Paste for use in screen printing

Abstract

The present invention generally concerns a paste for carrying an active pharmaceutical ingredient (API), preferably for use in a screen printing process for printing a pharmaceutical composition. The present disclosure further relates to a method for preparing a paste, a pharmaceutical composition, and the use of a paste in an additive manufacturing process.

Description

[0001]May 31, 2024Laxxon Medical AG L173252WO MAJ / Moh / KtaPASTE FOR USE IN SCREEN PRINTING TECHNICAL FIELD The present disclosure generally relates to a paste for carrying an active pharmaceutical5 ingredient (API), preferably for use in a screen printing process for printing apharmaceutical composition. The present disclosure further relates to a method for preparing a paste, a pharmaceutical composition, and the use of a paste in an additive manufacturing process. BACKGROUND 0 Pharmaceutical manufacturing involves the production of medications in various dosage forms, including tablets, capsules, injectables, and topical formulations. Since the oral route is the most convenient administration route for the patient, new techniques to produce solid orals dosage forms are of greatest interest in pharmaceutical manufacturing. To date, the standard process in pharmaceutical5 manufacturing focuses on tablet pressing processes. One of the most common methodsfor producing solid oral dosage forms such as tablets is tablet pressing, i.e. thecompression of powdered or granulated pharmaceutical ingredients into compact, discrete units. This process is carried out using specialized tablet presses, which exert controlled pressure to form tablets of uniform size, shape, and weight. 0 During this process of tablet pressing, ensuring consistent tablet hardness throughoutthe batch is challenging. Variations in powder properties, compression force, andmachine settings lead to tablets with different hardness levels. The hardness level is aparameter that directly impacts the dissolution and drug release profiles. Moreover,5 several active pharmaceutical ingredients are not processable due to their low flowability. Furthermore, the uniform distribution of active pharmaceutical ingredients (APIs) andexcipients in each tablet is highly relevant for dosage accuracy. During tablet pressing,0 variations in powder flow properties and inadequate blending result in content non-uniformity. This directly leads to inconsistent drug delivery within the patient, whichcan impair the therapeutic benefit and patient safety. Moreover, no significantvariations in term of structure and shape are possible, as these parameters are limited by the tablet pressing machine itself.When compressing the powder batch, dust is inevitably generated which posespotential health hazards to operators. Furthermore, dust generation negatively impacts the efficiency of the manufacturing process as it contaminates the production line, which makes it necessary for additional cleaning steps. These additional steps are costly in terms of time and materials. As a result, the conventional process of tablet pressing has room for improvement, in particular in terms of process efficiency and sustainability.It is known to use screen-printing techniques for producing drug delivery systems. Apaste comprising an API may be applied by a squeegee onto a screen. The screen has open mesh areas which eventually creates the layout of the drug delivery system. By flooding the screen with a homogeneous layer of the paste, it is desired that the paste fills the open mesh. By means of a second squeegee, it is desired to squeeze the paste through the mesh onto a substrate or printing plate. Then, a drying step is typically applied. Afterwards, the screen can be lifted incrementally by the height of the driedlayer, before the cycle is repeated to build the drug delivery system.It is, however, challenging to prepare a paste suitable for the use in screen-printing a drug delivery system, particularly for printing a pharmaceutical composition such as adrug delivery system. It is particularly challenging to provide a paste comprising an APIand having suitable characteristics for use in a screen printing process. The viscosity of the paste must be such that it can be pressed through the mesh of the screen printer, and such that it does not lose the printed structure after the printing / squeezing and before drying. Against this background, an object of the present invention is to improve the deficiencies of the prior art at least partially and to address one or more or all of the above-mentioned shortcomings of the prior art. It is a particular object of the present invention to provide an improved paste for use inscreen printing pharmaceutical compositions.SUMMARY OF THE INVENTION The above-mentioned objects are at least partially achieved by the subject-matter of the independent claims. Preferred embodiments are set out in the dependent claims, and other suitable aspects of the present invention are described through the overall disclosure of the present application. It is noted that the headlines in the present disclosure are provided solely for the purpose to assist in keeping an overview during reading. The headlines do not mean that features of the respective embodiments cannot be combined.A first aspect of the present disclosure is directed to a paste for carrying an activepharmaceutical ingredient (API), preferably for use in a screen printing process forprinting a pharmaceutical composition. According to the first aspect of the presentdisclosure, the paste comprises: the API, a binder, a filler, and a solvent. The paste is anaqueous dispersion. The paste is for carrying an API, i.e. the API may be fully dissolved in and / or dispersedthroughout the paste. When using the paste to form an article, the resulting article alsocomprises the API. For example, when using the paste in a screen printing process, thepaste carrying the API is screen-printed to produce an article which is build up (at least partially) by the paste and thus also comprises the API.A paste according to the present disclosure is a substrate that may be used in anadditive manufacturing process. The paste may be a solid-liquid mixture and may beplastically deformable and adhesive. However, it is conceivable that the paste is non- adhesive. It has been found that the paste of the present disclosure allows for a scalable manufacturing process. This reaches from small-scale personalized approaches up to mass market production capacity. Furthermore, by way of using the paste during screen printing, no formation of dust isgenerated. This is crucial when handling high potent APIs, which may lead todeviations of the API content, especially when the therapeutic breadth of the API is narrow. Furthermore, the paste of the present invention allows for pharmaceuticalcompositions that are highly versatile in structure, integrity and geometry.Specifically, the paste may be used as a substrate in the process of screen printing. In particular, the paste may allow for the formation of pharmaceutical formulations applicable to screen printing. Specifically, the paste may allow for versatile release properties due to wide range of possible excipients and excipient contents in the paste. By using the paste, no limitation of excipients from conventional tableting exist,allowing that all known excipients may be processed in the paste of the presentinvention. In this manner, standard formulations can be used in the paste for screenprinting, allowing for a more efficient and safe manufacturing process. Moreover, customized formulations are feasible in a time and cost-efficient manner. Furthermore, when targeting high potent API formulations, e.g. with a narrow therapeutic breadth, the paste allows for precise and safe dosing of the API.Furthermore, there are no limitations in the choice of the API, as almost any API can beused independent from its solubility or flow ability. This is also true for the choice ofthe excipients. Screen printing may be understood by the skilled person as a process, particularly a manufacturing process in the context of additive manufacturing. It may involve the repetition of defined cycles, wherein each of the cycles can be divided into different steps. For example, one step may relate to the positioning of the printing screen abovethe substrate plate. A paste may then be urged, e.g. with the help of a floodingsqueegee, to fill the mesh openings. Afterwards, the printing squeegee may be pressedinto the mesh to ensure contact with the printing plate. Behind the squeegee, the screenmay snap back to its initial position whereas the paste remains on the substrate. If thepaste has beneficial properties, among others shear-thinning properties, the movementand thus the force applied by the squeegee results in a lower viscosity of the paste.Accordingly, the paste easily penetrates through the meshes, which leads to animproved and superior printing behavior. Furthermore, if the paste is non-thixotropic,a fast reformation of its initial viscosity occurs once the squeegee force is released,which allows for a stable form until drying. The subsequent drying may be achieved byconvection with e.g. dry and heated air. Afterwards, the substrate plate may return tothe printing station, where the printing screen may be lifted by the thickness of theprinted layer. Then, the cycle can start all over again and may be repeated until thedesired tablet height is reached. The paste according to the present disclosure shows beneficial properties which allow for usage thereof in a screen-printing process. In particular, the paste has shear- thinning properties. The viscosity of the paste is changing upon stress (when a force is applied, e.g. by the printing squeeze), such that it easily fills the meshes and is able to reach the printing substrate. After leaving the mesh, the viscosity changes back in a very fast