阅读说明：本技术 生产药物递送系统的方法 (Method for producing a drug delivery system ) 是由 阿希姆·施尼伯格 克劳斯·克尼 赫尔穆特·克什鲍默 斯丹·瓦西克 于 2017-12-29 设计创作，主要内容包括：本发明涉及生产药物递送系统的方法。该方法包括以下步骤：丝网印刷基础浆料,并固化该基础浆料。此外,该方法包括以下步骤：丝网印刷与基础浆料分开的第一浆料,并固化第一浆料。(The present invention relates to a method of producing a drug delivery system. The method comprises the following steps: screen printing a base paste, and curing the base paste. Furthermore, the method comprises the steps of: a first paste, which is separate from the base paste, is screen printed and cured.)

1. A method of producing a drug delivery system, the method comprising:

screen printing of a base paste;

curing the base slurry;

screen printing a first paste separate from the base paste;

curing the first slurry;

wherein the first slurry comprises a therapeutically effective amount of a first active pharmaceutical ingredient, API.

2. The method of claim, wherein the drug delivery system is produced layer by layer.

3. The method of claim 1 or 2, wherein the base paste and the first paste are screen printed such that the resulting planar layer of the drug delivery system comprises both the base paste and the first paste.

4. The method of claim 3, wherein the planar layer of the drug delivery system is produced by:

screen printing and curing the base paste to partially form the planarization layer,

screen printing and curing the first paste separated from the base paste to partially form the planarization layer.

5. The method of claim 4, wherein after the production of the planar layer is completed, another planar layer is produced on top of the completed planar layer.

6. The method of any of the preceding claims, wherein the base paste is screen printed on a screen printer, and wherein the first paste is screen printed using another screen printer.

7. The method of any preceding claim, wherein the base slurry and the first slurry are cured using a shared curing apparatus.

8. The method of any of the preceding claims, wherein the base slurry and the first slurry are soluble in a body fluid.

9. The method of any of the preceding claims, wherein

The paste is screen printed such that in the resulting drug delivery system the first paste is non-uniformly disposed in the base paste.

10. The method of any of the preceding claims, wherein

The paste is screen printed such that in the resulting drug delivery system, the base paste is provided as a three-dimensional object and the separate first pastes are non-uniformly disposed throughout the base paste.

11. The method of any of the preceding claims, wherein

The slurry is screen printed such that in the resulting drug delivery system, the concentration of the first API varies throughout the drug delivery system.

12. The method of claim 11, wherein

The slurry is screen printed such that in the resulting drug delivery system, the concentration of the first API is highest at the center, edge or middle region of the drug delivery system.

13. The method of claim 11 or 12, wherein

The slurry is screen printed such that in the resulting drug delivery system, the concentration gradient of the first API increases towards or away from the center of the drug delivery system.

14. The method of any one of claims 11-13, wherein

The slurry is screen printed such that in the resulting drug delivery system, the concentration profile of the first API throughout the drug delivery system comprises a smooth transition to a high concentration region.

15. The method of any one of claims 11-14, wherein

The slurry is screen printed such that in the resulting drug delivery system, the concentration of the first API throughout the drug delivery system comprises more than one high concentration region.

16. The method of any one of claims 11-15, wherein

The slurry is screen printed such that in the resulting drug delivery system the concentration of the first API in the whole of the drug delivery system varies by at least 5%, further preferably by at least 10%, further preferably by at least 15%, further preferably by at least 20%, further preferably by at least 25%, further preferably by at least 30%, further preferably by at least 35%, further preferably by at least 40%, further preferably by at least 45%, further preferably by at least 50%, further preferably by at least 55%, further preferably by at least 60%, further preferably by at least 65%, further preferably by at least 70%, further preferably by at least 75%, further preferably by at least 80%, further preferably by at least 85%, further preferably by at least 90%, further preferably by at least 95%, further preferably by about 100%.

17. The method of any one of claims 11-16, wherein

The slurry is screen printed such that in the resulting drug delivery system the concentration of the first API in the whole of the drug delivery system varies by at most about 100%, further preferably by at most 95%, further preferably by at most 90%, further preferably by at most 85%, further preferably by at most 80%, further preferably by at most 75%, further preferably by at most 70%, further preferably by at most 65%, further preferably by at most 60%, further preferably by at most 55%, further preferably by at most 50%, further preferably by at most 45%, further preferably by at most 40%, further preferably by at most 35%, further preferably by at most 30%, further preferably by at most 25%, further preferably by at most 20%, further preferably by at most 15%, further preferably by at most 10%, further preferably by at most 5%.

18. The method of any one of claims 11-17, wherein

The slurry was screen printed such that in the resulting drug delivery system, the concentration profile of the first API was such that: upon application of the drug delivery system, the first API is released from the drug delivery system with a predetermined release profile, which preferably comprises a portion that is released at a constant rate.

19. The method of any of the preceding claims, wherein

The slurry was screen printed such that in the resulting drug delivery system, the concentration profile of the first API was such that: upon application of the drug delivery system, the first API is released in two or more doses, wherein release of the first API in one of the doses begins 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 preferably 10 minutes to 30 minutes before release of the first API in another of the doses.

20. The method of any of the preceding claims, wherein

The paste is screen printed such that the base paste encapsulates the resulting drug delivery system, and the first paste is not disposed on an outer surface of the resulting drug delivery system.

21. The method of any one of the preceding claims, further comprising the steps of:

screen printing a second paste separate from the base paste and the first paste;

curing the second slurry;

wherein the second slurry comprises a therapeutically effective amount of a second API.

22. The method of claim 21, wherein the paste is screen printed such that the resulting planar layer of the drug delivery system comprises the base paste and the first and second pastes.

23. The method of claim 22, wherein the planar layer of the drug delivery system is produced by:

screen printing and curing the base paste to partially form the planarization layer,

screen printing and curing the first paste separated from the base paste to partially form the planarization layer.

Screen printing and curing the second paste separated from the base paste and the first paste to partially form the planarization layer.

24. The method of any one of claims 21-23, wherein the second slurry is soluble in a bodily fluid.

25. The method of any one of claims 21-24, wherein

The paste is screen printed such that in the resulting drug delivery system, the second paste is non-uniformly disposed in the base paste.

26. The method of any one of claims 21-25, wherein

The paste is screen printed so that in the resulting drug delivery system,

the concentration profile of the first API throughout the drug delivery system is different from the concentration profile of the second API throughout the drug delivery system.

27. The method of any one of claims 21-26, wherein

The slurry is screen printed such that upon application of the resulting drug delivery system, release of the first API begins before release of the second API, wherein release of the first API preferably begins 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 preferably 10 minutes to 30 minutes before release of the second API.

28. The method of any one of claims 21-27, wherein

The slurry is screen printed such that upon application of the resulting drug delivery system, the release profile of the first API is different from the release profile of the second API.

29. The method of any preceding claim, wherein the first paste is screen printed to form a geometric shape, preferably the shape is

The pipe-shaped structure is characterized in that the pipe-shaped structure,

the shape of the spot is that the spot,

the shape of the oval is that of the oval,

plate-shaped, and/or

A polygon.

30. The method of any of the preceding claims, wherein the resulting drug delivery system has the form:

the dosage form of the tablet is,

the capsule is prepared by mixing the raw materials,

the shape of the disc is such that,

the film is a film of a polymeric material,

an implant is provided with a plurality of implant bodies,

a subcutaneous implant which is implanted under the skin,

a patch preparation comprises a patch preparation and a patch preparation,

the pellets are made of a mixture of pellets,

and (4) granules.

31. The method of any preceding claim, wherein the first API is selected from the list comprising: anthelmintic, anesthetic and anesthetic antagonist, antihistamine, adrenergic agent, adrenergic blocker, sedative hypnotic, CNS agent, reviving agent, anti-Parkinson agent, steroid, coronary vasodilator, anticoagulant, anti-hypercholesterolemic agent, antibiotic, antifungal, antiviral agent, bone growth promoter, anticancer agent, vitamin, anti-inflammatory agent, or antihypertensive agent.

