Method for producing patient-optimised dosage forms

Abstract

The present application relates to methods of personalised pharmaceutics. More specifically, the invention relates to methods for the production of pharmaceutical dosage forms, which are produced by 3D and / or 2D printing, whereby a wide variety of parameters relevant to the administration of the dosage form can be changed depending on the analysis of patient- and disease-specific data and can be adapted in the course of the patient's treatment. In this way, the quality of treatment for the patient can be improved in the future and significantly increased from the point of view of patient safety.

Description

[0001] Process for the production of patient-optimized dosage forms

[0002] This application relates to methods of personalized pharmacy. More specifically, the invention relates to methods for producing pharmaceutical dosage forms produced by 3D and / or 2D printing, whereby various administration-relevant parameters of the dosage form can be modified and adapted over the course of the patient's treatment based on the analysis of patient- and disease-specific data. This can improve the quality of treatment for the patient in the future and significantly increase patient safety.

[0003] With current pharmaceutical manufacturing processes, the implementation of personalized medicine for each individual patient is either not feasible or can only be achieved with considerable effort and complexity, as preparations of individual active ingredients or, even more rarely, combinations of active ingredients are available in only a few standardized doses and dosage forms. This particularly applies to solid dosage forms, which, however, are usually the dosage forms best tolerated by patients (e.g., tablets, capsules, thin films, etc.).

[0004] The object of the invention is therefore to provide a method which makes it possible to provide a dosage form of the required active ingredient(s) which is continuously optimized for each individual patient depending on his / her individual and disease-specific parameters during the course of therapy with one or more active ingredients.

[0005] This object is achieved by the embodiments of the present invention characterized in the present description and claims.

[0006] In particular, the invention provides a method for producing patient-optimised pharmaceutical dosage forms comprising the steps:

[0007] (1) analysis of individual and / or disease-related data of a patient suffering from a disease state, where the patient may be exposed to an active substance for the treatment of the patient's disease state; (1a) selection of one or more active substances for the treatment of the patient's disease state, where the patient is not already exposed to an active substance for the treatment of the disease state; or

[0008] (1 b) where appropriate, selection of one or more other active substances for the treatment of the patient's disease state, provided that the analysis of step (1) shows that the existing active substance(s) has disadvantages compared with the other active substance for the treatment of the patient's disease state;

[0009] (2) Determining at least one administration-relevant parameter of the previous active ingredient or of the active ingredient(s) selected according to step (1a) or (1b) for a dosage form from the analysis of the data according to step (1), if necessary taking into account potential side effects and / or influences of other active ingredients for the treatment of the same or other diseases of the patient to which the patient is exposed;

[0010] (3) printing a first dosage form containing the active ingredient(s) according to the at least one administration-relevant parameter determined in step (2) by means of 3D and / or 2D printing, wherein the at least one administration-relevant parameter is converted into one or more corresponding printing parameters for the 3D and / or 2D printing;

[0011] (4) Analysis of individual and disease-related patient data under administration of the first dosage form;

[0012] (5) adapting the at least one administration-relevant parameter of the active ingredient or ingredients for a dosage form from the analysis of the data according to step (4);

[0013] (6) Printing a further dosage form containing the active ingredient(s) according to the at least one administration-relevant parameter adapted in step (5) by means of 3D and / or 2D printing; and if necessary

[0014] (7) Repeating steps (4) to (6).

[0015] The method according to the invention can be designed such that the patient has not yet been treated with an active ingredient. This case is described in the optional step (1a), in which one or more active ingredients indicated for the specific disease are first selected.

[0016] According to the invention, the term “illness” or “disease” of a patient encompasses, on the one hand, any pathological condition that is treatable with pharmaceutical dosage forms, where “treatable” means, according to the invention, that the course of the pathological condition is positively influenced under the respective medical circumstances. In the case of serious illnesses such as cancer and tumors, for example, this can be a statistically significant increase in the probability of survival over a period of time typically observed for the respective illness compared to the course of the illness without treatment. In other cases, “treatable” usually means that the pathological condition at least does not worsen, preferably improves, and ideally that the pathological condition is cured. In yet other illnesses, such as, for example,In the case of transplants, the term "treatable" implies that the transplant has a longer survival rate than in the untreated state. The term "disease" or "pathological condition" also includes, according to the invention, an existing risk of the patient developing a pathological condition in the future, so that the method according to the invention naturally also includes the production of dosage forms that serve to prevent or rehabilitate pathological conditions.

[0017] The method according to the invention can, as characterized in the optional step (1b), be applied to cases in which the patient has been treated with one or more active substances (i.e. one or more "previous" active substances), but due to any circumstances (e.g. intolerance, interactions between active substances, unsatisfactory course of the disease under treatment with the previous active substance(s)) the previous active substance(s) are replaced by one or more other active substance(s) which are also indicated for the respective disease.

[0018] In other embodiments, the method is used to optimize existing therapies with one or more active ingredients without first selecting one or more active ingredients after the data analysis in step (1), ie the method process is continued after step (1) with step (2).

[0019] In step (1) of the method according to the invention, individual and / or disease-related data (hereinafter also referred to as “individual parameters” or “disease-related parameters”) of the patient are analyzed. These are usually available in a medical record at a healthcare provider such as a treating physician or in a medical facility such as a hospital, a clinic and / or a health resort, preferably in digital form. “Individual” data of a patient are personal parameters of the patient which are generally independent of the disease per se, but which typically have or at least can have an influence on the disease itself or on its progression. Individual data which are analyzed orcan be analyzed are preferably age, developmental stage, gender, genetic predispositions, height, weight, body surface area, body mass index, general physical condition, drug use (such as the use of "soft" drugs such as alcohol, nicotine, marijuana, etc. and / or the use of "hard" drugs such as cocaine, heroin, methadone, etc.), eating habits (such as fat, carbohydrate and protein content, time of food intake, regularity of food intake) and drinking habits (such as the preferred daily amount drunk), sleeping habits, physical activity and combinations of two or more of these. "Disease-related data" of a patient refers to parameters that provide information about the patient's disease state and are usually collected using diagnostic procedures. Disease-related data collected in this way, which are analyzed in step (1) orcan be analyzed are preferably selected from blood pressure, heart rate, ECG findings, EEG findings, sonographic findings, CT findings, MRI findings, biopsy findings of diseased tissue, blood count, electrolyte blood levels, blood liver values, nephrological blood and urine values, blood lipid values, blood sugar levels, vitamin metabolism data, metabolic interactions, medication plan, side effect profiles, urine status, virological findings, bacteriological findings, findings of fungal infection, parasitic findings, stage of the disease, course of the disease and combinations of two or more thereof.

