EP4264617A1

EP4264617A1 - Method for producing patient-optimised dosage forms

Info

Publication number: EP4264617A1
Application number: EP21820273.7A
Authority: EP
Inventors: Markus Dachtler; Gerald Huber
Original assignee: Dihesys Digital Health Systems GmbH
Current assignee: Dihesys Digital Health Systems GmbH
Priority date: 2020-12-21
Filing date: 2021-12-07
Publication date: 2023-10-25
Also published as: CN117203709A; WO2022135919A1

Abstract

The present application relates to methods in the field of personalised pharmaceuticals. More specifically, the invention relates to methods for producing pharmaceutical dosage forms which are produced by 3D and/or 2D printing, wherein a wide range of administration-relevant parameters of the dosage form can be altered depending on the analysis of patient- and illness-specific data and can be adapted during the course of the treatment of the patient. The treatment quality for the patients can thus be improved in the future and significantly enhanced in respect of patient safety.

Description

Process for the production of patient-optimized dosage forms

The present application relates to methods of personalized pharmaceutics. More precisely, the invention relates to methods for producing pharmaceutical dosage forms that are produced by 3D and/or 2D printing, with a wide variety of administration-relevant parameters of the dosage form being changed depending on the analysis of patient and disease-specific data and being adapted during the course of the patient's treatment. As a result, the quality of treatment for the patient can be improved in the future and significantly increased from the point of view of patient safety.

With previous pharmaceutical manufacturing processes, the implementation of personalized medicine for each individual patient is either not feasible or can only be realized at great expense and awkwardly, since the preparations of individual active ingredients or, even more rarely, combinations of active ingredients are only available in a few standardized doses and dosage forms . This applies above all to solid dosage forms, which, however, are the dosage forms usually best tolerated by patients (e.g. tablets, capsules, thin films, etc.)

The object of the invention is therefore to provide a method that makes it possible to provide a dosage form of the required active ingredient(s) that is constantly optimized for each individual patient, depending on his/her individual and disease-specific parameters in the course of therapy with one or more active ingredients To make available.

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

In particular, the invention provides a method for producing patient-optimized pharmaceutical dosage forms that the steps:

(1) analyzing individual and/or disease-related data of a patient suffering from a disease state, where the patient may be exposed to an agent to treat the patient's disease state; (1a) optionally selecting one or more agents to treat the patient's disease state if the patient is not already exposed to an agent to treat the disease state; or

(1 b) If necessary, selection of one or more other active substances for the treatment of the disease state of the patient, provided that the previous active substance(s) have disadvantages compared to the other active substance based on the analysis of step (1) for the treatment of the disease state of the patient having;

(2) Determination of at least one administration-relevant parameter of the previous 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), possibly taking into account potential side effects and /or influences of other active ingredients for the treatment of the same or another 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, the at least one administration-relevant parameter being converted into one or more corresponding printing parameters implemented for 3D and/or 2D printing;

(4) analysis of individual and disease-related data of the patient with administration of the first dosage form;

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

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

(7) repeating steps (4) through (6).

The method according to the invention can be designed in such a way that the patient has not yet undergone any treatment with an active substance. This case is described in the optional step (1a), in which first one or more active ingredients indicated for the specific disease are selected.

According to the invention, the term “disease” or “disease” of a patient includes, on the one hand, any pathological condition that can be treated with pharmaceutical dosage forms, where “treatable” according to the invention means that the course of the pathological condition is positively influenced under the respective medical circumstances. In the case of serious diseases such as cancer and tumor diseases, for example, this can be a statistically significant increase in the probability of survival over a period of time typically observed for the respective disease compared to the course of the disease in the event of no treatment. In other cases, "treatable" usually means that the condition is at least not getting worse, preferably improving, ideally the condition is cured. In still other diseases, such as transplantation, the term "treatable" implies that the graft has a greater survival rate over the untreated course than in the untreated state. According to the invention, the expression “disease” or “pathological condition” also includes an existing risk of the patient of 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 .

As indicated in optional step (1b), the method according to the invention can be used in cases where the patient has been treated with one or more active substances (i.e. one or more "previous" active substance(s)), but for whatever reason (e.g. Intolerance, interactions between active substances, unsatisfactory progression of the disease under treatment of the current 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 is/are.

In other embodiments, the method is used to optimize existing therapies with one or more active substance(s) without first selecting one or more active substance(s) after the data analysis in step (1), i.e. the method process after step ( 1) continues with step (2).

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 present in a medical file at a health service provider such as a treating doctor or in a medical facility such as a hospital, a clinic and/or a spa facility, preferably in digitized form. "Individual" data of a patient are personal parameters of the patient, which are generally independent of the disease, but related to it or its progression typically have or at least can have an impact. Individual data that are or can be analyzed in step (1) of the method according to the invention are preferably from age, developmental status, gender, genetic predispositions, height, weight, body surface area, body mass index, general physical condition, drug use (e.g Use of "soft" drugs such as preferably alcohol, nicotine, marijuana, etc. and/or use of "hard" drugs such as cocaine, heroin, methadone, etc.), eating habits (such as fat, carbohydrate and protein content, time food intake, regularity of food intake) and drinking habits (such as preferably daily amount to drink), sleeping habits, physical activity and combinations of two or more thereof. "Disease-related data" of a patient relate to parameters that provide information about the patient's disease state and are usually collected through diagnostic procedures. Disease-related data collected in this way, which are or can be analyzed in step (1), are preferably obtained from blood pressure, heart rate, ECG findings, EEG findings, sonographic findings, CT findings, MRT findings, biopsy findings of the patient Tissue, blood count, electrolyte blood levels, blood and 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 infestation, parasitic findings, stage the disease, course of the disease, and combinations of two or more thereof.

