A solution of dexmedetomidine in a low-density polyethylene container

Abstract

The present invention relates to a container comprising a compartment filled with an aqueous solution of dexmedetomidine, optionally closed with a cap, at least an inner surface of the compartment in contact with the aqueous solution of dexmedetomidine being made from low density polyethylene (LDPE). The present invention further relates to the use of said container for storing an aqueous solution of dexmedetomidine. Finally, the present invention relates to a method for producing a container filled with an aqueous solution of dexmedetomidine, the method comprising the steps of providing a container, filling the compartment of the container with an aqueous solution of dexmedetomidine, sealing the compartment of the container and, optionally, providing a cap for the container.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a container (or vessel). The container comprises a compartment (or section or chamber). The compartment is filled with an aqueous solution of dexmedetomidine. The compartment is optionally closed (or sealed or closed) with a cap (or stopper or lid). In the container, at least the interior surface (or inner surface or inner surface) of the compartment, which is in contact with the aqueous solution of dexmedetomidine, is formed (or made or manufactured) from low density polyethylene (LDPE). Furthermore, the present invention also relates to the use (or method of use) of the container described above for preserving (or storing) an aqueous solution of dexmedetomidine. Finally, the present invention relates to a method for manufacturing a container (or vessel) filled with an aqueous solution of dexmedetomidine, said method comprising the following steps: providing a container; filling a compartment of the container with an aqueous solution of dexmedetomidine; a step of sealing (or sealing or seal forming or sealing) a compartment of the container; and Optionally, providing a cap (or bung or lid) for the container. [Background technology]

[0002] BACKGROUND OF THEINVENTION Dexmedetomidine is known as a pharmacologic active compound. It has medicinal effects, including reducing anxiety and acting as a painkiller, sedative, and / or analgesic, respectively. Dexmedetomidine is available commercially. For example, it is available as a solution for injection in various containers (e.g., glass vials) that can be used after dilution or is ready-to-use.

[0003] Diluting the dexmedetomidine solution before using it and keeping it in a glass container face many disadvantages or problems, such as the risk of handling errors (e.g., miscalculation or glass breakage) and / or the risk of contamination (e.g., microbial contamination). These may be due to, for example, microcracks in the glass container or from the dilution process.

[0004] In this regard, US Patent No. 10,632,043 discloses a single-layer or multi-layer film pack. Such a film pack comprises a contact layer of a homopolymer of polypropylene. Such a contact layer is for packaging a premixed (ready-to-use) injectable formulation of dexmedetomidine. Also, as a comparative example, a multi-layer bag (having HDPE / LLDPE / HDPE layers) is described (Table 4). The disclosed film bag is not self-supporting.

[0005] WO 2019 / 164765 also discloses a ready-to-use injectable composition comprising dexmedetomidine, in which the final dosage form is provided in a sealed polymeric container, wherein the polymeric container comprises a cyclic olefin polymer.

[0006] Furthermore, containers (or vessels) are described in U.S. Patent Nos. 9,320,712B2, 9,649,296B1, 9,717,796B1, International Publication (WO) No. 2017 / 184188A1, Japanese Patent No. 5921928B2, and U.S. Patent Publication (US) 2020 / 138788A1. Summary of the Invention [Problem to be solved by the invention]

[0007] Furthermore, depending on the respective material of the container (cap and / or seal under the cap, if they may be present), there is a risk of leachable compounds, which potentially contribute to contamination of the aqueous dexmedetomidine solution. Furthermore, when considering to provide a ready-to-use solution, it may be the case that in particular the respective pharma- ceutically active ingredient (i.e., here the active pharmaceutical ingredient (API) dexmedetomidine) is present in such a solution in a relatively low concentration, in particular when compared to the respective undiluted composition. This can result in the API dexmedetomidine being adsorbed onto the inner walls of the compartment of the container containing the active pharmaceutical ingredient (API), which in turn can result in an inaccurate amount of the API being administered to the patient. The problem of adsorption is particularly known for solutions of dexmedetomidine, which are known to have a strong tendency to be adsorbed onto or into plastic materials.

[0008] There is therefore a need to provide improved containers containing aqueous solutions containing dexmedetomidine, particularly for ready-to-use (RTU) (also sometimes referred to as "premix") applications, for example with regard to handling and / or to avoiding or reducing impurities and, where necessary, at the same time, reducing adsorption of dexmedetomidine to the inner walls of the container. [Means for solving the problem]

[0009] Summary of the Invention It has been unexpectedly found that one or more of the disadvantages and problems mentioned in the present disclosure are overcome by a container (or vessel) that includes a compartment (or section or chamber) filled with an aqueous solution of dexmedetomidine when used to store (or preserve) an aqueous solution of dexmedetomidine, in which at least the entire surface of the compartment is formed (or made or manufactured) from low density polyethylene (LDPE), which compartment may come into contact with the aqueous solution of dexmedetomidine at least in an upright position. In particular, it has been found that: The combination of the specific material of the container with a ready-to-use ("RTU") aqueous solution (containing the active pharmaceutical ingredient (API) dexmedetomidine at a relatively low concentration) can substantially contribute to reducing or even avoiding contamination (e.g., microbial contamination or contamination due to broken glass). Since the application of the RTU is safe, no further dilution is required before administration of the aqueous dexmedetomidine solution, thereby further reducing the risk of operational errors.

