Modified starch-based materials for fast disintegrating tablets

Abstract

The instant invention relates to a powder layer for use in 3D binder jetting printing comprising a hydrolyzed and functionalized starch compound. It also relates to a process for 3D binder jetting printing using the same. It also relates to products, in particular solid dosage forms, obtained thereof by 3D binder jetting printing.

Description

DescriptionTitle: Modified starch-based materials for fast disintegrating tabletsTechnical Field

[0001] The present invention relates to 3D printing ingredients, in particular to the use of modified starch-based materials in powders in a manufacturing process of solid forms with 3D binder jetting printing.Background Art

[0002] 3D printing (3DP), also known as additive manufacture (AM), is a process for constructing 3D physical objects from digital models through the successive layer-by-layer deposition of materials such as plastic, metal, ceramics, or even living cells.

[0003] In addition to many applications unrelated to healthcare, 3DP is currently used or under research for oral drugs, implantable drug delivery devices, tissue bioprinting, devices such as prosthesis and even food products.

[0004] When compared to traditional drug manufacturing, it was observed that 3DP is capable of producing reasonably priced, on-demand, patient tailored drugs and / or an increased product complexity. The shapes and internal structures of current drug products are limited by current technologies. When using additive manufacturing, these characteristics can be as complex as one can imagine, and this could prove useful especially for multiple drug release profiles embedded in the same dosage form. Some of the goals are minimising side effects, by achieving near-zero-order release by printing toroidal, cylindrical or perforated oral formulations or by using radial gradients of erosion or diffusion-controlling excipients. The ability to produce unique, individual or multi-drug and / or multi-dose formulations, can be the other important advantage of 3DP medicines, as demand for personalized medicine is increasing and becoming a megatrend.

[0005] The common 3D printing process chain includes the following step:- Creation or adjustment of a CAD model, using specialized software, a 3D scan of an already existing object or medical imagery. The CAD file describes the geometry and size of the 3D structure.-Conversion to one of the printer-ready STL or AMF file formats. These files describe the surface of the model in triangulated sections, depending on the surface curvature degree. Increasing the number of the triangulated sections will increase the resolution of the printed piece.-Slicing the 3D model into layers of specified thickness using specialist software that can also determine the amount and position of support material, which prevents the collapsing of the printed object. The infill density of the printed object has to be specified as well - with 0% for a hollow structure and with 100% for a solid fill part.- Transfer to and setting up of the files on the actual 3D printer.- Layer-by-layer manufacturing of the 3D product.- Occasionally, drying or removal and discarding of support material and postprocessing are required.

[0006] Although research in the field started in the early 1990’s, the FDA has approved only a single 3D printed drug since 2015: Spritam®, an orodispersible dosage form obtained by binder jetting method 3DP, and having the following excipients: colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate20, povidone, sucralose, butylated hydroxyanisole, natural and artificial spearmint flavor.

[0007] The 3DP methods that were adapted to handle pharmaceutical agents and biocompatible materials are: Extrusion printing (in particular Fused Deposition Modeling (FDM), pressure assisted microsyringe (PAM), and more recently, direct powder extrusion), Binder jetting (BJ), Material jetting (MJ), Stereolithography (SLA), Selective laser sintering (SLS). For more information about the 3DP classification, mention may be made of publication of reference Ion-Bogdan Dumitrescu et al. “The age of pharmaceutical 3D printing technological and therapeutical implications of additive manufacturing. Farmacia, 2018, Vol. 66, 3 (365-389)”, in particular Table I.

[0008] Binder jetting or drop-on-powder (DoP) 3D printing is a powder-based technology designed to 3D print highly porous solid dosage forms capable of rapid oral disintegration. This technology is promising for the development of customizable medicine for pediatric and geriatric patients, as well as patients with medical related swallowing difficulties. It works by depositing a small amount of binder ink via an inkjet nozzle onto a layer of powder which has been previously spread onto a surface. Fresh powder is then spread over the previous layer and thecycle is repeated until the 3D object is formed from the bonded powder. Another advantage of this technology is the possibility to produce high drug load tablets.

[0009] Due to the loosely packed nature of the powder bed, the mechanical strength of the solid dosage form is highly dependent on the properties of the composition used to deliver the active drug, which can be formulated into the powder blend or into the binder ink. However, binder ink formulations containing a polymeric ingredients are usually avoided due to the high probability of clogging the inkjet nozzle.

[0010] Although 3DP represents a promising technology in the pharmaceutical field, there are still a limited variety of available, environmentally friendly, edible and printer-friendly materials, which is a bottleneck to the wide-scale adoption of 3D printing technologies. The most commonly used polymers (pharmaceutical grades) as drug carriers for the manufacture of dosage forms by 3D printing are polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polylactic acid (PLA), which are all synthetic fossil oil-based materials.

[0011] In line with the current focus on the sustainable economy, the exploring of natural-derived and renewable biopolymers, instead of fossil oil-based materials, for the fabrication of various products has received tremendous attention.

[0012] A variety of natural derived biopolymers such as cellulose, hemicellulose, pectin, starch, alginate, agarose, and chitosan show potential to be utilized in 3D printing of edible dosage forms, owing to their nontoxicity, edibility, high abundancy, bioactivity (e.g. serve as dietary fibers), and long history of utilization in traditional food or medicine production.

[0013] However, such biomaterials need to be printable and need to allow the obtaining of a final product having satisfying properties (satisfying mechanical and / or biological and / or pharmacokinetic properties etc.). The problem is even more complex since according to the 3DP technology employed, the requirements for processability are different.

[0014] Overall, there is an unsatisfied need for printable materials derived from renewable resources, which would allow the obtaining of products, specifically using binder jetting 3D printing technology, and in particular of solid dosage forms rapidly disintegrating, which would be specially suited for pediatric and geriatric patients, aswell as patients with medical related swallowing difficulties, having all required properties.Objectives of the invention

[0015] Therefore, it is an object of the instant invention to provide materials for use in 3D printing using a binder jetting technology, using ingredients obtained from renewable resources.

[0016] It is another object of the present invention to provide materials for 3D binder jetting manufacturing processes which are safe for both the operators and consumers.

[0017] It is another object of the present invention to provide materials for 3D binder jetting manufacturing processes which are easy to handle.

[0018] It is another object of the present invention to provide materials for 3D binder jetting manufacturing processes which allow the obtaining of products - in particular of solid dosage forms rapidly disintegrating, which would be especially suited for pediatric and geriatric patients, as well as patients with medical related swallowing difficulties - having satisfying mechanical properties (tensile strength, friability, etc.).

[0019] It is another object of the present invention to provide materials for 3D binder jetting manufacturing processes allowing the obtaining of products containing active ingredients in a high concentration - in particular solid dosage forms - and with satisfying disintegrating and active ingredient release properties.Presentation of the invention

[0020] The inventors found that specific starch compounds were very useful in powder layers used in the manufacturing of objects by binder jetting 3DP processes. These starch compounds are hydrolyzed and chemically modified by the addition of functional groups.

[0021] As it will be apparent from the Examples hereinafter, the hydrolyzed and functionalized starch compound according to the invention is particularly useful in binder jetting 3DP technologies. The powder layers obtained for use in said binder jetting 3D printing processes show good properties, especially when compared to starch compounds which are not functionalized, or when compared to standards PVA-based materials. In particular, the hydrolyzed and functionalized starchcompound according to the invention allows obtaining powders for use in binder jetting 3DP manufacturing processes without clogging of the printer nozzles, which is a particular issue encountered with this 3D printing technique.

[0022] The hydrolyzed and functionalized starch compounds according to the invention can be used in a 3DP binder jetting manufacturing method of a product, preferably orally disintegrating solid forms, and more in particular orally disintegrating tablets (ODT), to provide rapidly disintegrating solid forms.

[0023] The hydrolyzed and functionalized starch compounds according to the disclosure are derived from renewable resources and can be formulated with ingredients derived from renewable resources as well.

[0024] This offers great and new perspectives not only for the development of environmentally friendly dosage forms by 3DP; but also for the development of dosage forms having pharmacokinetic properties that cannot be obtained otherwise, i.e. by using standard processes like tablet compression, and in particular to obtain dosage forms which are rapidly disintegrating and therefore, are especially suited for pediatric and geriatric patients, as well as patients with medical related swallowing difficulties.Summary of the invention

[0025] The instant invention thus first relates to a process for the manufacture of a product by 3D binder jetting printing, said process comprising: i. depositing a layer of a powder composition, said powder composition comprising a hydrolyzed and functionalized starch compound; ii. applying an ink binder onto the layer obtained in step (i); iii. repeating steps (i) and (ii) successively until said product is obtained.

