Solid Dosage Form Manufacturing

Abstract

The present invention provides methods for preparing solid dosage forms, in particular pharmaceutical dosage forms, using extrusion and 3D printing, as well as the solid dosage forms themselves, compositions for preparing the solid dosage forms, uses of the solid dosage forms and containers used in their preparation.

Description

[0001] introduction

[0002] The present invention relates to methods for producing solid dosage forms (in some cases, more generally solid articles), in particular methods of production using extrusion and / or deposition. The present invention also relates to solid dosage forms (or solid articles) themselves, precursor compositions for preparing solid dosage forms, and apparatus for producing solid dosage forms and methods of operating the same. The present invention also relates to solid dosage forms obtainable by such methods and apparatus, solid dosage form packaging, related materials and compositions for preparing solid dosage forms (and methods of making them), computers for controlling related preparation processes (and software and computer-implemented methods connected thereto), and systems for collecting data related to solid dosage form production processes (and databases associated therewith). Background Art

[0003] The production and consumption of drugs, nutraceuticals, and food supplements (collectively referred to herein as "health care dosage forms") in solid dosage forms (e.g., tablets, implants, etc.) are increasing, especially because of the increasing dependence of national health services, etc. on these products in a society that is increasingly health-conscious. Where possible, solid dosage forms tend to be the most preferred due to their ease of administration (i.e., usually oral) relative to other formulations (e.g., injectable liquid formulations), which leads to better patient compliance, storability and transportability (low space requirements and easy packaging), high stability (longer life span-less disintegration). However, despite significant advantages over other dosage forms, the manufacture of solid dosage forms is usually more cumbersome (in terms of the number of both ingredients and processing steps) and is usually only cost-effective for large-scale production, which means that large-scale manufacturing equipment with sophisticated equipment is usually required. These manufacturing limitations have a deleterious effect on the customization of consumer choice and / or health care dosage forms, because, for example, it is impractical and cost-ineffective to mass-produce a variety of different doses for a given drug via conventional manufacturing techniques. Consumers (eg, patients) and healthcare professionals (eg, physicians, pharmacists) must therefore make the best use of the limited variety of available dosages based on the supplier's instructions rather than the consumer's needs.

[0004] Since the emergence of 3D (3D) printing in the early 1980s, many researchers have tried to use 3D printing technology to manufacture healthcare solid dosage forms. For example, for more than ten years, MIT has worked with Therics to develop a feasible pill printer that uses a 3D printer to print solid drug dosage forms in situ. The technology forms pills via a multi-layer 3D printing process, which involves accurately printing the dosage of a liquid drug solution onto a thin fine powder layer before applying another layer (e.g., another powder, adhesive, etc.). Examples of such methods are disclosed in early publications such as WO 95 / 11007 (MIT) and WO 03 / 092633 (THERICS), which particularly describe the production of solid dosage forms with various structures and drug release profiles. However, regulatory approval for such 3D drug printing systems (e.g., by FDA or MHRA) remains elusive, and the system is currently only applicable to low-dose drug products, partly because the solubility of many drugs in related ink solutions is limited. Therefore, the patient's options remain very limited, as do the physician's or pharmacist's options in providing specifically tailored treatments. In addition, the resolution and shape of solid dosage forms remain an issue. A particular problem with prior art 3D printing systems is the use of high temperatures in printing the solid dosage form itself and / or in preparing the filaments used in the printing process. The use of high temperatures in the production of printed solid dosage forms can lead to thermal degradation of certain components of the solid dosage form. Therefore, printing processes utilizing high temperatures are not suitable for use with heat-sensitive components, such as heat-sensitive active ingredients, and / or heat-sensitive components at high loading levels. This may severely limit the application of 3D printed solid dosage forms, as only heat-stable components can be used, and / or only low dosage forms can be prepared. Biologically active ingredients, such as monoclonal antibodies, are particularly susceptible to thermal degradation.

[0005] The applicant's previous work is outlined in WO2016 / 038356 (University of Central Lancashire), which focuses on the use of drug-containing FDM filaments in 3D printing, aiming to solve one or more of the above problems. However, alternative solutions are still needed. For example, although WO2016 / 038356 provides various innovative options to reduce the melting / softening temperature of drug-containing filaments, for some drugs (especially those with lower decomposition temperatures), the printing temperature of the filaments may still be too high, and decomposition may occur during the printing process. Such drug decomposition may also occur during the preparation of the filaments themselves, especially for filaments produced by hot melt extrusion, which involves batch heating of the pre-extruded composition before extrusion. In addition, the technology described in WO2016 / 038356 utilizes a large amount of thermoplastics in the formation of the dosage form, which may be undesirable and limit the maximum drug load. It is expected to expand the scope of application of the 3D printing technology described in WO2016 / 038356, for example by allowing a wider range of input materials. For example, 3D printing of solid dosage forms containing peptides, proteins, and other biopharmaceuticals is considered desirable, although they present stability challenges. In addition, it is desirable to be able to provide solid dosage forms with immediate, enteric, and / or extended release properties.

[0006] It is therefore an object of the present invention to provide an improved and / or alternative process for producing a solid dosage form and to suitably address at least one of the problems inherent in the prior art. Summary of the invention

[0007] According to a first aspect of the present invention, there is provided a method for preparing an extruded product, the method comprising:

[0008] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier; and

[0009] ii. extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core);

[0010] in:

[0011] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0012] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0013] In one aspect, there is provided a method for preparing a solid dosage form of a pharmaceutical, nutraceutical or food supplement, the method comprising:

[0014] i) providing an extrudable composition comprising an extrudable carrier; and

[0015] ii) extruding the extrudable composition into the desired form, optionally in association with one or more auxiliary elements (e.g. shell, coating, core);

[0016] in:

[0017] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0018] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0019] According to another aspect of the present invention, there is provided a method for preparing an extruded product, the method comprising:

[0020] i. extruding the extrudable composition into a desired form, wherein the extrudable composition is as defined herein. According to another aspect of the present invention, there is provided a method for preparing an extruded article, the method comprising:

[0021] i. providing an extrudable composition as defined herein;

[0022] ii. Optionally, further treating the mixture from step i to form:

[0023] a. Extrudable fluid;

[0024] b. Extrudable compressed form; or

[0025] c. Extrudable components; and

[0026] iii. Extruding the extrudable composition of step i (or step ii, as applicable) into a desired form.

[0027] According to another aspect of the present invention, there is provided a method for preparing an extruded product, the method comprising:

[0028] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0029] ii. Optionally, further treating the mixture from step i to form:

[0030] a. Extrudable fluid;

[0031] b. Extrudable compressed form; or

[0032] c. Extrudable components.

[0033] iii. Extruding the extrudable composition obtained from step i. (or step ii., if applicable) into the desired form.

[0034] According to another aspect of the present invention, there is provided an extruded article obtainable by, obtained by or directly obtained by the method for preparing an extruded article as defined herein.

[0035] According to another aspect of the present invention, there is provided an extruded product comprising:

[0036] i. an extrudable carrier; and

[0037] ii. Optionally, a temporary plasticizer.

[0038] According to another aspect of the present invention there is provided an extruded article for use in therapy (or for use in the manufacture of a medicament), suitably as defined herein.

[0039] According to another aspect of the present invention there is provided the use of an extruded article, suitably as defined herein.

[0040] In another aspect, there is provided a method of preparing an extrudable composition, the method comprising:

[0041] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0042] ii. Optionally, further treating the mixture from step i to form:

[0043] a. Extrudable fluid;

[0044] b. Extrudable compressed form; or

[0045] c. Extrudable components.

[0046] According to another aspect of the present invention, there is provided an extrudable composition obtainable by, obtained by or directly obtained by a method for preparing an extrudable composition as defined herein.

[0047] According to another aspect of the present invention, there is provided an extrudable composition comprising:

[0048] i. an extrudable carrier; and optionally

[0049] ii. Temporary plasticizer.

[0050] As described above, the extrudable composition can be provided in a variety of forms, optionally as an extrudable fluid, optionally as an extrudable compressed form, and / or optionally as an extrudable element (e.g., a 3D printable filament). Although any form of an extrudable composition can be converted into another form, the resulting product can still be considered an extrudable composition.

[0051] According to another aspect of the present invention there is provided a method of processing an extrudable composition to produce an extrudable fluid, the method comprising melting or softening the extrudable composition (suitably by heating).

[0052] According to another aspect of the present invention, there is provided a method of processing an extrudable composition to produce an extrudable compressed form, the method comprising compressing the extrudable composition.

[0053] According to another aspect of the present invention, there is provided a method of processing an extrudable composition to produce an extrudable element, the method comprising extruding or molding the extrudable composition into an extrudable element.

[0054] According to another aspect of the present invention, a method of converting an extrudable fluid into an extrudable compressed form is provided.

[0055] According to another aspect of the present invention, a method of converting an extrudable fluid into an extrudable element is provided.

[0056] According to another aspect of the present invention, a method of converting an extrudable compressed form into an extrudable fluid is provided.

[0057] According to another aspect of the present invention, a method of converting an extrudable compressed form into an extrudable element is provided.

[0058] According to another aspect of the present invention, a method of converting an extrudable element into an extrudable compressed form is provided.

[0059] According to another aspect of the present invention, a method of converting an extrudable element into an extrudable fluid is provided.

[0060] According to another aspect of the present invention there is provided an extrusion apparatus comprising an extruder and suitably further comprising an extrudable composition as defined herein.

[0061] According to another aspect of the present invention, there is provided a method of producing a package of extruded articles, the method comprising: packaging one or more extruded articles as defined herein, wherein the one or more extruded articles are optionally the same or different.

[0062] According to another aspect of the present invention, there is provided an extruded article package obtainable by, obtained by or directly obtained by the method for producing an extruded article package as defined herein.

[0063] According to another aspect of the present invention, there is provided a package of extruded articles comprising: one or more extruded articles as defined herein, wherein the one or more extruded articles are optionally the same or different within the package.

