Container for Storing a Drug such as Insulin

Abstract

A polymeric container for storing a drug such as insulin which comprises a hard shell (2) and a flexible film (1), wherein both elements are made from the same material.

Claims

1-13. (canceled)

14. A device for storage of a drug, the device including a flexible film bonded to a hard shell defining a liquid-tight container between the flexible film and the hard shell, wherein the hard shell is made of a first material, the flexible film includes of a blend of the first material and a second material, the second material being an elastomeric formulation of the first material, and the liquid-tight container is configured to be filled with a liquid pharmaceutical solution.

15. The device according to claim 14, wherein the hard shell is made of a single layer.

16. The device according to claim 14, wherein the first material includes a cyclic olefin copolymer (CoC).

17. The device according to claim 14, wherein the flexible film is thermoformed and shaped to closely fit the shape of the hard shell.

18. The device according to claim 14, wherein the container is transparent.

19. The device according to claim 14, wherein the flexible film is enclosed into an additional hard shell, the additional hard shell having openings to guarantee pressure equilibrium between an inside of the additional hard shell and an outside environment.

20. The device according to claim 14, wherein the container is connected to a pumping mechanism configured to infuse a content of the container into a patient.

21. The device according to claim 14, wherein the flexible film and the hard shell are welded between each other.

22. The device according to claim 14, wherein the liquid pharmaceutical solution includes an active ingredient and at least one preservative selected from the group consisting of phenol and m-cresol.

23. The device according to claim 14, wherein the liquid pharmaceutical solution includes insulin.

24. The device according to claim 14, wherein the thickness of the flexible film is above about 5 μm and is below about 100 μm.

25. The device according to claim 14, further comprising: an outlet port protected by a filter that is connected to a fluid delivery device to prevent entrapment of air bubbles.

26. The device according to claim 25, wherein the filter is arranged on the hard shell to cover the outlet port.

27. The device according to claim 14, wherein the first material includes rigid polymeric material.

28. The device according to claim 14, wherein the first material is a non-elastomeric material.

29. The device according to claim 14, wherein the flexible film exerts a pressure to an interior of the liquid-tight container within +/−20 mbar during a steady state.

30. The device according to claim 14, wherein the flexible film is configured to expand upon filling with the liquid pharmaceutical solution, configured to collapse upon depletion of the liquid pharmaceutical solution, and configured to reach a pre-formed shape in which an inner surface of the flexible film closely fits an inner surface of the hard shell upon emptying of the liquid-tight container.

31. The device according to claim 30, wherein the collapsing of the flexible film by virtue of the pre-formed shape is not caused by an external force that is applied to the flexible film.

32. The device according to claim 14, wherein the flexible film is configured to expand and collapse to provide for a deformation of the liquid-tight container.

33. The device according to claim 14, wherein the liquid-tight container is defined by a peripheral edge of the hard shell that is connected to a peripheral edge of the flexible film.

34. The device according to claim 14 further comprising: a sealed inlet for permitting filling of the liquid-tight container by a fluid transfer device.

35. The device according to claim 34, wherein the sealed inlet includes a septum.

36. The device according to claim 14, wherein the flexible film has a concave shape.

37. A medical device comprising a storage device according to claim 1 and a pumping mechanism.

38. The medical device according to claim 37, wherein the hard shell is interfaced with the pumping mechanism.

Description

LIST OF FIGURES

[0017] FIG. 1 is an exploded view of a container.

[0018] FIG. 2 shows the flexible film (1) collapsed onto the hard shell (2).

[0019] FIG. 3 is a bottom view of the hard shell (2) interfaced with pumping mechanism (7).

[0020] FIG. 4 represents the procedure of testing is described by the flowchart

[0021] FIG. 5 shows the Insulin potency of insulin Aspart

[0022] FIG. 6 shows preservative levels of m-cresol in insulin Aspart.

[0023] FIG. 7 shows preservative levels of phenol in insulin Aspart.

[0024] FIG. 8 represents high molecular weight protein levels of Aspart.

[0025] FIG. 9 shows B3Asp+A21Asp+B3isoAsp related compounds levels of Aspart.

[0026] FIG. 10 shows B28isoAsp related compound level of Aspart.

[0027] FIG. 11 represents the evaporation monitoring for different film having the same thickness and mounted in the hard shell.

[0028] FIG. 12 shows the pressure in the container according to the infused volume.

