WO2025221759A1

WO2025221759A1 - Reconstituable drug formulation, medicament container and method of preparing an injectable medicament

Info

Publication number: WO2025221759A1
Application number: PCT/US2025/024732
Authority: WO
Inventors: Daniel Auernhammer; Yvonne WANNER
Original assignee: Genzyme Corp
Current assignee: Genzyme Corp
Priority date: 2024-04-17
Filing date: 2025-04-15
Publication date: 2025-10-23
Anticipated expiration: 2026-10-17

Abstract

In one aspect the present disclosure relates to a reconstituable drug formulation (10) for preparing an injectable medicament (6) by interaction with a diluent (5), the reconstituable drug formulation (10) comprising: - a support structure (20), and - a lyophilized active pharmaceutical ingredient (15), which is at least one of arranged inside the support structure (20), adhered to the support structure (20) or integrated into the support structure (20), and wherein the lyophilized active pharmaceutical ingredient (15) is releasable in the diluent (5) in response to at least one of an immersion of the support structure (20) in the diluent (5) and a contact of the support structure (20) with the diluent (5).

Description

Reconstituable Drug Formulation, Medicament Container and Method of Preparing an Injectable

Medicament

Description

Field

The present disclosure relates to the field of reconstituable drug formulations, and in particular, for preparing injectable medicaments for intravenous or subcutaneous injection or infusion. In further aspects the present disclosure relates to medicament containers for reconstituable drug formulations and to methods of preparing or reconstituting an injectable medicament.

Background

Patients suffering from certain diseases like, for example, haemophilia or requiring enzyme replacement therapy have to take regular intravenous (IV) infusions. The infusions often have to be mixed and prepared, sometimes to the specific needs of the patient, (and sometimes a short time prior to drug administration) which may include reconstitution of the drug powder from multiple vials using an exact amount of sterile liquids like water and/or saline. As this preparation process is typically complex and tedious, it is usually performed by a health care professional in a clinic or pharmacy, potentially using lab equipment.

Generally, administering a medicament by way of infusion may require a rather clean or sterile environment. A patient may therefore have to regularly visit an ambulance or health care center.

Self-medication or home-medication for administering a medicament through infusion or injection is and remains quite challenging but is very attractive for patients thereby avoiding problems and circumstances involved in visiting a health care center. With home- or self- medication a patient or user, e.g. intending to establish a vascular access to a patient's body, may be obliged to use only one hand, which might be rather cumbersome and thus challenging.

In addition, it is often required to establish or maintain a clean and/or sterile environment especially in the field of home-medication or self-medication as well as providing of a clean and sterile storage environment for medicaments and medicament containers, medical device accessory and medical devices. It is therefore desirable to provide improvements in the field of home medication or self- medication, which allow a user or caregiver to prepare and to administer a medicament by way of injection or infusion. It is further desirable to provide an improved storage and transportation of medical devices, medicaments, medical device accessory and the like components required for home- or self-medication. Furthermore, there should be provided improvements in guiding and assisting a user in conducting or executing numerous steps in the course of preparing medicaments and/or in the course of preparing administration of a medicament, e.g. by way of infusion or injection.

Summary

In one aspect there is provided a reconstituable drug formulation for preparing an injectable medicament by interaction with a solvent or diluent. The reconstituable drug formulation comprises a support structure and a lyophilized active pharmaceutical ingredient (API), which is at least one of arranged inside the support structure, adhered to the support structure or integrated into the support structure.

The lyophilized active pharmaceutical ingredient is releasable in the diluent and in response to at least one of an immersion of the support structure in the development and a contact of the support structure with the diluent.

In some examples, the lyophilized active pharmaceutical ingredient is bound or adhered to the support structure, which may be mechanically stable. The lyophilized active pharmaceutical ingredient may be released or detached from the support structure in response to a contact with the diluent. Here, the support structure may be rather passive and it may be only operable to release the lyophilized active pharmaceutical ingredient that interacts with the diluent for a release in the diluent.

In some examples, it may be the support structure of the reconstituable drug formulation that is configured to release the lyophilized active pharmaceutical ingredient in response to an immersion in the diluent or upon contact with the diluent. Here, it may be the support structure that interacts with the diluent so as to release the lyophilized active pharmaceutical ingredient into the diluent. Here, the support structure may play an active role and may interact with the diluent to release the lyophilized active pharmaceutical ingredient.

In some examples the support structure is configured for immersion in the diluent. When immersed in the diluent the lyophilized active pharmaceutical ingredient is released into the diluent and is reconstituted by mixing with the diluent or solvent. In other examples the support structure is configured to get in contact with the diluent. Establishing of a mechanical contact between the diluent and the support structure may be sufficient to release at least portions of the lyophilized active pharmaceutical ingredient into the diluent thereby reconstituting the injectable medicament. A mechanical contact between the diluent and the support structure may cause to release at least portions of the lyophilized active pharmaceutical ingredient into the diluent.

The support structure may be mechanically stable. It may comprise a mechanically rigid structure that allows for an easy handling of the support structure and hence of the reconstituable drug formulation. The support structure may provide a gripping of the lyophilized active pharmaceutical ingredient, which facilitates overall handling and use of the reconstituable drug formulation. Specifically, the support structure is configured to keep the lyophilized active pharmaceutical ingredient inside a predefined or well-defined cavity or volume.

The support structure may be the configured to prevent an uncontrolled dispersion of the lyophilized active pharmaceutical ingredient. The support structure may be particularly configured to bind or to enclose the lyophilized active pharmaceutical ingredient, which lyophilized active pharmaceutical ingredient may be provided in a powdered or granular form. In this way the reconstituable drug formulation comprising or containing a well-defined amount of the lyophilized active pharmaceutical ingredient, e.g. in form of a predefined or numerous predefined doses of the lyophilized active pharmaceutical ingredient, can be easily gripped, taken and manipulated by a user or caregiver.

According to a further example of the drug formulation the support structure comprises one of a cavity and a recess to receive the active pharmaceutical in ingredient. Here, the active pharmaceutical ingredient may be stored or provided inside the cavity or recess. When immersed or when getting in contact with the diluent and or solvent the respective diluent or solvent is configured to enter the cavity and/or the recess to thereby dilute or dissolve the lyophilized active pharmaceutical ingredient thereby reconstituting the injectable medicament.

In some examples the cavity forms a closed cavity, which is entirely enclosed by the support structure. Here, the cavity may be provided as a hollow interior of a hollow support structure. The support structure may comprise a sidewall, which is at least one of dissolvable by the diluent or which is permeable for the diluent and which forms a reservoir for the reconstituted injectable medicament. In this way it may be provided that the support structure with the lyophilized active pharmaceutical ingredient located inside the cavity of the support structure can be immersed in the diluent thereby providing ingress of the diluent into the interior of the cavity. By the ingress of the diluent into the interior of the cavity there can be provided a mechanical contact between the lyophilized active pharmaceutical ingredient and the diluent thereby providing a reconstitution of the injectable medicament.

By way of the reconstitution, i.e., by combining the diluent and the lyophilized active pharmaceutical ingredient there can be provided a liquid injectable and reconstituted medicament, which is capable to escape from the support structure. In other words, the lyophilized active pharmaceutical ingredient may be released from the support structure by dissolving in the diluent and or by dissipating into the diluent when the support structure is in mechanical contact with the diluent and/or when the support structure is immersed in the diluent.

