ADDITIVE METHOD FOR THE THREE-DIMENSIONAL PRINTING OF OBJECTS CONTAINING ACTIVE INGREDIENTS

Description

[0001] The present invention relates to an additive manufacturing process for producing solid or semi-solid three-dimensional objects containing one or more pharmaceutical active ingredients, as well as the objects produced by the process, such as semi-solid or solid dosage forms or medical devices. The process is an additive, preferably three-dimensional, printing process in which individual, defined volume increments are printed, which are essentially freely selectable with respect to the active ingredients contained, the carrier materials used, the shape, size, color, active ingredient concentrations, and arrangement in the produced object.

[0002] WO 2016 / 038356 A1 discloses an additive 3D printing process for the production of pharmaceutical dosage forms using filament fusion fabrication (FFF). WO 2017 / 158172 discloses 3D printing processes for pharmaceutical products, where the voxels have different volumes.

[0003] The object of the present invention is to provide a method for the manufacture of drug-containing objects such as pharmaceutical dosage forms or drug-containing medical devices, which allows for increased flexibility in the choice of different base materials, active ingredients and their distribution in the drug-containing object.

[0004] The above problem is solved by the embodiments of the present invention as disclosed in the claims, the present description and the accompanying figures.

[0005] In particular, the present invention provides a method for producing a three-dimensional object containing at least one pharmaceutical active ingredient, comprising the steps of: (i) Creating a two- or three-dimensional representation of the object to be manufactured by means of predefined volume increments; (ii) Printing a predefined volume increment onto a build-up device oder on an object placed on the build-up device; (iii) printing a further volume increment such that the volume increments at least partially touch or overlap; and (iv) repeating steps (ii) and (iii) until the object is created; wherein at least one of the volume increments contains at least one pharmaceutical active ingredient and the volume increments comprise a base composition or base substance that is flowable at a printing temperature compatible with the at least one active ingredient, which solidifies after printing the respective volume increment and / or the volume increments are superficially bonded to one another, characterized in that the volume of the volume increments is different such that the volume of the volume increments in the printed object increases from the outside to the inside.

[0006] The term "three-dimensional object" is to be understood according to the invention as meaning that in the real world, every object produced by two- or three-dimensional printing processes, especially pharmaceutical dosage forms and medical devices, extends in three spatial directions. If, in the process according to the invention, only one layer of at least partially contacting volume increments is printed on the build-up device or on an object already present on the build-up device, the process according to the invention can also be described as a 2D printing process. If the volume increments are applied, for example, as droplets, which are subsequently removed, for example, by dehydration, the process can also be described as a 2D printing process.Although they appear macroscopically as two-dimensional extended units through drying, they are microscopically three-dimensional structures, so that in such embodiments according to the invention the object also has a three-dimensional extension.

[0007] According to a preferred embodiment of the method according to the invention, the object is built up layer by layer, i.e., in steps (ii) and (iii) the volume increments are printed layer by layer. Preferably, the volume increments are printed row by row or column by column.

[0008] The present invention is characterized in particular by the high flexibility of the composition and the multitude of possible configurations of the produced semi-solid or solid object. Thus, in preferred embodiments of the method, different volume increments can contain different active ingredients and / or different amounts of active ingredients and / or different base compositions or base substances. Furthermore, the shape and / or volume of the volume increments (hereinafter also referred to as "voxels") can be the same or different, with the claims requiring that the volume of the volume increments be different such that the volume of the volume increments in the printed object increases from the outside to the inside.

[0009] However, according to the invention, it is also provided that the object is built entirely from volume increments, all of which contain a single, identical active ingredient, and it is also provided according to the invention that each volume increment can contain the same amount of the active ingredient or the same concentration of the active ingredient.

[0010] The volume increments are essentially freely definable and can, for example, assume droplets, spheres, dots, cylinders, cubes, cuboids, or other shapes. According to the invention, the aforementioned geometric shapes (spheres, cylinders, cubes, cuboids) are to be understood as meaning that the voxels essentially assume this shape, preferably when solidified after printing. Therefore, pellets, which preferably approximate a spherical or cylindrical shape, and granules are also considered preferred voxel shapes according to the invention. Preferred voxel shapes are thus, in particular, droplet-, pellet-, cylinder-, and granulate-shaped voxels. As already explained above, the shape (e.g., the examples mentioned above) and the volume size of the volume increments can be freely combined essentially independently of one another.

