Starch-Based Printable Materials

Abstract

The present invention relates to a printable material for 3D printing comprising a hydrolyzed and functionalized starch compound. The present invention also relates to a process for 3D printing using it. The present invention also relates to products, in particular solid dosage forms, obtained therefrom by 3D printing.

Description

[Technical field]

[0001] The present invention relates to printable materials, in particular printable materials for use in 3D printing of solid dosage forms. [Background technology]

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

[0003] Apart from the many applications not related to healthcare, 3DP is currently used or being investigated for oral medications, implantable drug delivery devices, tissue bioprinting, devices such as prostheses, and even food.

[0004] It is acknowledged that 3DP can produce reasonably priced, on-demand, patient-tailored drugs, and / or increased product complexity when compared to traditional drug manufacturing. The shape and internal structure of current drug products are limited by current technology. When using additive manufacturing, these features can be as complex as imaginable, which may prove especially useful for multiple drug release profiles embedded in the same dosage form. Some of the goals are to minimize side effects by printing donut-shaped, cylindrical or perforated oral formulations, or by achieving near zero-order release by using radial gradients of erodible or diffusion-controlling excipients. As the demand for personalized medicine increases and becomes a major trend, the ability to produce unique, individual or multiple drugs and / or multi-dose formulations may be another important advantage of 3DP medicines.

[0005] Although research in this field started in the early 1990s, the FDA has approved only one 3D printed drug since 2015: Spritam®, an orodispersible dosage form obtained by binder jet method 3DP and with the following excipients: colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate 20, povidone, sucralose, butylated hydroxyanisole, natural and artificial spearmint flavors.

[0006] 3DP methods adapted to handle pharmaceutical 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) and Selective laser sintering (SLS). For further information on the 3DP classification, reference can be made to the literature of 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.

[0007] Extrusion printing, specifically FDM, is the most widely used method in the 3D printing field, characterized in that a preheated polymer filament or semi-solid is extruded through a nozzle to a precise location on the platform using xyz positioning. Once the first layer has cooled, the next layer is applied. Depending on the shape of the printed product, a different material may be needed to provide structural support until the object has completely cooled and solidified, after which it can be removed. The PAM technique is similar, except that the printer is supplied with a non-molten viscous material. This is particularly useful for 3D bioprinting. 3D bioprinting refers to a method that uses living cells. The main advantage of biomedically manufactured scaffolds is the proliferation of living cells, but from a pharmaceutical point of view, they can also be a source for drug delivery, with antimicrobial agent-eluting implants as an example. Finally, we can mention a recently developed technique, direct powder extrusion. According to this technique, printable powders are directly extruded, thus avoiding the need for the preparation of filaments.

[0008] A typical 3D printing process chain includes the following steps: - Creation or adjustment of a CAD model using dedicated software, 3D scanning of an existing object or medical image. 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 triangular sections according to the surface curvature. Increasing the number of triangular sections increases the resolution of the printed piece. - Slicing the 3D model into layers of specified thickness using specialized software that can also determine the amount and location of support material that will prevent the printed object from collapsing. The infill density of the printed object must be specified as well - 0% for hollow structures and 100% for solid filled parts. - Transfer and setup of the file to the actual 3D printer. -Layer-by-layer manufacturing of 3D products. In some cases, drying or removal and disposal of the support material and post-processing may be required.

[0009] 3DP is a promising technology in the pharmaceutical field, but the variety of available, environmentally friendly, edible, and printer-friendly materials remains limited, which represents a bottleneck to the large-scale adoption of 3D printing technology.The most commonly used polymers (pharmaceutical grade) as drug carriers for the production of dosage forms by FDM are polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polylactic acid (PLA), which are all synthetic fossil fuel-based materials.

[0010] In line with the current interest in a sustainable economy, the exploration of naturally derived renewable biopolymers as an alternative to fossil fuel-based materials for the manufacture of various products has attracted considerable attention.

[0011] Various naturally derived biopolymers, such as cellulose, hemicellulose, pectin, starch, alginate, agarose, and chitosan, show potential for use in 3D printing of edible dosage forms due to their non-toxicity, edibility, high abundance, bioactivity (e.g., serving as dietary fiber), and long history of use in traditional food or pharmaceutical manufacturing.

[0012] However, such biomaterials need to be printable and make it possible to obtain final products with satisfactory properties (such as satisfactory mechanical and / or biological and / or pharmacokinetic properties).The problem is even more complex, since according to the 3DP technique used, the requirements for processability are different.

[0013] Overall, there is an unmet need for printable materials derived from renewable resources that make it possible to obtain products with all the required properties, especially products in solid dosage form. Summary of the Invention [Problem to be solved by the invention]

[0014] It is therefore an object of the present invention to provide printable materials and 3DP processes that use components derived from renewable resources.

[0015] Another object of the present invention is to provide printable materials that are safe for both operators and consumers.

[0016] Another object of the present invention is to provide a printable material that is easy to handle.

[0017] Another object of the present invention is to provide a printable composition and a 3DP process that makes it possible to obtain products, especially solid dosage forms, with satisfactory mechanical properties.

[0018] Another object of the present invention is to provide a printable material and a 3DP process which makes it possible to obtain products, in particular solid dosage forms, containing active ingredients, which have a satisfactory release behavior and / or a satisfactory pharmacokinetic behavior, e.g. immediate or modified release properties, and / or provide an improved water solubility of the active ingredient.

[0019] Presentation of the invention The inventors have found that certain starch compounds are highly useful in the 3DP process: these starch compounds are hydrolyzed and chemically modified by the addition of functional groups.

[0020] As is evident from the following examples, the hydrolyzed and functionalized starch compound according to the present invention is very versatile.It can be used in various 3DP techniques, especially in 3DP techniques using extrusion, such as FDM or PAM.The filaments obtained for FDM show good mechanical properties, especially when compared with non-functionalized starch compounds or with standard PVA-based filaments.

[0021] The hydrolyzed and functionalized starch compounds according to the present invention can be used in immediate release dosage forms and in regulated or controlled release dosage forms.They can also be used to increase the water solubility of water-insoluble active ingredients.This increase is higher than that observed in dosage forms obtained by standard compression methods.In particular, the inventors have shown that by 3DP it is possible to obtain tablets in which the water solubility of water-insoluble active ingredients is increased by 10 times compared to tablets obtained by direct compression.

[0022] The hydrolyzed and functionalized starch compounds according to the present disclosure are derived from renewable resources and can be formulated with ingredients that are also derived from renewable resources.

[0023] This offers great new perspectives not only for the development of environmentally friendly dosage forms by 3DP, but also for the development of dosage forms with pharmacokinetic properties that cannot be obtained in other ways, i.e. by using standard processes such as tablet compression. [Means for solving the problem]

[0024] Thus, the present invention relates firstly to the use of hydrolyzed and functionalized starch compounds for 3D printing.

[0025] Preferably, the hydrolyzed and functionalized starch compounds have a cold water solubility of 30% or more, said percentage being expressed as the dry weight of soluble starch relative to the total weight of starch.

[0026] Preferably, the hydrolyzed and functionalized starch compounds have a molecular weight (Mw) of less than 10,000 kDa as determined by size-exclusion chromatography (HPSEC) coupled with a multiangle laser-light scattering (MALLS) and refractive index (RI) detector.

[0027] Preferably, the hydrolyzed and functionalized starch compound is at 20° C. for 100 s, as determined in an aqueous solution containing 10% by dry weight of the starch compound. -1 The viscosity of the composition is less than 10,000 mPa.s at a shear rate of 10,000 mPa.s.

[0028] Preferably, the hydrolyzed and functionalized starch compound is selected from hydrolyzed starch compounds functionalized with alkyl groups having 1 to 5 carbon atoms, amphiphilic hydrolyzed and functionalized starch compounds, or mixtures thereof. A preferred hydrolyzed starch compound functionalized with alkyl groups having 1 to 5 carbon atoms is hydrolyzed hydroxypropyl starch. A preferred amphiphilic hydrolyzed and functionalized starch compound is starch octenyl succinate.

[0029] Preferably, the hydrolyzed and functionalized starch compounds are used in a printable material. Preferably, the printable material is a powder, filament, or gel mass.

[0030] Preferably, the use is for 3D printing of a dosage form, preferably a modified release dosage form or an immediate release dosage form.

[0031] Preferably, the use is for 3D printing by a process using extrusion, preferably by a process using hot melt extrusion (HME) or cold extrusion.

[0032] The present invention also relates to a process for the manufacture of products by 3D printing, including the 3D printing of printable materials comprising hydrolyzed and functionalized starch compounds.

[0033] The present invention also relates to 3D printing filaments comprising the hydrolyzed and functionalized starch compounds. [Brief description of the drawings]

[0034] [Figure 1]1 is a table showing the properties of the starch compounds used in the examples. [Diagram 2] 1 shows the release profile of a 3D printed dosage form prepared by FDM technology according to the present disclosure, containing the water-soluble active ingredient diprophylline. [Diagram 3] 1 shows the release profile of a 3D printed dosage form prepared by FDM technology according to the present disclosure containing the water insoluble active ingredient itraconazole, and the release profile of a printed dosage form prepared by standard direct compression. [Figure 4] 1 shows the release profiles of 3D printed dosage forms prepared by PAM technology according to the present disclosure, containing the water-soluble active ingredient diprophylline, printed at 50% and 80% print density. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The present invention relates first to the use of a starch compound for 3D printing (3DP), the starch compound comprising: - hydrolyzed, and -functionalized, relating to use.

[0036] Starch Compounds: The expression "starch compound" typically refers to a raw material derived from starch. It should be borne in mind that the expression "starch" typically refers to starch isolated from any suitable plant material, such as corn, tapioca, barley, etc., by any technique known to the skilled artisan. Isolated starch typically contains not more than 3% by weight of impurities. The percentage is expressed as the dry weight of the impurities relative to the total dry weight of the isolated starch. These impurities typically include proteins, colloidal substances, and fibrous residues. Suitable plant materials include, for example, legumes, cereals, and tubers. The starch compounds according to the present disclosure may be derived from any suitable plant material, including, for example, legumes (e.g., peas), cereals (e.g., corn, rice, wheat, oats), and tubers (e.g., potato, tapioca).