[0020] Naturally, the disease-related data depend on the specific dosage forms being manufactured for the disease being treated. These are explained below using some typical examples: Diseases that are commonly treated with oral dosage forms include diseases of the internal organs such as the intestine, kidney, liver, pancreas, gall bladder, etc. In the case of a kidney, liver, or pancreas transplant, very precise adjustment of the immunosuppressive medication is required, i.e., one or more immunosuppressants such as a calcineurin inhibitor (such as cyclosporin and / or tacrolimus and / or everolimus), a glucocorticoid (such as hydrocortisone and / or methylprednisolone), and / or an inosine monophosphate dehydrogenase inhibitor (such as a mycophenolic acid derivative or salt, such as mycophenolate mofetil or mycophenolate sodium). In this case, for example,individual data of the patient in step (a), such as in particular weight, gender and / or age or body surface area, as well as disease-related data influencing the administration-relevant parameters (including the amount of active ingredient, required coatings (e.g. enteric coating(s), etc.; see step (s)) of the immunosuppressants, such as whether it is a first or subsequent transplantation, whether and if so which previous and / or concomitant diseases of the patient that may influence the dosage of the immunosuppressants, such as existing allergies, intolerances, potential interactions of the immunosuppressants to be administered, are analyzed. In another embodiment, if, as in step (1b), the transplanted patient, for example, is already undergoing therapy with one or more immunosuppressants, e.g.due to one or more intolerances of the patient to the immunosuppressant(s) administered so far, another immunosuppressant (e.g. instead of ciclosporin (previous active ingredient) tacrolimus (the other active ingredient) or several other immunosuppressants (e.g. instead of ciclosporin (previous active ingredient) tacrolimus (another active ingredient) and instead of mycophenolate mofetil (previous active ingredient) mycophenolate sodium (another active ingredient)) is selected. In yet another embodiment (i.e. without selection of one or more first active ingredients (step (1a)) and without selection of one or more other active ingredients (step (1b)), the analysis result from step (1) is passed on to the next step (2) for the selection of the administration-relevant parameter(s) of the immunosuppressant(s). In certain embodiments, at the start of an immunosuppressive therapy, i.e.In processes which include step (1a), a low dosage is initially established in order then, in the further course of the process (steps (2) to (6), to produce successively higher-dose dosage forms of the immunosuppressant(s) according to the analysis of the corresponding individual and / or disease-related parameters (so-called uptitration). In still other embodiments (e.g. in the case of corticoid dosage forms), in the case of existing therapy or in the further course of therapy, a tapering off of one or more active ingredients is achieved by the process according to the invention in that dosage forms with successively lower doses of the immunosuppressant(s) (as in the example of corticoids here) are produced in steps (2) and (3).

[0021] Of course, the titration and down-titration procedures described above with regard to immunosuppressants can also be applied to other active substances.

[0022] In another exemplary embodiment, dosage forms for the treatment of rheumatological diseases are produced. Individual patient parameters are analyzed as already described above. The disease-specific parameters preferably include, in addition to typical physical characteristics such as the presence and extent of joint swelling, blood values ​​such as inflammatory parameters, in particular the so-called rheumatoid factor (see, for example, E. Feist, K. Egerer, G.-R. Burmester, Z. Rheumatol. 2007, 66:212-21) and antibodies against cyclic citrullinated peptides (ACPA). In addition to the immunosuppressive agents already mentioned, other active ingredients or classes of active ingredients, such as tyrosine kinase inhibitors, e.g., erlotinib, are also used within the scope of the inventive manufacturing process.

[0023] Non-limiting further preferred indication areas and related active ingredients or classes of active ingredients are, for example, oncology (example substances here are also tyrosine kinase inhibitors), neurological diseases such as Parkinson's disease (active ingredients are, for example, dopamine antagonists such as ropinirole), hematology, i.e. hematological diseases such as, for example, anemia (example active ingredients include iron supplements, vitamin B12 and folic acid) and myelodysplastic syndrome (MDS), and cardiovascular diseases (active ingredients are, for example, anticoagulants such as acetylsalicylic acid, vitamin K antagonists such as phenprocoumon and warfarin, thrombin inhibitors such as dabigatran, factor Xa inhibitors such as apixaban, for the treatment of stroke, ventricular fibrillation and for the prophylaxis of myocardial infarction, i.e. the risk of a heart attack).In the case of cardiovascular diseases, high blood pressure is particularly important, as it often occurs together with or is a starting point for the later development of the aforementioned diseases, such as stroke and heart attack (or the risk of suffering a stroke and / or heart attack). Active ingredients that can be used according to the invention in connection with high blood pressure are, in particular, antihypertensives such as calcium antagonists, beta-blockers, ACE inhibitors, diuretics, and AT1 blockers. Thus, according to the invention, it is advantageously possible, for example, to adapt the medication according to the method according to the invention depending on the clinical parameters, in particular blood pressure, ECG, sonographic findings, preferably of the peripheral vessels, coronary vessels, pulmonary vessels, and / or cerebral vessels, as well as blood parameters such as levels of creatine kinase and / or troponin I, e.g.Selection of the respective anticoagulant(s) and / or antihypertensive(s) as well as appropriately adapted combinations of these and / or their amount(s) of active ingredient(s).

[0024] The method according to the invention allows for the adaptation of administration-relevant parameters for the additive printing of dosage forms with optimized dose-effect or dose-side-effect relationships to be advantageously used in pediatrics and geriatrics. For younger patients, especially children, the method according to the invention allows for individual patient adaptation, particularly with regard to the size of the printed dosage form, especially since orally administered dosage forms are difficult to swallow beyond a size that naturally varies from person to person.The method according to the invention also makes it possible to produce dosage forms for pediatric patients with particularly fine-tuning of the dose-relevant parameters, since, in particular for children and adolescents, dosage precisely tailored to the patient's age and developmental stage, minimizing side effects and reducing cross-reactions with other active ingredients is particularly important. In geriatrics, the method according to the invention can be used to print patient-optimized dosage forms that are also tailored to the specific needs of older patients, particularly those aged 70 or over, preferably 75 or over, and particularly preferably 80 or over. This affects, among other things, the print volume, since older patients may have difficulty gripping small-volume dosage forms.With the help of the method according to the invention, an elderly patient can also be efficiently switched from a classic dosage form such as a tablet to a suckable dosage form, since geriatric patients often suffer from swallowing difficulties. Both pediatric and geriatric patients will benefit from the method according to the invention, among other things, in that if several active ingredients need to be administered per day or per time of administration, polypharmaceutical dosage forms, i.e. dosage forms with several active ingredients, can be produced and individually adapted. In general, all patients benefit from the optimization of individual dosage forms with several active ingredients because, for example, if the patient is to take another active ingredient, an existing dosage form, e.g.with one or more other, already administered active ingredient(s), is modified in such a way that the new active ingredient (it can of course also be several new active ingredients) together with the other active ingredient(s), optionally through defined areas within the dosage form, each of which contains an active ingredient and which are separated from the other areas with the other active ingredient(s), for example by barrier layers, is printed in a new, patient-individual dosed dosage form (step (3) and / or step(s) (6) of the method according to the invention).

[0025] Other diseases within the scope of the present invention include, for example, those of the cardiovascular system, such as high blood pressure, arteriosclerosis, cardiac arrhythmias, angina pectoris, myocardial infarction, stroke, etc. It is apparent to a person skilled in the art that the dosage forms that can be produced using the method according to the invention are in no way limited with regard to the active ingredient and the parameters related to the treatment of the respective disease. A person skilled in the art can select the disease-related parameters to be considered for a specific indication based on their specialist knowledge and consider them for the production of the respective dosage form.

[0026] In step (2) of the method according to the invention, at least one administration-relevant parameter of the (previous) active ingredient or of the active ingredient(s) selected according to step (1a) or (1b) for a dosage form is selected from the analysis of the data according to step (1), optionally taking into account potential side effects and / or influences of other active ingredients for the treatment of the same or other diseases of the patient to which the patient is exposed.

[0027] An “administration-relevant parameter” of a dosage form of the active ingredient(s) (either one or more active ingredients already administered to the patient (i.e. without step (1a) or step (1b)) or one or more new active ingredients for the disease (i.e. step (1a) is carried out) or one or more other active ingredients (i.e. step (1b)) is carried out) is any parameter of a dosage form that influences the active ingredient dose, active ingredient concentration, active ingredient release, administration route, administrability, tolerability and / or stability (with respect to physical and / or chemical parameters) and the efficacy of a dosage form of the active ingredient(s). Typical and preferred administration-relevant parameters are, for example:Amount of active ingredient(s) per unit dose of the dosage form, release kinetics of the active ingredient(s) from the dosage form at the site of administration and / or via the route of the dosage form in the patient (pharmacokinetics and pharmacodynamics), concentration of the active ingredient(s) in the dosage form, concentration distribution of the active ingredient(s) in the dosage form, size of the dosage form, geometric shape of the dosage form, coating parameters of the dosage form, surface structure of the dosage form, internal structure of the dosage form, distribution of the active ingredient(s) in the dosage form and combinations of two or more of these parameters.