32. The method of any preceding claim, wherein the first API is selected from the list comprising: pregabalin, lurasidone, fentanyl, rivaroxaban, sildenafil/tadalafil, dessertib, sorafenib, valacyclonidine, memantine, dexlansoprazole, sunitinib, nebivolol, zolmitriptan, sitagliptin, lacosamide, venlafaxine, lenalidomide, ledipasvir/sofosbuvir, aripiprazole, levodopa, or ondansetron/granisetron.

33. A drug delivery system produced according to any of the preceding claims.

34. System for producing a drug delivery system comprising means for performing the method according to any of claims 1-32.

35. A system for producing a drug delivery system, the system comprising:

means for screen printing a base paste;

means for curing the base slurry;

means for screen printing a first paste separate from the base paste;

means for curing the first slurry;

wherein the first slurry comprises a therapeutically effective amount of a first active pharmaceutical ingredient, API.

1. Field of the invention

The present invention relates to a method for producing a drug delivery system, preferably for controlled administration, further preferably systemic administration, of one or more active pharmaceutical ingredients to the body. Furthermore, the invention relates to a system for producing a drug delivery system.

2. Background of the invention

Drugs or medicinal drugs are commonly used for the diagnosis, cure, treatment or prevention of diseases. The Active Pharmaceutical Ingredient (API) may be part of any drug that produces its effect. Some drugs may have multiple APIs to treat different symptoms or to act in different ways. Thus, one or more APIs may be delivered by a drug. Drug delivery or drug delivery may refer to the transport of a drug compound into a patient's body as needed to safely achieve its desired (therapeutic) effect. The drug may be delivered or administered into the patient in various ways. Routes of administration include, inter alia, intravenous (by venipuncture into the blood compartment) and oral routes (through the mouth of the patient, e.g. via the oral mucosa or into the gastrointestinal tract to reach the blood cavity via the gastric or intestinal mucosa). The medicament may further be administered by inhalation, by injection into tissue (e.g. subcutaneous, intramuscular) or by topical application (e.g. cream for use on the skin). The drug may be provided in different dosage forms. Dosage forms may include, inter alia, pills (pils), tablets, capsules, solutions, dispersions, emulsions, implants.

The tablet may be a pharmaceutical dosage form. The tablet may be a solid unit dosage form of the drug comprising the API and with or without suitable excipients. Tablets may be produced by moulding or by compression. In the manufacture of tablets, the primary guideline is generally to ensure that there is an appropriate amount of active pharmaceutical ingredient in each tablet. Therefore, all ingredients should be well mixed. Thus, a homogeneous mixture of the ingredients was obtained. A specific amount of the mixture may then be compressed to obtain tablets. Thus, the API is typically uniformly distributed throughout the tablet or portions thereof.

Upon application of the tablet, for example upon oral administration, the tablet may dissolve and the API may be released therefrom. It then passes through the intestinal mucosa to the blood lumen and finally to the affected tissue. For a commonly produced drug delivery system, the concentration of an API within the blood lumen is typically such that it is above the efficacy threshold of a given API for only a certain period of time. However, during this period of time, the release of API from the drug delivery system to the gastrointestinal tract is typically much higher than actually required, whereby excess API may (i) not pass through the membrane in sufficient quantities and be absorbed by the human body and thus excreted, or (ii) may reach the body's blood lumen/tissue, leading to toxic effects.

Depending on the respective context of the pharmaceutical application or the specific therapeutic procedure, it may be desirable to have a specific release profile of the API. For example, it may be desirable to release the API at a constant rate over a long period of time. In other cases, it may be desirable to provide a particularly slow release of the API to the body at a rate slightly above the efficacy threshold of the API, where the release rate may be substantially time independent. In other cases, it may be desirable to release the API at specific time intervals (e.g., on and off over time). In other cases, it may be desirable to release multiple APIs in an API-specific release profile, one after another, or simultaneously at separate release rates.

Release of API from conventional tablets is driven primarily by the size of the disintegrating tablet, particularly the surface exposed to the surrounding liquid; conventional tablets are characterized by a uniform distribution of the API due to the requirements and limitations of conventional manufacturing techniques. Thus, it is predetermined and fixed by the form and size of the tablet, e.g. high release at the start and decreasing over time. The resulting blood/tissue concentration of the API may well exceed the corresponding efficacy threshold in order to obtain a desired concentration period above said threshold.

Such a release profile is particularly disadvantageous for APIs with a narrow therapeutic window (minimal difference between therapeutic and toxic doses). APIs with a Narrow Therapeutic Index (NTI) include aminoglycosides, cyclosporine (ciclosporin), carbamazepine (carbamazepine), digoxin (digoxin), digitoxin (digitoxin), flecainide (flecainide), lithium (lithium), phenytoin (phenylytoin), phenobarbital (phenobarbital), rifampin (rifampicin), theophylline (theophylline), warfarin (warfarin). The reference US 3,854,480 describes a drug delivery system for releasing an active pharmaceutical ingredient at a controlled rate over a long period of time. Thus, the drug delivery system comprises a solid inner matrix material having solid particles of a drug distributed throughout, and an outer polymeric membrane permeable and insoluble to body fluids and surrounding the inner matrix. Thus, the outer polymer membrane continuously meters the flow of drug from the inner matrix material to the outside of the system at a controlled constant rate for an extended period of time. However, the drug delivery system according to US 3,854,480 does not allow for more complex release profiles. Furthermore, it may be disadvantageous to apply an insoluble polymer film to the body of a patient.

The reference US 5,674,530 a relates to a drug delivery system wherein a first water-permeable half-capsule is filled with a drug and an osmotic agent. The reference US 2010/0068271 a1 relates to osmotic delivery systems used in tablets which can be divided into two usable semi-strong tablets. Release by osmosis is dependent, inter alia, on the environment of the drug delivery system in the patient, making precise release of the drug at the desired target challenging. Furthermore, controlled and precise drug release is difficult to achieve with such systems. Furthermore, such systems do not allow for more complex release profiles.

Reference WO 1993/007861 a1 relates to a drug delivery system comprising microcapsules or microspheres. The multiphase microspheres thus described comprise molecular compounds contained within a fixed oil within a polymer matrix. Before the molecular compound can diffuse out of the microsphere, it may first have to pass through the water-oil barrier and the polymeric barrier of the polymeric matrix. Thus, a constant and fixed delivery rate of the molecular compound can be provided without sacrificing high drug loading efficiency in the microspheres. However, this prior art system does not allow for more complex release profiles.

The reference WO 1999/008662 a1 relates to a drug delivery system suitable for oral administration that promotes a two-step release of the active agent. The drug delivery system disclosed therein comprises a first drug compartment, a first polymer compartment substantially enclosing the first drug compartment, a second drug compartment enclosing the first polymer compartment, and a second polymer compartment enclosing the second drug compartment. The second polymeric compartment may have one or more water-insoluble polymers that control the release of the active agent from the second drug compartment. However, this prior art system does not allow for more complex release profiles.

The present invention aims to overcome the above-mentioned disadvantages. It is therefore a problem to be solved by the present invention to provide a method for producing a more efficient drug delivery system which advantageously can provide the body with a controlled administration of one or more active pharmaceutical ingredients with a specific release profile for the application, for the treatment and/or API. It is a further object of the present invention to provide a method for producing a drug delivery system which allows a controlled administration of several APIs to the body such that the APIs are released in a defined manner relative to each other, preferably in a desired API-specific release profile. The general object of the present invention may be tailored to provide an improved technique for producing drug delivery systems, which allows for the mass production of advanced drug delivery systems with high quality. Advanced drug delivery systems can thus optimize pharmacokinetics and pharmacodynamics.

These objects and other objects, which will be apparent to a person skilled in the art from the following description, are solved by a method of producing a drug delivery system according to claim 1, a drug delivery system according to claim 33 and by a system for producing a drug delivery system according to claims 34 and 35.

3. Summary of the invention

The present invention relates to a method of producing a drug delivery system. The drug delivery system may allow for the delivery of an Active Pharmaceutical Ingredient (API) in the body of a patient as needed to safely achieve its desired therapeutic effect. Thus, the drug delivery system may comprise one or several APIs, or other ingredients (e.g. vitamins and minerals). The drug delivery system may be a bioerodible drug delivery system. Thus, the drug delivery system may erode after its application to the body of the patient and may, for example, dissolve after application, for example in the oral cavity of the patient. The drug delivery system produced according to the present invention is particularly suitable for controlled administration of one or more APIs to the body. The body may be the body of a patient, which may be a human or an animal. Further particularly, the drug delivery system produced according to the present invention may be used for oral administration of one or more APIs to the body, wherein the drug delivery system may be dissolved in the oral cavity of a patient. Thus, with the drug delivery system produced according to the present invention, the API can be administered in a controlled manner depending on the particular treatment or application.