[0029] List of Elements: [0030] (1) flexible film, [0031] (2) hard shell, [0032] (3) filter, [0033] (4) inlet port, [0034] (5) outlet port, [0035] (6) bottom shell, [0036] (7) pumping mechanism

DETAILED DESCRIPTION OF THE INVENTION

[0037] The invention will be better understood with the following non-exclusive examples, some of them being illustrated.

[0038] The present invention preferably proposes the use of cyclic olefin copolymers (COC) as special class of polymeric materials with property profiles which can be varied over a wide range during polymerisation as the base material to produce a transparent, semi-flexible, watertight container made of a single layer soft film thermo-formed and collapsed onto a hard shell, made with same material, which should include one or more of the following properties:

[0039] 1. Compatible with the active ingredient of the drug (insulin)

[0040] 2. Impervious or substantially impervious to fluid loss, e.g., water and preservatives, e.g., m-cresol, present in the contained fluid;

[0041] 3. Suitable MVTR and thickness;

[0042] 4. Mechanical properties enabling flexibility and collapsibility.

[0043] 5. Sterilisable (e.g. gamma irradiation, steam, ethylene oxide);

[0044] 6. Non leachable or substantially non leachable;

[0045] 7. Weld capable.

[0046] The high transparency of Topas COC in the visible and near ultraviolet regions coupled with a refractive index of 1.53 (Topas 5013) makes the polymer suitable for application where transparency is necessary. Topas COC exhibits a unique combination of properties—glass-clear transparency, superior water vapour barrier, low water absorption and good chemical resistance to aqueous media, acids and alkalis and to polar organics. Thus, together with their excellent biocompatibility, these materials are of particular interest for primary packaging of pharmaceuticals, medical devices and diagnostic disposables.

[0047] Container Design

[0048] A possible design of the container is described in the figures. The container includes inlet port for the filling as septum, a filter to protect the downstream fluidic path as well as the pumping mechanism which is a MEMS in this case, and the cannula connector exit port. The flexible film is also protected from mechanical contact by a bottom shell.

[0049] FIG. 1 is an exploded view of a container showing the main components (1) flexible film, (2) hard shell, (3) filter, (4) inlet port, (5) outlet port and (6) bottom shell.

[0050] FIG. 2 shows the flexible film (1) collapsed onto the hard shell (2).

[0051] FIG. 3 is a bottom view of the hard shell (2) interfaced with pumping mechanism (7) forming the downstream fluidic path protected by the filter (3) and connected to exit port (5).

[0052] In one embodiment, the flexible film (1) is enclosed into an additional hard shell, said additional hard shell containing openings to guarantee pressure equilibrium between the inside of said additional hard shell and the outside.

[0053] Drug Compatibility and Integrity

[0054] The container should demonstrate good compatibility of insulin solutions (Aspart) for a period of 12 days, which represents a safety margin of two compared to the labelled intended use (6 days). The compatibility of the drug will be assessed through stability and appearance.

[0055] The procedure of testing is described by the flowchart represented on FIG. 4.

[0056] The target stability of this study being of 6 days, for safety reasons the study has been run for 13 days to simulate a worst-case scenario at 37° C. For the insulin, two sampling points had been selected, after 6 and 13 days of incubation.

[0057] The acceptance criteria and the reference for each test to demonstrate drug integrity are listed in Table 1. The methods of analysis and data treatment are performed using an external protocol and a validated method.

TABLE-US-00001 TABLE 1 Acceptance criteria for tests conducted obtained from the British Pharmacopoeia 2009 (BP) and from insulin manufacturer certificate of analysis (COA). Study Acceptance criteria Unit Appearance* Clear, colorless N/A liquid, no particles Insulin content * 90-110 [%] m-cresol content* 90-110 [%] Phenol content* 90-110 [%] HMWP content* ≤1.5 [%] B3Asp + A21Asp + B3isoAsp content* ≤5   [%] B28isoAsp content* ≤2.5 [%] Other impurities* ≤3.5 [%]

[0058] The results regarding insulin content are presented in FIG. 5, which more precisely shows the Insulin potency of insulin Aspart. The results for three Disposable Unit samples are presented as relative percentages to a standard solution; the error bar is RSD (1.4%) of the HPLC analysis. The “Pharmacopeia” lines are the limit acceptance criteria (90-110%), another line is the Control T at 5° C. (CTRL0 bulk solutions of the insulin vial) and another line is Control T at 37° C. (CTRL37 bulk solutions of the insulin vial) where insulin was exposed to thermal stresses in its original packaging.

