Paste with an API and a permeation enhancer for 3d-printing

Abstract

The present disclosure generally relates to a paste for carrying an active pharmaceutical ingredient (API), preferably a GLP-1 agonist and a permeation enhancer, preferably a fatty acid and / or a pharmaceutical acceptable salt thereof, such as sodium decanoate, 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, and the use of a paste in an additive manufacturing process.

Description

[0001] PASTE WITH AN API AND A PERMEATION ENHANCER FOR 3D-PRINTING

[0002] TECHNICAL FIELD

[0003] The present disclosure generally relates to a paste for carrying an active pharmaceutical ingredient (API), preferably a GLP-1 agonist and a permeation enhancer, referably a fatty acid and / or a pharmaceutical acceptable salt thereof, such as sodium decanoate, , 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, and the use of a paste in an additive manufacturing process.

[0004] BACKGROUND

[0005] 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 pharmaceutical manufacturing focuses on tablet pressing processes. One of the most common methods for producing solid oral dosage forms such as tablets is tablet pressing, i.e. the compression 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.

[0006] During this process of tablet pressing, ensuring consistent tablet hardness throughout the batch is challenging. Variations in powder properties, compression force, and machine settings lead to tablets with different hardness levels. The hardness level is a parameter that directly impacts the dissolution and drug release profiles. Moreover, several active pharmaceutical ingredients are not processable due to their low flowability.

[0007] Furthermore, the uniform distribution of active pharmaceutical ingredients (APIs) and excipients in each tablet is highly relevant for dosage accuracy. During tablet pressing, variations in powder flow properties and inadequate blending result in content non- uniformity. This directly leads to inconsistent drug delivery within the patient, which can impair the therapeutic benefit and patient safety. Moreover, no significant variations in term of structure and shape are possible, as these parameters are limited by the tablet pressing machine itself.

[0008] When compressing the powder batch, dust is inevitably generated which poses potential 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.

[0009] As a result, the conventional process of tablet pressing has room for improvement, in particular in terms of process efficiency and sustainability.

[0010] It is known to use screen-printing techniques for producing drug delivery systems. A paste 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 dried layer, before the cycle is repeated to build the drug delivery system.

[0011] 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 a drug delivery system. It is particularly challenging to provide a paste comprising an API and 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.

[0012] Further, peptide and protein therapeutics have developed significantly in the past decades, however, drug delivery limits their therapeutical use significantly. Although oral administration is the most preferred route for drug delivery, most peptide and protein therapeutics are delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract.

[0013] 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.

[0014] It is a particular object of the present invention to provide an improved paste for use in screen printing pharmaceutical compositions, to print a pharmaceutical composition comprising an API and a permeation enhancer.

[0015] SUMMARY OF THE INVENTION

[0016] 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.

[0017] 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.

[0018] A first aspect of the present disclosure is directed to a paste for carrying an active pharmaceutical ingredient (API), preferably a GLP-i agonist, and a permeation enhancer, preferably a fatty acid and / or a pharmaceutical acceptable salt thereof, such as sodium decanoate, preferably for use in a screen printing process for printing a pharmaceutical composition, the paste comprising: a binder; a solvent; the API, and the permeation enhancer.

[0019] The paste may be an aqueous dispersion. The paste is for carrying an API, i.e. the API may be fully dissolved in and / or dispersed throughout the paste. When using the paste to form an article, the resulting article also comprises the API. For example, when using the paste in a screen printing process, the paste 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.

[0020] A paste according to the present disclosure is a substrate that may be used in an additive manufacturing process. The paste maybe a solid-liquid mixture and maybe plastically deformable and adhesive. However, it is conceivable that the paste is nonadhesive.

[0021] 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.

[0022] The paste may comprise an API e.g. a peptide and a permeation enhancer, which is not processable with conventional methods such as tablet pressing. The paste can allow for the usage of excipients, which may be non-flowable material, such as sodium caprate. In this manner, these excipients can become useable for tablet manufacturing. The paste allows for the formation of e.g. an oral dosage form for peptide delivery, which provides for tunable pharmacokinetic (PK) profiles. Further, a combination with different APIs and moreover temperature sensitive APIs maybe processable. The API may not be solvent compatible. The solvent may be water. Additional excipients can be used to facilitate the production and finetune the release properties. In this manner, the paste provides for a reliable and consistent process and material with specifically tailored PK profiles which increases its effectiveness, duration of action and safety. Furthermore, the paste provides for an increase of patient compliance by oral administration instead of (intravenous) injection. In other words, APIs, which may commonly not be orally administered, such as peptide and protein therapeutics, are made processable for oral administration.

[0023] Furthermore, by way of using the paste during screen printing, no formation of dust is generated. This is crucial when handling high potent APIs, which may lead to deviations of the API content, especially when the therapeutic breadth of the API is narrow. Furthermore, the paste of the present invention allows for pharmaceutical compositions that are highly versatile in structure, integrity and geometry.

[0024] 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 present invention. In this manner, standard formulations can be used in the paste for screen printing, 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.