According to a further example the active pharmaceutical ingredient is located inside the cavity or in the recess. Insofar, the support structure is not only capable to provide a cavity or a recess for the active pharmaceutical ingredient. In this example the lyophilized active pharmaceutical ingredient is actually located inside the cavity of the support structure and/or in the bulk of the support structure. Hence, the support structure is at least partially filled or provided with the lyophilized active pharmaceutical ingredient. Mechanical contact with the diluent or immersion in the diluent then provides a reconstitution of the injectable medicament.

According to a further example of the drug formulation the shell and/or the support structure is dissolvable by the diluent. A dissolvable shell may provide mechanical stability to the support structure and hence to the reconstituable drug formulation as long as the support structure is not immersed or is not in contact with the diluent. By immersing the support structure and hence by immersing the shell in the diluent the shell may dissolve and/or disintegrate and may thereby release the lyophilized active pharmaceutical ingredient into the diluent. As a consequence, the lyophilized active pharmaceutical ingredient may disseminate in the diluent thereby allowing to reconstitute the injectable medicament.

A dissolvable shell enclosing the cavity, which is filled by the lyophilized active pharmaceutical ingredient allows for a rather easy and straightforward handling, transportation and storage of the lyophilized active pharmaceutical ingredient. The support structure and hence the intact shell may be simply immersed into the diluent. The reconstituable drug formulation and hence the support structure, e.g. the shell filled with the lyophilized active pharmaceutical ingredient, may be initially provided in an outer packaging, e.g. in a blister packaging. For reconstitution of the injectable medicament the reconstituable drug formulation, e.g. the support structure with the shell and the lyophilized active pharmaceutical ingredient contained inside the cavity, which is enclosed by the shell, may be simply taken out of the outer packaging and may be dropped or immersed in the diluent.

The support structure, e.g. the shell and/or the cavity formed or provided by the support structure may be provided with a well-defined amount of the lyophilized active pharmaceutical ingredient. In this way, the support structure may be associated with a well-defined amount of lyophilized active pharmaceutical ingredient. It may comprise a single dose or a number of predefined doses of the injectable medicament, which becomes immediately available by immersing the support structure in the diluent.

In some examples the shell is made of a biocompatible and/or hemocompatible material, which may dissolve in the diluent and which may be pharmaceutically, biologically and/or physiologically inert. In this way, the dissolvable shell and hence the dissolvable support structure may dissolve in the diluent or solvent and may be administered together with the injectable medicament without any interaction with biological tissue or with the body of a patient.

In some examples the support structure comprises or is made of a polyvinyl alcohol (PVA). Such a material or group of materials may exhibit excellent biocompatibility and/or hemocompatibility. It is water dissolvable and biodegradable. It is void of micro plastic and is easy to use and manufacture. By way of a shell made of PVA the reconstituable drug formulation can be provided in form of a pod, suitable for immersing or dissolving in the development, e.g. a waterfall injection.

According to a further example at least one of the shell and the sidewall enclosing the cavity is permeable for at least one of the diluent and the active pharmaceutical ingredient. Here, the shell and/or the sidewall may be insoluble by the diluent. They may remain in a medicament cavity upon reconstitution of the injectable medicament. By way of the permeability of at least one of the shell and the sidewall, the diluent and the active pharmaceutical ingredient can be mixed or may interact provided that either the diluent penetrates at least one of the shell and the sidewall and/or provided that the reconstituable drug formulation located inside the cavity dissipated through the shell or sidewall.

The shell and/or the sidewall may be also permeable for the dissolved or reconstituted liquid injectable medicament, which may then be released from the interior enclosed by the shell or sidewall into the surrounding of the support structure, e.g. into the outside facing surrounding of at least one of the shell and the sidewall. In further examples at least one of the shell and the sidewall is permeable for the active pharmaceutical ingredient. In this way, the shell and/or the sidewall allow for a direct release, e.g. a release of a number of molecules of the lyophilized active pharmaceutical ingredient into the environment of the shell and/or of the sidewall, e.g., when getting in contact with the diluent or when immersed in the diluent.

In some examples of the drug formulation at least one of the shell and the sidewall is void of the lyophilized active pharmaceutical ingredient. Here, the lyophilized active pharmaceutical ingredient may be exclusively provided inside the cavity, which is enclosed or directly partially enclosed by at least one of the shell and the sidewall. It is then required that at least one of the shell and the sidewall is permeable for at least one of the diluent and the active pharmaceutical ingredient.

In other examples, at least one of the shell and/or the sidewall comprises the lyophilized active pharmaceutical ingredient. Here, the pharmaceutical ingredient may be provided on at least one of an inside and an outside of at least one of the shell and the sidewall. It is even conceivable, that the bulk of at least one of the shell and/or the sidewall is provided with the lyophilized active pharmaceutical ingredient, which may be released into the environment of the shell and/or of the sidewall in response to a mechanical contact with the diluent or in response to an immersion of the support structure in the diluent.

According to a further example the support structure comprises a polymeric matrix. The active pharmaceutical ingredient may be then embedded in this polymeric matrix.

Here, the polymeric matrix may be dimensionally stable. It may comprise a rather rigid body, which allows for a direct and easy mechanical handling of the drug formulation. In further examples, the support structure may comprise a gel-like or jelly-like matrix.

Embedding or integrating the active pharmaceutical ingredient inside the polymeric matrix inherently provides an integration of the lyophilized active pharmaceutical ingredient into the support structure. The polymeric matrix of the support structure may be particularly configured to release the active pharmaceutical ingredient into the diluent when the support structure is either immersed in the diluent or when the support structure gets in contact with the diluent. Providing the active pharmaceutical ingredient inside a polymeric matrix and/or on a surface of a polymeric matrix may provide a well-defined release rate of disseminating the active pharmaceutical ingredient in the diluent over time.

Insofar, and when immersing the polymeric matrix in the diluent, the concentration of the active pharmaceutical ingredient dissolved in the diluent may increase over time, e.g. at a constant or predefined rate over time. The support structure and hence the polymeric matrix may provide or exhibit a constant or predefined release rate for the active pharmaceutical ingredient. Accordingly, a constitution rate at which the lyophilized active pharmaceutical ingredient is dissolved in the diluent can be controlled, e.g. by controlling the duration and/or the time interval during which the support structure is immersed in the diluent.

In some examples the polymeric matrix comprises at least one of the following materials: elastomeric polymers, e.g., ethylene-vinyl acetate copolymers (EVA), silicones, e.g., polydimethylsiloxane and polyurethane (PU).

EVA is a transparent copolymer made of ethylene and vinyl acetate monomers. The vinyl acetate content plays a key role in determining the mechanical properties, ease of manufacture, and drug release rates from the copolymer. The rigidity of the polymer increases as the level of the vinyl acetate decreases. Reduction of the content also leads to an increase in the relative amounts of amorphous structures and reduces the degree of crystallinity, resulting in a rubbery and more permeable polymer which allows drugs to be released more rapidly from the substrate. In addition to these properties, EVA is biocompatible, nontoxic, does not stimulate inflammatory reactions, and can be easily processed. More importantly, the solubility and diffusion coefficient of each drug through the EVA polymeric chain can be tailored by changing the amount of vinyl acetate. Hence, EVA can be used as a carrier material for the support structure.

