WO2000071191A2

WO2000071191A2 - Cartridge assembly for medicament suspensions

Info

Publication number: WO2000071191A2
Application number: PCT/US2000/011230
Authority: WO
Inventors: Michael Rosario Defelippis; Richard Dennis Dimarchi; Bruce Hill Frank; Paul Arthur Hines; Mary Patricia Lents
Original assignee: Eli Lilly And Company
Priority date: 1999-04-30
Filing date: 2000-04-27
Publication date: 2000-11-30
Also published as: AU4492800A; WO2000071191A3

Abstract

A cartridge assembly for use in a pen-type medicament injector. The cartridge assembly comprises a cartridge for receiving a medicament suspension, the cartridge having a needle-pierceable outlet for the liquid medicament at one end thereof. A movable plunger positioned within the cartridge seals the other end. First and second mixing elements are provided within the cartridge to assist in mixing the medicament suspension. A first disk-shaped mixing element is disposed within the cartridge between the plunger and the outlet, the disk-shaped element being sized and shaped to permit its axial movement within the cartridge but to prevent any significant lateral movement. A second bead-shaped mixing element is disposed within the cartridge between the disk-shaped element and the outlet, the bead-shaped element being sized and shaped for free random movement between the disk-shaped element and the outlet.

Description

CARTRIDGE ASSEMBLY FOR MEDICAMENT SUSPENSIONS Background of the Invention

The present invention relates to containers for medicament suspensions, and more particularly, to a cartridge assembly for use in delivering medicament suspensions to a patient from a pen-type injector.

Cartridge-type containers for parenteral medicament solutions and suspensions are known in the art. Typically, such containers are used in connection with pen-type injection devices of the type commonly used by diabetics to inject doses of insulin. The cartridges are generally of cylindrical shape, and are sealed at one end by a movable plunger, or piston. The other, or outlet, end of the cartridge includes a cap having a needle-pierceable membrane extending across the outlet. An adjustable mechanism is used to advance the plunger a predetermined distance toward the outlet end of the cartridge. This action forces a predetermined dosage of the medicament through the needle for injection. Generally, the volume of the cartridge is sufficient to accommodate more than one dose of the liquid medicament. When a medicament includes suspended particles, such as protracted acting insulin suspensions, the suspended particles tend to settle out of the liquid vehicle. Larger medicament containers of the type commonly used with syringes, such as 10 ml insulin vials, include a headspace since these vials are not completely filled with formulation. When vials include a headspace, homogeneous dispersion of the particles may normally be achieved by mild agitation of the vial. The headspace in the vial allows greater freedom for the preparation to move within the container during agitation, thereby enhancing re-suspendability of the particles. As a result, additional mixing aids are generally not required with larger containers.

Pen-type injectors, however, are normally designed to utilize smaller medicament containers. It is common to use 1.5 and 3.0 ml medicament cartridges with such devices. Since no significant air headspace is present interiorly of such cartridges, much greater effort is normally required on the part of the patient in order to obtain a homogeneous dispersion of the particles. Improper re-suspension of these particles can result in a non-homogeneous suspension. Thus, prior to the initial use of the cartridge, and prior to successive uses, it is important that the cartridge be thoroughly agitated, or shaken.

In order to enhance re-suspendability of the particles, some prior art cartridges have included mixing aids. For example, commercially available cartridge preparations of NPH insulin and regular insulin/mixture suspensions may include one or more mixing beads, having a diameter of approximately 2.5-3 mm, to aid re-suspension as the container is shaken or inverted. A container including mixing beads is described in U.S. Patent No. 4,850,966.

An alternate mixing aid is described in U.S. Patent No. 5,549,5 /4. In the cartridge described in this patent, the plunger is equipped with one or more mixing vanes, which extend from the plunger inwardly into the cartridge. When the cartridge is twisted back and forth about its axis, the vanes help create small currents and eddies within the cartridge, thereby aiding the mixing of the suspension.