[0025] Furthermore, there are no limitations in the choice of the API, as almost any API can be used independent from its solubility or flow ability. This is also true for the choice of the excipients.

[0026] 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 above the substrate plate. A paste may then be urged, e.g. with the help of a flooding squeegee, to fill the mesh openings. Afterwards, the printing squeegee may be pressed into the mesh to ensure contact with the printing plate. Behind the squeegee, the screen may snap back to its initial position whereas the paste remains on the substrate. If the paste has beneficial properties, among others shear-thinning properties, the movement and 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 an improved 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 by convection with e.g. dry and heated air. Afterwards, the substrate plate may return to the printing station, where the printing screen may be lifted by the thickness of the printed layer. Then, the cycle can start all over again and may be repeated until the desired tablet height is reached.

[0027] 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 shearthinning 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.

[0028] An API maybe understood as the biologically active component in a pharmaceutical drug that produces a desired therapeutic effect. The API maybe solid, or liquid, or of any form. The paste may comprise more than one API.

[0029] The pharmaceutical composition which may be produced by means of the paste may be solid, or liquid, or of any form. The pharmaceutical composition may be an oral dosage form, such as a tablet. The pharmaceutical composition may be coated. The pharmaceutical composition may be combined with amino acids, fatty acids, macromolecules and may comprise additives, such as sweeteners, and thickeners and the like. In particular, the pharmaceutical composition may be combined with protein powder.

[0030] The pharmaceutical composition maybe provided in a sachet and / or a kit. In particular, when combining the pharmaceutical composition, it is desirable that the pharmaceutical composition is provided in a sachet.

[0031] A permeation enhancer may be understood as an excipient. The permeation enhancer maybe a fatty acid and / or a pharmaceutical salt thereof. The permeation enhancer may be a derivate of the fatty acid. For example, a derivate of a fatty acid is a triglyceride.

[0032] The fatty acid may comprise a carbon chain length of at least C-6, preferably C-8, more preferably C-io. The carbon chain length maybe shorter and / or longer than C-io. The pharmaceutical salt of the fatty acid may be for example sodium, potassium or the like. The permeation enhancer may be sodium decanoate. The permeation enhancer enables an improved permeation of other chemical ingredients, such as the API. The permeation enhancer may comprise triglycerides. Triglycerides may be middle (medium) and / or long-chain triglycerides.

[0033] A binder and / or a filler may be understood as an excipient. The binder and / or the filler may ensure that the paste obtain its shape and integrity. These excipients may be either dry and / or liquid. The binder may ensure that the active pharmaceutical ingredient and the other excipients present in the paste maybe hold together.

[0034] A filler may allow for an increase in the bulk volume. In this manner, the filler can help in achieving the desired paste volume and / or weight. Especially, when the amount of API is small, fillers are desirable.

[0035] A solvent may be any solvent. Preferably the solvent is water. It is not required that the solvent dissolves all excipients and / or API. In other words, the excipients and / or the API may completely dissolve in the solvent. The API and / or the excipients may be soluble in the solvent. It is sufficient that the excipients and / or the API are present or dispersed in the solvent, forming for example a dispersion. This dispersion is preferably an 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.

[0036] The paste used for the manufacturing of a pharmaceutical composition may be used in the therapy of a disease such as Adiposity, Hypertension, Hyperlipidemia, Coronary Artery Disease, Type 1 Diabetes, Type 2 Diabetes, Obesity, Depression, Anxiety Disorders, Bipolar Disorder, Bacterial Infections, HIV / AIDS, Asthma, Chronic Obstructive Pulmonary Disease (COPD), Gastroesophageal Reflux Disease (GERD), Peptic Ulcer Disease, Epilepsy, Parkinson's Disease, Hypothyroidism, Osteoarthritis, Rheumatoid Arthritis, Cancer, Systemic Lupus Erythematosus, (Benign) Prostatic Hyperplasia, Opioid Dependence or combination thereof. In this context the API(s) may be selected from one or more of Angiotensin-Converting Enzyme (ACE)- inhibitors, beta-blockers, calcium channel blockers, 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.

[0037] Additionally, the paste used for the manufacturing of a pharmaceutical composition maybe used in the therapy of a disease such as Diabetes Mellitus, Type 2 Diabetes, hormone-dependent diseases, such as endometriosis and / or prostate carcinoma, cancer diseases, osteoporosis, autoimmune diseases, infectious diseases, viral infections, genetic disorders, rheumatologic diseases, severe bacterial infections, such as MRSA, breast cancer, lung cancer, leukemia, lymphoma, multiple sclerosis, viral infections, metabolic diseases, Morbus Gaucher, Fabry disease.

[0038] The API may be characterized in that it has a poor oral bioavailability.