The method of producing a drug delivery system according to the present invention comprises the step of screen printing a base paste. The base slurry may comprise water, polyvinylpyrrolidone, citric acid, hypromellose (hypromellose), stearate, silicic acid, glycerol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, cellulose croscarmellose (cellulose), ethylene glycol, crystalline gelatin, collagen, hydroxyapatite, bicarbonate (hydrocarbonate), lactide, lactic acid, silicon dioxide, poloxamers (polaxamers), xylitol, erythritol, ethanol, isopropanol, triacetin, aspartame, sodium bicarbonate, and/or acetone. The viscosity of the base slurry can be between 1 and 10^-2-1·10¹⁴mPas range, preferably 1.10^-1-1·10⁸mPas range, more preferably 1. multidot.10⁰-1·10⁷mPas range, more preferably 1. multidot.10¹-1·10⁶mPas range. For screen printing the base paste, a corresponding printing screen may be used, which allows providing the base paste according to a desired printing pattern (profile), such that, for example, only certain areas of the resulting drug delivery system are formed from the base paste.

Further, the method includes the step of curing the base slurry. Thereby, the base paste can be cured, thereby hardening it. The curing temperature and curing time may depend on the composition of the base slurry. For example, the base paste may be cured at a temperature of 30 ℃ to 180 ℃, preferably 35 ℃ to 150 ℃, further preferably 40 ℃ to 110 ℃, further preferably 45 ℃ to 90 ℃, further preferably 50 ℃ to 70 ℃. Preferably, a curing time of 10 seconds to 1 hour, preferably 30 seconds to 30 minutes, preferably 1 minute to 10 minutes may be applied.

Furthermore, the method comprises screen printing a first paste separate from the (preferably cured) base paste. Thus, the first slurry is provided separately from the base slurry. Thereby, the first paste is arranged separately from the base paste, i.e. preferably without overlap, as the first paste may be screen printed such that it is arranged at a position where the base paste is not screen printed. The components of the first slurry are not mixed in a classical manner with the components of the base slurry to form a homogeneous mixture. Instead, the first slurry is provided separately from the base slurry. Thus, within the resulting drug delivery system, the base slurry can be distinguished from the first slurry. The first slurry may comprise [ HM1]Water, polyvinylpyrrolidone, citric acid, hypromellose, stearate, silicic acid, glycerol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, cellulose croscarmellose, ethylene glycol, crystalline gelatin, collagen, hydroxyapatite, bicarbonate, lactide, lactic acid, silicon dioxide, poloxamer, xylitol, erythritol, ethanol, isopropanol, triacetin, aspartame, sodium bicarbonate and/or acetone. The viscosity of the base slurry can be between 1 and 10^-2-1·10¹⁴mPas range, preferably 1.10^-1-1·10⁸mPas range, more preferably 1. multidot.10⁰-1·10⁷mPas range, more preferably 110¹-110⁶mPas range. For screen printing the first paste, a corresponding printing screen may be used, which allows providing the first paste according to a desired printing pattern (profile), such that, for example, only certain areas of the resulting drug delivery system are formed by the first paste.

Further, the method includes the step of curing the first slurry. The curing temperature and curing time may depend on the composition of the first slurry. For example, the first slurry may be cured at a temperature of 30 ℃ to 180 ℃, preferably 35 ℃ to 150 ℃, further preferably 40 ℃ to 110 ℃, further preferably 45 ℃ to 90 ℃, further preferably 50 ℃ to 70 ℃. Preferably, a curing time of 10 seconds to 1 hour, preferably 30 seconds to 30 minutes, preferably 1 minute to 10 minutes may be applied. The first slurry may be cured together with the base slurry. Alternatively, screen printing and curing the first paste may be performed after curing the screen printed base paste.

Furthermore, according to the present invention, the first slurry comprises a therapeutically effective amount of the first active pharmaceutical ingredient. Thus, the first slurry may comprise an API to be delivered or administered by the resulting drug delivery system. The first API may be uniformly distributed within the first slurry. One skilled in the art understands that the first slurry may include a plurality of APIs, which may be uniformly distributed within the first slurry. Furthermore, the base slurry may contain an active pharmaceutical ingredient.

Thus, the method allows for the production of an enhanced drug delivery system, whereby the base slurry and the first slurry may be provided in the drug delivery system, such that a particularly desired release of the first API may be achieved. By controlling the arrangement of the first paste with respect to the base paste in the respective screen printing step, e.g. by selecting an appropriate printing pattern, it is possible to control when and at what rate the first API is released from the drug delivery system. This allows the production of a drug delivery system with optimal API release for a given controlled administration of the API to the body.

The use of screen printing technology allows for high-precision mass production of drug delivery systems. For example, a first slurry of nanoscale geometry may be printed, and thus a first API of nanoscale geometry may be printed, such that the placement of the first API throughout the resulting drug delivery system may be controlled with high precision. The screen printing technique further allows providing the first paste such that it forms a particularly preferred geometry in the cured state in the resulting drug delivery system. The use of screen printing technology also allows several drug delivery systems to be produced in a parallel manner. For example, while screen printing the base paste, a large number of drug delivery systems can be produced simultaneously by using a corresponding printer having a screen that allows printing the base paste to form an array of, for example, 100 x 100 tablets. Similarly, the first slurry may also be printed to ultimately form an array of 100 x 100 tablets simultaneously. An array of 100 x 100 tablets can also be cured simultaneously.

The resolution of the screen printed pattern depends inter alia on the composition of the paste. Preferably, the provided resolution is in the range of 10dpi to 10000dpi, further preferably 100dpi to 5000dpi, further preferably 200dpi to 2000dpi, further preferably 500dpi to 1000dpi, so that finally the first API can be arranged in a refined manner in the drug delivery system. Thus, the two-dimensional or three-dimensional structure formed by the base slurry and the first slurry in the drug delivery system may be characterized by a resolution in the range of 10dpi to 10000dpi, more preferably 100dpi to 5000dpi, further preferably 200dpi to 2000dpi, further preferably 500dpi to 1000 dpi.

Preferably, the drug delivery system is produced layer by layer. Thus, when producing the drug delivery system in a layer-by-layer manner, one layer may be formed on top of another layer to build the drug delivery system. For example, a first layer of the drug delivery system may be produced by screen printing and curing the base paste and the first paste, then another layer may be produced on top of the first layer, and so on. The drug delivery system may be produced using a movable platform, which may be disposed below the printing screen. After each layer is completed, the movable platform can be lowered vertically by a corresponding step size, and then the next layer can be produced on top of it. The skilled person understands that the arrangement of the (possibly cured) first slurry relative to the (possibly cured) base slurry may be different in adjacent layers.

In a preferred embodiment, the paste is screen printed such that the resulting planar layer of the drug delivery system comprises the cured base paste and the cured first paste. Thus, the planar layer of the resulting drug delivery system may comprise a cured base paste and a cured first paste separate from the base paste. Thus, both (cured) slurries can be distinguished from each other as no homogeneous mixture is provided.

Further preferably, the planar layer of the drug delivery system is produced by: the base paste is screen printed and cured to partially form the planarization layer, and the first paste, which is separated from the base paste, is screen printed and cured to partially form the planarization layer. Preferably, by producing planar layers, the paste is not screen printed in an overlapping manner. Thus, by screen printing and curing the base paste, a portion of the resulting planar layer may be formed. Another portion of the resulting planar layer, preferably the remaining portion of the resulting planar layer, may then be formed by screen printing and curing the first paste. Thus, for example, the resulting planar layer may comprise a region in which only the base slurry is disposed (e.g., in an outer region of the layer) and another region in which only the first slurry is disposed (e.g., in an inner region of the layer). The slurry cannot form a continuous region, but rather can form individual regions, i.e., "islands".