Yet another known mixing aid is described in U.S. Patent No. 5,725,500. A mixing disk is inserted into the container between the plunger and the outlet end. The disk has an internal diameter slightly smaller than the internal diameter of the cartridge body, and may have a central bore and scored grooves around its circumference. The disk normally lays flat on the plunger, when the cartridge is stored in an upright position. When the cartridge is inverted and then re-inverted, the disk traverses up and down the length of the cartridge body, thereby agitating the particles to aid in their re-suspension.

Although each of these prior art designs provides assistance to the patient in enabling him/her to properly re-suspend the contents of the cartridge prior to use, the search continues for a medicament cartridge that is even more "user-friendly" to the patient, i. e. , that requires less overall agitative effort to achieve homogeneity of the particles in the medicament suspension. Summary of the Invention

The present invention comprises a cartridge assembly for use in injecting a medicament suspension from a pen-type medicament injector. The cartridge assembly comprises a cartridge for receiving the medicament suspension, the cartridge having an outlet for the medicament at one end thereof, and a movable plunger positioned for axial movement within the cartridge sealing the other end. A first generally disk-shaped mixing element is disposed within the cartridge between the plunger and the outlet, the first mixing element being sized and shaped to permit axial movement within the cartridge but to constrain significant lateral movement. The disk-shaped mixing element is configured to permit flow of suspension from either side of this element to the other side as the mixing element moves axially in the cartridge. At least one bead-shaped second mixing element is disposed within said cartridge between the first mixing element and the outlet. The second mixing element is sized and shaped for free random movement between the first mixing element and the outlet. The movement of the respective mixing elements within the cartridge agitates the medicament, and assists in re-suspending the particles.

An advantage of the present invention is that it provides a medicament cartridge having two different types of mixing elements, thereby providing increased assurance to a patient that a medicament suspension will be adequately mixed before injection.

Another advantage of the present invention is that it provides a cartridge that requires less agitative effort on the part of the patient to re-suspend the particles in the suspension.

A further advantage of the present invention is that it combines in a single cartridge the re-suspension advantages obtained with the use of two different types of mixing elements.

Additional and further advantages of the present invention will become apparent from the following description of the preferred embodiments. Brief Description of the Drawings

Fig. 1 is a partially cross-sectioned side view of a cartridge assembly filled with medicament, in accordance with a preferred embodiment of the present invention. Fig. 2 is a partially cross-sectioned side view of the cartridge assembly of

Fig. 1, illustrating the position of the plunger and the mixing elements after a substantial amount of the medicament has been injected.

Fig. 3 is an end view of a mixing disk, in accordance with a preferred embodiment of the present invention.

Description of the Preferred Embodiments

Referring to Figs. 1 and 2, there is shown a side view, partially in cross- section, of a cartridge assembly 10 for use in a conventional pen-type injection device (not shown). An example of a pen-type injection device is illustrated in European Patent Application No. 730876, entitled Recyclable Medication

Dispensing Device. The cartridge assembly 10 of the present invention includes generally cylindrical cartridge 12, which has an open end 14 and an opposite, or outlet, end 16. Open end 14 is sealed by axially-movable plunger 18.

The cartridge illustrated in Fig. 1 is substantially filled with medicament suspension. The medicament may comprise a suspension of either microcrystalline or amorphous particles, or a combination of them. The term "microcrystalline" is used herein to define particle structures having a distinct morphology. The term "amorphous" is used to define particle structures not having a distinct morphology. When a cartridge is filled, or substantially filled, with medicament, plunger 18 is positioned at the axially opposite end of the cartridge from outlet end 16. A piston rod (not shown) is operably connected to plunger 18 in known fashion, for advancing plunger 18 axially forward from the position shown in Fig. 1 to outlet end 16, to force medicament through a hypodermic needle (not shown) for injection into a patient. Fig. 2 illustrates the position of plunger 18 after a substantial amount of the medicament has been injected.