[0039] In particular, the API maybe selected from GLP-i agonists; peptide-based therapeutics; protein-based therapeutics, preferably insulin, hormone analogues and / or monoclonal antibodies; nucleic acid-based therapeutics, preferably, antisense oligonucleotides (ASOs) and / or small interfering RNAs (siRNAs); macromolecular therapeutics, preferably liposomes and / or polymer-based therapeutics, such as polymer-drug conjugates; antibiotics and / or antimycotics, preferably vancomycin and / or amphotericin B; chemotherapeutics; biologies, preferably interferon and / or enzyme replacement therapies; lipophobic APIs, such as heparin; vitamin- and / or mineral supplements, such as vitamin B12; antiviral therapeutics; antihypertensive drugs, such as enalaprilat. The API may be exenatide, liraglutide, leuprolide, goserelin, rituximab, infliximab, mipomersen, patisiran, liposomal doxorubicine, vancomycine, amphotericin B, paclitaxel, (liposomal)doxorubicin, imiglucerase, agalsidase, heparin, vitamin B12, tenofovir, acyclovir, enalaprilat.

[0040] Different API and permeation enhancer combinations may be chosen by the skilled person for preparing a paste for screen printing a pharmaceutical composition providing for the desired therapeutic effect. The paste of the present disclosure provides for a suitable carrier of the API and permeation enhancer and having suitable screen printing characteristics allowing for using the paste in a screen printing process for producing the pharmaceutical composition.

[0041] The bioavailability of the API is enhanced when orally administered based on the formulation described herein. In particular, the permeation enhancer may augment the absorption of the API and thus allows for an improved bioavailability of the API, when orally administered.

[0042] The paste used for the manufacturing of a pharmaceutical composition may be used in the therapy of obesity and / or adiposity.

[0043] The paste may comprise the permeation enhancer in an amount of 0.1-65 wt.-%, preferably 1-50 wt.-%, further preferred 5-40 wt.-%, further preferred 5-30wt.-%, further preferred 10-25 wt.-% of the total mass of the paste.

[0044] This range of permeation enhancer has shown the best improvement of boral bioavailability as well as applicability and processability of the paste for use in screen printing a pharmaceutical composition.

[0045] The paste may comprise a filler, preferably in the amount of 4-15 wt.-%, preferably 5-13 wt.-%, further preferred 6-12 wt.-%, further preferred 7-11 wt.-%, further preferred 8-10 wt.-% of the total mass of the paste. IO

[0046] The inventors have found that this range of filler allows for an improved formulation of the paste. The filler maybe a matrix material and / or a thickener. For example, as a matrix material, the filler provides a structural framework, which can support and stabilize the API. This matrix can influence 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 the paste, as well as its texture. In this manner, the filler may provide for the right consistency for the paste. The filler can differ from the binder e.g. in its function. For example, 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 only the API would be present in a formulation, the formulation would likely have a too little mass to be further processed. The preferred range of filler has shown the best applicability and processability of the paste for use in screen printing, in particular of a pharmaceutical composition. The filler maybe selected from one or more of microcrystalline cellulose, starch, lactose and maltose.

[0047] In particular, several fillers regularly used in tablet pressing processes are applicable fillers for the paste of the present disclosure. In this manner, known formulations can be used for the paste, which allows for an improved and efficient substrate for the production of pharmaceutical compositions.

[0048] The paste may comprise one or more humectants, preferably glycerol and / or xylitol.

[0049] The humectant prevents from drying out of the paste, in particular during the process of screen printing.

[0050] The paste may comprise the one or more humectants in an amount of 1-5 wt.-%, preferably 2-3.5 wt.-%, further preferred 2.2-2.9 wt.-%, further preferred 2.4-2.7 wt.-%, further preferred 2.5-2.6 wt.-%.

[0051] The use of the humectant in the specific range prevents the paste to dry out, which is undesirable when used during screen printing.

[0052] The paste may comprise an anti-tacking agent, preferably talc.

[0053] The anti-tacking agent impacts the physical properties when handling the paste. In particular, the anti-tacking agent allows for a non-sticky paste. The paste may comprise the anti-tacking agent in an amount of 1.0-2.5 wt.-%, preferably 1.1-2.3 wt.-%, further preferred 1.2-2.1 wt.-%, further preferred 1.3-2. o wt.- %, further preferred 1.4-1.9 wt.-%, further preferred 1.5-1.8 wt.-%.

[0054] 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.

[0055] The paste may comprise an anti-foaming agent, preferably a polydimethylsiloxane (e.g. Silfar 350).

[0056] By using an anti-foaming agent, the paste allows for a bubble-free dispersion.

[0057] The paste may comprise the anti-foaming agent in an amount of preferably o.1-3.0 wt.- %, preferably, further preferred 0.3-2.8 wt.-%, further preferred 0.5-2.6 wt.-%, further preferred o.6-2.4 wt.-%, further preferred 0.7-2.2 wt.-%, further preferred o.8-2.0 wt.- % of the total mass of the paste.

[0058] By using an anti-foaming agent in the specific range, the paste allows for a processable bubble-free paste, in particular during the processing in screen printing.

[0059] It has been found that common excipients widely used for tablet pressing are processable in the form of the paste according to present invention. In this manner, most pharmaceutical compositions can be reproduced by using the paste according to the present invention in screen printing.