[0011] Embodiments of the method according to the invention utilize the principle of freely selectable volumes of the printed volume increments: In principle, the volume of a pharmaceutical dosage form shrinks from the outside inwards as it degrades towards or at the release site. This causes the amount of active ingredient released per unit of time to decrease. In order to achieve the most uniform possible release of the active ingredient over the course of the dosage form's degradation, the invention provides for printing the volume increments in such a way that the volume of the printed volume increments increases from the outside inwards. According to the invention, this is achieved by printing corresponding layers of volume increments, wherein the volume of the volume increments increases from the outside inwards from layer to layer or from group of layers of the same volume to further layers of the same volume.

[0012] As already explained, different pharmaceutical active ingredients (APIs) can be contained in the object using the method according to the invention. Furthermore, the volume increments can contain several (i.e., two or more) active ingredients. Of course, volume increments can also be printed such that each volume increment contains one API, but different APIs (two or more) are present in separate volume increments. It is also possible to print volume increments containing different concentrations (i.e., amount of active ingredient per volume increment) of a pharmaceutical active ingredient.In one embodiment of the method, the process can be designed such that volume increments containing the active ingredient are structured and printed in such a way that at least one first group of touching or overlapping volume increments containing the active ingredient contains the same amount of active ingredient, and at least one second group of touching volume increments contains an amount of active ingredient that differs from the amount of active ingredient in the first group. In this way, concentration gradients can be created in an object produced by the method. This embodiment of the invention is also used in preferred variants of the invention to provide a uniform release of the active ingredient, as described above for increasing the volumes of the volume increments in the dosage form from the outside in.In order to provide the most uniform release possible of the active ingredient(s), the volume increments are preferably printed in such a way that the active ingredient concentration preferably increases from the outside to the inside in the volume increments.

[0013] In the production of objects according to the inventive method, groups of volume increments containing different pharmaceutical active ingredients can be formed. At least one first group of active ingredient-containing volume increments can be present, containing a first pharmaceutical active ingredient, and at least one second group of active ingredient-containing volume increments can be present, containing a second pharmaceutical active ingredient different from the first. The different groups of volume increments can be printed in such a way that they are grouped together within the object. This means that the volume increments of the first and / or the second group (and, if applicable, of each further group, if more than two active ingredients are to be present in the object to be printed) are printed in such a way that the volume increments of the respective group are in contact with each other.

[0014] In further embodiments of the invention, it is also provided that volume increments containing active ingredients are printed in such a way that they form one or more groups within the object, which are at least partially, and in other embodiments also completely, surrounded by volume increments not containing active ingredients. These non-active ingredient volume increments separate or shield the volume increments containing active ingredients from the external environment, so that, for example, an object with an active ingredient-containing core, or at least an inner group of interconnected volume increments containing active ingredients (or several inner groups of adjacent volume increments with the same or different active ingredients or the same or different amounts of active ingredients), is created, around which volume increments not containing active ingredients are arranged. The "external environment" can be the environment surrounding the object.In the present context, "external environment" around a core area or an inner group of directly connected volume increments also includes any other area within the printed object, i.e., non-active-ingredient-containing volume increments can, in the object according to the invention, at least partially, and optionally completely, surround active-ingredient-containing groups of volume increments with other individual or groups of volume increments that, for example, contain another (or several other) active ingredient(s), in order to form separating layers or separating areas between the differently equipped volume increments.

[0015] In preferred embodiments, such arrangements can be used for the spatial isolation of the individual volume increments containing the active ingredient, in order to, for example, avoid chemical instabilities of the individual active ingredients and / or to separate different active ingredients that are chemically incompatible with each other (because, for example, they react with each other or otherwise impair their structure and / or efficacy).

[0016] In other embodiments of the aforementioned type, for example, drug abuse deterrent tablets or capsules can also be provided, which prevent, for example, an active ingredient (e.g., opioids or substances with addictive potential) from being extracted from a dosage form, for example, by comminution or in some other way, and from being subjected to misuse. Thus, in preferred embodiments of the invention, groups or layers of volume increments containing the active ingredient(s) (e.g., the aforementioned potentially misusable substances) are printed, which are surrounded by groups or layers of volume increments containing a substance that counteracts the effect of the active ingredient(s), degrades the active ingredient(s), or otherwise at least limits, and particularly preferably prevents, the potentially misused use of the active ingredient(s).Between the groups (or layers) of active ingredient(s) and anti-abuse substance(s), one or more groups or layers of volume increments may also be provided which do not contain any active ingredient or anti-abuse substance (in preferred embodiments, these volume increments will only contain the base composition used) and separate the volume increments containing the active ingredient from the volume increments containing the anti-abuse substance(s).