[0064] According to another aspect of the present invention, there is provided a method of producing a package of an extrudable composition, the method comprising: packaging one or more extrudable compositions as defined herein, wherein the one or more extrudable compositions are optionally the same or different.

[0065] According to another aspect of the present invention, there is provided an extrudable composition package obtainable by, obtained by or directly obtained by the method for producing an extrudable composition package as defined herein.

[0066] According to another aspect of the present invention, there is provided an extrudable composition package comprising:

[0067] i. an extrudable composition as defined herein; and

[0068] ii. A container (eg, a cartridge or a syringe), wherein the container comprises the extrudable composition.

[0069] According to another aspect of the present invention, there is provided an extrudable composition package comprising: one or more extrudable compositions as defined herein, wherein the one or more extrudable compositions are optionally the same or different within the package.

[0070] The method of using the extrusion apparatus and appropriate variations thereof may (suitably) be applied to any extrusion apparatus defined herein and further, aspects of operating the extrusion apparatus may be applied to the method of the invention defined herein.

[0071] In another aspect of the present invention, there is provided a method for preparing an embedded article, the method comprising:

[0072] i. Providing a curable body material in the form of a fluid or semi-fluid;

[0073] ii. embedding an embeddable substance in the curable body material;

[0074] iii. curing the curable body material having the embeddable material therein.

[0075] In another aspect of the present invention there is provided an embedded article obtainable by, obtained by or directly obtained by a method for preparing an embedded article as defined herein.

[0076] According to another aspect of the present invention, there is provided an embedding article comprising an embeddable substance within a curable body substance.

[0077] According to another aspect of the present invention there is provided an embedded article for use in therapy (or for use in the manufacture of a medicament), suitably as defined herein.

[0078] According to another aspect of the present invention there is provided the use of an embedding article, suitably as defined herein.

[0079] According to another aspect of the present invention, there is provided an embedding apparatus comprising an embedder and, suitably, also an embeddable substance and a curable body substance.

[0080] According to another aspect of the present invention, there is provided a method of producing an embedded article package, the method comprising: packaging one or more embedded articles as defined herein, wherein the one or more embedded articles are optionally the same or different.

[0081] According to another aspect of the present invention, there is provided an embedded article packaging obtainable by, obtained by or directly obtained by the method of producing an embedded article packaging as defined herein.

[0082] According to another aspect of the present invention, there is provided an embedded article package comprising: one or more embedded articles as defined herein, wherein the one or more embedded articles are optionally the same or different within the package.

[0083] According to another aspect of the present invention, there is provided a curable body substance kit comprising a cartridge filled with a curable body substance as defined herein.

[0084] According to another aspect of the present invention, there is provided an embeddable substance kit comprising a cartridge filled with an embeddable substance as defined herein.

[0085] According to another aspect of the present invention, there is provided an embeddable and curable body substance kit comprising a cartridge filled with an embeddable substance and a curable body substance as defined herein.

[0086] According to another aspect of the present invention, there is provided an embeddable and curable body substance kit comprising a cartridge filled with an embeddable body substance as defined herein, and a cartridge filled with a curable body substance as defined herein.

[0087] The method of using an embedded device and appropriate variants thereof may (suitably) be applied to any embedded device defined herein, and further, aspects of operating an embedded device may be applied to the method of the invention defined herein.

[0088] Any feature (including optional, suitable and preferred features) described in relation to any particular aspect of the invention may also be a feature (including optional, suitable and preferred features) of any other aspect of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] In order to better understand the present invention, and to show how to implement an embodiment of the present invention, reference is now made by way of example to the following schematic diagram, in which:

[0090] Figure 1 : DSC thermograms of extruded filament, 3D printable filament (dried for 1 hour), and 3D printable filament (dried for 4 hours)

[0091] Figure 2 : Water content of powder mix (control), extruded filaments, extruded filaments dried at 100 °C for 1 h, and 3D printed tablets.

[0092] Figure 3 : Photos of PVA tablets loaded with theophylline printed under the following conditions: a). 210°C, excluding water, b). 150°C, containing water, and photos of PVA tablets loaded with hydrocortisone printed under the following conditions: c). 210°C, excluding water, d). 150°C, containing water.

[0093] Figure 4 : Photographs of 3D printed tablets loaded with lisinopril dihydrate, indapamide, rosuvastatin calcium and amlodipine as well as multi-drug tablets (unimatrix).

[0094] Figure 5 : In vitro drug release analysis of individual tablets containing lisinopril, indapamide, rosuvastatin, and amlodipine in gastric fluid.

[0095] Figure 6 : Photo of filament produced by TASFEX 3D printing

[0096] Figure 7 : Photo of a tablet produced via TASFEX 3D printing

[0097] Figure 8 : In vitro drug release analysis of caplet tablets produced by TASFEX printing

[0098] Fig. 9 : Photographs and SEM images of theophylline-loaded PVA cylindrical tablets produced by TASFEX 3D printing

[0099] Fig.10 : In vitro release analysis of theophylline-loaded PVA cylindrical tablets produced by TASFEX printing.

[0100] Fig.11 : In vitro release analysis of 10% hydrocortisone loaded tablets in pH 1.2 medium.

[0101] Fig.12 : Schematic diagram of the embedded device.

[0102] Fig.13 : In vitro release analysis of chewable tablets containing ibuprofen in intestinal media.

[0103] Fig.14 : Schematic diagram showing potential applications of embedded 3D printing: for dose titration (1), dose personalization (2), combining two active ingredients (3) and sequential release of drugs in multidrug modified release systems.

[0104] Fig.15 : Photo shows the modification of the dual FDM 3D printer to accommodate the combination of the liquid dispenser (right) and the FDM 3D printer head (left).

[0105] Fig.16 : Photograph of molds used for gelatin casting.

[0106] Fig.17 : The graph shows the relationship between the dose of paracetamol embedded in the article and the percentage of the printed design.

[0107] Fig.18 : The photo shows the percentage of the pattern printed.

[0108] Fig.19 : The photo shows an embedded article in which a 300% pattern is printed (embedded) within the curable body substance.

[0109] Fig. 20 : The photos show embedded articles produced using printing speeds of 50.00 mm / min, 60.00 mm / min, 65.00 mm / min and 70 mm / min.

[0110] Fig.21 : Schematic diagram of a printer used for ink direct writing printing.

[0111] Fig. 22 : Time course drug (theophylline) release profiles using various fillers (lactose, mannitol and sorbitol).

[0112] Fig.23 : Time course drug (theophylline) release profiles using various concentrations of filler / plasticizer (sorbitol).

[0113] Fig.24 : Time course drug (theophylline) release profiles using various grades of PVA polymers.

[0114] Fig.25: Time course drug (theophylline) release profiles using different types of PVA polymers (PVP K29-32). DETAILED DESCRIPTION

[0115] definition

[0116] Unless otherwise stated, the following terms used in the specification and claims have the following meanings as set out below.

[0117] Throughout the description and claims of this specification, the words "comprise" and "contain" and their variations mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, when the indefinite article is used, the specification should be understood to contemplate the plural as well as the singular unless the context requires otherwise.

[0118] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process so disclosed.

[0119] The reader's attention is directed to all papers and documents which are filed concurrently with or before this specification in conjunction with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0120] For the avoidance of doubt, it is hereby stated that the information previously disclosed under the heading "Background Art" in this specification is relevant to the present invention and should be construed as part of the disclosure of the present invention.

[0121] Unless otherwise stated, any reference to the term "melt" (or its derivatives) herein, particularly in the context of melt-extrudable compositions (e.g., filaments, mini-tablets, blends), suitably includes the glass transition or softening of a given material, suitably to allow its extrusion (e.g., through a nozzle). However, the term "melting" in the context of a defined "melting point" of a substance is a phase change from solid to liquid as defined in the art.

[0122] Herein, reference to "glass transition temperature" or "Tg" suitably refers to the temperature at which a material softens (e.g., to allow it to be extruded). Suitably, the glass transition temperature (Tg) of the materials described herein can be determined by standard test methods, suitably using dynamic mechanical analysis suitable tests, including the test protocol defined by ASTM E1640. Differential scanning calorimetry (DSC) can also be used. For example, the protocols listed in ASTM E1356 and ASTM D7426 can be used to distinguish the glass transition temperature. It will be understood by those skilled in the art that the reference herein to the glass transition temperature of a particular material falling within a certain temperature range is intended to mean that at least one glass transition temperature of the material (which may or may not have multiple glass transition temperatures) falls within the temperature range. Suitably unqualified reference to "glass transition temperature" means at least one, suitably means the lowest glass transition temperature, and can suitably mean the glass transition temperature that absorbs the most thermal energy (or the most endothermic). The key point, which will be self-evident to one skilled in the art, is that the material softens sufficiently under a specific set of circumstances (e.g., at the print nozzle, where the filament needs to be softened in order to be extruded during the printing process, and where re-solidification or re-hardening may occur thereafter).

[0123] Unless otherwise indicated, the term "viscosity" as used herein refers to the viscosity according to Ph. Eur. [European Pharmacopoeia] 2.2.10 or USP <912> Method II defines the test protocol for determining viscosity by Brookfield viscometer (UL adapter / 30 rpm / 20°C).

[0124] Unless otherwise stated, any reference herein to an "average" value is intended to relate to the mean value.

[0125] Where a composition / article is said to contain a plurality of specified ingredients (optionally in specified concentrations), the composition / article may optionally include additional ingredients in addition to those specified. However, in certain embodiments, a composition / article said to contain a plurality of specified ingredients may actually consist essentially of or consist of all of the specified ingredients.

[0126] Herein, when a composition is said to "consist essentially of a particular component", the composition suitably comprises at least 70 wt% of the component, suitably at least 90 wt%, suitably at least 95 wt%, most suitably at least 99 wt%. Suitably, a composition said to "consist essentially of a particular component" consists of the component except for one or more trace impurities.

