:CONTAINERS FOR LIQUID MEDICINESFIELD OF THE INVENTIONThis invention relates to containers for liquid medicaments, especially for suspensions of liquid medicament, ie for formulations having liquid and particulate solid components in which at least one of the components, usually at least the solid component, has medicinal or medicinal properties .
BACKGROUND OF THE INVENTIONIt is known how to provide containers for liquid medicaments, for example solutions and suspensions, wherein the container takes the form of a cartridge or ampule formed from a tube, suitably, of glass sealed at one end by a piston and ending at the other end in an outlet piece sealed by a lid. In use, the cartridge is placed in a device similar to a ballpoint pen provided with a mechanism that operates by means of a piston. This mechanism, when operated, serves to move the piston a predetermined distance along the tube of the cartridge to inject a dose of the liquid medicament through a hypodermic needle, which is attached to the end of the cap so as to pierce the cover and establish communication with the inside of the cartridge. The volume of the cartridge is usually sufficient to accommodate various doses of medication, and the mechanism operated by the piston allows individual doses to be administered in controlled amounts and predetermined by the user or the patient. Even the multi-day supply of medication may be present in the cartridge. Such a pen-like device and multi-dose cartridges are described in European Patent Application 0058536. They are especially suitable for use with insulin formulations, and diabetic patients appreciate its convenience. To make sure that exact doses of those cartridges and pen devices are administered, the cartridge, whether containing a suspension or solution, should be free of any gas bubbles, although a small gas bubble or air bag may be present. present initially and be removed before the administration of the first dose by holding the device with the needle pointing upwards and then squeezing any gas by using the mechanism operated by the piston. Instructions on the needle and how to do this are usually included in the patient information leaflets that accompany the refilled cartridges. In the case of suspensions of liquid medication, however, the absence of an air gap or gas bubble of any significant size can make it difficult or fully consume the resuspended suspension in time, which will settle over time as the The cartridge / pen remains unused, for example in the patient's pocket or handbag, or during the storage of the cartridge before being loaded into the pen. Resuspension before injection is, of course, essential if the correct dose of the active ingredient, usually the solid component, is to be administered, and a failure in the total resuspension can have dangerous consequences, for example the case of suspensions. of insulin can lead to coma and other complications that endanger life. It is known to include in such medicament suspension cartridges one or more mixed elements, for example as taught in European Patent Application 0235691. The commercialized versions, which contain suspensions of insulin crystals, include one or more glass or metal spheres which, when the cartridge is shaken or inverted several times, are free to move and move within the cartridge, thus facilitating the mixing or homogenization of the suspension. Similarly, devices for the controlled infusion of medicaments are known. For example, U.S. Patent Application No. 4568335 describes a device that has a container for a suspension of medicament., a piston movable along the container, and an outlet piece connected by means of a tube to a hypodermic needle at an infusion site. It is taught that the mixing of the suspension is facilitated by the inclusion of an air bag or a small steel sphere within the container / suspension, air bag or sphere which can be made to move by spinning and inverting the end container to extreme several times before the infusion of each dose, the action is described as essential for the safe and effective operation of the device. Again, those devices are described as particularly suitable for the administration of a variable range of insulin suspension formulations, either commercially available or spontaneously blended with the faster acting forms in solution. The present invention also seeks to address the problem of adequately and rapidly resuspending suspensions of liquid medicament in containers such as those described above, furthermore it seeks to provide a container that allows an even faster or more reliable mixing, or with less agitation than required for the mixing elements used and described above.