[0017] Furthermore, such embodiments with active ingredient-containing volume increments, which are at least partially surrounded by non-active ingredient-containing volume increments, can be used according to the invention, for example, for the production of the active ingredient(s) slowly releasing embodiments such as sustained-release tablets or capsules or gastro-resistant tablets or capsules.

[0018] The method of the present invention can thus be used to manufacture objects, in particular pharmaceutical dosage forms, which release the API(s) at a selected site or area of ​​the desired application (so-called "drug targeting"), i.e., preferably for controlling the release of the drug(s) from the printed dosage form. Such embodiments therefore serve to deliver the drug(s) to the optimal site of action or target, for example (and preferably) after oral administration.In certain embodiments of the invention, the volume increments are printed such that a core region of the volume increments of a pharmaceutical dosage form according to the invention contains one or more desired active ingredient(s), and one or more layers of volume increments are arranged around this core region (or around this core volume). These layers are degraded or dissolved in the intestine in a pH-dependent manner, so that the core region is only exposed to the surrounding environment in the preselected region of the intestine through the pH-dependent degradation of the outer layer(s), thereby releasing the active ingredient(s). This is usually achieved by polymers present in the formulation substance that are well known in the field (such as shellac, copolymers of methacrylic acid and methacrylate methacrylate, modified celluloses, etc.), whose pH-dependent degradation or dissolution is controlled by the pH-dependent degradation of the outer layer(s).pH-dependent solubility can be very finely controlled, so that pH-dependent release of the active ingredient-containing core region of the dosage form can be provided for each section of the intestine, in particular the small intestine (duodenum, jejunum, and ileum) according to the invention. The provision of targeted release at a specific site of action or target location, such as the intestine or a selected intestinal segment, is not limited to pH-dependently degradable or pH-dependently soluble layers of volume increments with corresponding pH-dependently degradable or pH-dependently soluble polymers contained in such build-up substances. Alternative or additional mechanisms can also be implemented. For example, according to the invention, the volume increments can be printed such that one or more layers of volume increments are deposited, for example, directly onto an active ingredient-containing core region or onto one or more optionally...The existing intermediate layer(s) are formed, the constituent material of which contains or consists of a bacteriably degradable component. Bacteriogenically degradable polymers known to those skilled in the art, such as starches or celluloses, are suitable for this purpose. Such layers preferably serve to release active ingredients in the colon. In preferred embodiments, the aforementioned layers, e.g., pH-dependent degradable layers (one or more) and bacteriogenically degradable layers, can be combined. For example, dosage forms for pharmaceutical drug combinations can be printed in this way, in which volume increments containing a first active ingredient are arranged in a core region, surrounded by one or more layers of volume increments that contain (or consist of) bacteriogenically degradable substances in their constituent material.This is followed by one or more layers with volume increments containing a second active ingredient, followed by one or more layers containing (or consisting of) one or more pH-dependent degradable polymer(s) in the matrix. Alternatively, in such an embodiment with multiple drug-targeting layers, only the core region can contain one or more active ingredients.

[0019] Since the process can also be carried out under sterile conditions, the printing process according to the invention can also be used to provide implants and / or drug-releasing injections or drug depots.

[0020] Furthermore, according to the invention, the increased flexibility of the process is also enhanced by the fact that very different materials (active ingredients and base compositions or substances) can be used for the volume increments to be printed.

[0021] The bonding between the individual applied volume increments can be achieved in various ways. In one embodiment, for example, when using a fusible material, the bonding between such voxels can occur through solidification after application to the support structure. This solidification can be carried out by various mechanisms, such as simple cooling and / or chemically using known substances. In another embodiment, a suitable binder can be added to the voxel material, e.g., a dispersion or a solution, which causes the voxel to harden after application. This hardening by the binder can be achieved, for example, through heat supplied by a suitable heat source in the printing device, such as a light source, preferably a laser device.The curing by the binder can also be achieved chemically using appropriate starter molecules and / or light of a suitable wavelength, the latter preferably being emitted by means of a laser device. In a further embodiment, the fluid of the volume increment can contain one or more starting compounds, typically monomers, of one or more polymers, and after the voxel is applied, polymerization is initiated by suitable means such as light, heat, or other polymerization initiators, which cures the applied voxel and bonds it to adjacent voxels.