[0127] When the quantity or concentration of a particular component of a given composition is specified as a weight percentage (weight %, wt% or %w / w), the weight percentage refers to the weight percentage of the component relative to the total weight of the composition as a whole. It will be understood by those skilled in the art that the sum of the weight percentages of all components of a composition will add up to 100wt%. However, in the case where not all components are listed (e.g., when it is said that a composition "includes" one or more specific components), the weight percentage balance can be optionally supplemented to 100wt% by unspecified ingredients (e.g., diluents (e.g., water), or other non-essential but suitable additives).

[0128] Herein, unless otherwise specified, when used in relation to multiple ingredients / components, the term "parts" (e.g., parts by weight, pbw) refers to the relative proportions between the multiple ingredients / components. To express the molar or weight ratios of two, three or more components to produce the same effect (e.g., the molar ratios of x, y, and z are x, y, and z, respectively), the term "parts" (e.g., parts by weight, pbw) refers to the relative proportions between the multiple ingredients / components. 1 :y 1 :z 1 , or the range x 1 -x 2 :y 1 -y 2 :z 1 -z 2 ). Although in many embodiments, the amount of a single component in a composition may be given as a "wt%" value, in alternative embodiments, any or all of such wt% values ​​may be converted to parts by weight (or relative ratios) to define a multi-component composition. This is so because in the composition of the present invention (e.g., a solid dosage form, such as an extruded article / embedded article and / or a mixture for preparing the solid dosage form, such as an extrudable composition / embeddable substance / solidifiable body substance), the relative proportions between the components are generally more important than their absolute concentrations. When a composition comprising a plurality of ingredients is described individually in parts by weight (i.e., only the relative proportions of the ingredients are indicated), it is not necessary to specify the absolute amounts or concentrations of the ingredients (whether all or individually), because the advantages of the present invention may be derived from the relative proportions of the individual ingredients rather than their absolute amounts or concentrations. However, in certain embodiments, such compositions consist essentially of or consist of the specified ingredients and a diluent (e.g., water).

[0129] The term "mole percent" (i.e., mol%) is well understood by those skilled in the art, and the mol% of a particular component means the amount of the particular component (expressed in moles) divided by the total amount of all components (including the particular component) and converted to a percentage (i.e., by multiplying by 100). The concept of mol% is directly related to the molar fraction.

[0130] When used in reference to a given component of a composition (e.g., "a liquid pharmaceutical composition substantially free of Compound X"), the term "substantially free" refers to a composition in which the component is substantially absent. When a composition is "substantially free" of a given component, the composition suitably comprises no more than 0.001 wt% of the component, suitably no more than 0.0001 wt% of the component, suitably no more than 0.00001 wt%, suitably no more than 0.000001 wt%, suitably no more than 0.0000001 wt%, most suitably no more than 0.0001 parts per billion (by weight).

[0131] When used in reference to given components of a composition (eg, "a liquid pharmaceutical composition completely free of Compound X"), the term "completely free" refers to a composition that does not contain all of the recited components.

[0132] Suitably, unless otherwise stated, where reference is made to a parameter (e.g. pH, pKa, etc.) or state of a material (e.g. liquid, gas, etc.) (which may depend on pressure and / or temperature), suitably in the absence of further clarification, such reference refers to the parameter at standard ambient temperature and pressure (SATP). SATP is a temperature of 298.15K (25°C, 77°F) and an absolute pressure of 100kPa (14.504psi, 0.987atm).

[0133] Suitably, unless otherwise stated, when reference is made to the boiling point, melting point or glass transition (softening) temperature of a component, such reference refers to that parameter measured at standard ambient pressure.Standard ambient pressure is an absolute pressure of 100 kPa (14.504 psi, 0.978 atm).

[0134] General aspects and advantages associated with the present invention

[0135] The present invention uses a temporary plasticizer in an extrudable composition. The extrudable composition is used to prepare an extruded article, and / or is used to produce an extrudable composition of another form. Compared with the absence (or less) of a temporary plasticizer, the temporary plasticizer (temporarily) reduces the temperature required for extruding the extrudable composition. Advantageously, the use of a temporary plasticizer is particularly suitable for components of heat-sensitive extrudable compositions, such as active ingredients, such as medicines, nutraceuticals and / or food supplement active ingredients, which are prone to degradation when heated. Therefore, in an extrudable composition and corresponding extruded articles, it is possible to have a higher loading of heat-sensitive components.

[0136] The use of a transient plasticizer allows the extrudable composition to be extruded at a lower temperature than an equivalent composition without (or at a lower level of) the transient plasticizer. After extrusion, the transient plasticizer can be removed (or partially removed) so that the composition of the extruded article (or an alternative form of an extrudable component, such as a 3D printable filament) is similar to the extruded equivalent composition, but because a lower extrusion temperature can be used, a lower level of thermal degradation is observed in the extruded article.

[0137] Advantageously, the temporary plasticizer reduces the glass transition (or softening) temperature of the extrudable composition. In addition, after extrusion or during extrusion, the temporary plasticizer is removed or partially removed. This causes the glass transition (or softening) temperature of the product obtained to increase, thereby changing the physical properties of the product obtained. For example, reducing the flexibility of the extruded product.

[0138] The present invention uses extrusion to produce extruded products, particularly pharmaceutical dosage forms, but those skilled in the art will readily appreciate that the principles of the present invention are readily applicable to nutraceuticals and food supplements. Extrusion types include 3D printers, including Fused Filament Fabrication (FFF) 3D printing.

[0139] A standard extrusion assembly may include an extrusion nozzle (e.g., a nozzle such as those used in 3D printing (e.g., fused FFF 3D printing)), and any associated delivery and / or heating means that allow the extrudable composition to be printed (typically in a sequential layered manner) onto a surface.

[0140] The method of the present invention overcomes many disadvantages of the extrusion process. For example, the commonly used extrudable carrier polyvinyl alcohol (PVA) can only be extruded at a temperature higher than 180°C. The use of a permanent plasticizer (e.g., sorbitol) can reduce the extrusion temperature of PVA to about 140°C. However, the use of water as a temporary plasticizer can further reduce the extrusion temperature of the PVA and sorbitol mixture to about 90°C. Advantageously, the temporary plasticizer can be removed or partially removed after or during the extrusion of the extruded product (e.g., extruded article and / or extrudable element). This means that the content of the temporary plasticizer can be reduced to a content suitable for the intended use of the extruded article, such as a content suitable for use in a pharmaceutical, nutraceutical, or food supplement product. As an alternative, and / or additionally, the level of the temporary plasticizer can be removed or partially removed in the extruded product (e.g., extruded article and / or extrudable element), thereby reducing the possibility that any component of the extruded product reacts with the temporary plasticizer. Finally, the removal or partial removal of the temporary plasticizer will change the physical properties of the extruded product (e.g., extruded article and / or extrudable element), for example, increasing the glass transition (softening) temperature of the article. This results in the physical properties of the extruded product, such as brittleness / flexibility, being changed. Therefore, the physical and chemical properties of the extruded product can be optimized depending on the intended use of the article (i.e., as a medicament (e.g., extruded article) or for the preparation of an extruded article (e.g., an extrudable element)).

[0141] The present invention extends the applicability of extrusion (including 3D printing) to a wider range of physical forms, thereby allowing components (including extrudable carriers and / or active ingredients) to be extruded with minimal thermal degradation of the components.

[0142] However, when developing extruded articles, the chemical and physical compatibility between the temporary plasticizer and the other components of the extrudable composition (e.g., the extrudable carrier, the active ingredient (if present), the permanent plasticizer (if present), and other components (if present)) must be considered.

[0143] The present invention embeds the embeddable substance into the solidifiable body substance. Advantageously, the method for preparing the embedded product is carried out at ambient temperature, or needs to be heated to a relatively low temperature, for example to 40°C. In this way, the method for preparing the embedded product is particularly suitable for use with heat-sensitive components, for example, heat-sensitive active ingredients, such as bioactive ingredients (i.e., proteins, amino acids, peptides, etc.). Advantageously, the embeddable substance can be in a liquid-like state (e.g., liquid, solution, semi-solid (suitably gel or gelling substance), emulsion, solid or suspension) in the solidifiable body substance. This can result in the embedded product having a wide range of applicability with a variety of active ingredients.

[0144] Suitably, the embedding step of each portion of the embeddable substance is digitally controlled, ie by a computer. Advantageously, embedding the embeddable substance in portions results in less variation in the amount of the embeddable substance dispensed during the embedding process, thus resulting in a more precise dosing of the embeddable substance within the embedded article.

[0145] The present invention employs embedding (suitably using a 3D printer) to produce embedded articles, particularly pharmaceutical dosage forms, but those skilled in the art will readily appreciate that the principles of the present invention are readily applicable to nutraceuticals and food supplements.

[0146] The extruded articles and embedded articles of the present invention can be produced "on demand" and in a personalized and customized manner to suit the needs of specific consumers (i.e., patients), thereby avoiding certain undesirable medical compromises (e.g., the dosage obtained by the patient is not perfect due to the limited range of mass-produced dosage forms provided).

[0147] It is expected that the present invention will make a significant contribution to the art in the production, distribution and consumption of pharmaceutical products and that this will have a positive health impact on all concerned.

[0148] It should be understood that although the technology of the present invention is described herein with respect to solid dosage forms (particularly pharmaceutical dosage forms), the technology is more generally applicable and can be effectively used to produce solid articles of various shapes and sizes, whether extruded articles or embedded articles. In addition, the development of the technology can go beyond the limitations of 3D printing and / or hot melt extrusion and can be used on an industrial scale, such as in large-scale manufacturing facilities, whether batch production, continuous flow production, or a combination thereof.

[0149] It should be understood that the term solid dosage form includes dosage forms that can be filled with a fluid-like substance (i.e., a liquid, solution, emulsion, suspension, or semisolid such as a gel) within the dosage form body, and the dosage form body provides the structure of the dosage form. For example, an insert containing a liquid embeddable substance should be considered a solid dosage form.

[0150] It is to be understood that the term solid dosage form also includes semisolid dosage forms, such as inserts comprising gelatin as the solidifiable body material.

[0151] Method for preparing extrudable composition

[0152] The present invention provides a process for preparing an extrudable composition, suitably as defined herein.