[0060] The binder may be a polyethylene oxide and / or wherein the solvent may be distilled water. The paste may comprise the binder and the solvent in a total amount of 50-85 wt.-%, preferably 55-80 wt.-%, further preferred 60-75 wt.-% of the total mass of the paste.

[0061] This range of binder and solvent has shown the best applicability and processability of the paste for use in screen printing a pharmaceutical composition. It has been found that the binder used in the paste provides for stabilizing characteristics. In particular, the binder stabilizes the paste, especially the aqueous dispersion.

[0062] Without intended to be limiting, the binder allows for thickening of the paste and at the same time functions as a matrix for the API. The binder may be a matrix material and / or a thickener. The binder maybe 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.

[0063] The solvent allows for tuning the flow and rheological properties and achieving superior 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 printing behavior. These beneficial properties allow the paste to be used in a screen printing process. In particular, these rheological properties provide for the resulting precise pattern, homogenous surfaces and heigh buildup during screen printing.

[0064] The paste may have a viscosity of 5 to 5000 Pa-s, preferably 500 to 2000 Pa-s at a shear rate of 0.1 s1and 250C.

[0065] “Viscosity” as referred to in this disclosure may be understood as the dynamic viscosity.

[0066] The viscosity of the paste may be measured using an oscillatory rheometer. In particular, a Kinexus Rheometer maybe used, which comprises a plate-plate geometry equipped 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 diying of the paste during longer measurements. The gap size may be set to 500 pm (> 10 times particle size).

[0067] 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 i to 200, preferably 10 to 160, more preferably 20 to 100 at shear rates of 0.1 s1and 100 s1at 25°C.

[0068] The thixotropy index may be understood as a measure of thixotropy, describing the property 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 the agitation 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 viscosity before agitation. For example, a higher thixotropy index indicates a greater degree of thixotropy in the material and vice versa.

[0069] The thixotropy index of the paste may be measured using an oscillatory rheometer. In particular, a Kinexus Rheometer maybe used, which comprises a plate-plate geometry equipped with a passive solvent trap. After a low shear rate of 0.1 s1is applied for 60 sec, a high shear rate of 100 s1may be applied for 30 sec to simulate the flooding / printing process. Subsequently, the shear rate maybe lowered again to 0.1 s1and the structural rebuild may be monitored via the viscosity.

[0070] The paste maybe 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 1 when measuring the strain-controlled amplitude sweep at 1 Hz.

[0071] The complex shear strain value of the paste maybe measured using an oscillatory rheometer. In particular, a Kinexus Rheometer may be used, which comprises a plateplate geometry equipped with a passive solvent trap. After a low shear rate of 0.1 s1is applied for 60 sec, a high shear rate of too s1may be applied for 30 sec to simulate the flooding / printing process. Subsequently, the shear rate maybe lowered again to 0.1 s1and the structural rebuild may be monitored via the viscosity.

[0072] 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.

[0073] 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.

[0074] The paste may have a particle size D90 of less than 100 pm, preferably of less than 50 pm, further preferred of less than 30 pm, further preferred of less than 20 pm, further preferred of less than 15 pm. Preferably, the particle size D90 is in the range of 1 to 70 pm, preferably 20 to 60 pm.

[0075] 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.

[0076] It has been found that this particle size range facilitates the application of the paste in a screen printing process. The particle size D90 maybe of at most 250 pm, preferably of at most 180 pm, more preferably of at most 170 pm, even more preferably of at most 160 pm, most preferably 150 pm. The particle size D90 may be chosen in view of the size of the mesh of the screen used during the screen printing process.

[0077] The D90 value for the particle size distribution maybe measured using dynamic light scattering (DLS). The particle size distribution may be measured with a particle size analyzer (e.g. PSA 990 D; Anton Paar) via dry dispersion method, a light attenuation of 0.5-8 %, according to venturi at 43 Hz, 60% and 500 mbar.

[0078] Dry dispersion may be performed by dispersing and separating the particles without using a liquid, but instead, by using airflow. This can also be performed by using mechanical means. The sample may be thoroughly mixed before measurement. The venturi principle may be used to disperse the particles by creating a vacuum through a constriction 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 based on light scattering. The light attenuation may be between 0.5 and 8%, the shaking may occur at a frequency of 43 Hz with 60% intensity, and the applied pressure may be 500 mbar. The solvent (or water) content of the paste is preferably in the range of 35-60 wt.-%, preferably in the range of 40-50 wt.-%. This provides for a desired viscosity of the paste (500-2000 Pa-s at a shear rate of 0.1 s1and 250C) such that it can be used in a screen printing process, and such that the paste offers additional advantage of resisting dust formation.

[0079] 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, an anti-foaming agent, an antioxidant, a plasticizer, and / or a disintegrant; e) adding the active pharmaceutical ingredient; f) mixing the composition; g) homogenizing the mixture.

[0080] 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 energy and at the same time enhances the precision and accuracy of the manufacturing process of the pharmaceutical composition. In this way, the therapeutic benefit and thus the overall treatment is eventually improved.