[0026] Preferably, said hydrolyzed and functionalized starch compound has a cold- water solubility equal to or higher than 30%, said percentage being expressed in dry weight of soluble starch with respect to the total weight of starch. Preferably, said hydrolyzed and functionalized starch compound has a weight average molecular weight (Mw) lower than 10,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to multiangle laser-light scattering (MALLS) and refractive index (Rl) detectors. Preferably, said hydrolyzed and functionalized starch compound has a viscosity lower than 10,000 mPa.s at 20°C, at a shear rate of 100s-1 , as determined on an aqueous solution comprising 10% dry weight of said starch compound. Preferably, said hydrolyzed and functionalized starch compound is selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof. Preferably, said hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms is hydrolyzed hydroxypropyl starch. Preferably, said amphiphilic hydrolyzed and functionalized starch compound is octenylsuccinate starch. Preferably, said powder composition comprises more than 10% of the hydrolyzed and functionalized starch compound; said percentage being expressed by weight with respect to the total weight of said powder composition. Preferably, said product is a solid form, preferably an orally disintegrating tablet.

[0027] The instant disclosure also relates to an orally disintegrating tablet obtainable by said process.

[0028] The instant disclosure also relates to the use, in a 3D binder jetting printing process of a product, of a powder composition comprising more than 10 % of a hydrolyzed and functionalized starch compound; said percentage being expressed by weight with respect to the total weight of said powder composition; said hydrolyzed and functionalized starch compound being preferably selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.

[0029] Preferably, said hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms is hydrolyzed hydroxypropyl starch and said amphiphilic hydrolyzed and functionalized starch compound is octenylsuccinate starch. Preferably, said product is a solid form, preferably an orally disintegrating tablet.

[0030] The instant disclosure also relates to a powder composition for 3D binder jetting printing, comprising more than 10 % of a hydrolyzed and functionalized starch compound, said percentage being expressed by weight with respect to the total weight of said powder composition; said hydrolyzed and functionalized starch compound being selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and anamphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.Brief Description of DrawingsFig. 1

[0031] [Fig. 1 ] is block diagram showing the protocol of the 3D binder jetting printing process carried out in the examples.Fig. 2

[0032] [Fig. 2] shows the tensile strength (MPa) of 3D printed solid dosage forms prepared by 3D binder jetting technology according to the disclosure containing the active ingredient levetiracetam.Fig. 3

[0033] [Fig. 3] shows the disintegration time of 3D printed solid dosage forms prepared by 3D binder jetting technology according to the disclosure containing the active ingredient levetiracetam.Fig. 4

[0034] [Fig. 4] shows the friability of 3D printed solid dosage forms prepared by 3D binder jetting technology according to the disclosure containing the active ingredient levetiracetam.Description of Embodiments

[0035] The hydrolyzed and functionalized starch compound or powder composition according to the disclosure can be used for binder jetting 3DP.

[0036] 3D printing process

[0037] The invention thus covers a process for the manufacture of a product by 3D binder jetting printing comprising: i. depositing a layer of a powder composition, said powder composition comprising a hydrolyzed and functionalized starch compound; ii. applying an ink binder onto the layer obtained in step (i); iii. repeating steps (i) and (ii) successively until said product is obtained.

[0038] In processes of 3D binder jetting printing, after step (ii) of applying the ink binder, the unbound (or “loose”) powder composition is removed. Preferably, said removed powder composition may be recycled to be used again in step (i). Typically, the powder composition may be used in the printing process and may be recycled for further use in the printing process, after undergoing a step of sieving, to remove eventual agglomerates.

[0039] After printing, the tablets may be dried and brushed to remove the loose powder surrounding the tablet.

[0040] Hydrolyzed and functionalized starch compounds

[0041] The expression “starch compound” classically refers to a substance obtained from starch. It is reminded that the expression “starch” classically refers to the starch isolated from any suitable botanical source such as maize, tapioca barley by any technique well known to those skilled in the art. Isolated starch typically contains no more than 3% of impurities; said percentage being expressed in dry weight of impurities with respect to the total dry weight of isolated starch. These impurities typically comprise proteins, colloidal matters and fibrous residues. Suitable botanical source includes for instance legumes, cereals, and tubers. The starch compounds according to the disclosure can be derived from any suitable botanical source, including for example legumes (e.g. pea), cereals (e.g. maize, rice, wheat, oat), and tubers (e.g. potato, tapioca).

[0042] Hydrolyzed starch compounds according to the disclosure might be hydrolyzed by any suitable technique, for instance by acid treatment, heat treatment, enzymatic treatment, or a combination thereof. They can be dextrins, including maltodextrins or pyrodextrins, but excluding cyclodextrins. “Maltodextrins” classically refers to hydrolyzed starch compounds having a dextrose equivalent from 2 to 20. They are generally obtained by acid or enzymatic hydrolysis. “Pyrodextrins” are classically obtained from the action of high temperatures (generally of at least 100°C), combined with the action of an acid or alkaline or not (“British gums”), in the presence of small amounts of water. Such treatment classically leads to rebranchings and to the formation of so-called “atypical bonds” and pyrodextrins are therefore structurally different from the other hydrolyzed starch compounds, notably from maltodextrins. Preferably, the hydrolyzed starch compounds according to thedisclosure are obtained by acid and / or enzymatic hydrolysis, for instance by [3- or a- amylase hydrolysis, preferably by a-amylase hydrolysis.

[0043] Hydrolyzed starches have to be well differentiated from glucose, glucose syrups and cyclodextrins, the level of hydrolysis of which is too high to still be referred as “starches” as commonly understood by the person skilled in the art. In other words, glucose, glucose syrups and cyclodextrins, are not hydrolyzed starches within the meaning of the invention.

[0044] The functionalized starch compound according to the disclosure is hydrolyzed. This means that it has a reduced molecular weight, as compared to the native starch from which it is derived. Therefore, alternatively or complementarily, the hydrolyzed and functionalized compound according to the disclosure can be defined by its weight average molecular weight (Mw) which is preferably lower than 10,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to multiangle laser-light scattering (MALLS) and refractive index (Rl) detectors. Preferably, the Mw is determined by the following method: samples of starch compounds are diluted in a mixture of dimethylsulfoxide and sodium nitrate 0.1 M. Two columns are used having a porosity of 100 and 1000 Angstrom. Elution is performed in aqueous media at a flow rate of 0.5 mL / min. The system is maintained at a temperature of 40°C. This Mw can be for instance determined according to the detailed protocol as disclosed in the Examples. Preferably, the hydrolyzed and functionalized starch compound according to the disclosure has a weight average molecular weight (Mw) lower than 10 000 kDa, preferably equal to or lower than 9 000 kDa, still preferably equal to or lower than 8 000 kDa, still preferably equal to or lower than 7 000 kDa, still preferably equal to or lower than 6 000 kDa, still preferably equal to or lower than 5 000 kDa, still preferably equal to or lower than 4 000 kDa, still preferably lower than 4 000 kDa, still preferably equal to or lower than 3 500 kDa. It is preferably equal to or higher than 10 kDa, still preferably equal to or higher than 30 kDa, still preferably equal to or higher than 50 kDa, still preferably equal to or higher than 70 kDa, still preferably equal to or higher than 90 kDa, still preferably equal to or higher than 100 kDa, still preferably equal to or higher than 120 kDa, still preferably equal to or higher than 140 kDa, still preferably equal to or higher than 160 kDa, still preferably equal to or higher than 180 kDa, still preferably equal to or higher than 200 kDa. It is for example equal to 3 500 kDa, or equal to 1 000 kDa, or equal to 600 kDa, or equal to 200 kDa.