As illustrated in Figs. 1 and 2, outlet end 16 includes neck portion 20, which is sealed by cap 22. Cap 22 is of a type commonly used with medicament containers, and includes a central aperture covered by a synthetic rubber membrane or septum 24. In use, the hypodermic needle is attached to neck portion 20 of cartridge end 16 by any conventional attachment means, in a manner such that one end of the needle pierces the membrane, thereby entering and communicating with the interior space of the cartridge. Cartridge assembly 10 includes a mixing element 30, such as the disk- shaped element shown in Fig. 3. As illustrated in Figs. 1 and 2, mixing element 30 is axially positioned in the cartridge between plunger 18 and outlet end portion 16. Mixing element 30 has an outer diameter that is only slightly smaller than the internal diameter of cartridge 12, to enable mixing element 30 to axially traverse the length of the cartridge during inversion of the cartridge, but to prevent any substantial lateral movement of the element within the cartridge. Preferably, mixing element 30 is freely rotatable about the axis of the cartridge. Conventional 3.0 ml cartridges have an inner diameter of approximately 10 mm. The outer diameter of a mixing element for use in such cartridges is approximately 9 mm. The axial sliding movement of element 30 within cartridge 12 is limited only by the axial position of the plunger 18 relative to outlet end 16 of the cartridge.

In order to enable it to freely move within the cartridge under the influence of gravity, the mixing element must have a density greater than that of the medicament suspension. In addition, the mixing element must be substantially inert to the medicament suspension. "Inert" is used herein to mean that the mixing element does not react chemically or physically with the medicament suspension in a manner that substantially interferes with the ability of the medicament to provide its intended beneficial activity. Preferably, the mixing element is made from sintered glass, such as Type I (pharmaceutical specification) sintered glass, supplied by Schott Glasswerke, Mainz, Germany, under the trademark FIOLAX. Although sintered glass is the presently preferred composition of the mixing element, those skilled in the art will recognize that the disk may be formed from other suitable compositions, such as other forms of glass, as well as plastic, metal and ceramics. In a preferred embodiment of the mixing element illustrated in Fig. 3, mixing element 30 is generally disk-shaped, having an axial central bore 32 and spaced notches 34 scored about its circumference. Although the disk-shaped embodiment illustrated in Fig. 3 is preferred, the invention is not so limited. An important feature of the mixing element is that it has sufficient surface area to provide agitation to the medicament as the mixing element traverses the inner surface of cartridge 12. Thus, any configuration that includes such surface area, and is sized and shaped to cooperate with the inner surface of the cartridge to allow a close but unrestricted sliding fit within the cartridge, may be utilized. Numerous examples of suitably-shaped mixing elements are illustrated in U.S. Patent No. 5,725,500, incorporated by reference herein.

In addition to mixing element 30, cartridge assembly 10 also includes one or more mixing beads 40. Mixing beads 40 are also inert to the medicament suspension, and have a density greater than that of the medicament suspension. As illustrated in Figs. 1 and 2, a mixing bead 40 is positioned within cartridge assembly 10 such that it is located between mixing element 30 and cartridge outlet end 16. Preferably mixing bead 40 is generally spherical, and has a diameter larger than the diameter of any of the apertures, bores, notches, etc., that may be present in mixing element 30. As a result, bead 40 cannot pass through any such apertures, etc., in mixing element 30, thereby maintaining the position of mixing bead 40 between mixing element 30 and outlet end 16. When a 3.0 ml cartridge is utilized, a mixing bead having a diameter of about 2.5 mm is preferred. Preferably, the mixing beads are made of Type I borosilicate glass (surface polished), available from Sigmund Lindner GmbH, Warmenstinach, Germany. Although borosilicate glass is the presently preferred composition of the mixing beads, those skilled in the art will recognize that the beads may be formed from other suitable compositions, such as other types of glass, as well as plastic, metal and ceramics.

Examples

A series of tests was performed in order to compare the redispersibility of certain microcrystalline particles into the medicament in cartridges containing the inventive combination of a mixing element and a mixing bead, with the redispersibility of such particles in similarly-sized cartridges containing either a mixing element or a mixing bead. Tests were performed at various medicament levels in the cartridges, at various cartridge storage temperatures, and at two different cartridge storage orientations, namely, upright and side storage. Sample preparation: Human insulin 70/30 (NPH/R) was selected as a representative medicament product for use in these tests. Human insulin 70/30 is a mixture of 70% isophane human insulin suspension (NPH), and 30% human insulin suspension (R). 3.0 ml cartridges were used. The cartridge samples containing a mixing disk were prepared by inserting a suitably sized sintered glass-mixing disk having the configuration shown in Fig. 3 into an empty cartridge. The open end of each cartridge was sealed by inserting the plunger. Prior to adding the NPH/R human insulin via the outlet end of the cartridge, the microcrystalline particles were fully re-suspended in the insulin by stirring using a magnetic stir bar. The cartridges were then hand-filled using standard laboratory procedures. Filled cartridges were capped and crimped with a West capper machine.