[0081] Step g) of homogenizing the mixture may comprise stirring the mixture with stirring speeds of between 10-5000 rpm, preferably wherein the stirring speed increases during the homogenization. Vacuum may be applied during this step g).

[0082] 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.

[0083] In a third aspect, the present invention relates to a pharmaceutical composition produced from a paste as described herein. In a fourth aspect, the present invention relates to the use of the paste disclosed herein in an additive manufacturing process, in particular for printing a pharmaceutical composition.

[0084] Screen printing may comprise 3D screen printing or 3D direct screen printing. Screen printing is an additive manufacturing process. In particular, 3D screen printing may comprise the application of the paste to the screen. A squeegee may be used to force the paste through the mesh of the screen, depositing it onto the substrate below. The paste may 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 pharmaceutical composition. A digital design or model of the pharmaceutical composition can be prepared using computer-aided design (CAD) software.

[0085] The screen may be moved or repositioned between each layer to deposit subsequent layers of paste. In this manner, the pharmaceutical composition can gradually be 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.

[0086] After printing each layer, the deposited paste may undergo a curing or solidification process, e.g. drying, such as evaporation to remove the solvent and to ensure that the paste hardens and adheres properly to the previous paste layers. The drying may comprise heat curing, UV curing, or chemical curing. For example, the drying maybe evaporation of e.g. water.

[0087] The printed pharmaceutical composition may undergo additional post-processing steps. These post-processing steps comprise cleaning, coating, surface finishing, or support removal. In this manner, the desired final appearance and properties are achieved.

[0088] 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 pharmaceutical composition can be individually designed based on e.g. the patient’s needs, in terms of API, release characteristics, coating, and choice of excipients.

[0089] 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.

[0090] BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1: shows the shear rate dependent viscosity of a paste according to an embodiment of the present disclosure;

[0092] Figure 2: shows the time dependent shear viscosity of the paste of Figure 1;

[0093] Figure 3: shows the shear strain dependent shear modulus of the paste of Figure 1;

[0094] Figure 4: a method for preparing a paste according to a preferred embodiment;

[0095] Figure 5: shows rheology characteristics of a paste according to a preferred embodiment.

[0096] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0097] In the following, exemplary embodiments of the present invention are described in more 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

[0098] 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 i

[0099] Method for preparing the paste

[0100] General

[0101] Fig. 4 shows a flow chart illustrating the steps of a method 100 for preparing a paste according to a preferred embodiment. The method starts with step no of adding the binder and the solvent into a container. Afterwards, the binder and solvent in the container are stirred in step 120, which is followed by step 130 of adding the filler into the container.

[0102] 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 step 150, an API is added into the container.

[0103] After step 150, the content of the container is mixed, which provides for a mixture. In the last step 170, the mixture is homogenized.

[0104] Preparation of Formulation 1

[0105] 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 homogenous swelling and no excessive air entrapment. To do so, 960 mL of distilled water is filled in a clean container to which 40 g of Polyox WSR N12K is added slowly under stirring at 600 rpm with a Heidolph mixer (Hei-Torque Precision 400).

[0106] All ingredients are weighted in a vessel. Then, the ingredients are added to the container, starting from the binder, then all liquid ingredients, followed by all solid or powdery ingredients. Subsequently, the API is added, and the specified amount of water is added last.

[0107] Subsequently, the mixture is homogenized with a Herbst planetary mixer HRV-S 2 DP equipped with a stirring bar mixing tool, a scraper, and a dissolver. In this context, the following 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 prevent bubble 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.

[0108] Table 2

[0109] Starting value End value

[0110] Stirrer 50 rpm 200 rpm

[0111] Dissolver 500 rpm 2000 rpm

[0112] Scraper

[0113] Vacuum (Atmospheric pressure) -0.900 mbar

[0114] Fig. 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 thinning behavior). In detail, Fig. 1 shows the shear-viscosity curve of the paste according to formulation 1. The shear-viscosity curve is measured based on the shear rate dependent viscosity of the paste. As can be seen, a shear thinning behavior can be observed. This helps to facilitate extrusion of the paste during the additive manufacturing process, e.g. extrusion through the mesh. Shear thinning, also known as pseudoplasticity, is a property exhibited by the paste where their viscosity decreases under shear stress. In other 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 and more fluid-like.

[0115] The shear thinning is quantified by fitting viscosity vs. shear rate to a power law where r| is the viscosity, K is a consistency factor, y 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.

[0116] As can be seen, the paste shows that the viscosity of the paste decreases when increasing the shear rate. Specifically, the paste has a low shear thinning parameter n.

[0117] 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 o.i s-i for 90 sec, 100 s-i for 30 sec and 0.1 s-i 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 of the shear force. Thus, the paste shows no thixotropic behavior, which is desirable. In other words, the thixotropy is measured by structural deconstruction under shear stress and its subsequent restoration upon relive of the shear stress.

[0118] 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.

[0119] Thixotropy index (TI) measurement

[0120] The thixotropy index (TI) is a measure used to quantify the thixotropic behavior of the paste. Thixotropy refers to the property of the paste to exhibit a time-dependent decrease 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.

