WO2006117340A1

WO2006117340A1 - Cartridge containing a medicament suspension and mixing elements having different densities

Info

Publication number: WO2006117340A1
Application number: PCT/EP2006/061922
Authority: WO
Inventors: Dan Noertoft Soerensen
Original assignee: Novo Nordisk A/S
Priority date: 2005-05-03
Filing date: 2006-04-28
Publication date: 2006-11-09
Also published as: US20080161756A1; JP2008539838A; CN100571802C; CN101171043A; EP1890747A1

Abstract

The present invention relates to a device for storage and administration of a medicament suspension comprising a container (1) for receiving a medicament suspension wherein the container has two mixing elements (5, 6) which differ with respect to their density such that the first mixing element (5) has a density significantly above the background liquid and significantly above the fully mixed suspension density and the second mixing element (6) has a density significantly below the background liquid and significantly below the fully mixed suspension density.

Description

CARTRIDGE CONTAINING A MEDICAMENT SUSPENSION AND MIXING ELEMENTS HAVING

DIFFERENT DENSITIES

THE TECHNICAL FIELD OF THE INVENTION:

The present invention relates to a device for the administration of a medicament suspension, particularly a device holding a medicament container filled with a medicament suspension and including two mixing elements of a predetermined size and density for mixing of medicaments that includes suspended particulates.

DESCRIPTION OF RELATED ART:

Medicaments are usually filled in containers, which also contain a gas space above the suspension. During the storage of the container, the suspended particulate in the medicament suspension frequently settles down to form a deposit. For shaking the medicament so as to make it uniform, the patient uses a combination of the rolling of the container between the palms and by turning the container upside down. The former procedure mainly loosens deposit from the walls whereas the latter mainly ensures proper mixing along the length of the cartridges. Also the suspension can be homogenized by shaking the suspension and all this mobility is essentially due to the presence of the gas space in the container.

However, in containers from which multiple administration has to take place, there is no gas space and a gas free filling is necessary since only then is a reproducible dose administration ensured. Therefore, homogenous mixing in such containers is normally not possible in a reasonable time as gas bubble free crystal suspensions cannot be converted into necessary homogenous form by shaking in an acceptable period of time.

Use of steel balls as mixing elements for lubricant dispersions and paints, which are filled into spray cans is known. However, the lubricants are easily dispersible substances such as molybdenum sulfide and graphite which can easily be converted into a sprayable form by a few shaking movements.

In medicament containers for multiple administrations, due to unfavorable ratio of diameter to length, which changes constantly during use when the piston or plunger is advanced, and due to lack of gas space, it is not expected that simple mixing elements as known for spray cans could also be used for homogenization in medicament suspensions.

In case of an insulin suspension, too few crystals i.e. too small a concentration of insulin are administered because the suspension has been inadequately shaken or has already settled again.

Hitherto, a single mixing bead such as a glass sphere with a diameter of approximately 2.5 mm was used to ensure proper re-suspension of the material within the cartridges. Also, it is known that many medicament crystals are sensitive to mechanical load and therefore the alteration of the particle size of the medicament was also feared in the use of mixing elements in medicament containers.

One such patent, which uses a mixing element, is EP 235.691 , which discloses a medica- ment container, such as an injection ampoule or cartridge, for multiple administration of a medicament suspension. The container is filled with medicament so as to be free of gas bubbles, and includes at least one inert mixing element of suitable size whose density is different from that of the suspension. The mixing element acts to homogenize the medicament suspension as the container is shaken. Also, in the event the medicament container has more than one mixing element, the material of which all the mixing element is made are the same for instance, as mentioned in example 2, two glass beads are used for homogenization of the medicament suspension.

One disadvantage of the above patent is that for suspensions that have rested for a signifi- cant amount of time, the above procedure must be repeated several times before a suitable mixing is achieved. Also, there is a possibility that the mixing element/bead as especially observed for cartridges that have been centrifuged, is buried within the deposit and that the mixing procedure is insufficient for resuspension.

DESCRIPTION OF THE INVENTION:

The object of the present invention is to overcome the before-mentioned disadvantages and provide for several advantages for the resuspension of the particulates that are initially deposited at a side-or end-wall of a cartridge. It is yet another object of the present invention to ensure that one of the mixing beads is never buried within the deposited particulate.

Yet still another object of the present invention is to improve the efficiency of the current mixing procedure.

To achieve the before mentioned objects, the present invention provides for a container for storage and administration of a medicament suspension which container has two mixing elements which differ with respect to their density such that one element has a density significantly above the background liquid density and above the fully mixed suspension density and the other element has a density significantly below the background liquid density and below the fully mixed suspension density.