[0153] The method suitably comprises:

[0154] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0155] ii. Optionally, further treating the mixture from step i to form:

[0156] a. Extrudable fluid;

[0157] b. Extrudable compressed form; or

[0158] c. Extrudable components.

[0159] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0160] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0161] ii. Optionally, further treating the mixture from step i to form:

[0162] a. Extrudable fluid;

[0163] b. Extrudable compressed form; or

[0164] c. Extrudable components;

[0165] Wherein the temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) which is capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa).

[0166] Suitably, the extrudable carrier and the transient plasticizer are mixed together by shear mixing.

[0167] Suitably, with the mixing rate being greater than or equal to 10rpm, 25rpm, 50rpm, 75rpm, 100rpm, 125rpm, 150rpm, 175rpm, 200rpm, 250rpm, 300rpm, 400rpm or 500rpm, can be extruded carrier and temporary plasticizer mix together. Suitably, with the mixing rate being less than or equal to 500rpm, 400rpm, 300rpm, 200rpm or 100rpm, can be extruded carrier and temporary plasticizer mix together. Suitably, with the mixing rate of 10 to 500rpm, can be extruded carrier and temporary plasticizer mix together.

[0168] Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at room temperature. Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at a temperature greater than or equal to 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at a temperature less than or equal to 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C, 25°C, 20°C or 10°C. Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at a temperature of 10-100°C.

[0169] Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at a temperature lower than the boiling point of the temporary plasticizer. Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at a temperature higher than the melting point of the temporary plasticizer. Suitably, the mixing of the extrudable carrier and the temporary plasticizer is carried out at a temperature between the boiling point and the melting point of the temporary plasticizer.

[0170] Suitably, the method further comprises spraying a transient plasticizer onto the extrudable carrier during the mixing step.

[0171] Suitably, the method further comprises the mixture of further processing step i., to form an extrudable fluid. Suitably, the extrudable fluid is an extrudable semifluid. Suitably, the extrudable fluid is a molten extrudable composition. Suitably, the extrudable fluid has a property suitable for being directly used for extrusion. Advantageously, the extrudable fluid can be used in the process of preparing an extruded article without further processing the extrudable composition, that is, the extrudable fluid can be extruded without manipulating the physical properties of the extrudable composition, for example, by (further) heating the extrudable composition.

[0172] Suitably, the extrudable fluid is obtained by heating the mixture of step i. to a temperature greater than or equal to the melting point or glass transition (softening) temperature of the mixture, suitably greater than or equal to 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C or 120°C. Suitably, the extrudable fluid is obtained by heating the mixture of step i. to a temperature less than or equal to 200°C, 180°C, 160°C, 150°C, 140°C, 130°C, 120°C, 110°C or 100°C. Suitably, the extrudable fluid is obtained by heating the mixture of step i. to a temperature of 20 to 200°C.

[0173] Advantageously, a container, such as a syringe or ink cartridge, can be filled with the extrudable composition. Suitably, the method further comprises filling a container, such as a syringe or ink cartridge, with the extrudable composition. Suitably, the method further comprises filling a container, such as a syringe or ink cartridge, with the mixture of step i, optionally, the mixture of step i is then further processed, such as by heating the container, thereby forming an extrudable fluid in the container. Suitably, the method comprises: heating the container (e.g., syringe) to a glass transition (or softening) temperature higher than the mixture formed in step i. Suitably, the method comprises heating the container (e.g., syringe) to a temperature greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Suitably, the method comprises heating the container (e.g., syringe) to a temperature of 25-100°C. Suitably, the method further comprises filling the container with an extrudable fluid, such as suitably filling a syringe with an extrudable fluid. Suitably, the extrudable fluid is optimized for syringe delivery, for example, the viscosity of the extrudable fluid allows the fluid to flow out of the syringe when pressure is applied to the syringe. Advantageously, the syringe can be used to extrude the extrudable composition. In one embodiment, the container is a metal syringe,

[0174] Suitably, the method further comprises further processing the mixture from step i. to form an extrudable compressed form, such as a tablet or multiple tablets, such as (one or more) mini tablets. Suitably, the compressible form is formed by compressing the mixture from step i. Suitably, the compression step utilizes a punching tool. Suitably, the diameter of the punching tool is 1 to 10 mm, 2 to 8 mm, 4 to 7 mm, 5 to 7 mm or about 6 mm. Suitably, the punching tool is circular, oval, square or rectangular.

[0175] Suitably, each extrudable compressed form is formed by compressing 10 to 100 mg, 20 to 80 mg, 30 to 70 mg, 40 to 60 mg, or about 50 mg of the mixture of step i per extrudable compressed form.

[0176] Suitably, each extrudable compressed form weighs from 10 to 100 mg, from 20 to 80 mg, from 30 to 70 mg, from 40 to 60 mg or about 50 mg.

[0177] Suitably, the method further comprises further processing the mixture of step i. to form an extrudable element. Suitably, the extrudable element is a filament. Suitably, the method comprises extruding the mixture from step i. to form an extrudable element. Suitably, the extrusion temperature is greater than or equal to the glass transition (softening) temperature of the mixture from step i., for example, suitably greater than or equal to -50°C, -30°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C or 120°C. Suitably, the extrusion temperature is less than or equal to 200°C, 180°C, 160°C, 140°C, 130°C, 120°C, 110°C, 100°C or 90°C. Suitably, the extrusion temperature is between -50°C and 200°C, 60°C and 100°C, 65°C and 95°C or 70°C and 90°C.

[0178] Suitably, the extrusion step uses a hot melt extruder. Suitably, the hot melt extruder includes an extrusion nozzle. Suitably, the extrusion nozzle includes an output opening. The size of the output opening is suitable for the property of the corresponding extrudable composition, to allow the extrudable composition to be deposited therefrom (e.g., deposited onto a build platform). Suitably, the output opening has a diameter of 50 to 2000 μm, 100 to 1500 μm, 200 to 1500 μm, 500 to 1500 μm, 750 to 1250 μm or about 1000 μm. In an embodiment, the nozzle has an output opening, and the output opening has a diameter between 750 μm and 1250 μm.

[0179] Suitably, the thickness (i.e., diameter or maximum thickness) of the extrudable element (e.g., filament) is 0.1 mm to 5 mm, 0.5 mm to 2 mm, 0.5 mm to 1.5 mm, or 0.8 mm to 1.2 mm. In a specific embodiment, the thickness of the filament is about 1 mm. However, the thickness can be adjusted to be suitable for the extrusion nozzle (particularly the size / diameter of each opening thereof) through which it is extruded.

[0180] Suitably, during the extrusion step, the mixture of step i. is mixed at a mixing rate of greater than or equal to 10 rpm, 25 rpm, 35 rpm, 50 rpm, 75 rpm, 100 rpm, 125 rpm, 150 rpm, 175 rpm, 200 rpm, 250 rpm, 300 rpm, 400 rpm or 500 rpm. Suitably, the mixture of step i. is mixed at a mixing rate of less than or equal to 500 rpm, 400 rpm, 300 rpm, 200 rpm or 100 rpm. Suitably, during the extrusion step, the mixture of step i. is mixed at a mixing rate of 10 to 500 rpm.

[0181] Suitably, the method further comprises coating the extrudable element with a lubricant and / or a glidant. Suitable lubricants may include silicon dioxide; fats, such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable glidants may include fumed silica, talc, magnesium carbonate and / or colloidal silicon dioxide. The lubricant facilitates the flow of the extrudable element through the extruder during the preparation of the extruded article.

[0182] Suitably, the extrusion step of forming the extrudable element may optionally further comprise a step of removing or partially removing a temporary plasticizer by vaporization. Suitably, the temporary plasticizer is removed or partially removed by heating the extrudable element and / or maintaining the extrudable element under vacuum. Suitably, the extrudable element is heated and / or maintained under vacuum until the properties (e.g., flexibility) of the extrudable element are suitable for use in a method for preparing an extruded article (e.g., a solid dosage form). Suitably, the extrudable element is heated and / or maintained under vacuum until the glass transition (softening) temperature of the extrudable element is from -50°C to 100°C, -40°C to 80°C, -40°C to 75°C, -40°C to 60°C, -40°C to 50°C, -40°C to 30°C, -20°C to 50°C, -35°C to 25°C, -30°C to 25°C, -25°C to 25°C, -20°C to 25°C, -20°C to 20°C, -20°C to 15°C, -20°C to 10°C, -20°C to 5°C, -20°C to 0°C, -20°C to -5°C, -15°C to -5°C, -15°C to -10°C or -12°C to -8°C. Suitably, the extrudable element is heated and / or maintained under vacuum until the glass transition (softening) temperature of the extrudable element is less than or equal to 70° C., 60° C., 50° C., 40° C., 30° C., 20° C., 10° C., 5° C., 0° C., -5° C., -10° C., -15° C., or -20° C. Suitably, the extrudable element is heated and / or maintained under vacuum until the glass transition (softening) temperature of the extrudable element is about -10° C. or about 15° C.

[0183] Suitably, the extrudable element is heated and / or maintained under vacuum until the temporary plasticizer is less than or equal to 20%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1% or 0.05% by weight or until substantially free of the temporary plasticizer. Suitably, the extrudable element is heated and / or maintained under vacuum until the temporary plasticizer is 0-20% by weight.

[0184] Suitably, the extrudable element is heated and / or maintained under vacuum until the transient plasticizer content of the extrudable composition is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0185] Suitably, the extrudable element is heated and / or maintained under vacuum for greater than or equal to 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes or 120 minutes. Suitably, the extrudable element is heated and / or maintained under vacuum for less than or equal to 120 minutes, 100 minutes, 80 minutes or 60 minutes. Suitably, the extrudable element is heated and / or maintained under vacuum for 10-120 minutes.

[0186] Suitably, the extrudable element is heated. Suitably, the extrudable element is heated to a temperature below the melting point of the extrudable element. Suitably, the extrudable element is heated to a temperature greater than or equal to 30°C, suitably, a temperature greater than or equal to 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Suitably, the extrudable element is heated to a temperature less than or equal to 200°C, suitably, a temperature less than or equal to 180°C, 160°C, 140°C, 130°C, 120°C, 110°C, 100°C, 90°C or 80°C. Suitably, the extrudable element is heated to a temperature of 30-200°C.

