Starch-based printable material

Abstract

The present invention relates to a printable material for hot melt extrusion-based 3D printing (HME-3DP) comprising pregelatinized crosslinked starch and hydroxypropyl methylcellulose (HPMC). The present invention also relates to a process for 3D printing using said printable material. The present invention also relates to products, particularly controlled release solid dosage forms, obtained from said printable material by 3D printing.

Description

Technical Field

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

Background Art

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

[0003] In addition to many applications not related to healthcare, 3DP is currently being used or is under investigation for oral drugs, implantable drug delivery devices, tissue bioprinting, devices such as prostheses, and even for food.

[0004] When compared to traditional drug manufacturing, it has been observed that 3DP can produce drugs at reasonable prices, on demand, tailored to the patient, and / or with increased product complexity. 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 can prove particularly useful for multiple drug release profiles embedded in the same dosage form. Some of the goals are to minimize side effects by achieving near-zero order release by printing donut-shaped, cylindrical, or perforated oral formulations, or by using a radial gradient of eroding or diffusion-controlling excipients. The ability to manufacture customized, individual, or multiple drugs and / or multiple-dose formulations can be another important advantage of 3DP pharmaceuticals, as the demand for personalized medicine is increasing and becoming a megatrend.

[0005] Research in this field began in the early 1990s, but since 2015, the FDA has approved only one 3D-printed drug: Spritam®, obtained by 3DP (3D Printing Deposition), with the following excipients: colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate 20, povidone, sucralose, butylhydroxyanisole, and an orally dispersible dosage form with natural and artificial spearmint flavors.

[0006] 3D printing (3D printing) methods adapted for handling pharmaceuticals and biocompatible materials include: extrusion printing (particularly 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 3DP classification, refer to the publication of Ion-Bogdan Dumitrescu et al., "The age of pharmaceutical 3D printing technological and therapeutic implications of additive manufacturing. Farmacia, 2018, Vol. 66, 3 (365-389)" (especially Table I).

[0007] Extrusion printing, specifically FDM, is the most widely used method in the field of 3D printing, characterized by the extrusion of a preheated polymer filament or semi-solid material through a nozzle to a precise position on a platform using xyz positioning. Once the first layer cools, the next layer is applied. Depending on the shape of the printed product, different materials may be required to provide structural support until the object has completely cooled and solidified, after which it can be removed. PAM technology is similar, except that a non-melting viscous material is supplied to the printer. 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, for example, antimicrobial agent eluting implants. Finally, we can mention direct powder extrusion, a recently developed technology. According to this technology, the printable powder is extruded directly, thus avoiding the need for filament preparation.

[0008] A typical 3D printing process chain includes the following steps: - Creation or adjustment of CAD models using specialized software, and 3D scanning of existing objects or medical images. CAD files describe the geometry and size of 3D structures. - Conversion to either STL or AMF file format, which can be printed on a printer. These files describe the surface of the model in triangulation sections, depending on the surface curvature. Increasing the number of triangulation sections will increase the resolution of the printed piece. - Using specialized software that can also determine the amount and location of support material to prevent the collapse of the printed object, the 3D model is sliced ​​into layers of a specified thickness. The filling density of the printed object must also be specified, which is 0% for hollow structures and 100% for solid-filled parts. - Transfer the files to the actual 3D printer and set it up. - Manufacturing of 3D products layer by layer. - Sometimes, drying or removal and disposal of the support material, as well as post-processing, are required.

[0009] While 3D printing (3DP) represents a promising technology in the pharmaceutical field, the limited variety of available, environmentally friendly, food-grade, and printable materials remains a bottleneck to the widespread adoption of 3D printing technology. The most commonly used pharmaceutical-grade polymers as drug carriers for the manufacture of dosage forms by FDM are polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polylactic acid (PLA), all of which are synthetic petroleum-based materials.

[0010] In line with the current focus on a sustainable economy, the exploration of naturally derived, renewable biopolymers as an alternative to these petroleum-based materials for the manufacture of various products is attracting considerable attention.

[0011] Various naturally derived biopolymers, such as cellulose, hemicellulose, pectin, starch, alginates, 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., acting as dietary fiber), and long history of use in traditional food or pharmaceutical manufacturing.