Silicones are a class of synthetic polymers with a backbone made of repeating silicon-oxygen bonds; the main repeating unit is known as a siloxane. Silicon atoms bond to organic groups, usually methyl groups. The most common silicone is polydimethylsiloxane (PDMS). Other groups such as phenyl, vinyl, and trifluoropropyl may be used as methyl substituents. Silicones are used as fluids, emulsions, resins or elastomers, depending on the concurrent presence of organic groups attached to the inorganic backbone. Because of their flexibility and biocompatibility, silicone elastomers can be used in almost any drug delivery systems. The main characteristics of silicones are chemical stability, low surface energy, and hydrophobicity. Because of their biocompatibility and low toxicity, silicones are widely used in the manufacture of medical products that come into direct contact with the human body, silicones can be used as a carrier material for the support structure.

Polyurethanes (PU) are synthesized by a polymerization reaction between isocyanates and polyols in the presence of a catalyst or ultraviolet light activation. Polyurethanes have segmented polymeric characteristics, i.e., hard and soft parts. The hard part is composed of isocyanate components and the soft part of polyol. The mechanical strength of the polymer relies on the hard part and its flexibility depends on the weight percentage of the soft part. Because of its segmented polymeric structure, range of physical properties, and good biocompatibility, PU can be used as a carrier material for the support structure.

In some examples the polymeric matrix comprises elastomeric polymers, such as described above. Such polymers are particularly suitable to form or to constitute or to contribute to the support structure. They may provide a well-defined control of a release rate of the active pharmaceutical ingredient when immersed in the diluent.

According to a further example the support structure comprises a perforated scaffold. The active pharmaceutical ingredient may be coated or adhered on the perforated scaffold. The scaffold may comprise a rigid or mechanically rigid structure. In the present context, a mechanically rigid structure may exhibit a certain degree of deformability, elasticity and/or compressibility. In the present context a mechanical stable support structure provides an inherent stiffness that is at least sufficient to maintain the overall geometric structure of the support structure when exposed to gravitation. Such a degree of rigidity and mechanical stability is sufficient for an overall handling of the reconstituable drug formulation and may clearly distinguish from a liquid or gel-like constitution.

The support structure may be gripped by a user either directly or indirectly. It may provide and define a well-defined amount of medicament, which can be individually used for preparing the injectable medicament. The perforated scaffold may comprise a metallic material, such as stainless steel, nitinol and/or cobalt chromium, which are chemically and physiologically inert.

According to a further example the support structure comprises a core and an active layer provided on the core. The active layer comprises the active pharmaceutical ingredient. The core may be void of the active pharmaceutical ingredient. Here, the core and the active layer may be made of different materials. The material of the core comprises a degree of elasticity or compressibility that is lower than the degree of elasticity or compressibility of the active layer. Here, the core may provide mechanical stabilization for the active layer. The active layer can be coated or laminated on the core.

In some examples the active layer may be dissolvable by the diluent whereas the core may be insoluble and hence non-dissolving by the diluent. In this way and in the course of reconstitution of the medicament the active layer may dissolve or may at least release the active pharmaceutical ingredient when the support structure is immersed in the diluent. Here, the core may remain in the diluent. It may comprise a geometric size and structure that is immediately detectable by a person or by a device. It may comprise a size that is incompatible for administration into biological tissue of a patient by way of injection or infusion.

According to a further example the support structure comprises an outer membrane enclosing the core and enclosing the active layer. Here, the outer membrane is permeable for at least one of the diluent and the active pharmaceutical ingredient. The outer membrane may be void of the active pharmaceutical ingredient. Hence, it may be a drug-free membrane. The outer membrane may be made of a polymeric material. It may comprise a polymeric rate-controlling membrane, which provides a well-defined release rate of the medicament, hence of the active pharmaceutical ingredient from the active layer through the outer membrane into the diluent surrounding the support structure.

With a support structure comprising a polymer matrix a single injection of an elastomer mix containing drug molecules that are dispersed homogeneously in the matrix of the polymer may result in a so-called matrix type support structure. Here, the solubility of the polymer may be lower than the loaded drug in insoluble matrix. The entire surface area of the support structure may be exposed to the diluent. In a first stage, burst release may occur due to the presence of immobilized drug particles separated from the crystal lattice at the surface of the support structure. This may result in the creation of a concentration gradient that drives the release process thermodynamically. In a second stage, the drug molecules closest to the surface of the support structure may be diffused through the polymer and released into the diluent.

As the drug release continues, the unmedicated surface can be separated from the inner drug- loaded segment of the matrix by the creation of a drug exhaustion zone. As the thickness of the unmedicated zone increases, the surface area of the inward-moving depletion border decreases. Consequently, the pathway from where the remaining drug is diffused increases as the amount of the released drug reduces over time and the drug near the surface of the ring becomes depleted.

Silicone elastomers, EVA, and PU are biostable polymers which can be used in principle to create insoluble homogeneous dispersion matrix-type support structures. Biosoluble polymers can control the release of drugs by means of degradation mechanisms instead of diffusion. This enables the delivery of both hydrophilic and hydrophobic APIs, including those with large molecular weights.

During the manufacture of core-type support structures as mentioned above, a drug can be placed in a central zone and surrounded by a drug-free polymeric rate-controlling membrane (RCM). The drug carrier at the core can be either a polymer (the same as the RCM or a different polymer) or another type of biomaterial, e.g., a sugar-based membrane or a combination of gelatin and natural latex. With the latter, gelatin and/or gelatin or gelatinized sago starch biomembranes can be used as a drug delivery system. Here, deproteinized natural rubber latex can be chosen to blend as a plasticizer in biomembranes due to its elasticity.

The molecules of the drug have to first detach themselves from the core crystal lattice, then diffuse into the drug-free RCM and then disseminate into the medium surrounding the support structure. The drug is constantly released until the drug’s concentration at the core is depleted. One advantage of core-type support structure is that release of drugs occurs in zero order compared to matrix-type support structures. Aside from that, the release characteristics of this type of support structure can be easily modified. Modifications can be achieved by changing the thickness of the RCM. A reduction in RCM thickness leads to an enhanced release rate, due to the shorter diffusion pathway.

In sandwich-type support structures a layer containing the drug is located below the surface of the support structure. This layer can be located between a non-medicated polymer surface and a central core that may or may not contain a drug. Since the drug layer may be located a fraction of a millimeter below the surface, this particular support structure may be suitable for delivering drugs with poor polymer diffusion characteristics. A sandwich-type support structure can minimize side effects due to the constant drug release compared to other types such as matrix-type and core-type support structures.

According to another aspect the present disclosure also relates to a medicament container. The medicament container comprises a container cavity and a reconstituable drug formulation as described above, which is located inside the container cavity. The medicament container may contain the reconstituable drug formulation inside a cavity in a lyophilized format. The drug formulation comprises the support structure and the lyophilized active pharmaceutical ingredient as described above. Insofar, all effects, properties and benefits as described above in connection with the reconstituable drug formulation equally apply to the medicament container; and vice versa.

The medicament container may seal the drug formulation inside the container cavity. Hence, the container cavity may be sealed in a liquid tight and/or gas tight manner with regards to the surrounding environment. In this way the medicament container may provide a sterilized environment for the drug formulation. The medicament container may be used as a container for transportation, storage and retail. Accordingly, the medicament container may comprise or may constitute at least one of a transportation container, a storage container and a retail container. The medicament container may form or constitute a tradable product, which can be directly handed out to patients, users or healthcare providers, which in turn may then use the medicament container for reconstituting the injectable medicament.