Cartridge samples containing a combination of a glass mixing bead and a mixing disk were prepared in a similar manner. A suitably sized mixing disk and glass bead were inserted into an empty cartridge. The open end of each cartridge was sealed by inserting the plunger, the elements being arranged such that the mixing disk was axially positioned in the cartridge between the plunger and the mixing bead. Prior to the addition of the insulin, the microcrystalline particles were fully re-suspended by stirring using a magnetic stir bar. The cartridges were hand-filled via the outlet end using standard laboratory procedures, and the filled cartridges were capped and crimped as before. The glass bead was of the borosilicate type described above, and was of a size (2.5 mm diameter) commonly used in commercial cartridges. The 3.0 ml cartridges including a mixing bead as the only mixing aid were taken from Eli Lilly and Company HUMULIN^® commercial stock.

As discussed below, some of the cartridges were dosed (with a 3.0 ml pen device) prior to testing so that they included only 20 Units or 100 Units, respectively, of the original 300 Unit medicament volume normally present in a 3.0 ml cartridge. The remaining cartridges were filled (i.e., 300 Units) with liquid medicament when tested.

Test Procedure: Prior to use in these tests, the microcrystalline particles in each of the cartridges were fully re-suspended in the medicament. The cartridges were then either maintained upright or placed on their respective sides, as described hereinafter, and the microcrystalline particles were allowed to settle. Some of the cartridges were maintained at room temperature, while others were maintained at refrigerated conditions (between about 2-8 °C.)

Cartridge samples were then subjected to one or more of the agitation procedures described below:

Inversions: With this technique, a cartridge was grasped at the plunger end between the index finger and thumb, and held upright with the stoppered (outlet) end up. The tester's wrist was then turned so that the cartridge was turned upside down, with the stoppered end now facing down. The tester then returned the cartridge to its original position. This entire operation was defined as one inversion. The procedure was repeated as necessary. When cartridges having a mixing disk were inverted, care was taken to ensure that the disk traveled the length of the cartridge in each direction.

Wrist Flicks: The cartridge was grasped at the plunger end between the second knuckle of the index finger and thumb, and held in an upright position. The tester then snapped ("flicked") his wrist forwardly. This operation was defined as one wrist flick. The procedure was repeated as needed.

Shaking: The cartridge was grasped with the index finger on the stopper end of the cartridge and the thumb on the plunger end. The tester then moved his wrist back and forth in a shaking motion. This technique was based upon shaking time, rather than upon any predetermined number of "shakes. "

Palm Rolls: The cartridge was held between the palms of the tester's hands, and rolled a designated number of times. One roll was complete when one hand moved completely up and down the other (stationary) hand. Results of the tests were reported as "yes" or "no", depending upon whether suspension homogeneity was judged complete or not. The completeness was determined by a visual assessment under low-power magnification (6.7x), as it was often difficult to determine whether homogeneity was complete without magnification. Results

Re-suspension of full cartridges containing a mixing disk: The inversion technique was found to be the most appropriate method of re-suspension for full cartridges containing a mixing disk. When such cartridges that had been stored in an upright condition at room temperature were subjected to one complete inversion, some streaking of the solids was visible in the cartridge. With two to four inversions, some solid material was still observed on top of the plunger. Five inversions resulted in an acceptably re-suspended cartridge. When testing cartridges that had been stored on their respective sides at room temperature, acceptable re-suspension was obtained after three inversions.