[0010] Thus, in one embodiment, the present invention relates to a container (or vessel) comprising a compartment filled with an aqueous solution of dexmedetomidine, in which at least the interior surface (or inner surface) of the compartment is formed (or made or manufactured) from low density polyethylene (LDPE), such interior surface (or compartment) being capable of contacting the aqueous solution of dexmedetomidine.

[0011] Surprisingly, it has been found that when the compartment of the container in which the aqueous solution of dexmedetomidine is filled is formed (or made or manufactured) from LDPE, i.e. at least the inner surface of the compartment with which the dexmedetomidine solution comes into contact, and preferably the entire compartment or the entire container (including or excluding the stopper and cap) is formed (or made or manufactured) from LDPE, this results in reduced levels of extractables (or leachables or leachables) as well as reduced adsorption (or sorption) (or absorption and / or adsorption) of the API dexmedetomidine into and / or on the inner surfaces of the compartment. This is even more surprising since dexmedetomidine is known to have a strong tendency to be adsorbed or absorbed by plastic materials (plastic materials or plastic materials).

[0012] Moreover, it has been surprisingly found that the aqueous solution of dexmedetomidine also has a significant long-term stability in the container of the present invention (e.g., at least 2 years at room temperature). In comparison with known glass bottles, the container is almost free from breakage, and even if broken, there are no glass fragments. This provides an advantageous handling, since the generation of fragments such as glass breakage (when a glass bottle breaks) is avoided.

[0013] In a further aspect, the present invention relates to the use (or method of use) of a container (or vessel) according to the present invention for storing (or preserving) an aqueous solution of dexmedetomidine.

[0014] In another aspect, the present invention relates to a method for manufacturing a container comprising a sealed compartment filled with an aqueous solution of dexmedetomidine, the method comprising the following steps: Providing a container of the present invention; filling a compartment of the container with an aqueous solution of dexmedetomidine; and a process (or step) of sealing (or sealing or seal-forming or sealing) a compartment of a container (with or without a sealing member); and Providing stoppers and / or caps to the containers, if required.

[0015] In a further aspect of the invention, a premixed aqueous solution of dexmedetomidine is used prophylactically and / or therapeutically in a medical treatment (or procedure) where the aqueous solution is filled into a compartment of a container (or vessel) such that the surface of the wall of the compartment that can come into contact with the aqueous solution of dexmedetomidine is formed (or made or manufactured) from low density polyethylene (LDPE). Useful medical treatments (or procedures) are typically selected from reducing anxiety, acting as a sedative, and acting as analgesic. [Brief description of the drawings]

[0016] [Figure 1]FIG. 1 shows the "Compound Analytical Threshold" (CAT) concentration levels (%) for each of the previously identified leachables in various container closure systems, including a comparison with a container according to an embodiment of the present invention (after 12 months storage at 25° C.). The "% of CAT" parameter takes into account both concentration and toxicological level aspects. FIG. 1 shows the following values:

number

[0017] Detailed Description of the Invention The present invention relates to the following embodiments.

[0018] 1. 1. A container (or vessel), the container (preferably a bottle having a bottle head / bottle neck, preferably having a neck / tapered end portion) comprising a compartment (or section or chamber) filled with an aqueous solution of dexmedetomidine, at least an inner surface (or inner surface) of the compartment which comes into contact with the aqueous solution of dexmedetomidine when the container is in an upright position (or state or place or position) is formed (or made or manufactured) from low density polyethylene (LDPE).

[0019] 2. 2. A container as described in claim 1, wherein the container is self-supporting and / or the compartment of the container is formed (or made or manufactured) exclusively from a single layer of low density polyethylene (LDPE).

[0020] 3. The density of the above LDPE is 0.910 to 0.937 g / cm 3 Container according to paragraph 1 or 2, which is within the range of

[0021] 4. 4. A container according to any one of claims 1 to 3, wherein the container is provided with a cap (or stopper or lid), preferably the cap comprises an elastomer, more preferably the cap comprises a high density polyethylene (HDPE) shell (or a shell or a shell or sheath made of high density polyethylene (HDPE)), a thermoplastic elastomer stopper and an HDPE attachment (or an HDPE attachment or an HDPE fitting) (manufactured (or prepared) by ring moulding (or ring mould)).

[0022] 5. A container as described in any one of claims 1 to 4, wherein the entire surface of a compartment of the container that can come into contact with an aqueous solution of dexmedetomidine at any position (or state or place or position) of the container is formed (or made or manufactured) from LDPE.

[0023] 6. A container according to any one of claims 1 to 5, wherein the compartment of the container is closed by sealing (or sealing or seal forming).

[0024] 7. (i) the entire inner layer of the sealed compartment of said container is formed (or made or manufactured) from LDPE; (ii) the sealed compartment of the container consists of a single layer of LDPE (meaning that the compartment has a single wall consisting of a single layer of LDPE), or (iii) a separate sealing member (e.g. a membrane or sealing foil) is provided to close a compartment of the container, preferably the separate sealing member having an inner layer formed (or made or manufactured) from LDPE or consisting of LDPE, A container according to any one of paragraphs 1 to 6.

[0025] 8. 8. A container according to claim 6 or 7, wherein the compartments of the container are closed by sealing (or sealing or seal forming) with a membrane (or film), the membrane (or film) being preferably formed as an integral part of the container using a blow-fill-seal (BFS) process (or form-fill process).