In some examples the container cavity may be exclusively filled with the reconstituable drug formulation. Apart from the reconstituable drug formulation the cavity of the container may be empty. Inside the container cavity there may be only provided the reconstituable drug formulation and air or any other kind of an inert gas, which is incapable to react with the reconstituable drug formulation. Here, the container cavity may be also vacuumized. A gaseous substance or gaseous fraction inside the container cavity may be provided at a comparatively low pressure, e.g., lower than the surrounding atmospheric pressure.

In some examples, e.g. when the support structure comprises a cavity filled with the lyophilized active pharmaceutical ingredient, the cavity may be enclosed by a shell of the drug formulation, which shell may inherently provide or constitute at least one of a chemical and a physical barrier against ingress of any substances into the interior of the cavity. Insofar, the shell of the drug formulation may be beneficial for a prolongation of the shelf life of the reconstituable drug formulation.

According to a further example the medicament container comprises an outer packaging enclosing the container cavity. Here, the outer packaging may be configured to be opened by a user or care giver in order to provide access to the reconstituable drug formulation inside the container cavity. Here, the reconstituable drug formulation may be intended to be taken out of the container cavity and to be immersed in a diluent, which is provided separately.

According to a further example the medicament container, e.g., the outer packaging thereof, comprises a blister packaging. Here, the reconstituable drug formulation may be removed from the medicament container by applying a mechanical force or pressure onto the medicament container, e.g. to tear apart and/or to introduce a breakage of at least a portion of the outer packaging or blister packaging in order to obtain access to interior of the container cavity.

In a further example the medicament container may provide a two-fold function or may serve multiple purposes. It may provide at least one of transportation, storage and retail. In addition it may provide a mixing of the lyophilized active pharmaceutical ingredient of the reconstituable drug formulation and the diluent. For this the medicament container comprises a first access port in fluid connection with the container cavity. The first access port is configured to transfer the diluent from outside into the container cavity. In this way, a well-defined amount of diluent may be introduced into the container cavity. The diluent may then dissolve the lyophilized active pharmaceutical ingredient or may mix with the pharmaceutical ingredient when interacting with the reconstituable drug formulation inside the container cavity. Here, the medicament container, and in particular its container cavity, may also provide a mixing chamber or reconstitution chamber for reconstituting the drug formulation with the diluent.

According to a further example the medicament container comprises a second access port, which is configured to fluidically connect the container cavity with an injection device. In some examples the first access port may be used for both, filling of the diluent into the container cavity and withdrawing the reconstituted injectable medicament from the container cavity. In further examples and when the medicament container comprises a first access port and a second access port the first access port may be exclusively used or usable for transferring the diluent into the container cavity and the second access port may be exclusively used or configured for withdrawing the reconstituted injectable medicament from the container cavity.

Here, at least one of the first access port and the second access port may comprise a seal to seal the respective port with regards to the outside environment. The seal may comprise a standardized sealable connector, such as a Luer-type connector. In some examples the seal may comprise a pierceable septum, which can be penetrated by a hollow injection needle. By way of a hollow injection needle there can be established a fluid transferring coupling across the respective first or second access port or respective seals, which allows for introducing the diluent into the container cavity and which also allows for extracting the prepared injectable medicament from the container cavity.

According to a further example the medicament container may be a flexible medicament container. The medicament container may comprise a flexible bag. The medicament container may comprise a flexible sidewall, e.g. made of a chemically and/or a pharmaceutically and/or physiologically inert material, which is flexible. The flexible medicament container allows and supports a rather easy and straightforward mechanical treatment of the diluent and the reconstituable drug formulation for conducting or executing the reconstitution of the injectable medicament.

In some examples the medicament container is transparent or at least partially transparent. In some examples only a portion of the medicament container is transparent. By way of a transparent medicament container or a transparent portion thereof, the reconstitution and/or the properties of the reconstituable drug formulation and hence of the injectable medicament can be visually inspected. This may enhance patient safety because only a reconstituted injectable medicament passing a visual inspection should be used by or for a patient.

According to a further example the medicament container comprises a diluent container in addition to the container cavity. The diluent container is fluidically connectable with the container cavity. Here the diluent container may be detachably connectable with the container cavity. The diluent container may comprise a third or a further access port, which may be detachably connectable with the first access port of the medicament container. In this way, the diluent container can be fluidically connected with the container cavity and the diluent initially provided inside the diluent container can be then transferred from an interior of the diluent container into the container cavity of the medicament container.

In some examples the diluent container and the container cavity of the medicament container may be integrally formed. They may be permanently connected by a fluid guiding line. The fluid guiding line may the fluidically interrupted by at least one of a breakable seal, a frangible plug and a user operable valve, which may be adjustable by a user or care giver. In this way there can be provided a fluidic connection between the interior of the diluent container and the container cavity for transferring the diluent from the diluent container into the container cavity of the medicament container. During transportation, storage and retail the diluent container may be fluidically disconnected from the container cavity in order to avoid a premature contact between the diluent and the reconstituable drug formulation.

According to a further aspect the present disclosure also relates to a method of preparing an injectable medicament. The method comprises the steps of using or providing a medicament container, which comprises a container cavity. The method further comprises the step of inserting a drug formulation as described above into the container cavity. In some examples the container cavity may be filled with a diluent, e.g. with a predefined amount of the diluent. By inserting the drug formulation into the container cavity the drug formulation may get at least in mechanical contact with the diluent or it may be immersed in the diluent.

Further, and by bringing the reconstituable drug formulation as described above in mechanical contact with the diluent or by immersing the reconstituable drug formulation in the diluent the lyophilized active pharmaceutical ingredient is released or disseminated into the diluent. It may be dissolved in the diluent and may contribute to the preparation or generation, e.g. to the reconstitution of the injectable medicament inside the medicament container. In general, the methods as described herein are to be conducted by making use of a reconstituable drug formulation as described herein and/or by a medicament container as described above. Insofar, all effects, features and benefits as described above in connection with the reconstituable drug formulation and the medicament container equally apply to the method of reconstituting or preparing the injectable medicament.

According to a further example the drug formulation may be removed from the container cavity and may be immersed in the diluent provided separately. Also here, the injectable medicament may be reconstituted by bringing the reconstituable drug formulation, e.g. the support structure with the lyophilized active pharmaceutical ingredient in mechanical and/or fluidic and hence in direct contact with the diluent.

According to a further example the method comprises the step of pouring a predefined amount of the diluent into the container cavity or immersing the drug formulation in the diluent.

Immersing the drug formulation in the diluent may take place inside the container cavity or may take place in a separate diluent container. For the latter the reconstituable drug formulation may have to be removed from the medicament container and may have to be inserted into a separate container that is provided with the diluent. In a further example the diluent may be filled into the medicament container, in which container cavity there is already provided the reconstituable drug formulation. Here, and as soon as a predefined fill level of the diluent has been reached inside the medicament container, the reconstituable drug formulation, hence the support structure thereof may be immersed in the diluent.

Hence, in some examples of the method of preparing the injectable medicament there may be provided or used a medicament container with the container cavity and with the reconstituable drug formulation provided inside the medicament container. The diluent may then be only added to the medicament container, which may then provide a reconstitution or mixing of the diluent and the reconstituable drug formulation.