Of course, the disease-related data depend on the dosage forms to be produced for the disease to be treated. These are explained below using a few typical examples: Diseases that are usually treated with oral dosage forms include diseases of the internal organs such as intestines, kidneys, liver, pancreas, gallbladder, etc. A transplant of the kidney, liver or pancreas is a very precise adjustment of the immunosuppressive medication, ie one or more immunosuppressants such as a calcineurin inhibitor (such as ciclosporin 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, the patient's individual data in step (a), such as in particular weight, gender and/or age or body surface area and the parameters relevant to administration (including the amount of active ingredient, required coatings (e.g. enteric coating(s) etc.; s. step (s)) the Disease-related data influencing immunosuppressants, such as in particular whether it is a first or further transplant, whether and if so which previous and/or concomitant diseases of the patient that can influence the dosage of immunosuppressants, such as existing allergies, intolerances , potential interactions of the administered immunosuppressants analyzed. In another embodiment, if you like. Step (1b) the transplanted patient, for example, is already undergoing therapy with one or more immunosuppressants, for example due to one or more intolerances of the patient to the previously administered immunosuppressant(s), another immunosuppressant (e.g. instead of ciclosporin (current active ingredient) should be given tacrolimus ( the other active substance) or several other immunosuppressants (e.g. instead of ciclosporin (previous active substance) tacrolimus (previous active substance) should be administered and instead of mycophenolate mofetil (previous active substance) mycophenolate sodium (previous active substance) should be administered). In yet another embodiment ( ie 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 becomes step (1) the next step (2) for the selection of the administration-relevant parameter or parameters of the immunosuppressive agent(s) In certain embodiments is at the beginning of an immunosuppressive therapy, ie methods that include step (1a), initially set a low dosage, and then in the further course of the method (steps (2) to (6) according to the analysis of the course of the corresponding individual and / or disease-related parameters to produce successively higher-dosed dosage forms of the immunosuppressive agent(s) (so-called uptitration). In still other embodiments (e.g. in the case of cortiocoid dosage forms) a tapering off of one or more active ingredients is realized by the method according to the invention in the case of existing therapy or in the further course of therapy by using dosage forms with in steps (2) and (3). successively lower doses of the immunosuppressive agent(s) (such as corticoids in the example here) are produced.

Of course, the up and down titrations described above in relation to immunosuppressants can also be applied to other active substances.

In another exemplary embodiment, dosage forms are produced for the treatment of rheumatological diseases. Individual patient parameters are analyzed as already described above. The disease-specific parameters preferably include not only typical physical characteristics such as the presence and extent of joint swelling Blood values, such as inflammation parameters, in particular the so-called rheumatoid factor (see e.g. E. Feist, K. Egerer, G.-R. Burmester, Z. Rheumatol. 2007, 66:212-21) and antibodies against cyclically citrullinated peptides (ACPA ). In addition to the immunosuppressive active ingredients already mentioned above, other active ingredients or classes of active ingredients such as tyrosine kinase inhibitors, for example erlotinib, are also used, for example, within the scope of the production process according to the invention.

Other non-restrictive, preferred indication areas and associated active substances or active substance classes are, for example, oncology (example substances here are also tyrosine kinase inhibitors), neurological diseases such as Parkinson's disease (active substances are e.g. dopamine antagonists such as ropinirole), hematology, i.e. hematological diseases, such as anemias (example active ingredients include iron supplements, vitamin B12 and folic acid) and myelodysplastic syndrome (MDS), and cardiovascular diseases (active ingredients include e.g. anticoagulants such as acetylsalicylic acid, vitamin K antagonists e.g. 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 heart attacks, i.e. the risk of a heart attack). In the case of cardiovascular diseases, high blood pressure should also be mentioned in particular, which often occurs together with or is a starting point for the later development of the diseases mentioned, such as stroke and heart attack (or the risk of suffering a stroke and/or a heart attack). form. Active ingredients that can be used according to the invention in connection with high blood pressure are, in particular, antihypertensives such as, for example, calcium antagonists, beta-blockers, ACE inhibitors, diuretics and AT1 blockers. For example, it is advantageously possible according to the invention, depending on the clinical parameters, in particular the blood pressure, ECG, the sonographic finding, preferably the peripheral vessels, the coronary vessels, the pulmonary vessels and/or the cerebral vessels, as well as blood parameters such as the level of creatine kinase and/or troponin I, the medication should be adapted according to the method according to the invention, e.g. selection of the respective anticoagulant(s) and/or the antihypertensive(s) as well as correspondingly adapted combinations of these and/or their amount(s) of active ingredients.

An adaptation of parameters relevant to administration for the additive printing of dosage forms with an optimized dose-effect relationship or the dose-side effect relationship by the method according to the invention can advantageously also be used in pediatrics and in geriatrics. In younger patients, especially children, using the method according to the invention, in particular with regard to the Size of the printed dosage form can be adjusted individually for each patient, especially since dosage forms to be administered orally can only be taken with difficulty from an individually different size, of course. The method according to the invention also makes it possible to implement dosage forms for pediatric patients with a particularly fine adjustment of the dose-relevant parameters, since precisely in children and adolescents dosing, reduction of side effects and reduction of cross-reactions with other active substances is particularly important for the age and developmental status of the patient. In geriatrics, in turn, patient-optimized administration forms are printed with the method according to the invention, which are also tailored to the special needs of older patients, in particular those aged 70 or over, preferably 75 years or over, particularly preferably 80 years or over. This affects, among other things, the pressure volume, since older patients with small-volume dosage forms may have difficulties in grasping. With the aid 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 dosage form that can be sucked, 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 polypharmaceutical dosage forms, i.e. dosage forms with several active ingredients, can be produced and individually adapted if administration of several active substances per day or per time of administration is required. In general, all patients benefit from the optimization of individual dosage forms with several active ingredients, e.g. if the patient is to take another active ingredient, an existing dosage form, e.g. with one or more other active ingredient(s) already administered, is modified in such a way that by the new active ingredient (there can of course also be several new active ingredients) together with the other active ingredient(s), possibly through defined areas within the dosage form, each containing an active ingredient and those of the other areas with the other Active ingredient(s) are separated, for example, by barrier layers, is printed in a new, patient-specific dosage form (step (3) and/or step(s) (6) of the method according to the invention).

Other diseases within the scope of the present invention are, for example, those of the cardiovascular system such as high blood pressure, arteriosclerosis, cardiac arrhythmia, angina pectoris, heart attack, stroke, etc. It is apparent to a person skilled in the art that the dosage forms which can be produced using the method according to the invention are in no way restricted with regard to the active substance 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 taken into account for a specific indication on the basis of his specialist knowledge and take them into account for the production of the respective dosage form.