[0028] In the case of the method with step (1a) (new active ingredient or new active ingredients), previously no active ingredient), all of the administration-relevant parameters required according to the analysis of the data for the dosage form and adapted (at the current time), thus prima facie optimal, are usually determined. This will usually also be the case in the embodiment of the method according to the invention in which step (1b) is carried out (selection of one or more other active ingredients than the previous active ingredient(s). The method according to the invention is not limited to the optimisation of dosage forms for individual patients. Rather, the invention also provides for recording the parameters of optimised dosage forms for a plurality, preferably a multiplicity of patients, such as, for example,in a database on one computer or several or a plurality of connected computers and to make these available for the provision of optimized dosage forms for other patients who have similar individual and / or disease-related parameters as patients whose optimized dosage forms are already known, i.e. preferably stored in the database. Such embodiments can thus make the treatment of other patients more successful more quickly. Furthermore, the invention also provides for the evaluation and training of existing and therefore ever-increasing stored parameters of dosage forms using artificial intelligence methods and devices, such as deep learning methods and corresponding devices, in order to further improve the optimization method according to the invention.In such embodiments, one or more (initial) active ingredient(s) are therefore preferably selected and parameterized in a step (1a) and subsequently in step (2), and a corresponding first dosage form is printed in step (3), which is provided on the basis of the dosage forms known in the existing database from cases of identical and / or similar individual and / or disease-related parameters, after which the further method steps follow. In the embodiment of the method according to the invention in which a dosage form is created which already contains one or more ingredients with which the patient has already been treated, but the dosage form is to be adapted to the individual and disease-related parameters by the method according to the invention (i.e. the optional steps (1a) or (1b) are not carried out), one or more administration-relevant parameters are selected in step (2).In certain embodiments of the method, this can be just one parameter, such as a different dose of the active ingredient compared to the existing medication, a changed release kinetics, or a changed size of the dosage form, etc. Of course, any combination of administration-relevant parameters can also be selected in step (2), depending on the requirements based on the analysis performed in step (1), in order to adapt the dosage form to the analyzed individual and disease-related parameters of the patient. In this embodiment, too, according to the steps outlined above, already (pre-)optimized dosage forms can be created and then further adapted if necessary based on available parameters from previously identical or similar cases, preferably using artificial intelligence methods and devices such as deep learning methods and corresponding devices.

[0029] When determining the administration-relevant parameters, potential side effects and / or influences of other active ingredients used to treat the same or other diseases to which the patient is exposed are taken into account, if necessary. This is a particular advantage of the method according to the invention, since when creating the dosage form of the active ingredient(s), it not only takes into account the (variable) individual and disease-specific parameters of the patient, but also ensures that the active ingredients printed in the dosage form to be created exhibit at least an improved side effect or influence profile compared to these other active ingredients, both among themselves and with other active ingredients administered to the patient in other ways, compared to standardized dosage forms.Ideally, the optimal dose should be used to achieve maximum therapeutic success with minimal side effect profile in the patient.

[0030] After determining the parameter(s) relevant for administration (step (2), these are provided to a 3D and / or 2D printing process, generally an additive printing process, which, if not all required (new) parameters relevant for administration were determined in step (2), takes the additional parameters from otherwise usual or already existing parameter values ​​and creates the dosage form using a 2D or 3D printing process that can in principle be freely selected.

[0031] Usable printing processes for the production of the dosage form in step (3) and / or step(s) (6) of the method according to the invention include, for example, extrusion processes such as filament fusion fabrication (FFF) or fused layer modeling (FLM), jetting processes such as voxel printing (also called direct jetting) or binder jetting, and spot printing processes.

[0032] A preferred extrusion printing process according to the invention is described in WO 2020 / 240030 A1 and comprises the steps

[0033] Providing a pharmaceutical product designed for FFF or FLM 3D printing

[0034] printing device,

[0035] Providing starting objects designed for FLM or FFF 3D printing, wherein the starting objects form at least a first and a second group of starting objects, wherein the composition of the starting objects of the first group is different from the composition of the starting objects of the second group or at least one parameter according to the invention, as set out above, is different between the starting objects of the groups, and at least one group of the starting objects contains at least one active ingredient selected from the group consisting of pharmaceutical active ingredients, nutraceutical and dietary supplement active ingredients; and printing the starting objects of at least the first and second groups in the form of filaments or inks with the printing device until the dosage form is created.

[0036] The preferred extrusion process can in principle be carried out using known components of FFF 3D printing or FLM 3D printing, whereby with regard to FFF processes, reference can be made, for example, to the relevant disclosure in WO2016 / 038356 A1.

[0037] A "starting object" within the meaning of the preferred extrusion printing process is a material suitable for FFF 3D printing or FLM 3D printing, which can be processed in a generally known manner using appropriate printing devices and printed into a 3D object. In these processes, the starting object, or synonymously the starting material, comprises a base composition printable in filament form. Typically, the starting objects are converted into a flowable state during the extrusion printing process, typically by heating by a heating device located in a print head of the printing device, and then applied in filament form, preferably layer by layer, to a build platform using the print head, usually by extrusion.The method according to the invention can also be designed such that the starting objects are printed in filament form onto an already existing object placed on the build platform of the printing device.

[0038] The starting material or starting objects for the preferred FFF 3D process are filaments that typically have the shapes exemplified with regard to the filament structures.

[0039] The starting material or starting objects for an FLM process are typically granules, pellets, powder, and / or flakes. In one embodiment of the preferred extrusion process, the starting objects of one group contain at least one first active ingredient or a first active ingredient composition, and the starting objects of the or another group contain a second active ingredient or a second active ingredient composition, wherein the second active ingredient is different from the first active ingredient, or the second active ingredient composition is different from the first active ingredient composition.

[0040] In a further embodiment of the preferred extrusion process, the starting objects of the other or another group contain the same active ingredient, wherein the concentration of the active ingredient in the starting objects of one group differs from the concentration of the active ingredient in the starting objects in the other group(s). In other words, in this embodiment, starting objects or materials are printed which form at least two groups, wherein both groups or (in the case of more than two groups) at least two groups contain the same active ingredient, but each in a different concentration. In a further preferred embodiment, it is provided that more than two, preferably 3, 4, 6, 6, 7 or 8, groups of starting objects are provided and printed in the form of filaments, wherein each group contains an active ingredient which is different from the other active ingredients of the other groups of starting objects.In another embodiment, more than one active ingredient, e.g. 2, 3 or 4 active ingredients, with 2 active ingredients being particularly preferred, is present in a group or several groups of starting objects.

[0041] At least one group of initial objects can also be present, i.e. printed, which does not contain an active ingredient, so that the created dosage form contains solidified filament structures which do not contain an active ingredient.

[0042] In another embodiment of the preferred extrusion process, the groups of starting objects or materials may be such that the printed filaments differ in the drug release properties.

[0043] It is of course also possible to combine the above-mentioned different properties of the starting objects or the printed filaments in the preferred extrusion process.

[0044] In a further embodiment of the preferred extrusion process, each group of starting objects with the same composition (or in which at least one parameter essential to the invention, as stated above, is the same) has a detectable distinguishing feature that is different from the other group(s) of starting objects, so that the printed filaments with different compositions (or different parameters) can be differentiated. As already stated above, preferred distinguishing features include, for example, filament diameter, filament length, visible dyes, fluorescent dyes, surface textures, shape, gloss, porosity, roughness, and absorption or reflection properties with respect to electromagnetic radiation.