According to a further example the pharmaceutical ingredient is releasable in the diluent at a predefined release rate. A concentration of the active pharmaceutical ingredient in the injectable medicament may be then controlled by monitoring or controlling a time interval during which the drug formulation is immersed in the diluent or is in contact with the diluent. With the drug formulation providing a predefined release rate for the active pharmaceutical ingredient the concentration of the active pharmaceutical ingredient in the injectable medicament, e.g., in the diluent, may increase with the duration or extent of the time interval during which the reconstituable drug formulation is immersed in the diluent or is in contact with the diluent. Here, and according to a further example an injectable medicament with a first concentration of an active pharmaceutical ingredient can be obtained by keeping the reconstituable drug formulation inside the diluent over a first period of time. A second concentration of the active pharmaceutical ingredient can be obtained by maintaining or keeping the reconstituable drug formulation immersed in the diluent over a second period of time. When the first or second period of time has lapsed, the reconstituted injectable medicament may be either withdrawn from the mixing chamber or the support structure and hence the reconstituable drug formulation may be removed from the mixing container or mixing chamber. In this way the process of reconstituting the drug formulation and hence the process of preparing the injectable medicament can be interrupted prematurely, namely when a predefined medicament concentration or drug concentration has been reached after a predefined time interval.

By way of the controlled release of the active pharmaceutical ingredient from the support structure, e.g. from a polymeric matrix or through an outer membrane being permeable for at least one of the diluent and the active pharmaceutical ingredient, there can be provided an effective and rather easy way of controlling the concentration of the active pharmaceutical ingredient in the injectable medicament.

The terms “drug” or “medicament” are used synonymously herein and describe a pharmaceutical formulation containing one or more active pharmaceutical ingredients or pharmaceutically acceptable salts or solvates thereof, and optionally a pharmaceutically acceptable carrier. An active pharmaceutical ingredient (“API”), in the broadest terms, is a chemical structure that has a biological effect on humans or animals. In pharmacology, a drug or medicament is used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. A drug or medicament may be used for a limited duration, or on a regular basis for chronic disorders.

As described below, a drug or medicament can include at least one API, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Examples of API may include small molecules having a molecular weight of 500 Da or less; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more drugs are also contemplated. The drug or medicament may be contained in a primary package or “drug container¹’ adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other solid or flexible vessel configured to provide a suitable chamber for storage (e.g., shorter long-term storage) of one or more drugs. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years. Storage may occur at room temperature (e.g., about 20°C), or refrigerated temperatures (e.g., from about - 4°C to about 4°C). In some instances, the drug container may be or may include a dualchamber cartridge configured to store two or more components of the pharmaceutical formulation to-be-administered (e.g., an API and a diluent, or two different drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components prior to and/or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body.

The drugs or medicaments contained in the drug delivery devices as described herein can be used for the treatment and/or prophylaxis of many different types of medical disorders. Examples of disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further examples of disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs and drugs are those as described in handbooks such as Rote Liste 2014, for example, without limitation, main groups 12 (antidiabetic drugs) or 86 (oncology drugs), and Merck Index, 15th edition.

Examples of APIs for the treatment and/or prophylaxis of type 1 or type 2 diabetes mellitus or complications associated with type 1 or type 2 diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the terms “analogue” and “derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, by deleting and/or exchanging at least one amino acid residue occurring in the naturally occurring peptide and/or by adding at least one amino acid residue. The added and/or exchanged amino acid residue can either be codable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues. Insulin analogues are also referred to as "insulin receptor ligands". In particular, the term ..derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, in which one or more organic substituent (e.g. a fatty acid) is bound to one or more of the amino acids. Optionally, one or more amino acids occurring in the naturally occurring peptide may have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or amino acids, including non-codeable, have been added to the naturally occurring peptide.

Examples of insulin analogues are Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulin glulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28) human insulin (insulin aspart); human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Vai or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.

Examples of insulin derivatives are, for example, B29-N-myristoyl-des(B30) human insulin, Lys(B29) (N- tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®); B29-N- palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-gamma-glutamyl)-des(B30) human insulin, B29-N-omega- carboxypentadecanoyl-gamma-L-glutamyl-des(B30) human insulin (insulin degludec, Tresiba®); B29-N-(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N-(co- carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(co-carboxyheptadecanoyl) human insulin.

Examples of GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, for example, Lixisenatide (Lyxumia®), Exenatide (Exendin-4, Byetta®, Bydureon®, a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide (Victoza®), Semaglutide, Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®), rExendin-4, CJC- 1134-PC, PB-1023, TTP-054, Langlenatide / HM-11260C (Efpeglenatide), HM-15211, CM-3, GLP-1 Eligen, ORMD-0901, NN-9423, NN-9709, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1 , ZYD-1 , GSK-2374697, DA-3091, MAR-701 , MAR709, ZP- 2929, ZP-3022, ZP-DI-70, TT-401 (Pegapamodtide), BHM-034. MOD-6030, CAM-2036, DA- 15864, ARI-2651 , ARI-2255, Tirzepatide (LY3298176), Bamadutide (SAR425899), Exenatide- XTEN and Glucagon-Xten.

An example of an oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia or RG012 for the treatment of Alport syndrom.

Examples of DPP4 inhibitors are Linagliptin, Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.

Examples of hormones include hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.

Examples of polysaccharides include a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra-low molecular weight heparin or a derivative thereof, or a sulphated polysaccharide, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. An example of a hyaluronic acid derivative is Hylan G-F 20 (Synvisc®), a sodium hyaluronate.

The term “antibody”, as used herein, refers to an immunoglobulin molecule or an antigenbinding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab')2 fragments, which retain the ability to bind antigen. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. The term antibody also includes an antigen-binding molecule based on tetravalent bispecific tandem immunoglobulins (TBTI) and/or a dual variable region antibody-like binding protein having cross-over binding region orientation (CODV).

The terms “fragment” or “antibody fragment” refer to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy and/or light chain polypeptide) that does not comprise a full-length antibody polypeptide, but that still comprises at least a portion of a full- length antibody polypeptide that is capable of binding to an antigen. Antibody fragments can comprise a cleaved portion of a full length antibody polypeptide, although the term is not limited to such cleaved fragments. Antibody fragments that are useful in the present invention include, for example, Fab fragments, F(ab')2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, tetraspecific and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), monovalent or multivalent antibody fragments such as bivalent, trivalent, tetravalent and multivalent antibodies, minibodies, chelating recombinant antibodies, tribodies or bibodies, intrabodies, small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins, camelized antibodies, and immunoglobulin single variable domains. Additional examples of antigen-binding antibody fragments are known in the art.

The term “immunoglobulin single variable domain” (ISV), interchangeably used with “single variable domain”, defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. As such, immunoglobulin single variable domains are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain. The binding site of an immunoglobulin single variable domain is formed by a single heavy chain variable domain (VH domain or VHH domain) or a single light chain variable domain (VL domain). Hence, the antigen binding site of an immunoglobulin single variable domain is formed by no more than three CDRs.

An immunoglobulin single variable domain (ISV) can be a heavy chain ISV, such as a VH (derived from a conventional four-chain antibody), or VHH (derived from a heavy-chain antibody), including a camelized VH or humanized VHH. For example, the immunoglobulin single variable domain may be a (single) domain antibody, a "dAb" or dAb or a Nanobody® ISV (such as a VHH, including a humanized VHH or camelized VH) or a suitable fragment thereof. [Note: Nanobody® is a registered trademark of Ablynx N.V.]; other single variable domains, or any suitable fragment of any one thereof.