[0045] Preferably, the hydrolyzed and functionalized starch compound according to the disclosure has a viscosity in water which is preferably lower than 10 000 mPa.s at 20°C, at a shear rate of 100 s-1, as determined on an aqueous solution comprising 10% dry weight of said starch compound. Preferably, the viscosity is determined on a rheometer with a 5 cm 1 ° cone-plate geometry. This viscosity can be for instance determined according to the detailed protocol as disclosed in the Examples. Preferably, said viscosity is lower than or equal to 8 000 mPa.s, still preferably equal to or lower than 6 000 mPa.s, still preferably equal to or lower than 4 000 mPa.s, still preferably equal to or lower than 2 000 mPa.s, still preferably equal to or lower than 1 000 mPa.s, still preferably equal to or lower than 500 mPa.s, still preferably equal to or lower than 300 mPa.s, still preferably equal to or lower than 200 mPa.s, still preferably equal to or lower than 100 mPa.s, still preferably equal to or lower than 50 mPa.s. It is preferably equal to or higher than 1 mPa.s, still preferably equal to or higher than 2 mPa.s. it is for example equal to 2 mPa.s, or equal to 7 mPa.s, or equal to 18 mPa.s, or equal to 42 mPa.s.

[0046] The hydrolyzed starch compound according to the disclosure is also functionalized. In other words, the starch compound according to the disclosure has functional groups added to at least one of its hydroxyl functions. In other words the expression “functionalized” within the meaning of the invention excludes crosslinking. Preferably, the functionalized starch compound according to the disclosure is etherified and / or esterified. Preferably, said starch compound is functionalized, still preferably etherified and / or esterified, with groups having 1 to 20 carbon atoms, still preferably 1 to 15 carbon atoms, still preferably 2 to 12 carbon atoms, still preferably 3 to 12 carbon atoms.

[0047] The functionalized starch compound according to the disclosure might be etherified or esterified or both etherified and esterified. However, it is preferably either esterified or etherified. It can be substituted (i.e. functionalized) with groups of the same or different nature. However, it is preferably substituted with groups of same nature, for example substituted only with hydroxyropyl groups, or acetyl groups, or octenylsuccinyl groups.

[0048] Preferably, the functionalized starch compound according to the disclosure is selected from hydroxypropyl starch, acetyl starch, hydroxyethyl starches, octenylsuccinate starch or from a mixture thereof. It is preferably selected fromhydroxypropyl starch, octenylsuccinate starch, or from a mixture thereof. Hydroxypropyl starches, acetyl starches, hydroxyethyl starches and octenylsuccinate starches are well known to those skilled in the art. Hydroxypropyl starch can be obtained for instance by etherification with propylene oxide. Acetyl starch can be obtained for instance by esterification with acetic anhydride. Octenylsuccinate starches can be obtained for instance by esterification with octenyl succinic anhydride. Hydroxyethyl starches starch can be obtained for instance by reaction of starch with ethylene oxide under alkaline conditions.

[0049] The hydrolyzed and functionalized starch compound according to the disclosure can be amphiphilic as it is the case for instance of octenylsuccinate starches.

[0050] Preferably, the hydrolyzed and functionalized starch compound according to the disclosure has a cold-water solubility equal to or higher than 30%, said percentage being expressed in dry weight of soluble starch with respect to the total weight of starch. Preferably, this cold-water solubility is equal to or higher than 40%, still preferably equal to or higher than 50%, still preferably equal to or higher than 60%, still preferably equal to or higher than 70%, still preferably equal to or higher than 80%, still preferably equal to or higher than 85%, still preferably equal to or higher than 90%, still preferably equal to or higher than 95%. It is for example equal to 95%, or equal to 97%, or equal to 98%. This solubility can be determined for instance by putting 5 grams of the starch compound in 200 mL distilled water, at 20°C. The dry weight dissolved can be determined after centrifugation, and desiccation of the supernatant. This solubility can be for instance determined according to the detailed protocol as disclosed in the Examples. Preferred hydrolyzed and functionalized starch compounds are those having a cold-water solubility of at least 80% in dry weight of starch compound dissolved in water at room temperature (i.e. between 15 to 30°C, for example between 18 to 25°C, for example at 20°C). They are called “cold-water soluble” hydrolyzed and functionalized starch compounds.

[0051] Cold water-soluble starch compound can be commonly obtained from insoluble starch or insoluble starch compound by cooking and / or hydrolyzing said insoluble starch or insoluble starch compound. Said cooking can typically be performed by heating a starch or starch compound suspension, in order for theinsoluble granules to burst and solubilize. The functionalized starch compound according to the disclosure being hydrolyzed, it is sometimes cold-water soluble without the need of additional treatment, depending of course on the level of hydrolysis.

[0052] Preferably, the hydrolyzed and functionalized starch compound according to the disclosure is pregelatinized. Pregelatinization classically means that the starch compound particles no longer present birefringence (lack of crystalline phase) under an optical microscope in polarized light. Pregelatinization can be commonly obtained from birefringent starch or birefringent starch compound, via a thermal treatment (50-90°C in general, notably depending on the botanical origin of the starch) in presence of water (also often referred, like in the previous paragraphs, as “cooking”) with further drying (after the cooking and / or concomitantly). Other chemical(s) might be used as process aid(s). Pregelatinization can be performed for example by drum-drying. In that case, the starch can be cooked before or during the drum-drying step. It can also be cooked and then spray-dried. It can also be obtained by extrusion. It is preferably performed by cooking and spray-drying.

[0053] In a preferred embodiment, the hydrolyzed and functionalized starch according to the disclosure is derived from starch having an amylose content by weight between 0 and 80%; said percentage being expressed in dry weight of amylose with respect to the total dry weight of starch. This amylose content can be determined by the person skilled in the art byway of potentiometric analysis of iodine absorbed by amylose to form a complex. It is preferably between 0 and 60%, still preferably between 0 and 50%, still preferably between 0 and 45%, still preferably between 0 and 40%.

[0054] The hydrolyzed and functionalized starch compound according to the disclosure might undergo other chemical and / or physical modification than the preferred ones exposed in the claims and embodiments included in the present specification, as long as it does not interfere with the desired properties, notably in term of safety and properties of the powder composition to be used in the 3D binder jetting manufacturing process herein disclosed and printed product obtained thereof. However, and because it appears that it is not necessary in the present invention, the hydrolyzed and functionalized starch compound according to the disclosure is preferably no further modified.

[0055] In a preferred embodiment, the hydrolyzed starch compound according to the disclosure is functionalized, still preferably etherified and / or esterified, with alkyl groups having 1 to 5 carbon atoms, preferably 2 to 4 carbon atoms, preferably 2 or 3 carbon atoms, preferably 3 carbon atoms. Preferably the alkyl group is an aliphatic alkyl group, still preferably a saturated aliphatic group.

[0056] Preferably, the hydrolyzed starch compound substituted with C1-C5 alkyl groups according to the disclosure is etherified.

[0057] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is hydrolyzed acetyl starch or hydrolyzed hydroxypropyl starch. In the case of hydrolyzed hydroxypropyl starch, the starch compound preferably has a content of hydroxypropyl groups between 0.5 and 10%; said percentage being expressed in dry weight of hydroxypropyl groups with respect to the total dry weight of hydrolyzed hydroxypropyl starch. The content of hydroxypropyl groups can be determined by the person skilled in the art for instance by Proton nuclear magnetic resonance (proton NMR), preferably according to a method complying with the European Pharmacopeia (“STARCH, HYDROXYPROPYL PREGELATINISED”) as in force on March 1st, 2021. It is preferably between 0.5 and 9%, still preferably between 0.5 and 8%, still preferably between 0.5 and 7%, for example between 5 and 9%, for example equal to 7%.

[0058] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is derived from legume and / or cereal starch, still preferably from pea or maize starch, still preferably from pea starch, still preferably from smooth pea starch. Preferably, the pea starch has an amylose content between 20 and 50%, still preferably between 30 and 45%, still preferably between 30 and 40%, for example equal to 35%. Preferably, the maize starch has an amylose content greater than 5%, preferably between 10 and 40%, still preferably between 15 and 35%, still preferably between 20 and 30%, for example equal to 25%.

[0059] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure has a Mw lower than 9 000 kDa as determined by size-exclusion chromatography (HPSEC) attached to multiangle laser-light scattering (MALLS) and refractive index (Rl) detectors. It is preferably equal to or lower than 8 000 kDa, still preferably equal to or lower than 7 000 kDa, still preferably equal to or lower than 6 000 kDa, still preferably equal to or lower than5 000 kDa, still preferably equal to or lower than 4 000 kDa, still preferably lower than 4 000 kDa, still preferably equal to or lower than 3 500 kDa. It is preferably equal to or higher than 100 kDa, still preferably equal to or higher than 200 kDa, still preferably equal to or higher than 400 kDa, still preferably equal to or higher than 600 kDa, still preferably equal to or higher than 800 kDa, still preferably equal to or higher than 900 kDa, still preferably equal to or higher than 1 000 kDa. It is for example equal to 3 500 kDa, or equal to 1 000 Da.