[0187] Suitably, the extrudable element is maintained under reduced pressure, suitably maintained under vacuum. Suitably, the pressure of the vacuum is less than atmospheric pressure, suitably less than or equal to 90 kPa, 10 kPa, 5 kPa, 1 kPa, 0.5 kPa, 0.1 kPa, 0.05 kPa, 0.01 kPa or 0.005 kPa. Suitably, the pressure of the vacuum is 0.005-90 kPa.

[0188] Suitably, the transient plasticizer is removed or partially removed by exposing the extrudable element to a relative humidity (RH) less than ambient, suitably less than or equal to 60% RH, 50% RH, 40% RH, 30% RH, 20% RH, 10% RH or about 0% RH. Suitably, the transient plasticizer is removed or partially removed by exposing the extrudable element to a relative humidity of 0 to 60% RH.

[0189] Suitably there is provided a method of processing an extrudable composition to produce an extrudable fluid, the method comprising melting or softening the extrudable composition (suitably by heating).

[0190] Suitably, there is provided a method of processing an extrudable composition to produce an extrudable compressed form, the method comprising compressing the extrudable composition.

[0191] Suitably, there is provided a method of processing an extrudable composition to produce an extrudable element, the method comprising extruding or moulding the extrudable composition into an extrudable element.

[0192] Suitably, there is provided a method of converting an extrudable fluid into an extrudable compressed form.

[0193] Suitably, there is provided a method of converting an extrudable fluid into an extrudable element.

[0194] Suitably, there is provided a method of converting an extrudable compressed form into an extrudable fluid.

[0195] Suitably, there is provided a method of converting an extrudable compressed form into an extrudable element.

[0196] Suitably, there is provided a method of converting an extrudable element into an extrudable compressed form.

[0197] Suitably, there is provided a method of converting an extrudable element into an extrudable fluid.

[0198] Suitably, a further processing step comprises converting an extrudable fluid into an extrudable compressed form. Suitably, a further processing step comprises converting an extrudable fluid into an extrudable element. Suitably, a further processing step comprises converting an extrudable compressed form into an extrudable fluid. Suitably, a further processing step comprises converting an extrudable compressed form into an extrudable element. Suitably, a further processing step comprises converting an extrudable element into an extrudable compressed form. Suitably, a further processing step comprises converting an extrudable element into an extrudable fluid.

[0199] Suitably, a further processing step comprises converting an extrudable fluid into an extrudable compressed form, followed by converting the extrudable compressed form into an extrudable element. Suitably, a further processing step comprises converting an extrudable fluid into an extrudable element, followed by converting the extrudable element into an extrudable compressed form. Suitably, a further processing step comprises converting an extrudable compressed form into an extrudable fluid, followed by converting the extrudable fluid into an extrudable element. Suitably, a further processing step comprises converting an extrudable compressed form into an extrudable element, followed by converting the extrudable element into an extrudable fluid. Suitably, a further processing step comprises converting an extrudable element into an extrudable compressed form, followed by converting the extrudable compressed form into an extrudable fluid. Suitably, a further processing step comprises converting an extrudable element into an extrudable fluid, followed by converting the extrudable fluid into an extrudable compressed form.

[0200] Suitably, the conversion step comprises heating, compression, dry compression, wet compression, molding and / or extrusion. Suitably, the extrudable composition is converted into the form of an extrudable fluid by heating. Suitably, the extrudable composition is converted into the form of an extrudable element by extrusion. Suitably, the extrudable composition is converted into an extrudable compressed form by compression, dry compression and / or wet compression.

[0201] Suitably, the extrudable compressed form of the extrudable composition is converted into an extrudable fluid form, suitably by heating.

[0202] Suitably, converting the extrudable compressed form of the extrudable composition into the form of an extrudable element, such as a filament for 3D printing, is suitably performed by extrusion.

[0203] Suitably, a further processing step comprises converting the extrudable compressed form (e.g. a tablet) into an extrudable element (e.g. a filament for 3D printing) by extruding the extrudable compressed form.

[0204] Suitably, the further processing step comprises converting the extrudable compressed form (eg a tablet) into an extrudable fluid by heating the extrudable compressed form.

[0205] Suitably, the further processing step comprises converting the extrudable fluid into an extrudable element (eg a filament for 3D printing) by extruding the extrudable fluid.

[0206] Suitably, a further processing step comprises converting the extrudable element (eg a filament for 3D printing) into an extrudable fluid by heating the extrudable element.

[0207] Suitably, the method comprises compressing the extrudable composition to form an extrudable compressed form.

[0208] Suitably, the method comprises mixing the components of the extrudable composition and then compressing together to form an extrudable compressed form.

[0209] Suitably, the method comprises compressing the components of the extrudable composition together to form an extrudable compressed form, and then extruding the compressed form to form an extrudable element (eg a filament for 3D printing).

[0210] Suitably, the method comprises mixing the components of the extrudable composition and then compressing together to form an extrudable compressed form and then extruding the compressed form to form the extrudable element.

[0211] It will be understood that any of the above aspects and embodiments may be achieved with or without the inclusion of a temporary plasticizer (or mixed with a temporary plasticizer), and these aspects and embodiments are also considered to be within the scope of the present invention. For example, the present invention provides a method for preparing an extrudable composition, the method comprising:

[0212] i. providing an extrudable carrier, optionally mixed with a drug or active substance; and

[0213] ii. Optionally, further treating the mixture from step i to form:

[0214] a. Extrudable fluid;

[0215] b. Extrudable compressed form; or

[0216] c. Extrudable components.

[0217] In such aspects, step ii may, for example, comprise softening, melting or otherwise circulating an initial extrudable composition (which is initially suitably in solid form), such as an extrudable powder, extrudable granules, an extrudable compressed form (monolithic or multiple compressed forms, such as microtablets), to produce an extrudable fluid. Such circulation of the initial extrudable composition may comprise heating the composition, suitably in situ heating in a dispenser (such as a syringe, suitably a metal syringe with a heating jacket), so that the composition may be extruded into an extrudable element (such as a filament), or directly extruded into an extruded article (such as a tablet, suitably by direct ink 3D printing).

[0218] Alternatively, in such aspects, step ii may, for example, comprise compressing an initial extrudable composition (suitably a granular or powder composition) to form an extrudable compressed form. The extrudable compressed form may be fed back into the method to produce an extrudable fluid, an extrudable element or even an extrudable article (e.g. by direct ink 3D printing), with or without the addition of a temporary plasticizer or mixed with a temporary plasticizer.

[0219] Alternatively, in such aspects, step ii may, for example, comprise extruding an initial extrudable composition (which may be in the form of an extrudable powder, extrudable granules, extrudable compressed form(s)) into an extrudable element.

[0220] Suitably, whenever the invention is carried out without the use of a transient plasticiser, suitably any extrusion is carried out at a temperature of from 40 to 120°C, suitably at a temperature of from 60 to 100°C.

[0221] Unless incompatible in a given context, all optional features referred to above and below in relation to aspects or embodiments using a transient plasticizer are equally applicable to aspects or embodiments without a transient plasticizer.

[0222] Method for preparing extruded articles

[0223] The present invention provides a process for preparing an extruded article, suitably as defined herein.

[0224] The method suitably comprises:

[0225] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier; and

[0226] ii. extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core);

[0227] in:

[0228] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0229] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0230] The method suitably comprises:

[0231] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier; and

[0232] ii. extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core);

[0233] in:

[0234] The extrudable composition initially comprises greater than or equal to 5 wt% of a temporary plasticizer, the temporary plasticizer being a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0235] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0236] Suitably, the method suitably comprises:

[0237] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier; and

[0238] ii. 3D printing the extrudable composition into a desired form, optionally associated with one or more auxiliary elements (e.g., shell, coating, core);

[0239] in:

[0240] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0241] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0242] Suitably, the desired form is a solid dosage form, suitably a solid oral dosage form. Suitably, the extruded product is a pharmaceutical, nutraceutical or food supplement solid dosage form. Suitably, the extruded product comprises at least one active ingredient, suitably at least one pharmaceutical, nutraceutical or food supplement active ingredient. Most suitably, the active ingredient is a pharmaceutical active ingredient.

[0243] A method for preparing a solid dosage form of a pharmaceutical, nutraceutical or food supplement is provided, the method comprising:

[0244] i) providing an extrudable composition comprising an extrudable carrier; and

[0245] ii) extruding the extrudable composition into the desired form, optionally in association with one or more auxiliary elements (e.g. shell, coating, core);

[0246] in:

[0247] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0248] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0249] Suitably, there is provided a method of preparing a pharmaceutical, nutraceutical or food supplement solid dosage form, the method comprising:

[0250] i) providing an extrudable composition comprising an extrudable carrier; and

[0251] ii) extruding the extrudable composition into the desired form, optionally in association with one or more auxiliary elements (e.g. shell, coating, core);

[0252] in:

[0253] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0254] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0255] Suitably, there is provided a method of preparing a pharmaceutical, nutraceutical or food supplement solid dosage form, the method comprising:

[0256] i) providing an extrudable composition comprising an extrudable carrier; and

[0257] ii) extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (e.g. shell, coating, core) by 3D printing;

[0258] in:

[0259] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0260] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0261] Suitably, the extrudable composition is as defined herein. Suitably, the extrudable composition initially comprises a temporary plasticizer greater than or equal to 0.1 wt %, 0.2 wt %, 0.5 wt %, 0.8 wt %, 1 wt %, 2 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, 10 wt %, 12 wt %, 15 wt %, 18 wt %, 20 wt %, 25 wt % or 30 wt %. Suitably, the extrudable composition initially comprises a temporary plasticizer of 0.1 to 25 wt %.