It is further preferred that after the production of the planar layer is completed, a further planar layer is produced on top of the completed planar layer. Thus, different arrangements or printing patterns may be selected. Thus, a desired three-dimensional arrangement of the first slurry with respect to the base slurry may be obtained, such that finally a desired three-dimensional distribution of the first API may be obtained throughout the resulting drug delivery system.

Preferably, the base paste is screen printed using a screen printer and the first paste is screen printed using another screen printer. Thus, in a respective production line, several screen printers may be arranged, each configured for printing a single paste, for example a base paste or a first paste. By inserting or removing individual printers from the production line, the production line can be modified to create different drug delivery system designs according to the present invention. Thus, a high flexibility is arranged by this modular arrangement.

Preferably, the base slurry and the first slurry are cured using a shared curing apparatus. Therefore, preferably only one curing device is needed in the production line to produce the drug delivery system. Although several separate screen printers may be used, the build (build) may also be transferred to a shared curing apparatus to cure the respective pastes. This may save costs.

Preferably, the (cured) base slurry and the (cured) first slurry are soluble in a body fluid. As an example, the bodily fluid may comprise blood or bodily tissue fluid. The body fluids encountered will vary depending on the route of administration. Upon oral ingestion of the drug delivery system, the composition of the outer layer may determine whether dissolution of the drug delivery system begins in the oral cavity (dissolved in saliva) or during subsequent passage of the drug delivery system through the gastrointestinal tract, in particular the stomach (acidic environment), ileum, jejunum or elsewhere. Likewise, a drug delivery system produced according to the present invention may be placed directly in a tissue (e.g., subcutaneously, intramuscularly) or a body cavity (e.g., pleural cavity) or in the cerebrospinal fluid space. After placement in the ventricle, the drug delivery system may be dissolved in the cerebrospinal fluid and any released API may reach the brain tissue. Placement in natural body cavities (e.g. pleural, peritoneal) means that these locations can be reached in large numbers. Another possibility may include dissolution in the airway upon inhalation. The skilled person will understand that the dissolution characteristics of the (solidified) slurry and thus of the resulting drug delivery system may be selected such that a suitable release of the API is obtained according to the respective therapy or application. Thus, a rather immediate or rather slow dissolution may be chosen.

The (cured) first slurry and the (cured) base slurry may be dissolved in a similar manner. Preferably, both the base slurry and the first slurry are capable of dissolving in the same body fluid. Thus, by screen printing the first paste and the base paste separately from each other, and due to their dissolution properties, it is possible to control when, at what rate the first API is released from the resulting drug delivery system. Preferably, the release of the API depends only on the dissolution characteristics of the (solidified) slurry and the form or shape of the resulting drug delivery system. No additional release agent, such as an osmotic agent for releasing the API, is required.

Preferably, the paste is screen printed such that in the resulting drug delivery system the (cured) first paste is not uniformly arranged in the (cured) base paste. Thus, the base slurry and the first slurry are not provided as a homogeneous mixture in the resulting drug delivery system, but are provided separately from each other, preferably in a specific manner, wherein the first slurry is not homogeneously arranged in the base slurry. The first slurry may be provided non-uniformly or discontinuously in one, two or most preferably three spatial or orthogonal directions in the base slurry. By arranging the slurry in this manner, the first slurry is arranged in the resulting drug delivery system in a controlled and desired manner such that there is no uniform distribution of the first slurry (and thus the first API) throughout the resulting drug delivery system. Rather, the non-uniformity is specifically constituted by the specific arrangement of the slurry. Since the base paste and the first paste are provided as separate pastes by screen printing the base paste and the first paste separately, preferably in a non-overlapping manner, the first paste may be arranged non-uniformly within the matrix formed by the base paste. For example, the amount of the first slurry disposed within the base slurry may gradually increase in a particular direction throughout the resulting drug delivery system.

The paste may be screen printed such that in the resulting drug delivery system the (cured) base paste may be provided as or considered as a three-dimensional object and the (cured) first paste may be arranged non-uniformly throughout the base paste. Thus, the body of the resulting drug delivery system may be formed from the base slurry, and one or more specific portions of the drug delivery system (which may have only marginal dimensions) may be formed from the first slurry. The base paste and the first paste may be arranged on a virtual two-dimensional or three-dimensional grid, wherein each pixel of the grid may be occupied by the base paste or by the first paste. Thus, the first slurry is preferably arranged non-uniformly in the base slurry, and thus may be arranged non-uniformly in the resulting drug delivery system itself. The size or volume of each such pixel may be in the region of 1 μm³To 1cm³In the range of (1), preferably 10 μm³To 100mm³In the range of (1), preferably 100 μm³To 10mm³And most preferably about 1mm³。

Since the general principle of an even distribution of the API throughout the drug delivery system is preferably temporarily nullified, it is possible to provide a specific arrangement of the API in the resulting drug delivery system to obtain a drug delivery system with a customized API release profile. The slurry comprising the API may be arranged such that a stable release of the API is obtained, wherein the release preferably results in a blood tissue concentration slightly above the efficacy threshold of the API. Thus, with the preferred drug delivery systems produced according to the present invention, it is advantageously required to effectively reduce the amount of API while maintaining the same clinical outcome and reduced side effects as compared to drug delivery systems with evenly distributed APIs that are typically produced.

Preferably, the uneven distribution of APIs in the drug delivery system produced according to the present invention is exploited in a standardized way, thereby selecting or setting a specific arrangement. This concept allows the production of drug delivery systems with the advantageous release profiles described herein. Standardization, definition or specification of the placement of the slurry (specification) and thus of the heterogeneity of the API, makes it possible to consistently produce such drug delivery systems in large quantities (also referred to as mass production).

Those skilled in the art understand that by screen printing and curing the base paste, processes such as cross-linking can occur within the base paste, ultimately altering the base paste itself. It will be appreciated that although the viscosity of the cured base slurry may have changed significantly, the structure of the resulting cured base slurry may still be considered to be essentially formed by the corresponding base slurry. Thus, when referring to the base slurry in the resulting drug delivery system, the skilled person understands that the base slurry may be a corresponding cured base slurry. The same applies to other slurries.

In a preferred embodiment, the paste is screen printed such that in the resulting drug delivery system the concentration of the first API varies throughout the drug delivery system, or further preferably throughout the object defined by the base paste. For example, a printing pattern may be selected that allows screen printing of the first paste only at the central portion of the drug delivery system. Thus, specific regions of the resulting drug delivery system having a rather high first API concentration may be identified, and specific regions having a rather low first API concentration (or even no first API) may be identified. Thus, when and how the API is ultimately released can be precisely controlled, taking into account the particular form or shape of the drug delivery system and the dissolution characteristics of the base slurry and the first slurry.

Further preferably, the paste is screen printed such that in the resulting drug delivery system the concentration of the first API is highest at the center, edge or middle region of the drug delivery system. Thus, for example, if the resulting drug delivery system is provided in the form of a tablet, the first slurry may be arranged or screen printed such that the peak concentration of the first API is provided at the center or central portion of the tablet. Thus, upon administration of the tablet and dissolution of the base slurry and the first slurry, the release of the first API may increase over time or may remain nearly constant over time, also depending on the shape of the drug delivery system. This allows a specific release of the desired API to be obtained.

Further preferably, the slurry is screen printed such that in the resulting drug delivery system the concentration gradient of the first API increases towards the centre of the drug delivery system or away from the centre of the drug delivery system. For example, the printing pattern may be selected such that the amount of screen printed first paste increases towards the center of the drug delivery system. For example, if the resulting drug delivery system is provided in the form of a spherical tablet, the arrangement of the first slurry, and thus the first API, may be such that the release rate is nearly constant after application of the drug delivery system as the concentration increases towards the center of the tablet. By adjusting the concentration profile of the API throughout the drug delivery system by adjusting the print pattern during screen printing, the release profile of the API can be well controlled.

Further preferably, the slurry is screen printed such that in the resulting drug delivery system the concentration profile of the first API throughout the drug delivery system comprises a smooth transition to a high concentration region. For example, the printing pattern may be selected such that the amount of screen printed first paste gradually increases towards the center of the drug delivery system. Thus, the concentration profile may comprise a smooth transition between a low concentration (and possibly even zero concentration) region and a high concentration region. A smooth transition may be defined by the absence of abrupt or discontinuous steps in the concentration profile. The concentration profile may represent a profile of the concentration of the first API diagonally across the resulting drug delivery system, e.g. a profile of the concentration of the first API from one edge of the drug delivery system to its centre or possibly extending across the entire drug delivery system. By such a smooth transition, a smooth onset of API release may be obtained upon dissolution of the corresponding cured slurry.