[0022] Suitable carrier materials that flow at the printing temperature and in which the pharmaceutical active ingredient(s) is / are present are, for example, generally carriers suitable for hot melt extrusion (HME), such as low-melting waxes and polymers. The HME mixture, or more generally the volume increment mixture, may contain, in addition to the low-melting carrier, other processing aids and excipients such as binders, plasticizers, antioxidants, fragrances, sweeteners, or similar substances. Suitable HME carriers and plasticizers are disclosed, for example, in Crowley et al. (2007) Drug Development and Industrial Pharmacy, 33, 909-926 (carriers: pages 917 to 919, in particular Table 1; plasticizers: pages 917 and 920, in particular Table 2), and in the present description expressis verbis Reference is made to the aforementioned passages.

[0023] The method according to the invention is not based on a complete De-Novo -The assembly of dosage forms or medical devices is limited. The method can also be applied to objects already present on the assembly device. This includes, for example, dosage forms previously manufactured conventionally or otherwise, which are to be modified by the present method, or drug-free objects (also called placebo carriers) onto which drug-containing volume increments are printed according to the invention. For example, drug-free films or other flat materials such as edible paper can be provided to supply, for example, drug-containing ODF ("orally degradable film" or "orally dissolvable film") products. In other embodiments, provided plaster materials, for example, can be printed with volume increments according to the invention, which contain, for example, wound-healing agents. In further embodiments, placebo carriers, which, for example,produced by a fused layer modeling process, by which the inventive process is printed with API-containing volume increments and subsequent printing of solvent-containing liquids, wherein the printed layers can alternate.

[0024] The present additive 3D printing process is preferably computer-aided. Typically, in step (i), a calculated three-dimensional image of the object to be printed is created, for example, using a common CAD program. The computer-generated representation of the object to be printed can also be achieved by scanning an existing dosage form. In this process, the computer-generated model image is then divided into the desired, essentially freely selectable, volume increments (voxels), with the resolution of the real object increasing as the volume increments decrease. Each individual volume increment can be assigned, for example, an active ingredient, carrier or base substance, or carrier or base compositions, and / or other excipients such as colorants and other materials that may be required, as well as their quantity (concentration in the volume increment), and then printed.Suitable printing devices for the present procedure are described, for example, in US 2017 / 03,68755 A1 and US 6,070,107.

[0025] In a particularly preferred embodiment, the method according to the invention further comprises applying at least one colored substance by means of 2D and / or 3D printing, preferably also by printing corresponding, preferably small-volume voxels according to the present method, and / or by another method, such as two-dimensional printing as in inkjet printing, to the object or to at least a section of the object, such that the applied substance forms at least one information structure visible on the object. The colored substance(s) can be applied separately from the volume increment(s) containing the active ingredient. It is preferred to apply the colored substance(s) together with volume increments containing pharmaceutical active ingredients. In one embodiment, each substance can thus mark the area(s) or sections to which the respective active ingredient has been applied.This embodiment can therefore convey information about the active ingredients contained in the object and their distribution throughout the entire object by means of color coding. In a further development of this embodiment of the invention, different quantities or concentrations of the respective active ingredient can be stored in the active ingredient-containing sections, which in turn are reflected by the concentration of the corresponding colorant. Of course, different colorants can also be mixed, e.g., in a voxel according to the invention (e.g., embodiment), so that by appropriately selecting the mixture(s), the entire visible spectrum can generally be used.

[0026] According to the invention, the term "coloring substance" also includes substances that luminesce, in particular fluoresce.

[0027] The information structure created by the colorant(s) can represent a wide variety of information, and several different information structures can be used with different colorants, which are essentially freely selectable and combinable. In particular, according to the invention, the at least one information structure contains information about the type of active ingredient(s) printed in the object and / or about the amount(s) of active ingredient present in the object and / or about the time or period of administration intended for a dosage form and / or about the date of administration intended for the dosage form and / or about patient-related data (such as the patient's name, age, gender, medication, and illness(es)) and / or about the payer and / or about the treating physician and / or about the pharmaceutical company providing the dosage form and / or about the object, e.g.a medical facility dispensing a dosage form or medical device is coded.