[0045] Preferably, the extrusion process is carried out in such a way that one or more layers of the first group of starting objects are printed in the form of filaments, followed by one or more layers of the second group of starting objects in the form of filaments, and optionally one or more layers of the further groups of starting objects are printed in the form of filaments. The respective groups of starting objects can also be printed in alternating layers. This can also be done using layers without an active ingredient, for example, to optimize the chemical stability of the starting materials.

[0046] In a further preferred embodiment of the preferred extrusion process, the groups of starting objects are printed such that the dosage form created, as described above, has at least a partial volume that does not contain any printed filaments. This can be done in a manner known to the person skilled in the art, wherein in one embodiment a cavity is formed that contains air or an inert gas (such as nitrogen). In another embodiment, the filaments can also be printed around a (solid or semi-solid) composition that contains, for example, an active ingredient that is the same or different from the active ingredient(s) in the printed filaments. In another preferred embodiment, the filaments are printed such (e.g.by cross-layering in such a way that defects arise during the construction of the dosage form), so that several cavities, preferably a plurality of cavities, are formed, which are preferably connected to the environment, so that a sponge-like or porous, preferably highly porous, dosage form is created.

[0047] For further preferred embodiments and details of the preferred extrusion process and dosage forms printed therewith, reference is made to WO 2020 / 240030 A1, the entire disclosure of which is hereby incorporated by reference into the present description. In another embodiment, the printing process is configured such that, instead of printing filaments, inks are printed that cure after application either by cooling or chemically or physically. For such a process, the steps mentioned above for the FFF process apply accordingly.

[0048] A preferred jetting process for producing a dosage form in step (3) and / or step(s) (6) of the method according to the invention is described in WO 2020 / 240028 A1 and comprises the steps:

[0049] (i) creating a two- or three-dimensional representation of the object to be manufactured by means of predefined volume increments;

[0050] (ii) printing a predefined volume increment onto a build device or onto an object arranged on the build device;

[0051] (iii) printing a further volume increment such that the volume increments at least partially touch or overlap; and

[0052] (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 to be administered and the volume increments comprise a base composition or base substance which is flowable at a printing temperature compatible with the at least one active ingredient and which solidifies after printing of the respective volume increment and / or the volume increments are bonded to one another superficially.

[0053] In the sense of the jetting process preferred according to the invention, the dosage form to be created is a three-dimensional object, which is to be understood according to the invention in such a way that in the real world, every object produced by two- or three-dimensional printing processes, in this case pharmaceutical dosage forms, extends in three spatial directions. If in the jetting process preferred according to the invention only one layer of at least partially touching volume increments is printed on the construction device or on an object already present on the construction device, the jetting process preferred according to the invention can also be described as a 2D printing process. If the volume increments are applied, for example, as droplets, which, for example, due to subsequent moisture removal, e.g.Although the volume increments appear macroscopically as two-dimensional units, such as through drying, they are microscopically three-dimensional structures, so that, according to the invention, the dosage form also has a three-dimensional extension in such embodiments according to the invention. According to a preferred embodiment of the jetting process, the dosage form is constructed 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.

[0054] The preferred jetting process according to the invention is characterized in particular by the high flexibility of the composition and the multitude of possible configurations for the produced semi-solid or solid dosage form. Thus, in preferred embodiments of the jetting process, 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.

[0055] In the preferred jetting process, it is of course also intended that the dosage form is constructed entirely from volume increments, all of which contain a single, identical active ingredient, whereby it is also intended that each volume increment can contain the same amount of the active ingredient or the same concentration of the active ingredient, whereby

[0056] The volume increments are essentially freely definable and can, for example, take on drops, spheres, points, cylinders, cubes, cuboids or other shapes, wherein the aforementioned geometric shapes (spheres, cylinders, cubes, cuboids) are to be understood according to the invention such that the voxels essentially assume this shape, preferably when they are solidified after printing, so that more generally pellets, which preferably approximate a spherical or cylindrical shape, and granules can also be mentioned as voxel shapes that are also preferred according to the invention. Preferred voxel shapes are therefore in particular drop-, 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.

[0057] Certain preferred embodiments of the method according to the invention make use of the essentially free selectability of the volumes of the printed volume increments: In principle, the volume of a pharmaceutical dosage form shrinks from the outside to the inside 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 active ingredient over the course of the degradation of the dosage form, the invention provides for printing the volume increments such that the volume of the printed volume increments increases from the outside to the inside. This is achieved according to the invention by printing corresponding layers of volume increments, wherein the volume of the volume increments increases from the outside to the inside from layer to layer or from a group of layers of the same volume to further layers of the same volume.

[0058] As already explained, different active pharmaceutical ingredients (APIs) can be contained in the dosage form using the preferred jetting process. Furthermore, multiple (i.e., two or more) active ingredients can be contained in the volume increments. Of course, volume increments can also be printed so that each volume increment contains an API, but different APIs (two or more) are present in separate volume increments. Volume increments can also be printed that contain different concentrations (i.e., amount of active ingredient per volume increment) of an active pharmaceutical ingredient.In one embodiment, the method can be designed such that active ingredient-containing volume increments are constructed and printed in such a way that at least a first group of touching or overlapping active ingredient-containing volume increments contains the same amount of active ingredient, and at least a 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 a dosage form produced by the jetting process. This embodiment of the invention is also used in preferred variants of the invention to provide a uniform release of active ingredient, as described above for increasing the volumes of the volume increments in the dosage form from the outside to the inside.In order to ensure the most uniform possible release of the active ingredient or ingredients, the volume increments are preferably printed in such a way that the active ingredient concentration preferably increases in the volume increments from the outside to the inside.

[0059] In further embodiments, dosage forms can be created in which the ratio of active ingredient release per unit time is controlled by the surface area of ​​the printed volume body (i.e., the printed dosage form) that is accessible to a surrounding medium. For example, for a zero-order release, doubling the surface area accessible to the surrounding medium will, at least in a first approximation, result in a doubling of the active ingredient release. In preferred embodiments, for example, honeycomb structures can be printed that macroscopically have the shape of a conventional dosage form (e.g., a tablet), but have a much larger surface area while being approximately the same size.

[0060] When producing dosage forms according to the preferred jetting process, groups of volume increments with different pharmaceutical active ingredients can be formed. At least one first group of active ingredient-containing volume increments can be present, which contains a first pharmaceutical active ingredient, and at least one second group of active ingredient-containing volume increments can be present, which contains a second pharmaceutical active ingredient different from the first active ingredient. The different groups of volume increments can be printed in such a way that they are combined within the dosage form. This means that the volume increments of the first and / or second group (and, if applicable, each additional 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 touch each other.

[0061] In further embodiments of the preferred jetting process, it is also provided that active ingredient-containing volume increments are printed in such a way that they form one or more groups within the object, which are at least partially, in other embodiments also completely, surrounded by non-active ingredient-containing volume increments, which separate or shield the active ingredient-containing volume increments from the external environment, so that, for example, a dosage form with an active ingredient-containing core or at least an inner group of interconnected active ingredient-containing volume increments (or several inner groups of adjacent volume increments with the same or different active ingredients or the same or different active ingredient quantities) is created, around which non-active ingredient-containing volume increments are arranged. The "external environment" can be the environment surrounding the object.The term “external environment” around a core area or an inner group of directly connected volume increments is also understood to mean another area within the printed dosage form, i.e. volume increments not containing an active ingredient can, in the printed dosage form, surround groups of volume increments containing an active ingredient at least partially, and if necessary completely, by other individual volume increments or groups of volume increments which, for example, contain a different active ingredient (or several different active ingredients), in order to form separating layers or separating areas between the differently equipped volume increments. Such arrangements can be used in preferred embodiments for the spatial isolation of the individual volume increments containing an active ingredient, for example to avoid chemical instabilities of the individual active ingredients and / or to separate different active ingredients which are not chemically compatible with one another (because, for example, they contain different active ingredients).react with each other or otherwise impair their structure and / or effectiveness).