[0121] The TI is calculated from rheological data obtained using rotational rheometers or viscometers. The index provides a numerical value that indicates the degree of thixotropic behavior exhibited by the paste. The, namely the ratio of the viscosity at low shear rates and the viscosity at high shear rates, gives an indication of the paste’s ability to hold its shape. A highly thixotropic material with a high TI will strongly drop in viscosity as agitation or shear stress is increased.

[0122] After a low shear rate of o.i s1is applied for 6o sec, a high shear rate of too s1is applied for 30 sec to simulate the flooding / printing process. However, it is not possible to reproduce the high shear rates of the printing process (o >200 000 s1)- Test settings give an estimation on the shear thinning which can be expected in the flooding process or by printing with stencils (o ® 1000 s1)- Afterwards, the shear rate is lowered to 0.1 s1and 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.

[0123] By qualitatively analyzing the data, i.e. viscosity against time, the paste can be categorized as non-thixotropic, which is the most preferable for additive manufacturing process such as screen printing. A non-thixotropic paste shows no time-dependent shear thinning behavior. The viscosity of the non-thixotropic paste does not change over time when exposed to constant shear.

[0124] Strain controlled amplitude sweep measurement

[0125] Strain-controlled sweep amplitude is a rheological testing technique used to analyze the viscoelastic 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 the paste 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.

[0126] 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.

[0127] Storage Modulus (G7) represents the elastic (solid-like) behavior of the material. It measures the energy stored in the material during deformation. Loss Modulus (G77) represents the viscous (liquid-like) behavior of the material. It measures the energy dissipated as heat during deformation.

[0128] At

[0129] G ’> G ” the sample behaves like an elastic solid. At

[0130] G ' = G ' ' (phase angle 5 = 45°), the sample loses its structure. The paste changes to a viscous state at

[0131] G" > G'.

[0132] This is often referred to as yielding or flow point.

[0133] 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 by increased water addition (’’Starch binder + H20” data points). As can be seen from Fig. 3, the paste according to formulation 1 is stretchable enough to be flooded with the squeegee 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.

[0134] The same is true for the phase angle 8, a small value at low strains means that the paste has 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 pastes with 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, light blue curve), and HPC binder (Fig. 3, light grey curve). By addition of water (Fig. 3 light blue curve) or fine-tuning of the ratio of ingredients the flow- and printing properties of the paste can be adapted. The yield point is marked by vertical dashed line. The light blue curve shows the influence of increased water content on the yield point of a starch containing paste (blue curve).

[0135] 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.

[0136] Lower values indicate easier flow and lower resistance, which is desirable for many applications such as printing, where smooth and consistent flow is necessary.

[0137] The implications for the printability of a paste, particularly one that uses only a starch binder, can be taken from Fig. 3 (see dark blue curve). It follows that the paste with only starch binder is poorly printable.

[0138] The complex shear rate is a measure of the rate at which the material is deformed under shear. In Fig. 3, the acceptable range for a good printability behavior of the paste is i%-io%. It follows that within this range, the paste exhibits optimal flow properties for the intended screen printing.

[0139] In the following, further paste formulations according to other embodiments are described in more detail.

[0140] Formulation 2

[0141] To prepare a tablet with permeation enhancer, and preferably GLP-i agonists, the composition presented in Table 3 is used for the preparation of the paste. Table 3 lists preferred ranges and exemplary (particularly preferred) values.

[0142] Table 3

[0143] Formulation 3

[0144] In another preferred embodiment, a paste designed for printing a tablet for the oral delivery of GLP-1 Antagonists comprises the following components (preferred ranges and exemplary or particularly preferred values):

[0145] Formulation 4 In a most preferred embodiment, the paste comprises the following components (preferred ranges and exemplary or particularly preferred values): The paste produced with formulation 4 provides for the rheology characteristics as illustrated in Fig. 5. Fig. 5 exemplarily shows rheological measurements by a Shear rate ramp test (A), 3-step shear rate test (B) and an amplitude sweep (C) of a sodium caprate containing paste according to formulation 4. Diagram A illustrates the shear rate dependent viscosity. Diagram B illustrates the results of a 3-step sear rate test. Diagram C illustrates the results of an amplitude sweep. The paste produced with formulation 4 is characterized by improved printing properties.

[0146] The following compositions may be used in specific embodiments: Release-modified formulations

[0147] To prepare a tablet of the sequential release of different APIs (here: API i and API 2), two different pastes may be used which may carry a separate one of the APIs. The tablet may be build as a multi-component tablet, in which the components made of different pastes maybe layered adjacent to one another.

[0148] Sequential release refers to a drug delivery system designed to release multiple doses of an API over a specific period in a controlled and sequential manner. This leads to improved sustained therapeutic effects, reduced dosing frequency, and improved patient compliance.

[0149] Each compartment is designed to release its contents at a predetermined rate. The compartments release the API in response to specific stimuli, such as changes in pH, temperature, or enzymatic activity. This controlled release mechanism ensures that the drug is released gradually over time, rather than all at once.