manner, almost instantly, such that the printed structure maintains its form. Accordingly, the paste of the present disclosure is well suited for printing articles by means of a screen-printing process.An API may be understood as the biologically active component in a pharmaceuticaldrug that produces a desired therapeutic effect. The API may be solid, or liquid, or ofany form. The paste may comprise more than one API. The pharmaceutical composition which may be produced by means of the paste may besolid, or liquid, or of any form. The pharmaceutical composition may be an oral dosageform, such as a tablet.A binder and / or a filler may be understood as an excipient. The binder and / or the fillermay ensure that the paste obtain its shape and integrity. These excipients may be eitherdry and / or liquid. The binder may ensure that the active pharmaceutical ingredient andthe other excipients present in the paste may be hold together.A filler may allow for an increase in the bulk volume. In this manner, the filler can helpin achieving the desired paste volume and / or weight. Especially, when the amount ofAPI is small, fillers are desirable. A solvent may be any solvent. Preferably the solvent is water. It is not required that thesolvent dissolves all excipients and / or API. In other words, the excipients and / or theAPI may completely dissolve in the solvent. The API and / or the excipients may besoluble in the solvent. It is sufficient that the excipients and / or the API are present ordispersed in the solvent, forming for example a dispersion. This dispersion is preferablyan aqueous dispersion. The solvent may allow for tuning the flow properties of the paste. The inventors have found that in this manner, the paste shows shear thinning properties which are beneficial for use of the paste in a screen-printing process. In particular the shear thinning paste allows for its application in an automated additive manufacturing process.The paste used for the manufacturing of a pharmaceutical composition may be used inthe therapy of any disease, such as Hypertension, Hyperlipidemia, Coronary ArteryDisease, Type 1 / 2 Diabetes, Depression, Anxiety Disorders, Bipolar Disorder, Bacterial Infections, HIV / AIDS, Asthma, Chronic Obstructive Pulmonary Disease (COPD),Gastroesophageal Reflux Disease (GERD), Peptic Ulcer Disease, Epilepsy, Parkinson'sDisease, Hypothyroidism, Osteoarthritis, Rheumatoid Arthritis, Cancer, SystemicLupus Erythematosus, (Benign) Prostatic Hyperplasia, Opioid Dependence orcombination thereof. In this context, the API(s) may be selected from one or more ofAngiotensin-Converting Enzyme (ACE)- inhibitors, beta-blockers, calcium channelblockers, statins, antiplatelet agents, nitrates, metformin, sulfonylureas, DPP-4 inhibitors, selective serotonin / noradrenaline reuptake inhibitors (SSRIs, SNRIs), benzodiazepines, mood stabilizers, antipsychotics, antibiotics, antiretrovirals, (oral) corticosteroids, leukotriene receptor antagonists, bronchodilators, corticosteroids,proton pump inhibitors (PPIs), anticonvulsants, H2-receptor blockers, levodopa,dopamine agonists, levothyroxine, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs),acetaminophen, Disease-Modifying Antirheumatic Drugs (DMARDs), (oral)chemotherapy agents, hormone therapy agents, immunosuppressants, methadone,buprenorphine, alpha-blockers, 5-alpha-reductase inhibitors or the like. In certain embodiments, the paste may comprise one or more of these APIs, and may be free of other APIs. In certain embodiments, the API may not comprise sodium caprate. In certain embodiments, the paste may not comprise sodium caprate. The paste may comprise the binder in an amount of 0.1 to 50 wt. %, preferably 0.2 to 40 wt. %, more preferably 0.3 to 30 wt. %, even more preferably 0.4 to 20 wt. %, most preferably of 0.5 to 10 wt. % of the total mass of the paste. This range of binder has shown the best applicability and processability of the paste foruse in screen printing a pharmaceutical composition. It has been found that the binderused in the paste provides for stabilizing characteristics. In particular, the binder stabilizes the paste, especially the aqueous dispersion. Without intended to be limiting,the binder allows for thickening of the paste and at the same time functions as a matrixfor the API. The binder may be a matrix material and / or a thickener.The paste may comprise the filler in an amount of 0.2 to 70 wt. %, preferably 0.4 to 55 wt. %, more preferably 0.6 to 40 wt. %, even more preferably 0.8 to 30 wt. %, mostpreferably of 1.0 to 20 wt. % of the total mass of the paste. The filler may be a matrixmaterial and / or a thickener. For example, as a matrix material, the filler provides astructural framework, which can support and stabilize the API. This matrix caninfluence the release profile, stability, and / or bioavailability of the API. As a thickener,the filler can increase the viscosity of the paste. This can improve the stability of thepaste, as well as its texture. In this manner, the filler may provide for the rightconsistency for the paste. The filler can differ from the binder e.g. in its function. Forexample, the binder may be intended to hold the paste excipients together. A filler maybe used to e.g. ‘fill’ the paste and achieve the desired final weight. For example, if onlythe API would be present in a formulation, the formulation would likely have a too littlemass to be further processed. The preferred range of filler has shown the bestapplicability and processability of the paste for use in screen printing, in particular of apharmaceutical composition. The paste may comprise the solvent in an amount of 20 to 70 wt. %, preferably 15 to 65wt. %, more preferably 20 to 60 wt. % of the total mass of the paste. The solvent may bewater.The solvent allows for tuning the flow and rheological properties and achievingsuperior characteristics of the paste. Specifically, the paste obtains elastic properties. Furthermore, the inventors have found that this range of the solvent allows for beneficial shear thinning properties of the paste. Moreover, the paste has low to no thixotropy, that result in superior flooding of the paste as well as an improved printingbehavior. These beneficial properties allow the paste to be used in a screen printingprocess. In particular, these rheological properties provide for the resulting precisepattern, homogenous surfaces and heigh buildup during screen printing.The binder may be selected from one or more of hydroxy propyl cellulose, HPC,hydroxy propyl methyl cellulose, HPMC, starch, alpha-D-lactose monohydrate,carbomere, algin, blanose, natrosol and polyethylene glycol.The filler may be selected from one or more of microcrystalline cellulose, starch, lactoseand maltose.In particular, several fillers regularly used in tablet pressing processes are applicablefillers for the paste of the present disclosure. In this manner, known formulations canbe used for the paste, which allows for an improved and efficient substrate for the production of pharmaceutical compositions.The paste may have a particle size D90 of 1 to 50 µm, preferably of 2 to 40 µm, morepreferably of 3 to 30 µm, even more preferably of 4 to 20 µm, most preferably of 5 to 15µm. The particle size D90 may be understood as an indication of the diameter of a particle at which 90% of the cumulative particle mass is smaller. In other words, 90% of the total mass of the particles have a diameter smaller than the D90 value. It has been found that this particle size range facilitates the application of the paste in ascreen printing process. The particle size D90 may be of at most 250 µm, preferably ofat most 180 µm, more preferably of at most 170 µm, even more preferably of at most160 µm, most preferably 150 µm. The particle size D90 may be chosen in view of thesize of the mesh of the screen used during the screen printing process.The D90 value for the particle size distribution may be measured using dynamic lightscattering (DLS). The particle size distribution may be measured with a particle sizeanalyzer (e.g. PSA 990 D; Anton Paar) via dry dispersion method, a light attenuation of0.5-8 %, according to venturi at 43 Hz, 60% and 500 mbar.Dry dispersion may be performed by dispersing and separating the particles withoutusing a liquid, but instead, by using airflow. This can also be performed by usingmechanical means. The sample may be thoroughly mixed before measurement. Theventuri principle may be used to disperse the particles by creating a vacuum through aconstriction in the airflow, which draws the particles into the air and separates them. The Fraunhofer theory may be applied to determine the particle size distribution basedon light scattering. The light attenuation may be between 0.5 and 8%, the shaking mayoccur at a frequency of 43 Hz with 60% intensity, and the applied pressure may be 500 mbar. The paste may have a viscosity in the range of 10 to 5000 Pa·s, preferably 200 to 3000 Pa·s, more preferably 500 to 2000 Pa·s at a shear rate of 0.1 s-1at 25 °C.