gel remaining in the holes and slits, which could occur with the notch disks.

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

Fig. 4 demonstrates a slight modification of the embodiment of FIG. Instead of being open at the lower end, the tubular rod 30a has two opposing longitudinal slits 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. which functions similar to the opening 26 in the embodiment of FIG.

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

In another modification of the embodiment of FIG. 4, the sealing element 20a is integrated with the rod 30a and consists of a circular spring disc, see FIG. The advantage of this embodiment is that it requires only one operation to manufacture the rod 30a and the sealing member 20a.

In a further 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 evident in FIG. 9. The lower part thus consists of two longitudinally extending, perpendicular walls 48, 50 which extend from the lower part of the rod 30b to about half the height of the rod 30b. The cross-section 46 extending downwardly from the tubular portion 40 has a first constant cross-section portion that provides sufficient stiffness and guidance against the inner wall 8. The other portion 56 converges towards the bottom portion, which in turn has a circular flange 60 supporting the flexible disk 20b and preventing it from deflecting downwards. The lower portion also has an opening 62 into which the concave 24b of the flexible disk 20b is received (see FIG. 10).

In FIG. 11 shows a modification of the embodiment of FIG. 8 to 10. Similar to FIG. 7, the resilient sealing member 34 'b is an integral part of the rod 30b. which has 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 FIG. 8-11, water is added as before through the open end 40 of the rod 30b. however, unlike the embodiment described above, the water will not be located 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 element. The sealing element prevents water from entering the chamber 38. The rod is then moved backward to create a vacuum in the chamber 38. The combined effect of the weight of water and vacuum will swivel the sealing element downwardly so that water is sucked into the chamber 38. When the water disappears from the space above the sealing element into the chamber, the 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 chosen material must be a compromise between the necessary stiffness of the rod and the necessary elasticity of the sealing element. However, this latter 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 produced 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 and forms a handle to facilitate removal of said elements. It will be appreciated that this handle may be 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, in particular aqueous gels containing a proton pump inhibitor composition, for example 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 types of pharmaceuticals with other agents and for oral, rectal or any other suitable administration to 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 useful means, for example the main nutrients.

Claims (32)

PATENT CLAIMS Apparatus for mixing pharmaceutical, preferably dry and granular substances with preferably liquid agents for the purpose of making a composition, preferably a gel or gel-like gel, and subsequently administering the composition to a living individual, for example an animal or a human, comprising a hollow body (2) having an outlet (4) closed by a removable closure (12), a piston (6, 6a, 6'a, 6b, 6'b) slidably mounted in the hollow main body (2) and closely touching the inner wall of said a 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 defining a chamber for said substance with a hollow body and a removable closure, comprising a sealing member (20, 20a, 20'a, 20b, 20 * b) having a resilient edge (34, 34a) 34'a, 34b, 34'b) in close contact with the inner wall (8) of the hollow body (2) and one side of said edge directed into said chamber (38) thereby separating the chamber from the opposite side of said resilient edge, said edge being supported so that when the piston is displaced in the direction 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) for the purpose of establishing 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 the 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 to detachably attach the resilient sealing element (20) to the tie rod (30), the sealing element being circular and extending at least to the outer a wall of said tubular rod. Device according to claim 2, characterized in that said tubular rod (30a) has a closed lower part and axial slots (42) extending from said lower part. Device according to claim 5, characterized in that the resilient sealing element is a circular disc (20a) detachably fastened to the bottom. Apparatus 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) projecting radially from the bottom to the inner wall (8) of the hollow body. (2). Device according to any one of claims 2 to 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. Device according to claim 2, characterized in that 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 claims 11 or 12, characterized in that the rod has a flat bottom with a central opening (26) adapted to detachably attach the flexible sealing element (20b) to the rod (30b), the sealing element being circular and extending to the inner the 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) extending radially from the bottom to the inner wall (8) of the hollow main body. parts (2). Apparatus according to claims 11 to 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 the added substance. Device according to claim 16, characterized in that there are colored lines on this scale. Device according to any one of claims 11 to 17, characterized in that the second part (46) is colored. Device according to any one of claims 2 to 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 one of Claims 1 to 19, characterized in that the closure is a removable cap (12). Device according to any one of claims 1 to 19, characterized in that the removable closure (12) is a break-through or tear-off. Device according to any one of the preceding claims, characterized in that the chamber (38) is pre-filled with a pharmaceutical substance and the device is enclosed in a moisture-tight package comprising at least one moisture barrier. Device according to claim 22, characterized in that the at least one moisture barrier is formed by an aluminum layer. Apparatus according to claim 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, for example omeprazole pellets, mixed with a dry gelling agent. 26. A method of preparing a pharmaceutical composition by mixing a pharmaceutical, preferably dry, and granular mixture with a preferably liquid agent shortly prior to administration to an individual, comprising the steps of: 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 connection between the chamber (38) and the opposite side of the edge (34), b) closing the chamber with a closure (12), c) securing the filled chamber (38) against moisture, (d) storage of the equipment at the time of use; e) removing said moisture seal from the chamber (38), f) enlarging the chamber (38) by moving the piston (6) and thereby establishing a connection between the chamber (38) by opening the rim (34), thereby transferring the liquid agent to the chamber (38), (g) shaking the equipment, if necessary, to form a preparation; h) opening the chamber (38) by removing the closure (12) when the device is to be administered, allowing said device to be expelled from the device by moving the plunger (6) towards the opening. 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. The method of claim 27, wherein the at least one moisture barrier is an aluminum layer. Method according to any one of claims 26 to 28, characterized in that the pharmaceutical substance consists of enteric-coated pellets of a hydrogen ion transfer inhibitor, for example omeprazole pellets, mixed with a dry gelling agent, and wherein said preferably liquid agent is water. A method of oral administration of a pharmaceutical composition to an individual, characterized in that the preferably dry and grained substance is mixed with a preferably liquid agent by a device according to any one of claims 1 to 25. The method of claim 30, wherein said individual is an animal, such as a horse. The method of claim 31, wherein the device is inserted into the muzzle of the horse just in front of the first parietal tooth and said jig is pressed onto the root of the tongue.