[0059] Insulin analog solution contains antimicrobial preservatives: Aspart solution-m-cresol (1.72 mg/mL) and phenol

[0060] (1.5 mg/mL) that should be maintained in at a sufficient level to ensure antimicrobial efficiency as mentioned in the USP.

[0061] FIG. 6 shows preservative levels of m-cresol in insulin Aspart. The results for three Disposable Unit samples are presented as relative percentages to a standard solution; the error bar is RSD (0.8%) of the HPLC analysis. The COA lines are the limit acceptance criteria (90-110%), another line is the Control Tat 5° C. (CTRL0 bulk solutions of the insulin vial) and another line is Control T at 37° C. (CTRL37 bulk solutions of the insulin vial) where insulin was exposed to thermal stresses in its original packaging. The “Solo Micropump” dashed line represents the m-cresol level at the Solo MicroPump exit after 6 days of incubation in similar experimental conditions and the “USP” dash lines represent the m-cresol effectiveness level according to USP standard.

[0062] FIG. 7 shows preservative levels of phenol in insulin Aspart. The results for three Diposable Unit samples are presented as relative percentages to a standard solution; the error bar is RSD (1.1%) of the HPLC analysis. The COA lines are the limit acceptance criteria (90-110%), anotherline is the Control Tat 5° C. (CTRL0 bulk solutions of the insulin vial) and another line is Control T at 37° C. (CTRL37 bulk solutions of the insulin vial) where insulin was exposed to thermal stresses in its original packaging. The “Solo Micropump” dashed line represents the m-cresol level at the Solo MicroPump exit after 6 days of incubation in similar experimental condition and the “USP” dash lines represent the m-cresol effectiveness level according to USP standard.

[0063] High molecular weight protein values were maintained below the 1.50% threshold during 13 days

[0064] FIG. 8 represents high molecular weight protein levels of Aspart. The results for three Disposable Unit samples are presented as relative percentages of the insulin content (100%). The “Pharmacopeia” line is the limit acceptance criteria (1.5%), another line is the Control T at 5° C. (CTRL0 bulk solutions of the insulin vial) and another line is Control T at 37° C. (CTRL37 bulk solutions of the insulin vial) where insulin was exposed to thermal stresses in its original packaging.

[0065] Related substances were maintained below threshold during the 13-day test in all delivered samples.

[0066] FIG. 9 shows B3Asp+A21 Asp+B3isoAsp related compounds levels of Aspart. The results for three pump samples are presented as relative percentages of the insulin content (100%). The “Pharmacopeia” line is the limit acceptance criteria (5%), another line is the Control T at 5° C. (CTRL0 bulk solutions of the insulin vial) and another line is Control T at 37° C. (CTRL37 bulk solutions of the insulin vial) where insulin was exposed to thermal stresses in its original packaging.

[0067] FIG. 10 shows B28isoAsp related compound level of Aspart. The results for three Disposable Unit samples are presented as relative percentages of the insulin content (100%). The “Pharmacopeia” lines is the limit acceptance criteria (2.5%), another line is the Control T at 5° C. (CTRL0 bulk solutions of the insulin vial) and another line is Control T at 37° C. (CTRL37 bulk solutions of the insulin vial) where insulin was exposed to thermal stresses in its original packaging

[0068] No other related substances were detected after 13 days in the solution and pH after 6 days of incubation was 7.73.

[0069] The current study showed 13-day compatibility at extreme conditions for Aspart, with the container disclosed in this document. These results are in agreement with previous studies that demonstrated the compatibility of insulin analog insulin such as Aspart with “pager-like” CSII devices for extended use periods.

[0070] MVTR and Thickness

[0071] Comparative study was performed between tri-layer film (BK) and single layer COC film mounted on the same hard shell to demonstrate barrier evaporation rate. The relative thickness of the films are 42 um and 51 um, for BK and COC films, respectively

[0072] FIG. 11 represents the evaporation monitoring for different film having the same thickness and mounted in the hard shell.

[0073] COC film demonstrates with a similar thickness than the tri-layer film a better evaporation barrier. This ensures to maintain the integrity of the drug solution as presented in Table 1.

[0074] Mechanical Properties Enabling Flexibility and Collapsibility.

[0075] The film and its bonding onto the hard shell shall be made such as to resist to a possible overpressure due to an overfilling of the container. Moreover the part of elastomeric polymer added in the flexible film should sufficiently low to not induce any residual elastic strength in the container during the normal use.

[0076] FIG. 12 shows the pressure in the container according to the infused volume.