“Viscosity” as referred to in this disclosure may be understood as the dynamic viscosity.The viscosity of the paste may be measured using an oscillatory rheometer. Inparticular, a Kinexus Rheometer may be used, which comprises a plate-plate geometryequipped with a passive solvent trap. This geometry accounts for the Weissenberg-effect of elastic pastes which can be minimized using a plate-plate setup instead of a cone-plate setup. The passive solvent trap which is filled with water prevents the drying of the paste during longer measurements. The gap size may be set to 500 µm (> 10 times particle size). The inventors have found that the specific range of viscosity has shown to be the most beneficial viscosity for the paste to be applied to additive manufacturing processes, such as screen printing.The paste may have a thixotropy index in the range of 1 to 200, preferably 10 to 160,more preferably 20 to 100 at shear rates of 0.1 s-1 and 100 s-1 at 25°C.The thixotropy index may be understood as a measure of thixotropy, describing theproperty of the paste to become less viscous (e.g. more fluid-like) when subjected to agitation or shearing forces and to return to a more viscous (gel-like) state when theagitation ceases. The thixotropy index quantifies the degree of thixotropy in a material.It is expressed as the ratio of the viscosity after a period of agitation to the viscositybefore agitation. For example, a higher thixotropy index indicates a greater degree ofthixotropy in the material and vice versa.The thixotropy index of the paste may be measured using an oscillatory rheometer. Inparticular, a Kinexus Rheometer may be used, which comprises a plate-plate geometryequipped with a passive solvent trap. After a low shear rate of 0.1 s-1is applied for 60 sec, a high shear rate of 100 s-1may be applied for 30 sec to simulate theflooding / printing process. Subsequently, the shear rate may be lowered again to 0.1 s-1and the structural rebuild may be monitored via the viscosity.The paste may be elastic and may have a complex shear strain value in the range of 0.01% to 10 %, preferably 0.1 % to 9 %, more preferably 1 % to 8 % at a phase angle of 1when measuring the strain-controlled amplitude sweep at 1 Hz. The complex shear strain value of the paste may be measured using an oscillatoryrheometer. In particular, a Kinexus Rheometer may be used, which comprises a plate-plate geometry equipped with a passive solvent trap. After a low shear rate of 0.1 s-1is applied for 60 sec, a high shear rate of 100 s-1may be applied for 30 sec to simulate theflooding / printing process. Subsequently, the shear rate may be lowered again to 0.1 s-1and the structural rebuild may be monitored via the viscosity. It has been found that the paste with the specific shear strain value has improved deformability, that is beneficial for its application in an additive manufacturing process. The paste may comprise the API in an amount of 5 to 65 wt. %, preferably of 7 to 60 wt. %, more preferably of 10 to 50 wt. %, most preferably 12 to 40 wt. % of the total mass of the paste. The inventors have found that this specific range of API has shown to be the most beneficial range for the processability of the paste.The paste may comprise an anti-tacking agent in an amount of 0.05 to 6 wt. %,preferably 0.1 to 5 wt. %, more preferably 0.15 to 4 wt. %, most preferably 0.2 to 3 wt. % of the total mass of the paste. It has been shown that the specific range of anti-tacking agent has shown to provide for a non-tacking paste, which is desirable for the application in an additive manufacturing process.The paste may comprise a humectant in an amount of 0.3 to 8 wt. %, preferably 0.5 to 7wt. %, more preferably of 0.7 to 6 wt. %, most preferably 1 to 5 wt. % of the total mass of the paste.The use of the humectant in the specific range prevents the paste to dry out, which isundesirable when used during screen printing.The paste may comprise an anti-foaming agent in an amount of 0.05 to 4 wt. %,preferably 0.1 to 3 wt. %, more preferably of 0.15 to 2 wt. %, most preferably of 0.2 to 1.5 wt. % of the total mass of the paste. By using an anti-foaming agent, the paste allows for a bubble-free dispersion, in particular during the processing in screen printing.The paste may comprise an antioxidant in an amount of 0.01 to 1 wt. % of the totalmass of the paste. In this manner, the paste prevents the oxidation of the excipients and / or the API.The paste may comprise a disintegrant in an amount of 1 to 6 wt. % of the total mass ofthe paste. By using the disintegrant, the disintegration speed of the paste, and inparticular of the pharmaceutical composition, is increased.The paste may comprise a plasticizer in an amount of 0.5 to 1 wt. % of the total mass ofthe paste. The plasticizer allows for an increased pliability and softness. Moreover, theplasticizer impacts the release of the API, particularly in acid media, e.g. in the stomachof a patient.The anti-tacking agent may be selected from one or more of talc and magnesiumstearate. The anti-tacking agent impacts the physical properties when handling thepaste. In particular, the anti-tacking agent allows for a non-sticky paste.The humectant may be selected from one or more of glycerol, xylitol and / or D(-)-sorbitol. The anti-foaming agent may be selected from one or more of silicon oil andglyceryl monostearate. The antioxidant may be selected from one or more of L-ascorbicacid, citric acid and / or tocopherole. The disintegrant may be selected from one or moreof polyplasdone, polyvinylpyrrolidone, croscarmellose sodium and / or primellose. Theplasticizer may be selected from one or more of triethyl citrate, polyethylene glycol,propylene glycol, glycerol triacetin and / or miglyol. It has been found that commonexcipients widely used for tablet pressing are processable in the form of the pasteaccording to present invention. In this manner, most pharmaceutical compositions canbe reproduced by using the paste according to the present invention in screen printing.In one specific embodiment, the paste may comprise the binder in an amount of 0.5 to5 wt. %, preferably 0.8 to 4 wt. %, more preferably from 1 to 3 wt. % of the total mass ofthe paste. In this specific embodiment, the paste may comprise the disintegrant in anamount 0.5 to 8 wt. %, preferably 1.5 to 7 wt., more preferably 2.5 to 5 wt. % of the totalmass of the paste. In this specific embodiment, the paste may comprise the filler in anamount of 6 to 20 wt. %, preferably 8 to 18 wt. %, more preferably 10 to 16 wt. % of thetotal mass of the paste. In this context, the binder may be hydroxy propyl cellulose,HPC, wherein the disintegrant is croscarmellose sodium, and wherein the filler ismannitol. The active pharmaceutical composition may be carbidopa.The inventors have found that this specific formulation allows for the production of an immediate release formulation. Immediate release may relate to a fast or instantaneous release of the API (from the paste itself or from the printed pharmaceutical composition) in acidic, neutral and / or basic media. Preferably, the immediate release takes places in acidic media. For example, this may be when the pharmaceutical composition comes in contact with the gastric media of for example a patient.Accordingly, the paste according to this embodiment can be specifically designed andused based on the desired therapy. In this manner, the therapeutic compliance overall can be increased, which leads to an overall improved therapeutic benefit when using a pharmaceutical composition manufactured by the paste of the present invention. Specifically, the paste according to this embodiment may be used in the treatment of Parkinson’s disease (PD) or PD related diseases.In another specific embodiment, the paste may comprise the binder in an amount of0.5 to 5 wt. % preferably 0.8 to 4 wt. %, more preferably 1 to 3 wt. % of the total mass ofthe paste. In this specific embodiment, the paste may comprise the filler in an amountof 1 to 8 wt. %, preferably 2 to 7 wt. %, more preferably 3 to 6 wt. % of the total mass ofthe paste. In this specific embodiment, the paste may comprise the plasticizer in anamount of 0.5 to 5 wt. %, preferably 0.8 to 4 wt. % of plasticizer, more preferably 1 to 3 wt. % of plasticizer of the total mass of the paste. In this context, the binder may beHPC, the filler microcrystalline cellulose, and wherein the plasticizer may be glyceryltriacetate. The API may be levodopa or any API. The API may be entacapone,rasagiline, selegiline, safinamide, amantadine, levodopa, pramipexole, ropinirole, rotigotine, apomorphine, any prodrug or pharmaceutical salt thereof, preferably levodopa. The inventors have found that this specific formulation allows for the production of an extended-release formulation. Extended release may relate to a slow or delayed release of the API (from the paste itself or from the printed pharmaceutical composition) in acidic, neutral and / or basic media. In particular, the paste according to this specificembodiment may be used in the treatment of PD or related diseases. Moreover, theextended release of the API (e.g. levodopa) enables an enhanced bioavailability of theAPI. This is highly desirable as patients treated with levodopa (LD) face LD- or LDrelated tolerance in the long-term. Accordingly, by using the paste according to this specific embodiment, long-term side effects in the treatment of PD can be decreased. Furthermore, as the bioavailability is improved, the total dosage of the API consequently is reduced. This further positively impacts the reduction of side-effects related to the treatment with LD.In one embodiment, the paste may comprise the binder in an amount of 0.5 to 5 wt. %of binder, preferably 0.8 to 4 wt. %, more preferably 1 to 3 wt. % of the total mass of thepaste. In this specific embodiment, the paste may comprise the filler in an amount of 5to 20 wt. %, preferably 8 to 18 wt. %, more preferably 11 to 16 wt. % of the total mass ofthe paste. In this context, the binder may be HPC and starch, and wherein the filler maybe microcrystalline cellulose. The API in this specific embodiment may be levodopa. The inventors have found that this specific formulation allows for the production of an extended-release formulation. Specifically, this extended-release formulation is beneficial for producing a pharmaceutical composition comprising levodopa. By the extended release of levodopa, it has been shown that the bioavailability of levodopa is enhanced. Accordingly, it has been shown that the therapeutic benefit based on the paste according to this specific embodiment was increased.In another specific embodiment, the paste may comprise the binder in an amount of0.4 to 5 wt. %, preferably 0.6 to 4 wt. %, more preferably 0.8 to 3 wt.