All though two mixing elements are the preferred number any number can be used as long as at least two of the mixing elements differ with respect to their density as explained.

As used herein, the term "medicament" or "drug" is meant to encompass any drug-containing flowable medicine capable of being passed through a delivery means such as a hollow nee- die in a controlled manner, such as a liquid, solution, gel or fine suspension. Representative drugs includes pharmaceuticals such as peptides, proteins (e.g. insulin, insulin analogues and C-peptide), and hormones, biologically derived or active agents, hormonal and gene based agents, nutritional formulas and other substances in both solid (dispensed) or liquid form.

Correspondingly, the term "subcutaneous" injection is meant to encompass any method of transcutaneous delivery to a subject.

"Inert" as used in the present application is taken to mean that a mixing element neither in- teracts chemically nor physically in an interfering manner with the medicament preparation. Thus, neither a chemical change nor a physical impairment such as adsorption or abrasion may occur to a significant extent.

"Supension" is taken to mean a background liquid in which particulate matter is suspended. Further the term "injection needle" defines a piercing member adapted to penetrate the skin of a subject for the purpose of delivering or removing a liquid.

All references, including publications, patent applications, and patents, cited herein are incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only and should not be constructed as limiting the invention in any way.

The use of any and all examples, or exemplary language (e.g. such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

BRIEF DESCRIPTION OF THE DRAWINGS:

In order that the invention may be more readily understood, embodiments thereof will now be described by way of example with reference being made to the accompanying drawings. The accompanying drawings constitute a part of the specification and the detailed description of the preferred embodiment given below serves to explain the principles.

Fig. 1 illustrates a situation where the cartridge/container have rested for a long time and particulates with a density above the background liquid have settled at the distal end near the outlet port. Fig. 2 illustrates a situation where the cartridge/container has rested for a long time and particulates with a density below the background liquid have settled at the proximal end near the plunger.

Fig. 3 shows the rolling motion of the cartridge during the resuspension procedure.

Fig. 4 shows the upside-down turning motion of the cartridge during the resuspension procedure.

Fig. 5 illustrates that the cartridge has been stored on the side for some time with the deposited material having a larger density than the liquid.

Fig. 6 illustrates upside down turning procedure of the cartridge having two mixing beads according to the present invention.

Fig. 7 illustrates a proper dimensioning of the beads for achieving a suitable passing position in the cartridge.

DETAILED DESCRIPTION OF THE INVENTION

When in the following terms as "upper" and "lower", "right" and "left", "horizontal" and "vertical", "clockwise" and "counter clockwise" or similar relative expressions are used, these only refer to the appended figures and not to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as there relative dimensions are intended to serve illustrative purposes only.

In that context it may be convenient to define that the term "proximal end" in the appended figures is meant to refer to the end of the filled cartridge carrying the plunger whereas the term "distal end" is meant to refer to the opposite end of the filled cartridge carrying the outlet port to which an injection needle is coupled in use.

A preferred embodiment of the invention is now described with reference to the figures where like reference numbers indicate identical or functionally similar elements. While specific configurations and arrangements are discussed, it should be understood that this is done for il- lustrative purposes only. A person skilled in the relevant art will recognize that other configurations and arrangements can be used without departing from the spirit and scope of the invention.

Also, in the figures, the mixing element preferably has a spherical shape but it is to be understood to a person skilled in the art that the shape of the mixing element is not to be limited to being a sphere. As shown in Fig. 1 , the container 1 has a movable plunger 2 at the proximal end and is filled with a medicament suspension so as to be bubble free and contains one or more spherical mixing element 5, 6. In the opposite distal end, the container 1 is provided with an outlet port 4 typically covered by a rubber membrane which can be penetrated by the injection needle.

Figure 1 shows a situation where the cartridge 1 has rested for a long time and the particulate 3 has settled with a density above the density of the background liquid and with the first mixing element 5 buried in the particulate 3. The second mixing element 6 is outside the region of the particulate 3. The reason for the second mixing element 6 being outside the region of the particulate 3 is because the density of the second mixing element 6 is smaller than the density of the background liquid. Buoyancy therefore ensures that the second mixing element 6 that is lighter is available for the mixing procedure.

Similarly as shown in Figure 2, buoyancy ensures that the first mixing element 5 which is heavier is outside the region of the suspension and is available for the mixing procedure.

Figures 1 and 2 therefore are illustrative of the fact that one of the two mixing elements is never buried within the deposited particulate and is always available for mixing.