“VHH domains”, also known as VHHs, VHH antibody fragments, and VHH antibodies, have originally been described as the antigen binding immunoglobulin variable domain of “heavy chain antibodies” (i.e., of “antibodies devoid of light chains”; Hamers-Casterman et al. 1993 (Nature 363: 446-448). The term “VHH domain” has been chosen in order to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4- chain antibodies (which are referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VL domains”). For a further description of VHH’s, reference is made to the review article by Muyldermans 2001 (Reviews in Molecular Biotechnology 74: 277-302).

For the term “dAb’s” and “domain antibody”, reference is for example made to Ward et al. 1989 (Nature 341 : 544), to Holt et al. 2003 (Trends Biotechnol. 21: 484); as well as to WO 2004/068820, WO 2006/030220, WO 2006/003388. It should also be noted that, although less preferred in the context of the present invention because they are not of mammalian origin, single variable domains can be derived from certain species of shark (for example, the so-called “IgNAR domains”, see for example WO 2005/18629).

The terms “Complementarity-determining region” or “CDR” refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term “framework region” refers to amino acid sequences within the variable region of both heavy and light chain polypeptides that are not CDR sequences, and are primarily responsible for maintaining correct positioning of the CDR sequences to permit antigen binding. Although the framework regions themselves typically do not directly participate in antigen binding, as is known in the art, certain residues within the framework regions of certain antibodies can directly participate in antigen binding or can affect the ability of one or more amino acids in CDRs to interact with antigen.

Examples of antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

Pharmaceutically acceptable salts of any API described herein are also contemplated for use in a drug or medicament in a drug delivery device. Pharmaceutically acceptable salts are for example acid addition salts and basic salts.

Those of skill in the art will understand that modifications (additions and/or removals) of various components of the APIs, formulations, apparatuses, methods, systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.

An example drug delivery device may involve a needle-based injection system as described in Table 1 of section 5.2 of ISO 11608- 1:2014(E). As described in ISO 11608-1 :2014(E), needlebased injection systems may be broadly distinguished into multi-dose container systems and single-dose (with partial or full evacuation) container systems. The container may be a replaceable container or an integrated non-replaceable container. As further described in ISO 11608-1 :2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).

As further described in ISO 11608-1 :2014(E), a single-dose container system may involve a needle-based injection device with a replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation). As also described in ISO 11608-1 :2014(E), a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In one example for such a system, each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation). In a further example, each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).

Brief description of the drawings

In the following, numerous examples of a reconstituable drug formulation, a medicament container and methods of preparing an injectable medicament will become apparent in greater detail by making reference to the drawings, in which:

Fig. 1 . shows an example of a reconstituable drug formulation initially packed in a medicament container,

Fig. 2 shows the reconstituable drug formulation removed from the medicament container before or in the course of immersing in the diluent,

Fig. 3 shows the reconstituable drug formulation when immersed in the diluent,

Fig. 4 shows a further example of a reconstituable drug formulation inside a container cavity of a medicament container,

Fig. 5 shows a cross-section through the medicament container according to Fig. 4,

Fig. 6 shows a further example of a medicament container connectable or provided with a diluent container,

Fig. 7 shows a flowchart of a method of reconstituting a liquid medicament,

Fig. 8 shows an example of a support structure of the reconstituable drug formulation, Fig. 9 shows a cross-section through the support structure according to Fig. 8, Fig. 10 shows a further example of a reconstituable drug formulation comprising an annular ring-like shape,

Fig. 11 shows a cross-section through the ring structure of Fig. 10 according to one example, Fig. 12 shows a cross-section through a ring structure according to a further example, Fig. 13 shows a further example of a reconstituable drug formulation, and Fig. 14 shows a cross-section through the ring structure according to Fig. 13.

Detailed description.

In Fig. 1 there is shown an example of a reconstituable drug formulation 10 for preparing an injectable medicament 6 by interaction with a diluent 5. The reconstituable drug formulation 10 comprises a support structure 20 and a lyophilized active pharmaceutical ingredient 15. The active pharmaceutical ingredient 15 is at least one of arranged inside the support structure 20, adhered to the support structure 20 or integrated into the support structure 20.

The lyophilized active pharmaceutical ingredient 15 is releasable in the diluent 5 when getting in contact with the diluent or when the entire drug formulation 10, e.g., the support structure 20, is immersed in the diluent 5.

In some examples, the support structure 20 may be configured to release the lyophilized active pharmaceutical ingredient 15 in response to an immersion in the diluent 5 or upon a contact with the diluent 5. In the example as shown in Fig. 1 the support structure 20 comprises a shell 21 enclosing a cavity 22. The cavity 22 may be entirely filled or occupied by the active pharmaceutical ingredient. The active pharmaceutical ingredient 15 may be provided inside the cavity 22 and hence inside the shell 21 in a lyophilized state. It may be provided in form of a powder, a compressed powder, in granular form and/or in the form of a semi-solid cake-like structure. The shell 21 may be a closed and homogenous shell. It may comprise a continuous layer void of recessed or through openings.

The support structure 20 provides mechanical stability to the lyophilized active pharmaceutical ingredient 15. The support structure 20 may be of predefined size. Hence, the shell 21 and/or the cavity 22 formed or constituted by the support structure 20 may be configured to contain or to enclose a predefined amount of the lyophilized active pharmaceutical ingredient 15.

In the example according to Fig. 1 the drug formulation 10 may be provided e.g. in form of a tablet or pill, which is intended for dissolving in the diluent 5 as shown in Fig. 2. Hence, for reconstituting the injectable medicament 6 it is intended to immerse or to introduce the reconstituable drug formulation 10 in a predefined amount of a diluent 5. The diluent 5 may be provided in a separate diluent container 40. The diluent container 14 may enclose or confine a container cavity 41, which is configured to contain or to provide a predefined amount of the diluent 5. Upon immersing or upon introducing the reconstituable drug formulation 10 in the diluent 5 as indicated in Fig. 5 the shell 2T may at least partially or section-wise dissolve or disintegrate thereby supporting and providing a release of the lyophilized active pharmaceutical ingredient 15 into the diluent 5. Mixing of the active pharmaceutical ingredient 15 with the diluent 5 provides dissolving ingredient 15 in the diluent 15, e.g. water for injection, and leads to the reconstitution of the injectable medicament 6.

Hence, the support structure 20 is configured to enclose, to adhere or to embed the lyophilized active pharmaceutical ingredient 15. The support structure 20 provided with the active pharmaceutical ingredient 15 can be easily handled and manipulated. The reconstituable drug formulation 10 is particularly configured for insertion into an amount of diluent 5 thereby releasing the lyophilized active pharmaceutical ingredient 15 from the support structure 20 into the diluent 5 for producing or for reconstituting the injectable medicament 6.

The reconstituable drug formulation 10 may be initially provided inside a medicament container 30 as indicated in Fig. 1. The medicament container 30 comprises a container cavity 31, which is sized to receive the entirety of the reconstituable drug formulation 10. The medicament container 30 may comprise or may constitute an outer packaging 28 for transportation, storage and retail of the reconstituable drug formulation 10. The container cavity 31 may be vacuumized.

In some examples the container cavity 31 may be filled with an inert gas, which is chemically and/or a pharmaceutically inert in view of the reconstituable drug formulation 10. In this way, a dry powder, e.g. a lyophilized active pharmaceutical ingredient 15 can be e.g. encapsulated or integrated in a support structure 20, which support structure 20 itself is further located or stored inside a container cavity 31 .