BRIEF DESCRIPTION OF THE INVENTIONThus, in accordance with the present invention, there is provided a container for a suspension of liquid medicament, for example of the type described above, having a piston operable therein and an outlet therefrom, and containing a solid mixing element. , characterized in that the mixing element and the internal surface of the container are shaped to cooperate and restrict the mixing element against significant lateral movement but allow axial movement, the mixing element is shaped to allow the flow of the suspensions on either side from the element to the other side as the element moves axially, for example by tilting or inverting the container from end to end. The mixing element is solid since, in spite of an air bubble, the element has a fixed self-deformed external shape; however, as mentioned below, the mixing element may be hollow. The mixing element can be shaped to have a continuous or discontinuous peripheral surface cooperating with the internal surface of the container. The element can be shaped to present and define a plurality of angularly spaced regions, for example surfaces or points or contact lines to cooperate with the internal surface of the container. The general, and as preferred, the container and its internal surface should be cylindrical and the total cross section of the mixing element should be circular, ie the radially outermost parts of the element will be on a circle. Other corresponding forms of cooperation are possible for containers of different cross sectional shape.
The significant restriction against lateral movement of the mixing element within the container is suitably achieved by sizing the mixing element appropriately so that it is in a tight fit but slides freely within the container. Some lateral movement is tolerable, but should not be so large as to allow the mixing element to move significantly out of the axial alignment with the container with the undesirable result that the element is free to jump and rotate as long as the The container is inclined or inverted or, in fact, tilts by itself out of alignment with the wall of the container and therefore runs the risk of being trapped or squeezed into the container so that its mixing function is compromised. The mixing element may, however, be free to rotate axially and may be properly shaped to promote or reduce such rotary movement as it slidably moves within the container. This is an important difference between the mixing element employed in the present invention and the mixing elements proposed and used in the prior art, ie the movement of the element within the container is mainly a sliding movement along the length of the container (optionally with the axial rotary action), instead of being primarily a rolling or tumbling action as in the prior art. In addition, and as preferred, the mixing element of the present invention extends, at least in part, through essentially the entire diameter of the container, with the result that a greater proportion of the cross-section of the container is subject to the action of sweeping and mixing the element as it moves from one end of the container to the other. The shaping of the mixing element, to allow the flow of the suspension from one side to the other, appropriately takes the form of one or more openings through the element or, additionally or alternatively, one or more passages defined by the mixing element in combination with the internal surface of the container, such as by cavities or channels formed in the periphery of the mixing element. These openings, cavities or channels can, if desired, be profiled, for example with projections or constructions, to increase turbulence in the suspension as it flows from either side of the mixing element to another, and / or can be angularly placed in relation to the axis of the mixing element and in relation to its direction of travel to impart an axial rotational movement to the element as it moves axially within the container. Additionally or alternatively, the mixing element can be provided with blades, for example radially placed blades, angled with respect to the axis of movement of the element. The blades may all be angled in the same orientation, to make or promote the mixing element to develop a rotational movement as it moves axially within the container, or it may be arranged in opposite orientation to increase the turbulence in the medium flow of suspension as it flows between the blades. Where the mixing element is driven to move axially within the container by the simple action of tilting or end-to-end inversion of the latter, the material of which the element is made should have a density sufficiently different from that of the suspension medium, preferably at least a difference of 10%, more preferably at least a difference of 50% and more preferably at least a difference of 100%, to allow the element to fall or rise as the container is manipulated . Suitable materials that are more dense include metals, such as stainless steel, ceramics, certain plastics and glass, especially sintered glass. Materials less dense than the suspension medium, and which could float therein, include, for example, certain foamed plastics. Alternatively, the mixing element can be hollow and filled with gas, for example air, and therefore reach to float in the suspension medium. In addition, the mixing element can be formed or have implanted thereon a magnetic or magnetically sensitive material so that the axial movement of the element is caused and controlled by the movement of a corresponding magnetic device external to the container, such as a slidable collar, for example, it forms part of any body similar to a ballpoint pen in which the container in use is housed. Where the mixing element is magnetic or magnetically sensitive, its total density is less relevant. However, the material from which the element is made, or at least that part in contact with the suspension medium, must, however, be pharmaceutically acceptable, that is, it must not be toxic and inert to the components of the suspension.