[0026] 9. 9. The container of claim 8, wherein the membrane is a separately formed sealing member for sealing the container neck after filling.

[0027] 10. 10. A container according to claim 8 or 9, wherein the membrane is part of the cap (or stopper or lid) and separates the filled fluid from the elastomeric component (or elastomeric element or elastomeric component) during preservation (or storage) / shelf life (or storage life or shelf life).

[0028] 11. 11. The container according to any one of claims 1 to 10, wherein the LDPE is free of stabilizers and plasticizers, in particular the LDPE is free of additives.

[0029] 12. 12. The container according to any one of claims 1 to 11, wherein the container is formed (or made or manufactured) by applying an injection molding technique (or an injection molding technique) or a blow molding technique (or a blow molding technique), preferably the container is formed (or made or manufactured) by applying a blow-fill-seal technique (or a mold-and-fill technique).

[0030] 13. 13. The container according to any one of claims 1 to 12, wherein the capacity (or capacity or volume or volume) of the compartment is within the range of 10 ml to 500 ml.

[0031] 14. 14. A container according to any one of claims 1 to 13, wherein the wall thickness of the compartment of the container is at least 200 μm, preferably at least 250 μm.

[0032] 15. The above dexmedetomidine solution is 0.6 cm 2 / ml~1.8cm 2 / ml range, preferably 1.2 cm 2 / ml~1.4cm 215. A container as described in any one of claims 1 to 14, having a contact surface (or contact surface or contact surface) with the inside (or inner side) of a compartment of the container in the range of 1 / ml.

[0033] 16. 16. The container according to any one of claims 1 to 15, wherein the aqueous solution of dexmedetomidine is an aqueous dexmedetomidine / NaCl solution, preferably the NaCl solution is 0.5% to 1.0% weight / volume (wt / vol).

[0034] 17. 17. The container according to any one of claims 1 to 16, wherein the aqueous solution of dexmedetomidine is preferably a premixed, ready-to-use solution of dexmedetomidine, more preferably a ready-to-use injectable or infusable solution.

[0035] 18. 18. The container according to any one of items 1 to 17, wherein the concentration of dexmedetomidine in the aqueous solution of dexmedetomidine is 2 μg / ml to 12 μg / ml, preferably, the concentration of dexmedetomidine is 4 μg / ml to 10 μg / ml, and more preferably, the concentration of dexmedetomidine is 4 μg / ml to 8 μg / ml.

[0036] 19. 19. The container according to any one of items 1 to 18, wherein the concentration of the dexmedetomidine is 4 μg / ml to 8 μg / ml, and preferably the concentration of the dexmedetomidine is 4 μg / ml.

[0037] 20. Use of a container, the container comprising a compartment, the compartment having an inner wall surface (or inner wall surface) formed (or made or manufactured) from low density polyethylene (LDPE) for storing (or storing) an aqueous solution of dexmedetomidine, or alternatively the container comprising a compartment, the compartment being formed (or made or manufactured) from low density polyethylene (LDPE) for storing (or storing) an aqueous solution of dexmedetomidine, preferably wherein the concentration of dexmedetomidine in the aqueous solution of dexmedetomidine is in the range of 4 μg / ml to 8 μg / ml, preferably wherein the concentration of dexmedetomidine is 4 μg / ml to 8 μg / ml, more preferably wherein the concentration of dexmedetomidine is 4 μg / ml.

[0038] twenty one. A method for manufacturing (or making) a container, said container comprising a sealed compartment, said compartment being filled with an aqueous solution of dexmedetomidine, said container being optionally provided with a cap (or stopper or lid), said method comprising the following steps: (i) Providing a container, the container comprising a compartment, the interior surface of which is made from low density polyethylene (LDPE), preferably by applying a blow moulding process or an injection moulding process, (ii) filling a compartment of said container with an aqueous solution of dexmedetomidine (preferably an aqueous solution of dexmedetomidine as disclosed herein); (iii) sealing (or sealing or seal forming or sealing) the filled compartment of said container; A method comprising:

[0039] twenty two. 22. The method according to claim 21, wherein in steps (i) to (iii) the blow-fill-seal technique (or form-fill technique) is applied.

[0040] twenty three. The following additional step (iv): (iv) sterilizing the filled, sealed and optionally locked containers. followed by: The following step (v) (v) Labeling (or marking) the containers, thereby obtaining the final ready-to-use containers (finished medicinal products). 23. The method of claim 21 or 22, further comprising:

[0041] twenty four. 24. The method according to any one of claims 21 to 23, wherein the container is a container according to any one of claims 1 to 15, and / or the aqueous solution of dexmedetomidine is an aqueous solution according to any one of claims 16 to 19.

[0042] twenty five. 1. A premixed aqueous solution of dexmedetomidine, the aqueous solution being filled in a container, the container comprising a compartment, the interior surface of the compartment of the container being formed (or made or manufactured) from low density polyethylene (LDPE), the interior surface of the compartment being adapted to come into contact with the aqueous solution of dexmedetomidine, for use in a medical treatment (or procedure or therapy) (or medical procedure).