In step (2) of the method according to the invention, at least one administration-relevant parameter of the (previous) 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), possibly .Selected taking into account potential side effects and/or influences of other active ingredients for the treatment of the same or another disease of the patient to which the patient is exposed.

An "administration-relevant parameter" of a dosage form of the active substance(s) (either one or more active substances already administered to the patient (i.e. without step (1a) or step (1b)) or one or more new active substances 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 affects drug dose, drug concentration, drug release, route of administration, deliverability, tolerability and/or, stability (to physical and/or chemical parameters) and the effectiveness of a dosage form of the active ingredient(s). Typical and preferred parameters relevant to administration are, for example, amount of active ingredient or active ingredients per unit dose of the dosage form, release kinetics of the active ingredient or active ingredients from the dosage form at the administration site and / or via the route of the dosage form in the patient (pharmacokinetics and pharmacodynamics), concentration of the active ingredient or of the active ingredients in the dosage form, concentration distribution of the active ingredient or ingredients 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 or ingredients in the dosage form, and combinations of two or more of these parameters.

In the case of the method with step (1a) (new active substance or new active substances), previously no active substance), all of the data required for the dosage form according to the analysis of the data and adapted (at the current point in time) are usually, therefore great facie optimal, administration-relevant parameters 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 active substances other than the previous active substance(s)). The method according to the invention is not limited to the optimization of dosage forms for individual patients. Rather, it is also provided according to the invention to record the parameters of optimized dosage forms of a plurality, preferably a large number of patients, such as storing them in a database on a computer or several or a large number of connected computers and making them usable for providing optimized dosage forms for other patients that have similar individual and/or disease-related parameters as patients whose optimized administration forms are already known, ie are preferably stored in the database. Such embodiments can thus make the therapy of other patients more successful more quickly. In addition, it is also provided according to the invention to evaluate and train on the basis of existing and therefore more and more stored parameters of dosage forms with methods and devices of artificial intelligence, such as deep learning methods and corresponding devices, in order to further improve the optimization method according to the invention to enhance. In such embodiments, one or more (initial) active ingredient(s) is therefore preferably selected and parameterized in step (1a) and subsequently in step (2) and a corresponding first dosage form is printed in step (3), which is based on the existing database of cases of the same and/or similar individual and/or disease-related parameters known dosage forms is provided, after which the further method steps follow. In the embodiment of the method according to the invention, in which a dosage form is created that already contains one or more 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 (ie the optional steps (1a) or (1b) are not carried out), one or more parameters relevant to administration are selected in step (2). In certain versions of the method, this can only be a parameter, such as a dose of the active ingredient compared to the existing medication, changed release kinetics or a changed size of the dosage form, etc. It can of course also, depending on the requirement, based on the analysis carried out in step (1), any combination of administration-relevant parameters can be selected in step (2) in order to adapt the administration form to the analyzed individual and disease-related parameters of the patient. In this embodiment, too, according to the steps set out above, using available parameters of already equal or Similar cases, preferably using methods and devices of artificial intelligence such as deep learning methods and corresponding devices, already (pre-)optimized dosage forms are created and then, if necessary, further adapted.

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

After determining the parameter or parameters relevant to administration. In step (2), these are provided to a 3D and/or 2D printing process, generally an additive printing process, which, if not all the necessary (new) parameters relevant to administration have been determined in step (2), the other parameters from otherwise usual or already existing ones parameter values and creates the dosage form with the help of a basically freely selectable 2D or 3D printing process.

Printing processes that can be used for creating the dosage form in step (3) and/or step(s) (6) of the method according to the invention include, for example, extrusion methods such as filament fusion fabrication (FFF) or fused layer modeling (FLM), jetting methods such as voxel printing (also called direct jetting) or binder jetting, and spot printing processes.

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

Providing a pharmaceutical designed for FFF or FLM 3D printing

printing device,

Provision of initial objects designed for FLM or FFF 3D printing, wherein the starting objects form at least a first and a second group of starting objects, the composition of the starting objects of the first group being different from the composition of the starting objects of the second or at least one parameter according to the invention, as explained above, between the starting objects of the groups being different, and at least a group of source 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 the at least first and the second group in the form of filaments or inks with the printing device until the dosage form is created.

The preferred extrusion process can in principle be carried out with known components of FFF 3D printing or FLM 3D printing, with reference to FFF methods being possible, for example, to the relevant disclosure in WO2016/038356 A1.

A "starting object" in the sense of the preferred extrusion printing process are suitable materials for FFF 3D printing or FLM 3D printing, which can be processed in a basically known manner by corresponding printing devices and printed into a 3D object, with the mentioned method the starting object or synonymously the starting material comprises a base composition that can be printed in filament form. In the extrusion printing process, the starting objects are usually converted into a flowable state, typically by heating by a heating device located in a print head of the printing device, and then applied with the print head, usually by extrusion, in filament form to a build platform, preferably in layers. The method according to the invention can also be designed in such a way that the starting objects are printed on an already existing object in filament form that is placed on the construction platform of the printing device.

Starting material or starting objects for the preferred FFF 3D process are filaments, which typically have the shapes given as examples in relation to the filament structures.

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 substance or a first active substance composition and the starting objects of the or another group contain a second active substance or a second active substance composition, the second active substance being different from the first active substance or the second Drug composition is different from the first drug composition.

In a further embodiment of the preferred extrusion process, the starting objects of the other group contain the same active substance, the concentration of the active substance in the starting objects of one group being different from the concentration of the active substance in the starting objects in the other group(s). In other words, in this embodiment, starting objects or materials are printed that form at least two groups, both groups or (if there are more than two groups) at least two groups containing the same active ingredient, but each in a different concentration. It is provided in a further preferred embodiment 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, each group containing an active ingredient that is other active substances of the other groups of starting objects is different. In another embodiment, more than one active substance, e.g. 2, 3, or 4 active substances, with 2 active substances being particularly preferred, are present in one or more groups of starting objects.

At least one group of starting objects can also be present, i.e. printed, which does not contain any active substance, so that solidified filament structures which have no active substance are present in the administration form created.