Further preferably, the slurry is screen printed such that in the resulting drug delivery system the concentration profile of the first API throughout the drug delivery system comprises more than one high concentration region. Thus, with the resulting drug delivery system, multiple doses of API may be administered over time. It is especially preferred that the deposition of the first API within the drug delivery system in the dissolution direction (e.g. from periphery to centre) may be discontinuous and repeated in an onion skin type manner due to the corresponding printing pattern during screen printing. In each such housing of the drug delivery system, the first slurry may be provided non-uniformly, such that the release of the first API preferably does not start in an abrupt manner, but may be arranged such that the release gradually starts and/or ends. Thus, the release of the APIs may occur in distinct waveforms, with intervals of high release followed by intervals of low or no release of the first API. Furthermore, the API may be applied in multiple stages over time. These phases (and in particular the start of these phases) can be controlled by: the placement of the high concentration areas within the drug delivery system is controlled and the corresponding print patterns during screen printing are selected or adjusted.

Further preferably, the slurry is screen printed such that in the resulting drug delivery system the concentration of the first API in the whole system varies by at least 5%, further preferably by at least 10%, further preferably by at least 15%, further preferably by at least 20%, further preferably by at least 25%, further preferably by at least30%, further preferably at least 35%, further preferably at least 40%, further preferably at least 45%, further preferably at least 50%, further preferably at least 55%, further preferably at least 60%, further preferably at least 65%, further preferably at least 70%, further preferably at least 75%, further preferably at least 80%, further preferably at least 85%, further preferably at least 90%, further preferably at least 95%, further preferably about 100%. Further preferably, the paste is screen printed such that in the resulting drug delivery system the concentration of the first API in the whole system varies by at most about 100%, further preferably at most 95%, further preferably at most 90%, further preferably at most 85%, further preferably at most 80%, further preferably at most 75%, further preferably at most 70%, further preferably at most 65%, further preferably at most 60%, further preferably at most 55%, further preferably at most 50%, further preferably at most 45%, further preferably at most 40%, further preferably at most 35%, further preferably at most 30%, further preferably at most 25%, further preferably at most 20%, further preferably at most 15%, further preferably at most 10%, further preferably at most 5%. Thus, by providing a corresponding local arrangement of the first paste with respect to the base paste using screen printing techniques, the variation of the concentration may be set in a controlled manner, thereby ultimately obtaining a desired controlled application of the first API with the resulting drug delivery system. The change in concentration of the first API may be defined as the difference between the maximum concentration and the minimum concentration of the API in the drug delivery system. In this case, the concentration may be a mass ratio concentration. The corresponding sampling volume for measuring the concentration may be any suitable volume and may be, for example, 1 μm³. For example, if the highest concentration in the sampling volume in the drug delivery system is about 80% and the lowest concentration in the sampling volume in the drug delivery system is about 10%, the variation may be 70%. Thus, for example, the concentration of the first API may be at least 10% in the entire drug delivery system, and the concentration of the first API may increase to 80% at the central portion of the drug delivery system.

Further preferably, the paste is screen printed such that in the resulting drug delivery system the concentration profile of the first API is such that: upon application of the system, the first API is released from the system with a predetermined release profile, the predetermined release profile further preferably comprising a portion that is released at a constant rate. Thus, due to the specific screen printing pattern, the first paste may be arranged within the base paste such that: upon application of the resulting drug delivery system, and upon dissolution of the (cured) base slurry and the (cured) first slurry, a specific API release profile is obtained, in a preferred embodiment with a constant release portion.

It is especially preferred that the paste is screen printed such that in the resulting drug delivery system the first paste is arranged in the base paste such that upon dissolution of the drug delivery system or the (cured) paste, the total amount of the first API at the outer surface of the drug delivery system remains nearly constant for a predetermined time, wherein the predetermined time is preferably in the range of 1 second to 180 days. For example, a print pattern may be selected that allows screen printing of the first paste such that the amount of printed first paste increases only towards the central portion of the drug delivery system. It is understood by the skilled person that longer or shorter release times may be applicable depending on the respective application and form of the drug delivery system. For example, if the drug delivery system is produced in the form of an implant, the API may be released over an extended period of time, up to 180 days. For example, if the drug delivery system is produced in tablet form, the API may be released over a period of up to 12 hours. Therefore, it is further preferable that the predetermined time of the nearly constant release is 5 seconds to 24 hours, further preferably 10 seconds to 12 hours, further preferably 1 minute to 6 hours, further preferably 10 minutes to 1 hour. Thus, in the exemplary case of a spherical tablet, the concentration gradient of the first API may be directed inwards such that the amount of API at the surface of the drug delivery system remains constant when the drug delivery system dissolves (i.e. the volume and surface of the system shrinks). Thus, the first slurry may be arranged such that the concentration of the final first API depends on the distance to the surface of the drug delivery system. Therefore, by arranging the first paste unevenly in the base paste using the screen printing technique, a constant release of the first API can be set.

It is further preferred that the paste is screen printed such that in the resulting drug delivery system the concentration profile of the first API is such that: in applying the system, the first API is released in two or more doses, wherein release of the first API in one of said doses preferably starts from 1 second to 10 days (e.g. higher values may be used if the drug delivery system is produced in the form of an implant), more preferably from 2 seconds to 1 day, more preferably from 5 seconds to 12 hours, more preferably from 10 seconds to 6 hours, more preferably from 20 seconds to 2 hours, more preferably from 1 minute to 1 hour and most preferably from 10 minutes to 30 minutes before release of the first API in another of said doses. For example, the printing pattern may be selected such that the first slurry is provided at a plurality of separate locations towards the centre of the drug delivery system. Thus, for example, if the drug delivery system is provided in the form of a tablet and the tablet is administered orally, the first API may be released in a first dose shortly after administration and then released in a second dose at a later time. The doses may be uniform or different from one another. Any duration of API release mentioned herein may be measured by Dissolution testing, for example according to USP guidelines "General Chapter <711> Dissolution" (General Chapter <711> Dissolution).

In another preferred embodiment, the paste is screen printed such that in the resulting drug delivery system, the base paste encapsulates the system and the first paste is not disposed on the outer surface of the system. Thus, the first slurry comprising the first API may be provided such that the first slurry is not in contact with the outside at least prior to application of the drug delivery system. Thus, the first API may be effectively isolated from the environment, thereby reducing the risk of contamination. Furthermore, if produced, for example, in the form of tablets, the dissolution of the first syrup is delayed upon oral administration, since the base syrup must first (at least partially) dissolve. Thus, a delayed application of the first API may be obtained. Preferably, the drug delivery system is produced such that the release of the first API does not start until 1 second to 1 day, further preferably 10 seconds to 12 hours, further preferably 30 seconds to 6 hours, further preferably 1 minute to 4 hours, further preferably 10 minutes to 2 hours, further preferably 30 minutes to 1 hour after application of the drug delivery system.

In another preferred embodiment, the method further comprises the steps of: a second paste, which is separate from the base paste and the first paste, is screen printed and cured. The second slurry may comprise a therapeutically effective amount of a second active pharmaceutical ingredient. Thus, the method allows for the production of a drug delivery system characterized by controlled administration of multiple APIs in a particular application. The APIs may interact after dissolution of the respective slurry, and thus may provide a synergistic effect in vivo. The first API and the second API may differ in form and concentration. Preferably, the (solidified) second slurry is soluble in a body fluid. The respective specifications given with reference to the first slurry and the base slurry apply analogously here.

Those skilled in the art understand that the screen printing and curing steps given herein for the base paste and the first paste and for the first API may be similarly applied to the second paste and the second API. Those skilled in the art understand that the method may include further steps of screen printing and curing further pastes comprising further active pharmaceutical ingredients (e.g. a third paste comprising a third API, a fourth paste comprising a fourth API, etc.).