The container 30 may be implemented as a blister packaging 29, which at least in part may disintegrate or may be opened for removing the reconstituable drug formulation 10 from the container 30 in order to immerse the reconstituable drug formulation 10 in the diluent 5, when the diluent should be provided by a separate diluent container 40.

In a further example as shown in Figs. 4 and 5 the medicament container 30 may comprise or provide a two-fold function. The medicament container 30 comprises a container cavity 31 housing or enclosing the reconstituable drug formulation 10. The container 30 further comprises at least one of a first access port 37 and a second access port 38. Apart from the drug formulation 10 the container cavity 31 may be initially empty. It may be sized to receive a well- defined or predefined amount of the diluent 5 in addition to the drug formulation 10.

The diluent 5 may be inserted into the container cavity 31 through at least one of the first and the second access ports 37, 38. In this way, the medicament container 30 may not only provide transportation, storage and retail of the reconstituable drug formulation 10 but may also provide a mixing or reconstitution of the lyophilized active pharmaceutical ingredient 15 with the diluent 5. The access ports 37, 38 may be sealed or may be sealable. In this way there may be provided a sterile environment for both transportation, storage and retail as well as for the mixing of the lyophilized active pharmaceutical ingredient 15 with the diluent 5.

The medicament container 30 may comprise a flexible bag 33. The flexible bag 33 may comprise a first sidewall portion 34 and a second sidewall portion 35. The sidewall portions 34, 35 may be mutually connected along an outer circumference. Here, the first sidewall portion 34 and the second sidewall portion 35 may be mutually interconnected by a surrounding or circumferentially seam 36 or seal. The sidewall portions 34, 35 may comprise a transparent plastic material, e.g. coated with a metal layer in order to provide a good container closure integrity even when the diluent 5 is located inside the container cavity 31. Here, at least a portion of the first and the second sidewall portion 34, 35 and hence at least a portion of the enclosure 32 formed by the container 30 is at least partially transparent thus allowing to visually inspect the content inside the container cavity 31.

The bag 33 may be pliable or flexible. This allows and facilitates transportation, storage as well as retail of the reconstituable drug formulation 10. A flexible bag 33 may provide also a kind of mechanical dampening effect such that a rather sensitive drug product inside the container cavity 31 can be inherently protected against mechanical shock or against a respective force impact. Likewise, a flexible bag 33 is less prone to damage compared to a vial or barrel made of a vitreous material, e.g., glass.

In addition, the flexible bag 33 may provide a well-defined squeezing or otherwise mechanical deformation, which may be necessary to reconstitute the injectable medicament when the diluent 5 is in mechanical contact with the support structure 20 and hence with the lyophilized active pharmaceutical ingredient 15. In some examples the first access port 37 is configured for flushing or for introducing the diluent 5 into the container cavity 31. The second access port 38 may be further configured for a withdrawal of the injectable medicament 6 from the container cavity 31. Both or at least one of the access ports 37, 38 may be provided with a seal and/or with a standardized connector by way of which a fluid transfer can be provided into the interior of the container cavity 31 and to the outside of the container cavity 31.

In a further example as shown in Fig. 6 the container 30 may be further provided or connected with a separate diluent container 40. Also here, the diluent container 40 comprises a container cavity 41, which is sized and configured to receive and to hold a predefined amount of the liquid diluent 5. The diluent container 40 may also comprise a flexible bag 43. It may also comprise first and second sidewall portions as described in connection with the medicament container 30 according to Fig. 5. At least a portion or a section of the diluent container 40 may be made of a transparent material allowing to visually inspect the content of the diluent container 40.

The diluent container 40 may be filled with the liquid diluent 5. The diluent container 40 may comprise an outlet 48, which can be fluidically connected to the first access port 37 of the medicament container 30. The outlet 48 and the first access port 37 may be fluidically interconnected by a fluidic connection 50. The fluidic connection 50 may comprise a flexible fluid line 51 or flexible hose.

The fluid line 51 may be further provided with a breakable and/or frangible seal 55 or with a valve by way of which the fluidic connection between the outlet 48 and the access port 37 may be initially interrupted. In this way, and upon delivery to a patient or user the seal 55 may be intact and may block a fluid transfer across or through the fluid line 51.

In this way, the diluent 5 as provided inside the diluent bag 43 and the reconstituable drug formulation 10 as provided inside the medicament container 30 can be kept separated from each other during transportation, storage and delivery of retail. It may be only upon use and for preparing the injectable medicament that the seal 55 is broken or that a respective valve is opened thereby establishing a flow connection between the outlet 48 and the access port 37. Consequently, the diluent 5 initially provided inside the container cavity 41 may flow into the container cavity 31 and may interact with the lyophilized active pharmaceutical ingredient for reconstitution of the injectable medicament 6.

As further illustrated in Fig. 6 the second access port 38 may be connected with an injection device 52 comprising an injection needle 54. The injection device 52 may comprise an injection needle 54. The injection device 52 may be configured for injecting or infusing the reconstituted medicament 6 into biological tissue of a patient. The injection device 52 is connected in a fluid transferring manner to the access port 38 by a further fluid line 51.

In the flowchart of Fig. 7 numerous steps of the method of preparing an injectable medicament are indicated. In a first step 100 there is provided or used a medicament container 30 that comprises a container cavity 31. The medicament container 30 may comprise a drug formulation 10 as described herein, which is located inside the container cavity 31. In a subsequent step 102 the diluent 5 is introduced into the container cavity 31. In a subsequent step 104 the diluent 5 interacts with the support structure 20 and/or with the lyophilized active pharmaceutical ingredient 15 of the reconstituable drug formulation 10.

Further, and in step 104 the active pharmaceutical ingredient 15 is released and/or disseminated into the diluent 5 and is dissolved in or with the diluent 5 and the injectable medicament 6 is reconstituted. In a subsequent optional step 106 the reconstituted liquid injectable medicament 6 may be withdrawn from the mixing chamber and may be provided to an injection device for a subsequent injection or infusion procedure.

In Fig. 8 there is shown a further example of a reconstituable drug formulation 10. Here, the support structure 20 comprises a perforated scaffold 23. The perforated scaffold may be implemented similar to a drug eluting stent. The perforated scaffold 23 may comprise a hollow interior 24, which may be formed or enclosed by a sidewall 25, which may be of tubular shape. The sidewall 25 may comprise numerous through recesses 26. Hence, the sidewall 25 may comprise a comparatively large surface. It may be coated with a drug-eluting layer, which is configured to release the lyophilized active pharmaceutical ingredient into the diluent 5 when immersed in the diluent 5.

The scaffold 23 may be dimensionally stable. It may be made of a metallic material or may comprise a metallic material, which is chemically and/or pharmaceutically inert to the diluent, to the active pharmaceutical ingredient as well as to the injectable medicament.

The perforated scaffold 23 and hence the support structure 20 may allow and provide a rather easy handling of the reconstituable drug formulation 10 for reconstituting a predefined amount of the injectable medicament 6. The support structure 20 may be provided with a well-defined and known amount of lyophilized active pharmaceutical ingredient 15, which in response to mechanical contact with the diluent 5 or which in response to immersion in the diluent 5 may entirely dissolve in the diluent 5. The further examples as shown in Figs. 10-14 comprise a support structure 20 featuring a toroidal like shape or a ring-shape. Here, the support structure 20 comprises a drug-eluting annular structure 60. The annular structure 60 may comprise a closed drug-eluting ring 61 . In Fig. 11 there is shown a cross section through an example of such a drug-eluting ring. Here, the ring 61 may be of a matrix type implementation. The material of the drug-eluting ring 61 may comprise a polymeric matrix 27, wherein the active pharmaceutical ingredient 15 is embedded or dispersed in the polymeric matrix 27. The polymeric matrix 27 and the active pharmaceutical ingredient 15 may constitute the drug-eluting structure 60 and hence the drug eluting ring 61.