In another embodiment of the preferred extrusion process, the groups of starting objects or materials can be constituted in such a way that the printed filaments differ in the nature of the active ingredient release.

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

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 explained above is the same) has a detectable Distinctive feature that is different from the / the other groups of starting objects, so that the printed filaments with different compositions (or different parameters) are differentiable. As already stated above, preferred distinguishing features are, for example, filament diameter, length of the filament, visible dyes, fluorescent dyes, surface textures, shape, gloss, porosity, roughness and absorption or reflection properties with regard to electromagnetic radiation.

The extrusion process is preferably carried out in such a way that one or more layer(s) of the first group of starting objects is/are printed in the form of filaments and then one or more layer(s) of the second group of starting objects are printed in the form of filaments and, if necessary, In each case one or more layer(s) of the further groups of starting objects are printed in the form of filaments. The respective groups of starting objects can also be printed alternately in layers. This can also be done by means of layers without an active ingredient, e.g. to optimize the chemical stability of the starting materials.

In a further preferred embodiment of the preferred extrusion process, the groups of starting objects are printed in such a way that the administration form created, as described above, has at least one partial volume that contains no printed filaments. This can be done in any manner known to those skilled in the art, in one embodiment forming a cavity containing air or an inert gas (such as nitrogen). In another embodiment, the filaments can also be printed around a (solid or semi-solid) composition, e.g. containing the same or different active substance (compared to the active substance(s) in the printed filaments). In another preferred embodiment, the filaments are printed in such a way (e.g. by cross-layering in such a way that defects occur in the structure of the dosage form) so that several cavities, preferably a large number of cavities, are formed, which are preferably connected to the environment, so that a spongy or porous, preferably highly porous, dosage form is formed.

With regard to further preferred embodiments and details of the preferred extrusion process and thus printed dosage forms, reference is made to WO 2020/240030 A1, the entire disclosure content of which is hereby incorporated by reference into the present description. In another embodiment, the printing process is designed in such a way that, instead of printing filaments, inks are printed which, after application, either harden by cooling or chemically or physically. The steps mentioned above for the FFF method also apply to such a method.

A preferred jetting process for creating 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:

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

(ii) printing a predefined volume increment on a building device or on an object placed on the building device;

(iii) printing another 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 to be administered and the volume increments comprise a base composition or base substance that is flowable at a printing temperature that is tolerable for the at least one active ingredient, which solidifies after the respective volume increment has been printed and/or the volume increments are superficially bonded to one another .

In terms 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 as meaning that in the real world every object produced by two- or three-dimensional printing methods, here pharmaceutical dosage forms, extends in three spatial directions. If only one layer of at least partially touching volume increments is printed on the assembly device or on an object already present on the assembly device in the jetting process preferred according to the invention, the jetting process preferred according to the invention can also be described as a 2D printing method. If the volume increments are applied, for example, as droplets, which appear macroscopically as two-dimensionally expanded units as a result of subsequent removal of moisture, e.g. drying, these are, however, microscopically three-dimensional structures, so that the dosage form also has a three-dimensional expansion in such inventive embodiments. According to a preferred embodiment of the jetting process, the dosage form is built up in layers, ie in steps (ii) and (iii) the volume increments are printed in layers. The volume increments are preferably printed in rows or columns.

The jetting process which is preferred according to the invention is characterized in particular by the high flexibility of the composition and the large number of possible construction options for the semi-solid or solid dosage form produced. Thus, in preferred embodiments of the jetting process, different volume increments can have different active ingredients and/or different amounts of active ingredient and/or different basic compositions or basic substances. In addition, the shape and/or the volume of the volume increments (also called “voxels” below) can be the same or different.

In the preferred jetting process, it is of course also provided that the dosage form is made up entirely of volume increments, all of which contain a single, identical active ingredient, it also being provided that each volume increment contains the same amount of active ingredient or the same concentration of active ingredient may contain, where

The volume increments are essentially freely definable and can, for example, take the form of drops, spheres, points, cylinders, cubes, cuboids or other shapes, with the geometric shapes mentioned (spheres, cylinders, cubes, cuboids) being understood according to the invention in such a way that the voxels essentially assume this shape, preferably when they have solidified after printing, so that voxel shapes that are also preferred according to the invention are also more generally pellets, which preferably approximate a spherical shape or a cylinder, and granules. Preferred voxel shapes are therefore, in particular, voxels in the form of drops, pellets, cylinders and granules. As already explained above, the shape (e.g. the above examples) and the size of the volume of the volume increments can be freely combined essentially independently of one another.

Certain preferred embodiments of the method according to the invention make use of the fact that the volumes of the compressed volume increments can, in principle, be freely selected: In principle, the volume of a pharmaceutical dosage form shrinks from the outside inward when it is broken down towards or at the point of release. This causes the amount of drug released per unit time to decrease. To one in that regard In order to achieve the most uniform possible release of active ingredient over the course of the breakdown of the dosage form, it is provided according to the invention to print 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 realized by printing corresponding layers of volume increments, the volume of the volume increments increasing from layer to layer or from group of layers of the same volume to further layers of the same volume from the outside inwards.

As already explained, different active pharmaceutical ingredients (so-called APIs) can be contained in the dosage form with the aid of the preferred jetting process. In addition, several (ie two or more) active substances can be contained in the volume increments. Of course, volume increments can also be printed in such a way that each volume increment contains an API, but different APIs (two or more) are present in separate volume increments. It is also possible to print volume increments that contain different concentrations (i.e. amount of active substance per volume increment) of a pharmaceutical active substance. In a related embodiment, the method can be designed in such a way that volume increments containing active substance are constructed and printed in such a way that at least a first group of touching or overlapping volume increments containing active substance contains the same amount of active substance and at least a second group of touching volume increments contains an amount of active substance, which is different from the amount of active ingredient of the first group. In this way, concentration gradients can be built up 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 inwards. In order to provide a release of the active ingredient or active ingredients which is as uniform as possible, the volume increments are preferably printed in such a way that the active ingredient concentration preferably increases in the volume increments from the outside inwards.