[0262] The method suitably comprises operating an extrusion apparatus to produce an extruded article on a build platform by extruding the extruded article therein. Suitably, such production is carried out by a computer-implemented process (i.e., the extrusion is controlled and suitably initiated by a computer connected to or connectable to or within the apparatus, either by wire or wirelessly).

[0263] Suitably, the extrusion apparatus comprises a container for containing the extrudable composition prior to the extrusion step, and a nozzle for dispensing the extrudable composition during the extrusion step, wherein the container is heated to a temperature to maintain the extrudable composition in a (substantially) fluid state.

[0264] The method suitably involves extruding the extrudable composition onto a build platform. Such extrusion suitably involves 3D printing, preferably FFF 3D printing. Thus, extrusion may comprise extruding with one or more extrudable compositions. The extrudable composition (or its precursor) is suitably extruded through an extrusion nozzle of an extrusion device of the present invention.

[0265] Extruding the extrudable composition onto a building platform is suitably carried out by an extruder (e.g. a 3D printer), suitably with one or more extrudable compositions. Such (one or more) extrudable composition is suitably extruded through an extrusion nozzle as described herein.

[0266] Initially, the extrudable composition (or its precursor) is suitably resident in a storage location in the device, suitably in an ink cartridge such as a filament spool. The extrudable composition is suitably delivered to the extrusion nozzle via one or more conveyors (e.g., rollers). The extrudable composition is then extruded by the extrusion nozzle (suitably, when the extrudable composition continues to be delivered toward the extrusion nozzle from the storage location). Extruding by the extrusion nozzle suitably includes melting and / or softening the extrudable composition so that it is deposited on the building platform, suitably in a layer-by-layer manner. Suitably, the relevant extrudable composition is solidified after being deposited on the building platform or deposited on the layer that has been extruded on the building platform. Suitably, according to a predetermined blueprint, a 3D shape is constructed in a layer-by-layer manner by a judicious deposition. Suitably, after or during extrusion, a temporary plasticizer is removed or partially removed. Suitably, by extruding the extrudable composition being exposed to conditions higher than ambient temperature and / or vacuum, the temporary plasticizer is removed or partially removed.

[0267] The extrusion nozzle is suitably heated at an operating temperature as described herein to facilitate melting and / or softening of the extrudable composition.The nozzle suitably extrudes the extrudable composition at one or more operating speeds as described herein.

[0268] During extrusion, the extrusion nozzle is suitably moved in any or all of the X, Y, and Z directions.

[0269] Once extruded, the extruded article is suitably laid down on a build platform, suitably similar to a solid dosage form.

[0270] Suitably, a plurality of extruded articles are printed on a build platform.

[0271] Those skilled in the art will appreciate that the, each or any extrusion nozzle may be adjusted to suit the properties of the respective extrudable composition it is configured to extrude thereto. The properties / design of the nozzle and the properties of the extrudable composition are suitably complementary to facilitate controlled extrusion of the composition (continuously or discontinuously, for example where more than one extrudable composition is used in the extrusion of an extruded article), suitably without any nozzle blockage or impedance, and suitably without any unacceptable degradation of ingredients in the extrudable composition during extrusion.

[0272] In one embodiment, the composition of the extruded article comprises less transient plasticizer than the extrudable composition used to prepare the extruded article.

[0273] Extrusion steps

[0274] Suitably, the extrusion step is carried out at a temperature above the glass transition temperature of the extrudable composition. Suitably, the extrusion step is carried out at a temperature greater than or equal to -50°C, -30°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C or 150°C. Suitably, the extrusion step is carried out at a temperature less than or equal to 200°C, 180°C, 160°C, 150°C, 140°C, 130°C, 120°C, 110°C, 100°C or 90°C. Suitably, the extrusion step is carried out at a temperature of -50 to 200°C.

[0275] Suitably, the extrusion step uses an extruder. Suitably, the extruder is a 3D printer. Suitably, the 3D printer is a FFF 3D printer. Suitably, the extrusion step uses ink direct writing printing. Suitably, the extrusion step uses a syringe, suitably, a heated syringe. Suitably, the syringe or heated syringe contains an extrudable composition, suitably, the extrudable composition is a mixture or an extrudable fluid.

[0276] Suitably, the extrusion step comprises extruding an extrudable composition to form a first layer of an extruded article, and optionally subsequently extruding an extrudable composition to form subsequent layers. Suitably, the thickness of each layer is 10 to 1000 μm, 20 to 800 μm, 30 to 500 μm, 40 to 300 μm, 50 to 200 μm, 100 to 200 μm, 125 to 200 μm, 140 to 190 μm, 155 to 175 μm, 250 to 350 μm, 750 to 850 μm, about 166 μm, about 300 μm or about 800 μm. Suitably, each layer of the extruded article can have the same thickness, or each layer can have different thicknesses. Advantageously, the first layer (i.e., the layer in contact with the build platform) is thicker and can result in greater adhesion of the extruded article during its production.

[0277] Suitably, the extruding step uses a 100% internal fill. Suitably, the extruding step uses a concentric fill pattern.

[0278] The method comprises removing or partially removing the temporary plasticizer by vaporization. Suitably, before the extrusion step (from an extrudable composition, such as an extrudable element), during and / or after, remove or partially remove the temporary plasticizer from the extruded article. Suitably, during and / or after the extrusion step, remove or partially remove the temporary plasticizer from the extruded article. Suitably, after the extrusion step, remove or partially remove the temporary plasticizer from the extruded article. Suitably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the temporary plasticizer is removed. Suitably, 10% to 90% of the temporary plasticizer is removed. Suitably, remove or partially remove the temporary plasticizer until the temporary plasticizer in the extruded article is less than or equal to 20 wt %, 16 wt %, 14 wt %, 12 wt %, 10 wt %, 8 wt %, 6 wt %, 5 wt %, 4 wt %, 3 wt %, 2 wt %, 1 wt %, 0.5 wt % or 0.1 wt %. Suitably, the extruded article is substantially free of temporary plasticizer. Suitably, the extruded article is fully free of temporary plasticizer. Suitably, the temporary plasticizer is removed or partially removed until the weight of the temporary plasticizer in the extruded article is 0 to 20%.

[0279] Suitably, the step of removing or partially removing the temporary plasticizer comprises heating and / or maintaining the extrudable composition (suitably, the extrudable element) and / or the extruded article (during the formation of the extruded article, or after the extruded article has been formed) under reduced pressure, such as vacuum. Suitably, the extrudable composition and / or the extruded article are heated to a temperature greater than or equal to 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Suitably, the extrudable composition and / or the extruded article are heated to a temperature less than or equal to 200°C, 180°C, 160°C, 140°C, 130°C, 120°C, 110°C, 100°C, 90°C or 80°C. Suitably, the extrudable composition and / or the extruded article are heated to a temperature of 30 to 200°C. Suitably, the extrudable composition and / or the extruded article are maintained under reduced pressure, such as under vacuum. Suitably, the pressure of the vacuum is less than atmospheric pressure, suitably less than or equal to 90 kPa, 10 kPa, 5 kPa, 1 kPa, 0.5 kPa, 0.1 kPa, 0.05 kPa, 0.01 kPa or 0.005 kPa. Suitably, the pressure of the vacuum is 0.005-90 kPa.

[0280] Suitably, the extrudable composition is as defined herein.

[0281] Suitably, step i. further comprises extruding the extrudable composition onto a building platform. Suitably, the building platform is maintained at a temperature below the extrusion temperature. Suitably, the building platform is maintained at a temperature of less than or equal to 100°C, suitably less than or equal to 90°C, 80°C, 70°C, 60°C, 50°C, 40°C or 30°C. Suitably, the building platform is maintained at a temperature of 0 to 100°C, for example 30 to 100°C. Advantageously, making the temperature of the building platform less than the extrusion temperature helps to solidify it when forming the extruded article. In addition, making the temperature of the building platform higher than the ambient temperature helps to remove or partially remove the temporary plasticizer.

[0282] Suitably, the extruded article is heated by the construction platform until the extruded article comprises a temporary plasticizer that is less than or equal to 20 % by weight, 16 % by weight, 14 % by weight, 12 % by weight, 10 % by weight, 8 % by weight, 6 % by weight, 5 % by weight, 4 % by weight, 3 % by weight, 2 % by weight, 1 % by weight, 0.5 % by weight or 0.1 % by weight, or does not contain a temporary plasticizer substantially, or does not contain a temporary plasticizer fully. Suitably, the extruded article is heated by the construction platform until the extruded article comprises a temporary plasticizer that is less than or equal to 0 to 20 % by weight.

[0283] Suitably, the extruded article is heated by the construction platform until the temporary plasticizer content of the extruded article is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% relative to the temporary plasticizer content of the extruded composition. Suitably, the extruded article is heated by the construction platform until the extruded article is substantially free of or completely free of temporary plasticizer. Suitably, the extruded article is heated by the construction platform until the temporary plasticizer content of the extruded composition is reduced by 10 to 100%, for example 10 to 90%.

[0284] Suitably, the extruder includes an extrusion nozzle. Suitably, the extrusion nozzle includes an input opening (the extrudable composition is fed therein) and an output opening (the molten extrudable composition is deposited therefrom). Suitably set the size of the input opening so as to receive the extrudable composition therethrough (e.g., an extrudable element, a blend of extrudable composition components, an extrudable fluid or an extrudable compressed form). Suitably, the diameter of the input opening is 0.1 to 100 mm, 0.2 to 10 mm, 0.5 to 5 mm, 0.5 to 1.5 mm, 1.0 to 2.5 mm, 1.5 to 2.0 mm, 0.75 to 1.25 mm, about 1.75 mm or about 1 mm. The size of the output opening is suitable for the properties of the corresponding extruded product to allow the molten extrudable composition to be deposited therefrom (e.g., deposited onto a build platform). Suitably, the output opening has a diameter of 0.01 to 10 mm, 0.05 to 5 mm, 0.1 to 1 mm, 0.1 to 0.8 mm, 0.2 to 0.6 mm or about 0.4 mm. In one embodiment, the nozzle has an output opening having a diameter of between 0.3 mm and 0.5 mm.