[0037] The hydrolyzed starch compounds according to the present disclosure may be hydrolyzed by any suitable technique, for example, by acid treatment, heat treatment, enzymatic treatment, or a combination thereof. They may be dextrins, including maltodextrins or pyrodextrins, but excluding cyclodextrins. "Maltodextrins" classically refer to hydrolyzed starch compounds having a dextrose equivalent of 2 to 20. They are generally obtained by acid or enzymatic hydrolysis. "Pyrodextrins" classically are obtained from the combination of the action of high temperature (generally at least 100°C) in the presence of a small amount of water, with or without the action of acid or alkali ("British gums"). Such treatments classically lead to rebranching and the formation of so-called "atypical bonds", and therefore pyrodextrins are structurally different from other hydrolyzed starch compounds, especially maltodextrins. Preferably, the hydrolyzed starch compounds according to the invention are obtained by acid and / or enzymatic hydrolysis, for example by β- or α-amylase hydrolysis, preferably by α-amylase hydrolysis.

[0038] Hydrolyzed starch must be sufficiently distinct from glucose, glucose syrup and cyclodextrins, the level of hydrolysis of which is still too high to be called "starch" as generally understood by those skilled in the art. In other words, glucose, glucose syrup and cyclodextrins are not hydrolyzed starches within the meaning of the present invention.

[0039] The functionalized starch compound according to the present disclosure is hydrolyzed. This means that it has a reduced molecular weight compared to the native starch from which it originates. Therefore, alternatively or complementary, the hydrolyzed and functionalized compound according to the present disclosure can be defined by its weight average molecular weight (Mw), which is preferably less than 10,000 kDa, determined by size-exclusion chromatography (HPSEC) attached to a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector. Preferably, Mw is determined by the following method: A sample of the starch compound is diluted in a mixture of dimethyl sulfoxide and sodium nitrate 0.1 M. Two columns with porosities of 100 and 1000 angstroms are used. Elution is performed in an aqueous medium at a flow rate of 0.5 mL / min. The system is maintained at a temperature of 40° C. This Mw can be determined, for example, according to the detailed protocol disclosed in the examples. Preferably, the hydrolyzed and functionalized starch compounds according to the present disclosure have a weight average molecular weight (Mw) of less than 10,000 kDa, preferably less than 9,000 kDa, more preferably less than 8,000 kDa, more preferably less than 7,000 kDa, more preferably less than 6,000 kDa, more preferably less than 5,000 kDa, more preferably less than 4,000 kDa, more preferably less than 4,000 kDa, more preferably less than 3,500 kDa, preferably greater than 10 kDa, more preferably greater than 30 kDa, more preferably greater than 50 kDa, more preferably greater than 70 kDa, more preferably greater than 90 kDa, more preferably greater than 100 kDa, more preferably greater than 120 kDa, more preferably greater than 140 kDa, more preferably greater than 160 kDa, more preferably greater than 180 kDa, more preferably greater than 200 kDa. For example, equal to about 3,500 kDa, or equal to about 1,000 Da, or equal to about 600 kDa, or equal to about 200 kDa.

[0040] Preferably, the hydrolyzed and functionalized starch compounds according to the present disclosure have a solubility in water of 10% by dry weight at 20° C. for 100 s. -1Preferably, the viscosity is less than 10,000 mPa.s in water at a shear rate of 100 / min. Preferably, the viscosity is determined in a rheometer with a 5 cm 1° cone and plate geometry. The viscosity can be determined, for example, according to the detailed protocol disclosed in the Examples. Preferably, the viscosity is 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1,000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less. Preferably, the viscosity is 1 mPa.s or more, more preferably 2 mPa.s or more, for example, equal to about 2 mPa.s, or equal to about 7 mPa.s, or equal to about 18 mPa.s, or equal to about 42 mPa.s.

[0041] The hydrolyzed starch compounds according to the present disclosure are also functionalized. In other words, the starch compounds according to the present disclosure have a functional group attached to at least one of its hydroxyl functional groups. In other words, the term "functionalized" in the sense of the present invention excludes cross-linking. Preferably, the functionalized starch compounds according to the present disclosure are etherified and / or esterified. Preferably, the starch compounds are functionalized with a group having 1 to 20 carbon atoms, more preferably 1 to 15 carbon atoms, more preferably 2 to 12 carbon atoms, more preferably 3 to 12 carbon atoms, more preferably etherified and / or esterified.

[0042] The functionalized starch compound according to the present disclosure may be etherified or esterified, or both etherified and esterified. However, it is preferably esterified or etherified. It may be substituted (i.e. functionalized) with groups of the same or different nature. However, it is preferably substituted with groups of the same nature, for example, only with hydroxypropyl groups, or acetyl groups, or octenylsuccinyl groups.

[0043] Preferably, the functionalized starch compound according to the present disclosure is selected from hydroxypropyl starch, acetyl starch, hydroxyethyl starch, octenyl succinate starch, or mixtures thereof. Preferably, it is selected from hydroxypropyl starch, octenyl succinate starch, or mixtures thereof. Hydroxypropyl starch, acetyl starch, hydroxyethyl starch, and octenyl succinate starch are well known to those skilled in the art. Hydroxypropyl starch can be obtained, for example, by etherification with propylene oxide. Acetyl starch can be obtained, for example, by esterification with acetic anhydride. Octenyl succinate starch can be obtained, for example, by esterification with octenyl succinic anhydride. Hydroxyethyl starch can be obtained, for example, by reacting starch with ethylene oxide under alkaline conditions.

[0044] The hydrolyzed and functionalized starch compounds according to the present disclosure may be amphiphilic, as is the case for example with starch octenyl succinate.

[0045] Preferably, the hydrolyzed and functionalized starch compounds according to the present disclosure have a cold water solubility of 30% or more, the percentage being expressed as the dry weight of soluble starch relative to the total weight of starch. Preferably, this cold water solubility is 40% or more, more preferably 50% or more, more preferably 60% or more, more preferably 70% or more, more preferably 80% or more, more preferably 85% or more, more preferably 90% or more, more preferably 95% or more. For example, equal to about 95%, or equal to about 97%, or equal to about 98%. This solubility can be determined, for example, by placing 5 grams of starch compound in 200 mL of distilled water at 20°C. The dissolved dry weight can be determined after centrifugation and drying of the supernatant. This solubility can be determined, for example, according to the detailed protocol disclosed in the examples. Preferred hydrolyzed and functionalized starch compounds are those that have a cold water solubility of at least 80% of the dry weight of the starch compound dissolved in water at room temperature (i.e. about 20°C). They are referred to as "cold water soluble" hydrolyzed and functionalized starch compounds.

[0046] Cold water-soluble starch compounds can usually be obtained from insoluble starch or insoluble starch compounds by boiling and / or hydrolysis of the insoluble starch or insoluble starch compounds. The boiling is typically carried out by heating a starch or starch compound suspension to rupture and solubilize the insoluble granules. Since the functionalized starch compounds according to the present disclosure are hydrolyzed, they may be cold water-soluble without the need for additional processing, depending on the level of hydrolysis, of course.

[0047] Preferably, the hydrolyzed and functionalized starch compounds according to the present disclosure are pregelatinized. Pregelatinization classically means that the starch compound particles no longer show birefringence (lack of crystalline phases) under an optical microscope in polarized light. Pregelatinization can generally be obtained from birefringent starch or birefringent starch compounds through heat treatment in the presence of water (often called "boiling", as in the previous paragraph) (generally 50-90 ° C, depending in particular on the plant origin of the starch) and further by drying (after and / or simultaneously with boiling). Other chemicals may be used as processing aids. Pregelatinization can be carried out, for example, by drum drying. In that case, the starch can be boiled before or during the drum drying step. It can also be boiled and then spray-dried. It can also be obtained by extrusion. It is preferably carried out by boiling and spray drying.

[0048] In a preferred embodiment, the hydrolyzed and functionalized starch according to the present disclosure is derived from starch having an amylose content of 0-80% by weight, the percentage being expressed as the dry weight of amylose relative to the total dry weight of starch. This amylose content can be determined by the skilled artisan by potentiometric analysis of iodine absorbed by amylose to form a complex. It is preferably 0-60%, more preferably 0-50%, more preferably 0-45%, even more preferably 0-40%.

[0049] The starch compounds hydrolyzed and functionalized according to the present disclosure may be subjected to other chemical and / or physical modifications than those to which they have been preferably previously subjected, so long as they do not interfere with the desired properties, particularly in terms of the safety and properties of the printable materials and the printed products obtained therefrom. However, it is preferred that the starch compounds hydrolyzed and functionalized according to the present disclosure are not further modified, as this does not appear to be essential in the present invention.

[0050] In a preferred embodiment, the hydrolyzed starch compounds according to the present disclosure are functionalized, more preferably etherified and / or esterified, with an alkyl group 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, more preferably a saturated aliphatic group.

[0051] Preferably, the hydrolyzed starch compounds substituted with C1-C5 alkyl groups according to the present disclosure are etherified.

[0052] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the present 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 of 0.5 to 10%, the percentage being expressed as the dry weight of hydroxypropyl groups relative to the total dry weight of hydrolyzed hydroxypropyl starch. The content of hydroxypropyl groups can be determined by a person skilled in the art, for example by proton nuclear magnetic resonance (proton NMR), preferably according to the method according to the European Pharmacopoeia as in force on March 1, 2021 ("STARCH, HYDROXYPROPYL PREGELATINISED"). It is preferably 0.5 to 9%, more preferably 0.5 to 8%, more preferably 0.5 to 7%, for example equal to about 7%.

[0053] Preferably, the hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure are derived from legume and / or cereal starches, more preferably from pea or corn starches, more preferably from pea starches, more preferably from smooth pea starches. Preferably, the pea starches have an amylose content of 20-50%, more preferably from 30-45%, more preferably from 30-40%, for example equal to about 35%. Preferably, the corn starches have an amylose content of more than 5%, preferably from 10-40%, more preferably from 15-35%, more preferably from 20-30%, for example equal to about 25%.