The support structure 27 as formed or constituted by the polymeric matrix 27 may provide a well-defined dispersion or release of the active pharmaceutical ingredient 15 when the support structure 20 is immersed in the diluent 5.

In the further example as shown in Fig. 12, the cross-section of the drug-eluting ring 61 may comprise a core 62, e.g. in form of an inner core 52, which is coated by a layer 63 and which is further enclosed by a membrane 64. Here, the lyophilized active pharmaceutical ingredient 15 may be exclusively provided in the active layer 63. The core 62 as well as the outer membrane 64 may be void or free of a pharmaceutically active substance 15. Here, the core 62 may provide mechanical stability for the active layer 63 and the outer membrane 64 may provide a controlled or controllable dispersion or release of the active substance 15 from the active layer 63 and hence of the soluble lyophilized active pharmaceutical ingredient 15 into the diluent 5 when the drug-eluting ring 61 is immersed in the diluent 5.

The example according to Fig. 12 may provide a kind of a sandwich structure. The active layer 63 is located between a non-medicated surface of the membrane 64 and the central core 62.

The further example according to Fig. 13 comprises another drug-eluting structure 60 formed as a drug-eluting ring 61. Here, the drug eluting ring 61 comprises numerous recesses 65 that are each filled with an insert 66, wherein the insert 66 is doped or provided with the lyophilized active pharmaceutical ingredient. Here, a recess 65 forms or constitutes a drug containing sector, which when the drug-eluting ring 61 is immersed in the diluent 5, provides a controlled or well-defined release or dissemination of the lyophilized active pharmaceutical ingredient 15 into the diluent.

The drug-eluting ring 61 and the drug-eluting structure 60 as shown in Figs. 10-14 as such may not entirely dissolve or disintegrate when immersed in the diluent 5. The drug-eluting structure 60 may comprise a non-dissolvable component, which may remain inside the medicament container 30 or inside the diluent container 40 after immersion in the diluent 5. In other examples and when the support structure 20 is made of a shell 21 or comprises a sidewall 25 that is dissolvable by the diluent 5 the reconstituable drug formulation 10 may restlessly dissolves inside the diluent container 40 or medicament container 30 when or after being in contact with the diluent over a predefined period of time.

Reference Numbers

5 diluent

6 injectable medicament

10 drug formulation

15 active pharmaceutical ingredient

20 support structure

21 shell

22 cavity

23 scaffold

24 interior

25 sidewall

26 through recess

27 matrix

28 packaging

29 blister packaging

30 container

31 container cavity

32 enclosure

33 bag

34 sidewall portion

35 sidewall portion

36 seam

37 access port

38 access port

40 diluent container

41 container cavity

42 enclosure

43 bag

48 outlet

50 fluid connection

51 line

52 injection device

53 line

54 injection needle

55 seal

60 drug eluting structure 61 drug eluting ring

62 core

63 layer

64 membrane 65 recess

66 insert

Claims

1. A reconstituable drug formulation (10) for preparing an injectable medicament (6) by interaction with a diluent (5), the reconstituable drug formulation (10) comprising: a support structure (20), and a lyophilized active pharmaceutical ingredient (15), which is at least one of arranged inside the support structure (20), adhered to the support structure (20) or integrated into the support structure (20), and wherein the lyophilized active pharmaceutical ingredient (15) is releasable in the diluent (5) in response to at least one of an immersion of the support structure (20) in the diluent (5) and a contact of the support structure (20) with the diluent (5).

2. The drug formulation (10) according to claim 1 , wherein the lyophilized active pharmaceutical ingredient (15) is releasable or detachable from the support structure (20) in response to a contact with the diluent (5).

3. The drug formulation (10) according to claim 1 or 2, wherein the support structure (20) is configured to interact with the diluent (5) to release the lyophilized active pharmaceutical (15) ingredient into the diluent (5).

4. The drug formulation (10) according to any one pf the preceding claims, wherein the support structure (20) comprises one of a cavity (22) and a recess (65) to receive the active pharmaceutical ingredient (15).

5. The drug formulation (10) according to claim 4, wherein the support structure (20) comprises one of a shell (21) and a sidewall (25) enclosing the cavity (22).

6. The drug formulation (10) according to claim 5, wherein the shell (21) is dissolvable by the diluent (5).

7. The drug formulation (10) according to claim 5 or 6, wherein at least one of the shell (21) and the sidewall (25) is permeable for at least one of the diluent (5) and the active pharmaceutical ingredient (15).

8. The drug formulation (10) according to any one of the preceding claims, wherein the support structure (20) comprises a polymeric matrix (27) and wherein the active pharmaceutical ingredient (15) is embedded or dispersed in the polymeric matrix (27).

9. The drug formulation (10) according to any one of the preceding claims, wherein the support structure (20) comprises a perforated scaffold (23) and wherein the active pharmaceutical ingredient (15) is coated on the perforated scaffold (23).

10. The drug formulation (10) according to any one of the preceding claims, wherein the support structure (20) comprises a core (62), an active layer (63) provided on the core (62) and wherein the active layer (63) comprises the active pharmaceutical ingredient (15).

11 . The drug formulation (10) according to claim 10, wherein the support structure (20) further comprises an outer membrane (64) enclosing the core (62) and the active layer (63), wherein the outer membrane (64) is permeable for at least one of the diluent (5) and the active pharmaceutical ingredient (15).

12. A medicament container (30) comprising: a container cavity (31), and a drug formulation (10) according to any one of the preceding claims located inside the container cavity (31).

13. The medicament container (30) according to claim 12, further comprising a first access port (37) in fluid connection with the container cavity (31) and configured to transfer the diluent (5) into the container cavity (31).

14. The medicament container (30) according to claim 12 or 13, further comprising a second access port (38) configured to fluidically connect the container cavity (31) with an injection device (52).

15. The medicament container (30) according to any one of the preceding claims 12 to 14, wherein the medicament container (30) comprises a flexible bag (33) enclosing or forming the container cavity (31).

16. The medicament container (30) according to any one of the preceding claims 12 to 15, further comprising a diluent container (40) fluidically connectable with the container cavity (31).

17. The medicament container (30) according to any one of the preceding claims 12 - 16, further comprising an outer packaging (28) enclosing the container cavity (31), and wherein the outer packaging comprises a blister packaging (29).

18. A method of preparing an injectable medicament (6) the method comprising the steps of: using a medicament container (30), which comprises a container cavity (31), inserting a drug formulation (10) according to any one of the preceding claims 1 - 11 into the container cavity (31).

19. The method according to claim 18, further at least one of comprising: pouring a predefined amount of the diluent (5) into the container cavity (31), or immersing the drug formulation (10) in the diluent (5).

20. The method according to any one of the preceding claims 18 and 19, wherein the drug formulation (10) is configured to release the active pharmaceutical ingredient (15) in the diluent (5) at a predefined release rate and wherein a concentration of the active pharmaceutical ingredient (10) in the injectable medicament (6) is controlled by monitoring or controlling a time interval during which the drug formulation (10) is immersed in the diluent (5) or is in contact with the diluent (5).