[0062] In other embodiments of the aforementioned type, drug abuse deterrent tablets or capsules can also be provided, for example, which prevent, for example, an active ingredient (e.g., opioids or active substances with addictive potential) from being extracted from a dosage form, for example by comminution or in some other way, and then 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 neutralizes the effect of the active ingredient(s), degrades the active ingredient(s), or otherwise at least limits, and particularly preferably prevents, the potentially misuse of the active ingredient(s).Between the groups (or layers) of active ingredient(s) and abuse prevention substance(s), there may also be provided one or more groups or one or more layers of volume increments which do not contain any active ingredient or abuse prevention substance (in preferred embodiments, these volume increments will only contain the base building substance used) and which separate the active ingredient-containing volume increments from the volume increments with the abuse prevention substance(s).

[0063] 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 embodiments which release the active ingredient(s) slowly, such as sustained-release tablets or capsules or gastro-resistant tablets or capsules.

[0064] The preferred jetting method within the scope of the present invention can thus be used to produce objects, in particular pharmaceutical dosage forms, that release the API(s) at a selected location or a selected area of ​​the desired application (so-called "drug targeting"), i.e., are preferably used to control the release of the drug(s) from the printed dosage form. Such embodiments thus serve to deliver the drug(s) to the optimal site of action or target location, for example (and preferably) after oral administration.Thus, in certain embodiments of the invention, it is provided that the volume increments are printed in such a way that a core region of volume increments of a pharmaceutical dosage form according to the invention contains one or more desired active ingredients, and one or more layers of volume increments are arranged around this core region (or around this core volume), which are, for example, degraded or dissolved in the intestine in a pH-dependent manner, so that the core region is only exposed to the surrounding environment through the pH-dependent degradation of the outer layer(s) in the preselected region of the intestine, where it releases the active ingredient(s). This is usually achieved by polymers present in the anabolic substance that are well known in the art (such as shellac, copolymers of methacrylic acid and methacrylic methacrylate, modified celluloses, etc.) and / or polyvinyl alcohol derivatives, the pH-dependent degradation orpH-dependent solubility can be very finely controlled, so that a pH-dependent exposure of the active ingredient-containing core region of the dosage form for each section of the intestine, in particular the small intestine (duodenum, jejunum and ileum), can be provided according to the invention. The provision of a targeted release at a specific site of action or target location, such as the intestine or a selected section of the intestine, 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 that are contained in such building substances. Other mechanisms can also be implemented alternatively or additionally. For example, according to the invention, the volume increments can be printed in such a way that one or more layers of volume increments are located, for example directly on a core region containing the active ingredient or on one or more optionallyexisting intermediate layer(s) whose building substance contains or consists of a bacterially degradable portion. Suitable for this purpose are, for example, bacterially degradable polymers known to a person skilled in the art, such as starches or celluloses. Such layers preferably serve to release active ingredients in the colon. In preferred embodiments, the aforementioned layers, e.g. pH-dependent degraded layers (one or more) and bacterially degradable layers, can be combined. In this way, for example, dosage forms for pharmaceutical active ingredient combinations can also be printed, in which volume increments with a first active ingredient are arranged in a core region, which is surrounded by one or more layers of volume increments that contain (or consist of) bacterially degradable substances in the building substance.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 build-up substance. Alternatively, of course, in such an embodiment with multiple drug-targeting layers, only the core region can contain one or more active ingredients.

[0065] Since the preferred jetting 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.

[0066] Furthermore, the increased flexibility of the preferred jetting process is also due to the fact that very different materials (active ingredients and base compositions or substances) can be used for the volume increments to be printed.

[0067] The bonding between the individual applied volume increments can occur in different 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, whereby this 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 it has been applied. The hardening by the binder can occur, for example, through heat, which can be supplied by a suitable heat source in the printing device, such as a light source, preferably a laser device.Curing by the binder can also occur chemically using appropriate starter molecules and / or light of a suitable wavelength, the latter preferably being emitted by 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. After the voxel is applied, a polymerization is initiated by suitable means such as light, heat, or other polymerization initiators, which cures the applied voxel and connects or bonds it to neighboring voxels.

[0068] With regard to further preferred embodiments and details of the preferred jetting process and dosage forms printed therewith, reference is made to WO 2020 / 2400288 A1, the entire disclosure content of which is hereby incorporated by reference into the present description. Suitable carrier materials which are flowable at the printing temperature and in which the pharmaceutical active ingredient(s) are present are carriers which can be used in both the extrusion and jetting processes, e.g. generally for hot melt extrusion (HME), such as low-melting waxes and polymers. The HME mixture or generally the volume increment mixture can contain, in addition to the low-melting carrier, other processing agents and excipients such as binders, fillers, plasticizers, antioxidants, fragrances, sweeteners or the like. Suitable HME carriers and plasticizers are described, for example, in Crowley et al.(2007) Drug Development and Industrial Pharmacy, 33,909-926, (carrier: pages 917 to 919, in particular Table 1; plasticizer: pages 917 and 920, in particular Table 2), whereby in the present description express / s verbis reference is made to the said passages.

[0069] A spot printing method suitable according to the invention in step (3) and / or step(s) (6) comprises the following steps:

[0070] (a) Providing a printer capable of at least 3D printing the solid dosage form, which printer has a build-up platform on which the dosage form is printed, a print head designed to apply an arrangement of spots of a build-up substance containing at least one pharmaceutical active ingredient for the dosage form on the build-up platform, wherein the build-up substance is flowable in the printed state, preferably by heating, and becomes at least semi-solid by solidification, preferably cooling,

[0071] (b) applying an array of spots of the build substance to the build platform, wherein the spots may overlap, touch, or not touch; or

[0072] (c) at least semi-solidifying, preferably solidifying, the spots of the build-up substance applied in step (b);

[0073] (d) applying a further arrangement of spots to the previous arrangement of spots such that the spots of the further arrangement at least partially overlap with the spots of the previous arrangement; and

[0074] (e) repeating steps (b) to (d) until the dosage form is formed.

[0075] A "spot" in the sense of the above printing process is an essentially round, essentially three-dimensional structure that results from the impact of a volume unit during the application of the build substance, which is output from a print head of the printing device in liquid, but at least flowable, form, usually in the form of a drop, (approximate) rotational ellipsoid or (approximate) sphere and is deposited on the build platform (in step (b)) or, at least partially, on previously deposited spots (in step (c) or steps (c)).

[0076] As already mentioned above, dosage forms can be produced using the invention, wherein anabolic substances containing at least one pharmaceutically active ingredient are used. In preferred embodiments, synergistic combinations of two or more pharmaceutically active ingredients are provided, which can be present in a single anabolic substance. In another embodiment, different active ingredients can be present in different anabolic substances.