[0028] The information structure can be selected from a wide range of application possibilities. The substance(s) can be printed in the form of QR codes, letters, and / or numbers. Various patterns, such as lines, grids, dots, and solids, can also be printed, with voxel printing being the preferred method and offering the greatest versatility. The printed code can thus contain the active ingredient and simultaneously encode the desired data, as described above, regarding the patient, physician, pharmacist, and / or medical or pharmaceutical personnel.

[0029] It is apparent to those skilled in the art that, depending on the specific additive manufacturing process chosen, the colorant(s) present may be present together with the pharmaceutical active ingredient(s) in the respective printed base composition. In the present process, it is preferred that the colorant (or several thereof) is present, preferably together with the active ingredient(s), in the build-up material intended for a given volume increment.

[0030] As already explained above, the dosage form can contain a wide variety of information structures, preferably those mentioned in the procedure described above.

[0031] The printable drug-containing objects are, in particular, semi-solid or solid pharmaceutical dosage forms, such as tablets, capsules, implants, patches, suppositories, or thin films. Tablets that can be produced using the inventive method are diverse and include oblong tablets, lozenges, implant tablets, multiple-dose tablets, dispersible tablets, sustained-release tablets, vaginal tablets and suppositories, ophthalmic tablets, coated tablets, matrix tablets, chewable tablets, film-coated tablets, modified-release tablets, lacquered tablets, and margarine-resistant tablets, as well as drug abuse deterrent tablets.

[0032] Other particularly suitable objects are medical devices such as topical drug formulations containing active ingredients, contact lenses, and plasters, which preferably release the active ingredient(s) for local application.

[0033] The present invention also relates to the two- or three-dimensional objects produced by the method (preferably those mentioned above), wherein these contain at least one pharmaceutical active ingredient.

[0034] The present invention is explained in more detail by the accompanying figures. Fig. 1 shows a schematic representation of a cross-section of a three-dimensional object that is divided into individual volume increments (square in cross-section) (hereinafter also called "voxelized"). Fig. 2 shows schematic representations of a three-dimensional object subdivided into cube-shaped volume increments (i.e., voxelized), where in Fig. 2A The resolution of the object is smaller due to larger voxels (i.e., coarser resolution), and in Fig. 2B By dividing the data into smaller volume increments, the resolution is greater (i.e., finer resolution). Fig. 3 Figure 1 shows a schematic representation of a cross-section of a three-dimensional object in which volume increments (shown as squares in the cross-section) without active ingredient or containing an active ingredient voxel (shown in light colors) and volume increments with active ingredient (shown in dark colors) are present, resulting in a concentration of voxels with active ingredient of, for example, 50%. Fig. 4 Figure 1 shows a schematic representation of a cross-section of a three-dimensional object in which individual voxels contain an active ingredient (shown in dark), such that 25% of the voxels contain the active ingredient. According to the invention, the ratio of voxels containing the active ingredient to voxels without the active ingredient, or the volume fraction of the voxels containing the different active ingredients, can be varied arbitrarily between 0.1% and 99.9%. Fig. 5 Figure 1 shows a schematic cross-section of a three-dimensional object in which drug-containing voxels (dark) are grouped together in the interior and surrounded by non-drug-containing voxels (light), thus protecting the drug-containing voxels from the environment, such as body fluids. This structure allows for controlled release of the drug. In other embodiments, as disclosed above, release control can be achieved using pH-dependent soluble or biodegradable polymers. The various concentrations and materials can be used in the presented and described procedure to produce very high-resolution dosage forms. For example, in Fig. 5 e.g., the dark voxels each Fig. 3 correspond and the bright voxels of Fig. 4 In this way, for example, tablets with abuse deterrent properties, as already explained above, can also be produced. Fig. 6 shows a schematic representation of an object that can be produced according to the invention, which includes the in Fig. 5 The described embodiment is further developed as follows: Voxels with a first active ingredient (blue) are surrounded by voxels with a second active ingredient (red), which in turn are surrounded by voxels without active ingredient. This embodiment can also be designed, for example, such that different active ingredients are not used, but rather different concentrations of the active ingredient. Fig. 7 shows a schematic representation of a cross-section of a three-dimensional object, in which a concentration gradient of the active ingredient is built up in the object by decreasing density of the active ingredient-containing voxels (dark) from left to right. Fig. 8Figure 1 shows a schematic representation of an object that can be produced according to the invention, in which voxels containing three different active ingredients or concentrations of active ingredients (blue, red, green) are distributed in the object and surrounded by voxels that do not contain active ingredients.