[0060] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure has a viscosity lower than 8 000 mPa.s at 20°C, at a shear rate of 100 s’1, as determined on an aqueous solution comprising 10% dry weight of said starch compound. It is preferably lower than or equal to 7 000 mPa.s, still preferably equal to or lower than 6 000 mPa.s, still preferably equal to or lower than 4 000 mPa.s, still preferably equal to or lower than 2 000 mPa.s, still preferably equal to or lower than 1 000 mPa.s, still preferably equal to or lower than 500 mPa.s, still preferably equal to or lower than 300 mPa.s, still preferably equal to or lower than 200 mPa.s, still preferably equal to or lower than 100 mPa.s, still preferably equal to or lower than 50 mPa.s. It is preferably equal to or higher than 1 mPa.s, still preferably equal to or higher than 2 mPa.s, still preferably equal to or higher than 5 mPa.s, still preferably equal to or higher than 7 mPa.s, still preferably equal to or higher than 10 mPa.s, still preferably equal to or higher than 15 mPa.s. it is for example equal to 18 mPa.s, or equal to 42 mPa.s..

[0061] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is hydrolyzed by acid-treatment.

[0062] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is cold water-soluble.

[0063] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is pregelatinized. It is preferably cooked. Still preferably, it is cooked and then spray-dried.

[0064] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is derived from a starch having an amylose content between 10 and 60%; said percentage being expressed in dry weight of amylose with respect to the total dry weight of starch. This amylose content is stillpreferably between 20 and 50%, still preferably between 30 and 45%, still preferably between 30 and 40%, for example equal to 35%.

[0065] The hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure might undergo other chemical and / or physical modification than the preferred ones exposed in the claims and embodiments included in the present specification, as long as it does not interfere with the desired properties, notably in term of safety and properties of the powder composition to be used in the 3D binder jetting manufacturing process herein disclosed and printed product obtained thereof. However, and because it appears that it is not necessary in the present invention, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is preferably no further modified.

[0066] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is a product of CAS N° 9049-76-7.

[0067] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the disclosure is complying with European Pharmacopeia (“STARCH, HYDROXYPROPYL PREGELATINISED”) as in force on March 1st, 2021.

[0068] Hydrolyzed starch compound functionalized with C1-C5 alkyl groups particularly useful are commercially available. Mention can be made for instance of hydrolyzed hydroxypropyl starches LYCOAT® RS 720 (CAS N°113894-92-1 ), or LYCOAT® RS 780 (CAS N°113894-92-1 ) commercialized by the Applicant.

[0069] In another preferred embodiment, the hydrolyzed and functionalized starch compound according to the disclosure is amphiphilic. It is preferably functionalized, still preferably etherified and / or esterified, with groups having 8 to 20 carbon atoms, still preferably 9 to 15 carbon atoms, still preferably 11 to 13 carbon atoms, still preferably 12 carbon atoms. The added function is preferably anionic. It is preferably a sodium salt.

[0070] Preferably, the amphiphilic hydrolyzed starch compound according to the disclosure is esterified.

[0071] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is octenylsuccinate starch. In the case of hydrolyzed octenylsuccinate starch, the starch compound preferably has a content ofoctenylsuccinate groups between 0.5 and 5%; said percentage being expressed in dry weight of octenylsuccinyl groups with respect to the total dry weight of hydrolyzed octenylsuccinate starch. The content of octenylsuccinyl groups can be determined by the person skilled in the art for instance by a method complying with the FAO JECFA Food Starch, Modified, INS No. 1450 as in force on March 1st, 2021 . It is preferably lower or equal to 3%, preferably between 0.5 and 3%, for example equal to 2%.

[0072] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is derived from maize starch, preferably from waxy maize starch.

[0073] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure has Mw a lower than 9 000 kDa as determined by sizeexclusion chromatography (HPSEC) attached to multiangle laser-light scattering (MALLS) and refractive index (Rl) detectors. It is preferably equal to or lower than 8 000 kDa, still preferably equal to or lower than 7 000 kDa, still preferably equal to or lower than 6 000 kDa, still preferably equal to or lower than 5 000 kDa, still preferably equal to or lower than 4 000 kDa, still preferably equal to or lower than 3 000 kDa, still preferably equal to or lower than 2 000 kDa, still preferably equal to or lower than 1 000 kDa, still preferably equal to or lower than 800 kDa, still preferably equal to or lower than 600 kDa, still preferably lower than 600 kDa, still preferably equal to or lower than 500 kDa, still preferably equal to or lower than 400 kDa, still preferably equal to or lower than 300 kDa. It is preferably equal to or higher than 10 kDa, still preferably equal to or higher than 30 kDa, still preferably equal to or higher than 50 kDa, still preferably equal to or higher than 70 kDa, still preferably equal to or higher than 90 kDa, still preferably equal to or higher than 100 kDa, still preferably equal to or higher than 120 kDa, still preferably equal to or higher than 140 kDa, still preferably equal to or higher than 160 kDa, still preferably equal to or higher than 180 kDa. It is for example equal to 600kDa or equal to 200 kDa.

[0074] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure has a viscosity lower than 8 000 mPa.s at 20°C, at a shear rate of 100 s’1, as determined on an aqueous solution comprising 10% dry weight of said starch compound. It is preferably lower than or equal to 7 000 mPa.s,still preferably equal to or lower than 6 000 mPa.s, still preferably equal to or lower than 4 000 mPa.s, still preferably equal to or lower than 2 000 mPa.s, still preferably equal to or lower than 1 000 mPa.s, still preferably equal to or lower than 500 mPa.s, still preferably equal to or lower than 300 mPa.s, still preferably equal to or lower than 200 mPa.s, still preferably equal to or lower than 100 mPa.s, still preferably equal to or lower than 50 mPa.s, still preferably equal to or lower than 40 mPa.s, still preferably equal to or lower than 30 mPa.s, still preferably equal to or lower than 20 mPa.s, still preferably equal to or lower than 10 mPa.s, still preferably equal to or lower than 5 mPa.s It is preferably equal to or higher than 1 mPa.s, still preferably equal to or higher than 2 mPa.s. it is for example equal to 2 mPa.s, or equal to 7 mPa.s.

[0075] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is hydrolyzed by enzymatic treatment, preferably with [3- amylase and / or a-amylase, still preferably with a-amylase.

[0076] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is cold water-soluble. Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is pregelatinized. It is preferably cooked. Still preferably, it is cooked and then spray- dried. Preferably, the hydrolysis is performed on the cooked starch. The slurry thus obtained is then preferably filtered before being spray-dried.

[0077] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is derived from a starch having an amylose content equal to or lower than 50%, said percentage being expressed in dry weight of amylose with respect to the total dry weight of starch. It is still preferably equal to or lower than 40%, still preferably equal to or lower than 30%, still preferably equal to or lower than 20%, still preferably equal to or lower than 10%, still preferably equal to or lower than 5%, still preferably equal to or lower than 3%, still preferably equal to or lower than 2%, still preferably equal to or lower than 1 %, still preferably equal to or lower than 0.5%. Still preferably, the hydrolyzed octenylsuccinate starch according to the disclosure is derived from waxy starch, still preferably from maize waxy starch. Such starches typically have amylose content of 0 to 5%.

[0078] The amphiphilic hydrolyzed and functionalized starch compound according to the disclosure might undergo other chemical and / or physical modification thanthe preferred ones exposed in the claims and embodiments included in the present specification, as long as it does not interfere with the desired properties, notably in term of safety and properties of the powder composition to be used in the 3D binder jetting manufacturing process herein disclosed and printed product obtained thereof. However, and because it appears that it is not necessary in the present invention, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is preferably no further modified.

[0079] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is a product of CAS N° 66829-29-6.

[0080] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the disclosure is complying with USP monograph as in force on March 1st, 2021 and / or with the FAO JECFA Food Starch, Modified, INS No. 1450 as in force on March 1st, 2021.

[0081] Amphiphilic hydrolyzed and functionalized starch compounds particularly useful are commercially available. Mention can be made for instance of octenylsuccinate starches CLEARGUM® CO03 (CAS N° 66829-29-6) or CLEARGUM® CO01 (CAS N°66829-29-6) commercialized by the Applicant.