In particular, the pastes are screen printed such that the resulting planar layer of the drug delivery system comprises all of the cured base paste and the cured first paste and the cured second paste. Thus, the resulting planar layer of the drug delivery system may comprise a cured base slurry, a cured first slurry separate from the base slurry, and a cured second slurry separate from the base slurry and the first slurry. Thus, all of the (solidified) slurry can be distinguished from the other slurries as no homogeneous mixture is provided.

Further preferably, the planar layer of the drug delivery system is produced by: screen printing and curing the base paste to partially form a planar layer; screen printing and curing a first paste separated from a base paste to partially form a planar layer; and screen printing and curing a second paste separated from the base paste and the first paste to partially form a planarization layer. Preferably, by producing planar layers, the paste is not screen printed in an overlapping manner. Thus, by screen printing and curing the base paste, a portion of the resulting planar layer may be formed. Another portion of the resulting planarization layer may then be formed by screen printing and curing the first paste. Another portion of the resulting planar layer, preferably the remaining portion of the resulting planar layer, may then be formed by screen printing and curing the second paste. Thus, for example, the resulting planar layer may comprise regions in which only the base slurry is disposed (e.g., in the outer regions of the layer), regions in which only the first slurry is disposed (e.g., in the inner regions of the layer), and regions in which only the second slurry is disposed (e.g., in the middle regions of the layer). The slurry cannot form a continuous region, but rather can form individual regions, i.e., "islands".

Preferably, the paste is screen printed such that in the resulting drug delivery system the (cured) second paste is not uniformly arranged in the (cured) base paste. Thus, by controlling the uneven arrangement of the respective first and second slurries in the base slurry, the release of the first and second APIs from the drug delivery system may also be controlled with respect to each other. The above explanations regarding the uneven arrangement apply here as well.

Further preferably, the slurry is screen printed such that in the resulting drug delivery system the concentration profile of the first API throughout the drug delivery system is different from the concentration profile of the second API throughout the drug delivery system. For example, the printing pattern may be selected such that the amount of screen printed first paste increases towards the center of the drug delivery system and the amount of screen printed second paste decreases towards the center of the drug delivery system. Thus, the drug delivery system may be designed and manufactured such that the first API and the second API are released to the body in different doses.

It is further preferred that the pastes are screen printed such that they are eventually arranged in a discontinuous manner within the resulting drug delivery system such that the first active substance is released at a unique time after the drug delivery system starts to dissolve, typically starting from the periphery. Similar to the onion skin type arrangement, for example, the layer with the first slurry can be adjacent to another layer that does not contain an API or contains a second API. The release of the API may be controlled by varying parameters such as the thickness of the layers, the composition of the layers, and the distribution of the API within the layers.

Further preferably, the paste is screen printed such that in the resulting drug delivery system the first paste and the second paste are arranged such that upon application of the drug delivery system the release of the first API starts before the release of the second API. For example, the printing pattern may be selected such that the second paste is printed closer to the center of the drug delivery system and the first paste is printed closer to the edge of the drug delivery system. The release of the first API may further preferably start 1 second to 10 days (e.g. higher values may apply if the drug delivery system is produced as an implant) before the release of the second API, more preferably 2 seconds to 1 day, more preferably 5 seconds to 12 hours. More preferably from 10 seconds to 6 hours, more preferably from 20 seconds to 2 hours, more preferably from 1 minute to 1 hour, most preferably from 10 minutes to 30 minutes. Thus, due to the specific inhomogeneous or discontinuous arrangement (preferably with respect to the dissolving direction) of the first and second slurry in the base slurry, it is possible to control when the respective first and second API are released with respect to each other. Depending on the spatial arrangement of the first API and the second API within the layers, the release of the two APIs may be separated by a defined time interval, or the release of the first API may continue when the release of the second API begins. Thereby, a specific synergy of the API may be obtained. Generally, APIs may be released into the body within hours, days, and months, depending on the unique form of application.

Preferably, the paste is screen printed such that in the resulting drug delivery system the first paste and the second paste are arranged such that the release profile of the first API is different from the release profile of the second API upon application of the drug delivery system. For example, a first API may be released at a fairly constant rate, while a second API may be released intermittently. This allows the design of complex drug delivery systems.

In a preferred embodiment, the total amount of the first API in the first slurry in the resulting drug delivery system is from 1 μ g to 100g, preferably from 10 μ g to 10g, more preferably from 100 μ g to 1g, more preferably from 500 μ g to 500mg, more preferably from 1mg to 100mg, more preferably from 10mg to 50 mg. The skilled person understands that any description regarding the first API may also apply to a possible second or further API provided in a second or further slurry of the drug delivery system.

In another preferred embodiment, the one or more slurries comprise a ceramic, a metal, a polymer (preferably an acrylic polymer) and/or a mineral.

In a preferred embodiment, one or more slurries comprise a disintegrant, which may facilitate the dissolution of the respective (solidified) slurry. Disintegrants may include cellulose (preferably microcrystalline cellulose), croscarmellose sodium, crospovidone, starch (preferably modified starch), crospovidone, sodium starch glycolate, and/or sodium carboxymethylcellulose.

Preferably, the one or more slurries may comprise one or more ingredients selected from the following list: coloring agents, sweetening agents, flavoring agents, antimicrobial preservatives (e.g., sorbic acid, benzoic acid, parabens, scrose, benzalkonium chloride), chemical stabilizers useful for increasing the chemical stability of the API (e.g., antioxidants such as ascorbic acid or sodium metabisulfite, chelating agents such as ethylenediaminetetraacetic acid), viscosity modifiers useful for reducing particle settling (e.g., polymeric or inorganic materials such as clays), cellulosic materials useful as viscosity enhancers in suspensions (e.g., cellulose ethers, alginic acid).

Preferably, the one or more slurries may comprise one or more excipients selected from the following list: fillers (e.g. lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, cellulose), solution binders (e.g. gelatin, polyvinylpyrrolidone, cellulose derivatives, polyethylene glycol), dry binders (e.g. cellulose, polyethylene glycol, methyl cellulose), glidants (e.g. silicon dioxide, magnesium stearate, talc).

In a preferred embodiment, the first paste is screen printed to form the geometric shape. The shape may preferably be tubular (which may be a hollow tube), spot-shaped (which may be a local small cluster or mass), oval (e.g. in the form of a hollow circle or ellipse), plate-shaped and/or polygonal (e.g. square). Thus, the first slurry may be provided in a shape such that the desired release of the first API is obtained, even possibly with respect to other APIs provided in other slurries of the system. Within a particular geometry, the concentration of the API may vary.

In a preferred embodiment, the resulting drug delivery system is in the form of a tablet, capsule, disc, membrane, implant, subcutaneous implant, patch, pellet or granule. Thus, the drug delivery system produced according to the present invention may have various forms and thus allow for a desired administration and a desired API release according to a particular therapeutic application.

Preferably, the paste is screen printed such that the resulting drug delivery system is characterized by a structured surface. For example, the printing pattern may be selected such that the protrusions and depressions form the surface of the resulting drug delivery system. Thereby, the surface of the resulting drug delivery system may be enlarged, which may ultimately provide a high release of the corresponding API.

It should be understood that the drug delivery system produced according to the present invention is not limited to a particular API. In general, any suitable API may be used, which may be provided in the respective slurry to be non-uniformly arranged within the base slurry. For example, the API may be any of an anti-infective agent, an anti-inflammatory agent, a cardiac active agent, an antipsychotic agent, or even a nutritional agent. Those skilled in the art will appreciate that this list is not limiting. Furthermore, the drug delivery system produced according to the present invention may comprise other components or substances, such as additives and the like.