[0043] 26. 26. A dexmedetomidine premixed aqueous solution (or premixed aqueous solution) for the use (or method of use) according to item 25, wherein said medical treatment (or procedure or therapy) (or medical procedure) is selected from reducing anxiety, acting as a sedative and acting as analgesic, in particular for the sedation of non-intubated adult patients prior to and / or during diagnostic or surgical procedures requiring sedation (or sedation or sedatives) and / or for the sedation of adult Intensive Care Unit patients (or adult ICU patients) requiring a level of sedation not deeper than alertness to verbal stimuli.

[0044] The compartments of the containers of the present invention include an inner surface (contact surface) that comes into contact with the aqueous solution of dexmedetomidine contained therein. The inner surface is formed (made or manufactured) from low density polyethylene (LDPE). The container compartments may be sealed (sealed or seal molded or sealed) with the same wall material. That is, the entirely sealed compartment is formed from an inner layer or single layer wall of LDPE. Alternatively, it may be closed with a separate sealing member and / or cap. The sealing member and / or cap may also be formed (or made or manufactured) from an inner surface of LDPE. Optionally, the container may be sealed with a sealing foil or membrane as a separate sealing member as mentioned above, under any cap as required. If a sealing foil or membrane is present, such sealing foil or membrane may also have at least its inner surface (the inner surface forming the compartment) formed (or made or manufactured) from LDPE. In other words, at least the entirety of the surfaces of the compartments of the container and the entirety of the surfaces of the sealing members (if present) (i.e., the entirety of the surfaces that may come into contact with an aqueous solution of dexmedetomidine (e.g., when a container filled with an aqueous solution of dexmedetomidine is stored upside down, shaken, or turned on its side)) are formed (or made or manufactured) from LDPE.

[0045] The term "dexmedetomidine" as used in this disclosure means ((+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride (or monohydrochloride) / 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole), including all pharma- ceutically acceptable salts. Dexmedetomidine HCl, prodrugs, complexes, free base forms, and any combinations thereof are preferred. Aqueous solutions of dexmedetomidine as used in this disclosure preferably contain less than 1% levomedetomidine based on the weight of dexmedetomidine. Levomedetomidine is 4-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. The enantiomeric purity of dexmedetomidine is preferably at least 99%. The enantiomeric purity is preferably determined (or measured) by HPLC (high performance liquid chromatography).

[0046] At least the contact surfaces (or contact surfaces or contact surfaces or contact surfaces) of the container compartment, and preferably the entire interior surfaces (or inner surfaces) of the container compartment as well as any sealing members (or sealing members or sealing members), at least the interior surfaces of which form the compartment, if present, are formed (or made or manufactured) from LDPE, so that aqueous solutions of dexmedetomidine will only come into contact with the LDPE, at least when the container is in an upright position. In one embodiment, the container compartment is filled with an aqueous solution of dexmedetomidine as described herein and is sealed with a separate sealing member (e.g., a membrane or sealing foil). The sealing foil or membrane may be covered by a cap. In other words, the liquid inside the container compartment (aqueous solution of dexmedetomidine) is surrounded by the inner wall / layer / surface of the container compartment and the inner side of the sealing member (if any).

[0047] In a further / preferred embodiment, the compartments (and sealing members, if present) of the container are preferably formed (or made or manufactured) exclusively from LDPE (along the inner wall surfaces of the compartments). That is, such compartments do not contain any amount of polypropylene (PP), very low density polyethylene (VLDPE), linear low density polyethylene (LLDPE), high density polyethylene (HDPE) or other polymers. In this embodiment, the walls of the compartments are formed (or made or manufactured) exclusively from a single layer, as distinguished from multi-layer walls (e.g. an inner layer of LDPE and an outer layer formed from PP). In other words, the wall layers of such a single-composition compartment comprise (i.e. consist of) only LDPE. The container / compartment does not have multiple layers (where each layer is made of a different polymer). In a preferred embodiment, the sealing foil also consists of only one layer. This layer is made (or made or manufactured) only from LDPE.

[0048] The LDPE therefore constitutes a compartment (or packaging) for the aqueous solution of dexmedetomidine. The aqueous solution of dexmedetomidine is then in contact with the LDPE. At least at this time, the container is either upright / vertical (the opening / closure / neck of the container is opposite / above the aqueous solution of dexmedetomidine) or facing downwards (in contact with the sealing foil). In all cases, the aqueous solution of dexmedetomidine can only come into contact with the LDPE.

[0049] The expression "at least the inner surface of the compartment in contact with the aqueous solution of dexmedetomidine" refers to the position (upright position) of the container, in which the opening / closure / neck of the container is opposite the aqueous solution of dexmedetomidine (whether closed by a cap or not). This means the following: The expression "at least the inner surface in contact with the aqueous solution of dexmedetomidine" includes embodiments in which the entire inner surface of the closed / sealed compartment is made (or made or manufactured) from LDPE or in which the inner surface does not have a surface that closes the opening of the compartment. The surface of the compartment in contact with the aqueous solution of dexmedetomidine (the surface at the given location) can also refer to the "contact surface (or contact surface or contact surface or contact surface or contact surface)".

[0050] In a preferred embodiment, the density of the LDPE is 0.910 to 0.937 g / cm 3 The test method for density is based on Archimedes' principle and is described in ISO 1183-1 method A. Further characteristics of LDPE are described in Europ. Pharmacopoeia, 10th edition, chapter 3.1.4. th edition, chapter 3.1.4).