The material from which the body is formed is preferably glass, although other pharmaceutically acceptable materials include metals, such as aluminum, rigid plastic materials and ceramics.
BRIEF DESCRIPTION OF THE DRAWINGSThe invention can be carried out in several ways, and now only several specific embodiments with possible modifications will be described by way of example, with reference to the accompanying drawings, in which: Figure 1 is a perspective view of a cylindrical cartridge or ampule for a suspension of liquid medicament and constructed in accordance with the invention; Figure 1A is a section of a part of the outlet of the cartridge of Figure 1; Figure 2 is a view from the end of the mixing element; Figure 3 is a section through the mixing element of Figure 2;Figure 4 is a perspective view of the mixing element of Figure 2; Figures 5 to 10 are views from the end of several mixing elements shaped differently; Figures 5A to 10A are respective sections on lines 5-5, 6-6, 7-7, 8-8, 9-9 and 10-10 of Figures 5 to 10; Figures 11 and 12 are perspective views of additional different mixing elements; Figures 13 and 13A are views from the end and in perspective, respectively, of another element; Figure 14 is an end view of a modified version of the element shown in Figures 13 and 13A; Figures 15 and 15A are views from the end and in perspective, respectively, of an additional element; and Figures 16 and 17 are perspective views of additional elements.
DETAILED DESCRIPTION OF THE INVENTIONReferring to Figures 1 to 4, a container in the form of a single-compartment cartridge or bullet 10 comprises a cylindrical glass tube with an open end 11 which has a neck of reduced diameter 12 at one end and which is sealed in the other end by means of a synthetic rubber piston 13 having, for example, three annular edges 14 engaging the inner surface of the tube 11. The cartridge 10 is filled with a suspension of liquid medicament, for example an aqueous suspension of insulin such as insulin isofane (NPH), and is free of air bubbles. The neck 12 is closed by an aluminum lid with an opening 16 and a synthetic rubber membrane or septum 17. When the cartridge 10 is loaded in one of the commercially available pen-like devices and a hypodermic needle is mounted, the needle perforates the membrane or septum 17, thereby entering and communicating with the interior of the cartridge 10. A mixing element 20 is located in the container and moves axially in the tube 11 between the inner end 21 of the piston 13 and a flange 22 at the inner end of the neck 12 of the outlet. The element 20 is shaped to cooperate with the inner surface 15 of the tube 11, which has three angularly spaced surfaces 31 which conform closely to the surface 15. The element 20 is sized to be in a narrow but non-restricted sliding fit. the tube 11 (see especially Figure 2), being therefore restricted against significant lateral movement. The mixing element 20 is free to rotate about the axis of the tube 11, but the lack of significant lateral movement prevents the element from rotating around any other axis so that it is not free to rotate or jump along the tube 11. , neither to tilt and be tightened in the tube 11. The mixing element 20 is also shaped to allow the flow of the medication suspension from one side to the other having an opening 34 extending therethrough, there are also passages 33. which extend from one side to the other of the element 20, defined and formed by three recesses 32 on the element 20 in combination with the surface 15 of the tube 11. Any of the opening 34 or the passages 33 could be omitted, but if it is preferred to have at least one internal passage, for example central, and an external one, for example peripheral, to increase the turbulence produced in the suspension by the movement of the mixing element 20 along the tube 11, since it is the turbulence produced in the flow of the suspension medium which is mainly responsible for the stirring action necessary to resuspend the particles in suspension leading to the desired homogenization of the drug. Element 20 in this mode