[0082] Powder composition

[0083] Of course, the hydrolyzed and functionalized starch compounds according to the disclosure might be used alone or in combination. In particular, the two preferred starch compounds (octenylsuccinate starches CLEARGUM® CO03, CAS N° 66829-29-6 and CLEARGUM® CO01 , CAS N°66829-29-6) described in the claims and embodiments included in the present specification might be used alone or in combination.

[0084] The hydrolyzed and functionalized starch compounds according to the disclosure are used in a powder composition, in particular a powder composition deposited as a powder layer during the manufacturing of a product using a 3D binder jetting printing process according to the present disclosure.

[0085] Accordingly, the invention also covers a powder composition, particularly useful to the process according to the disclosure, comprising a hydrolyzed and functionalized starch compound, said powder composition being preferably as described in the claims and embodiments of the present specification. In particular,the invention also relates to a powder composition for 3D binder jetting printing, comprising more than 10 % of a hydrolyzed and functionalized starch compound, said percentage being expressed by weight with respect to the total weight of said powder composition; wherein said hydrolyzed and functionalized starch compound is selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.

[0086] Preferably, the hydrolyzed and functionalized starch compound used is as described in the claims and embodiments included in the present specification. It is in particular reminded here that the hydrolyzed starch compound functionalized with C1-C5 alkyl groups, preferably is hydrolyzed hydroxypropyl starch. It is reminded here that the amphiphilic hydrolyzed and functionalized starch compound, preferably is octenylsuccinate starch.

[0087] In a preferred embodiment, the amount of hydrolyzed and functionalized starch compound in the powder composition according to the disclosure is higher than 10%, preferably equal to or higher than 15%, still preferably equal to or higher than 20%, still preferably equal to or higher than 30%, still preferably equal to or higher than 35%, still preferably equal to or higher than 40%; said percentages being expressed by weight with respect to the total weight of said powder composition. It is in general equal to or lower than 97%, still preferably equal to or lower than 90%, still preferably equal to or lower than 80%, still preferably equal to or lower than 70%, still preferably equal to or lower than 60%, still preferably equal to or lower than 50%, %, still preferably equal to or lower than 40%, still preferably equal to or lower than 30%, still preferably equal to or lower than 20% but higher than 10%. It is for example between 15 to 25%, for example between 18 to 22%, for example equal to 20%.

[0088] Preferably, the powder composition according to the disclosure further comprises a sweetener, preferably selected from sugars, sugar alcohols, or from any mixtures thereof. It is still preferably selected from sugar alcohols e.g., mannitol, sorbitol, maltitol, xylitol, erythritol, lactitol, isomalt, or from any mixture thereof. It is preferably mannitol.

[0089] Preferably, the amount of sweetener, in particular of mannitol, is equal to or higher than 1 %, still preferably equal to or higher than 5%, still preferably equal toor higher than 10%; said percentages being expressed by weight with respect to the total weight of said powder composition. It is preferably equal to or lower than 60%, still preferably equal to or lower than 50%, still preferably equal to or lower than 40%, still preferably equal to or lower than 30%, still preferably equal to or lower than 20%. It is for example from 10 to 20%, for example from 12 to 18%, for example equal to 15%.

[0090] Preferably, the powder composition according to the disclosure further comprises a filler. Preferably, the filler according to the disclosure is selected from maltodextrins, pregelatinized starches, partially pregelatinized starches, sugar alcohols (e.g., mannitol), lactose, microcrystalline cellulose (MCC), or from any mixture thereof.

[0091] Preferably, the amount of said filler, preferably of MCC, is equal to or higher than 1 %, still preferably equal to or higher than 2%, still preferably equal to or higher than 5%, still preferably equal to or higher than 10%; said percentages being expressed by weight with respect to the total weight of said powder composition. It is preferably equal to or lower than 87%, still preferably equal to or lower than 80%, still preferably equal to or lower than 70%, still preferably equal to or lower than 60%, still preferably equal to or lower than 50%, still preferably equal to or lower than 40%, still preferably equal to or lower than 30%, still preferably equal to or lower than 20%. It is for example from 10 to 20%, for example from 12 to 18%, for example equal to 15%.

[0092] Preferably, said filler, preferably MCC, has a volume mean diameter D(4;3) equal to or higher than 40 pm, preferably equal to or higher than 50 pm, preferably equal to or higher than 60 pm, preferably equal to or higher than 70 pm, preferably equal to or higher than 80 pm. It is preferably equal to or lower than 300 pm, preferably equal to or lower than 200 pm, preferably equal to or lower than 150 pm, preferably equal to or lower than 140 pm, preferably equal to or lower than 130 pm, preferably equal to or lower than 120 pm, preferably equal to or lower than 110 pm, preferably equal to or lower than 100 pm, preferably equal to or lower than 90 pm.

[0093] Preferably, said filler, preferably MCC, has a D10 in volume equal to or higher than 5 pm, preferably equal to or higher than 10 pm, preferably equal to or higher than 20 pm. It is preferably equal to or lower than 70 pm, preferably equal toor lower than 60 pm, preferably equal to or lower than 50 pm, preferably equal to or lower than 40 pm, preferably equal to or lower than 30 pm.

[0094] Preferably, said filler, preferably MCC, has a D50 in volume equal to or higher than 20 pm, preferably equal to or higher than 30 pm, preferably equal to or higher than 40 pm, preferably equal to or higher than 50 pm, preferably equal to or higher than 60 pm, preferably equal to or higher than 70 pm. It is preferably equal to or lower than 200 pm, preferably equal to or lower than 150 pm, preferably equal to or lower than 100 pm, preferably equal to or lower than 90 pm, preferably equal to or lower than 80 pm.

[0095] Preferably, said filler, preferably MCC, has a D90 in volume equal to or higher than 50 pm, preferably equal to or higher than 100 pm, preferably equal to or higher than 110 pm, preferably equal to or higher than 120 pm, preferably equal to or higher than 130 pm, preferably equal to or higher than 140 pm, preferably equal to or higher than 150 pm. It is preferably equal to or lower than 300 pm, preferably equal to or lower than 250 pm, preferably equal to or lower than 200 pm, preferably equal to or lower than 190 pm, preferably equal to or lower than 180 pm, preferably equal to or lower than 170 pm, preferably equal to or lower than 160 pm.

[0096] It is reminded that the values of D10, D50 and D90 in volume are the size in pm for which 10%, 50% and 90% respectively of particles, in volume, have lower granulometry.

[0097] Preferably, said filler, preferably MCC, has a % in volume of particles having a size from 10 to 150 pm that is equal to or higher than 50%, preferably equal to or higher than 60%, preferably equal to or higher than 70%, preferably equal to or higher than 80%. It is in general equal to or lower than 95%, even equal to or lower than 90%.

[0098] The volume mean diameter D(4;3), and particle size distribution may be determined by the person skilled in the art by means of a laser diffraction particle size analyzer in the dry mode, for example according to the method given the Example section herein after.

[0099] Preferably, the powder composition according to the disclosure further comprises an active ingredient. The active ingredient according to the disclosure includes non-pharmaceutical and pharmaceutical agents. The expression "active" classically refers to any substance of pharmaceutical, veterinary, food, nutraceutical,cosmetic or agrochemical interest. Preferably, the active ingredient according to the disclosure is a pharmaceutical, nutraceutical, cosmetic or veterinary active ingredient. The active ingredient, in particular when it is a pharmaceutical active ingredient, may be chosen from so-called small molecules, but also from so-called "biological" active ingredients, as is the case for example of active substance based on or derived from proteins, nucleic acids - such as those derived from DNA or RNA - cells or viruses. Preferably, the active ingredient of the disclosure is selected from small molecules e.g., levetiracetam.

[0100] The active ingredient according to the disclosure might be very soluble in water, freely soluble in water, soluble in water, sparingly soluble in water, slightly soluble in water, very slightly soluble in water or practically insoluble in water. This solubility in water is well defined for instance in 9thedition of The International Pharmacopeia (2019), Section “General Notice, Solubility”. In the instant disclosure, the expression “water-insoluble” classically refers to active ingredients which are from sparingly soluble in water to practically insoluble in water. In the instant disclosure, the expression “water-soluble” classically refers to active ingredients which are from soluble in water to very soluble in water. Preferably, the active ingredient according to the disclosure is water soluble, still preferably is very soluble.