[0285] As described elsewhere herein, the feeding of (one or more) extrudable compositions to and through their respective (one or more) extrusion nozzles is suitably facilitated by a conveyor (or roller). Such a conveyor is suitably placed along the path of the extrudable composition, suitably between an extrudable composition source (e.g., a filament spool or ink cartridge) and the extrusion nozzle, wherein a given extrusion composition is assigned to flow to and through the extrusion nozzle.

[0286] Suitably, prior to the extrusion step, the extrudable composition is in or converted to the following form:

[0287] a. Extrudable fluid;

[0288] b. Extrudable compressed form; or

[0289] c. Extrudable components.

[0290] Suitably, the method comprises extruding an extrudable compressed form to form an extruded article. Suitably, the method comprises extruding an extrudable fluid to form an extruded article. Suitably, the method comprises extruding an extrudable element to form an extruded article.

[0291] Extrudable fluids, extrudable compressed forms, and extrudable elements are as defined herein.

[0292] Suitably, prior to the extrusion step, the extrudable composition is in the form of an extrudable fluid, or is converted into the form of an extrudable fluid, suitably by heating, and the extrudable composition is subsequently extruded directly in the fluid state.

[0293] Suitably, prior to the extrusion step, the extrudable composition is in the form of, or is converted into, an extrudable compressed form, suitably in the form of a plurality of tablets.

[0294] Suitably, prior to the extrusion step, the extrudable compressed form of the extrudable composition is converted into an extrudable fluid form, suitably by heating, and the extrudable composition is subsequently extruded directly in the fluid state.

[0295] Suitably, prior to the extrusion step, the extrudable compressed form of the extrudable composition is converted into the form of an extrudable element, such as a filament for 3D printing, suitably by extrusion, and the extrudable element is subsequently extruded directly, suitably, through a 3D printing nozzle as a filament.

[0296] Squeeze from dispenser

[0297] Suitably, the method comprises providing a dispenser filled with an extrudable composition and then extruding the extrudable composition into a desired form, wherein the extrudable composition is as defined herein.

[0298] Suitably, the method comprises providing a dispenser filled with an extrudable fluid. Suitably, the method comprises providing a dispenser filled with an extrudable compressed form or a plurality of extrudable compressed forms. Suitably, the method comprises providing a dispenser filled with an extrudable element.

[0299] Suitably, the method comprises conveying the extrudable composition from a dispenser and through an extruder. Suitably, from the dispenser to (and through) an extrusion nozzle.

[0300] Suitably, the dispenser is a container, such as an ink cartridge, suitably a 3D printer ink cartridge.

[0301] Suitably, the container is a filament spool containing the filament.

[0302] Suitably, the container is a syringe. Suitably, the syringe is filled with an extrudable fluid.

[0303] Suitably, the method further comprises filling the container, suitably filling the syringe, with the extrudable fluid.

[0304] Suitably, the extrudable fluid is formed in situ by heating a container (e.g., a syringe) filled with the components of the extrudable composition. Suitably, the method comprises heating the container (e.g., a syringe) to a temperature greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C. Suitably, the method comprises heating the container (e.g., a syringe) to a temperature of 25 to 100°C.

[0305] Suitably, the extrudable fluid is squeezed out of the syringe (that is, the syringe serves as an extruder). Suitably, the extrudable fluid is optimized for syringe delivery, for example, when pressure is applied to the syringe, the viscosity of the extrudable fluid allows the fluid to flow out from the syringe. Advantageously, the extrusion of the extrudable fluid is carried out in a single process. For example, the component of the extrudable composition can be added to the syringe, the syringe is heated to form the extrudable fluid, and then directly extruded to form an extruded product. This direct extrusion reduces the overall exposure of the extrudable composition at high temperatures, for example, by contrast, when using an extrudable element (such as a filament) to prepare an extruded product, first the component of the extrudable composition is exposed to high temperature in the process of preparing the element, then exposed to high temperature in the process of preparing the extruded product.

[0306] Other methods and steps

[0307] The method may include one or more further steps before, during and / or after any of the aforementioned steps. The surface(s) of the extruded article may be pre-treated or post-treated by extruding additional layers or partial layers, or by other coating techniques known in the art.

[0308] Suitably, the method comprises extruding the extrudable composition into a desired form in combination with one or more auxiliary elements. Suitably, the auxiliary elements comprise a shell, a coating and / or a core.

[0309] Suitably, the method further comprises the steps of incorporating at least one further excipient and / or at least one further active ingredient into the extruded article, suitably surrounding the desired form with the at least one further excipient and / or the at least one active ingredient. Suitably, the desired form is an extruded article.

[0310] The extruded article produced by the method of the present invention can then be treated in various ways to provide an extruded article for further processing. Suitably, the method also includes coating the product obtained by the extrusion step. Suitably, coatings are described herein. For example, the extruded article can be enteric coated by standard enteric coating treatments known in the art. Similarly, the extruded article can be given other controlled release properties by further processing.

[0311] Most suitably, all steps (including any other processing steps) are performed by the extrusion equipment. Suitably, all steps (including further processing steps) are controlled by the same computer.

[0312] Computer implementation of the method

[0313] The method of preparing the extruded article is suitably a computer implemented method, suitably as defined herein.

[0314] The method suitably comprises providing an extrusion device, suitably an extrusion device as defined herein, and operating the device to extrude the extrudable composition, thereby forming an extruded product. Suitably, the extrusion device comprises a computer or is otherwise connected to a computer. Operating the extrusion device suitably comprises operating a computer, which is suitably connected to or connected within the relevant extrusion device (in a wired or wireless manner) (so that the computer can control and coordinate other parts of the extrusion device, including the extruder), so that the extrudable composition is extruded to form an extruded product and / or an extrudable element.

[0315] The computer consisting of or associated with the extrusion apparatus of the present invention may be suitably referred to as an extrusion control computer. The extrusion control computer may serve a different function (and may be a different entity) than other "computers" referred to herein, such as monitoring computers and analysis computers, but a single computer may perform the (one or more) functions of any one or more combinations of these computers. The extrusion control computer suitably controls the extrusion of the extrudable composition through the extrusion nozzle, and optionally further processing steps, such as coating the formed article after extrusion. As long as different computers are used to implement each of these operations, the computers will be suitably coordinated and therefore can be considered as part of an integral computer.

[0316] Extrusion of (one or more) extrudable compositions to form (one or more) extruded articles and / or (one or more) extrudable elements is suitably controlled by a computer running according to extrusion software, suitably based on information provided to the computer by user input (drug type, drug dosage level), databases (e.g., patient databases and / or extruded article databases) and / or data files (e.g., design and / or parameter files), as described herein. Suitably, the extrusion device is configured to extrude according to instructions provided by the computer by: feeding (one or more) extrudable compositions to and through their respective (one or more) extrusion nozzles at suitable intervals and / or suitable rates; heating (one or more) relevant extrusion nozzles at (one or more) suitable temperatures for a suitable time; and moving (one or more) extrusion nozzles and / or building platforms to achieve systematic layer-by-layer extrusion according to the relevant information obtained and the calculations performed by the computer.

[0317] The (one or more) extrusion nozzles are suitably controlled by a computer according to the "obtained information" (e.g., design and / or other parameters) related to the extruded article. The extrusion nozzle is suitably controlled to extrude a given extrudable composition onto a build platform (or onto an extruded article partially constructed on the build platform) to form a pattern predefined by the "obtained information". In this way, the or each extrusion nozzle can be controlled to "open" and "close" according to a predefined plan to deliver the desired pattern in the construction of the extruded article. The extrusion nozzle can be adjusted to "open" by opening the output opening, by adjusting the operating temperature of the extrusion nozzle (e.g., increasing the extrusion temperature to melt the relevant extrudable composition), by operating a conveyor to pass the extrudable composition through the nozzle, or any one or all of the above combinations. Naturally, the extrusion nozzle can be adjusted to "close" by closing the output opening, by adjusting the operating temperature of the extrusion nozzle (e.g., lowering it to a temperature that does not cause the relevant extrudable composition to melt), by operating a conveyor to limit or stop feeding the extrudable composition through the extrusion nozzle, or any one or all of the above combinations. As described elsewhere herein, the temperature of the extrusion nozzle is suitably set and controlled by a computer according to the properties of the extrudable composition discussed. Suitably, the operating temperature of the extrusion nozzle through which the extrudable composition passes is 50 to 220°C, 60 to 150°C or 70 to 120°C. However, the operating temperature of the extrusion nozzle may be lower, for example, lower than 50°C, particularly in systems using extrudable compositions with low glass transition temperatures. Suitably, the temperature of the extrusion nozzle is set to at least 65°C, more suitably at least 70°C. In a particular embodiment, the extrusion nozzle temperature is 50-130°C, 60-120°C, 70-110°C or 80-100°C. Suitably, the operating temperature of the extrusion nozzle assigned to a given extrudable composition is lower than that of a corresponding extrudable composition having a lower level of (i.e., substantially no) transient plasticizer.

[0318] The building platform is suitably controlled by a computer according to "obtained information" (e.g., design and / or other parameters) related to the extruded article, suitably as described elsewhere herein. This may include controlling the operating temperature of the building platform, in particular the operating temperature of the surface of the building platform. Suitably, during the extrusion process, the operating temperature of the building platform or its surface remains substantially constant, suitably maintained at a constant temperature of + / -5°C. Such temperature control can facilitate the removal or partial removal of temporary plasticizers, cooling and / or hardening of (one or more) extrudable compositions after deposition, thereby ensuring the structural integrity of the extruded article when it is extruded. Such temperature control can facilitate the adhesion of the extruded article presented during the extrusion process to the surface of the building platform. Such temperature control can facilitate the release (i.e., non-stickiness) of the extruded article after extrusion (e.g., the surface of the building platform can be suitably heated or cooled to reduce the adhesion of (one or more) extruded articles thereon). During extrusion, the building platform is suitably configured or operable to maintain a surface temperature (i.e., a surface for contacting the extruded article) of less than or equal to 100°C, suitably less than or equal to 90°C, 80°C, 70°C, 60°C, 50°C, 40°C or 30°C. During extrusion, the build platform is suitably configured or operated to maintain a surface temperature (ie, the surface intended to come into contact with the extruded article) of 30-100°C.