is made of sintered glass, specifically Type I glass(pharmaceutical specification), such as that supplied by Schott Glasswerke, Mainz, Germany, under the trademark "FIOLAX". By tilting the tube 11 (for example when it is loaded in the pen-like housing) so that its axis is at an angle of 45 ° with respect to the horizontal, the mixing element 20 moves inside the tube 11 under the gravity and because its density is greater than that of the aqueous suspension, it is guided in its movement by the inner surface of the tube 15 in three angularly separated places defined by the three peripheral portions 31. In an example, of a container with a capacity of 3.0 cm3 with a total length of 6.5 cm, wherein the inner surface 15 has a diameter of 9.5 mm, the portions 31 are on a diameter of 9 mm, the recesses 32 have a length of 5.88 mm, the axial length of the element 20 is 4 mm and the diameter of the opening 34 is 3 mm. As with the variations in the measurements given above, other variations in the construction of the mixing element 20 are possible, of course. For example, the peripheral portions may vary in angular degree and may also vary in number. For example, there could be 2, 4, 5 or 6 or more peripheral portions separated by recesses. Alternatively, the periphery of the mixing element could have a completely continuous surface, the passages (32) would therefore be omitted. Similarly, mixing elements with openings (34) of different sizes, and in shapes other than circular, can be provided. Also, instead of a single opening, there may be a plurality of openings extending through the element (20), in fact, there may be an absence of an opening, provided the passages (32) are present to allow the flow of the suspension from either side of the element (20) to the other. Other variations include providing transverse edges or corrugations on the recesses 32 or on the wall of the openings 34 to increase the turbulence in the flow of the suspension medium. In addition, the diameter of the openings (34) may vary along the axial axis thereof, again to promote a greater turbulent flow in the suspension medium. For example the openings could be used from one axial end to the other, and where there are, for example, two openings or more, the direction of the lift can be reversed between the different openings. Also, any tapering inward opening from each axial end to a minimum cross section can be constructed, say halfway along the element. Those variations of the different characteristics of the mixing element can, of course, be made independently of the other characteristics. For example, the variations described above with respect to the openings are equally applicable to the mixing elements having different peripheral shapes, for example as described below. A selection of other examples of mixing elements is shown in Figures 5 to 10. In Figures 5 and 5A, the mixing element 40 has a single central opening 34 and eight angularly spaced peripheral portions 31 present on the radially placed teeth 41. having flat sides 42, the angle between the adjacent sides 42 of the nearby tooth is 60 °. In a specific example, the surface portions 31 are of a diameter of 9.3 mm, for use in a cartridge with an internal diameter of 9.5 mm. In Figures 6 and 6A, the mixing element 43 is similar to the mixing element 40 but has two openings of equal size 44, each 2 mm in diameter. The mixing element, shown in theFigures 7 and 7A are provided with 4 channels or generally rectangular grooves 45 equiangularly spaced around the periphery and which, when the element is located inside a cylindrical container serve to define, with the surface of the inner wall of the container, the passages to allow the flow of the suspension from either side of the element to the other. Between the channels or grooves 45 there are four equiangular peripheral portions with angled surfaces to cooperate with the inner surface of the container. Typically, the channels or grooves are 1 mm deep. The element is also shown with a single central opening, but which can be omitted or replaced by two or more openings.