[0101] In general, the amount of active ingredient in the powder composition according to the disclosure is equal to or higher than 1 %, preferably equal to or higher than 2%, preferably equal to or higher than 5%, preferably equal to or higher than 10%, preferably equal to or higher than 20%, preferably equal to or higher than 30%, preferably equal to or higher than 40%, preferably equal to or higher than 50%; said percentages being expressed by weight with respect to the total weight of said powder composition. It is in general equal to or lower than 87%, even equal to or lower than 80%, even equal to or lower than 70%, even equal to or lower than 60%. It is for example from 40 to 60%, for example from 45 to 55%, for example equal to 50%.

[0102] The powder composition according to the disclosure may include ingredients other than the ones mentioned in the claims and embodiments included in the present specification, as long as those do not interfere with the desired properties, notably in term of safety and properties of the powder composition to be used in the 3D binder jetting manufacturing process herein disclosed. Examples ofsuch other ingredients are:- colors;- flavors;- glidants e.g., colloidal / fumed silicon dioxide, magnesium stearate, talc;- preservatives e.g., butylated hydroxyanisole.

[0103] Preferably, the amount of other ingredients is lower than 86%, still preferably lower than 50%, still preferably lower than 30%, still preferably lower than 10%, still preferably lower than 5%, still preferably lower than 1 %; said percentages being expressed by weight with respect to the total weight of said powder composition. Still preferably, the powder composition according to the disclosure is devoid of such other ingredients.

[0104] Preferably, and because it appears that it is not needed in the present disclosure (in particular for obtaining ODTs), the powder composition according to the disclosure is devoid of superdisintegrants. Examples of such superdisintegrants are crospovidone, sodium starch glycolate, croscarmellose. Preferably, the powder composition according to the disclosure is devoid of crospovidone, and / or of sodium starch glycolate, and / or of croscarmellose.

[0105] In a preferred embodiment the powder composition comprises an amount of non-functionalized hydrolyzed starch, in particular of non-functionalized maltodextrin, lower than 15%; said percentage being expressed by weight with respect to the total weight of said powder composition preferably lower than 10%, more preferably lower than 5%, even more preferably lower than 2%, still more preferably lower than 1 %, still more preferably lower than 0.1 %, still more preferably the powder layer is devoid of non-functionalized hydrolyzed starch, in particular of non-functionalized maltodextrin.

[0106] Therefore, in a preferred embodiment, the powder composition according to the disclosure consists of:- from 11 to 97%, preferably from 15 to 80%, still more preferably from 15 to 60%, still more preferably from 15 to 40%, still more preferably from 18 to 35%, still more preferably from 18 to 22%, even more preferably 20%, of hydrolyzed and functionalized starch compound which is preferably a hydrolyzed starch compound functionalized with C1-C5 alkyl groups, more preferably hydrolyzed hydroxypropyl starch; or an amphiphilic hydrolyzed and functionalized starch compound, morepreferably octenylsuccinate starch;- from 1 to 87%, preferably from 2 to 80%, still more preferably from 10 to 60%, still more preferably from 20 to 70%, still more preferably from 40 to 60%, still more preferably from 45 to 55%, even more preferably 50% of active ingredient;- from 1 to 60%, preferably from 5 to 50%, still more preferably from 5 to 40%, still more preferably from 10 to 30%, still more preferably from 10 to 20%, still more preferably from 12 to 18%, even more preferably 15% of a sweetener, preferably mannitol;- from 1 to 87%, preferably from 2 to 60%, still more preferably from 5 to 40%, still more preferably from 10 to 30%, still more preferably from 10 to 20%, still more preferably from 12 to 18%, even more preferably 15% of a filler, preferably microcrystalline cellulose;- up to 86%, preferably up to 80%, still more preferably up to 50%, still more preferably up to 30%, still more preferably up to 10%, still more preferably up to 5%, even more preferably up to 1 % of other ingredients, preferably no other ingredient; said percentages being expressed by weight with respect to the total weight of said powder composition and their sum being equal to 100%.

[0107] More preferably, the powder composition according to the disclosure consists of:- from 12 to 40%, preferably from 15 to 25%, still more preferably from 18 to 22%, even more preferably 20%, of hydrolyzed and functionalized starch compound which is preferably a hydrolyzed starch compound functionalized with C1-C5 alkyl groups, more preferably hydrolyzed hydroxypropyl starch; or an amphiphilic hydrolyzed and functionalized starch compound, more preferably octenylsuccinate starch;- from 20 to 70%, preferably from 40 to 60%, still more preferably from 45 to 55%, even more preferably 50% of active ingredient;- from 10 to 30%, preferably from 10 to 20%, still more preferably from 12 to 18%, even more preferably 15% of a sweetener, preferably mannitol;- from 5 to 40%, preferably from 10 to 20%, still more preferably from 12 to 18%, even more preferably 15% of a filler, preferably microcrystalline cellulose;- up to 30%, preferably up to 10%, still more preferably up to 5%, even more preferably up to 1 % of other ingredients, preferably no other ingredient;said percentages being expressed by weight with respect to the total weight of said powder composition and their sum being equal to 100%.

[0108] Preferably, the amount of ingredients obtained from renewable sources in the powder composition is equal to or higher than 50%, said percentage being expressed by weight with respect to the total weight of said powder composition. Such ingredients obtained from renewable sources are in particular not obtained from fossil-oils. Still preferably, this amount is equal to or higher than 60%, still preferably equal to or higher than 70%, still preferably equal to or higher than 80%, still preferably equal to or higher than 90%, still preferably equal to 100%. Examples of ingredients which can be obtained from renewable sources are starch compounds, including the hydrolyzed and functionalized starch compounds according to the disclosure, cellulose derivatives like HPMC, HPC, EC, HPMCAS, or MCC, sugars and sugar alcohol.

[0109] Preferably, when an active ingredient is present, the other ingredients (i.e., other than the active ingredient) of the powder composition according to the disclosure consists of at least 50% of ingredients obtained from renewable sources, in particular not obtained from fossil-oils; said percentage being expressed by weight with respect to the total weight of other ingredients of said powder composition. Still preferably, the other ingredients of the powder composition according to the disclosure are composed of at least 60% by weight of ingredients obtained from renewable sources, still preferably of at least 70%, still preferably of at least 80%, still preferably of at least 90%, still preferably of 100%.

[0110] Typically, the powder composition herein described is used as powder layers in the 3D binder jetting printing process. Preferably, said composition is for use in the 3D binder jetting printing process according to this disclosure.

[0111] Preferably, the powder composition according to the disclosure is for the 3D binder jetting printing of an orally disintegrating solid form, preferably an orally disintegrating tablet (ODT), and / or for the 3D jet binding printing of a solid dosage form comprising an active ingredient, preferably a water-soluble active ingredient.

[0112] Preferably, said active ingredient is as described in the claims and embodiments included in the present specification.

[0113] Ink

[0114] In addition, the binder jetting 3DP process comprises the use of an ink. This ink comprises or consist of a solvent. Preferably, said solvent is selected from water, ethanol, 2-propanol, acetone, or from a mixture thereof. It is preferably a mixture of water and 2-propanol. Preferably, in said mixture of water and 2-propanol, the quantity of 2-propanol is from 5 to 50% volume / volume (v / v), preferably from 10 to 40% v / v, preferably from 15 to 35% v / v, preferably from 20 to 30 % v / v, for example of 25% v / v.

[0115] The ink may include other compounds, as long as it does not interfere with the desired properties, notably in term of safety and properties of the ink to be used in the 3D binder jetting manufacturing process herein disclosed and printed product obtained thereof. Such other compounds may be selected from surfactants e.g., polysorbate 20; viscosity modifiers e.g., propylene glycol, polyethylene glycol, glycerol; binders e.g., polyvinylpyrrolidone, hydroxypropyl cellulose, hydrolyzed hydroxypropyl starch.

[0116] Preferably, and because the inventors found that it could be detrimental, the ink according to the disclosure comprises less than 10% of hydrolyzed hydroxypropyl starch; said percentage being expressed by weight of binder with respect to the total weight of said ink. Preferably, this amount is lower than 5%, preferably lower than 2%, preferably lower than 1 %, preferably equal to 0%. Still preferably, the ink according to the disclosure is devoid of hydrolyzed hydroxypropyl starch.