[0035] In exemplary embodiments, the method according to the invention can, for example, adapt the drug release to the physiological needs of patients with heart disease or hypertension. For instance, a cholesterol-lowering drug (e.g., a statin) and two antihypertensive substances (e.g., a sartan and a beta-blocker) can be compressed into a single dosage form in such a way that the drug release over 24 hours optimally corresponds to the patient's physiological conditions. If the patient takes the dosage form in the morning, the antihypertensive substances can be released quickly, while the cholesterol-lowering drug is released only after a 12-16 hour delay in order to reduce nocturnal cholesterol synthesis.

[0036] In further examples of the method according to the invention, titration can be provided for newly diagnosed patients with diseases such as Parkinson's disease, multiple sclerosis, myocardial infarction, strokes, or transplant patients, as well as for applications in geriatrics and pediatrics. In all these cases, patient-specific dosing or release of active ingredients can optimize the effect and reduce side effects.

Claims

1. A method for producing an object containing at least one pharmaceutical active agent, comprising the steps: (i) generating a two- or three-dimensional representation of the object to be manufactured using predefined volume increments; (ii) printing a predefined volume increment onto a building platfoum or onto an object placed on the building platform; (iii) Printing a further volume increment in such a way that the volume increments at least partially contact or overlap each other; and (iv) repeating steps (ii) and (iii) until the object is generated; wherein at least one of the volume increments contains at least one pharmaceutical active agent and the volume increments comprise a base composition or base substance being flowable at a printing temperature compatible with the at least one active agent and that solidifies and / or bonds after printing of the respective volume increment, characterized in that the volume of the volume increments is different in a manner such that the volume of the volume increments in the printed object increases from the outside to the inside.

2. The method of claim 1, wherein steps (ii) and (iii) are carried out in a manner such that the volume increments are printed in layers.

3. The method of claim 1 or 2, wherein each volume increment contains an active agent.

4. The method of claim 1 or 2, wherein different volume increments have different active agents and / or different amounts of active agents and / or different base compositions or base substances.

5. The method according to any one of the preceding claims, wherein the shape of the volume increments is selected from the group consisting of drops, spheres, dots, cylinders, cubes, and cuboids.

6. The method according to any one of the preceding claims, wherein active agent-containing volume increments are constructed and printed in such a way that at least a first group of contacting or overlapping active agent-containing volume increments contains an equal amount of active agent and at least a second group of contacting volume increments contains an amount of active agent that differs from the amount of active agent in the first group.

7. The method according to any one of the preceding claims, wherein at least one first group of active agent-containing volume increments is present, which contains a first pharmaceutical active agent, and at least one second group of active agent-containing volume increments is present, which contains a second pharmaceutical active agent that is different from the first active agent.

8. The method according to any one of the preceding claims, wherein the volume increments are printed in a manner such that volume increments containing active agent form one or more groups within the object, which are surrounded by volume increments not containing active agents, which shield the volume increments containing active agents from the environment.

9. The method of claim 8, wherein the volume increments containing active agent form an active agent-containing core in the object, around which volume increments not containing active agent are arranged.

10. The method of claim 9, wherein the volume increments are printed in such a manner such that active agent-containing volume increments form several groups, each of which is surrounded by non-active agent-containing volume increments.

11. The method of claim 9 or 10, wherein the non-active agent-containing volume increments contain a substance which at least limits the effect of the active agent or agents, preferably one or more active agents with addictive potential, in the active agent-containing volume increments when the printed object is disintegrated.

12. The method of claim 9, wherein the non-active agent-containing volume increments are printed in a manner such that they form one or more layers around an active agent-containing core, which layer(s) is / are pH dependently degraded in the intestine of a patient.

13. The method of claim 10 or 11, wherein non-active agent-containing volume increments cause a delayed release of the active agent or active agents.

14. The method according to any one of the preceding claims, wherein the active agent-containing object is a semi-solid or solid pharmaceutical dosage form, preferably selected from the group consisting of tablets, capsules, suppositories, patches, or thin films, or medical device.

15. Three-dimensional object containing at least one pharmaceutical active agent, produced by the method according to any one of the preceding claims.