[0077] The active ingredients in the preferred spot printing process can be present in groups of building substances that form the applied spots. According to the invention, one active ingredient can be present in a building substance from which a first group of spots is formed, and one (or more) other active ingredients can be contained in another group of spots (i.e. there are at least two building substances that contain the respective active ingredient(s). Preferably, the different active ingredients are contained in different building substances. It is possible that the respective building substances, with the exception of the active ingredient(s), can otherwise be the same or different, e.g. in order to provide properties tailored to the respective active ingredient, such as pH, solubility, consistency, ionic environment, particle size, color, viscosity, dissolution rate, temperature, isotonicity, etc.In certain embodiments of the invention, combinations of two or more pharmaceutical active ingredients are provided, in which, for example, a pharmaceutical active ingredient intended for a specific indication is contained in a building substance and a further pharmaceutical active ingredient is present in the same or a different building substance, such that, for example, a side effect potentially caused by the first active ingredient is at least reduced, or at best suppressed, which represents a particularly preferred embodiment of the preferred spot printing process.

[0078] In preferred embodiments of the preferred spot printing process within the scope of the invention, spots with the same active ingredient or the same combination of active ingredients or the same concentration of active ingredients are located in a common section of the dosage form, so that the spots of the same group are at least partially adjacent to one another on at least one side. Thus, the spots with the same active ingredient or the same combination of active ingredients or the same concentration of active ingredients preferably each form at least one common section (e.g., at least one common layer or at least one contiguous part of at least one layer), whereby these can be aligned horizontally or vertically, relative to the longest dimension of the dosage form. Spots with the same active ingredient, the same combination of active ingredients or the same concentration of active ingredients can, in other embodiments, also be printed in several sections (e.g.,2 or more layers and / or sub-layers). Such sections can also have different drug release properties such as different pH conditions, solubility, gastric juice resistance, other solubility behavior (e.g. in the spots of certain sections or of a certain section contain a burst release substance, wherein a method for forming a burst release embodiment is preferably designed such that the spots of the burst release sections are applied such that the burst release sections envelop the spot sections without burst release agent in the ancillary substance, i.e. at least one, preferably several layers of spots with burst release substance(s) in the ancillary substance(s) in each dimension of the dosage form surround the sections of the dosage form without a burst release function).

[0079] The printer provided for the preferred spot printing method within the scope of the invention preferably has at least one print head which is connected to a reservoir containing the build-up substance, such that the at least one print head is capable of withdrawing a quantity of the build-up substance for applying the build-up substance in steps (b) to (e). The reservoir can be designed in different ways depending on the type and consistency of the build-up substance. In the case of liquid build-up substances, the reservoir can be a liquid container which is connected to the print head via a line for the build-up substance, through which it is transported to the print head, usually by pumping. In another embodiment, the build-up substance can be in the reservoir in solid, liquid or semi-solid form, e.g.as a powder or granulate, with a transport mechanism feeding the solid or semi-solid build substance to the print head. In this embodiment, the print head typically has a heating or melting device that converts the build substance into an at least flowable, in preferred embodiments liquid, form, which is then dispensed by the print head through a typically present dispensing device onto the build platform as a volume unit forming a spot on the build platform, i.e., printed.

[0080] In another embodiment of the preferred spot printing process, the build substance can also be in the form of a solid or at least semi-solid filament, wherein the filament is present, for example, in a feed channel or feed tube that forms the reservoir. These reservoir shapes can be designed in different ways, although linear embodiments are usually provided for completely solid filament build substances. Preferred filament build substances are usually elongated, cylindrical structures that are typically more or less elastic and can therefore also be accommodated in curved, such as spiral-shaped, reservoir spools and fed to the print head, for example, by a pushing or pushing mechanism. If the elasticity is not sufficient to feed the filament spirally into reservoir spools, the filament can also be fed in short, straight filament rods from a reservoir magazine.

[0081] In the case of liquid build-up substances, the print head can comprise piezoelectrically operated devices for dispensing the unit volume, so that the build-up substance is dispensed as in an inkjet printer. Such an embodiment can also be designed as a 2D printing process, as explained in more detail below. In a 2D printing process, a liquid (examples are mentioned below) is usually applied using known techniques such as piezoelectric dispensing devices, for example, to at least a portion of the surface of a dosage form created by the above 3D printing steps, for example in an additional step (vi), wherein the liquid is usually dried or fixed in some other way to the at least one portion of the surface (e.g. chemically, physically and / or by exposure to light, which is usually effected by a laser device).Of course, it is also possible to apply one or more 2D-printed layers within a dosage form and to continue with the 3D printing steps after applying a 2D layer (although a final 2D printing layer can of course follow).

[0082] In a further preferred embodiment, the printer has more than one print head, with 2 to 10 print heads being particularly preferred. Embodiments of the invention with multiple print heads can serve different functions: In one embodiment, it is provided that printing takes place on a unit of the dosage form, e.g., in order to print different building substances with the different properties as set out above. In an embodiment with multiple printers, 3D and 2D print heads can also be provided, wherein it is also possible, as explained below, for print heads that can be used according to the invention to be designed for both 3D printing and 2D printing. The invention further provides for the use of more than one print head in order to print multiple dosage forms simultaneously.It is of course also possible according to the invention to print several different dosage forms simultaneously, i.e. print head sets are formed, so to speak, or at least referred to as sets, which simultaneously print with different building substances on several dosage forms, wherein the simultaneously printed dosage forms can again be the same or different in their structure. The number of print heads can therefore also be well in excess of 10 print heads in order to be able to increase the number of printed dosage forms accordingly. In the embodiment of the method with more than one print head, it is further preferred that each of the print heads is connected to a reservoir with the building substance, so that the respective print head is capable of withdrawing a quantity of the building substance for applying the building substance in steps (ii) to (v).The above reservoir designs can be the same or different for the print heads, independently of one another.

[0083] According to the invention, the spots are preferably created by applying a volume unit of the build-up substance, with one volume unit preferably having a volume of 20 pl to 30 pl. If necessary, several volume units can, of course, also be applied consecutively.

[0084] According to another preferred embodiment of the sports printing process, the print head or, in the case of multiple print heads, at least one of the print heads is designed for both 2D printing and 3D printing. In another embodiment of the invention, the device comprises at least one or more 3D print heads and, if necessary, a 2D print head. 3D print heads are designed for applying semi-solid and molten build-up substances, while 2D print heads are designed for applying build-up substances that are already liquid without heating in the print head, such as inks or active ingredient solutions, active ingredient emulsions, and active ingredient suspensions.

[0085] In a preferred embodiment, the spots are applied such that the spots used in step (b) and the further steps (b) (according to step (e) of the method according to the invention) overlap with the spots used in the previous step (step (b) or each step (b) of the further build-up steps, e.g., step (e)). This embodiment thus results in a dosage form that can form a particularly stable arrangement in the sense of a brick arrangement of the applied spots if the spots of one layer have a complete overlap with the previous layer.On the other hand, by applying a layer of spots which partially overlap with the previous layer, a particularly light arrangement with spaces is provided, whereby the solubility or degradation rate of the dosage form in the surrounding environment, in particular in the digestive tract of the subject ingesting the dosage form, for example a human patient, can be controlled by creating a larger surface area of ​​the dosage form exposed to the surrounding environment.

[0086] As described above, in preferred embodiments of the invention, the build substance is present as a filament and the print head is designed, in the case of 3D printing, to melt a quantity of the filament, preferably by the print head comprising a heating device as described above, in order to apply the arrangement of spots of the build substance on the build platform in step (c) as well as the further arrangement(s) of spots on the previous arrangement of spots in step (d).