[0051] In a preferred embodiment, the container is self-supporting. Preferably, the container is a bottle. The container is in particular a bottle for infusion. It is also possible that the container comprises a thread, allowing a cap to be screwed onto it. If a sealing foil or sealing membrane is present, this sealing foil / membrane is arranged on the underside of the cap.

[0052] The container can be manufactured (or prepared) without additives by using LDPE type polyethylene, which is polymerized under high pressure in the presence of oxygen or in the presence of an initiator (catalyst) that generates free radicals.

[0053] The compartments of the container may be sealed, with or without the presence of a sealing member. In a blow-fill-seal (BFS) process, the compartment and the compartment closure (preferably with a neck) are made of the same material, i.e. no separate sealing member is used. In a blow-fill-seal process, the container / compartment is blown, filled directly and then sealed (by welding). No further components are included in the process (e.g. the two walls of the compartment are melted and fused together). Such an embodiment is used in EcoflacPlus® or Miniplasco®.

[0054] In another embodiment, the compartment is sealed (or sealed or seal moulded or hermetically sealed) with an additional ingredient (or element or component) (formed (or made or manufactured) from (LD)PE) (for example a foil or moulded article (the inner surface of which may come into contact with the solution and which is also formed (or made or manufactured) from (LD)PE)).

[0055] In another embodiment, the compartment is sealed with a port system assembly in which at least one element or component (that does not form the interior surface of the compartment) is not formed (or made or manufactured) from PE (e.g., the stopper is formed (or made or manufactured) from an elastomeric material).

[0056] In one embodiment, the container is manufactured by blow molding or injection molding techniques. More preferably, the corresponding container is a closed system, preferably sealed with a sealing foil or membrane, such that the container (preferably the sealed container) is exclusively composed of LDPE.

[0057] For bags, the prior art typically involves welding a plastic film to a connector system. The connector system typically includes a rubber stopper. Such a rubber stopper typically comes into direct contact with the aqueous solution of the product. Such direct contact can result in higher levels of extractables (leachables) and potentially increased drug adsorption and absorption. In contrast, in the container of the present invention, the solution does not come into contact with any other components other than the LDPE, at least when the container is in an upright position.

[0058] Another advantage is that the labelling of the containers of the invention can only be carried out after sterilisation (e.g. autoclaving), thereby avoiding leaching of compounds (originating from the ink or label paper) during this heat treatment. In the case of prior art bags, the printing is done on the primary plastic foil before terminal sterilisation, thereby creating a risk of leachables during the heat sterilisation process.

[0059] In a preferred embodiment, the LDPE is stabilizer and plasticizer free (or stabilizer and plasticizer free). It is further preferred that the LDPE is additive free (or additive free). The absence of additives is in accordance with Europ. Pharmacopoeia, 10th edition, chapter 3.1.4 (Europ. Pharmacopoeia 10th edition, chapter 3.1.4). th The additive can be determined by testing based on thin layer chromatography according to the International Standards for Polymers, Vol. 13, No. 1, 2003, pp. 111-114, Chapter 3.1.4, where the presence of only one spot for the oligomer in the chromatogram indicates the absence of the additive.

[0060] One advantage of LDPE over HDPE is that LDPE can be produced (or prepared) without additives. The use of LDPE with additives or the use of HDPE with additives both result in undesirably high levels of impurities in aqueous solutions of dexmedetomidine. Such impurities are those present in the container. The use of LLDPE is disadvantageous, for example, because its melting point (or melting point) is too low. As a result, certain treatments (e.g. thermal treatments such as sterilization) result in significant disadvantages.

[0061] Surprisingly, it has been found that: Containers or at least their compartments (for storing API solutions) can be made only from polyethylene (PE), especially LDPE. Usually, pharmaceutical containers such as bags are made from polypropylene (PP) or contain some grades of PE in the layers that form the container. The difficulty with PE containers is that sterilization at 121°C (or higher) causes melting / deformation, as a result of which the containers end up becoming opaque and hard. Also, the grades of PE that can overcome such difficulties are more expensive. So it seems reasonable why almost all bags for intravenous infusion (iv) are made from PP.

[0062] In contrast, the container of the invention can be subjected to terminal sterilisation, thereby sterilising the aqueous dexmedetomidine solution contained in the container. Sterilisation by heat is usually carried out using steam, preferably saturated steam. Pressure can thereby be used as a means of temperature control. The duration of sterilisation is selected so that the sterility requirements of a medicinal product (e.g. an injectable or infusible product) are met over a sufficiently long period of time. For example, an aqueous dexmedetomidine solution will be contained in the container of the invention.

[0063] When the containers of the present invention are formed (or made or manufactured) from LDPE, they may preferably be formed (or made or manufactured) as self-supporting (or self-supporting or self-supporting) such that the self-supporting container is capable of standing on its own in a filled state, or may be useful during the manufacturing process of the filled container in an unfilled state.

[0064] The container may include threads onto which a cap may be screwed. The cap may be configured to have a re-sealing ability, for example, after removal of an injection needle.

[0065] In a preferred embodiment, the capacity (or capacity or volume) of the container compartment is in the range of 10 ml to 500 ml. The wall thickness (or thickness of the wall) of the container compartment may be at least 200 μm, preferably at least 250 μm. A preferred upper limit for the wall thickness is 2 mm, or 1 mm, preferably 500 μm.