In a preferred embodiment, the first API may be any of the following: anthelmintic, anesthetic and anesthetic antagonist, antihistamine, adrenergic agent, adrenergic blocker, sedative hypnotic, CNS agent, reviving agent, anti-Parkinson agent, steroid, coronary vasodilator, anticoagulant, anti-hypercholesterolemic agent, antibiotic, antifungal, antiviral agent, bone growth promoter, anticancer agent, vitamin, anti-inflammatory agent, or antihypertensive agent. In a preferred embodiment, the first API may comprise Pregabalin (Pregabalin), lurasidone (Lurasidon), Fentanyl (Fentanyl), Rivaroxaban (Rivaroxaban), Sildenafil (Sildenafil)/Tadalafil (Tadalafil), dessertib (Desatinib), Sorafenib (Sorafenib), vareniam (Varenicline), Memantine (Memantine), Dexlansoprazole (Dexlansoprazole), Sunitinib (Sunitinib), Nebivolol (Nebivolol), Zolmitriptan (Zolmitriptan), Sitagliptin (Sitagliptin), lacosamide (lacosamide), venlafaxine (Desvenlafaxin), lenalidomide (len), lenalidomide (lenalidol), radixaber (len), leflazidine (lexapridoparn), lexapridopar (levamisole)/leveiron (lasofovir), levofloxacin (lasalovir (lasalor), or levofloxacin (lasofovir). Again, the skilled person understands that this list is not limiting.

The present invention further relates to a drug delivery system produced by the method described herein.

Furthermore, the invention relates to a system for producing a drug delivery system. The system (or production system) thus comprises a device for producing a drug delivery system in the manner described herein. The production system for producing a drug delivery system according to the present invention may thus comprise means for screen printing a base paste, means for curing the base paste, means for screen printing a first paste separate from the base paste, and means for curing the first paste. Again, the first slurry thus comprises a therapeutically effective amount of the first API. It is understood by those skilled in the art that within the concept of the present invention, the production system may further comprise means for screen printing, for example, a second paste comprising a therapeutically effective amount of a second API.

4. Description of the preferred embodiments

Hereinafter, the present invention will be described with reference to the accompanying drawings. Accordingly, similar features are provided using the same reference numerals. It can be seen that:

fig. 1 a part of a production system for producing a drug delivery system according to the present invention;

FIG. 2 a production system for producing a drug delivery system according to the present invention;

FIG. 3 a production system for producing a drug delivery system according to the present invention;

FIG. 4 a production system for producing a drug delivery system according to the present invention;

FIG. 5 shows a design of a drug delivery system produced according to the present invention and the corresponding concentration profile;

FIG. 6 several API release profiles for a drug delivery system produced according to the present invention;

FIG. 7 is an additional design of a drug delivery system produced according to the present invention;

FIG. 8 shows an additional design of a drug delivery system produced according to the present invention;

FIG. 9 shows a design of a drug delivery system produced according to the present invention; and

fig. 10 is a structured drug delivery system produced according to the present invention.

Fig. 1 illustrates a part of a production system for producing a drug delivery system according to the present invention. It can be seen that a screen 10 is provided which allows for screen printing of a paste, for example a base paste, in the sense of the present invention. Thus, the screen 10 includes a corresponding mask 11 that masks particular portions of the screen for printing the desired pattern according to the corresponding print pattern. Furthermore, the screen 10 comprises a blade 13 which can draw the material or paste 12 to be printed on the screen, in particular on the entire mask 11.

As can be seen in part a) of fig. 1, a movable platform 20 is provided below the screen 10. On the platform 20 there is already a specific construction 40, which may have been produced layer by layer according to the invention.

As can be seen in part b) of fig. 1, blade 13 may draw slurry 12 along screen 10 so that additional layers of slurry 12 are screen printed onto build 40. Because the mask 11 masks portions, the paste 12 is printed only at specific locations on the build 40. Thus, the placement of the slurry 12 within the resulting drug delivery system can be precisely controlled.

Thereafter, as can be seen in section c) of fig. 1, the screen 10 is raised and the platform 20 with the construct 40 containing another layer of screen printed slurry is moved horizontally to place the construct 40 under the dryer 30. By means of this dryer 30, the screen-printed layer is cured. Thereby, the printed paste can be hardened.

The platform 20 may then be moved to another screen at another printing station to complete another portion of the layer by screen printing and curing another slurry.

After the layer is completed, the platform may be returned to the printer and screen 10 as shown in section d) of fig. 1 to print the corresponding paste 12 on top of the build 40. The platform 20 is lowered by an amount corresponding to the thickness of the previously built up layer and the screen 10 is moved to its lower printing position so that a further layer can be provided on top of the cured layer.

Fig. 2-4 show different design concepts of a production system for producing a drug delivery system according to the present invention. In fig. 2, two screen printers 10a, 10b are arranged with a dryer 30 in between. With the printer 10a, the base paste according to the present invention can be printed, and then can be cured by the dryer 30, and then the first paste can be printed on the portion not covered with the base paste by the printer 10 b. The first slurry may then also be cured with the dryer 30, and the build is then moved back to the first printer 10a to begin production of a new layer. The three-dimensional layout of the slurry in the resulting drug delivery system can be modified by changing the screen or print design of the printers 10a, 10 b.

According to the concept of fig. 3, five printers 10 are arranged in addition to a single dryer 30. With each of these printers, a different paste may be screen printed to ultimately form a single continuous layer, which may then be cured in one step with a single dryer 30. Thereafter, a new layer may be created on top of it.

According to the design of fig. 4, several printers 10 may be arranged with several dryers 30. Thus, three successive printers 10 can print a first complete planar layer, which is then cured with respective dryers 30, and subsequently print additional planar layers thereon, which may be different from the previously printed and cured layers. Those skilled in the art will appreciate that the process may be repeated with additional printers and dryers.

Fig. 5 shows a design of a drug delivery system produced according to the present invention. Thus, a planar layer of the drug delivery system is shown, which may extend through the drug delivery system. In which an API-containing paste and a base paste are arranged on a grid-like structure, each "pixel" being defined by either the API paste or the base paste. As can be seen, the two slurries are arranged such that the density of the "API pixels" is higher at the central portion of the drug delivery system. This can also be seen from the API concentration curve, which is also shown in fig. 5. The curve is characterized by a high API concentration peak at the center of the system and a low API concentration at the edges of the system. The transition from a low API concentration at the edge to a high API concentration at the center is smooth because it does not have any abrupt steps. With such a drug delivery system, the release profile of the drug delivery system upon dissolution of the two slurries is adjusted or configured in a desired manner.

Fig. 6 shows the release profile of a common drug delivery system with a uniform distribution of API (legend (1) in fig. 3), and two release profiles of a drug delivery system produced according to the present invention (legends (1), (2) and (3) in fig. 3). The design of the corresponding drug delivery system is shown next to the figure. The drug delivery system is provided in a circular shape and may be, for example, a tablet that dissolves upon oral administration. Each respective legend shows the release of the API of the respective drug delivery system over time.

With respect to legend (1) in fig. 6, the design of the respective drug delivery system is such that the API is evenly distributed throughout the drug delivery system. The principle of such uniformity is a key feature of common prior art drug delivery systems, which are derived from the respective manufacturing process. Upon dissolution of a classical drug delivery system, the corresponding API is released. Due to the dissolution properties of the homogeneous system and the shape of the drug delivery system, a specific and fixed release profile is obtained. As can be seen from legend (1) in fig. 6, the release of the API gradually increases over time, reaches a maximum and then gradually decreases.

Due to the uneven arrangement of the API according to the invention, different release profiles can be obtained. The design associated with legend (2) in fig. 6 is different from the design associated with legend (1) in fig. 6 because the API is disposed at the edge of the drug delivery system. Therefore, the principle of an even distribution of the API in the drug delivery system is negated, as the API is not evenly arranged in the drug delivery system, which provides a high concentration at the edge of the drug delivery system here. The concentration of the API decreases smoothly towards the center of the drug delivery system. In the application of the drug delivery system associated with legend (2) of fig. 6, the release of the API was initially quite high and then gradually decreased. Those skilled in the art will appreciate that such a high-onset API release may be advantageous for certain applications.

In the design associated with legend (3) in fig. 6, the API accumulates at the central portion of the drug delivery system. Thus, the concentration of the API is highest at the center of the system, and the concentration gradient points from the edge of the system to its center. As can be seen from the corresponding legend (3) in fig. 6, the release is nearly gradual over an extended period of time and the maximum release rate is delayed in time compared to common designs. The release of the API may be considered more constant over an extended period of time compared to common designs. Those skilled in the art will appreciate that such a release profile may be advantageous for particular applications.