[0077] Delivery system can be sensitive to elevated over and under-pressures in the container (risk of over infusion in the first case and blockage of the Pump in the second case), the film shall be made so as to avoid large pressure variation due to its deformation during the container emptying (phase 1).

[0078] Moreover, the container membrane may ensure the null or slightly negative pressure in the container during the normal use of the pump (phase 2).

[0079] During the container depletion (phase 3), the softness of the film ensures a slow decrease of the pressure. This makes possible to have a large reserve volume between the time at which the depletion alarm is triggered and the time at which the pump cannot effectively infuse more liquid.

[0080] In a preferred embodiment, the flexible film (1) may exert a pressure within the of +/−20 mbar during the steady state regime. (Note: by steady state regime we understand the so-called “normal use” of FIG. 12, i.e. the period after the priming phase—where the amount of liquid in the container is superior to the nominal value of said container—and the depletion phase—where some parts of the film are in contact with the hard shell of the container.)

[0081] Sterilisable and Biocompatible

[0082] The use of plastics in the pharma and diagnostics sector in many cases requires sterilizability of the plastic material. The effect of various sterilization methods, using high energy radiation (gamma and electron beam), ETO, hot air and hot steam, has been investigated for Topas. Standard test specimens were subjected to conditions simulating one time exposure. Topas should not be used in applications requiring more than one or two sterilization cycles. Topas COC test specimens maintain mechanical properties after exposure to gamma radiation doses of 50 kGy. Like many other plastics, Topas COC shows a dose-dependent discoloration after exposure to gamma radiation. Grades with improved color stability in gamma irradiation can be requested.

[0083] Criteria for the use of plastics in the pharma and diagnostics sector are specified in the national pharmacopoeias

[0084] (US, EU and JP), and by the appropriate regulatory agencies. Material test program guidelines are given by the FDA, and the International Organization for Standardization (ISO 10993). The test program depends on the particular application and the duration of contact with the human body. Topas COC material biocompatibility testing was carried out according to guidelines given in the FDA Blue Book Memorandum, and by the International Organization for Standardization (ISO 10993). A range of Topas grades were subjected to this material biocompatibility test program. The protocol included the following: Acute Systemic and Intracutaneous Toxicity, Muscle Implantation, Physico-Chemical tests, Blood Compatibility (Hemolysis), and Cytotoxicity. These grades meet the specification of US Pharmacopoeia XXIII—Class VI. Corresponding certificates for specific grades are available. Chemical characterization and extraction tests have been carried out successfully according to the protocols described in the US, EU and Japanese Pharmacopoeia. These tests are intended as a general screening of the materials. The information discussed here should only be used as a starting point for the package/device manufacturer's consideration of the protocol to be used for testing specifically to the particular application. The presentation of these results is thus not intended to replace the testing required of the manufacturer of the package or device. Nor should it be considered a recommendation of the material for any particular application. It is the package/device manufacturer's responsibility to ensure that the materials used for a particular application are suitable for the intended use.

[0085] Non Leachable or Substantially Non Leachable

[0086] The container should demonstrate acceptable extractables results, under aggressive conditions. In principle, all organic and inorganic compounds eluting under forced conditions have to be monitored. In practice, compounds detection is limited to a concentration above the Analytical Evaluation Threshold.

ICP-MS Results

[0087] The analyses of the extractable per ICP-MS through the pump chip have shown the following results: The extraction has presented for the following elements a significant amount of compounds resulting from the pump chip extraction for [0088] Bore in a concentration range of 500-1300 μg/L [0089] Sodium in a concentration range of 100-1100 μg/L [0090] Calcium in a concentration range of 16-20 μg/L

[0091] All these elements are not known to have toxic effect; however these results shall be reviewed by a toxicologist for a safety assessment

GC-MS Results

[0092] The results of this analysis of semi-volatile compounds are presented here. The only peak resulting from the test item which was not also present in the Placebo which was used as a control (not contacting the container material) was tentatively identified phthalate with single nitrogen. However, semi quantitative analysis of this peak indicates that the compound is present in range between 0.1 and 0.2 mg/L. By taking a safety factor of 10, this amount remains in the limit threshold for genotoxic elements.

[0093] Results from this extraction study suggest that even using exaggerated extraction conditions, the material of the container does release limited amount of compounds and therefore substantially non leachable.

[0094] Weld Capable

[0095] Various welding methods, except for high-frequency welding, can be used to join molded parts made from Topas COC resin. The most suitable welding method will depend primarily on the specific part.