The re-suspendability of the microcrystalline particles in full cartridges containing a mixing disk was also investigated using the other techniques described above. Full cartridges containing a mixing disk were found to be ineffectively re- suspended by the palm roll technique (ten rolls), regardless of whether the cartridge had been stored upright or on its side. However combining palm rolls and inversions provided satisfactory re-suspension. In addition, shaking for ten seconds or ten wrist flicks was found to provide adequate re-suspension. Results of these tests are provided in Table 1. Cartridges containing a mixing disk that were stored under refrigeration did not provide acceptable re-suspension after five inversions, regardless of whether the cartridge was stored upright or on its side. Acceptable re- suspension of refrigerated cartridges was obtained after ten wrist flicks. Results of these tests are provided in Table 2. Re-suspension of full cartridges containing a glass bead: Unlike the results obtained with a mixing disk, inversions alone were generally not found to be sufficient for achieving a homogeneous suspension with full cartridges containing a single glass mixing bead stored at room temperature, regardless of whether the cartridges were stored in upright or side orientation. Shaking for ten seconds, or ten wrist flicks, each provided satisfactory re-suspension of medicament in full cartridges stored upright at room temperature (Table 1).

With samples stored under refrigeration, acceptable homogeneity could not be obtained after ten wrist flicks (Table 2). Table 1. Re-suspension of full cartridges containing either a mixing disk or a mixing bead stored at room temperature.

Table 2. Re-suspension of full cartridges containing either a mixing disk or a mixing bead stored at refrigerated conditions.

Re-suspension of dosed cartridges containing a mixing disk: The next set of tests was carried out on cartridges that had been dosed such that the cartridges contained either 20 U or 100 U of the medicament. The objective of this set of tests was to determine whether the more limited stroke displacement available with dosed cartridges affects the ability of the mixing disk to provide effective re-suspension. The limited stroke displacement of dosed cartridges is illustrated in Fig. 2, wherein it may be observed that the axial distance between plunger 18 and outlet end 16 is decreased when compared to the axial distance between these elements in a full cartridge, as illustrated in Fig. 1. Cartridges containing the mixing disk at the indicated dosage levels were tested using the techniques described in the preceding section. Unlike the results obtained with full cartridges at room temperature, homogeneous re-suspension could not be achieved after five inversions for dosed cartridges stored upright at room temperature, regardless of whether the amount of medicament remaining in the cartridges tested was 20 U or 100 U. In these samples, it was found that most of the suspension solids remained on the plunger rather than on the top of the mixing disk. The limited distance the mixing disk can travel was found to reduce the efficiency of the re-suspension. Results of these tests are provided in Table 3. Despite the inability to achieve homogeneous re-suspension after five inversions with dosed cartridges stored upright at room temperature, five inversions did provide adequate re-suspension when dosed cartridges had been stored on their sides. This difference may have resulted from the settling of suspension crystals on the cartridge wall as a result of the side storage of the cartridges, thereby resulting in greater contact between the crystals and the moving mixing disk during inversion. Upright storage tended to trap solids between the mixing disk and the plunger.

Re-suspension of dosed cartridges containing a mixing bead: When testing dosed cartridges containing a mixing bead that had been stored upright at room temperature, the re-suspension results obtained were identical to those with cartridges containing a mixing disk (Table 3). With dosed cartridges containing a mixing bead that had been stored on their sides, neither five inversions nor ten flicks of the cartridge provided satisfactory re-suspension of the particles. The WO 00/71191 PCT/USOO/l 1230 combined palm roll and inversion techniques did provide appropriate suspension homogeniety.

Table 3. Re-suspension of dosed cartridges containing either a mixing disk or 5 a mixing bead stored at room temperature.

Re-suspension of full cartridges containing a mixing disk and a mixing

10 bead: Re-suspension tests were carried out using full cartridges containing a combination of a mixing disk and a mixing bead. Results from tests utilizing these cartridges were compared to previous re-suspension results from cartridges containing individual mixing aids. The results obtained for full cartridges containing both mixing aids are provided in Table 4. Due to the presence of both

15 mixing aids in the full cartridge, a homogeneous suspension was achieved in most cases after only three inversions. After five inversions, a homogeneous suspension was obtained in all cartridge samples tested. The other techniques listed in Table 4 were also successful in achieving a homogeneous suspension in full cartridges, with the exception of the palm rolls.