The element 46 in Figures 8 and 8A is similar to that of Figures 7 and 7A, but the channels are more numerous and each extends over a larger radial arc, with the result that the peripheral portions take the shape of teeth radially placed 47. The element 46 has a single central opening therethrough. The mixing element of Figures 9 and 9A is similar to 1 of Figures 8 and 8A, but is provided with two openings 44. Alth those openings are shown to have straight perforations, the perforations may, as described above, be tapered, either in the same or opposite directions. The mixing element illustrated in Figures 10 and 10A present three angularly spaced surfaces to cooperate with the inner surface of a tubular shaped container, similarly to the surfaces 31 of the mixing element 20 shown in Figures 1 to 4 but a instead of being separated by recesses, the cooperating surfaces are separated by circular peripheral cuts in part 48, for example of radius 1.5 mm. The mixing element 50 shown in Figure 11, alth having a plurality of peripheral surfaces to cooperate with the internal surface of a cylindrical cartridge, has deep grooves 51 cut in the periphery and running parallel to the axis of the element and its direction of travel . Figure 12 shows a similar mixing element but where the grooves, alth individually straight, are inclined towards the central axis of the element and its direction of displacement to induce the rotary movement towards the element as it moves axially inside the cartridge and through the suspension. This rotational movement is a feature of the examples of mixing elements shown in Figures 13 to 15A. The mixing elements of Figures 13 and 14 are of a cup or plate shape in general, having a base portion 60 and an edge representing a peripheral outer continuous surface 61 for cooperating with the inner surface of a cartridge container cylindrical. The angularly spaced portions are removed from the base 60 to provide openings therein, and internal and external radial grooves 63, 64 are cut into the base to allow the portions 65 to be brought in from the plane of the base 60. The degree The angle of the portions 65 may vary, as can the number of such portions -see Figure 14- as well as the angle at which the portions are bent from the plane of the base 60. The base 60 is connected to a tube axial 66, which defines a central opening 34. The mixing element shown in Figures 15 and 15A is similar to that shown in Figure 12 with channels 70 whose side faces 71 are inclined at an angle towards the axis of the mixing element of so that the axial movement of the element within the container of the liquid medicament causes a rotation of the element about its axis. The number of channels and their angle of inclination may vary. Figures 16 and 17 show arrangements that induce turbulence at the center of a mixing element. In those embodiments, the mixing elements comprise internal and external coaxial tubular members 80 and 81 connected by means of the angularly spaced blades 82. In Figure 16, two sets of blades are shown, one set being both axially and radially displaced from the other. . The vanes 82 can be arranged so that their planes are parallel to the axis of the tubes 80 and 81, or if it is desired to induce a rotary movement to the elements as they pass through the container, they can be placed at an angle towards this, in propellant form. To increase the turbulence in the liquid medicament as the element passes, the vanes 82 in each set as shown in Figure 16 can be placed at an angle towards those in the other set, for example at an equal angle but opposite the axis of the tubes 80 and 81. It is desirable that the medicament suspension be homogenized to an acceptable degree by the minimum number of passages through the mixing element along the length of the container, for example, by tilting or by reversing movement from end to end of the container. Ideally, one or two tilting movements would be required: that is, if the cartridge has been stored in a horizontal position, it is desirable that a single inclination in a 45 ° direction, accompd by a complete passage of the mixing element in a direction, produce an acceptable homogeneous suspension, or, failing that, a second complete step reversing the inclination of the container through 90 ° is sufficient. The desirability of this facility is to bring the suspension to homogeneity is that patients or users who inadvertently forget to follow the instructions to invest the cartridge / pen a set number of times may, in any case by its handling of the device and preparation to use it by example, simply removing the device from a pocket, handbag or carrying case and placing it for injection, for example, in a sufficiently executed, hermetic tilt and similar handling movements with the device to produce an acceptable level of homogeneity to be achieved in the suspension. The following Comparative Examples illustrate the ease with which insulin crystal suspensions can be homogenized using containers according to the present invention, in relation to prior art containers employing simple spherical mixing elements.
COMPARATIVE EXAMPLE 1In this example, the commercially available 3 ml cartridges of Basal-H-Insulin 100 (suspension) from Hoechst AG were used for use with the Opti-Pen, each holding a standard size of 6.5 cm in length and a diameter internal 9.5 mm. Half of the cartridges were tested as they were commercially supplied, that is, they contained conventional mixing elements in the form of three spheres of stainless steel, each sphere had a diameter of 2.0 mm. The other half was modified by removing the steel spheres and replacing them by a single mixing element according to the present invention, made of sintered glass, with a shape according to the elements shown in Figures 7 and 7A, with a total diameter of 9.0 mm, axial length (thickness) of 4.5 mm, diameter of the central opening of 3.0 mm, and in each of which the four grooves or channels that extend axially peripheral had a width of 1.0 mm and a depth of 1.0 mm. In each of the following tests, 3 cartridge samples from each set were used.