Figures 3 to 7 demonstrate the improved efficiency of the mixing procedure because of the presence of two mixing elements having different densities.

Figure 3 shows the rolling motion of the cartridge during the re-suspension procedure. Al- though the mixing elements 5, 6 play a minor role in the re-suspension procedure during rolling, the presence of these two elements approximately doubles the efficiency of the elements, compared to having one element. In a situation during the upside-down turning procedure of the cartridge as shown in Figure 4, the light mixing element 6 will be on the upward facing side of the cartridge whereas the heavy mixing element 5 will be at the downwards facing side and consequently mixing is achieved in a double acting way.

This is possible because the two mixing elements have different densities, higher and lower than the background liquid respectively and therefore they will always be at two different positions within the cartridge.

Another situation, which may arise, is when the cartridge has been lying down for some time, as a consequence the deposit material 7 having a larger density than the liquid will be deposited on the lower side of the cartridge as shown in Figure 5.

During the upside down turning procedure of the cartridge as shown in Figure 6, the deposit material may stick to the surface and if, by chance, the cartridge is turned so that the deposit material 7 is placed on the upper side of the cartridge, the heavy mixing element 5 is actually outside the deposit material 7 during the re-suspension procedure. Thus adding the second mixing element increases the likelihood of said elements passing through the deposit.

Another situation is as shown in Figure 7, which improves the mixing process because of the interaction between the mixing elements. In figure 7, the cartridge is shown in the upside down position and the heavy mixing element 5 will move downwards along the lower side of the wall whereas the low density mixing element 6 will move upwards along the upper side of the wall. With proper sizing and density of the beads, the velocity of the two beads 5, 6 may be adjusted as desired. For example, if the light mixing element travels with half the velocity of the heavy mixing element 5, the two elements will meet at 1/3 and 2/3 cartridge length respectively during a full upside down turn of the cartridge as shown in this figure.

The lighter mixing element 6 may be introduced as a hollow glass sphere. Alternatively, a low-density material like plastic material may be used. Said material should be inert with respect to the medicament suspension. The dimension of said lighter element is determined from the properties of the existing high-density element 5 such that the velocity of the light mixing element 6 is a fraction of the velocity of the high mixing element 5. This velocity is a function of the element and liquid densities, liquid viscosity and element size. The density of the suspension is not likely to vary very much and consequently, the range of the required low density elements/beads depends mainly on the range of viscosities. Estimates of suitable element size and density results from relatively simple calculations.

Some preferred embodiments have been shown in the foregoing, but it should be stressed that the invention is not limited to these, but may be embodied in other ways within the subject matter defined in the following claims. The present invention has been specifically described with reference to subcutaneous injections. But it will be fully understood that the invention is applicable in other situations.

Claims

CLAIMS:

1 . A device for storage and administration of a medicament suspension comprising a con- tainer (1 ) containing a medicament suspension which suspension comprises a background liquid with suspended particulate (3), characterized in that, the container (1 ) comprises two mixing elements (5, 6) which differ in density such that a first mixing element (5) has a density significantly above the density of the background liquid and significantly above the fully mixed suspension density and a second mixing element (6) has a density significantly below the density of the background liquid and significantly below the fully mixed suspension density.

2. A device according to claim 1 , characterized in that, the container (1 ) for receiving the medicament is a cylindrical cartridge (1 ) which is sealed at the top by a movable plunger (2) and at the bottom by an outlet port (4).

3. A device according to claim 1 or 2, characterized in that, the mixing elements (5, 6) are inert to the medicament suspension.

4. A device according to claim 1 , 2 or 3, characterized in that, the first mixing element (5) and/or the second mixing element (6) is a hollow sphere.

5. A device according to anyone of the claims 1 to 4, characterized in that, the first mixing element (5) and/or the second mixing element (6) is a glass or plastic sphere.

6. A device according to anyone of the claims 1 to 5, characterized in that, the density of the first mixing element (5) and of the second mixing element (6) depends on the viscosity of the suspension.

7. A device according to anyone of the claims 1 to 6, characterized in that, the first and second mixing elements are of the same diameter.

8. A device according to anyone of the claims 1 to 6, characterized in that, the first and second mixing elements (5, 6) are of different diameter.

9. A device according to anyone of the claims 1 to 8, characterized in that, the first mixing element (5) and the second mixing element (6) are of the same shape.

10. A device according to anyone of the claims 1 to 8, characterized in that, the first mixing element (5) and the second mixing element (6) are of different shape.