%, most preferred1 to 2 wt. % of the total mass of the paste. In this context, the binder may be a carbomerpolymer. According to this specific embodiment, the paste (or a respective printedpharmaceutical composition) can be adhered to mucous membranes in the body, e.g. inthe mouth or the whole gastrointestinal tract. In this manner, the release of the API ischanged which may be desirable when designing patient-individual treatments. This can be desirable if the patient for example has limitations in the uptake of the API. Accordingly, by using the paste according to the specific embodiment, the compliance may be increased in the treatment of the patient.In one embodiment, the paste may comprise the binder in an amount of 10 to 20 wt. %,preferably 12 to 18 wt. %, more preferably 14 to 16 wt.% of the total mass of the paste.In this context, the binder may be a pullulan polysaccharide polymer.The binder may be any pH sensitive polymer. The paste according to this specific embodiment allows for an enteric formulation. In particular, the paste (or the respectively printed pharmaceutical composition) releases the API in the enteric environment, e.g. the intestines.In this manner, the paste may protect the API from the acidic environment of e.g. thestomach, which may degrade certain APIs. Moreover, and by using the paste accordingto the specific embodiment, it is prevented that the API causes irritation to thestomach. By using this specific embodiment, the API can pass through the stomachintact and then released in the less acidic environment of e.g. the small intestine.In a second aspect, the present invention relates to a method for preparing a paste,wherein the paste is the paste as described herein. The method comprises the following steps, which are preferably applied in the given order: a) providing the binder and adding it to the solvent;b) stirring the binder and solvent;c) adding the filler;d) optionally adding one or more of a humectant, an anti-tacking agent, ananti-foaming agent, an antioxidant, a plasticizer, and / or a disintegrant; e) adding the active pharmaceutical ingredient;f) mixing the composition;g) homogenizing the mixture. The inventors have found that according to this method, the paste is manufactured in a more efficient and improved process, which reduces costs in term of time and energyand at the same time enhances the precision and accuracy of the manufacturing processof the pharmaceutical composition. In this way, the therapeutic benefit and thus the overall treatment is eventually improved.Step g) of homogenizing the mixture may comprise stirring the mixture with stirringspeeds of between 10-5000 rpm, preferably wherein the stirring speed increases duringthe homogenization. Vacuum may be applied during this step g).It has been found applying the vacuum provides for removing air from the paste and thus improves accuracy in the dosing and printing of the paste.In a third aspect, the present invention relates to a pharmaceutical compositionproduced from a paste as described herein. In a fourth aspect, the present invention relates to the use of the paste disclosed hereinin an additive manufacturing process, in particular for printing a pharmaceuticalcomposition. Screen printing may comprise 3D screen printing or 3D direct screen printing. Screen printing is an additive manufacturing process. In particular, 3D screen printing maycomprise the application of the paste to the screen. A squeegee may be used to force thepaste through the mesh of the screen, depositing it onto the substrate below. The pastemay adhere to the substrate in the shape defined by the stencil. By repeating this step, layers can be built to form the three-dimensional object, e.g. the pharmaceuticalcomposition. A digital design or model of the pharmaceutical composition can beprepared using computer-aided design (CAD) software. The screen may be moved or repositioned between each layer to deposit subsequent layers of paste. In this manner, the pharmaceutical composition can gradually formed in a layer-by-layer fashion. The thickness of each layer and the positioning of the screen can be precisely controlled to achieve the desired geometry and structural integrity.After printing each layer, the deposited paste may undergo a curing or solidificationprocess, e.g. drying, such as evaporation to remove the solvent and to ensure that thepaste hardens and adheres properly to the previous paste layers. The drying maycomprise heat curing, UV curing, or chemical curing. For example, the drying may be evaporation of e.g. water. The printed pharmaceutical composition may undergo additional post-processingsteps. These post-processing steps comprise cleaning, coating, surface finishing, orsupport removal. In this manner, the desired final appearance and properties areachieved. The pharmaceutical composition may be a solid pharmaceutical composition. In particular, the pharmaceutical composition may be an oral dosage form, preferably a tablet. The pharmaceutical composition may have a desired shape. The shape is defined during the printing process. The pharmaceutical composition may comprise more than one paste of the present invention. In this manner, the pharmaceutical composition comprises “layers” of pastes. Accordingly, each of the layers consist of different excipients, that have different release characteristics. In this way, the pharmaceuticalcomposition can be individually designed based on e.g. the patient’s needs, in terms ofAPI, release characteristics, coating, and choice of excipients. Each of the above-described advantages and benefits are valid for all aspects of the present invention. In particular, they can be combined with each embodiment of each aspect. BRIEF DESCRIPTION OF THE DRAWINGSFigure 1: shows the shear rate dependent viscosity of a paste according to anembodiment of the present disclosure;Figure 2: shows the time dependent shear viscosity of the paste of Figure 1;Figure 3: shows the shear strain dependent shear modulus of the paste of Figure 1;Figure 4: a method for preparing a paste according to a preferred embodiment.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTSIn the following, exemplary embodiments of the present invention are described inmore detail. The preparation and the rheological parameters are described in detail for a paste according to an embodiment of the present disclosure. The paste is prepared according to the formulation shown in Table 1 (“Formulation 1”). Formulation 1 Formulation 1 shown in Table 1 represents a general formulation of a paste according to an embodiment. Any API may be used in the formulation. Table 1 Method for preparing the paste GeneralFig. 4 shows a flow chart illustrating the steps of a method 100 for preparing a pasteaccording to a preferred embodiment. The method starts with step 110 of adding thebinder and the solvent into a container. Afterwards, the binder and solvent in thecontainer are stirred in step 120, which is followed by step 130 of adding the filler intothe container. In step 140 a humectant, an anti-tacking agent, an anti-foaming agent, an antioxidant, a plasticizer, and / or a disintegrant are added into the container. Subsequently, in step150, an API is added into the container.After step 150, the content of the container is mixed, which provides for a mixture. In the last step 170, the mixture is homogenized. Preparation of Formulation 1 In particular, the paste according to the formulation 1 is prepared according to the following protocol: The binder is prepared at least 24 h before usage to ensure good and homogenousswelling and no excessive air entrapment. To do so, 960 mL of distilled water is filled ina clean container to which 40 g of Polyox WSR N12K is added slowly under stirring at600 rpm with a Heidolph mixer (Hei-Torque Precision 400).All ingredients are weighted in a vessel. Then, the ingredients are added to the container,starting with the binder, then adding all liquid ingredients, followed by all solid orpowdery ingredients. Subsequently, the API is added, and the specified amount of water is added last.Subsequently, the mixture is homogenized with a Herbst planetary mixer HRV-S 2 DPequipped with a stirring bar mixing tool, a scraper, and a dissolver. In this context, thefollowing parameters in Table 2 are used. After 5 minutes of stirring at the starting speed,the speed is increased to the end value for 20 min. To remove entrapped air and preventbubble formation in the printing process, vacuum is applied for the duration of mixing.For applying the vacuum, a slow and steady decrease of the pressure in 0.1 bar steps is applied every 2-5 minutes until reaching -0.95 bar. It will be appreciated that the vacuum may also be applied only during part of the mixing. The mixing parameter for the paste preparation with the Herbst planetary mixer is summarized in Table 2. Table 2 Starting value End valueStirrer 50 rpm 200 rpmDissolver 500 rpm 2000 rpmScraper - -Vacuum (Atmospheric pressure) -0.900 mbarFig. 