In further embodiments, dosage forms can be created in which the ratio of active ingredient release per unit of time is controlled by the surface area of the printed volume body (ie the printed dosage form) that is accessible to a surrounding medium. So becomes e.g. for a zero-order release when the surface accessible to the surrounding medium is doubled, at least in a first approximation, a doubling of the drug release can be realized. In preferred Embodiments can, for example, print honeycomb structures which macroscopically have the shape of a conventional administration form (eg tablet), but have a much larger surface area with approximately the same size.

In the production of dosage forms according to the preferred jetting method, groups of volume increments with different pharmaceutical active substances can be formed. At least one first group of active substance-containing volume increments can be present, which contains a first pharmaceutical active substance, and at least one second group of active substance-containing volume increments, which contains a second pharmaceutical active substance that is different from the first active substance. 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 the second group (and possibly each additional group if more than two active substances 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.

It is also provided in further embodiments of the preferred jetting process that active substance-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 volume increments that do not contain active substance Separate or shield volume increments from the external environment, so that, for example, a dosage form with an active substance-containing core or at least an inner group of interconnected active substance-containing volume increments (or several inner groups of adjacent volume increments with the same or different active substances or the same or different amounts of active substance) is created, around which volume increments that do not contain active substance are arranged. The "external environment" can be the milieu surrounding the object. The term "external environment" around a core area or an inner group of volume increments directly connected to one another is also understood here to mean another area within the printed dosage form, i.e. volume increments that do not contain active substance in the printed dosage form can at least partially, possibly also completely, contain active substance groups of volume increments other individual or groups of volume increments, which contain, for example, another (or several other) active substance(s) in order to form separating layers or separating areas between the differently equipped volume increments. In preferred embodiments, such arrangements can be used for the spatial isolation of the individual active substance-containing volume increments, for example to avoid chemical instabilities of the individual active substances and/or different active substances that are chemically incompatible with one another (since they react with one another or otherwise change their structure and/or impair effectiveness) from each other.

In other embodiments of the aforementioned type, e.g. Drug Abuse Deterrent tablets or capsules can be provided which prevent e.g Dosage form can be obtained and misused. Thus, in preferred embodiments of the invention, groups or layers of volume increments containing the active ingredient(s) (e.g. the potentially abusive substances mentioned above) are printed surrounded by groups or layers of volume increments containing a substance that has the effect of the active ingredient(s), breaks down the active ingredient(s), or otherwise at least limits, more preferably prevents, the potentially abusive use of the active ingredient(s). There may also be one or more groups or layers of volume increments between the groups (or layers) of drug(s) and anti-abuse substance(s) which contain no drug and no anti-abuse substance (in preferred embodiments these are volume increments containing only the base builder used) and separating the volume increments containing the active ingredient from the volume increments containing the anti-abuse substance(s).

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, e.g .

The preferred jetting method in the context of the present invention can thus be used to produce objects, in particular pharmaceutical dosage forms, which release the API(s) at a selected location or a selected area of the desired application (so-called “drug targeting "), ie preferably used to control the release of the drug or drugs from the printed dosage form will. Such embodiments thus serve to deliver the drug or drugs to the optimal site of action or target site, for example (and preferably) after oral administration. In certain embodiments of the invention, it is provided that the volume increments are printed in such a way that a core area of volume increments of a pharmaceutical dosage form according to the invention contains one or more desired active ingredient(s) and around this core area (or around this core volume) there are one or more layers are arranged in volume increments, which are broken down or dissolved in the intestine, for example, depending on the pH, so that the core area is only exposed to the surrounding environment through the pH-dependent breakdown of the outer layer(s) in the preselected area of the intestine and there releases the active ingredient(s).This is usually achieved by polymers (such as shellac, copolymers of methacrylic acid and methacrylic methacrylate, modified celluloses, etc.) and/or polyvinyl alcohol derivatives present in the building substance, which are well known in the art, and their pH-dependent degradation or pH-dependent solubility very finely controllable i st, so that a pH-dependent exposure of the active substance-containing core area of the dosage form can be provided according to the invention for each section of the intestine, in particular the small intestine (duodenum, jejunum and ileum). The provision of a targeted release at a specific site of action or target site, 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 , which are contained in such building substances, limited. Other mechanisms can also be implemented as an alternative or in addition. According to the invention, the volume increments can be printed in such a way that one or more layers of volume increments result, for example directly on an active substance-containing core area or on one or more intermediate layer(s), the structural substance of which 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, for example, starches or celluloses. Such layers preferably serve to release active ingredients in the colon. In preferred embodiments, the layers mentioned above, eg pH-dependent degraded layers (one or more) and bacterially degradable layers, can be combined. It is also possible, for example, to print dosage forms for pharmaceutical active substance combinations, in which volume increments with a first active substance are arranged in a core area, 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, after which one or several layers follow, which contain (or consist of) one or more pH-dependent degradable polymer(s) in the structural substance. Alternatively, of course, in such an embodiment with multiple drug-targeting layers, only the core area can also contain one or more active ingredients.

Since the preferred jetting method can also be carried out under sterile conditions, the printing method according to the invention can also be used to provide implants and/or active substance-releasing injections or active substance depots.

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

The binding between the individual applied volume increments can take place 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, which can be carried out by various mechanisms such as simple cooling and/or chemically by 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 Printing device can be supplied such as. A light source, preferably a laser device. The curing by the binder can also take place chemically by means of corresponding starter molecules and/or light of a suitable wavelength, the latter in turn preferably being emitted with the aid of a laser device. In a further embodiment, the fluid of the volume increment can contain one or more starting compounds, typically monomers, one or more polymers and after the application of the voxel, a polymerization is initiated by suitable means such as light, heat or other polymerization initiators, which applied voxel hardens and connects or glued to neighboring voxels.

With regard to further preferred embodiments and details of the preferred jetting process and thus printed dosage forms, 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 that are flowable at the printing temperature and in which the pharmaceutical active substance(s) is/are present are, for example, generally for hot melt extrusion (HME) in both extrusion and jetting processes ) usable carriers such as low-melting waxes and polymers. In addition to the low-melting carrier, the HME mixture or, in general, the volume increment mixture can contain other processing agents and auxiliaries 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 (support: pages 917 to 919, in particular table 1; plasticizers: pages 917 and 920, in particular table 2), where in the present description express/s verbis to those mentioned passages is referred to.