[0117] More generally, the ink according to the disclosure preferably comprises less than 10% of any binder(s); said percentage being expressed by weight of binder with respect to the total weight of said ink. Preferably, this amount is lower than 5%, preferably lower than 2%, preferably lower than 1 %, preferably equal to 0%. Still preferably, the ink according to the disclosure is devoid of any binder(s).

[0118] Preferably, and because it appears that such additional compounds are not required in the ink according to the disclosure, the ink according to the disclosure comprises less than 20% of ingredients other that solvent(s); said percentage being expressed by weight of other ingredients with respect to the total weight of said ink. It is preferably lower than 15%, preferably lower than 10%, preferably lower than 5%, preferably lower than 1 %, preferably lower than 0%. Still preferably, said ink isdevoid of any other ingredients. In other words, it preferably only consists of one or more solvents.

[0119] Printed products

[0120] The process and powder composition according to the disclosure can be used in a binder jetting 3DP manufacturing process of various products.

[0121] The printed product or product to be printed according to the disclosure typically is a solid or semi-solid product, preferably intended for oral administration, for instance a tablet, a gel, a film, a caplet, a softgel, a hard capsule. It can also be a drug loaded medical device. In a preferred embodiment, the printed product or product to be printed according to the disclosure is a solid product, typically a tablet. In a preferred embodiment, the printed product according to the disclosure is not a gel and / or not a film. In other words, it is preferably a solid form, preferably a tablet. The printed product or product to be printed according to the disclosure can be for instance of pharmaceutical, veterinary, nutraceutical, food, cosmetic, or agrochemical interest. It can be for humans or animals. It is preferably a pharmaceutical, veterinary, nutraceutical or cosmetic product. In a preferred embodiment, the printed product or product to be printed according to the disclosure is a dosage form (i.e. a product comprising an active ingredient), preferably a solid dosage form, preferably an oral solid dosage form, in particular a pharmaceutical oral solid dosage form.

[0122] Preferably, the printed product according to the disclosure is an orally disintegrating solid form, preferably an orally disintegrating solid dosage form, preferably an orally disintegrating tablet (ODT). Preferably, the orally disintegrating property of the solid form, is determined according to the guidance as provided by US FDA.

[0123] The invention also covers a product, preferably as described above, obtained or obtainable by the 3DP binder jetting process according to the disclosure.

[0124] The invention also covers an orally disintegrating solid form, preferably as described in the present specification and claims, wherein said orally disintegrating solid form is obtained or is obtainable with said powder composition, in particular said orally disintegrating solid form is obtained or is obtainable according to the binder jetting 3DP manufacturing process herein disclosed.

[0125] Use, in a 3D binder jetting printing process of a product, of a powder composition according to the disclosure.

[0126] The invention also relates to the use, in a 3D binder jetting printing process of a product, of a powder composition according to the disclosure.

[0127] In particular, the invention also relates to the use, in a 3D binder jetting printing process of a product, of a powder composition comprising more than 10 % of a hydrolyzed and functionalized starch compound, said percentage being expressed by weight with respect to the total weight of said powder composition; wherein said hydrolyzed and functionalized starch compound is selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.

[0128] Preferably, the hydrolyzed and functionalized starch compound used is as described in the claims and embodiments included in the present specification. It is in particular reminded here that the hydrolyzed starch compound functionalized with C1-C5 alkyl groups, preferably is hydrolyzed hydroxypropyl starch. It is reminded here that the amphiphilic hydrolyzed and functionalized starch compound, preferably is octenylsuccinate starch.

[0129] Preferably, said powder composition is used as powder layers in the 3D binder jetting printing process.

[0130] Preferably, said powder composition is used for the manufacture of a product as described in the claims and embodiments included in the present specification.

[0131] Preferably, said use is for the 3D binder jetting printing of an orally disintegrating solid form, preferably an orally disintegrating tablet (ODT), and / or for the 3D jet binding printing of a solid dosage form comprising an active ingredient, preferably a water-soluble active ingredient.

[0132] Preferably, said active ingredient is as described in the claims and embodiments included in the present specification.

[0133] In the instant disclosure, the expression “between” classically includes the recited upper and lower limits.

[0134] For the purposes of the present disclosure the % provided in relation to the powder composition herein disclosed refer to the amounts (weights) of each of the ingredients or components, relative to the total weight of the powder composition at the moment of preparing the composition.

[0135] In the instant disclosure, the amounts of ingredients are generally expressed in percentages by weight. Unless otherwise specified these weights are amounts of ingredients as such, in their typical powdery, oily or liquid (for solvents) form. Powdery ingredients generally include small amount of water (also referred to as %moisture or as “loss on drying”) and / or small amounts of impurities. With that respect: starch compounds according to the disclosure generally contain no more than 15% by weight of water, generally 3 to 12%; sugar alcohol like mannitol and sorbitol generally contain no more than 1 % water. This means that when it is for example referred to 10% by weight of a starch compound, this generally corresponds to 8.8 to 9.7% in dry weight (i.e. , anhydrous weight).

[0136] By opposition, in the instant disclosure, when it is referred to dry weight, this well refers to anhydrous weights.

[0137] Other characteristics and advantages of the present invention will emerge clearly on reading the examples given hereinafter, which illustrate the invention without however limiting it.Examples

[0138] A. Materials

[0139] A.1. Starch compounds used and characterization thereof.

[0140] Mw measurement. The Mw was determined by size-exclusion chromatography (HPSEC) attached to multiangle laser-light scattering (MALLS) and refractive index (Rl) detectors, by the following method: samples of starch compounds were diluted in a mixture of dimethylsulfoxide and sodium nitrate 0.1 M. Two columns were used (SUPREMA) which had a porosity of 100 and 1000 Angstrom. Elution was performed in aqueous media at a flow rate of 0.5 mL / min. The system was maintained at a temperature of 40°C.

[0141] Viscosity measurement. Measurements were performed on a rheometer (Physica MCR301 , Anton Paar) with a 5 cm 1 ° cone-plate geometry (CP50). Thetemperature was regulated by way of Peltier. The measurements were performed at 20°C on an aqueous solution comprising 10% dry starch compound as follow: 1 minute equilibrium at 20°C; shear rates from 0.006 to 1 ,000 s_1(log) applied in 3 minutes at 20°C.

[0142] Solubility measurement. In a 250 ml beaker, 200 ml of distilled water were added. 5 grams weigh of starch compound were added and the mixture was homogenized by magnetic agitation for 15 minutes. The resulting solution I suspension was centrifuged 10 minutes at 4,000 rpm. 25 mL of the supernatant were taken out and introduced into a crystallizer and place into an oven at 60°C, until the water evaporates. It was then placed into an oven at 103°C ± 2°C for 1 hour. The residue was placed into a desiccator to cool down at room temperature and then weighted for calculating the solubility in dry weight.

[0143] The characteristics of the various starchy compounds used are presented in Table 1 .

[0144] A.2. Other ingredients used

[0145] The following other ingredients were used: crystalline mannitol PEARLITOL® 25C (ROQUETTE); crystalline mannitol PEARLITOL® 50C (ROQUETTE); microcrystalline cellulose MICROCEL® MC-101 (ROQUETTE); microcrystalline cellulose MICROCEL® MC-102 (ROQUETTE); co-processed hydroxypropylmethyl cellulose (HPMC) and mannitol (PEARLITOL® CR-H, ROQUETTE); co-processed granular starch and mannitol (PEARLITOL® Flash, ROQUETTE); hydroxypropylmethyl cellulose (HPMC E50, Shandong Head Co., Ltd); Polyvinylpyrrolidone (PVP VA 64, MERCK); and Levetiracetam (Zhejiang Huahai Pharmaceutical Co., LtdSpritam).

[0146] A.3. Particle size of the excipient used

[0147] The average diameter D(4;3), D10, D50 and D90 (in volume), and the % in volume of particle having a size ranging from 10 to 150 pm of some of the materials used were measured by dry laser diffraction, applying Fraunhofer theory. The measurement was carried out with the MASTERSIZER 3000 (MALVERN) equipment in the dry mode (using the dispersion unit Aero S), following the manufacturer's specifications. The dispersion unit had a modular hopper with an opening of 0 to 4 mm. The measurement range was 0.01 m to 1000pm and the obscuration was targeted between 0.1 % and 30%. We worked at a pressure of 0.

[0148] The parameters specifically used for PEARLITOL® Flash, PEARLITOL® CR-H, MICROCEL® MC-101 and MICROCEL® MC-102 were the followings: vibration: 75%; hopper opening: 1.0 mm.

[0149] The parameters used specifically for PEARLITOL® 25C were the followings: vibration: 100%; hopper opening: 0.5 mm.

[0150] The parameters used specifically for PEARLITOL® 50C were the followings: vibration: 75%; hopper opening: 1.5 mm.

[0151] 2 measurements were carried out for each sample. The result is the average of the two measurements. The data recorded in volume were: D(4;3) = volume mean diameter. The data recorded in volume mode were the D10, D50 and D90.

[0152] Results are presented in Table 2.

[0153] B. Preparation of orally disintegrating tablets comprising a water- soluble active ingredient by 3D binder jetting printing

[0154] In this Example, the inventors tested the use of different starch compounds for their printability by binder jetting 3DP, and in particular for their ability to print orally disintegrating solid dosage forms. The tablets were prepared according to the protocol shown in Figure 1 using the different powders shown in tables 3 (tables 3A and 3B) and 4 (tables 4A and 4B) below and an ink blend prepared with 25 % volume / volume (v / v) of 2-propanol in ultrapure water (Milli-Q).0155] [Table 1]0156] [Table 2]0157] [Table 3]able 3A: Powder formulations (F1-F12) prepared. Two commonly used polymeric binders (F11 & F12) were also tested for comparison.58] [Table 3B]comparison.0159] [Table 4A]Table 4A: Powder formulations (F13-F17) prepared0160] [Table 4B]Table 4B: Powder formulations (F13-F17) prepared (cont.)

[0161] In tables 3 (3A and 3B) and 4 (4A and 4B), percentages are expressed by weight, with respect to the total weight of the powder composition.

[0162] The ComeTrue® M10 Ceramic Binder Jetting 3D Printer together with the accompanying ComeTrue® Slice software were used for the tablet fabrication.

[0163] Ingredients were sieved through a 355 pm sieve and blending was done at 40 rpm for 20 minutes.

[0164] The final powder blend was transferred to the printer’s powder feed box and compacted lightly. Powder levelling was done using the software’s ‘Prepare to Print’ function, ensuring both the feed box and build box is covered with powder.

[0165] Before commencing the printing process, the tablet design file was first loaded onto the software interface, positioned, and then the following printing parameters were configured in the software settings: Thickness - 0.16 mm, Feedbox - 1 .4, Printing - 1 , Nozzle - 3, Slow axis - 4000 pps.

[0166] After the printing process had concluded, the tablets were left to set in the build box for 15 minutes before being removed individually and transferred to a fume hood to be air dried for 24 hours.

[0167] Once the tablets have fully dried, the loose powder surrounding the tablets were dusted with a brush followed by compressed air.

[0168] The used powder was sieved through a 355 pm sieve before being re-used for further printing.

[0169] The tablets thus obtained were characterized for their tensile strength, disintegration time and friability.

[0170] Tensile strength was calculated from the tablet’s hardness and dimensions. Tablet’s hardness was measured with a tablet hardness tester (ERWEKA TBH 425, ERWEKA GmBH).

[0171] Friability was measured as follow: sample of whole tablets corresponding minimally to 6.5 g was used for the evaluation. The tablets were carefully dedusted over a 355 pm sieve prior to evaluation before weighing the tablet samples and placing them in the drum of the friability tester (PTF 20E, Pharma Test Apparatebau AG). The drum was rotated 100 times and tablets were removed after. Removeloose dust from the tablets as before and weigh the tablets. The percentage loss of mass as a function of the initial mass was determined.

[0172] Disintegration time was measured using a disintegration tester (PTZ AUTO 3, Pharma Test). Water was used as the disintegration media and maintained at 37 ± 2 °C. Individual tablets were placed in each tube before commencing the test. The disintegration time recorded was taken from the time the tablet comes into contact with the media, until it fully disintegrates and passes the screen mesh. As shown in figure 2, of the materials tested, LYCATAB® PGS, PEARLITOL® CR-H and NUTRIOSE® FB-06 (F2, F4-F5) could not achieve intact tablets after the drying step, hence they were deemed to be unsuitable binders for binder jetting. The other formulations (F1 , F3, F6-F10) containing 20% of modified or pregelatinized starch were able to produce tablets of sufficient tensile strength for handling. Two commonly used polymeric binders (F11 & F12) were also tested for comparison and both binders produced tablets with good tensile strength.

[0173] Due to the porous nature of binder jetted tablets, the tensile strength data obtained is accompanied by its friability percentage, as well as its disintegration time; both of which are crucial considerations for a successful formulation.

[0174] Printed tablets from selected formulations were tested for their disintegration time (figure 3) and friability (figure 4). Since the only relevant FDA guideline is for the disintegration time of ODTs (< 30 seconds), Spritam® tablets were characterized as a benchmark for its tensile strength (0.2 MPa) and friability (2.96%). Disintegration data for F10 and F11 have been omitted since the duration exceeded 10 minutes.

[0175] Both formulations containing CLEARGUM® starches (F6 & F8) imparted good tensile strength (> 0.2 MPa), relatively low friability (3-4%) and fast disintegration (< 30s). In comparison, PVP VA 64 (F12), when used at the same concentration, imparted high tensile strength (0.8 MPa), very low friability (0.04%) but slightly longer disintegration time (30-40s).

[0176] To further improve the formulation, other grades of the materials with different particle sizes (F13 & F14), as well as other types of materials (F15-F17) were evaluated as filler and / or sweetener substitutions. We observed that generally for materials with larger particle size, the overall particle size distribution of the blendincreases, resulting in an increase in tablet friability although the tensile strength might remain high.

Claims

Claims

1. A process for the manufacture of a product by 3D binder jetting printing, said process comprising: i. depositing a layer of a powder composition, said powder composition comprising a hydrolyzed and functionalized starch compound; ii. applying an ink binder onto the layer obtained in step (i); iii. repeating steps (i) and (ii) successively until said product is obtained.

2. The process of claim 1 , wherein said hydrolyzed and functionalized starch compound has a cold-water solubility equal to or higher than 30%, said percentage being expressed in dry weight of soluble starch with respect to the total weight of starch.

3. The process of any of claims 1 or 2, wherein said hydrolyzed and functionalized starch compound has a weight average molecular weight (Mw) lower than 10,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to multiangle laser-light scattering (MALLS) and refractive index (Rl) detectors.

4. The process of any of claims 1 to 3, wherein said hydrolyzed and functionalized starch compound has a viscosity lower than 10,000 mPa.s at 20°C, at a shear rate of 100 s’1, as determined on an aqueous solution comprising 10% dry weight of said starch compound.

5. The process of any of claims 1 to 4, wherein said hydrolyzed and functionalized starch compound is selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.

6. The process of claim 5, wherein said hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms is hydrolyzed hydroxypropyl starch.

7. The process of claim 5, wherein said amphiphilic hydrolyzed and functionalized starch compound is octenylsuccinate starch.

8. The process of any of claim 1 to 7, wherein the powder composition comprises more than 10% of the hydrolyzed and functionalized starch compound; said percentage being expressed by weight with respect to the total weight of said powder composition.

9. The process of any of claims 1 to 8, wherein the product is a solid form.

10. The process of claim 9, wherein the solid form is an orally disintegrating tablet.

11. Use, in a 3D binder jetting printing process of a product, of a powder composition comprising more than 10 % of a hydrolyzed and functionalized starch compound; said percentage being expressed by weight with respect to the total weight of said powder composition; said hydrolyzed and functionalized starch compound being preferably selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.

12. Use according to claim 11 , wherein said hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms is hydrolyzed hydroxypropyl starch and said amphiphilic hydrolyzed and functionalized starch compound is octenylsuccinate starch.

13. Use according to any of claims 11 or 12, wherein the product is a solid form, preferably an orally disintegrating tablet.

14. A powder composition for 3D binder jetting printing, comprising more than 10 % of a hydrolyzed and functionalized starch compound, said percentage being expressed by weight with respect to the total weight of said powder composition; said hydrolyzed and functionalized starch compound being selected from the group consisting of a hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms and an amphiphilic hydrolyzed and functionalized starch compound; or from a mixture thereof.

15. An orally disintegrating tablet obtainable by the process of any of claims 1 to 10.

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