[0066] The dexmedetomidine aqueous solution may include a contact surface. The contact surface is one that is in contact with the inside of the compartment of the container and the sealing member (e.g., sealing foil), if present. The contact surface is one that is in contact with the inside of the compartment of the container and the sealing member (e.g., sealing foil), if present. The contact surface is one that is in contact with the inside of the compartment of the container and the sealing member (e.g., sealing foil), if present. 2 / ml~1.8cm 2 / ml, preferably in the range of 1.2 cm 2 / ml~1.4cm 2 / ml.

[0067] The compartment of the container of the present invention is filled with an aqueous solution of dexmedetomidine. The aqueous solution of dexmedetomidine is preferably a dexmedetomidine / NaCl solution, more preferably 0.9% weight (w) / volume (v) NaCl. The aqueous solution of dexmedetomidine preferably has a dexmedetomidine concentration in the range of 4 μg / ml to 8 μg / ml, more preferably the concentration of dexmedetomidine is 4 μg / ml or 8 μg / ml. In a particularly preferred embodiment, the concentration of dexmedetomidine is 4 μg / ml.

[0068] In a preferred embodiment, the aqueous dexmedetomidine solution is a ready-to-use solution. Within the meaning of the present invention, the term "ready-to-use" ("RTU") means a stable pharmaceutical composition that is not further diluted and is not reconstituted from a lyophilisate before use. An RTU pharmaceutical composition is an injectable or infusable composition. Such a composition is premixed and is suitable for administration to a patient without dilution. An RTU pharmaceutical composition is suitable, for example, for parenteral administration. Parenteral administration includes intravenous, subcutaneous, intramuscular and intraperitoneal administration. In a preferred embodiment, the pharmaceutical compositions of the RTUs of the present invention are suitable for intravenous administration. Thus, the aqueous dexmedetomidine solutions of the invention are preferably ready-to-use injectable or infusable solutions. Particularly preferably, the aqueous dexmedetomidine solutions of the invention are ready-to-use upon removal of the composition from the sealed compartment of the container.

[0069] The term "ready-to-use container" may also refer to the final container of the present invention. In this context, "ready-to-use container" means that the container is filled, sealed, optionally locked, sterilized, and labeled. A "ready-to-use solution" is a composition that does not require a further dilution step and is directly infusible.

[0070] In accordance with the present invention, it has been found, inter alia, and surprisingly, that the aqueous dexmedetomidine solution of the present invention present in the container of the present invention exhibits sufficient or improved stability (e.g. long-term stability) compared to other conventional containers or bags. By "stability" is preferably meant both the chemical and physical stability of the aqueous dexmedetomidine solution. Within the meaning of the present invention, the term "stability" also means the suppression (or prevention) of contamination (or incorporation or contamination) with leachables (leachable products, compounds or ingredients (or elements or components)). Contamination (or incorporation or contamination) with leachables may occur when the container (or vessel) containing dexmedetomidine generates (or produces) said leachables. The leachable compounds (or leachable compounds or leachable compounds) may be known or unknown (or may be known or unknown). Examples of known leachables are benzaldehyde, vanillin, caprolactam, benzyl alcohol, di-n-butylamine and metilox acid. Surprisingly, it has been found that an aqueous solution of dexmedetomidine filled and stored in the container of the present invention exhibits sufficient stability, i.e., the concentration of identified leachable compounds is below the "Compound Analytical Threshold" (CAT). Thus, an aqueous solution of dexmedetomidine exhibits sufficient stability when stored in the container of the present invention.

[0071] The present invention also relates to the use of a container (as described in this disclosure) for storing (or preserving) an aqueous dexmedetomidine solution (as described in this disclosure).

[0072] Finally, the present invention also relates to a method (or manufacturing method) for producing a container (or vessel). The container comprises a sealed (or sealed or seal moulded or hermetically sealed) compartment (or compartment or chamber). The compartment is filled with an aqueous solution of dexmedetomidine and is optionally provided with a cap (or stopper or lid). The method comprises the following steps (or processes) (i) to (iii): (i) 1. A process (or step) of providing a container, the container comprising a compartment, the compartment comprising an inner surface (or an inner surface) formed (or made or manufactured) from low density polyethylene (LDPE), preferably by applying a blow molding process or an injection molding process. (ii) Filling the compartment of the container with an aqueous solution of dexmedetomidine (iii) The step of sealing (or sealing or seal-forming or sealing) the filled compartment of the container

[0073] Optionally, the filled and sealed compartment of the container may be locked (or locked), for example with a cap (or bung or lid).

[0074] As disclosed elsewhere in this disclosure, the container of the invention can be subjected to a heat treatment (e.g. sterilization) since LDPE can withstand the heat applied during the terminal sterilization procedure in an autoclave. Thus, in a preferred embodiment, the method for producing the container of the invention (or the manufacturing method) comprises the following additional step (iv) optionally followed by the following additional step (v): (iv) Sterilizing the filled, sealed and, if necessary, locked containers (v) The process (or step) of labelling (or labelling) said containers, thereby producing (or forming) the final product, a ready-to-use product (finished drug product) The process (or step) of labelling the container only after sterilisation (e.g. treatment in an autoclave) provides the following advantage: leaching components (e.g. components from the paper and / or ink) do not contaminate the container and / or the aqueous dexmedetomidine solution during heat treatment.