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

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

(b) depositing an array of spots of build substance on the build platform, which spots may or may not overlap or touch; or

(c) at least semi-solidifying, preferably solidifying, the spots of builder applied in step (b);

(d) applying a further arrangement of spots onto 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

(e) repeating steps (b) through (d) until the dosage form is formed

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

As already mentioned above, dosage forms can be produced with the aid of the invention, with structural substances containing at least one pharmaceutical active ingredient. In preferred embodiments, synergistic combinations of 2 or more active pharmaceutical ingredients are provided, which can be present in a single building substance. In another embodiment, different active ingredients can be present in different building materials.

The active substances in the context of the preferred spot printing process can be present in groups of structural substances which form the applied spots. Thus, according to the invention, an active substance can be present in a structural substance from which a first group of spots are formed and one (or more) other active substance(s) can be contained in another group of spots (i.e. there are at least two structural substances which form the or Contain the respective active substances), the various active substances are preferably contained in different structural substances. It is possible that the respective structural substances, with the exception of the active ingredient(s), can otherwise be the same or different, e.g. depending on the active ingredient in question, in order to have properties tailored to it, such as pH value, solubility, consistency, ionic environment, particle size, color , viscosity, dissolution rate, temperature, isotonicity, etc. to provide. In certain embodiments of the invention, combinations of 2 or more pharmaceutical active substances are provided, in which, for example, a pharmaceutical active substance intended for a specific indication is contained in a building substance and another pharmaceutical active substance is present in the same or a different building substance, such as one of the first active substance any potentially caused side effect is at least reduced, at best suppressed, which represents a particularly preferred embodiment of the preferred spot printing process.

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 in a common section of the dosage form, so that the spots of the same group at least partially adjoin one another on at least one side. The spots with the same active substance or with the same active substance combination or with the same active substance concentration preferably each form at least one common section such as (e.g. at least one common layer or at least one continuous part of at least one layer, which can be oriented horizontally or vertically, based on the longest dimension of the dosage form. In other embodiments, spots with the same active ingredient, the same combination of active ingredients or the same concentration of active ingredients can also be combined in several sections (eg 2 or more layers and/or partial 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 a certain section contain a burst-release substance, with a method for forming a burst-release embodiment is preferably designed such that the spots of the burst release sections are applied in such a way that the burst release sections enclose the spot sections without burst release means in the structural substance, i.e. at least one, preferably several layers of spots burst release substance(s) in the constituent(s) in each dimension of the dosage form surrounding the portions of the dosage form without a burst release function).

Preferably, the printer provided for the preferred spot printing method within the scope of the invention has at least one print head, which is connected to a reservoir with the building substance, so that the at least one print head for removing a quantity of the building substance for applying the building substance in the steps (b) to (e) is competent. The reservoir can be designed in different ways depending on the type and consistency of the structural substance. Thus, in the case of liquid building substances, the reservoir can be a liquid container which is connected to the print head via a line for the building substance, through which it is transported, usually pumped, to the print head. In another embodiment, the building substance in the reservoir can be in solid, liquid or semi-solid form, for example as a powder or granules, with a transport mechanism feeding the solid or semi-solid building substance to the print head. In this embodiment, the print head typically has a heating or melting device, which converts the building substance into an at least flowable, in preferred embodiments liquid form, which is then discharged from the print head through a usually present output device as a volume unit forming a spot on the building platform the construction platform is issued, i.e. printed.

In another embodiment of the preferred spot printing process, the building substance can also be in the form of a solid or at least semi-solid filament, the filament being present, for example, in a feed duct or feed tube forming the reservoir. These reservoir shapes can be designed in different ways, with completely solid filament structure substances usually being provided in linear configurations. Preferred filament build-up substances are mostly elongated, cylindrical structures that are typically more or less elastic and can therefore also be accommodated in curved, for example spiral-shaped, reservoir coils and can be 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.

In the case of liquid builders, the print head may include piezoelectrically operated means for dispensing the unit volume so that the builder is dispensed as in an ink jet 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 given below) is usually applied using known techniques such as piezoelectric dispensers, for example, to at least a portion of the surface of a dosage form created by the above steps in 3D printing, for example in an additional step (vi). , wherein the liquid is usually dried or fixed in some other way on the at least one portion of the surface (e.g. chemically, physically and/or by the action of 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 (which of course can be followed by a final 2D printed layer).

In another preferred embodiment, the printer has more than one printhead, with 2 to 10 printheads being particularly preferred. Embodiments of the invention with multiple print heads can serve different functions: In one embodiment, it is provided that more than one print head is used to print on a unit of the dosage form, eg to print different structural substances with the different properties as explained above. In an embodiment with multiple printers, 3D and 2D print heads can also be provided, it also being possible, as explained below, for print heads that can be used according to the invention to be designed both for 3D printing and for 2D printing. It is further provided according to the invention to use more than one print head in order to print several dosage forms at the same time. It is of course also according to the invention possible to print several different dosage forms at the same time, i.e. print head sets are formed, so to speak, or at least addressed as sets, which print simultaneously with different structural substances on several dosage forms, whereby the dosage forms printed at the same time can be the same or different in their structure. The number of print heads can therefore also go well beyond 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 for removing a quantity of the building substance for applying the building substance in steps (ii) to (v) is qualified. The above reservoir configurations can be the same or different for the print heads, independently of one another.

The spots are therefore preferably produced according to the invention by applying a volume unit of the building substance, with a volume unit preferably having a volume of 20 μl to 30 μl. If necessary, several volume units can of course also be applied one after the other.

According to a further preferred embodiment of the sports printing process, the print head or, in the case of a plurality of 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 has at least one or more 3D print heads and, if required, a 2D print head. 3D print heads are designed for the application of semi-solid and molten building substances, while 2D print heads are designed for the application of building substances that are already liquid without heating in the print head, such as inks or active substance solutions, active substance emulsions and active substance suspensions.