[0087] The solidification (at least into a semi-solid state of the printed build-up substance) as well as the bonding between the individual applied spots in step (c) can take place in different ways. In one embodiment, for example, when using a fusible material, the bonding between such spots can take place through solidification after application to the carrier structure, whereby this can be carried out through various mechanisms such as simple cooling and / or chemically using known substances. In another embodiment, a suitable binder can be added to the build-up substance, e.g. a dispersion or a solution, which causes the spot to harden after it has been applied. The hardening by the binder can take place, for example, through heat, which can be supplied by a suitable heat source in the printing device, such as a light source, preferably a laser device.Curing by the binder can also occur chemically using appropriate starter molecules and / or light of a suitable wavelength, the latter preferably being emitted by a laser device. In a further embodiment, the build-up substance can contain one or more starting compounds, typically monomers, of one or more polymers. After the spot(s) have been applied, a polymerization is initiated by suitable means such as, for example, light, heat, or other polymerization initiators, which cures the applied spot and bonds or bonds it to neighboring spots.

[0088] Suitable carrier materials that flow at the printing temperature and in which the active ingredient(s) are present are also, in the case of the preferred spot printing process, for example, carriers that can generally be used for hot melt extrusion (HME), such as low-melting waxes and polymers. The HME mixture or, in general, the building substance mixture can contain, in addition to the low-melting carrier, other processing agents and excipients such as binders, plasticizers, antioxidants, fragrances, sweeteners, or the like. Suitable HME carriers and plasticizers are known to the person skilled in the art and 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), whereby reference is also made to the passages mentioned in the present description of the preferred spot printing process express / s verbis.

[0089] The method according to the invention is not limited to a complete DeWovo construction of dosage forms or medical devices. The method can also be applied to objects already present on the construction device. This includes, for example, previously conventionally or otherwise produced dosage forms that are to be modified, for example, by the present method, or active ingredient-free objects (also called placebo carriers) onto which active ingredient-containing volume increments are printed in the manner according to the invention. For example, active ingredient-free films or other flat materials such as edible paper can be presented in order to provide, for example, active ingredient-containing ODF ("orally degradable film" or "orally dissolvable film") products. In other embodiments, pre-presented plaster materials can, for example, be printed with volume increments according to the invention that contain, for example, wound-healing-promoting active ingredients.In further embodiments, placebo carriers produced, for example, by a fused layer modeling process can be printed by the process according to the invention with API-containing volume increments and subsequent printing of solvent-containing liquids, wherein the printed layers can alternate.

[0090] The printing process steps (step (3) and / or step(s) (6) of the method according to the invention) are preferably carried out with computer support. Typically, a calculated three-dimensional image of the dosage form to be printed is created, for example, using a common CAD program. The computer-generated reproduction of the object to be printed can also be carried out by scanning an existing dosage form. In the present method, the computer-generated model image is then divided into the desired, in principle freely selectable volume increments (voxels), spots or desired filament elements, whereby the resolution of the real object increases the smaller the volume increments are. Each individual volume increment can be assigned, for example, an active ingredient, carrier or base substance or carrier or base compositions and / or further auxiliaries such as color substances and other optionallyThe required materials and their quantity (concentration in the volume increment) are assigned and finally printed. Suitable printing devices for the preferred jetting process are described, for example, in US 2017 / 03,68755 A1 and US 6,070,107.

[0091] In a particularly preferred embodiment, the method according to the invention in step (3) and / or step(s) (6) further comprises applying at least one colored substance by means of 2D and / or 3D printing, preferably likewise by printing corresponding, preferably small-volume voxels according to the preferred jetting process, and / or by another method, such as, for example, by two-dimensional printing as in inkjet printing, to the dosage form or to at least one section thereof in such a way that the applied substance forms at least one information structure visible on the dosage form. 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 the pharmaceutically active ingredients. In one embodiment, one substance can thus each cover the area(s) orMark 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 within the entire object through color coding. In a further development of this embodiment of the invention, different amounts 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 color substance.

[0092] Of course, different color substances can also be mixed, for example, in one voxel, so that by choosing the appropriate mixture(s) the entire visible spectrum can generally be used.

[0093] According to the invention, the term “color substance” also includes substances that luminesce, in particular fluoresce.

[0094] The information structure created by the color substance(s) can depict a wide variety of information, whereby several different information structures can also be used using different color substances, which can essentially be freely selected and combined. In particular, the invention provides that 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 dosage form and / or about the intended time or period of administration for a dosage form and / or about the intended date of administration for the dosage form and / or about patient-related data (such as, for example,Name, age, gender, medication and illness(es) of the patient) and / or via the cost carrier and / or via the treating physician and / or via the pharmaceutical company providing the dosage form and / or via the medical facility dispensing the dosage form (or a medical device).

[0095] The information structure can be selected from a wide range of possible applications. The substance(s) can be printed in the form of QR codes, letters, and / or numbers. Of course, a wide variety of patterns such as lines, grids, dots, flat patterns, etc. can also be printed, although the preferred embodiment of voxel printing generally offers the most diverse possibilities. The printed image of the code can thus contain the active ingredient and simultaneously encode the desired data about the patient, doctor, pharmacist, and / or medical or pharmaceutical personnel, as described above.

[0096] It will be apparent to those skilled in the art that, depending on the specific additive manufacturing process chosen, the coloring substance(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 coloring substance (or several of them) be present together with the active ingredient(s) in the build-up substance intended for a given volume increment.

[0097] As already explained above, the dosage form may contain a wide variety of information structures, preferably those mentioned in the method described above.

[0098] Active ingredient-containing objects that can be printed using the process according to the invention 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 process according to the invention are diverse and include oblong tablets, lozenges, implant tablets, multiple-application tablets, dispersible tablets, sustained-release tablets, vaginal tablets and suppositories, ophthalmic tablets, coated tablets, matrix tablets, chewable tablets, film-coated tablets, modified-release tablets, coated tablets, and margin-resistant tablets and drug-abuse deterrent tablets.

[0099] Further, particularly suitable objects which are suitable as a dosage form for pharmaceutical active ingredients within the scope of the present invention are medical devices such as topical dosage forms containing active ingredients, contact lenses, plasters, which preferably release the active ingredient(s) for local application.

[0100] In step (4) of the method according to the invention, the individual and disease-related parameters of the patient are again analyzed, whereby these parameters are now influenced by the dosage form(s) printed in step (3) after the patient has been provided with the dosage form(s) printed in step (3), the patient is now under therapy with this dosage form printed in step (3) (or the dosage forms printed in step (3)).

[0101] In step (5) of the method according to the invention, at least one administration-relevant parameter of the active ingredient or active ingredients is adapted based on the analysis of the parameters in step (4) and finally, in step (6), a new dosage form is created using 2D and / or 3D printing according to the at least one adapted parameter.

[0102] As set out in the optional step (7) of the method, the steps of analysis (4), adaptation of the administration-relevant parameter(s) of the active ingredient(s) (5) and printing of the dosage form(s) (6) can be repeated on the basis of the adapted parameter(s), which is preferred according to the invention, in particular in order to continuously adapt the dosage form(s) to the possibly changing individual and disease-related parameters.

[0103] It will be apparent to a person skilled in the art that the printing processes used in step (3) and step(s) (5) of the method according to the invention may be the same or different. Thus, in certain embodiments, an extrusion process (e.g., the preferred process explained in more detail above or another known 3D / 2D extrusion printing process) may be used in step (3), and a jetting process (e.g., the process of a preferred embodiment described in more detail above) or a spot printing process (e.g., the process described in more detail above), or vice versa, may be used in one or more further steps (6), wherein all possible combinations are selectable, in particular also depending on the administration-relevant parameter to be adjusted.Following on from the example of immunosuppressants, based on the analysis of the individual and disease-related parameters, a (first) dosage form is printed by selecting at least one administration-relevant parameter (such as the dose of one or more of the immunosuppressants) (whereby, according to the invention, this dosage form may contain one or more of the immunosuppressants mentioned as examples) either based on the initial parameter (if a new medication is administered (step (1a)) or a different active ingredient has been selected (step (1b)) or based on the changed parameter compared to the previous medication.With regard to the immunosuppressants exemplified above, it is possible according to the invention to print three different dosage forms (one dosage form for each of the three immunosuppressant classes mentioned) or to combine two or all three immunosuppressants into one dosage form, whereby appropriate release properties and / or suitable separating layers, if necessary, are typically incorporated into a multiple dosage form during the printing process, as described in detail within the scope of the preferred printing processes. As already explained above using the example of immunosuppressants and corticoids, the method according to the invention can also be used for patient-optimized uptitration and / or downtitration of one or more active ingredients.