[0075] The container is at least partially formed (or made or manufactured) from LDPE, preferably by applying a blow moulding process, and in a subsequent process (or step) the container is filled with an aqueous solution of dexmedetomidine. In a preferred embodiment, the compartments of the container filled with the aqueous dexmedetomidine solution are manufactured (or prepared) by applying blow-fill-seal technology (or form-fill-seal technology). The basic concept of blow-fill-seal (or form-fill-seal) is as follows: a container (or vessel) containing a compartment is formed (or produced or made), filled and sealed (or sealed or sealed) in a continuous process without human (or human) intervention. Advantageously, the container of the invention, which contains the aqueous dexmedetomidine solution of the invention, can be manufactured (or prepared) in an aseptic and sterile manner. Thus, in a preferred embodiment, the processes (or steps) (i) to (iii) represent a blow-fill-seal (or form-fill-seal) method.

[0076] The container that can be produced (or prepared) by the method of the present invention is preferably a container having the characteristics (or features) described in the present disclosure, and the aqueous solution of dexmedetomidine is preferably an aqueous solution having the characteristics (or features) described in the present disclosure.

[0077] In a further aspect of the invention, a premixed aqueous solution of dexmedetomidine (or a premixed aqueous solution) is packaged in a container of the invention for use in a medical treatment (or procedure or therapy) (or medical procedure). The medical treatment is typically selected from reducing (or decreasing) anxiety, acting as a sedative, and acting as analgesic. Particular advantages are provided when the medical treatment (or procedure or treatment) (or medical procedure) is for sedation of a non-intubated adult patient (i.e., procedural / awake sedation) prior to and / or during a diagnostic or surgical procedure requiring sedation (or sedation or sedatives), and / or for sedation of an adult Intensive Care Unit (ICU) patient (corresponding to a Richmond Agitation-Sedation Scale (RASS) of 0 to -3) requiring a level of sedation not deeper than wakefulness to verbal stimuli. EXAMPLES

[0078] (Example) Example 1: Preparation of a container A container (or vessel) for use in accordance with one embodiment of the present invention (Ecoflac Plus) has a monolayer wall formed solely from LDPE, and such a container is prepared (or prepared) by a blow-fill-seal technique (i.e., prepared by a machine operation) using a polymeric material of LDPE without additives (in particular, without DEHP, latex and PVC). Such a technique includes blowing a container form and filling the container with an aqueous solution of dexmedetomidine without interrupting the process. Such a container is closed (or sealed or closed) with a cap (or stopper or lid). The cap consists of an HDPE shell (or a shell made of HDPE or a shell portion made of HDPE), a thermoplastic elastomer stopper, and an HDPE attachment (or an attachment made of HDPE or a mounting tool made of HDPE).

[0079] Example 2: Comparison of containers according to the invention with comparative containers The following examples provide a summary of representative experimental data that may be used in the context of the present invention and relate to the preparation (or formulation) of dexmedetomidine (DMT) at low concentration (4 μg / ml) in various plastic containers (bags). Each of the containers tested contained the characteristics listed in Table 1 below. Table 1 also provides the material composition.

[0080] Tables 1-6 below describe the plastic containers that were investigated. The containers have configurations A-H for ready-to-use (RTU) solutions of dexmedetomidine (DMT), where configuration A is in accordance with an embodiment of the present invention (Example 1), and configurations B-H are for comparison.

[0081] [Table 1]

[0082] [Table 2]

[0083] [Table 3]

[0084] [Table 4]

[0085] [Table 5]

[0086] [Table 6]

[0087] Explanation of analytical method The impurities and assay of Dexmedetomidine (related compounds and leachables) in saline formulation (0.9% w / v NaCl) is determined by reversed-phase UPLC (UV and ESI-MS detection). The target concentration of base (Dexmedetomidine free base) in the formulation is 4 μg / ml. All weighing activities of dexmedetomidine drug products were performed in a safety weighing enclosure system (Safetech) with a calibrated analytical micro balance XPE056 (Mettler Toledo). For this analysis, 25 μL of the as-formulated drug product (or formulation) was injected through a UHPLC Gradient System (UPLC H-Class Waters with FTN injection module, 50 μL extension loop, PDA 25 mm high sensitivity cell and QDa detector) and passed through a BEH C18 column purchased from Waters (Acquity BEH C18, 50 × 2.1 mm, 1.7 μm, Cat. No. #186002350).

[0088] Example 3: Comparison of absorption (or adsorption or sorption) of DMT after sterilization Table 7 shows the results of DMT loss after sterilization in eight different plastic containers. The lowest adsorption (4 μg / ml) of DMT was obtained in the Ecoflac Plus 100 mL container (A). Table 8 shows a comparison of the five containers after 24 months of storage. Good stability of the DMT assay was confirmed in the Ecoflac Plus container.

[0089] [Table 7]

[0090] [Table 8]

[0091] Example 5: Comparison of extractables profiles Several leachable peaks were observed during the study and the most intense leachable peaks observed in the UV and MS chromatograms were identified and semi-quantified by comparison with commercially available calibrants. The identified compounds matched the leachable compounds observed during the relevant container screening leachable study and card box extractable study.

[0092] For each target compound, the Compound Analytical Threshold (CAT) required to reach a safety margin (safe level) of 1.0 (i.e., the minimum sensitivity of the method) was calculated as follows: The ratio obtained by dividing the Safety Index (RfD) by the Maximum Daily Dose (where the safety margin is 1) Such a threshold value was calculated for each of the identified elutable compounds.

