PACKAGING FOR PHARMACEUTICAL PRODUCTS

Description

[0001] The invention relates to a packaging for pharmaceutical products, comprising a primary packaging for receiving one or more doses of a pharmaceutical product, and a secondary packaging designed as a cardboard box in which the primary packaging is received, wherein the primary packaging is arranged in an insulating sleeve comprising a latent heat storage material and wherein the insulating sleeve is shaped to fit the primary packaging and lies flatly against it, in particular flatly on all sides.

[0002] The documents WO 2017 / 072638 A1, EP 3 147 598 A1, WO 03 / 101861 A2 and WO 2018 / 107049 A1 constitute the prior art relating to the subject matter of the present invention.

[0003] Ready-to-use pharmaceutical products are usually packaged or filled in blisters, vials, syringes, or injectors as a first step. The pharmaceutical products thus provided with primary packaging are then often packaged in small cardboard boxes, which serve as secondary packaging and on which the information required for marketing is printed.

[0004] A large number of such products, which are secondary packaged by the manufacturer, are combined into larger units for transport, and these units are provided with transport or freight packaging. In the case of temperature-sensitive pharmaceutical products, the transport or freight packaging can be provided with temperature-stabilizing properties. For example, temperature control modules made of a phase-change material are inserted into the transport or freight packaging and the transport or freight packaging is provided with a thermal insulation layer. The transport or freight packaging can contain temperature sensors with which compliance with a specified temperature window can be monitored. The transport or freight packaging can also be designed to protect the secondary-packaged products from mechanical influences.

[0005] When transporting pharmaceuticals over periods of several hours or days, specified temperature ranges must be maintained during storage and transport to ensure the usability and safety of the goods being transported. For various pharmaceuticals, temperature ranges of 2 to 25°C, in particular 2 to 8°C or 15 to 25°C, are specified as storage and transport conditions.

[0006] The problem here is that pharmaceutical products can only be stored and transported at controlled temperatures if they are in transport or freight packaging, such as a temperature-controlled freight container. It is therefore not possible to determine whether a secondary-packaged pharmaceutical product was outside the specified temperature range before being placed in the transport or freight packaging or after being removed from the transport or freight packaging. For example, an end consumer of a temperature-sensitive pharmaceutical product purchased from a pharmacy cannot determine whether the product became too warm or too cold during transport from the pharmacy to their home.Likewise, it is not possible to determine whether the product has become too warm or too cold during storage in the secondary packaging at the end consumer's home, or in a hospital or pharmacy.

[0007] Another disadvantage of conventional packaging systems is that it is not possible to determine with certainty whether the secondary packaging has been opened and the pharmaceutical product has been replaced by a counterfeit.

[0008] Furthermore, it is not possible to track the path of individual secondary-packaged products. With the appropriate equipment in conventional logistics systems, this is only possible for the shipping unit containing the transport or freight packaging, e.g., a transport pallet, which, however, does not allow for differentiation between each individual secondary packaging.

[0009] The problems described above mean that the end consumer cannot be sure whether they have taken a medically or pharmaceutically valid medication or whether its effectiveness has already been impaired due to temperature effects. Furthermore, the consumer cannot be sure whether they have actually taken the original medication or a counterfeit.

[0010] Due to these uncertainties, in most countries it is not permitted to ship medicines directly from the manufacturer or an intermediary to the end user, as the latter is unable to verify the authenticity and functionality of the medicine.

[0011] The invention therefore aims to further develop packaging for pharmaceutical products of the type mentioned above in such a way that the efficacy of temperature-sensitive pharmaceutical products is ensured for the end consumer and compliance with a prescribed temperature window can be verified throughout the entire transport chain up to the end consumer. Furthermore, the invention aims to make counterfeit pharmaceutical products of any kind identifiable.

[0012] To achieve these objects, the invention in a packaging of the type mentioned at the outset essentially consists in that the latent heat storage material contains a phase change material and that the latent heat storage material comprises a carrier material which is dimensionally stable at the use temperature and in which the phase change material is distributed or arranged, so that the latent heat storage material is dimensionally stable in a temperature range both below and above the melting point of the phase change material.

[0013] The invention is therefore based on the idea of arranging the temperature-stabilising elements inside a secondary packaging so that compliance with the prescribed temperature window does not depend on the temporary transport or freight packaging, such as a refrigerated freight container, a refrigerated transport vehicle or the like.

[0014] Secondary packaging is the cardboard packaging intended for handling by the end user and contains the primary packaging for one or more doses of the pharmaceutical product. Secondary packaging is used to sell the product it contains, which is why it is also referred to as sales packaging. It can be designed for promotional purposes to encourage the end user to purchase the contents. In contrast to primary packaging, such as glass bottles or blisters, secondary packaging does not have direct contact with the actual product. Nevertheless, the process steps in the production of secondary packaging are generally subject to GMP (Good Manufacturing Practice) or FDA compliance. Furthermore, the secondary packaging must provide initial information for consumers in accordance with the relevant pharmaceutical regulations, such as:the name of the pharmaceutical product, the active ingredient, the dosage form, the strength of the dosage form, the batch number, the expiry date, etc.

[0015] The cardboard box forming the secondary packaging is preferably designed as a folding box. The cardboard box, in particular a folding cardboard box, is preferably constructed of single- or multi-layer cardboard and has a wall thickness of a maximum of 1 mm, preferably a maximum of 0.5 mm.

[0016] The primary packaging is designed as a blister pack, ampoule, injection ampoule or vial.

[0017] The challenge of equipping secondary packaging with the temperature stabilization function lies in the very limited space available and the high cost pressure, as each individual package must be equipped with the technology. The invention retains the conventional concept of a cardboard box as secondary packaging and integrates a temperature stabilization element in the form of a latent heat storage material that envelops the inner packaging as an insulating shell.

[0018] Preferably, within the scope of the invention, the temperature stabilization function is realized by elements located within the secondary packaging, so that the external appearance of the secondary packaging remains unchanged.

[0019] Latent heat storage materials belong to the group of passive temperature control elements, which are characterized by the fact that they do not require an external energy supply during use, but rather utilize their heat storage capacity, whereby, depending on the temperature level, heat is released or absorbed to or from the primary packaging to be tempered, including the pharmaceutical product. Such passive temperature control elements are exhausted as soon as the temperature equilibrium with the primary packaging or its interior is complete. Latent heat storage materials are a special form of passive temperature control elements that can store thermal energy in phase-change materials whose latent heat of fusion, heat of solution, or heat of absorption is significantly greater than the heat they can store due to their normal specific heat capacity.

[0020] Particularly efficient temperature stabilization is preferably achieved by having the insulation cover surround the primary packaging on all sides.

[0021] As an additional barrier against temperature changes in the pharmaceutical product, a preferred embodiment of the invention provides that the insulating sleeve comprising the latent heat storage material is held in the secondary packaging at a distance from the secondary packaging on all sides to form an insulating gap. The insulating gap is preferably filled with air, thus significantly reducing heat transfer between the primary packaging and the secondary packaging at low cost.

[0022] According to the invention, the latent heat storage material contains a phase-change material. Phase-change materials exhibit a latent heat of fusion that is significantly greater than the heat they can store due to their normal specific heat capacity. Phase-change materials therefore lose their effectiveness once the entire material has completely undergone the phase change. However, the latent heat storage device can be recharged by performing the opposite phase change.

[0023] Depending on the type of pharmaceutical product, it must be kept within a temperature range of 2 to 20°C, e.g., within a temperature range of 2 to 8°C or within a temperature range of 15°C to 25°C. The phase-change material has a phase transition temperature tailored to the specified temperature range.

[0024] The phase change material preferably has a phase transition temperature of 3-10°C, in particular approximately 5°C.

[0025] Preferably, the phase change material is selected from the group consisting of paraffin, e.g. n-tetradecane or n-hexadecane, esters, e.g. methyl ester, linear alcohols, ethers, organic anhydrides, salt hydrates, water-salt mixtures, salt solutions and / or water-based solutions, or mixtures thereof.

[0026] Conventional phase-change materials undergo a phase change from the solid state to the liquid state and vice versa. The phase-change material must therefore be arranged in a suitable container so that it remains in its intended location even in the liquid state. A preferred embodiment of the invention provides, in this context, for the phase-change material to be enclosed in a dimensionally stable casing, in particular a plastic casing. The dimensionally stable casing, together with its contents, preferably forms the insulating shell and thus completely surrounds the primary packaging.

[0027] However, arranging the phase-change material in a suitable enclosure is associated with considerable effort and also carries the risk of the phase-change material diffusing through the enclosure or escaping from the enclosure due to a leak, thus contaminating the primary packaging. Furthermore, the enclosure's shape is limited, which in turn complicates handling when arranging the insulation sleeve in the secondary packaging and requires more space and weight.

[0028] To avoid these disadvantages, the invention provides that the latent heat storage material comprises a carrier material that is dimensionally stable at the service temperature and in which the phase-change material is distributed or arranged, so that the latent heat storage material is dimensionally stable in a temperature range both below and above the melting point of the phase-change material. The service temperature is understood here to be the temperature at which an end user uses, transports, or stores the pharmaceutical product. The service temperature therefore preferably covers a temperature range from -25°C to +60°C. This avoids the problems associated with handling the phase-change material. In particular, it is not necessary to arrange latent heat storage devices of this type in separate containers.

[0029] The carrier material forms a matrix or a three-dimensional network in which the phase-change material is distributed. The matrix or network consisting of the carrier material provides the latent heat storage device with the required mechanical stability at operating temperature and does not undergo any phase change at the operating temperature itself.

[0030] In addition to the phase change material, the latent heat storage element preferably comprises one or more copolymers, in particular styrene block copolymer, and / or ethylene-butylene copolymer, as a carrier material in order to ensure the dimensional stability of the latent heat storage element even above the melting point of the phase change material.

[0031] Nanoporous carbon, into which the phase-change material is incorporated, can also be used as a support material. Small-pore lattice structures made of a polymer or open-pore foams, such as synthetic resin foams based on crude oil or similar materials, can also be used as support materials.

[0032] Preferably, the latent heat storage material is dimensionally stable up to a temperature of 10°C, preferably 20°C, particularly preferably 40°C above the phase transition temperature of the phase-change material. This ensures that the latent heat storage element remains dimensionally stable even at higher temperatures.

[0033] Preferably, it can be provided that, with a corresponding design of the carrier material, the latent heat storage material can be converted into the molten state upon heating to a temperature significantly above the operating temperature. The transition to the molten state can occur, in particular, from a temperature that is at least 60-100°C above the operating temperature or room temperature (20°C). This enables the production of the insulation shell by means of a forming process, in particular a casting process.

[0034] A preferred embodiment provides that the insulation shell is produced by injection molding of the latent heat storage material.

[0035] Injection molding processes have been around for a long time and are therefore simple and safe to use. In particular, injection molding processes can be used to produce even complex shapes simply and cost-effectively.

[0036] According to the invention, the insulating sleeve is shaped to fit the primary packaging and lies flat against it, particularly on all sides. This allows for particularly efficient temperature stabilization of the primary-packaged product. The flat fit of the insulating sleeve against the primary packaging also includes embodiments in which a separating layer, e.g., in the form of a plastic film, is arranged between the shaped insulating sleeve and the primary packaging. The shaped formation of the insulating sleeve is achieved particularly easily by using a casting or injection molding process.

[0037] In particular, the insulation sleeve can be molded onto the primary packaging. This is particularly advantageous when the primary packaging is designed as an ampoule or vial. The insulation sleeve is then applied by using the ampoule or vial as a carrier for the injection molding process, meaning the latent heat storage material is either injected directly onto the primary packaging or the primary packaging is encapsulated with latent heat storage material.

[0038] The use of a dimensionally stable latent heat storage material offers the further advantage that the insulating sleeve can serve as additional protection for the primary packaging against mechanical influences. Depending on its rigidity, the latent heat storage material can also be used as a shock absorber and protect the primary packaging, for example made of glass, if the packaging is dropped, for example. The rigidity of the latent heat storage material can be optimally adapted to the product, as dimensionally stable latent heat storage materials can be manufactured with a high modulus of elasticity of up to 3000 N / mm2 or with a very low modulus of elasticity of up to 1 N / mm2. In the variant in which a phase change material is poured in liquid form into a plastic sleeve, the additional mechanical protection can be achieved through the rigidity of the plastic sleeve.

[0039] In the variant in which the phase-change material is distributed in a matrix or network of a carrier material that is dimensionally stable both above and below the melting point of the phase-change material, the carrier material can impart impact-damping properties to the latent heat storage element. For this purpose, the carrier material is preferably selected such that the elastic modulus of the insulation shell is <1000 N / mm², preferably 10-100 N / mm². For example, the carrier material can be selected from the group of elastomers.

[0040] The insulation shell can preferably consist of at least two layers, which particularly preferably comprise phase-change materials with different phase transition temperatures. This allows the desired temperature range to be determined simply and efficiently.

[0041] The insulation sleeve may be formed from two halves or from a plurality of parts which together enclose the primary packaging.

[0042] The insulation gap is preferably defined on the outside by the cardboard box and on the inside by the insulation sleeve. To achieve particularly good thermal insulation of the pharmaceutical product, it is preferred that the insulation gap be filled with a gas, such as air, CO2, krypton, xenon, or a mixture of these gases, or be evacuated.

[0043] The insulation gap preferably has a thickness of < 16 mm, in particular 5-10 mm. With a 10 mm thick insulation gap, the thermal conductivity of the air in the gap is approximately 2.6 W / m²< K. Measurements have shown that the heat transfer coefficient at the interface between the outer packaging and the air of the insulation gap, or between the insulation shell and the air of the insulation gap, is approximately 3-5 W / m²< K. With a gap width of less than 5 mm, the decisive insulating effect is no longer achieved via the air due to the two heat transfer coefficients of the surfaces adjacent to the air gap. The insulation gap can preferably also have a thickness of < 5 mm, in particular 1-3 mm.

[0044] The insulating performance of the insulation gap can be further improved by applying a heat-reflecting coating to both surfaces bordering the gap or to just one of the surfaces.

[0045] A preferred embodiment therefore provides that the insulation cover has a heat-reflecting coating on its outer side, such as a metallic coating or a metal foil.

[0046] Alternatively or additionally, it may be provided that the cardboard box has a heat-reflecting coating on its inner surface, such as a metallic coating or a metal foil.

[0047] The heat-reflecting coating is preferably formed by a metallic, in particular gas-tight coating, preferably a coating with an emissivity of < 0.5, preferably < 0.2, particularly preferably < 0.04, such as a coating made of aluminum.

[0048] The coating significantly reduces energy transfer due to thermal radiation and thus increases insulation performance without a significant increase in costs.

[0049] The insulation performance can be further increased by filling the insulation gap with additional layers of reflective foil or by removing the gas from the insulation gap (vacuum). Alternatively, the insulation gap can be filled with a highly insulating material, such as aerogel.

[0050] In order to further improve the insulating effect of an insulating gap filled with a gas, it is preferably provided that the insulating gap is divided by at least one intermediate layer, preferably a film, arranged in the insulating gap. The at least one intermediate layer is preferably arranged substantially parallel to the outer and inner surfaces bounding the insulating gap. If the thickness of the insulating gap is too great, undesirable convection can occur within the insulating layer. To prevent this, the at least one intermediate layer divides the insulating gap into at least two regions, each of which is of smaller thickness. The intermediate layer can preferably be provided on one or both sides with heat-reflecting properties, in particular with a heat-reflecting coating.The heat-reflecting coating is preferably formed by a metallic, in particular gas-tight coating, preferably a coating with an emissivity of < 0.5, preferably < 0.2, particularly preferably < 0.04, such as a coating made of aluminum.

[0051] Particularly preferably, at least one layer, in particular several superimposed layers, of a heat-reflecting foil, in particular metal foil, is arranged in the insulation gap.

[0052] According to a preferred embodiment, the insulation gap is created by arranging spacer elements to keep the insulation sleeve at a distance from the secondary packaging on all sides.

[0053] The spacer elements can be formed by separate parts that are arranged around the insulation sleeve and between the insulation sleeve and the secondary packaging, wherein the contact surfaces of the spacer elements on the insulation sleeve and the cardboard box are minimized in order to reduce heat transfer by thermal conduction.

[0054] Preferably, the spacer elements consist of the phase change material of the insulation sleeve or are formed by cardboard elements, in particular cardboard elements of the secondary packaging.

[0055] In order to monitor compliance with the prescribed temperature range and / or to detect unauthorized opening of the secondary or primary packaging for the purpose of introducing counterfeit goods, a preferred embodiment provides for a temperature sensor or a temperature control strip to be arranged in the insulation gap, in the latent heat storage material, between the latent heat storage material and the primary packaging, or in the primary packaging. Temperature control strips are a type of chemical paper thermometer in which a measuring strip irreversibly changes color when a predetermined temperature is reached.

[0056] Furthermore, in this context, an electronic memory for storing temperature measurements recorded at regular intervals or continuously can be provided in the packaging. The electronic memory is preferably connected to an electronic circuit for wirelessly reading the stored temperature measurements. For example, the stored temperature measurements can be fed to an antenna for wireless inductive transmission of the values to a reading device. Data transmission can be carried out, for example, via the RFID or NFC standard.

[0057] The temperature sensor is preferably located between the primary and secondary packaging or within the insulation. When located within the insulation, the temperature measurement can be used to determine whether the insulation has been opened. Without opening the insulation, a sudden temperature increase cannot occur. Opening the insulation inevitably results in a temperature jump, as the external temperature cannot be adjusted to within 0.1°C of the internal temperature before opening, for example, because the internal temperature is unknown to a third party. This ensures that a system automatically detects any replacement of the pharmaceutical product.

[0058] The invention will be explained in more detail below with reference to exemplary embodiments shown schematically in the drawing. Fig. 1 a perspective view of the packaging according to the invention and Fig. 2a cross-section of the packaging according to Fig. 1 .

[0059] In Fig. 1 and 2 A cardboard box is designated by 1, which represents the secondary packaging. An insulating sleeve 2 is arranged inside the cardboard box 1, which consists of or contains a latent heat storage material. The insulating sleeve encloses a primary packaging 3, which is designed, for example, as a glass ampoule, which contains a pharmaceutical product in its interior 4. The insulating sleeve 2 can, for example, consist of two half-shells, which can be separated from one another along a separation plane 5 in order to make the primary packaging 3 accessible. As shown in Fig. 2 As can be seen, the insulating sleeve is adapted to the outer shape of the primary packaging 3, so that the insulating sleeve 2 lies flat against the primary packaging 3, in the present case along a cylindrical surface.

[0060] Spacer elements 6 are arranged on all sides, i.e. on all six sides of the cuboid, between the insulating sleeve 2 and the cardboard box 1, which ensure that an insulating gap 7 is provided between the insulating sleeve 2 and the cardboard box 1. However, the insulating gap 7 can also be omitted. The insulating gap 7 is filled with a gas, such as air. To improve the thermal insulation, a heat-reflecting coating 8 or 9, e.g. in the form of a metal foil, can be applied to the outside of the insulating sleeve 2 and / or to the inside of the cardboard box 1. A heat-reflecting flat element, e.g. a metal foil, can also be arranged in the insulating gap 7, as is indicated by way of example with the dashed line 10 in the area between the two right-hand spacer elements 6.

[0061] To monitor the temperature of the pharmaceutical product, a temperature sensor 11 is also provided, which, if the insulating sleeve 2 is formed from two half-shells, is directed toward the parting plane 5. The temperature sensor 11 can not only monitor the temperature of the pharmaceutical product but also detect unauthorized opening of the packaging. If the two half-shells of the insulating sleeve are separated, the temperature detected by the temperature sensor 11 changes abruptly.

Claims

1. Packaging for pharmaceutical products, comprising a primary packaging (3) for receiving one or several doses of a pharmaceutical product, and a secondary packaging designed as a cardboard box (1) in which the primary packaging (3) is received, wherein the primary packaging (3) is arranged in an insulation shell (2) having a latent heat storage material, and wherein the latent heat storage material comprises a phase change material, the latent heat storage material comprising a carrier material which is dimensionally stable at the temperature of use, in which the phase change material is distributed or arranged so that the latent heat storage material is dimensionally stable in a temperature range both below and above the melting point of the phase change material, characterized in that the primary packaging (3) is designed as a blister pack, ampoule, injection ampoule or vial and wherein the insulation shell (2) is adapted in shape to the primary packaging (3) and resting flat, in particular flat on all sides, on the latter.

2. Packaging according to claim 1, characterized in that the insulation shell (2) surrounds the primary packaging (3) on all sides.

3. Packaging according to claim 1, characterized in that the phase change material is selected from the group consisting of paraffin, e.g. n-tetradecane or n-hexadecane, esters, e.g. methyl esters, linear alcohols, ethers, organic anhydrides, salt hydrates, water-salt mixtures, salt solutions and / or water-based solutions, or mixtures thereof.

4. Packaging according to claim 1, 2 or 3, characterized in that the phase change material has a phase transition temperature of 3-10°C, in particular approximately 5°C.

5. Packaging according to any one of claims 1 to 4, characterized in that the phase change material is present in a dimensionally stable enclosure, in particular a plastic enclosure.

6. Packaging according to any one of claims 1 to 5, characterized in that the latent heat storage material is dimensionally stable up to a temperature of 5 °C, preferably 10 °C, particularly preferably 15 °C above the phase transition temperature of the phase change material.

7. Packaging according to any one of claims 1 to 6, characterized in that the insulation shell (2) is produced by injection molding the latent heat storage material.

8. Packaging according to any one of claims 1 to 7, characterized in that the insulation shell (2) is moulded onto the primary packaging (3).

9. Packaging according to any one of claims 1 to 8, characterized in that the insulation shell (2) has a modulus of elasticity of 1 to 3,000 N / mm2.

10. Packaging according to any one of claims 1 to 9, characterized in that the insulation shell (2) has a heat-reflecting coating (8), such as a metallic coating or a metal foil, on its outside.

11. Packaging according to any one of claims 1 to 10, characterized in that the cardboard box (1) has a heat-reflecting coating (9), such as a metallic coating or a metal foil, on its inner surface.

12. Packaging according to claim 10 or 11, characterized in that the heat-reflecting coating (8, 9) is formed by a metallic, in particular gas-tight coating, preferably a coating with an emissivity of < 0.5, preferably < 0.2, particularly preferably < 0.04, such as a coating made of aluminium.

13. Packaging according to any one of claims 1 to 12, characterized in that the insulation shell (2) is held in the secondary packaging (1) at a distance from the latter on all sides in order to form an insulation gap (7).

14. Packaging according to claim 13, characterized in that the insulation gap (7) is filled with a gas, such as air, CO2, krypton, xenon or a mixture of these gases, or is evacuated.

15. Packaging according to claim 13 or 14, characterized in that at least one layer (10), in particular several superimposed layers, of a heat-reflecting foil, in particular metal foil, is arranged in the insulation gap (7).

16. Packaging according to any one of claims 13 to 15, characterized in that the insulation gap (7) has a thickness of < 16 mm, in particular 5-10 mm.

17. Packaging according to any one of claims 13 to 16, characterized in that spacer elements (6) are arranged in order to hold the insulation shell (2) at a distance on all sides from the secondary packaging (1) in the latter.

18. Packaging according to claim 17, characterized in that the spacer elements (6) consist of the phase change material of the insulation shell (2) or are formed from cardboard elements, in particular cardboard elements of the secondary packaging (1).

19. Packaging according to any one of claims 1 to 18, characterized in that a temperature sensor (11) or a temperature control strip is arranged in the insulation gap (7), in the latent heat storage material, between the latent heat storage material and the primary packaging (3) or in the primary packaging (3).