20 Table 4. Re-suspension of full cartridges containing a mixing disk and a mixing bead stored at room temperature or at refrigerated conditions.

Re-suspension of dosed cartridges containing a mixing disk and a mixing bead. In addition to the tests carried outs on full cartridges, re-suspension tests were also carried out on dosed cartridges containing a combination of the two mixing aids. As shown in Table 5, five inversions were sufficient to achieve a homogeneous suspension, regardless of the volume remaining in the cartridge. Under upright storage conditions, dosed cartridges containing either the mixing disk alone, or the mixing bead alone, could not be re-suspended after five inversions (Table 3).

Table 5. Re-suspension of dosed cartridges containing a mixing disk and a mixing bead stored at room temperature.

While the embodiments of the invention disclosed herein are presently considered to be preferred, various changes and modifications can be made without departing from the spirit and scope of the invention. The scope of the invention is indicated in the appended claims, and all modifications that fall within the meaning and range of equivalents are intended to be embraced therein.

Claims

We claim:

1. A cartridge assembly for a medicament suspension, said cartridge assembly comprising: a cartridge for receiving said medicament suspension, said cartridge having an outlet for said medicament at one end thereof; a movable plunger positioned for axial movement within said cartridge; a first mixing element disposed within said cartridge between said plunger and said outlet, said first mixing element being sized and shaped to permit axial movement within said cartridge but to constrain significant lateral movement, said first mixing element further being sized and shaped to permit flow of suspension from either side of the first mixing element to the other side as said first mixing element moves axially; and at least one second mixing element disposed within said cartridge, said at least one second mixing element being positioned between said first mixing element and said outlet, and being sized and shaped for free random movement therebetween.

2. The cartridge assembly of claim 1, wherein said first mixing element is disk-shaped, and includes a bore for permitting said flow of liquid suspension therethrough.

3. The cartridge assembly of claim 2, wherein said bore is generally centrally-located in said disk-shaped element, and wherein said disk-shaped mixing element includes one or more scored grooves positioned along its circumference.

4. The cartridge assembly of claim 1, wherein the first mixing element is freely axially rotatable.

5. The cartridge assembly of claim 1 , wherein the first mixing element includes one or more apertures extending therethrough for permitting the flow of suspension from either side of said first mixing element to the other.

6. The cartridge assembly of claim 5, wherein said first mixing element includes a plurality of circumferentially-arranged scored grooves.

7. The cartridge assembly of claim 1, wherein said at least one second mixing element comprises a mixing bead.

8. The cartridge assembly of claim 7, wherein said mixing bead is generally spherical, and is made from glass, plastic, metal or ceramic.

9. The cartridge assembly of claim 7, wherein said mixing bead comprises a generally spherical glass bead.

10. The cartridge assembly of claim 2, where the first mixing element is formed from sintered glass.

11. A cartridge assembly for a medicament suspension, said cartridge assembly comprising: a cartridge for receiving said medicament suspension, said cartridge having a needle-pierceable outlet for said medicament at one end thereof; a plunger sized to be received in and to seal the other end of said cartridge, said plunger being axially movable within said cartridge; a mixing disk axially disposed within said cartridge between said plunger and said outlet, said mixing disk being sized and shaped to permit axial movement within said cartridge but to constrain significant lateral movement, said mixing disk further being shaped to permit flow of suspension from either side of the mixing disk to the other side as the mixing disk moves axially within said cartridge; and at least one mixing bead axially disposed within said cartridge between said mixing disk and said outlet, said at least one mixing bead being sized and shaped for free random movement in said cartridge between said disk and said outlet.

12. The cartridge assembly of claim 11, wherein said mixing disk includes a central bore.

13. The cartridge assembly of claim 11, wherein said mixing disk includes a plurality of scored grooves positioned along the circumference of the disk.

14. The cartridge assembly of claim 11, wherein said mixing disk is made from sintered glass.

15. The cartridge assembly of claim 11, wherein said at least one mixing bead comprises a generally spherical bead, and is formed from glass, plastic, metal or ceramic.

16. The cartridge of claim 15, wherein said generally spherical bead is formed from borosilicate glass.