[0104] After analysis of the individual and disease-related parameters of the patient during therapy with the dosage form(s) initially printed according to the invention, one or more administration-relevant parameters are again adapted based on the analysis and one or more dosage forms of the immunosuppressants are again printed in order to optimize the immunosuppression therapy and adapt it to the current requirements, so that the long-term success of the therapy can be improved, and in the case of immunosuppressants, the survival of the transplant can be prolonged in the context of preventing transplant rejection.

[0105] In addition to steps (3) and (6), which are preferably carried out in a computer-aided manner as already described above, the further steps of the method according to the invention are preferably also designed in a computer-aided manner.

[0106] Thus, according to the invention, the analysis in step (1) and in step(s) (4) is computer-assisted, whereby the respective influencing parameters (i.e., individual and / or disease-related parameters) for a dosage adjustment can be determined by the physician or pharmacist. Possible influencing parameters have already been outlined above and include, for example, age, weight, body surface area, height, liver status, kidney status, metabolic influences, general condition of the patient, gender, pre-existing conditions, social status and therapy adherence, drug safety, adherence, active ingredient, active ingredient concentration(s), intolerances, allergies, interactions, and medication compliance.

[0107] The algorithm is calculated using statistical analysis and questionnaires, which are then calculated using mathematical models to determine the optimal dose for a broad spectrum of patients treated with a specific active ingredient. The formulation of the personalized medication can also influence the evaluation and the resulting dose adjustment.

[0108] Likewise, according to the invention, the determination of at least one administration-relevant parameter in step (2) and the adjustment of the at least one administration-relevant parameter in step(s) (5) are carried out computer-assisted. For this purpose, questionnaires and therapy success factors are generally determined, which then correspond to the patient's variable parameters and vital data. These form the basis for the subsequent evaluation via a computer learning system.

[0109] This also preferably applies to the conversion of the at least one administration-relevant parameter into one or more printing parameters for 3D and / or 2D printing.

Claims

Claims for a process for the manufacture of patient-optimized pharmaceutical dosage forms, comprising the following steps: (1) Analysis of individual and / or disease-related data of a patient suffering from a disease condition, where the patient may be exposed to an active substance for the treatment of the patient's disease condition; (1a) where appropriate, selection of one or more active substances to treat the patient's condition, provided the patient has not already been exposed to an active substance to treat the condition; or (1 b) where appropriate, selection of one or more other active substances to treat the patient's condition, provided that the existing active substance(s) have disadvantages compared to the other active substance based on the analysis in step (1) for treating the patient's condition; (2) Determine at least one administration-relevant parameter of the existing active substance or of the active substance(s) selected according to step (1a) or (1b) for a dosage form from the analysis of the data according to step (1), if necessary taking into account potential side effects and / or effects of other active substances for the treatment of the same or a different disease of the patient to which the patient is exposed; (3) Printing a first dosage form containing the active substance(s) according to the at least one administration-relevant parameter determined in step (2) by means of 3D and / or 2D printing, wherein the at least one administration-relevant parameter is translated into one or more corresponding printing parameters for 3D and / or 2D printing; (4) Analysis of individual and disease-related data of the patient following administration of the first dosage form; (5) Adjusting at least one administration-relevant parameter of the active substance(s) for a dosage form from the analysis of the data according to step (4); 33 (6) Printing a further dosage form containing the active substance(s) according to at least one administration-relevant parameter adapted in step (5) by means of 3D and / or 2D printing; and, if applicable, (7) Repeat steps (4) to (6).

2. The method of claim 1, wherein the administration-relevant parameter(s) is / are selected from the group consisting of the amount of the active ingredient(s) per unit dose of the dosage form, the release kinetics of the active ingredient(s) from the dosage form at the administration site and / or via the dosage form in the patient, the concentration of the active ingredient(s) in the dosage form, the concentration distribution of the active ingredient(s) in the dosage form, the size of the dosage form, the geometric shape of the dosage form, the coating parameters of the dosage form, the surface structure of the dosage form, the internal structure of the dosage form, the distribution of the active ingredient(s) in the dosage form, and combinations of two or more thereof.

3. Method according to claim 1 or 2, wherein the individual parameters of the patient are selected from the group consisting of age, sex, developmental stage, genetic predispositions, height, weight, body surface area, body mass index, general physical condition, drug use, eating and drinking habits, sleeping habits, physical activity and combinations of two or more thereof.

4. A method according to any of the preceding claims, wherein the disease-related parameters are selected from the group consisting of blood pressure, heart rate, ECG findings, EEG findings, sonographic findings, CT findings, MRI findings, biopsy findings of diseased tissue, blood count, electrolyte blood levels, blood liver values, nephrological blood and urine values, blood lipid levels, blood glucose levels, vitamin metabolism data, metabolic interactions, medication plan, side effect profiles, urine status, virological findings, bacteriological findings, findings of fungal infection, parasitic findings, stage of the disease, disease course and combinations of two or more thereof.

5. Method according to any of the preceding claims, wherein the disease state is from the group consisting of diseases of internal organs, rheumatological diseases, oncological diseases, cardiac 34 The method of claim 5, wherein the disease of internal organs is selected from the group consisting of kidney, liver, and pancreas transplants. The method of claim 6, wherein the active substance(s) is / are selected from the group consisting of glucocorticoids, calcineurin inhibitors, and inosine monophosphate dehydrogenase inhibitors. The method of claim 5, wherein the disease condition is a rheumatological disease and the active substance(s) is / are selected from the group consisting of glucocorticoids, calcineurin inhibitors, inosine monophosphate dehydrogenase inhibitors, and tyrosine kinase inhibitors. The method of claim 5, wherein the disease condition is an oncological disease and the active substance(s) is / are selected from the tyrosine kinase inhibitors.The method of claim 5, wherein the neurological disease is Parkinson's disease and the active substance(s) is / are selected from dopamine antagonists. The method of claim 5, wherein the hematological disease is anemia. The method of claim 11, wherein the active substance(s) is / are selected from iron preparations, vitamin B12, and folic acid. The method of claim 5, wherein the cardiovascular diseases are selected from the group consisting of hypertension, stroke, ventricular fibrillation, and risk of myocardial infarction. The method of claim 13, wherein the active substance(s) is / are selected from the group consisting of antihypertensives and anticoagulants.

15. The method of claim 14, wherein the anticoagulants are selected from the group consisting of vitamin K antagonists, thrombin inhibitors and factor Xa inhibitors.

16. The method of claim 14, wherein the antihypertensives are selected from the group consisting of calcium antagonists, beta-blockers, ACE inhibitors, diuretics and AT1 blockers.

17. Method according to one of the preceding claims, wherein the analysis in step (1) and in step(s) (4) is computer-aided.

18. Method according to one of the preceding claims, wherein the determination of at least one administration-relevant parameter in step (2) and the adjustment of the at least one administration-relevant parameter in step(s) (5) are computer-aided.

19. Method according to one of the preceding claims, wherein the conversion of the at least one administration-relevant parameter into one or more printing parameters for 3D and / or 2D printing is computer-aided.