In a preferred embodiment, the spots are applied in such a way that in step (b) and the further steps (b) (according to step (e) of the method according to the invention) with the in the previous step (step (b) or each step ( b) of the further construction steps according to step (e)) overlaps the used up spots. This embodiment thus results in a form of administration which can form a particularly stable arrangement in the sense of a brick arrangement of the spots applied if the spots of one layer have a complete overlap with the preceding layer. On the other hand, by applying a layer of spots partially overlapping the previous layer, a particularly easy spaced arrangement becomes possible 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, e.g. a human patient, can be controlled by creating a larger surface area of the dosage form exposed to the surrounding environment,

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

The solidification (at least in a semi-solid state of the printed structural substance and the binding 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 binding between such spots can be strengthened by the solidification the application to the carrier 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 structural substance, e.g. a dispersion or a solution, that after the application of the Spots causes this to harden, with the hardening by the binding agent being able to take place, for example, by heat, which can be supplied by a suitable heat source in the printing device, such as, for example, a light source, preferably a laser device can also be done chemically by appropriate starter molecules and/or light of a suitable wavelength, the latter in turn preferably being emitted with the aid of a laser device. In a further embodiment, the building substance can contain one or more starting compounds, typically monomers, one or more polymers, and after the application of the spot(s), a polymerization is initiated by suitable means such as, for example, again light, heat or other polymerization initiators, which each applied spot hardens and connects or glued to neighboring spots.

Suitable carrier materials which are flowable at the printing temperature and in which the active ingredient(s) are present are also in the case of the preferred spor printing process, for example generally suitable for hot melt extrusion (HME) carriers such as low melting waxes and polymers. The HME mixture or in general In addition to the low-melting carrier, the building substance mixture can contain other processing agents and auxiliaries such as binders, plasticizers, antioxidants, fragrances, sweeteners or the like. Suitable HME carriers and plasticizers are known to those skilled in the art and are described, for example, in Crowley et al. (2007) Drug Development and Industrial Pharmacy, 33, 909-926 (support: pages 917 to 919, in particular table 1; plasticizer: pages 917 and 920, in particular table 2), whereby also in the present description of the preferred spot Printing process express/s unless reference is made to the passages mentioned.

The method according to the invention is not limited to a complete DeWovo structure of dosage forms or medical products. The method can also be applied to objects already present on the assembly device. This includes, for example, dosage forms previously produced conventionally or in some other way, which are to be modified by the present method, for example, or objects free of active substances (also called placebo carriers) on which volume increments containing active substances are printed in a manner according to the invention. For example, films without active ingredients or other flat materials such as edible paper can be provided in order to provide ODF (orally degradable film or orally dissolvable film) products containing active ingredients. In other embodiments, submitted paving materials can bpsw. are printed with volume increments according to the invention, which contain, for example, active ingredients that promote wound healing. In further embodiments, placebo carriers, which were produced, for example, by a fused layer modeling method, can be printed using the method according to the invention with API-containing volume increments and subsequent printing of solvent-containing liquids, with the printed layers being able to alternate.

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. A calculated three-dimensional image of the dosage form to be printed is thus typically created, for example with the aid of a common CAD program. The computer-generated reproduction of the object to be printed can also be done by scanning an already existing dosage form. In the present method, the computer-generated model image is then subdivided into the desired, in principle freely selectable volume increments (voxels), spots or desired filament elements, the resolution of the real object increasing the smaller the volume increments are. Each individual volume increment can, for example, have an active ingredient, carrier or base substance or carrier or base compositions and/or other auxiliaries such as coloring substances and other materials that may be required as well assigned to their quantity (concentration in the volume increment) 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.

In a particularly preferred embodiment, the method according to the invention in step (3) and/or step(s) (6) also includes the application of 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 preferred jetting process, and/or by another method, such as, for example, by two-dimensional printing as in inkjet printing, on the dosage form or on at least a portion thereof in such a way that the substance applied 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 substance. It is preferred to apply the colored substance(s) together with volume increments containing pharmaceutical active ingredients. In one embodiment, a substance can mark the area(s) or sections to which the respective active ingredient has been applied. This embodiment can therefore convey the information about the active ingredients in the object and their distribution in the complete object by color coding. In a further development of this embodiment of the invention, different amounts or concentrations of the respective active substance can be deposited in the sections containing the active substance, which in turn are reflected by the concentration of the relevant colored substance.

Of course, different color substances can also be mixed, e.g. in a voxel, so that the entire visible spectrum can generally be used by selecting the mixture(s) appropriately.

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

The information structure brought about by the color substance(s) can depict diverse information, in which case several different information structures can also be used due to different color substances, which can essentially be freely selected and combined. In particular, it is provided according to the invention 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(s) present in the dosage form and/or about the administration time or period of administration provided for a dosage form and/or or via that for the dosage form planned intake date and/or patient-related data (e.g. name, age, gender, medication and disease(s) of the patient) and/or the payer and/or the treating doctor and/or the pharmaceutical company providing the dosage form and/or via the medical facility issuing the dosage form (or a medical device).

The information structure can be selected from a wide range of possible applications. The substance or substances 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, planar patterns, etc. can also be printed, with the preferred embodiment of voxel printing fundamentally offering the most diverse possibilities. The printed image of the code can thus contain the active ingredient and at the same time encodes the desired data, as described above, about the patient, doctor, pharmacist and/or medical or pharmaceutical specialist.

It is apparent to the person skilled in the art that, depending on the specific additive manufacturing process selected, the colored substance(s) that may be present can be present together with the pharmaceutical active ingredient(s) in the respective printed base composition. In the present method it is preferred that the coloring matter (or several thereof) is present, preferably together with the active ingredient(s), in the builder matter intended for a given volume increment.

As already explained above, the dosage form can contain a wide variety of information structures, preferably those that are mentioned in the method described above.

Active substance-containing objects that can be printed with the method 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, dispersing tablets, sustained-release tablets, vaginal tablets and suppositories, eye tablets, coated tablets, matrix tablets, chewable tablets, film-coated tablets, modified-release tablets, coated tablets and enteric coated tablets and drug abuse deterrent tablets.

Other particularly suitable objects that are considered in the context of the present invention Dosage form of active pharmaceutical ingredients are medicinal products such as topical dosage forms containing active ingredients, contact lenses, plasters, which preferably release the active ingredient(s) for local application.