[0012] However, such biomaterials must be printable, and it must be possible to obtain a final product with satisfactory properties (such as satisfactory mechanical and / or biological and / or pharmacokinetic properties). The problem is further complicated by the fact that the processability requirements differ depending on the 3DP technology used.

[0013] Among the materials obtained from already explored renewable resources, hydroxypropyl methyl cellulose (HPMC) is noteworthy, and it is particularly used in FDM 3DP in various studies.

[0014] However, obtaining printable materials always requires the addition of fossil fuel-based polymers, and HPMC itself was not printable.

[0015] Overall, the demand for printable materials derived from renewable raw materials that would enable the creation of products with all the required properties, particularly solid dosage forms, remains unmet.

[0016] (the purpose) Therefore, an object of the present invention is to provide printable materials and 3DP processes that use components obtained from renewable resources.

[0017] Another object of the present invention is to provide a printable material that is safe for both operators and consumers.

[0018] Another object of the present invention is to provide a printable material that is easy to handle.

[0019] Another object of the present invention is to provide a printable composition and a 3DP process that enables the acquisition of products, particularly in solid dosage form, having satisfactory mechanical properties.

[0020] Another object of the present invention is to provide a printable material and a 3DP process that enables obtaining a product containing an active ingredient, particularly in solid dosage form, having satisfactory release behavior and / or satisfactory pharmacokinetic behavior.

[0021] (Presentation of the invention) The inventors have found that by combining HPMC with an alpha-crosslinked starch compound, a printable material with good printing suitability for HME-3DP can be obtained. In particular, filaments with good mechanical properties can be obtained, which are particularly useful for use in FDM 3DP.

[0022] As is apparent from the examples in the following specification, it can be advantageously used for formulating modified release dosage forms, particularly controlled release dosage forms.

Summary of the Invention

[0023] The present invention relates first to the use of a printable material comprising an alpha-crosslinked starch and hydroxypropylmethylcellulose (HPMC) for hot melt extrusion-based 3D printing (HME-3DP).

[0024] Preferably, the weight ratio of the alpha-crosslinked starch compound of the printable material to HPMC is greater than 0.3:1 and less than 3:1.

[0025] Preferably, the printable material further comprises an active ingredient.

[0026] Preferably, the printable material further comprises a plasticizer and / or a sugar alcohol. Preferably, the sugar alcohol is selected from mannitol, sorbitol, xylitol, or a mixture thereof.

[0027] Preferably, the printable material further comprises an anti-sticking agent.

[0028] Preferably, the use is for HME-3DP of a dosage form. Preferably, the dosage form is a solid dosage form. Preferably, the dosage form is an oral dosage form. Preferably, the dosage form is a controlled release dosage form.

[0029] The present invention also relates to a process for manufacturing products by HME-3DP, comprising hot-melt extrusion of a printable material comprising pregelatinized cross-linked starch and HPMC.

[0030] The present invention also relates to a filament for HME-3DP comprising pregelatinized cross-linked starch and HPMC. [Brief explanation of the drawing]

[0031] [Figure 1] The release profile of a 3D-printed dosage form according to this disclosure, containing the water-soluble active ingredient diprophylline, is shown. [Modes for carrying out the invention]

[0032] The present invention relates, firstly, to the use of a printable material comprising hydroxypropyl methylcellulose (HPMC) and a starch compound for hot-melt extrusion-based 3D printing (HME-3DP), wherein the starch compound is gelatinized and crosslinked.

[0033] The term "printable material" refers to a material that can be used in a 3DP process, either by itself or with the addition of other components. In other words, it may be a ready-to-use material for supplying to a 3D printer, or a material that can be used in the preparation of feedstock for a 3D printer. The printable material according to the present invention is preferably in a solid state. It is preferably a powder, granules, or filament. A printable powder may be used as a powder in 3DP (as in direct powder extrusion) or may be used in the preparation of another form of printable material (granules, filament, etc.). Preferably, the printable material according to the present invention is a powder or a filament, and more preferably a filament.

[0034] The term "starch compound" classically refers to a substance derived from starch. It should be noted that the term "starch" typically refers to starch isolated from any suitable plant material, such as maize, tapioca, or barley, by any technique known to those skilled in the art. The isolated starch typically contains impurities of 3% by weight or less. This 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 this disclosure may be derived from any suitable plant source, including, for example, legumes (e.g., peas), cereals (e.g., maize, rice, wheat, oats), and tubers (e.g., potatoes, tapioca).

[0035] The pregelatinized cross-linked starch compounds according to this disclosure are preferably derived from tubers, preferably from potatoes.

[0036] The pregelatinized starch compounds according to this disclosure are crosslinked. They can preferably be obtained by crosslinking with a compound selected from sodium metaphosphate, sodium trimetaphosphate, phosphorus oxychloride, adipate, epichlorohydrin, or a mixture thereof. They can preferably be obtained by crosslinking with sodium metaphosphate, sodium trimetaphosphate, phosphorus oxychloride, or a mixture thereof. They can more preferably be obtained by crosslinking with sodium trimetaphosphate.

[0037] The starch compounds of the crosslinked starch according to this disclosure are also gelatinized. Classically, gelatinization means that the starch compound particles no longer exhibit birefringence (absence of the crystalline phase) under an optical microscope in polarized light. Gelatinization can generally be obtained from birefringent starch or birefringent starch compounds by heat treatment in the presence of water (generally 50-90°C, especially depending on the plant origin of the starch) (often also called "digestion"), accompanied by further drying (after and / or simultaneously with digestion). Other chemicals may be used as processing aids. Gelatinization can be carried out, for example, by drum drying. In this case, the starch can be digested before or during the drum drying process. It can also be digested and spray-dried. It can also be obtained by extrusion. Preferably, the starch compounds of the crosslinked starch according to this disclosure are gelatinized by digestion and drum drying.

[0038] Preferably, the starch compounds according to this disclosure have a cold water solubility of 10% 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 20% or more, more preferably 30% or more, more preferably 35% or more, and more preferably 40% or more. This solubility can be determined, for example, by adding 5 grams of the starch compound to 200 mL of distilled water. 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. This cold water solubility is generally less than 100%, more preferably 90% or less, more preferably 80% or less, more preferably 70% or less, more preferably 60% or less, and more preferably 50% or less. It is, for example, equal to about 42%.

[0039] The pregelatinized crosslinked starch compound according to this disclosure is preferably measured in an aqueous solution containing 10% by dry weight of the starch compound at 20°C for 100 seconds. -1It has a viscosity in water higher than 10 mPa.s at a shear rate. Preferably, the viscosity is determined with a rheometer having a 5 cm 1° cone-plate shape. This viscosity can be determined, for example, according to the detailed protocol disclosed in the Examples. Preferably, the viscosity is 50 mPa.s or more, more preferably 100 mPa.s or more, more preferably 1,000 mPa.s or more, more preferably 3,000 mPa.s or more, more preferably 5,000 mPa.s or more, more preferably 6,000 mPa.s or more, and more preferably 7,000 mPa.s or more. Preferably, the viscosity is 15,000 or less, more preferably 10,000 mPa.s or less, more preferably 9,000 mPa.s or less, and more preferably 8,000 mPa.s or less, which is, for example, equal to about 7,000 mPa.s.

[0040] In preferred embodiments, the pregelatinized crosslinked starch compounds according to this disclosure are derived from starch having an amylose content of 0 to 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 those skilled in the art by potentiometric analysis of iodine absorbed by amylose to form a complex. It is preferably 5% or more, more preferably 10% or more, and even more preferably 15% or more. It is preferably 70% or less, even more preferably 50% or less, even more preferably 40% or less, even more preferably 30% or less, and even more preferably 25% or less. It is, for example, equal to about 20%.

[0041] The pregelatinized cross-linked starch compounds according to this disclosure may undergo chemical and / or physical modifications other than those previously exposed to them, as long as these modifications do not impair the desired properties, particularly from the viewpoint of safety and performance of printable materials and printed products obtained therefrom. However, since these modifications are not considered essential in the present invention, the pregelatinized cross-linked starch compounds of the present invention are preferably not further modified.

[0042] Preferably, the pregelatinized cross-linked starch according to this disclosure conforms to the FOOD CHEMICALS CODEX, which came into effect on March 1, 2021. Preferably, the pregelatinized cross-linked starch according to this disclosure conforms to the JECFA monograph on food additives, which came into effect on March 1, 2021. Preferably, the pregelatinized cross-linked starch according to this disclosure conforms to the U.S. code for Federal Regulation 21 CFR §172.892, which came into effect on March 1, 2021. Preferably, the pregelatinized cross-linked starch according to this disclosure conforms to Commission Regulation (EU) nr. 231 / 2012 of March 9, 2012 (OJ EC L-83 / 1 dated March 22, 2012) on food additives, which came into effect on March 1, 2021.

[0043] Preferably, the pregelatinized cross-linked starch according to this disclosure is the product with CAS number 55963-33-2.

[0044] Particularly useful pregelatinized cross-linked starches are commercially available. For example, PREGEFLO® PI10, which is commercially available from the applicant, can be cited.

[0045] In preferred embodiments, the amount of the pregelatinized cross-linked starch compound in the printable material according to the Disclosure is 1% or more, more preferably more than 5%, more preferably more than 10%, more preferably more than 15%, and more preferably more than 20%, the percentage being expressed by weight relative to the total weight of the printable material. It is preferably 90% or less, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 40%, more preferably less than 40%, more preferably less than 35%, and more preferably less than 30%. It is, for example, equal to about 25%.

[0046] The HPMC provided in this disclosure may be any preferred grade selected from, for example, K4M, K15M, and K100M. It is preferably K4M. Preferably, the product AFFINISOL® HPMC HME is excluded.

[0047] In preferred embodiments, the amount of HPMC 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 15%, and more preferably more than 20%, the percentage being expressed by weight relative to the total weight of the printable material. It is preferably 90% or less, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 40%, more preferably less than 35%, and more preferably less than 30%. It is, for example, equal to about 25%.

[0048] Preferably, the HPMC according to this disclosure is the product with CAS number 9004-65-3.

[0049] Particularly useful HPMCs are commercially available. For example, HPMC K4M, commercially available from SHANDONG, is one such example.

[0050] Preferably, the total amount of pregelatinized crosslinked starch compounds and HPMC 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 40%, more preferably more than 45%, and more preferably more than 45%, the percentage being expressed by weight relative to the total weight of the printable material. It is preferably 99% or less, more preferably less than 90%, more preferably less than 70%, more preferably less than 75%, more preferably less than 60%, more preferably 55% or less, and more preferably less than 55%. It is, for example, equal to about 50%.

[0051] Preferably, the ratio of the pregelatinized cross-linked starch compound:HPMC in the printable material according to this disclosure is greater than 0.3:1 and less than 3:1. It is preferably 0.4:1 or greater, more preferably 0.5:1 or greater, more preferably 0.6:1 or greater, more preferably 0.7:1 or greater, more preferably 0.8:1 or greater, and more preferably greater than 0.9:1. It is preferably 2.5:1 or less, more preferably 2:1 or less, more preferably 1.8:1 or less, more preferably 1.6:1 or less, more preferably 1.4:1 or less, and more preferably 1.2:1 or less. It is, for example, equal to about 1:1.

[0052] Generally, the printable materials according to this disclosure further include other components besides the pregelatinized crosslinked starch compounds and HPMCs according to this disclosure. Examples of such other components include active ingredients, sugars, sugar alcohols, colorants, flavorings, lubricants, other starches, and starch compounds. Other examples include excipients classically used in 3D printing, particularly FDM, such as polylactic acid (PLA), hydroxypropylcellulose acetate (HPC), ethylcellulose (EC), hydroxypropyl methylcellulose 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®, and 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.

[0053] Preferably, the printable material according to this disclosure further comprises an active ingredient. The active ingredient according to this disclosure includes non-pharmaceuticals and pharmaceuticals. The term “active” classically refers to any substance that is the subject of a pharmaceutical, veterinary, food, dietary supplement, cosmetic, or pesticide. Preferably, the active ingredient according to this disclosure is a pharmaceutical, dietary supplement, cosmetic, or veterinary active ingredient. Pharmaceutical ingredients may be selected from so-called small molecules, in particular if they are pharmaceutical active ingredients, but may also be selected from so-called “biological” active ingredients, such as 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 according to this disclosure is diprophylline.

[0054] The active ingredients described herein may be very soluble in water, readily soluble, soluble in water, sparingly soluble in water, slightly soluble in water, very sparingly soluble in water, or substantially insoluble in water. This solubility in water is well defined, for example, in the section "General Notice, Solubility" of The International Pharmacopeia, 9th edition (2019). In this disclosure, the term "water-insoluble" classically refers to active ingredients that are sparingly soluble to substantially insoluble in water. In this disclosure, the term "water-soluble" classically refers to active ingredients that are soluble to very soluble in water.

[0055] Preferably, the active ingredient according to the present invention is water-soluble, and more preferably readily soluble or very soluble in water. It is preferably diprophylline, which is readily soluble.

[0056] Generally, the amount of active ingredients in a printable composition is 1% or more, more preferably 2% or more, more preferably 5% or more, more preferably 10% or more, and more preferably 15% or more, and this percentage is expressed as weight relative to the total weight of the printable material. It is generally 99% or less, more preferably 90% or less, more preferably 70% or less, more preferably 50% or less, more preferably 40% or less, more preferably 30% or less, more preferably 20% or less, and more preferably 25% or less. It is, for example, equal to about 20%.

[0057] Preferably, the printable material according to this disclosure further comprises a sugar alcohol or a plasticizer. The plasticizer and sugar alcohol according to the present invention are preferably selected from glycerol, sorbitol, sorbitol anhydride, maltitol, mannitol, xylitol, polyethylene glycol having a molecular weight of 400 to 10,000 daltons, polyethylene glycol stearate, propylene glycol, triethyl citrate, acetyl triethyl citrate, tributyl citrate, polysorbate, acetylated monoglycerides, lactic acid esters, fatty acids and ethoxylated salts or derivatives thereof, for example particularly stearic acid, phthalate, ethyl sebacate, butyl sebacate, migliol, glycerol triacetate, liquid paraffin, lecithin, carnauba wax, hydrogenated castor oil, urea, or mixtures thereof. It is preferably selected from sugar alcohols, preferably from mannitol, sorbitol, or mixtures thereof.

[0058] Preferably, the amount of plasticizer or sugar alcohol in the printable material is 1% or more, preferably more than 5%, more preferably more than 8%, more preferably more than 10%, more preferably more than 15%, more preferably more than 18%, more preferably more than 20%, more preferably more than 23%, and more preferably more than 23%, where the percentage is expressed as weight relative to the total weight of the printable material. It is preferably 80% or less, more preferably less than 70%, more preferably less than 60%, more preferably less than 50%, more preferably less than 48%, more preferably less than 38%, more preferably less than 35%, more preferably 33% or less, and more preferably less than 33%.

[0059] When a mixture of mannitol and sorbitol is used, the weight ratio of sorbitol to mannitol is preferably greater than 1:1, more preferably 2:1 or greater. It is preferably 6:1 or greater, more preferably 5:1 or less, and even more preferably 4:1 or less. It is, for example, about 3:1.

[0060] Preferably, the printable material further comprises an anti-sticking agent, preferably selected from meltable thermal lubricants, such as metal salts of fatty acids, fatty acids, fatty alcohols, fatty acid ester hydrocarbons, or mixtures thereof. It is selected from, for example, glyceryl monostearate, magnesium stearate, calcium stearate, sodium stearate, hexadecane, octadecane, sodium stearyl fumarate, glyceryl behenate, stearic acid, or mixtures thereof. It preferably contains stearic acid. It is even more preferably stearic acid alone. Preferably, the amount of the anti-sticking agent is 0.5 to 5%, preferably 1 to 4%, preferably 1 to 3%, for example, equal to about 2%, and the percentage is expressed by weight relative to the total weight of the printable material.

[0061] Preferably, the printable material according to the present invention is - 1-96.5% pregelatinized cross-linked starch compounds, - 1-96.5% HPMC and - 1-96.5% active ingredients, - 1-80% plasticizer or sugar alcohol, preferably a mixture of mannitol and sorbitol, - 0.5-5% anti-sticking agent, - Composed of 0-95.5% other ingredients, The percentage is expressed as the weight relative to the total weight of the printable material, and the sum of these amounts equals 100%.

[0062] 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%, and more preferably less than 1%, and such percentages are expressed by weight relative to the total weight of the printable material. More preferably, the printable material does not contain such other components.

[0063] Preferably, the amount of components obtained from renewable raw materials in the printable material is 50% or more, and this percentage is expressed by weight relative to the total weight of the printable material. Such components obtained from renewable raw materials are not obtained from fossil fuels in particular. More preferably, this amount is equal to 60% or more, more preferably 70% or more, more preferably 80% or more, more preferably 90% or more, and more preferably 100%. Examples of components that can be obtained from renewable raw materials are starch compounds (including pregelatinized cross-linked starch compounds as disclosed), cellulose derivatives (including HPMC as disclosed), sugars, and sugar alcohols. Examples of components that cannot be obtained from renewable raw materials are PLA, PVP, crospovidone, Carbopol® 794, polyethylene oxide, polyethylene glycol, Eudragit®, PCL, triethyl citrate, tricalcium phosphate, PVA, Soluplus®, Kollidon®, Kollicoat®, or Polyox®.

[0064] Preferably, in the presence of an active ingredient, the excipient of the printable material according to the Disclosure comprises at least 50% of components obtained from renewable sources, particularly those not obtained from fossil fuels, the percentage being expressed by weight relative to the total weight of the excipient of the printable material. More preferably, the excipient of the printable material according to the Disclosure comprises at least 60% by weight, more preferably at least 70% by weight, more preferably at least 80% by weight, more preferably at least 90% by weight, and more preferably 100% by weight of components obtained from renewable sources.

[0065] The printed or printed products according to this disclosure are typically solid or semi-solid products, preferably intended for oral administration, such as tablets, gels, films, caplets, softgels, and hard capsules. They may also be drug-loading medical devices. In preferred embodiments, the printed or printed products according to this disclosure are solid products, typically tablets. In preferred embodiments, the printed products according to the present invention are not gels and / or films. The printed products according to the present invention may be, for example, pharmaceutical, veterinary, nutritional supplements, foods, cosmetics, or pesticides. They may be for human or animal use. They are preferably pharmaceutical, veterinary, nutritional supplements, or cosmetic products. In preferred embodiments, the printed or printed products according to this disclosure are dosage forms (i.e., products containing active ingredients), preferably solid dosage forms, preferably oral solid dosage forms, and especially pharmaceutical oral solid dosage forms.

[0066] Preferably, the printed products according to this disclosure are in a controlled-release dosage form, preferably a regulated-release dosage form. Preferably, the controlled-release properties of the dosage form comply with US FDA (General Methods; 32(2) Second Interim Revision Announcement: DISSOLUTION, <711> The dissolution method is determined using dissolution method A (pH transition method, 2 hours of artificial gastric fluid, then 10 hours of artificial intestinal fluid) in accordance with the guidance provided by DISSOLUTION; 11 / 21 / 2016). In the case of a controlled-release dosage form, in contrast to an immediate-release dosage form, no more than 80% of the active ingredient by dry weight should be released in 30 minutes. In the case of a controlled-release dosage form, no more than 80% of the active ingredient by dry weight should be dissolved in 8 hours. Of course, the active ingredient must still be released. Therefore, preferably, at least 20% of the active ingredient by dry weight should be dissolved in 8 hours. More preferably, the controlled-release dosage form according to this disclosure releases at least 30%, more preferably at least 40%, more preferably at least 50%, more preferably at least 60%, and more preferably at least 80% of the active ingredient by dry weight.

[0067] HME-3DP can be carried out by any suitable method well known to those skilled in the art. Preferably, 3D printing is performed by a method selected from fused deposition modeling (FDM) or direct powder extrusion, preferably by FDM.

[0068] The present invention also encompasses products obtained or obtainable by HME-3DP, comprising a pregelatinized crosslinked starch compound and HPMC, wherein the starch compound and HPMC are preferably as described herein. Preferably, the printed product is as described herein. Preferably, the printed product of this disclosure has the composition described herein for the printable material, excluding the solvent to be added last or the water content of the components used, which are negligible.

[0069] The present invention also encompasses a process for manufacturing products by HME-3DP, which includes hot-melt extrusion of a printable material as defined above. Preferably, the printed product or product to be printed is as defined above. Preferably, HME-3DP is carried out by a method selected from fused deposition modeling (FDM) or direct powder extrusion, preferably by FDM.

[0070] In this disclosure, the expression "between" classically includes the stated upper and lower limits.

[0071] In this disclosure, the amounts of components are generally expressed in weight percent. Unless otherwise specified, these weights are the amounts of the components in their original form, which is generally in powder form. These powdered components generally contain small amounts of water (also called moisture percent or "loss on drying"). In this regard, the starch compounds according to this disclosure generally contain 15% by weight or less, generally 5-10% water, and sugar alcohols such as mannitol and sorbitol generally contain 1% water or less. This means, for example, when it refers to 10% by weight of a starch compound, this generally corresponds to 9.0-9.5% in dry weight (i.e., anhydrous weight).

[0072] Conversely, in this disclosure, when quantities are expressed by dry weight, anhydrous weight is taken into consideration.

[0073] Other features and advantages of the present invention will be clearly understood by reading the following examples. The following examples are illustrative and not limiting of the present invention. [Examples]

[0074] A. Material A.1. Starch compounds used and their characterization Viscosity measurement. Measurements were performed using a rheometer (Physica MCR301, Anton Paar) with a 5 cm 1° cone plate shape (CP50). The temperature was controlled by Peltier. Measurements were performed at 20°C with an aqueous solution containing 10% dry starch compound as follows: equilibration at 20°C for 1 minute; application at 20°C for 3 minutes for 0.006-1,000 s. -1 The shear rate.

[0075] Solubility measurement. 200 ml of distilled water was added to a 250 ml beaker. 5 grams by weight of the 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 out and introduced into a crystallizer, and placed in a 60°C oven until the water evaporated. It was then placed in a 103+°C ± 2°C oven for 1 hour. The residue was placed in a desiccator, cooled to room temperature, and then weighed to calculate solubility by dry weight.

[0076] The following starch compounds were used: 6.0% by weight moisture, solubility in 42% water, and viscosity of 7,090 mPa·s (10%, 20°C, 100s). -1 Pregelatinized cross-linked starch (PREGEFLO® PI10, ROQUETTE) cross-linked with sodium trimetaphosphate, which contains ).

[0077] A.2. Other ingredients used The following other ingredients were used: HPMC K4M (SHANDONG), containing approximately 5% by weight of water; sorbitol (NEOSORB® 100C, ROQUETTE); mannitol (PEARLITOL® 100 SD, ROQUETTE); diprophylline (Shanghai Star); stearic acid (Stearic Acid 50, SIGMA-ALDRICH); ungelatinized cross-linked potato starch (CLEARAM® PI10); HPC (SIGMA).

[0078] Preparation of controlled-release tablets containing water-soluble active ingredients by B.FDM In this example, the inventors tested the effect of using pregelatinized cross-linked starch in combination with HPMC on HME-3DP.

[0079] The inventors prepared filaments from various formulations, as shown in Table 1.

[0080] [Table 1]

[0081] In this table, percentages are expressed as weight relative to the total weight of the printable material (the powder mixture used to prepare the filament).

[0082] 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 outlet) to prepare the filament, with temperatures of 120°C, 160°C, 160°C, and 120°C in each zone.

[0083] Printing was performed at 180°C using an Ultimaker S5 printer equipped with a BB core printhead (primarily for water-soluble materials), at a speed of 4 mm / second, and a print height of 0.065 mm. The tablets printed were cylindrical tablets with a diameter of 10 mm and a height of 5 mm.

[0084] Only the filaments obtained from formulation F1 were able to achieve continuous printing. Formulation F3, which does not contain starch compounds according to this disclosure, was not extrudeable, and as a result, no filaments were formed. Formulation F2, which does not contain HPMC, was able to produce filaments, but they were too brittle to print.

[0085] For formulation F4, the extrusion temperature profile was adapted to reach the optimal profile that would allow filament to be obtained. However, browning occurred even before the components were completely melted. Firstly, when preparing the filament, the blend was passed through a twin-screw extruder consisting of four zones (from the feed zone, mixing, kneading, and exit) at a higher temperature, with temperatures of 140°C, 180°C, 180°C, and 140°C in each zone. The extruded filaments were not suitable for printing as they still had powder residue on their surface. Secondly, the blend was passed through a twin-screw extruder at the following zone temperatures: 140°C, 180°C, 180°C, and 160°C. The extruded filaments were not suitable for printing as they were too soft and still contained unmelted powder. Thirdly, the blend was passed through a twin-screw extruder at the following zone temperatures: 160°C, 180°C, 180°C, and 140°C. The extruded filament was too brittle and not yet suitable for printing.

[0086] For formulation F5, the extrusion temperature profile and screw speed values ​​were adapted to achieve the optimal profile that would allow for the acquisition of filaments. Firstly, when preparing filaments, the blend was passed through a twin-screw extruder consisting of four zones (from the feed zone, mixing, kneading, and exit) at 10 rpm at a higher temperature, with temperatures of 120°C, 170°C, 170°C, and 125°C in each zone. However, the filaments still had powder residue on their surface after extrusion. Secondly, when preparing filaments, the blend was passed through a twin-screw extruder consisting of four zones (from the feed zone, mixing, kneading, and exit) at 5 rpm at a higher temperature, with temperatures of 140°C, 175°C, 175°C, and 140°C in each zone. However, they still had powder residue on their surface after extrusion.

[0087] For formulation F6, the extrusion temperature profile was adapted to reach the optimal profile that would allow for the acquisition of filament. Firstly, when preparing the filament, the blend was passed through a twin-screw extruder consisting of four zones (from the feed zone, mixing, kneading, and exit) at a higher temperature, with temperatures of 120°C, 160°C, 140°C, and 110°C in each zone. The extruded filament was too soft and still not suitable for printing. Secondly, the blend was passed through a twin-screw extruder at the following zone temperatures: 120°C, 140°C, 140°C, and 110°C. The extruded filament was still too soft and still not suitable for printing.

[0088] Tablets (at least 6 tablets) obtained from formulation F1 were submitted to the US FDA (General Methods; 32(2) Second Interim Revision Announcement: DISSOLUTION, <711> Their controlled release characteristics were tested using dissolution method A (pH shift method, 2 hours of artificial gastric fluid followed by 10 hours of artificial intestinal fluid) in accordance with the guidance provided by DISSOLUTION;11 / 21 / 2016).

[0089] The resulting release profile is shown in Figure 1. 79% of the active ingredient was released by dry weight in 8 hours.

[0090] These results first demonstrate that the combination according to this disclosure (i.e., the combination of pregelatinized cross-linked starch compound and HMPC) is printable. It makes it possible to obtain a filament with good mechanical properties. It also demonstrates that the combination according to this disclosure can be advantageously used to formulate controlled-release dosage forms.

[0091] Tablets (at least 6 tablets) obtained from formulation 1 were also tested for their stability. A 3-month stability test showed no significant changes in the release profile of the active ingredient under two storage conditions (i.e., 25°C / 60% relative humidity and 40°C / 75% relative humidity).

Claims

1. Use of printable material containing pregelatinized cross-linked starch and hydroxypropyl methylcellulose (HPMC) for hot-melt extrusion-based 3D printing (HME-3DP).

2. The use according to claim 1, wherein the weight ratio of the printable material to the pregelatinized cross-linked starch compound:HPMC is greater than 0.3:1 and less than 3:

1.

3. The use according to claim 1 or 2, wherein the printable material further comprises an active ingredient.

4. The use according to claim 1 or 2, wherein the printable material further comprises a plasticizer and / or a sugar alcohol.

5. The use according to claim 4, wherein the sugar alcohol is selected from mannitol, sorbitol, xylitol, or a mixture thereof.

6. The use according to claim 1 or 2, wherein the printable material further comprises an anti-adhesion agent.

7. The use according to claim 1 or 2 for the dosage form HME-3DP.

8. The use according to claim 7, wherein the dosage form is a solid dosage form.

9. The use according to claim 7, wherein the dosage form is an oral dosage form.

10. The use according to claim 7, wherein the dosage form is a controlled-release dosage form.

11. A process for manufacturing products using HME-3DP, comprising hot-melt extrusion of a printable material comprising pregelatinized cross-linked starch and HPMC.

12. A filament for HME-3DP containing pregelatinized cross-linked starch and HPMC.

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