1 shows the shear rate dependent viscosity of a paste according to this disclosure.While subjected to increasing shear forces the paste´s viscosity decreases (shear thinningbehavior). In detail, Fig. 1 shows the shear-viscosity curve of the paste according toformulation 1. The shear-viscosity curve is measured based on the shear rate dependentviscosity of the paste. As can be seen, a shear thinning behavior can be observed. Thishelps to facilitate extrusion of the paste during the additive manufacturing process, e.g.extrusion through the mesh. Shear thinning, also known as pseudoplasticity, is aproperty exhibited by the paste where their viscosity decreases under shear stress. Inother words, when the paste is subjected to an applied force or stress, such as stirring,shaking, or flowing, the resistance to flow decreases, making the paste less viscous andmore fluid-like.The shear thinning is quantified by fitting viscosity vs. shear rate to a power law where η is the viscosity, K is a consistency factor, γ is the shear rate and n is the shear thinning parameter. A lower shear thinning parameter n equals a more pronounced liquification under shear stress, which facilitates the extrusion through the mesh.As can be seen, the paste shows that the viscosity of the paste decreases when increasingthe shear rate. Specifically, the paste has a low shear thinning parameter n. Fig.2 shows the shear rate dependent viscosity of two processable pastes with different content ratios according to this disclosure. The performance of the paste of the upper data points is superior to the paste of the lower data points due to a higher thixotropic index and a faster regain of the initial viscosity after high shear rates were applied. (Shear rate 0.1 s-1 for 90 sec, 100 s-1 for 30 sec and 0.1 s-1 for the remaining 10 minutes). In detail, Fig.2 shows the time-dependent viscosity and shear rate characterizing the thixotropic behavior of the paste according to formulation 1. Specifically, the paste shows a fast regain of the initial paste strength after removal ofthe shear force. Thus, the paste shows no thixotropic behavior, which is desirable. Inother words, the thixotropy is measured by structural deconstruction under shear stress and its subsequent restoration upon relive of the shear stress. Accordingly, the viscosity of the paste changes when applying stress (during screen printing) allowing for the paste to fill the meshes. When the paste is released from the meshes onto the substrate, the viscosity almost instantly changes back to its initial value. This provides for good printing characteristics of the paste, and ensures that the printed structure is maintained at least until it is cured.Thixotropy index (TI) measurementThe thixotropy index (TI) is a measure used to quantify the thixotropic behavior of thepaste. Thixotropy refers to the property of the paste to exhibit a time-dependentdecrease in viscosity under constant shear stress or strain. In other words, thixotropic pastes become less viscous and flow more easily when subjected to agitation or shearing forces, but they gradually regain their original viscosity when left undisturbed. The TI is calculated from rheological data obtained using rotational rheometers or viscometers. The index provides a numerical value that indicates the degree ofthixotropic behavior exhibited by the paste. The, namely the ratio of the viscosity at lowshear rates and the viscosity at high shear rates, gives an indication of the paste’s abilityto hold its shape. A highly thixotropic material with a high TI will strongly drop in viscosity as agitation or shear stress is increased. After a low shear rate of 0.1 s-1is applied for 60 sec, a high shear rate of 100 s-1is applied for 30 sec to simulate the flooding / printing process. However, it is not possibleto reproduce the high shear rates of the printing process (σ >200000 s-1). Test settingsgive an estimation on the shear thinning which can be expected in the flooding process or by printing with stencils (σ ≈ 1000 s-1). Afterwards, the shear rate is lowered to 0.1 s-1and the structural rebuild is monitored via the viscosity. The resulting data includes the time-dependent viscosity and shear rate, and the harmonic distortion which can be used as a quality criterion.By qualitatively analyzing the data, i.e. viscosity against time, the paste can becategorized as non-thixotropic, which is the most preferable for additive manufacturingprocess such as screen printing. A non-thixotropic paste shows no time-dependentshear thinning behavior. The viscosity of the non-thixotropic paste does not changeover time when exposed to constant shear. Strain controlled amplitude sweep measurementStrain-controlled sweep amplitude is a rheological testing technique used to analyze theviscoelastic properties of the paste. In this technique, the amplitude of strain, i.e. deformation applied to the paste is varied systematically while keeping other parameters, such as frequency or temperature, constant.To evaluate the viscoelastic properties of the paste, which determine, e.g., whether thepaste will tend to tear while flooding or if the paste is too elastic, so it will not spread homogeneously on the screen, strain-controlled amplitude sweeps were performed. Here, the strain imposed by oscillatory movements of the plate with a frequency of 1 Hz is varied. The resulting shear modi, the storage G´ and loss modulus G´´, which give information weather the sample is of elastic / solid or viscous nature, are recorded. Storage Modulus (G’) represents the elastic (solid-like) behavior of the material. Itmeasures the energy stored in the material during deformation. Loss Modulus (G’’)represents the viscous (liquid-like) behavior of the material. It measures the energy dissipated as heat during deformation. At G´> G´´the sample behaves like an elastic solid. AtG´ = G´´ (phase angle δ = 45°),the sample loses its structure. The paste changes to a viscous state atG´´ > G´. This is often referred to as yielding or flow point. Fig. 3 shows the influence of binder type on the crossover of elastic and viscous shear module by amplitude sweep at 1 Hz. The paste corresponding to the “Starch binder” data points would not be processable (crossover > 10 %), however it can be adapted byincreased water addition (”Starch binder + H2O” data points). As can be seen from Fig.3, the paste according to formulation 1 is stretchable enough to be flooded with thesqueegee by the strain at phase angle delta = 1. The height of the shear modulus gives an estimation how strong or “hard” the paste is, where a high shear modulus is beneficial for improved height build-up in the printing process. The same is true for the phase angle δ, a small value at low strains means that the pastehas a better developed internal structure and is therefore more stable. Values of 1 to 10% strain at a phase angle of 1 have been proven processable in 3D screen printing.In particular, Fig. 3 shows strain-controlled amplitude sweep measurements of pasteswith different fillers at similar ratios. The different pastes comprise starch binder (Fig.3, dark blue curve), HPMC binder (Fig.3, red curve), starch binder and water (Fig.3, lightblue curve), and HPC binder (Fig. 3, light grey curve). By addition of water (Fig. 3 lightblue curve) or fine-tuning of the ratio of ingredients the flow- and printing properties ofthe paste can be adapted. The yield point is marked by vertical dashed line. The light bluecurve shows the influence of increased water content on the yield point of a starch containing paste (blue curve). When the modules cross over, the flow properties as well as the printability changes. Modules crossover refers to the point where the storage modulus (G’) and the loss modulus (G’’') intersect on a rheological plot. This point signifies a transition in the material’s behavior from being more solid-like to more liquid-like, or vice versa. Lower values indicate easier flow and lower resistance, which is desirable for many applications such as printing, where smooth and consistent flow is necessary. The implications for the printability of a paste, particularly one that uses only a starchbinder, can be taken from Fig. 3 (see dark blue curve). It follows that the paste with onlystarch binder is poorly printable. The complex shear rate is a measure of the rate at which the material is deformedunder shear. In Fig. 3, the acceptable range for a good printability behavior of the pasteis 1%-10%. It follows that within this range, the paste exhibits optimal flow propertiesfor the intended screen printing.In the following, further paste formulations according to other embodiments aredescribed in more detail. Formulation 2 When printing a tablet designed for the sequential delivery of different APIs (API 1 and API 2), two pastes having the compositions as presented in Table 3 (containing API 1)and Table 4 (containing API 1) are used. The printed tablet may be a multi-component“sandwich” tablet, where separate pastes are used for printing separate compartments. Sequential release refers to a drug delivery system designed to release multiple doses ofan API over a specific period in a controlled and sequential manner. This leads toimproved sustained therapeutic effects, reduced dosing frequency, and improved patientcompliance. The following tables present preferred ranges and exemplary (further preferred) values. Table 3 In a specific embodiment, the API 1 is levodopa. Table 4 In a specific embodiment, the API 2 is carbidopa.The pastes according to Table 3 and 4 are used for printing separate compartments ofthe tablet, such that each compartment comprises a different dose and different API.These compartments are physically separated and are arranged adjacent to each other.Each compartment is designed to release its contents at a predetermined rate, which is determined among others by the constitution of the pastes used for printing the compartments. The compartments release the API in response to specific stimuli, such as changes in pH, temperature, or enzymatic activity. This controlled releasemechanism ensures that the drug is released gradually over time, rather than all atonce.The sequential release is designed to release the API in a specific order, with each dosebeing released at the appropriate time to maintain therapeutic levels of the API in thebody. In this specific embodiment, upon application of the printed tablet, API 2 is immediately released, whereas API 1 is released more slowly, i.e. according to anextended release profile. In this manner, the release profile of each API and paste istailored to match the desired therapeutic effect. For example, an initial burst release may provide rapid relief of symptoms, followed bysustained release to maintain therapeutic levels over an extended period. Theadvantages over conventional immediate-release formulations are improved patientcompliance, reduced side effects, and enhanced efficacy due to optimized dosingregimens. By delivering the API in a controlled and sequential manner, which iscontrolled by the pastes, fluctuations in drug levels in the body can be minimized,leading to more consistent therapeutic effects. Formulation 3 In the following, the formulation of a paste providing for extended-release characteristics of a tablet printed using this paste is shown in Table 5. The following table present preferred ranges and exemplary (further preferred) values. Table 5 Extended release (ER), (or sustained release (SR), controlled release (CR), or prolongedrelease (PR)), relates to the release of the API in a slow and steady manner over anextended period, typically several hours to days.It is conceivable that, in some embodiments of pastes with extended-releaseformulations, the API may be initially contained within a coating or matrix that delaysits release from the dosage form. This delay can be achieved through various mechanisms, such as diffusion through the coating or dissolution of the matrix.When releasing the API from a tablet printed using a delayed-release paste, the APImay be released slowly and steadily over time through controlled release mechanisms.These mechanisms include diffusion through a polymer matrix, osmotic pressure-driven release, and erosion of the oral dosage form.In this manner a more stable blood level over time is achieved as compared withimmediate-release formulations. This helps avoiding API peaks and troughs in bloodlevels. Accordingly, side effects are minimized, which are associated with fluctuationsin drug levels. Because extended-release formulations provide for a release of the API gradually over an extended period, a less frequent dosing is required as compared to immediate- release formulations. For example, a medication that needs to be taken multiple timesper day in an immediate-release form only needs to be taken once or twice daily in anextended-release form. In this manner, extended-release formulations improve patientcompliance. An extended-release paste may comprise one or more of hydrophilic polymers e.g.,HPMC, poly ethylene glycol, PEG, sodium carboxymethylcellulose, NaCMC,hydrophobic polymers e.g., ethylcellulose, Eudragit, matrix-forming agents e.g., carbomer, xanthan gum, coating agents e.g., cellulose derivatives, shellac, plasticizers e.g., glycerin, propylene glycol, disintegrants e.g., croscarmellose sodium, crospovidone, pH modifiers e.g., citric acid, sodium bicarbonate, and release modifiers e.g., lecithin, surfactants. Formulation 4 For printing a pharmaceutical composition providing for a slow release of the API, a paste may be used having the formulation shown in Table 6. This paste (or the printed pharmaceutical composition) shows mucoadhesive properties. The following table present preferred ranges and exemplary (further preferred) values. Table 6 Mucoadhesive pastes (or the respective printed pharmaceutical compositions) adhere to mucosal surfaces, such as those found in the gastrointestinal tract, and other mucous membranes in the body. Mucoadhesive pastes can adhere to mucosal surfaces, such as those found in the gastrointestinal tract, and other mucous membranes in the body.The polymer used in the paste can exhibit mucoadhesive properties and mediateattachment of themselves and the API. It is conceivable that the mucoadhesive paste comprising a mucoadhesive polymerand / or excipient may attach to mucous membranes. In this way, adhesion is enhanced.The advantage of this mucoadhesive paste is its ability (in the resulting pharmaceuticalcomposition) to increase the residence time of API at the site of release. This prolongedcontact allows for better API absorption, improved bioavailability and therapeuticoutcomes, and reduced dosing frequency.For drug delivery purposes, the term bioadhesion may imply attachment of a drugcarrier system to a specified biological location. The biological surface can be epithelial tissue or the mucus coat on the surface of a tissue. If adhesive attachment is to a mucus coat, the phenomenon may be referred to as mucoadhesion. The mucoadhesive paste may comprise one or more of HPMC, carbomer, NaCMC,polyacrylic acid, PAA, chitosan, PEG, and polycarbophil.Formulation 5 A paste with an enteric formulation is prepared according to the formulation shown in Table 7. The paste is designed to provide for enteric properties of the printed pharmaceutical composition and a release of the API in the duodenum. The following table present preferred ranges and exemplary (further preferred) values. Table 7 The enteric formulation is designed to protect the API of the printed pharmaceuticalcomposition from the acidic environment of the stomach. This paste facilitates the APIrelease in the alkaline environment of the small intestine. This paste is used for APIsthat are sensitive to gastric acidity, cause irritation to the stomach lining, and / or have optimal absorption in the intestine.Enteric coatings may be used in the enteric formulation. Furthermore, the printed solidorals dosage form may be coated with a polymer, which is resistant to acidic conditionsbut dissolves or becomes permeable in the higher pH environment of e.g. the smallintestine. Common polymers used for enteric coatings include cellulose acetatephthalate, CAP, hydroxypropyl methylcellulose phthalate, HPMCP, and methacrylicacid copolymers (i.e. Eudragit). For example, the enteric paste can be used to carry APIs such as non-steroidal anti- inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), antibiotics, and / orcorticosteroids. These APIs cause irritation to the stomach lining, undergo degradationin acidic conditions, and have optimal absorption in the intestine.The advantages of the enteric paste are protection of APIs from gastric degradation andirritation, improved bioavailability of APIs by targeting absorption sites in the intestine,and the reduction of gastrointestinal side effects associated with APIs.It is conceivable that the enteric paste is designed to print a pharmaceuticalcomposition providing for delayed release of the API. In this manner, the API isreleased gradually over time in the intestine rather than all at once in the stomach. The enteric paste may be used to carry APIs that require sustained therapeutic effects and / or that are absorbed more efficiently in the intestine. Formulation 6 The paste according to the formulation shown in Table 8 is an enteric formulation combined with mucoadhesive properties. Specifically, the API is released from a respective printed tablet in the duodenum. The following table present preferred ranges and exemplary (further preferred) values. Table 8 The paste according to the formulation shown in the table above is designed for printing pharmaceutical compositions from which, after application, APIs are released in the intestine. This paste combines the advantages of both the enteric and mucoadhesive formulation. Shape and geometry The pharmaceutical composition may be an oral dosage form, which is solid, such as atablet. They may be flat, oval, round, layered, sheet-like and / or disk-shaped. Further,they may be round, oval, oblong, square, or triangular, and may have flat or convexsurfaces. It is conceivable that the pharmaceutical composition is scored to facilitatesplitting for dose adjustment. The pharmaceutical composition may be a caplet. Caplets are elongated tablets with a shape resembling that of capsules. They are easier to swallow than traditional tablets and may be preferred by patients who have difficulty swallowing larger tablets. The paste may be used to manufacture orally disintegrating tablets, ODTs. ODTs, maybe understood as fast-dissolving or quick-dissolving tablets. These ODTs disintegraterapidly in the mouth without the need for water. They are particularly useful for patientswho have difficulty swallowing tablets or for API that require rapid onset of action.The paste may be used for the manufacturing of spheres and / or pellets. Spheres and pellets are small, spherical or pellet-shaped solid dosage forms. They are used incontrolled-release formulations and in multicompartment systems.It is conceivable that they are filled into capsules, compressed into tablets, or used as acomponent of oral suspensions. Furthermore, the paste may be used to manufacture chewable tablets. Chewable tablets are chewed before swallowing. They may comprise flavors and / or colors. These tabletsmay be used in particular for pediatric or geriatric formulations. These patient groupshave difficulty swallowing traditional tablets. Accordingly, these chewable tabletsimprove patient compliance and therapeutic benefit. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been describedwith reference to the aforementioned specification, the descriptions and illustrations ofthe embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein whichdepend upon a variety of conditions and variables. It should be understood thatvarious alternatives to the embodiments of the invention described herein may beemployed in practicing the invention. It is therefore contemplated that the inventionshall also cover any such alternatives, modifications, variations or equivalents. It isintended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1May 31, 2024Laxxon Medical AG L173252WO MAJ / Moh / KtaClaims 1. A paste for carrying an active pharmaceutical ingredient, API, preferably for usein a screen printing process for printing a pharmaceutical composition, thepaste comprising:5 the API, a binder, a filler, and a solvent, wherein the paste is an aqueous dispersion.0 2. The paste according to claim 1, wherein the paste comprises the binder in anamount of 0.1 to 50 wt. %, preferably 0.2 to 40 wt. %, more preferably 0.3 to 30 wt. %, even more preferably 0.4 to 20 wt. %, most preferably of 0.5 to 10 wt. % of the total mass of the paste.

3. The paste according to any of the preceding claims, wherein the paste comprises5 the filler in an amount of 0.2 to 70 wt. %, preferably 0.4 to 55 wt. %, more preferably 0.6 to 40 wt. %, even more preferably 0.8 to 30 wt. %, most preferably 1.0 to 20 wt. % of the total mass of the paste.

4. The paste according to any of the preceding claims, wherein the paste comprisesthe solvent in an amount of 20 to 70 wt. %, preferably 15 to 65 wt. %, more0 preferably 20 to 60 wt. % of the total mass of the paste.

5. The paste according to any of the preceding claims, wherein the binder isselected from one or more of hydroxy propyl cellulose, HPC, hydroxy propylmethyl cellulose, HPMC, starch, alpha-D-lactose monohydrate, carbomere,algin, blanose, natrosol, and polyethylene glycol.5 6. The paste according any of the preceding claims, wherein the filler is selectedfrom one or more of microcrystalline cellulose, starch, lactose, and maltose.

27. The paste according to any of the preceding claims, having a particle size D90 of1 to 50 µm, preferably of 2 to 40 µm, more preferably of 3 to 30 µm, even morepreferably of 4 to 20 µm, most preferably of 5 to 15 µm.

8. The paste according to any of the preceding claims, wherein the paste has aviscosity in the range of 10 to 5000 Pa·s, preferably 200 to 3000 Pa·s, morepreferably 500 to 2000 Pa·s at a shear rate of 0.1 s-1at 25 °C.