[0150] Extended release (ER) pastes, (or sustained release (SR), controlled release (CR), or prolonged release (PR)), are designed such that the API is released slowly and steadily over an extended period, typically several hours to days, from the printed pharmaceutical composition.

[0151] It is conceivable that some pastes with extended-release formulations, the API is initially contained within a coating or matrix that delays its release from the dosage form. This delay can be achieved through various mechanisms, such as diffusion through the coating or dissolution of the matrix.

[0152] When releasing the API from a tablet printed using the delayed-release paste, it is 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 with immediate-release formulations. This helps avoiding API peaks and troughs in blood levels. Accordingly, side effects are minimized, which are associated with fluctuations in drug levels.

[0153] Because extended-release formulations release the drug gradually over an extended period, less frequent dosing is required as compared to immediate-release formulations. For example, a medication that needs to be taken multiple times per day in an immediate-release form only needs to be taken once or twice daily in an extended-release form. In this manner, extended-release formulations improve patient compliance.

[0154] Extended-release pastes 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.

[0155] Mucoadhesive and enteric formulations

[0156] Mucoadhesive pastes can be used to print mucoadhesive pharmaceutical compositions which provide for mucoadhesive properties. Upon application, mucoadhesive polymers of the printed pharmaceutical composition (and thereby also the API) may adhere to mucosal surfaces, such as those found in the gastrointestinal tract, and other mucous membranes in the body. Accordingly, the polymer used in the corresponding mucoadhesive paste can exhibit mucoadhesive properties and mediate attachment of themselves and the API.

[0157] It is conceivable that the mucoadhesive paste comprising a mucoadhesive polymer and / or excipient may attach to mucous membranes. The advantage of this mucoadhesive paste is its ability to increase the residence time of API at the site of release. This prolonged contact allows for better drug absorption, improved bioavailability and therapeutic outcomes, and reduced dosing frequency.

[0158] For drug delivery purposes, the term bioadhesion may imply attachment of a drug carrier 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.

[0159] The mucoadhesive paste may comprise one or more of HPMC, carbomer, NaCMC, polyacrylic acid, PAA, chitosan, PEG, and polycarbophil.

[0160] Furthermore, it is conceivable that an enteric formulation is designed to protect the API from acidic environment of the stomach. This paste facilitates the API release in the alkaline environment of the small intestine. This paste is used for APIs that are sensitive to gastric acidity, cause irritation to the stomach lining, and / or have optimal absorption in the intestine.

[0161] Enteric-coatings may be used in the enteric formulation. Furthermore, the solid orals dosage form may be coated with a polymer, which is resistant to acidic conditions but dissolves or becomes permeable in the higher pH environment of e.g. the small intestine. Common polymers used for enteric coatings include cellulose acetate phthalate, CAP, hydroxypropyl methylcellulose phthalate, HPMCP, and methacrylic acid copolymers (i.e. Eudragit).

[0162] For example, this paste is used for APIs such as non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, and / or corticosteroids. These APIs cause irritation to the stomach lining, undergo degradation in acidic conditions, and have optimal absorption in the intestine.

[0163] The advantages of this paste are protection of APIs from gastric degradation and irritation, improved bioavailability of APIs by targeting absorption sites in the intestine, and the reduction of gastrointestinal side effects associated with APIs.

[0164] It is conceivable that this paste is designed to provide delayed release of the API. In this manner, the API is released gradually over time in the intestine rather than all at once in the stomach. This paste may be used for APIs that require sustained therapeutic effects and / or that are absorbed more efficiently in the intestine.

[0165] The paste may be designed for printing pharmaceutical compositions which provide for API release in the intestine. This paste combines the advantages of both the enteric and mucoadhesive formulation.

[0166] For example, sodium caprate based GLP-i tablets can be produced by using the paste in a screen printing process. In particular, microtablets may be coated with an enteric coating.

[0167] It is further conceivable that these microtablets may be combined with food additives, such as protein powder. It is conceivable that using the pharmaceutical composition produced using the paste according to present disclosure comprising GLP-i agonist in combination with protein powders can prevent muscle wasting and nausea / diarrhea, which are known side effects during a GLP-i agonist treatment. For example, the combination may be provided in a sachet comprising the tablet and the powder.

[0168] Shape and geometry

[0169] The pharmaceutical composition may be an oral dosage form, which can be solid. Preferably, it is a tablet. The composition may be flat, oval, round, layered, sheet-like and / or disk-shaped. Further, it may be round, oval, oblong, square, or triangular, and may have flat or convex surfaces. It is conceivable that the pharmaceutical composition is scored to facilitate splitting for dose adjustment.

[0170] When using the paste for printing a tablet by using screen printing process, the following properties may be desirable.