[0093]

number

[0094] The identified leachable compounds are compared with the percentage or % of CAT (% of CAT obtained instead of the amount of identified leachable compounds). Table 9 summarizes the results for packaging (24 months storage) and highlights only four identified leachable compounds (the others are 5 and 6) in Ecoflac Plus containers. Regardless of the packaging system, all of the concentrations of the identified leachable compounds were found to be below the CAT value of the identified leachable compounds (taking into account the currently accepted toxicological threshold (TTC)). As a result, the T6 month time point (40°C) exhibits the current worst case extractables profile (compared to the stable T24 month time point (25°C)).

[0095] [Table 9]

[0096] For unknown leachable components, the Analytical Evaluation Threshold (AET) is considered. The AET is the threshold above which leachable components are leached and above which a toxicological assessment (USP <1664> The AET (approximate) should be calculated using the following formula:

[0097]

number

[0098] (1) Proposed general toxicity limits (subject to PQRI) (2) Maximum daily dose volume (mL / day) (for a 70 kg patient)

[0099] General toxicity: AET (μg / mL) = AET (estimate) x 50% = 0.042μg / mL (42μg / L)

[0100] The Safety Concern Threshold (SCT) value proposed by the PQRI at 50 μg / day has not yet been accepted by the FDA and the value may be contested by the agency. A conservative approach would be to use a limit of 5 μg / day, which is arrived at by dividing the AET value by 10 (1 / 10).

[0101] For unidentified compounds, dexmedetomidine was used as an external calibrant to semi-quantify the concentration of unidentified compounds and compare it to the AET (calculated using a STC of 50 μg / day). With respect to this toxicological threshold, the concentration of unidentified peaks was found to be not higher than this AET. As packaging discrimination parameters, Table 10 details the number of unknown peaks observed above a conservative AET (STC of 5 μg / day) as well as the total amount of all unknowns. Table 10 also highlights (or emphasizes) the best results for the Ecoflac containers (25°C, 24 months).

[0102] [Table 10]

Claims

1. 1. A container comprising a compartment filled with an aqueous solution of dexmedetomidine, at least an inner surface of the compartment in contact with the aqueous solution of dexmedetomidine when the container is in an upright position, the container being formed from low density polyethylene (LDPE).

2. The density of the LDPE is 0.910 to 0.937 g / cm ３ 2. The container of claim 1, wherein the container volume is in the range of

3. 3. A container according to claim 1 or 2, wherein the compartment is closed by a seal.

4. (i) the entire inner layer of the sealed compartment of said container is formed from LDPE; (ii) the sealed compartment of the container consists of a single layer of LDPE; (iii) a separate sealing member is provided to close the compartment of the container, preferably said separate sealing member having an inner layer formed from LDPE or said separate sealing member consists of LDPE; 4. The container of claim 3.

5. 2. The container of claim 1, wherein the LDPE is free of stabilizers and plasticizers, preferably the LDPE is free of additives.

6. 2. The container of claim 1, wherein the container is formed by applying injection molding or blow molding techniques, preferably the container is formed by applying blow-fill-seal techniques.

7. 2. The container of claim 1, wherein the volume of the compartment is in the range of at least 10 ml to 500 ml and / or the wall thickness of the compartment is at least 200 μm, preferably at least 250 μm.

8. The container of claim 1 , wherein the container is provided with a cap.

9. 2. The container of claim 1, wherein the aqueous solution of dexmedetomidine is an aqueous dexmedetomidine / NaCl solution, preferably a premixed, ready-to-use solution of dexmedetomidine.

10. 2. The container of claim 1, wherein the concentration of dexmedetomidine in the aqueous solution of dexmedetomidine is in the range of 2 μg / ml to 12 μg / ml.

11. Use of a container, the container comprising a compartment, the compartment having an inner wall surface formed from low density polyethylene (LDPE) for storing an aqueous solution of dexmedetomidine, or alternatively, the container comprising a compartment, the compartment being formed from low density polyethylene (LDPE) for storing an aqueous solution of dexmedetomidine, preferably wherein the concentration of dexmedetomidine in the aqueous solution of dexmedetomidine is within the range of 4 μg / ml to 8 μg / ml.

12. 1. A method for manufacturing a container, the container comprising a sealed compartment, the compartment being filled with an aqueous solution of dexmedetomidine, the container being optionally provided with a cap, the method comprising the steps of: (i) Providing a container, the container including a compartment, the compartment including an inner surface formed from low density polyethylene (LDPE); (ii) filling a compartment of the container with an aqueous solution of dexmedetomidine; (iii) sealing the filled compartment of the container; (iv) Optionally, adding a cap to the top of the container. A method comprising:

13. Additional step (v) Sterilizing the filled, sealed and optionally capped containers. and optionally further comprising step (vi). labelling said container The method of claim 12 further comprising:

14. 13. The method according to claim 12, wherein the container is a container according to claim 1 and / or the aqueous solution of dexmedetomidine is an aqueous solution according to claim 9 or 10.

15. 1. A premixed aqueous solution of dexmedetomidine for use in a parenterally administered medical treatment, the aqueous solution being filled into a container, the container comprising a compartment, the interior surface of the compartment being formed from low density polyethylene (LDPE), the interior surface of the compartment being adapted to be in contact with the aqueous solution of dexmedetomidine.

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