Try theIn this first test, the cartridges were stored for 12 hours in a vertical position, ie vertically with the exit necks in the uppermost part. After this storage, each cartridge was carefully transferred, still maintaining the storage orientation, to an electronically controlled test machine and adjusted to invert each of the cartridges up to 180 ° for a period of 1.5 seconds, and to repeat that action until be stopped. The degree of homogenization was visually verified and evaluated on a per cent basis and the number of investments was noted.
Test 2aIn this second test the procedure of Test 1 above was followed, except that the cartridges were stored and transferred carefully to the test machine in inverted orientation ie vertically with their exit necks in the lower part. Again, the degree of homogenization was evaluated and the number of investments was noted.
Test 3aIn this third test, each of the cartridges were stored for 12 hours in the horizontal position, then the test machine was carefully transferred to that position. In this test the machine was controlled to tilt each cartridge to an angle of 45 ° (for 0.8 seconds), then it was returned to the horizontal (0.8 seconds) and then to a position at 45 ° from the horizontal in the opposite direction (0.8 seconds). Again, this action was repeated, the visual evaluation of the degree of homogenization was made, and the number of inclinations was noted (at an angle of 45 ° and again to the horizontal it is a single inclination).
Test 4aIn this fourth test the procedure in Test 3 above was repeated, except that the machine was programmed to tilt each cartridge from the horizontal to an angle of 90 ° (for 15 seconds), again to horizontal (1.5 seconds), and then up to 90 ° (1.5 seconds) in the opposite direction of the first movement. The machine repeated this action until it was stopped and again the degree of homogenization was evaluated and the number of inclinations was noted (a movement of 90 ° and again towards the horizontal is a single inclination). The results of these tests are shown in the following Table 1.
TABLE 1Number of DegreeInvestment Element No. / HomogenizationTEST Mixed Inclinings Average CartridgeSteel spheres 20 Incomplete. of 3 x 2.00 mm maximum 50% the Complete Element. 100% invention 2a Steel spheres 20 Incomplete. of 3 x 2.00 mm maximum 50%2nd Complete Element. 100% invention 3a Steel spheres 20 Incomplete. of 3 x 2.00 mm maximum 40%3rd Complete Element. 100% invention 4a Steel spheres 20 Incomplete. of 3 x 2.00 mm maximum 50%4th Complete Element. 100% invention COMPARATIVE EXAMPLE 2In this Example, commercially available Insulin Protamin HM Penfil (suspension) filling cartridges from Novo Nordisk, again 6.5 cm in standard length 9.5 mm in internal diameter, were used. Half were tested as they were commercially supplied, i.e. they contained a conventional mixing element in the form of a glass bead having a diameter of 2.5 mm, and the other half was modified by removing the glass loss and replacing it with an element of glass. mixed according to the invention in accordance as illustrated in Comparative Example 1, above.
Subsequently, tests Ib up to 4b were carried out in an identical manner to the tests up to the previous 4th, again 3 cartridges were used in each batch tested, and again the average degree of homogenization was visually evaluated and the number of samples was taken into account. investments / inclinations. The results are shown in the following Table 2.
TABLE 2Degree Number ofInvestment Element No. / HomogenizationTEST Mixed Inclinings Average CartridgeIb Glass beads 20 Incomplete. 1 x 2.5 mm maximum 50-60%Ib Complete Element. 100% invention 2b Glass beads 20 Incomplete. 1 x 2.5 mm maximum 50-60%2b Complete Element. 100% invention 3b Glass beads 20 Incomplete. 1 x 2.5 mm maximum 50-60%3b Complete element. 100% invention 4b Glass beads 20 Incomplete. 1 x 2.5 mm maximum 50-60%4b Complete Element. 100% invention It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is the one conventional for the manufacture of the objects to which it refers. Having described the invention as above, the content of the following is claimed as property: