DRUG DELIVERY SYSTEM

Abstract

The present invention relates to a drug delivery system, in particular for a controlled administration of one or more active pharmaceutical ingredients to a body, and further in particular for oral administration of one or more active pharmaceutical ingredients to a body. The system thereby comprises a base component soluble in body fluids and a separate first component soluble in body fluids. The first component thereby comprises a therapeutically effective amount of a first active pharmaceutical ingredient.

Claims

1. Drug delivery system, in particular for a controlled administration of one active pharmaceutical ingredients, API, or more APIs to a body, the system comprising: a base component soluble in body fluids, a separate first component soluble in body fluids, wherein the first component comprises a therapeutically effective amount of a first API, wherein the first component is inhomogeneously arranged in the base component.

2. The system of claim 1, wherein the base component is provided as a three-dimensional body, and wherein the separate first component is inhomogeneously arranged throughout the base component.

3. The system of claim 1 or 2, wherein the concentration of the first API varies throughout the system.

4. The system of claim 3, wherein the concentration of the first API is highest at a center, at an edge or at an intermediate region of the system.

5. The system of claim 3 or 4, wherein a gradient of the concentration of the first API increases towards or increases away from a center of the drug delivery system.

6. The system of any of claims 3-5, wherein a concentration profile of the first API throughout the system comprises a smooth transition to an area of increased concentration.

7. The system of any of claim 3-6, wherein a concentration profile of the first API throughout the system comprises more than one area of increased concentration.

8. The system of any of claims 3-7, wherein the variation of the concentration of the first API throughout the system is at least 5%, further preferred at least 10%, further preferred at least 15%, further preferred at least 20%, further preferred at least 25%, further preferred at least 30%, further preferred at least 35%, further preferred at least 40%, further preferred at least 45%, further preferred at least 50%, further preferred at least 55%, further preferred at least 60%, further preferred at least 65%, further preferred at least 70%, further preferred at least 75%, further preferred at least 80%, further preferred at least 85%, further preferred at least 90%, further preferred at least 95%, further preferred approximately 100%.

9. The system of any of claims 3-8, wherein the variation of the concentration of the first API throughout the system is at most approximately 100%, further preferred at most 95%, further preferred at most 90%, further preferred at most 85%, further preferred at most 80%, further preferred at most 75%, further preferred at most 70%, further preferred at most 65%, further preferred at most 60%, further preferred at most 55%, further preferred at most 50%, further preferred at most 45%, further preferred at most 40%, further preferred at most 35%, further preferred at most 30%, further preferred at most 25%, further preferred at most 20%, further preferred at most 15%, further preferred at most 10%, further preferred at most 5%.

10. The system of any of claims 3-9, wherein the concentration profile of the first API is such that upon application of the system, the first API is released from the system at a predetermined release profile, which preferably comprises a section with a release at a constant rate.

11. The system of any preceding claim, wherein the concentration profile of the first API is such that upon application of the system, the first API is released at two or more dosages, wherein release of the first API at one of the dosages starts preferably 1 second to 10 days, more preferably 2 seconds to 1 day, more preferably 5 seconds to 12 hours, more preferably 10 seconds to 6 hours, more preferably 20 seconds to 2 hours, more preferably 1 minute to 1 hour, and most preferred 10 minutes to 30 minutes before release of the first API at another one of the dosages.

12. The system of any preceding claim, wherein the base component envelops the system and the first component is not arranged at an outer face of the system.

13. The system of any preceding claim, comprising a separate second component soluble in body fluids, wherein the second component comprises a therapeutically effective amount of a second API.

14. The system of claim 13, wherein the second component is inhomogeneously arranged in the base component.

15. The system of claim 13 or 14, wherein a concentration profile of the first API throughout the system is different than a concentration profile of the second API throughout the system.

16. The system of any of claims 13-15, wherein the first component and the second component are arranged in the system such that upon application of the system, release of the first API starts before release of the second API, wherein the release of the first API preferably starts 1 second to 10 days, more preferably 2 seconds to 1 day, more preferably 5 seconds to 12 hours, more preferably 10 seconds to 6 hours, more preferably 20 seconds to 2 hours, more preferably 1 minute to 1 hour, and most preferred 10 minutes to 30 minutes before release of the second API.

17. The system of any of claims 13-16, wherein the first component and the second component are arranged in the system such that upon application of the system, a release profile of the first API differs from a release profile of the second API.

18. The system of any preceding claim, wherein the total amount of the first API in the system is between 1 g and 100 g, preferably between 10 g and 10 g, more preferably between 100 g and 1 g, more preferably between 500 g and 500 mg, more preferably between 1 mg and 100 mg, further preferred between 10 mg and 50 mg.

19. The system of any preceding claim, wherein one or more of the components comprises a ceramic, metal, polymer, minerals, filler, solution binder, dry binder, and/or glidant.

20. The system of any preceding claim, wherein one or more of the components comprises a disintegration agent.

21. The system of claim 20, wherein the agent comprises cellulose, croscarmelose sodium, crospovidone, starches, cross-linked polyvinylpyrrolidone, sodium starch glycolate, and/or sodium carboxymethylcellulose.

22. The system of any preceding claim, wherein the first component is provided in a geometrical shape, the shape preferably being a tube, a spot, an oval, a plate, and/or a polygon.

23. The system of any preceding claim, further comprising a marking component optically different from the base component, wherein the marking component is arranged such that it forms a two-dimensional pattern on the surface of the system, preferably visible from the outside.

24. The system of any preceding claim, wherein the first component is optically different from the base component and is arranged such that it forms a two-dimensional pattern on the surface of the system, preferably visible from the outside.

25. The system of claim 23 or 24, wherein the two-dimensional pattern is a discontinuous pattern.

26. The system of any preceding claim, wherein the system is in the form of a tablet, a capsule, a disk, a film, an implant, a subdermal implant, a patch, pellets, or granules.

27. The system of any preceding claim, wherein the first API is selected from a list comprising anthelmintic agents, narcotics and narcotic antagonists; anti-histamines, adrenergic agents, adrenergic blockers sedative hypnotics, CNS agents, analeptics, antiparkinson agents, steroids, coronary vasodilators, anticoagulants, antihypercholesterolemics, antibiotics, antifungal agents, antiviral agents, bone growth promotants, anticancer agents, vitamins, antiinflammatory agents, or antihypertensive agents.

28. The system of any preceding claim, wherein the first API is selected from a list comprising Pregabalin, Lurasidon, Fentanyl, Rivaroxaban, Sildenafil/Tadalafil, Desatinib, Sorafenib, Varenicline, Memantine, Dexlansoprazole, Sunitinib, Nebivolol, Zolmitriptan, Sitagliptin, Lacosamid, Desvenlafaxin, Lenalidomid, Ledipasvir/Sofosbuvir, Aripiprazole, Levodopa, or Ondansetron/Granisetron.

29. The system of any preceding claim, wherein the system is produced with a screen-printing technique.

30. The system of claim 29, wherein the system is produced by alternatingly performing the following steps: screen-printing and curing a base paste comprising the base component, and screen-printing and curing a first paste comprising the first component.

31. Use of a drug delivery system of any preceding claim for a controlled administration of one or more active pharmaceutical ingredients to a body.

Description

4. DESCRIPTION OF PREFERRED EMBODIMENTS

[0058] In the following, the present invention will be described with reference to the enclosed figures. It shows:

[0059] FIG. 1 several designs of drug delivery systems according to the present invention;

[0060] FIG. 2 a further design of a drug delivery system and respective concentration profile according to the present invention;

[0061] FIG. 3 several API release profiles of drug delivery systems according to the present invention;

[0062] FIG. 4 further designs of drug delivery systems according to the present invention;

[0063] FIG. 5 further designs of drug delivery systems according to the present invention;

[0064] FIG. 6 a further design of a drug delivery system according to the present invention; and

[0065] FIG. 7 a structured drug delivery system according to the present invention.

[0066] FIG. 1 illustrates nine design options for drug delivery systems according to the present invention. As can be seen, all these designs comprise a base component, which forms the overall body of the respective drug delivery system (DDS) and can be considered as a matrix, within which further components may be arranged. These further components are labeled as component A, component B, component C, and component D, and may each comprise a therapeutically effective amount of a separate active pharmaceutical ingredient (API). Thus, any of the components A-D may be considered as a first component within the context of the present invention. The base component and the components A-D are soluble in body fluids.

[0067] The design of DDS (a) in FIG. 1 has a round shape. DDS (a) may be in a form of a tablet, a disc or the like. It has a particular diameter D, which may be, for example, 15 mm. Within the base component of the DDS (a), a first component A comprising a first API, a second component B comprising a second API and a third component C comprising a third API are provided. As can be seen, the respective APIs are not distributed homogeneously through the drug delivery system, but are arranged inhomogeneously within the base component, as the components A, B, C are provided at particular positions within the drug delivery system. The components A, B, C are provided in a polygonal shape, with a hexagonal cross section.

[0068] Upon application of DDS (a) and dissolution thereof, the base component dissolves first, as the dissolution may begin at the edge of the system. After a particular period of time, component C and then component B start to dissolve, thereby releasing the respective APIs. Later on, component A eventually starts to dissolve, thereby releasing the respective first API provided therein. Thus, due to the particular arrangement of the components in the drug delivery system, the different APIs are released at different stages at different dosages after application of the drug delivery system. Due to the particular arrangement of the different components within DDS (a), each API is released at a particular time after application of the drug delivery system, with a particular and individual, API-specific release profile.

[0069] The design of DDS (b) in FIG. 1 is formed as a tablet, with a height of, for example, 2.5 mm, and a diameter of again 15 mm. Two components B and C comprising each an API are provided within the base component in an inhomogeneous manner according to the present invention. Upon application of the system, particular release profiles of the APIs contained in components B and C are obtained, which may feature smooth transitions between phases of increased release.

[0070] The design of DDS (c) in FIG. 1 is similar to that of DDS (a), however comprising, beside the base component, only two components B and C comprising each an API. Upon application of the system, particular release profiles of the APIs contained in components B and C are obtained, which may feature smooth transitions between phases of increased release.

[0071] In the design of DDS (d) in FIG. 1, two components with APIs are provided in a tube-like shape. Similarly, the components may also be provided in form of stacked plates.

[0072] DDS (e) in FIG. 7 has a design where the components comprising APIs are provided as spots within the base component. Upon application of the system, particular release profiles of the APIs contained in components B and C are obtained, which may feature smooth transitions between phases of increased release.

[0073] DDS (f) in FIG. 1 has a design of a particular heights of, for example, 25 mm, wherein only one component comprising an API is arranged inhomogeneously in the base component, in a tube-like manner. Similarly, the component may also be provided in form of plates.

[0074] DDS (g) in FIG. 1 is similar to DDS (e), however the components comprising APIs are arranged in a more random manner. Upon application of the system, particular release profiles of the APIs contained in components B and C are obtained, which may feature smooth transitions between phases of increased release.

[0075] DDS (h) in FIG. 1 has a design, where the components comprising the APIs are provided or arranged in the form of circles within the base component. Upon application of the drug delivery system, the base component and the first component dissolve in an alternating manner, such that the first API is released intermittently, for example in a rather periodic manner. After the first API is completely released, the second component starts dissolving, thereby releasing the second API. As can be seen, the circles of component A are not concentric, and are not having a uniform thickness. Due to this particularly inhomogeneous arrangement, a particular release profile is obtained, which may feature smooth transitions between phases of increased release.

[0076] DDS (i) in FIG. 1 has a design where a component comprising an API is provided in a particular pattern within a matrix of additives, which is arranged in the base component.

[0077] The person skilled in the art understands that each of the systems described above with regard to FIG. 1 has particular release characteristics with regard to the API(s) provided therein. Depending on the therapeutic application, the person skilled in the art understands to choose an appropriate design, with an inhomogeneous arrangement of the API in the base component according to the present invention.

[0078] FIG. 2 shows a further design of a drug delivery system according to the present invention. Therein, the component comprising the API and the base component are arranged on a grid-like structure, with each pixel defined either by the API component or the base component. As can be seen, the two components are arranged such that the density of API-pixels is higher at a central part of the drug delivery system. This is also apparent from the API concentration profile, which is also illustrated in FIG. 2. The profile features a peak of high API concentration at the center of the system, and low API concentration at the edges of the system. The transition from the low API concentration at the edges to the high API concentration at the center is smooth, as it does not feature any abrupt steps. With such a drug delivery system, the release profile of the system upon dissolution of the two components is adjusted or configured in a desired manner.

[0079] FIG. 3 shows the release profile of a common drug delivery system with a homogeneously distributed API (graph (1) in FIG. 3), as well as two release profiles of drug delivery systems according to the present invention (graphs (2) and (3) in FIG. 3). The design of the respective drug delivery system is shown next to the graphs. The drug delivery systems are provided in a round shape, and may be a tablet dissolving upon oral administration, for example. The respective graphs each show the release of the API of the respective drug delivery system over time.

[0080] Regarding graph (1) in FIG. 3, the design of the respective drug delivery system is such that the API is homogeneously distributed throughout the system. This principle of homogeneity, which is the key feature of common prior art drug delivery systems, derives from the corresponding manufacturing processes. Upon dissolution of classical drug delivery systems, the respective API is released. Due to the dissolution characteristics of the homogeneous system and the shape of the system, a particular and fixed release profile is obtained. As can be seen from graph (1) in FIG. 3, the release of the API increases gradually over time, reaches a maximum, and thereafter decreases gradually.

[0081] Due to the inhomogeneous arrangement of the API according to the present invention, different release profiles can be obtained. The design associated with graph (2) in FIG. 3 is different from that associated with graph (1) in FIG. 3, as the API is arranged at an edge of the drug delivery system. Hence, the principle of a homogeneous distribution of the API in the system is suspended, as the API is inhomogeneously arranged in the system, being provided here with a high concentration at the edge of the system. The concentration of the API smoothly decreases towards the center of the system. Upon application of the drug delivery system associated with graph (2) of FIG. 3, the release of the API is rather high in the beginning and then decreases gradually. Such a high initial API release may be beneficial for particular applications, as will be appreciated by the person skilled in the art.

[0082] In the design associated with graph (3) in FIG. 3, the API is accumulated at a central part of the drug delivery system. Thus, the concentration of the API is highest at the center of the system, and the gradient of the concentration points from the edge of the system to its center. As can be seen from the respective graph (3) in FIG. 3, the release increases approximately gradually over a prolonged period of time, and the maximum release rate is delayed in time as compared to the common design. In comparison to the common design, the release of the API can be considered to be more constant, for an extended period of time. Such a release profile may be beneficial for particular applications, as will be appreciated by the person skilled in the art.

[0083] FIG. 4 shows further design options for a drug delivery system according to the present invention. The overall shape of the systems is that of a round disk with a diameter of 5-25 mm, preferably 20 mm or 15 mm, and a thickness of 0.5-15 mm, preferably 2 mm or 6 mm. A cut into the tablets is provided to allow for a view on the arrangement of the components in the tablets.

[0084] The design of DDS (j) in FIG. 4 has a first component comprising a first API provided at the central part of the tablet, being surrounded by a base component, while the entire tablet is coated with a coating. The coating may be a hydrophilic coating, or may provide entericcoated properties, for example. The concentration of the API within the tablet is highest at the center of the tablet. The concentration profile of the API is such that it comprises a smooth transition from the edge of the tablet towards the center of the tablet.

[0085] The design of DDS (k) in FIG. 4 has a first component comprising a first API and a second component comprising a second API being provided within a base component. Again, also a coating is provided. The second component is arranged in the form or a sphere, and the concentration of the second API is highest on the surface of the sphere, decreasing smoothly towards the center of the sphere. Within the sphere formed of the second component, the first component is provided. Thus, upon application of the tablet and dissolution of the components, the second API is released prior to the first API, and during a transition period, both APIs are released.

[0086] The design of DDS (l) in FIG. 4 has two different APIs, with the second API being provided at a central part of the tablet, and the first API is provided around the second API. At an interface region between both APIs, there is an overlap of the APIs, such that in this interface region, both APIs are arranged. Thereby, a smooth crossover is achieved. Furthermore, layers are provided, extending through the system, which may be hydrophobic layers.

[0087] The design of DDS (m) in FIG. 4 does not have a coating. An API is inhomogeneously arranged in the tablet, such that areas or regions with different concentrations of the API are formed.

[0088] FIG. 5 shows further design options for a drug delivery system according to the present invention. The overall shape of the systems is that of a round disk with a particular thickness. As can readily be recognized, the systems comprise one or more markings being arranged at least partially on the surface of the tablets. The markings form a visible two-dimensional pattern on the surface of the tablets. As shown in FIG. 5, the pattern of the marking may be a discontinuous pattern. The pattern may comprise smooth curves, or sharp edges. Accordingly, the pattern may be arranged in an inhomogeneous manner. The markings may be formed by a particular marking component, or a component comprising an API. By providing drug delivery systems with such elaborate markings, particular security features are created which allows for a user to authenticate the origin of the drug delivery system.

[0089] FIG. 6 illustrates a further design option for a drug delivery system according to the present invention. The system is provided in a spherical shape, and has a hydrophobic coating. The coating comprises hydrophilic pores with sizes in the range of 1 m to 500 m. Inside the drug delivery system, there is provided a base component and three different active pharmaceutical ingredients, API A, API B, and API C. The API C is provided at a central part of the system with a peripheral pattern. The other two APIs A and B surround API C. Thereby, API B is provided as a hollow sphere, with a homogeneous distribution of the API. Furthermore, API A is inhomogeneously distributed, surrounding the API C. Thereby, the concentration of API A diminishes towards an edge of the illustrated drug delivery system.

[0090] FIG. 7 illustrates a cross-section of a drug delivery system according to the present invention. As can be depicted, the surface of the drug delivery system is structured, as six protrusions and respective recesses in between are formed on one side thereof. By increasing the surface in this manner, the dissolution of the drug delivery system and thus the release of the API can be enhanced. The person skilled in the art understands that the entire surface of the drug delivery system, or only one or several parts thereof may be structured.

[0091] Therefore, the person skilled in the art understands that with the drug delivery system according to the present invention, a particular inhomogeneous distribution of one or more APIs within the system can be arranged in order to provide a desired release of the API(s). The person skilled in the art understands that a prompt release or a delayed release of an API can be obtained. Furthermore, it is possible to release a particular single API at different dosages over a prolonged period of time, for example intermittently, thereby obtaining a release of the API(s) in phases.

[0092] Furthermore, it is possible to obtain a release of different APIs in distinct phases with a single, novel drug delivery system. For example, it is possible to design the system such that a first API is released before a second API is released. Examples for such systems integrating two or potentially more APIs include gastroprotective agents such as proton pump inhibitors or antihistamines and non-steroidal anti-inflammatory substances such as ibuprofen or diclofenac. Another example would be the combination of antiemetics (e.g. ondansetron, domperidon) and analgesics, especially those acting on structures of the central nervous system (e.g., tramadolhydrochloride). Another example would be the combination of Carbidopa and Levodopa, thus an agent that prevents the degradation of the pharmaceutically active ingredient. The person skilled in the art understands that the release of these two APIs may provide particular synergetic effects. Furthermore, controlled release could mean mimicry of physiology, e.g. a Cortisone therapy whereas the drug delivery system is administered at 10:00 pm, preferably releasing the steroid 6 hours later. As the steroid is desirably administered at 4:00 am, it is possible to administer the steroid with the drug delivery system according to the present invention, which can be designed such that it is ingested in the previous evening, but the respective API is released at the desired time during the night. Similarly, with the drug delivery system according to the present invention, it is possible to ensure a proper administration of antibiotics in phases, for example, over a prolonged period of time (e.g. over days). Thus, the negative effects of patients disregarding the prescribed administration routine can be reduced.

[0093] The design options resulting from the concept of an inhomogeneous arrangement of one or more APIs in a drug delivery system are numerous. The person skilled in the art understands that the above examples can be combined to obtain further elaborate designs with release profiles optimized to the particular application or therapy.