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

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

As set out in the optional step (7) of the method, the steps of analysis (4), adjustment of the administration-relevant parameter(s) of the active substance or active substances (5) and printing of the dosage form(s) (6) can be carried out based on the/ of the adapted parameter(s) are repeated, which is preferred according to the invention, in particular in order to continuously adapt the administration form(s) to the possibly changing individual and disease-related parameters.

It is 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. In certain embodiments, an extrusion process (e.g. the preferred process explained in more detail above or another 3D/2D extrusion printing process known per se) can be used in step (3) and jetting in one or more step(s) (6). method (e.g. the process of a preferred embodiment described in more detail above) or a spot printing process (e.g. the method described in more detail above), or vice versa, with all possible combinations being selectable, in particular also depending on the administration-relevant parameters to be adjusted. Based on the example of immunosuppressants, a (first) dosage form is printed based on the analysis of the individual and disease-related parameters by selecting at least one administration-relevant parameter (such as the dose of one or more of the immunosuppressants) (which according to the invention contains one or more of the immunosuppressants mentioned by way of example) either based on the initial parameter (if new medication takes place (step (1a)) or another active ingredient was selected (step (1b)) or based on the changed parameter compared to the previous medication. Based on the above examples Immunosuppressants, it is possible according to the invention that three different dosage forms are printed (one dosage form for each of the three immunosuppressive classes mentioned) or two or all three immunosuppressants are combined in one dosage form, with the usual appropriate release properties and/or suitable separating layers, if required, can be included in the printing process in a multiple dosage form, as described in detail in the context 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 to carry out a patient-optimized up-titration and/or down-titration of one or more active substances.

After analysis of the individual and disease-related parameters of the patient under therapy with the dosage form(s) initially printed according to the invention, one or more parameters relevant to administration are adjusted based on the analysis and one or more dosage forms of the immunosuppressants are printed again in order to optimize the immunosuppression therapy and adapt it to the current ones Adapt requirements so that the success of the therapy improves in the long term, in the case of immunosuppressants in the context of preventing transplant rejection, i.e. the survival of the transplant can be extended.

In addition to steps (3) and (6), which are preferably carried out with computer assistance, as already described above, the further steps of the method according to the invention are preferably also designed with computer assistance.

According to the invention, the analysis in step (1) and in step(s) (4) is computer-aided, with the respective influencing parameters (ie individual and/or disease-related parameters) for dose adjustment being able to be specified by the doctor or pharmacist . Possible influencing parameters have already been explained above and include, for example, age, weight, body surface area, size, liver status, kidney stature, Metabolic influences, general condition of the patient, gender, previous illnesses, social status and adherence to therapy, drug safety, adherence, drug €, drug concentration(s), intolerances, allergies, interactions and intake compliance(s).

The algorithm is calculated using statistical evaluation and questionnaires, which are calculated using mathematical models and thus calculate the optimal dose for a wide range of patients who are treated with a specific active ingredient. The formulation of the personalized medicines can also have an impact on the evaluation and the resulting dose adjustment.

According to the invention, at least one administration-relevant parameter is also determined in step (2) and the at least one administration-relevant parameter is adjusted in step(s) (5) with computer assistance. For this purpose, questionnaires and therapy success factors are usually determined, which then correspond to the variable parameters and vital data of the patient. These form the basis for the subsequent evaluation via a AI learning system.

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 Method for producing patient-optimized pharmaceutical dosage forms, comprising the steps:

(1) analyzing individual and/or disease-related data of a patient suffering from a disease state, where the patient may be exposed to an agent to treat the patient's disease state;

(1a) optionally selecting one or more agents to treat the patient's disease state if the patient is not already exposed to an agent to treat the disease state; or

(5) adjusting at least one administration-relevant parameter of the active ingredient or active ingredients 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 the at least one administration-relevant parameter adapted in step (5) by means of 3D and/or 2D printing; and possibly

(7) Repeat steps (4) through (6).

2. The method according to claim 1, wherein the administration-relevant parameter or parameters from the group consisting of the amount of active substance or active substances per unit dose of the dosage form, release kinetics of the active substance or active substances from the dosage form at the administration site and/or via the path of the dosage form in the Patients, concentration of the active substance or substances in the dosage form, concentration distribution of the active substance or substances 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 substance or substances in the dosage form and combinations of two or more thereof.

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

4. The method according to any one of the preceding claims, wherein the disease-related parameters 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 fat values, blood sugar levels, vitamin metabolism data, metabolic interactions, medication plan, side effect profiles, urine status, virological findings, bacteriological findings, findings of fungal infestation, parasitic findings, stage of the disease, course of the disease and combinations of two or more thereof.

5. The method according to any one of the preceding claims, wherein the disease state from the group consisting of diseases of internal organs, rheumatological diseases, oncological diseases, cardiac

34 circulatory diseases, neurological diseases and hematological diseases. The method of claim 5, wherein the visceral disease is selected from the group consisting of kidney, liver and pancreas transplants. Method according to claim 6, wherein the active substance or active substances is/are selected from the group consisting of glucocorticoids, calcineurin inhibitors and inosine monophosphate dehydrogenase inhibitors. A method according to claim 5, wherein the disease state is a rheumatological disease and the active ingredient(s) is/are selected from the group consisting of glucocorticoids, calcineurin inhibitors, inosine monophosphate dehydrogenase inhibitors and tyrosine kinase inhibitors. A method according to claim 5, wherein the disease state is an oncological disease and the active agent(s) is/are selected from tyrosine kinase inhibitors. A method according to claim 5, wherein the neurological disorder is Parkinson's disease and the active ingredient(s) is/are selected from dopamine antagonists. The method of claim 5, wherein the hematological disorder is anemia. Method according to claim 11, wherein the active substance or substances is or 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. A method according to claim 13, wherein the active ingredient(s) is/are selected from the group consisting of antihypertensive drugs and anticoagulants.

15. The method according to 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 antihypertensive drugs are selected from the group consisting of calcium antagonists, beta-blockers, ACE inhibitors, diuretics and AT1 blockers.

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

18. The method as claimed in one of the preceding claims, in which 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. The method as claimed in any 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 takes place with the aid of a computer.