[0054] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the present disclosure has a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector. Preferably, it is 8,000 kDa or less, more preferably 7,000 kDa or less, more preferably 6,000 kDa or less, more preferably 5,000 kDa or less, more preferably 4,000 kDa or less, more preferably 4,000 kDa or less, more preferably 3,500 kDa or less. Preferably, it is 100 kDa or more, more preferably 200 kDa or more, more preferably 400 kDa or more, more preferably 600 kDa or more, more preferably 800 kDa or more, more preferably 900 kDa or more, more preferably 1000 kDa or more. For example, equal to about 3,500 kDa, or equal to about 1,000 Da.

[0055] Preferably, the hydrolyzed starch compound functionalized with a C1-C5 alkyl group according to the present disclosure has a hydrolysis time of 100 s at 20° C., as determined in an aqueous solution containing 10% by dry weight of the starch compound. -1It has a viscosity of less than 8,000 mPa.s at a shear rate of 100 / min. It is preferably 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1,000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less. It is preferably 1 mPa.s or more, more preferably 2 mPa.s or more, more preferably 5 mPa.s or more, more preferably 7 mPa.s or more, more preferably 10 mPa.s or more, more preferably 15 mPa.s or more. For example, it is equal to 18 mPa.s or equal to about 42 mPa.s.

[0056] Preferably, the hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure are hydrolyzed by acid treatment.

[0057] Preferably, the hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure are cold water soluble.

[0058] Preferably, the hydrolyzed starch compound functionalized with a C1-C5 alkyl group according to the present disclosure is pregelatinized. It is preferably boiled. More preferably, it is boiled and then spray dried.

[0059] Preferably, the hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure are derived from starch having an amylose content of 10-60%, said percentage being expressed as the dry weight of amylose relative to the total dry weight of starch, more preferably between 20 and 50%, more preferably between 30 and 45%, more preferably between 30 and 40%, for example equal to about 35%.

[0060] The hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure may be subjected to other chemical and / or physical modifications than the preferred ones to which they have been previously subjected, so long as they do not interfere with the desired properties, particularly with regard to the safety and properties of the printable material and the printed products obtained therefrom. However, it is preferred that the hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure are not further modified, as this is not considered necessary in the present invention.

[0061] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups according to the present disclosure is the product with CAS number 9049-76-7.

[0062] Preferably, the hydrolyzed starch compounds functionalized with C1-C5 alkyl groups according to the present disclosure comply with the European Pharmacopoeia ("STARCH, HYDROXYPROPYL PREGELATINISED"), which came into force on March 1, 2021.

[0063] Particularly useful hydrolyzed starch compounds functionalized with C1-C5 alkyl groups are commercially available. Mention may be made, for example, of the hydrolyzed hydroxypropyl starch LYCOAT® RS 720 (CAS number 113894-92-1) or LYCOAT® RS 780 (CAS number 113894-92-1) marketed by the Applicant.

[0064] In another preferred embodiment, the hydrolyzed and functionalized starch compound according to the present disclosure is amphiphilic. It is functionalized, preferably with a group having 8-20 carbon atoms, more preferably with 9-15 carbon atoms, more preferably with 11-13 carbon atoms, more preferably with 12 carbon atoms, more preferably with etherification and / or esterification. The attached functional group is preferably anionic. It is preferably a sodium salt.

[0065] Preferably, the amphiphilic hydrolyzed starch compounds according to the present disclosure are esterified.

[0066] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the present disclosure is octenyl succinate starch. In the case of hydrolyzed octenyl succinate starch, the starch compound preferably has a content of octenyl succinate groups of 0.5 to 5%, the percentage being expressed as the dry weight of octenyl succinyl groups relative to the total dry weight of hydrolyzed octenyl succinate starch. The content of octenyl succinyl groups can be determined by a person skilled in the art, for example, by a method according to FAO JECFA Food Starch, Modified, INS No. 1450, which came into force on March 1, 2021. It is preferably less than or equal to 3%, preferably 0.5 to 3%, for example equal to about 2%.

[0067] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure are derived from corn starch, preferably waxy corn starch.

[0068] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure have a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) coupled with a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector, preferably 8,000 kDa or less, more preferably 7,000 kDa or less, more preferably 6,000 kDa or less, more preferably 5,000 kDa or less, more preferably 4,000 kDa or less, more preferably 3,000 kDa or less, more preferably 2,000 kDa or less, more preferably 1,000 kDa or less, more preferably 800 kDa or less, more preferably 600 kDa or less, more preferably less than 600 kDa, more preferably 500 kDa or less, more preferably 400 kDa or less, more preferably 300 kDa or less. Preferably, it is 10 kDa or more, more preferably 30 kDa or more, more preferably 50 kDa or more, more preferably 70 kDa or more, more preferably 90 kDa or more, more preferably 100 kDa or more, more preferably 120 kDa or more, more preferably 140 kDa or more, more preferably 160 kDa or more, more preferably 180 kDa or more, for example, equal to about 600 kDa or equal to about 200 kDa.

[0069] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure have a viscosity of 100 s at 20° C., as determined in an aqueous solution containing 10% by dry weight of the starch compound. -1At a shear rate of 1000 mmHg, the viscosity is preferably less than 8,000 mPa.s, more preferably less than 6,000 mPa.s, more preferably less than 4,000 mPa.s, more preferably less than 2,000 mPa.s, more preferably less than 1000 mPa.s, more preferably less than 500 mPa.s, more preferably less than 300 mPa.s, more preferably less than 200 mPa.s, more preferably less than 100 mPa.s, more preferably less than 50 mPa.s, more preferably less than 40 mPa.s, more preferably less than 30 mPa.s, more preferably less than 20 mPa.s, more preferably less than 10 mPa.s, more preferably less than 5 mPa.s. Preferably, the viscosity is 1 mPa.s or more, more preferably 2 mPa.s or more. For example, it is equal to 2 mPa.s or equal to about 7 mPa.s.

[0070] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure are hydrolyzed by enzymatic treatment, preferably with β-amylase and / or α-amylase, more preferably with α-amylase.

[0071] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the present disclosure is cold water soluble. Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the present disclosure is pregelatinized. It is preferably boiled. More preferably, it is boiled and then spray dried. Preferably, hydrolysis is carried out on the boiled starch. The slurry thus obtained is then preferably filtered before being spray dried.

[0072] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure are derived from starch having an amylose content of 50% or less, said percentage being expressed as the dry weight of amylose relative to the total dry weight of starch. More preferably, it is 40% or less, more preferably 30% or less, more preferably 20% or less, more preferably 10% or less, more preferably 5% or less, more preferably 3% or less, more preferably 2% or less, more preferably 1% or less, for example equal to about 0%. More preferably, the hydrolyzed octenyl succinate starch according to the present disclosure is derived from waxy starch, more preferably corn waxy starch. Such starches typically have an amylose content of 0-5%.

[0073] The amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure may be subjected to other chemical and / or physical modifications than those to which they have been preferably subjected previously, so long as they do not interfere with the desired properties, particularly in terms of the safety and properties of the printable materials and the printed products obtained therefrom. However, it is preferred that the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure are not further modified, as this does not appear to be essential in the present invention.

[0074] Preferably, the amphiphilic hydrolyzed and functionalized starch compound according to the present disclosure is the product with CAS number 66829-29-6.

[0075] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds according to the present disclosure comply with the USP monographs effective from March 1, 2021, and / or the FAO JECFA Food Starch, Modified, INS No. 1450, effective from March 1, 2021.

[0076] Particularly useful amphiphilic hydrolyzed and functionalized starch compounds are commercially available, for example the starch octenyl succinate CLEARGUM® CO03 (CAS number 66829-29-6) or CLEARGUM® CO01 (CAS number 66829-29-6) marketed by the applicant.

[0077] Of course, the hydrolyzed and functionalized starch compounds according to the present disclosure may be used alone or in combination. In particular, the two preferred starch compounds mentioned above may be used alone or in combination.

[0078] Printable materials: The hydrolyzed and functionalized starch compounds according to the present disclosure can be used in printable materials.

[0079] Thus, the present invention also encompasses the use of printable materials comprising hydrolyzed and functionalized starch compounds for 3D printing.

[0080] The expression "printable material" classically refers to a material that can be used by itself in the 3DP process, optionally with the addition of a solvent. In other words, it is a ready-to-use material for feeding into a 3D printer. The printable material according to the present disclosure can be in any suitable form. It can be in a liquid, semi-solid (e.g. gel mass) or solid (e.g. powder, filament) state. Preferably, the printable material according to the present disclosure is a gel mass, powder or filament, more preferably a filament. The printable powder can be used directly in 3DP (as in direct powder extrusion) or in the preparation of a printable filament (as in FDM) or for the preparation of a gel mass by simple addition of a solvent, preferably water.

[0081] Preferably, the hydrolyzed and functionalized starch compounds of the printable material according to the present disclosure are as described above.

[0082] The hydrolyzed and functionalized starch compounds may be included alone or in combination in printable materials according to the present disclosure.

[0083] Preferably, the hydrolyzed and functionalized starch compound of the printable material according to the present disclosure is selected from hydrolyzed starch compounds functionalized with C1-C5 alkyl groups, preferably as described above, amphiphilic hydrolyzed and functionalized starch compounds, preferably as described above, or mixtures thereof. It should be noted here that the hydrolyzed starch compound functionalized with C1-C5 alkyl groups is preferably hydrolyzed hydroxypropyl starch. It should be noted here that the amphiphilic hydrolyzed and functionalized starch compound is preferably octenyl succinate starch.

[0084] In a preferred embodiment, the amount of hydrolyzed and functionalized starch compounds in the printable material according to the present disclosure is 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 20%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 90%, more preferably less than 80%, more preferably less than 70%, more preferably less than 60%, more preferably less than 55%, more preferably less than 50%. For example, it is equal to about 42%, or equal to about 49%, or equal to about 50%.

[0085] Generally, the printable material according to the present disclosure further comprises other ingredients. Examples of such other ingredients are active ingredients, sugars, plasticizers and sugar alcohols, colorants, flavorings, lubricants, other starches and starch compounds. The plasticizers and sugar alcohols according to the present disclosure are preferably selected from glycerol, sorbitol, sorbitol anhydride, maltitol, mannitol, xylitol, polyethylene glycols with molecular weights between 400 and 10,000 Daltons, polyethylene glycol stearates, propylene glycol, triethyl citrate, acetyl triethyl citrate, tributyl citrate, polysorbates, acetylated monoglycerides, lactate esters, fatty acids and their ethoxylated salts or derivatives, such as in particular stearic acid, phthalates, ethyl sebacate, butyl sebacate, miglyol, glycerol triacetate, liquid paraffin, lecithin, carnauba wax, hydrogenated castor oil, urea, or mixtures thereof. Preferably, it is selected from sugar alcohols, preferably from mannitol, sorbitol, or from mixtures thereof.Other examples of other components are excipients classically used in 3D printing, especially FDM, such as polylactic acid (PLA); hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose acetate (HPC), ethyl cellulose (EC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone sigma (PVP), crospovidone, microcrystalline cellulose (MCC), Carbopol® 794, polyethylene oxide, polyethylene glycol, Eudragit®, polycaprolactone (PCL), triethyl citrate, tricalcium phosphate, poly(vinyl alcohol) (PVA), Soluplus®, Kollidon®, Kollicoat®, Polyox™.However, the use of fossil fuel based excipients such as PLA, PVP, crospovidone, Carbopol® 794, polyethylene oxide, polyethylene glycol, Eudragit®, PCL, triethyl citrate, tricalcium phosphate, PVA, Soluplus®, Kollidon®, Kollicoat®, or Polyox™ is preferably excluded.

[0086] In general, the amount of other components of the printable material according to the present disclosure (i.e., components other than the hydrolyzed and functionalized starch compounds according to the present disclosure) is 1% or more, more preferably more than 10%, more preferably more than 20%, more preferably more than 30%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 95%, more preferably less than 90%, more preferably less than 80%, more preferably less than 70%, more preferably less than 65%, more preferably less than 60%. For example, it is equal to about 50%, or equal to about 51%, or equal to about 58%.

[0087] Preferably, the printable material according to the present disclosure further comprises an active ingredient. The active ingredients according to the present disclosure include non-pharmaceutical and pharmaceutical. The term "active" classically refers to any substance of pharmaceutical, veterinary, food, nutraceutical, cosmetic or agrochemical interest. Preferably, the active ingredient according to the present disclosure is a pharmaceutical, nutraceutical, cosmetic or veterinary active ingredient. The active ingredient, especially if it is a pharmaceutical active ingredient, can be selected from so-called small molecules, but also from so-called "biological" active ingredients, as for example in the case of active substances 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 present disclosure is selected from itraconazole, diprophylline, living cells or mixtures thereof.

[0088] The active ingredient according to the present disclosure may be highly soluble in water, freely soluble in water, soluble in water, poorly soluble in water, slightly soluble in water, very slightly soluble in water, or substantially insoluble in water. This solubility in water is well defined, for example, in the 9th edition of The International Pharmacopeia (2019), section "General Notice, Solubility". In the present disclosure, the term "water-insoluble" classically refers to an active ingredient that is poorly soluble to substantially insoluble in water. In the present disclosure, the term "water-soluble" classically refers to an active ingredient that is soluble to very water-soluble.

[0089] When an active ingredient according to the present disclosure is water-insoluble, it is preferably slightly soluble to substantially insoluble in water, more preferably very slightly soluble or substantially insoluble in water, and even more preferably substantially insoluble in water.When an active ingredient according to the present disclosure is water-soluble, it is preferably freely soluble in water or highly soluble in water.

[0090] Generally, the amount of active ingredient in the printable material according to the present disclosure is 1% or more, even 2% or more, even 5% or more, even 10% or more, the percentage being expressed by weight relative to the total weight of the printable material, excluding the final solvent. It is generally 99% or less, even 90% or less, even 70% or less, even 50% or less, even 40% or less, even 30% or less, even 20% or less. For example, it is equal to about 10% or equal to about 20%.

[0091] Preferably, the printable material according to the present disclosure comprises: - 1 to 99% of a hydrolyzed and functionalized starch compound according to the present disclosure; -1~99% of other ingredients, -Consists of 0 to 98% solvent, The percentages are expressed by weight relative to the total weight of the printable material, the sum of which equals 100%.

[0092] Preferably, the amount of components derived from renewable resources in the printable material is 50% or more, the percentage being expressed by weight relative to the total weight of the printable material, excluding the final solvent. Such components derived from renewable resources are in particular not derived from fossil fuels. More preferably, the amount is 60% or more, more preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 100%. Examples of components that can be derived from renewable resources are starch compounds, including hydrolyzed and functionalized starch compounds according to the present disclosure, cellulose derivatives such as HPMC, HPC, EC, HPMCAS, or MCC, sugars and sugar alcohols. Examples of ingredients that cannot be obtained from renewable resources are PLA, PVP, crospovidone, Carbopol® 794, polyethylene oxide, polyethylene glycol, Eudragit®, PCL, triethyl citrate, tricalcium phosphate, PVA, Soluplus®, Kollidon®, Kollicoat®, or Polyox™.

[0093] Preferably, when active ingredients are present, the excipients of the printable material according to the present disclosure are comprised of at least 50% of ingredients derived from renewable resources, in particular not derived from fossil fuels, said percentage being expressed by weight relative to the total weight of the excipients of said printable material and excluding any final solvent.More preferably, the excipients of the printable material according to the present disclosure are comprised of at least 60% by weight, more preferably at least 70% by weight, even more preferably at least 80% by weight, even more preferably at least 90% by weight, even more preferably 100% by weight of ingredients derived from renewable resources.

[0094] Printed products: The printable materials according to the present disclosure can be used for 3DP of a variety of products.

[0095] The printed product or the product printed according to the present invention is typically a solid or semi-solid product, preferably intended for oral administration, e.g., a tablet, gel, film, caplet, soft gel, hard capsule. It may also be a drug-loaded medical device. In a preferred embodiment, the printed product or the product printed according to the present invention is a solid product, typically a tablet. In a preferred embodiment, the printed product according to the present invention is not a gel and / or a film. The printed product or the product printed according to the present invention may be, for example, a pharmaceutical, veterinary, nutraceutical, food, cosmetic, or agrochemical object. It may be for human or animal use. Preferably, it is a pharmaceutical, veterinary, nutraceutical or cosmetic. In a preferred embodiment, the printed product or the product printed according to the present disclosure is a dosage form (i.e. a product containing an active ingredient), preferably a solid dosage form, preferably an oral solid dosage form, in particular a pharmaceutical oral solid dosage form.

[0096] In a preferred embodiment, the printed product according to the present disclosure is an immediate release dosage form. Preferably, the immediate release characteristics of the dosage form are determined according to the guidance provided by the US Food and Drug Administration (Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances; Guidance for Industry; August 2018, Biopharmaceutics). This release can be determined in particular using USP Apparatus 2 (paddle method) in 900 mL of simulated gastric fluid medium for 30 minutes. At least 80% by dry weight of the active ingredient should be released within 30 minutes.

[0097] In another preferred embodiment, the printed product according to the present disclosure is a modified or controlled release dosage form. Preferably, the modified or controlled release characteristics of the dosage form are determined according to the same method as described immediately above for the immediate release characteristics, except that the duration is longer, e.g., at least 8 hours instead of 30 minutes. It is also in accordance with the U.S. Food and Drug Administration (General Methods; 32(2) Second Interim Revision Announcement: DISSOLUTION, <711> It is also possible to proceed using dissolution method A (pH shift method, simulating gastric fluid for 2 hours and changing to simulated intestinal fluid for the remaining 10 hours) according to the guidance of the International Journal of Clinical Chemistry (DISSOLUTION; 11 / 21 / 2016). For modified release dosage forms, in contrast to immediate release dosage forms, not more than 80% by dry weight of the active ingredient should be released in 30 minutes. For controlled release dosage forms, not more than 80% by dry weight of the active ingredient should be dissolved in 8 hours. Of course, the active ingredient must still be released. Thus, preferably, at least 20% by dry weight of the active ingredient should be dissolved in 8 hours, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, more preferably at least 60%.

[0098] The present invention also encompasses a product obtained or obtainable by 3D printing, comprising a hydrolyzed and functionalized starch compound, said starch compound being preferably as described hereinbefore. Preferably, the printed product of the present disclosure has a composition as described above for the printable material, except that any final added solvent or moisture of the components used is ignored. Preferably, the printed product is as described above.

[0099] 3D Printing Process: The hydrolyzed and functionalized starch compounds or printable materials according to the present disclosure can be used for 3DP.

[0100] 3D printing can be performed by any suitable method known to the person skilled in the art. Preferably, 3D printing is performed by a method selected from the following: - extrusion, preferably Fused Deposition Modeling (FDM), direct powder extrusion or Pressure Assisted Microsyringe (PAM); -Binder injection, -Material injection, - photopolymerization, preferably stereolithography (SLA) or direct / digital light processing (DLP), Powder Bed Fusion Bonding, preferably Selective Laser Sintering (SLS).

[0101] Preferably, the 3D printing is performed by a process using extrusion. In a preferred embodiment, the 3D printing is performed by a process selected from hot melt extrusion (HME), preferably FDM or direct powder extrusion, more preferably FDM. In another preferred embodiment, the 3D printing is performed by a process using cold extrusion, preferably PAM.

[0102] The present invention also encompasses a process for the manufacture of a product by 3D printing, comprising 3D printing of a printable material according to the present disclosure. Preferably, the printed product or printed product is as described above. Preferably, the 3D printing process is as described above.

[0103] Use in immediate release and / or for formulating water-soluble ingredients and / or in extrusion-based 3DP (especially FDM): As mentioned above, the hydrolyzed functionalized starch compounds or printable materials according to the present disclosure can be advantageously used for various purposes and in various 3DP processes.As is evident from the following examples, the compositions of the present invention can be used for the preparation of immediate release dosage forms and / or for formulating water-soluble active ingredients and / or in 3DP by extrusion methods, preferably by HME, preferably by FDM or direct powder extrusion, more preferably by FDM.

[0104] Thus, in a preferred embodiment the hydrolyzed functionalized starch compound or printable material according to the present disclosure is for 3D printing of immediate release dosage forms by extrusion methods, preferably by HME, in particular by FDM or direct powder extrusion, preferably by FDM, and / or for 3D printing of dosage forms comprising water soluble active ingredients and / or for 3D printing of dosage forms.

[0105] Preferably, the hydrolyzed functionalized starch compound or printable material is for 3D printing of a solid product, preferably a tablet. Preferably, the printable material is a powder or filament, more preferably a filament. The product is preferably intended for oral administration. Preferably, it is a solid oral dosage form.

[0106] Preferably, the dosage form of this embodiment comprises at least an active ingredient. Preferably, the active ingredient is water soluble, more preferably freely soluble in water or highly soluble in water. Preferably, the active ingredient is diprophylline, which is freely soluble in water.

[0107] Preferably, the hydrolyzed and functionalized starch compound used in this embodiment is functionalized with an alkyl group having 1 to 5 carbon atoms, preferably as described above. In particular, hydrolyzed hydroxypropyl starch is preferred. Preferably, the hydrolyzed starch functionalized with an alkyl group having 1 to 5 carbon atoms has a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector. Preferably, it is less than 8,000 kDa, more preferably less than 7,000 kDa, more preferably less than 6,000 kDa, more preferably less than 5,000 kDa, more preferably less than 4,000 kDa, more preferably less than 4,000 kDa. Preferably, the hydrolyzed starch compound functionalized with an alkyl group having 1 to 5 carbon atoms has a molecular weight of 100 kDa or more, more preferably 200 kDa or more, more preferably 400 kDa or more, more preferably 600 kDa or more, more preferably 800 kDa or more, more preferably 900 kDa or more, more preferably 1,000 kDa or more, more preferably more than 1,000 kDa, more preferably 1,500 kDa or more, more preferably 2,000 kDa or more, more preferably 2,500 kDa or more, more preferably 3,000 kDa or more. For example, it is equal to about 3,500 kDa. Preferably, the hydrolyzed starch compound functionalized with an alkyl group having 1 to 5 carbon atoms has a molecular weight of 10% by dry weight of the starch compound at 20°C for 100 s. -1The viscosity is preferably 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1,000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less. The viscosity is preferably 1 mPa.s or more, more preferably 2 mPa.s or more, more preferably 5 mPa.s or more, more preferably 7 mPa.s or more, more preferably 10 mPa.s or more, more preferably 15 mPa.s or more, more preferably 20 mPa.s or more, more preferably 30 mPa.s or more, more preferably 40 mPa.s or more. For example, it is equal to about 42 mPa.s.

[0108] Preferably, hydrolyzed and functionalized starch compounds are used in the printable material in this embodiment.

[0109] Preferably, the amount of hydrolyzed and functionalized starch compounds in the printable material is 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 20%, more preferably more than 24%, more preferably more than 30%, more preferably more than 35%, more preferably more than 36%, more preferably more than 40%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 90%, more preferably less than 70%, more preferably less than 60%, more preferably less than 56%, more preferably less than 55%, more preferably less than 50%, more preferably less than 45%, more preferably less than 44%. For example, it is equal to about 42%.

[0110] Typically, the amount of active ingredient in the printable material is 1% or more, even 2% or more, even 5% or more, even 10% or more, the percentage being expressed by weight relative to the total weight of the printable material, excluding final solvents. It is typically 99% or less, even 90% or less, even 70% or less, even 50% or less, even 40% or less, even 30% or less, for example equal to about 20%.

[0111] Preferably, the printable material further comprises a sugar alcohol or plasticizer. Preferably, the plasticizer or sugar alcohol is selected from sorbitol, mannitol, or a mixture thereof. Preferably, it is a mixture of mannitol and sorbitol. Preferably, the amount of sugar alcohol or plasticizer in the printable material is equal to or greater than 1%, more preferably greater than 5%, more preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 22%, more preferably greater than 24%, more preferably greater than 30%, more preferably greater than 34%, more preferably greater than 35%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is equal to or less than 60%, more preferably less than 55%, more preferably less than 54%, more preferably less than 50%, more preferably less than 45%, more preferably less than 42%, more preferably less than 40%. For example, equal to about 36%.

[0112] When a mixture of mannitol and sorbitol is used, the weight ratio of sorbitol:mannitol is preferably greater than 1:1, more preferably 2:1 or more, more preferably 3:1 or more, preferably 6:1 or less, more preferably 5:1 or less, for example about 4:1.

[0113] Preferably, the printable material further comprises an anti-adherent agent, preferably selected from meltable thermal lubricants, for example from metal salts of fatty acids, fatty acids, fatty alcohols, fatty acid ester hydrocarbons, or form mixtures thereof, for example selected from glyceryl monostearate, magnesium stearate, calcium stearate, sodium stearate, hexadecane, octadecane, sodium stearyl fumarate, glyceryl behenate, stearic acid, or form mixtures thereof, preferably comprising stearic acid, more preferably stearic acid alone. Preferably, the amount of anti-adherent agent is between 0.5 and 5%, preferably between 1 and 4%, preferably between 1 and 3%, for example equal to about 2%, said percentages being expressed by weight relative to the total weight of the printable material, excluding the final solvent.

[0114] As mentioned above, the printable material according to the present disclosure can be used with the final addition of a solvent, such as in 3DP. Preferably, the printable material in this embodiment is a powder or filament. Therefore, the printable material preferably does not have added solvents, such as water.

[0115] Preferably, the printable material comprises: - 1 to 97.5% hydrolyzed and functionalized starch compounds, in particular hydrolyzed hydroxypropyl starch, preferably functionalized with alkyl groups having 1 to 5 carbon atoms, -1~97.5% active ingredients, - 1 to 60% of a plasticizer or sugar alcohol, preferably a combination of mannitol and sorbitol; -0.5 to 5% anti-adhesive agent; -It is composed of 0~96.5% of other ingredients, The percentages are expressed by weight relative to the total weight of the printable material, the sum of which equals 100%.

[0116] Preferably, the amount of other components in the printable material is less than 90%, more preferably less than 50%, more preferably less than 30%, more preferably less than 10%, more preferably less than 5%, more preferably less than 1%, said percentages being expressed by weight relative to the total weight of the printable material and excluding any final solvents. More preferably, the printable material according to the present disclosure does not include such other components.

[0117] The present invention also includes a printable material comprising the hydrolyzed and functionalized starch compound as described in this embodiment. The present invention also includes a dosage form, preferably an immediate release dosage form, having the composition of this printable material, preferably including a water-soluble active ingredient, except for the final solvent obtained or obtainable from this printable material and / or ignored. The present invention also includes a process for the manufacture of products by 3D printing, including 3D printing of this printable material. Preferably, 3DP is performed by an extrusion method, preferably by FDM or direct powder extrusion, more preferably by FDM.

[0118] Use in modified release and / or for solubility enhancement and / or in extrusion-based 3DP (especially FMD): As will be evident from the examples below, the hydrolyzed functionalized starch compounds or printable materials according to the present disclosure can also be used for the preparation of modified release dosage forms, preferably controlled release dosage forms, by extrusion methods, preferably by HME, preferably by FDM or direct powder extrusion, more preferably by FDM, and / or for formulating water insoluble active ingredients and / or in 3DP.

[0119] Thus, in another preferred embodiment the hydrolyzed functionalized starch compound or printable material according to the present disclosure is for 3D printing of a modified release dosage form, preferably for 3D printing of a controlled release dosage form, and / or for 3D printing of a dosage form containing a water insoluble active ingredient, and / or for 3D printing of a dosage form by extrusion method, preferably by HME, in particular by FDM or direct powder extrusion, preferably by FDM.

[0120] Preferably, the hydrolyzed functionalized starch compound or printable material is for 3D printing of a solid product, preferably a tablet. Preferably, the printable material is a powder or filament, more preferably a filament. The product is preferably intended for oral administration. Preferably, it is a solid oral dosage form.

[0121] Preferably, the dosage form comprises at least one active ingredient that is preferably water insoluble, more preferably slightly soluble to substantially insoluble in water, more preferably very slightly soluble or substantially insoluble in water, more preferably substantially insoluble in water, preferably itraconazole, which is substantially insoluble in water.

[0122] Preferably, the hydrolyzed and functionalized starch compound used in this embodiment is selected from hydrolyzed starch compounds functionalized with C1-C5 alkyl groups, preferably as described above, amphiphilic hydrolyzed and functionalized starch compounds, preferably as described above, or mixtures thereof. More preferably, it is a mixture of these. It should be noted here that the hydrolyzed starch compound functionalized with C1-C5 alkyl groups is preferably hydrolyzed hydroxypropyl starch. It should be noted here that the amphiphilic hydrolyzed and functionalized starch compound is preferably hydrolyzed octenyl succinate starch.

[0123] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups used in this embodiment has a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector, preferably 8,000 kDa or less, more preferably 7,000 kDa or less, more preferably 6,000 kDa or less, more preferably 5,000 kDa or less, more preferably 4,000 kDa or less, more preferably 3,500 kDa or less, more preferably less than 3,500 kDa, more preferably 3,000 kDa or less, more preferably 2,500 kDa or less, more preferably 2,000 kDa or less, more preferably 1,500 kDa or less. Preferably, the molecular weight is 100 kDa or more, more preferably 200 kDa or more, more preferably 400 kDa or more, more preferably 600 kDa or more, more preferably 800 kDa or more, more preferably 900 kDa or more. For example, equal to about 1,000 Da. Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups has a molecular weight of 100 g / mol / L at 20° C., as determined in an aqueous solution containing 10% by dry weight of the starch compound. -1 It has a viscosity of less than 8,000 mPa.s at a shear rate of 100 / min. It is preferably 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less, more preferably 40 mPa.s or less, more preferably 30 mPa.s or less, more preferably 20 mPa.s or less. It is preferably 1 mPa.s or more, more preferably 2 mPa.s or more, more preferably 5 mPa.s or more, more preferably 7 mPa.s or more, more preferably 10 mPa.s or more, more preferably 15 mPa.s or more, for example equal to 18 mPa.s.

[0124] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds used in this embodiment have a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) coupled with a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector, preferably 8,000 kDa or less, more preferably 7,000 kDa or less, more preferably 6,000 kDa or less, more preferably 5,000 kDa or less, more preferably 4,000 kDa or less, more preferably 3,000 kDa or less, more preferably 2,000 kDa or less, more preferably 1,000 kDa or less, more preferably 800 kDa or less, more preferably 600 kDa or less, more preferably less than 600 kDa, more preferably 500 kDa or less, more preferably 400 kDa or less, more preferably 300 kDa or less. Preferably, the amphiphilic hydrolyzed and functionalized starch compound has a molecular weight of 10 kDa or more, more preferably 30 kDa or more, more preferably 50 kDa or more, more preferably 70 kDa or more, more preferably 90 kDa or more, more preferably 100 kDa or more, more preferably 120 kDa or more, more preferably 140 kDa or more, more preferably 160 kDa or more, more preferably 180 kDa or more. For example, equal to about 200 kDa. Preferably, the amphiphilic hydrolyzed and functionalized starch compound has a molecular weight of 100 kDa or more at 20° C., 100 s, determined in an aqueous solution containing 10% by dry weight of the starch compound. -1 It has a viscosity of less than 8,000 mPa.s at a shear rate of 100 / min. It is preferably 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less, more preferably 40 mPa.s or less, more preferably 30 mPa.s or less, more preferably 20 mPa.s or less, more preferably 10 mPa.s or less, more preferably 5 mPa.s or less. It is preferably 1 mPa.s or more, more preferably 2 mPa.s or more. For example, it is equal to 2 mPa.s.

[0125] Preferably, hydrolyzed and functionalized starch compounds are used in the printable material in this embodiment.

[0126] Preferably, the amount of hydrolyzed and functionalized starch compounds in the printable material is 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 20%, more preferably more than 30%, more preferably more than 35%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 90%, more preferably less than 70%, more preferably less than 60%, more preferably less than 55%, for example equal to about 50%.

[0127] When hydrolyzed starch compounds functionalized with C1-C5 alkyl groups are used in the printable material, the amount of said starch compounds is preferably 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 12%, more preferably more than 15%, more preferably more than 17%, more preferably more than 20%, more preferably more than 20%, more preferably more than 25%, more preferably more than 25%, said percentage being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably 99% or less, more preferably less than 90%, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 40%, more preferably less than 38%, more preferably less than 35%, more preferably less than 33%, more preferably less than 30%, more preferably less than 30%. For example, equal to about 26%.

[0128] When amphiphilic hydrolyzed and functionalized starch compounds are used in the printable material, the amount of said starch compounds is preferably 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 12%, more preferably more than 15%, and more preferably more than 15%, said percentage being expressed by weight relative to the total weight of the printable material and excluding the final solvent. It is preferably 99% or less, more preferably less than 90%, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 40%, more preferably less than 38%, more preferably less than 35%, more preferably less than 33%, more preferably less than 30%, and more preferably less than 30%. For example, it is equal to about 24%.

[0129] Generally, the amount of active ingredient in the printable material is 1% or more, even 2% or more, even 5% or more, the percentage being expressed by weight relative to the total weight of the printable material, excluding the final solvent. It is generally 99% or less, even 90% or less, even 70% or less, even 50% or less, even 40% or less, even 30% or less, even 20% or less, even 15% or less. For example, about 10%.

[0130] Preferably, the printable material further comprises a sugar alcohol or plasticizer. Preferably, the sugar alcohol or plasticizer is selected from sorbitol, mannitol, or a mixture thereof. Preferably, the amount of sugar alcohol or plasticizer in the printable material is 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 35%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 90% or less, more preferably less than 80%, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 45%, more preferably less than 45%. For example, equal to about 40%.

[0131] As mentioned above, the printable material according to the present disclosure can be used with the final addition of a solvent, such as in 3DP. Preferably, the printable material in this embodiment is a powder or filament. Therefore, the printable material preferably does not have added solvents, such as water.

[0132] Preferably, the printable material comprises: - 1 to 98% of a hydrolyzed and functionalized starch compound according to the present disclosure, in particular a combination of hydrolyzed hydroxypropyl starch and hydrolyzed octenyl succinate starch, -1~98% active ingredients, - 1 to 90% of a plasticizer or sugar alcohol, preferably sorbitol; -Composed of 0-97% other ingredients, The percentages are expressed by weight relative to the total weight of the printable material, the sum of which equals 100%.

[0133] Preferably, the amount of other components in the printable material is less than 90%, more preferably less than 50%, more preferably less than 30%, more preferably less than 10%, more preferably less than 5%, more preferably less than 1%, said percentages being expressed by weight relative to the total weight of the printable material and excluding any final solvents. More preferably, the printable material according to the present disclosure does not include such other components.

[0134] The present invention also encompasses a printable material comprising the hydrolyzed and functionalized starch compound as described in this embodiment. It also encompasses a dosage form, preferably a modified release dosage form, more preferably a controlled release dosage form, and / or a solid form comprising a water-insoluble active ingredient obtained or obtainable from this printable material, and / or a solid form having the composition of this printable material, except for the final solvent, which is ignored. The present invention also encompasses a process for the manufacture of products by 3D printing, including 3D printing of this printable material. Preferably, 3DP is carried out by an extrusion method, preferably by FDM or direct powder extrusion, more preferably by FDM.

[0135] Use in the controlled release of active ingredients and / or for formulating water-soluble active ingredients and / or in extrusion-based 3DP (especially PAM): As will be evident from the examples below, the hydrolyzed functionalized starch compounds or printable materials according to the present disclosure can be used for the preparation of modified release dosage forms and / or for formulating water-soluble active ingredients and / or in 3DP by extrusion methods, preferably by cold extrusion, preferably by PAM.

[0136] Thus, in a preferred embodiment, the hydrolyzed functionalized starch compound or printable material according to the present disclosure is for 3D printing of modified release dosage forms by extrusion methods, preferably by cold extrusion, in particular by PAM, and / or for 3D printing of dosage forms comprising water soluble active ingredients, and / or for 3D printing of dosage forms, and / or for 3D bioprinting.

[0137] Preferably, the hydrolyzed functionalized starch compound or printable material is for 3D printing of a solid product, preferably a tablet. Preferably, the printable material is a gel mass. The product is preferably intended for oral administration. Preferably, it is a solid oral dosage form.

[0138] Preferably, the dosage form comprises at least an active ingredient.

[0139] In a preferred embodiment, the active ingredient is water soluble, more preferably freely soluble in water or highly soluble in water. Preferably, it is diprophylline, which is freely soluble in water. In another preferred embodiment, the active ingredient is a cell.

[0140] Preferably, the hydrolyzed and functionalized starch compound used in this embodiment is selected from hydrolyzed starch compounds functionalized with C1-C5 alkyl groups, preferably as described above, amphiphilic hydrolyzed and functionalized starch compounds, preferably as described above, or mixtures thereof. More preferably, it is a mixture of these. It should be noted here that the hydrolyzed starch compound functionalized with C1-C5 alkyl groups is preferably hydrolyzed hydroxypropyl starch. It should be noted here that the amphiphilic hydrolyzed and functionalized starch compound is preferably octenyl succinate starch.

[0141] Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups used in this embodiment has a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) attached to a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector, preferably 8,000 kDa or less, more preferably 7,000 kDa or less, more preferably 6,000 kDa or less, more preferably 5,000 kDa or less, more preferably 4,000 kDa or less, more preferably 3,500 kDa or less, more preferably less than 3,500 kDa, more preferably 3,000 kDa or less, more preferably 2,500 kDa or less, more preferably 2,000 kDa or less, more preferably 1,500 kDa or less. Preferably, the molecular weight is 100 kDa or more, more preferably 200 kDa or more, more preferably 400 kDa or more, more preferably 600 kDa or more, more preferably 800 kDa or more, more preferably 900 kDa or more. For example, equal to about 1,000 Da. Preferably, the hydrolyzed starch compound functionalized with C1-C5 alkyl groups has a molecular weight of 100 g / mol / L at 20° C., as determined in an aqueous solution containing 10% by dry weight of the starch compound. -1 It has a viscosity of less than 8,000 mPa.s at a shear rate of 100 / min. It is preferably 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less, more preferably 40 mPa.s or less, more preferably 30 mPa.s or less, more preferably 20 mPa.s or less. It is preferably 1 mPa.s or more, more preferably 2 mPa.s or more, more preferably 5 mPa.s or more, more preferably 7 mPa.s or more, more preferably 10 mPa.s or more, more preferably 15 mPa.s or more, for example equal to 18 mPa.s.

[0142] Preferably, the amphiphilic hydrolyzed and functionalized starch compounds used in this embodiment have a Mw of less than 9,000 kDa as determined by size-exclusion chromatography (HPSEC) coupled with a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector, preferably 8,000 kDa or less, more preferably 7,000 kDa or less, more preferably 6,000 kDa or less, more preferably 5,000 kDa or less, more preferably 4,000 kDa or less, more preferably 3,000 kDa or less, more preferably 2,000 kDa or less, more preferably 1,000 kDa or less, more preferably 800 kDa or less, more preferably 600 kDa or less, more preferably less than 600 kDa, more preferably 500 kDa or less, more preferably 400 kDa or less, more preferably 300 kDa or less. Preferably, the amphiphilic hydrolyzed and functionalized starch compound has a molecular weight of 10 kDa or more, more preferably 30 kDa or more, more preferably 50 kDa or more, more preferably 70 kDa or more, more preferably 90 kDa or more, more preferably 100 kDa or more, more preferably 120 kDa or more, more preferably 140 kDa or more, more preferably 160 kDa or more, more preferably 180 kDa or more. For example, equal to about 200 kDa. Preferably, the amphiphilic hydrolyzed and functionalized starch compound has a molecular weight of 100 kDa or more at 20° C., 100 s, determined in an aqueous solution containing 10% by dry weight of the starch compound. -1 It has a viscosity of less than 8,000 mPa.s at a shear rate of 100 / min. It is preferably 8,000 mPa.s or less, more preferably 6,000 mPa.s or less, more preferably 4,000 mPa.s or less, more preferably 2,000 mPa.s or less, more preferably 1000 mPa.s or less, more preferably 500 mPa.s or less, more preferably 300 mPa.s or less, more preferably 200 mPa.s or less, more preferably 100 mPa.s or less, more preferably 50 mPa.s or less, more preferably 40 mPa.s or less, more preferably 30 mPa.s or less, more preferably 20 mPa.s or less, more preferably 10 mPa.s or less, more preferably 5 mPa.s or less. It is preferably 1 mPa.s or more, more preferably 2 mPa.s or more. For example, it is equal to 2 mPa.s.

[0143] Preferably, hydrolyzed and functionalized starch compounds are used in the printable material in this embodiment.

[0144] Preferably, the amount of hydrolyzed and functionalized starch compounds in the printable material is 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 20%, more preferably more than 30%, more preferably more than 40%, more preferably more than 45%, said percentages being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 90%, more preferably less than 80%, more preferably less than 70%, more preferably less than 60%, more preferably less than 55%, more preferably less than 50%, for example equal to about 49%.

[0145] When hydrolyzed starch compounds functionalized with C1-C5 alkyl groups are used in the printable material, the amount of said starch compounds is preferably 1% or more, more preferably more than 5%, more preferably more than 10%, said percentage being expressed by weight relative to the total weight of said printable material, excluding the final solvent. It is preferably 70% or less, more preferably less than 60%, more preferably less than 50%, more preferably less than 40%, more preferably less than 30%, more preferably less than 20%, more preferably less than 15%. For example, it is equal to about 12%.

[0146] When amphiphilic hydrolyzed and functionalized starch compounds are used in the printable material, the amount of said starch compounds is preferably 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 20%, more preferably more than 30%, more preferably more than 35%, said percentage being expressed by weight relative to the total weight of the printable material and excluding the final solvent. It is preferably 70% or less, more preferably less than 60%, more preferably less than 50%, more preferably less than 45%, more preferably less than 40%. For example, it is equal to about 37%.

[0147] Typically, the amount of active ingredient in the printable material is 1% or more, even 2% or more, or even 5% or more, the percentage being expressed by weight relative to the total weight of the printable material, excluding final solvents. It is typically 99% or less, even 90% or less, even 70% or less, even 50% or less, even 40% or less, even 30% or less, even 20% or less, or even 15% or less, for example about 10%.

[0148] Preferably, the printable material further comprises an additional starch compound selected from cold water soluble and / or pregelatinized crosslinked starches, cold water soluble and / or pregelatinized waxy starches, or mixtures thereof. Without wishing to be bound by any theory, the inventors believe that such starches improve the controlled release properties of the dosage form where such release properties are desirable.

[0149] Preferably, it is cold water soluble and pregelatinized.

[0150] Preferably, when the additional starch compound is a cold water soluble and / or pregelatinized crosslinked starch, it is derived from potato starch, which is preferably boiled and drum dried.

[0151] Preferably, when the additional starch compound is a cold water soluble and / or pregelatinized crosslinked starch, it is crosslinked with sodium trimetaphosphate.

[0152] Preferably, the cold water soluble and / or pregelatinized crosslinked starch according to the present disclosure is a product of CAS number 55963-33-2.

[0153] Particularly useful cold water-soluble and / or pregelatinized crosslinked starches are commercially available. Mention may be made, for example, of PREGEFLO® PI10, marketed by the Applicant.

[0154] Preferably, when the additional starch compound is a cold water soluble and / or pregelatinized waxy starch, it is derived from corn waxy starch.

[0155] Preferably, the amount of the additional starch compound in the printable material is 1% or more, more preferably more than 2%, more preferably more than 5%, more preferably more than 10%, more preferably more than 15%, said percentage being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 90%, more preferably less than 70%, more preferably less than 50%, more preferably less than 40%, more preferably less than 30%, more preferably less than 25%, for example equal to about 20%.

[0156] Preferably, the printable material further comprises microcrystalline cellulose (MMC).

[0157] Preferably, the MCC has an average particle size less than or equal to 400 μm, more preferably less than or equal to 200 μm, more preferably less than or equal to 100 μm, more preferably less than or equal to 80 μm, more preferably less than or equal to 60 μm, for example equal to about 50 μm.

[0158] Preferably, the amount of microcrystalline cellulose in the printable material is 1% or more, more preferably more than 2%, more preferably more than 5%, more preferably more than 10%, more preferably more than 15%, the percentage being expressed by weight relative to the total weight of the printable material and excluding the final solvent. Preferably, it is 99% or less, more preferably less than 90%, more preferably less than 80%, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 40%, more preferably less than 30%, more preferably less than 25%. For example, it is equal to about 20%.

[0159] As mentioned above, the printable material according to the present disclosure can be used with the final addition of a solvent, such as in 3DP. Preferably, the printable material of this embodiment is a gel mass. In that case, it is preferred that it further contains a solvent, preferably a polar solvent, preferably water.

[0160] The amount of solvent in the printable material is preferably 10% or more, more preferably more than 20%, more preferably more than 30%, more preferably 40% or more, said percentage being expressed by weight relative to the total weight of the gel mass. It is preferably 80% or less, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, for example equal to about 45%.

[0161] Preferably, the printable material comprises: (a) 1% to 100% of components other than the solvent, which are composed of the following: - 1 to 97% of hydrolyzed and functionalized starch compounds according to the present disclosure, in particular a combination of hydrolyzed hydroxypropyl starch and hydrolyzed octenyl succinate starch, -1~97% active ingredients, -1-97% additional starch compounds; -1 to 97% microcrystalline cellulose, -0~96% of other ingredients, (b) 0 to 99% of a solvent, preferably water; The percentages (a) and (b) are expressed by weight relative to the total weight of the printable material, and their sum equals 100%.

[0162] Preferably, the amount of other components in the printable material is less than 90%, more preferably less than 50%, more preferably less than 30%, more preferably less than 10%, more preferably less than 5%, more preferably less than 1%, said percentages being expressed by weight relative to the total weight of the printable material and excluding any final solvents. More preferably, the printable material according to the present disclosure does not include such other components.

[0163] The present invention also encompasses a printable material comprising a hydrolyzed and functionalized starch compound as described in this embodiment. The present invention also encompasses a dosage form, preferably a controlled release dosage form, which preferably comprises a water-soluble active ingredient, obtained or obtainable from the printable material, and / or has the composition of the printable material, except for the final solvent, which is ignored. It also encompasses a dosage form obtained or obtainable from the printable material, and / or has the composition of the printable material, except for the final solvent, which is ignored, which dosage form further comprises cells. The present invention also encompasses a process for the manufacture of a product by 3D printing or 3D bioprinting, including 3D printing of the printable material. Preferably, 3DP is carried out by an extrusion method, preferably by cold extrusion, preferably by PAM.

[0164] In this disclosure, the phrase "between" classically includes the upper and lower limits stated.

[0165] In the present disclosure, the amounts of ingredients are generally expressed as percentages by weight. Unless otherwise stated, these weights are the amounts of ingredients in their original form, which is generally in powder form. These powdered ingredients generally contain a small amount of water (also called % moisture or "loss on drying"). In that regard, starch compounds according to the present disclosure generally contain 15% or less by weight, generally 3-12% water, and sugar alcohols such as mannitol and sorbitol generally contain 1% or less water. This means that when referring to, for example, 10% by weight of a starch compound, this generally corresponds to 8.8-9.7% by dry weight (i.e. anhydrous weight).

[0166] Conversely, in this disclosure, when dry weight is referred to, the well refers to the anhydrous weight.

[0167] Other characteristics and advantages of the invention will emerge more clearly from a reading of the examples which follow, which are intended to illustrate but not limit the invention. EXAMPLES

[0168] A. Material A.1. Starch compounds used and their characterization. Mw measurement. Mw was determined by size-exclusion chromatography (HPSEC) attached to multi-angle laser-light scattering (MALLS) and refractive index (RI) detectors by the following method: A sample of starch compound was diluted in a mixture of dimethyl sulfoxide and sodium nitrate 0.1 M. Two columns (SUPREMA) with porosity of 100 and 1000 Angstroms were used. Elution was performed in aqueous medium at a flow rate of 0.5 mL / min. The system was maintained at a temperature of 40°C.

[0169] Viscosity measurements. Measurements were performed on a rheometer (Physica MCR301, Anton Paar) with a 5 cm 1° cone-plate geometry (CP50). Temperature was regulated by a Peltier. Measurements were performed at 20 °C on aqueous solutions containing 10% dry starch compounds as follows: 1 min equilibration at 20 °C, 0.006-1,000 s applied in 3 min at 20 °C. -1 (log) shear rate.

[0170] Solubility Measurement. To a 250 ml beaker, 200 ml of distilled water was added. 5 grams weight of starch compound was added and the mixture was homogenized by magnetic stirring for 15 minutes. The resulting solution / suspension was centrifuged at 4,000 rpm for 10 minutes. 25 mL of the supernatant was taken and introduced into a crystallizer and placed in an oven at 60°C until the water evaporated. It was then placed in an oven at 103+C±2°C for 1 hour. The residue was placed in a desiccator to cool at room temperature and then weighed to calculate the solubility in dry weight.

[0171] The characteristics of the different starchy compounds used are shown in FIG.

[0172] A.2. Other ingredients used The following other ingredients were used: sorbitol (NEOSORB® 100C, ROQUETTE), mannitol (PEARLITOL® 100SD, ROQUETTE); stearic acid (Stearic acid 50, SIGMA-ALDRICH), diprophylline (Shanghai Star), itraconazole (Shanghai Star), cross-linked cold water-soluble potato starch (PREGEFLO® PI10, ROQUETTE), microcrystalline cellulose with an average particle size of about 50 μm (MCC101, ROQUETTE).

[0173] B. Preparation of immediate release tablets containing water-soluble active ingredients by FDM In this example, the inventors tested the use of hydrolyzed and functionalized starch compounds, particularly for their printability by extrusion methods, and in particular for their ability to print immediate release dosage forms.

[0174] We prepared filaments from various formulations, as shown in Table 2.

[0175] [Table 1]

[0176] In this table, the percentages are expressed by weight relative to the total weight of the formulation (the powder mixture used to prepare the filaments).

[0177] The components were sieved through a 500 μm sieve and blended at 40 rpm. The blend was then passed through a twin screw extruder consisting of four zones (feed zone, mixing, kneading and exit) to prepare filaments. The temperatures of the zones were 120° C., 160° C., 160° C. and 120° C.

[0178] Printing was performed at 180° C. using an Ultimaker S5 printer equipped with a printhead BB core (mainly for water-soluble materials), the speed was 4 mm / s, and the print height was 0.065 mm. The printed tablets were cylindrical tablets with a diameter of 10 mm and a height of 5 mm.

[0179] Only the filaments obtained from formulation F1 were able to achieve continuous printing. Printing took about 1 hour per tablet. The filaments obtained from formulations F2, F3, F5 and F6 were too brittle to print. For formulations F4, F7 and F8, it was not possible to obtain filaments. Formulation F4 was not extrudable, the extrudate obtained from formulation F7 was liquid, and the extrudate obtained from formulation F8 was not a filament.

[0180] Tablets (at least 6 tablets) obtained from formulation F1 were tested for their immediate release properties in 900 mL of simulated gastric fluid medium for 30 min using USP apparatus 2 (Paddle method) according to the guidance provided by the US Food and Drug Administration (Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances; Guidance for Industry; August 2018, Biopharmaceutics). Drug concentration was assessed using a UV spectrophotometric apparatus.

[0181] The resulting release profile is shown in Figure 2. These results show that the hydrolyzed and functionalized starch compounds according to the present disclosure, especially the hydrolyzed etherified and / or esterified starch compounds, can be used in 3DP, especially using HME, especially by FDM. These results also show that the hydrolyzed and functionalized starch compounds according to the present disclosure can be used to prepare immediate release dosage forms by 3DP.

[0182] C. Example 2 - Preparation of Solubility Enhanced Tablets Containing Water Insoluble Active Ingredients with Controlled Release Properties by FDM In this example, the inventors tested the use of hydrolyzed and functionalized starch compounds for their printability, and in particular for their ability to print dosage forms containing water-insoluble active ingredients.

[0183] We prepared filaments from the formulations shown in Table 3.

[0184] [Table 2]

[0185] In this table, the percentages are expressed by weight relative to the total weight of the formulation (the powder mixture used to prepare the filaments).

[0186] The components were sieved through a 500 μm sieve and blended at 40 rpm. To prepare the filaments, the blend was then passed through a twin screw extruder consisting of four zones (feed zone, mixing, kneading and exit), the temperatures of each zone being 120° C., 160° C., 160° C. and 100° C.

[0187] Printing was performed at 180° C. using an Ultimaker S5 printer equipped with a printhead BB core (mainly for water-soluble materials), the speed was 4 mm / s, and the print height was 0.065 mm. The printed tablets were cylindrical tablets with a diameter of 10 mm and a height of 5 mm.

[0188] The filaments obtained from formulation F8 could achieve continuous printing. Furthermore, it is noted that we printed using filaments from different batches and showed similar release patterns and drug contents, reflecting the good content uniformity of the filaments.

[0189] The tablets (at least 6 tablets) obtained from formulation F8 were tested for their release characteristics in the same manner as described in Example B above, except that the duration was 8 hours. HPLC was used to assess the drug concentration using acetonitrile and water in a 60:40 ratio as the mobile phase.

[0190] For comparison, tablets were also prepared from formulation F8 by direct compression, with the same shape as that obtained by 3DP. We compressed the powder blend (500 mg) to 4 mm using a 10 mm flat face bevel edge (FFBE) tablet punch with a compression time of about 1000 ms. Upon removal from the machine (STYL'One tablet press), the cylindrical tablets were measured and the height, diameter and weight were recorded at about 5 mm, 10 mm and 500 mg, respectively.

[0191] The release profiles obtained for the 3D printed dosage forms and for the dosage forms obtained by standard direct compression are shown in FIG. 3. These results show that the hydrolyzed and functionalized starch compounds according to the present disclosure, in particular the hydrolyzed etherified and / or esterified starch compounds, can also be used to prepare dosage forms containing water-insoluble active ingredients by 3DP. The release is significantly improved compared to when a standard compression process is used to make the tablets. After 8 hours, 60% dry weight of the active ingredient was released for the 3D printed tablets, while a release of 5% was obtained for the tablets obtained by standard compression. These results show that the hydrolyzed and functionalized starch compounds according to the present disclosure, in particular the hydrolyzed etherified and / or esterified starch compounds, can be advantageously used to prepare dosage forms with increased solubility and / or to prepare controlled release dosage forms.

[0192] Example 3 - Preparation of modified release tablets containing water-soluble active ingredients with PAM In this example, the inventors have tested the use of hydrolyzed and functionalized starch compounds for their printability, in particular for their ability to print modified release dosage forms containing water-soluble active ingredients. Filaments were prepared from these formulations, and then tablets were prepared by PAM. The tablets thus obtained were tested for their release profile.

[0193] We prepared a gel mass as a printable material having the formulation shown in Table 4.

[0194] [Table 3]

[0195] In this table, the percentages are expressed by weight relative to the total weight of the formulation (powder mix for preparing the gel mass and gel mass).

[0196] The gel mass was prepared as follows: the powder mixture was blended manually for at least 10 min and then added to water at 90 °C under stirring conditions. The mixture was cooled under stirring conditions for at least 4 h and then transferred to a 3 mL print cartridge. The nozzle used was 0.41 mm (21 gauge). The print pattern was a cylinder with a diameter of 10 mm and a height of 5 mm. The print parameters were as follows: pressure 90-110 kPa, speed 1 mm / s, layer height 0.41 mm, first layer compensation 75%, printer BIoX. The print density was varied (i.e., 50% and 80%).

[0197] The formed tablets were then vacuum dried to ensure complete dryness.

[0198] Tablets (at least 6 tablets) from formulation F9 were tested in accordance with the U.S. Food and Drug Administration (General Methods; 32(2) Second Interim Revision Announcement: DISSOLUTION, <711> The modified release properties were tested using dissolution method A (pH shift method, simulating gastric fluid for 2 hours and then changing to simulated intestinal fluid for the remaining 10 hours) in accordance with the guidance of the International Journal of Clinical Chemistry (ICC 2016; DISSOLUTION; 11 / 21 / 2016).

[0199] The results are shown in Figure 4. After 30 minutes, 41% dry weight of the active ingredient is released for the tablet printed at 50% density. After 30 minutes, 29% dry weight of the active ingredient is released for the tablet printed at 80% density.

[0200] These results show that the hydrolyzed and functionalized starch compounds according to the present disclosure, especially the hydrolyzed etherified and / or esterified starch compounds, can be used in 3DP, especially by PAM, using cold extrusion. This can be useful for 3D bioprinting. These results show that the hydrolyzed and functionalized starch compounds according to the present disclosure, especially the hydrolyzed etherified and / or esterified starch compounds, can also be used to prepare controlled release dosage forms by 3DP. By changing the printing density, it is advantageously possible to change the release profile of the tablet.

Claims

1. Use of hydrolyzed and functionalized starch compounds for 3D printing.

2. 2. The use according to claim 1, wherein the hydrolyzed and functionalized starch compound has a cold water solubility of 30% or more, said percentage being expressed as the dry weight of soluble starch relative to the total weight of starch.

3. 3. The use according to claim 1 or 2, wherein the hydrolyzed and functionalized starch compound has a weight average molecular weight (Mw) of less than 10,000 kDa as determined by size-exclusion chromatography (HPSEC) coupled with a multi-angle laser-light scattering (MALLS) and refractive index (RI) detector.

4. The hydrolyzed and functionalized starch compounds are determined in an aqueous solution containing 10% by dry weight of the starch compounds, at 20° C. for 100 s. －１ 3. Use according to claim 1 or 2, wherein the composition has a viscosity of less than 10,000 mPa.s at a shear rate of 100 MPa.

5. 3. The use according to claim 1 or 2, wherein the hydrolyzed and functionalized starch compound is selected from hydrolyzed and functionalized starch compounds functionalized with alkyl groups having 1 to 5 carbon atoms, amphiphilic hydrolyzed and functionalized starch compounds, or mixtures thereof.

6. The use according to claim 5, wherein the hydrolyzed starch compound functionalized with an alkyl group having 1 to 5 carbon atoms is hydrolyzed hydroxypropyl starch.

7. 6. The use according to claim 5, wherein the amphiphilic hydrolyzed and functionalized starch compound is starch octenyl succinate.

8. 3. The use according to claim 1 or 2, wherein the hydrolyzed and functionalized starch compound is used in a printable material.

9. The method of claim 8, wherein the printable material is a powder, a filament, or a gel mass. For.

10. 3. Use according to claim 1 or 2 for 3D printing of a dosage form.

11. 11. The use according to claim 10 for 3D printing of a modified release dosage form or an immediate release dosage form.

12. 3. Use according to claim 1 or 2 for 3D printing by a process using extrusion.

13. 13. Use according to claim 12 for 3D printing by a process using hot melt extrusion (HME) or cold extrusion.

14. A process for the manufacture of products by 3D printing, comprising 3D printing of a printable material comprising a hydrolyzed and functionalized starch compound.

15. A 3D printing filament comprising a hydrolyzed and functionalized starch compound.

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