9. The paste according to any of the preceding claims, wherein the paste has athixotropy index in the range of 1 to 200, preferably 10 to 160, more preferably20 to 100 at shear rates of 0.1 s-1 and 100 s-1 at 25°C.

10. The paste according to any of the preceding claims, wherein the paste is elasticand has a complex shear strain value in the range of 0.01 % to 10 %, preferably0.1 % to 9 %, more preferably 1 % to 8 % at a phase angle of 1 when measuringthe strain-controlled amplitude sweep at 1 Hz.

11. The paste according to any of the preceding claims, wherein the paste comprisesthe API in an amount of 5 to 65 wt. %, preferably 7 to 60 wt. %, more preferably10 to 50 wt. %, most preferably 12 to 40 wt. % of the total mass of the paste.

12. The paste according to any of the preceding claims, wherein the paste comprisesan anti-tacking agent in an amount of 0.05 to 6 wt. %, preferably 0.1 to 5 wt. %,more preferably 0.15 to 4 wt. %, most preferably 0.2 to 3 wt. % of the total massof the paste.

13. The paste according to any of the preceding claims, wherein the paste comprisesa humectant in an amount of 0.3 to 8 wt. %, preferably 0.5 to 7 wt. %, morepreferably 0.7 to 6 wt. %, most preferably 1 to 5 wt. % of the total mass of thepaste.

14. The paste according to any of the preceding claims, wherein the paste comprisesan anti-foaming agent in an amount of 0.05 to 4 wt. %, preferably 0.1 to 3 wt. %,more preferably 0.15 to 2 wt. %, most preferably 0.2 to 1.5 wt. % of the totalmass of the paste.

315. The paste according to any of the preceding claims, wherein the paste comprisesan antioxidant in an amount of 0.01 to 1 wt. % of the total mass of the paste.

16. The paste according to any of the preceding claims wherein the paste comprisesa disintegrant in an amount of 1 to 6 wt. % of the total mass of the paste.

17. The paste according to any of the preceding claims, wherein the paste comprisesa plasticizer in an amount of 0.5 to 1 wt. % of the total mass of the paste.

18. The paste according to any of the preceding claims, wherein the anti-tackingagent is selected from one or more of talc, and magnesium stearate.

19. The paste according to any of the preceding claims, wherein the humectant isselected from one or more of glycerol, xylitol, and D(-)-sorbitol.

20. The paste according to any of the preceding claims, wherein the anti-foamingagent is selected from one or more of silicon oil, and glyceryl monostearate.

21. The paste according to any of the preceding claims, wherein the antioxidant isselected from one or more of L-ascorbic acid, citric acid, and tocopherole.

22. The paste according to any of the preceding claims, wherein the disintegrant isselected from one or more of polyplasdone, polyvinylpyrrolidone, croscarmellose sodium, and primellose.

23. The paste according to any of the preceding claims, wherein the plasticizer isselected from one or more of triethyl citrate, polyethylene glycol, propylene glycol, glycerol triacetin, and miglyol.

24. The paste according to any of the preceding claims, wherein the paste comprisesthe binder in an amount of 0.5 to 5 wt. %, preferably 0.8 to 4 wt. %, morepreferably from 1 to 3 wt. % of the total mass of the paste.

25. The paste according to any of the preceding claims, wherein the paste comprisesthe disintegrant in an amount 0.5 to 8 wt. %, preferably 1.5 to 7 wt., morepreferably 2.5 to 5 wt. % of the total mass of the paste.

426. The paste according to any of the preceding claims, wherein the paste comprisesthe filler in an amount of 6 to 20 wt. %, preferably 8 to 18 wt. %, more preferably 10 to 16 wt. % of the total mass of the paste.

27. The paste according to any of claims 24 to 26, wherein the binder is hydroxypropyl cellulose, wherein the disintegrant is croscarmellose sodium, andwherein the filler is mannitol.

28. The paste according to claims 24 to 27, wherein the API is carbidopa.

29. The paste according to any of claims 1 to 23, wherein the paste comprises thebinder in an amount of 0.5 to 5 wt. % preferably 0.8 to 4 wt. %, more preferably1 to 3 wt. % of the total mass of the paste.

30. The paste according to any of claims 1 to 23 or 29, wherein the paste comprisesthe filler in an amount of 1 to 8 wt. %, preferably 2 to 7 wt. %, more preferably 3to 6 wt. % of the total mass of the paste.

31. The paste according to any of claims 1 to 23 or 29 to 30, wherein the pastecomprises the plasticizer in an amount of 0.5 to 5 wt. %, preferably 0.8 to 4 wt.% of plasticizer, more preferably 1 to 3 wt. % of plasticizer of the total mass ofthe paste.

32. The paste according to any of claims 29 to 31, wherein the binder is HPC,wherein the filler is microcrystalline cellulose, and wherein the plasticizer isglyceryl triacetate.

33. The paste according to claims 29 or 32, wherein the API is entacapone,rasagiline, selegiline, safinamide, amantadine, levodopa, pramipexole, ropinirole, rotigotine, apomorphine, any prodrug or pharmaceutical salt thereof, preferably levodopa.

34. The paste according to any of claims 1 to 23, wherein the paste comprises thebinder in an amount of 0.5 to 5 wt. % of binder, preferably 0.8 to 4 wt. %, morepreferably 1 to 3 wt. % of the total mass of the paste.

535. The paste according to any of claims 1 to 23 or 34, wherein the paste comprisesthe filler in an amount of 5 to 20 wt. %, preferably 8 to 18 wt. %, more preferably 11 to 16 wt. % of the total mass of the paste.

36. The paste according to any of claims 34 or 35, wherein the binder is hydroxypropyl cellulose and starch, and wherein the filler is microcrystalline cellulose.

37. The paste according to any of claims 1 to 23, wherein the paste comprises thebinder in an amount of 0.4 to 5 wt. %, preferably 0.6 to 4 wt. %, more preferably0.8 to 3 wt.%, most preferred 1 to 2 wt. % of the total mass of the paste.

38. The paste according to the preceding claim, wherein the binder is a carbomerpolymer.

39. The paste according to any of claims 1 to 23, wherein the paste comprises thebinder in an amount of 10 to 20 wt. %, preferably 12 to 18 wt. %, morepreferably 14 to 16 wt.% of the total amount of the paste.

40. The paste according to the preceding claim, wherein the binder is a pullulanpolysaccharide polymer.

41. A method for preparing a paste according to any preceding claim, the methodcomprising: a) providing the binder and adding it to the solvent;b) stirring the binder and solvent;c) adding the filler;d) optionally adding one or more of a humectant, an anti-tacking agent, ananti-foaming agent, an antioxidant, a plasticizer, and / or a disintegrant; e) adding the active pharmaceutical ingredient;f) mixing the composition;g) homogenizing the mixture.

42. The method of claim 41, wherein step g) comprises stirring the mixture withstirring speeds of between 10-5000 rpm, preferably wherein the stirring speed increases during the homogenization.

643. The method of claim 41 or 42, wherein a vacuum is applied during step g).

44. A pharmaceutical composition produced from the paste according to any ofclaims 1 to 40.

45. Use of the paste according to any of claims 1 to 40 in an additive manufacturingprocess, in particular for printing a pharmaceutical composition carrying theAPI.

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