[0171] Friability: < 0.5 % mass loss

[0172] Permeation enhancer: 300 mg to 500 mg (tablet weight < 1 g)

[0173] Disintegration time: < 20 min (up to 22 min still acceptable)

[0174] Enteric coating: release at pH > 6.5; stable at pH < 6.0

[0175] For testing, different pastes (with formulations as presented further above) were printed as tablets of a height of 4-6 mm considering disk-shaped tablets of 15 mm in diameter and oval-shaped tablets of 20 mm in length and 10 mm in width. The following overview presents characteristics of the printed tables, wherein the first entry denotes to the disk-shaped tables, and the second entry denote to the oval-shaped tables:

[0176] 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 maybe preferred by patients who have difficulty swallowing larger tablets.

[0177] The paste may be used to produce orally disintegrating tablets, ODTs. ODTs, may be understood as fast-dissolving or quick-dissolving tablets. These ODTs disintegrate rapidly in the mouth without the need for water. They are particularly useful for patients who 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 in controlled-release formulations and in multicompartment systems.

[0178] It is conceivable that a paste of the present disclosure is filled into capsules, compressed into tablets, or used as a component of oral suspensions.

[0179] Furthermore, the paste of the present disclosure may be used to manufacture chewable tablets. Chewable tablets are chewed before swallowing. They may comprise flavors and / or colors. These chewable tablets may be used in particular in for pediatric or geriatric formulations. These patient groups have difficulty swallowing traditional tablets. Accordingly, these chewable tablets improve patient compliance and therapeutic benefit.

[0180] 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 described with reference to the aforementioned specification, the descriptions and illustrations of the 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.

[0181] 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 which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended 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

Claims1. A paste for carrying an active pharmaceutical ingredient (API), preferably a GLP-i agonist, and a permeation enhancer, preferably a fatty acid and / or a pharmaceutical acceptable salt thereof, such as sodium decanoate, preferably for use in a screen printing process for printing a pharmaceutical composition, the paste comprising: a binder; a solvent; the API, and the permeation enhancer.

2. The paste of claim i, wherein the paste comprises the permeation enhancer in an amount of 0.1-65 wt.-%, preferably 1-50 wt.-%, further preferred 5-40 wt.-%, further preferred 5-30wt.-%, further preferred 10-25 wt.-% of the total mass of the paste.

3. The paste of claim 1 or 2, wherein the paste comprises a filler, preferably in the amount of 4-15 wt.-%, preferably 5-13 wt.-%, further preferred 6-12 wt.-%, further preferred 7-11 wt.-%, further preferred 8-10 wt.-% of the total mass of the paste.

4. The paste of any preceding claim, wherein the paste comprises one or more humectants, preferably glycerol and / or xylitol.

5. The paste of claim 4, wherein the paste comprises the one or more humectants in an amount of 1-5 wt.-%, preferably 2-3.5 wt.-%, further preferred 2.2-2.9 wt.-%, further preferred 2.4-2.7 wt.-%, further preferred 2.5-2.6 wt.-%.

6. The paste of any preceding claim, wherein the paste comprises an anti-tacking agent, preferably talc.

7. The paste of claim 6, wherein the paste comprises the anti-tacking agent in an amount of 1.0-2.5 wt.-%, preferably 1.1-2.3 wt.-%, further preferred 1.2-2.1 wt.-%,further preferred 1.3-2. o wt.-%, further preferred 1.4-1.9 wt.-%, further preferred 1.5- 1.8 wt.-%.

8. The paste of any preceding claim, wherein the paste comprises an anti-foaming agent, preferably a polydimethylsiloxane (e.g. Silfar 350).

9. The paste of claim 8, wherein the paste comprises the anti-foaming agent in an amount of preferably o.1-3.0 wt.-%, preferably, further preferred 0.3-2.8 wt.-%, further preferred 0.5-2.6 wt.-%, further preferred o.6-2.4 wt.-%, further preferred 0.7-2.2 wt.- %, further preferred o.8-2.0 wt.-% of the total mass of the paste.

10. The paste of any preceding claim, wherein the binder is a polyethylene oxide and / or wherein the solvent is distilled water.

11. The paste of any preceding claim, wherein the paste comprises the binder and the solvent in a total amount of 50-85 wt.-%, preferably 55-80 wt.-%, further preferred 60-75 wt.-% of the total mass of the paste.

12. The paste of any preceding claim, wherein the paste has a viscosity of 5 to 5000 Pa-s, further preferred 500 to 2000 Pa-s at a shear rate of 0.1 s1and 250C.

13. The paste of any preceding claim, having a particle size D90 of less than 100 pm, preferably of less than 50 pm, further preferred of less than 30 pm, further preferred of less than 20 pm, further preferred of less than 15 pm.

14. A method for preparing a paste according to any preceding claim, the method comprising: 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, an anti-foaming agent, an antioxidant, a plasticizer, and / or a disintegrant; e) adding the active pharmaceutical ingredient; f) mixing the composition;g) homogenizing the mixture.

15. The method of claim 14, wherein step g) comprises stirring the mixture with stirring speeds of between 10-5000 rpm, preferably wherein the stirring speed increases during the homogenization.

16. The method of claim 14 or 15, wherein a vacuum is applied during step g).

17. Use of a paste according to any one of claims 1-13 in an additive manufacturing process, in particular for printing a pharmaceutical composition for administration of the API and the permeation enhancer.

Images