Figure 7 shows nine design options for a drug delivery system produced according to the present invention. It can be seen that all of these designs comprise a base slurry that forms the entire body of the respective Drug Delivery System (DDS) and can be considered as a matrix in which other slurries can be arranged. These additional slurries are labeled slurry a, slurry B, slurry C, and slurry D, and each may comprise a therapeutically effective amount of a separate Active Pharmaceutical Ingredient (API). Thus, any of the slurries a-D may be considered as the first slurry in the context of the present invention. The base slurry and slurries a-D are soluble in body fluids.

The design of dds (a) in fig. 7 is circular. Dds (a) may be in the form of tablets or discs or the like. It has a specific diameter D, which may be 15mm, for example. Within the base slurry of dds (a), a first slurry a comprising a first API, a second slurry B comprising a second API and a third slurry C comprising a third API are provided. It can be seen that because slurry A, B, C is provided at a particular location within the drug delivery system, none of the corresponding APIs are uniformly distributed throughout the drug delivery system, and none are uniformly disposed within the base slurry. The slurry A, B, C is provided in a polygon having a hexagonal cross section.

When dds (a) is applied and it dissolves, the base slurry dissolves first, as the dissolution can start at the edge of the system. After a certain period of time, slurry C and subsequently slurry B begin to dissolve, thereby releasing the corresponding API. Later, slurry a eventually begins to dissolve, releasing the corresponding first API provided therein. Thus, due to the specific arrangement of the slurry in the drug delivery system, different APIs are released at different dosages at different stages after application of the drug delivery system. Due to the specific arrangement of the different slurries within dds (a), each API is released at a specific time after application of the drug delivery system and has a specific and individual API-specific release profile.

The DDS (b) design in FIG. 7 forms a tablet with a height of, for example, 2.5mm and a diameter of likewise 15 mm. According to the present invention, two slurries B and C each comprising an API are provided in a heterogeneous manner within a base slurry. Upon application of the drug delivery system, a specific release profile of each API contained in slurries B and C was obtained, which may be characterized by a smooth transition between high release phases.

The dds (C) design in fig. 7 is similar to that of dds (a), but contains only two slurries B and C, each containing an API, except for the base slurry. Upon application of the drug delivery system, a specific release profile of each API contained in slurries B and C was obtained, which may be characterized by a smooth transition between high release phases.

In the dds (d) design of fig. 7, two slurries with API were provided in tubular shape. Similarly, the slurry may also be provided in the form of stacked plates.

Dds (e) in fig. 7 has a design where the slurry containing the API is provided as a spot within the base slurry. Upon application of the drug delivery system, a specific release profile of each API contained in slurries B and C was obtained, which may be characterized by a smooth transition between high release phases.

Dds (f) in fig. 7 has a design with a specific height, e.g. 25mm, where only one slurry containing API is arranged inhomogeneously in a tubular manner in the base slurry. Similarly, the slurry may also be provided in the form of a plate.

Dds (g) in fig. 7 is similar to dds (e), but the slurry containing the API is arranged in a random fashion. Upon application of the system, a specific release profile of each API contained in slurries B and C is obtained, which may be characterized by a smooth transition between high release phases.

Dds (h) in fig. 7 has a design where the slurry containing the API is provided in the form of a circle or arranged in the base slurry. Upon application of the drug delivery system, the base slurry and the first slurry are dissolved in an alternating manner such that the first API is released intermittently, e.g. in a rather periodic manner. After the first API is completely released, the second slurry begins to dissolve, thereby releasing the second API. It can be seen that the circles of slurry a are not concentric and their thickness is also not uniform. Due to this particular uneven arrangement, a particular release profile is obtained, which may be characterized by a smooth transition between high release phases.

Dds (i) in fig. 7 has a design where the API-containing slurry is provided in a specific pattern within a matrix of additives, which matrix is arranged in a base slurry.

Fig. 8 shows a further design option for a drug delivery system produced according to the present invention. The overall shape of the system is that of a disc 5-25mm, preferably 20mm or 15mm in diameter and 0.5-15mm, preferably 2mm or 6mm in thickness. A cut-out in the tablet is provided to allow viewing of the placement of the slurry in the tablet.

The dds (j) design in fig. 8 has a first slurry comprising a first API, which is provided at the central part of the tablet and surrounded by the base slurry, while the whole tablet is coated with a coating. For example, the coating may be a hydrophilic coating, or may provide enteric properties. The concentration of 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 to the center of the tablet.

The dds (k) design in fig. 8 has a first slurry comprising a first API and a second slurry comprising a second API provided within a base slurry. Also, a coating is provided. The second slurry is arranged in a spherical form, and the concentration of the second API is highest on the spherical surface, decreasing smoothly towards the center of the sphere. Within the spheres formed from the second slurry, the first slurry is provided. Thus, upon application of the tablet and dissolution of the slurry, the second API is released before the first API, and during the transition, both APIs are released.

The dds (l) design in fig. 8 has two different APIs, where the second API is provided in the central part of the tablet and the first API is provided around the second API. At the connection area between the two APIs, there is an overlap of the APIs, so that in this continuous area, the two APIs are arranged. Thereby, a smooth intersection is achieved. Furthermore, a layer is provided extending through the system, which may be a hydrophobic layer.

The dds (m) design in fig. 8 has no coating. The API is unevenly disposed in the tablet such that regions or zones having different API concentrations are formed.

Fig. 9 shows a further design option of the drug delivery system according to the present invention. The system is provided in spherical form and has a hydrophobic coating. The coating includes hydrophilic pores ranging in size from 1 μm to 500 μm. Inside the drug delivery system, a base slurry and three different active pharmaceutical ingredients, namely API a, API B and API C, are provided. API C provides a peripheral pattern at the central portion of the drug delivery system. The other two APIs a and B surround API C. Thus, API B is provided as hollow spheres with a uniform API distribution. In addition, API a is unevenly distributed and surrounds API C. Thus, the concentration of API a decreases towards the edge of the drug delivery system shown.

Fig. 10 shows a cross-section of a drug delivery system according to the present invention. As shown, the surface of the drug delivery system is structured in that six protrusions and corresponding recesses located between them are formed on one side thereof. By increasing the surface in this way, the dissolution of the drug delivery system can be enhanced, thereby enhancing the release of the API. It is understood by the skilled person that the entire surface of the drug delivery system or only one or several parts thereof may be structured.

Thus, it will be appreciated by those skilled in the art that with drug delivery systems produced according to the present invention, a particular non-uniform distribution of one or more APIs within the drug delivery system may be arranged so as to provide a desired release of the API. One skilled in the art understands that timely release or delayed release of the API may be obtained. Furthermore, a particular single API may be released in different doses over an extended period of time, e.g. intermittently, thereby releasing the API in stages.

Furthermore, different APIs can be released at different stages by a single novel drug delivery system. For example, the drug delivery system may be designed such that the first API is released before the second API is released. Examples of such drug delivery systems that integrate two or potentially more APIs include gastroprotectants (e.g. proton pump inhibitors or antihistamines) and non-steroidal anti-inflammatory substances (e.g. ibuprofen or diclofenac). Another example is the combination of antiemetics (e.g. ondansetron, domperidone) and analgesics, especially those acting on the structures of the central nervous system (e.g. tramadol hydrochloride). Another example is the combination of Carbidopa (Carbidopa) and Levodopa (Levodopa), and thus an agent that prevents degradation of a pharmaceutically active ingredient. Those skilled in the art understand that the release of these two APIs can provide specific synergy. Furthermore, controlled release may mean mimicking physiology, e.g. Cortisone (Cortisone) therapy, where the drug delivery system is administered 10:00 a night, preferably releasing steroids after 6 hours. Since steroids are best administered at 4:00 a.m., steroids may be administered using the drug delivery system of the present invention, which may be designed to be ingested the evening prior to the day, but to release the corresponding API at the desired time during the night. Similarly, with the drug delivery system according to the present invention, it may be ensured that the antibiotic is properly administered in stages, e.g. over an extended period of time (e.g. days). Thus, the negative impact of the patient neglecting the prescribed administration procedure can be reduced.

It is further understood by those skilled in the art that the use of screen printing techniques allows for high quality, high volume production of such complex drug delivery systems. Thereby, the drug delivery system can be produced in mass production.

The design options resulting from the concept of creating an uneven arrangement of one or more APIs in a drug delivery system are enormous. Those skilled in the art understand that the above examples can be combined to obtain further complex designs with release profiles optimized for a particular application or therapy.