[0319] It will be understood that any of the above aspects and embodiments may be implemented with or without the use or with or without the inclusion of a temporary plasticizer (or mixed with a temporary plasticizer), and these aspects and embodiments are also considered to be within the scope of the present invention. For example, the present invention provides a method for preparing an extruded article, the method comprising:

[0320] i. providing an extrudable composition comprising an extrudable carrier and, optionally, a drug or active substance; and

[0321] ii. Extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core).

[0322] In such aspects, providing an extrudable composition may involve providing an extrudable solid form as described above (e.g., powder, granules, mini-tablets, monoliths), but preferably involves providing an extrudable fluid, an extrudable compressed form or an extrudable element as described herein. Particularly preferred are extrudable compressed forms, suitably in the form of a plurality of compressed units (e.g., mini-tablets) or compressed monoliths (e.g., such as pre-compressed solid matter).

[0323] In such aspects, extruding the extrudable composition into a desired form (e.g. an oral dosage form) suitably comprises dispensing the extrudable composition from a dispenser (e.g. a syringe), suitably after sufficient mobilisation (e.g. melting by heating), suitably in situ within the syringe, to allow for ink direct writing 3D printing.

[0324] Unless incompatible in a given context, all optional features referred to above and below in relation to aspects or embodiments using a transient plasticizer are equally applicable to aspects or embodiments without a transient plasticizer.

[0325] Methods of making extrudable compositions and extruded articles

[0326] According to another aspect of the present invention, there is provided a method for preparing an extruded product, the method comprising:

[0327] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0328] ii. Optionally, further treating the mixture from step i to form:

[0329] a. Extrudable fluid;

[0330] b. Extrudable compressed form; or

[0331] c. Extrudable components;

[0332] iii. extruding the extrudable composition obtained in step i (or step ii, if applicable) into the desired form, optionally associated with one or more auxiliary elements (eg shell, coating, core);

[0333] in:

[0334] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0335] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0336] In one embodiment, there is provided a method of preparing an extruded article, the method comprising:

[0337] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0338] ii. Optionally, further treating the mixture from step i to form:

[0339] a. Extrudable fluid;

[0340] b. Extrudable compressed form; or

[0341] c. Extrudable components;

[0342] iii. 3D printing the extrudable composition obtained in step i (or step ii, if applicable) into a desired form, optionally associated with one or more auxiliary elements (e.g. shell, coating, core);

[0343] in:

[0344] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0345] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0346] The features of the method steps are described elsewhere herein. For example, method steps i. and ii. and method step iii are described above, respectively.

[0347] It will be understood that any of the above aspects and embodiments may be implemented with or without the use or with or without the inclusion of a temporary plasticizer (or mixed with a temporary plasticizer), and these aspects and embodiments are also considered to be within the scope of the present invention. For example, the present invention provides a method for preparing an extruded article, the method comprising:

[0348] i. providing an extrudable composition comprising an extrudable carrier and, optionally, a drug or active substance; and

[0349] ii. Optionally, further treating the mixture from step i to form:

[0350] a. Extrudable fluid;

[0351] b. Extrudable compressed form; or

[0352] c. Extrudable components;

[0353] iii. Extruding said extrudable composition obtained in step i (or step ii, if applicable) into the desired form, optionally associated with one or more auxiliary elements (eg shell, coating, core).

[0354] Unless incompatible in a given context, all optional features referred to above and below in relation to aspects or embodiments using a transient plasticizer are equally applicable to aspects or embodiments without a transient plasticizer.

[0355] Extrusion equipment and related equipment and software for preparing extruded products

[0356] The present invention provides an extrusion device for preparing (e.g. printing) an extruded article (e.g. a solid dosage form, such as a tablet), suitably as defined herein, and suitably further comprising an extrudable composition as defined herein. The extrusion device can be suitably operated to form an extruded article (e.g. a solid dosage form) by extruding the extrudable composition (suitably layer by layer) to produce an extruded article.

[0357] Suitably, the extrusion apparatus comprises an extrudable element. Suitably, the extrusion apparatus comprises an extrudable fluid. Suitably, the extrusion apparatus comprises an extrudable compressed form.

[0358] The extrusion apparatus is suitable for extruding the extrudable composition to form an extruded article, wherein the extrudable composition and the extruded article comprise at least one active ingredient.

[0359] Suitably, the extrusion apparatus comprises a container for containing the extrudable composition, and a nozzle for dispensing the extrudable composition, wherein the container is heatable. Suitably, the container is heatable to a temperature of 25 to 300°C, 25 to 250°C, 25 to 200°C or 25 to 150°C.

[0360] Extruder

[0361] The extrusion device suitably comprises an extruder. Suitably, the extruder is a 3D printer. Suitably, the 3D printer is a fused filament fabrication (FFF) 3D printer. Such printers are generally referred to as fabrication deposition modelling. TM (FDM) 3D printer. The extrusion device suitably comprises a fused filament fabrication 3D printer (FFF 3D printer).

[0362] Conventional extruders (including 3D printers, including FFF 3D printers) are well known in the art and are generally suitable for use with the present invention, although they can be judiciously modified according to the principles outlined herein to optimize the extrusion of extruded articles. For reference to the skilled person, the following research papers describe the feasible operation of FFF 3D printers: SH Masood, "Application of fused deposition modelling in controlled drug delivery devices", Assembly Automation, 27 / 3 (2007), pp. 215-221, and Khaled et al., "Desktop 3D printing of controlled release pharmaceutical bilayer tablets", International Journal of Pharmaceutics, 461 (2014), pp. 105-111 describe the use of FFF 3D printers for filament printing, although no active ingredient is contained within the printed filament (the drug compound is injected at a later stage). In addition, PCT publication WO 2016 / 038356 of the present application (which is incorporated herein by reference) also describes suitable apparatus suitable for use with the present invention.

[0363] The extruder suitable for the present invention generally includes a heated / heatable extruder nozzle, which melts / softens and deposits the molten extrudable composition in a layer-by-layer manner (suitably deposited on the build platform). The deposited molten composition is suitably hardened rapidly after deposition. Keeping the build platform surface temperature relatively low can promote this cooling / hardening, to improve the final structure of the solid dosage form being printed, and keeping the build platform surface temperature greater than the ambient temperature can promote the removal or partial removal of temporary plasticizers. The extruder also suitably includes one or more nozzle heaters (suitably, each nozzle is associated with a nozzle heater, but optionally, a nozzle heater serves multiple nozzles) and suitably one or more conveyors (suitably, each filament and / or nozzle is associated with a conveyor), as defined herein. Suitably, the extruder includes one or more filament spool areas (or filament spool attachment points) for keeping (one or more) related filament spools.

[0364] Suitably, in the present invention, the pharmaceutical compound is formulated in an extrudable composition(s) and printed directly as an extruded article.

[0365] Suitably, the extruder uses a filament as defined herein. Suitably, the extrusion apparatus employs pre-made filament(s) which are selectively extruded and deposited in a layer-by-layer printing process to produce an extruded article.

[0366] The extrusion apparatus of the present invention may include one or more other components, optionally extruding, printing or dispensing a material intended to form a part of the extruded article.For example, the extruded article may be coated with a coating.

[0367] Extrusion nozzle

[0368] Suitably, the extrusion device comprises at least one extrusion nozzle, through and from which an extrudable composition (or part thereof) can be extruded. Suitably, the or each extrusion nozzle can be a heated extrusion nozzle, suitably a heated extrusion nozzle with variable temperature control (e.g., to allow the extrusion nozzle to be selectively heated at a desired temperature). Therefore, the extrusion device can comprise an extrusion nozzle heating element, suitably for heating the extrusion nozzle to melt, soften or otherwise liquefy the related composition or part thereof. Suitably, the extrusion device can comprise a plurality of aforementioned extrusion nozzles, each of which can be assigned to one or more extrudable compositions. Suitably, this extrusion nozzle is a part of an extruder.

[0369] The temperature of the nozzle(s) is suitably computer controlled.

[0370] Suitably, the extrusion apparatus comprises a conveyor for conveying the extrudable composition(s) to and / or through at least one extrusion nozzle.

[0371] Suitably, the conveyor feeds the extrudable composition (e.g., by grabbing the filament) toward and / or through the associated extrusion nozzle by itself. Suitably, the control conveyor is suitable for providing a desired extruded product at a rate and / or interval to convey the extrudable composition. The conveyor or a portion thereof (e.g., a "feeder") (preferably reaching a portion of the extrusion nozzle) may be heated, suitably via a heating element associated therewith, optionally via a heating element separated and / or individually controllable from any heating element associated with the extrusion nozzle. If the extrusion device comprises more than one nozzle, the extrusion device suitably comprises more than one feeder, one feeder being associated with each extrusion nozzle.

[0372] The temperature of the extrusion nozzle(s) is suitably computer controlled. Suitably, the nozzle(s) are configured to operate at a temperature of 60 to 350°C, 80 to 300°C, 100 to 220°C or 120 to 190°C.

[0373] Suitably, the operating temperature of the extrusion nozzle through which (one or more) relevant extrudable compositions pass is high enough to enable extrusion, but low enough to avoid unacceptable degradation of any component, such as (one or more) active ingredients, at the relevant filament feed rate. Suitably, the operating temperature of the extrusion nozzle through which (one or more) relevant extrudable compositions pass is 50 to 220°C, 60 to 150°C or 70 to 120°C. However, the operating temperature of the extrusion nozzle may be lower, for example, lower than 50°C, particularly in systems using extrudable compositions with low glass transition temperatures. Most suitably, the extrusion nozzle temperature is set to at least 65°C, more suitably at least 70°C. In a particular embodiment, the nozzle temperature is 50 to 130°C, 60 to 120°C, 70 to 110°C or 80 to 100°C.

[0374] Suitably, each extrusion nozzle comprises an input opening (into which the extrudable composition is fed) and an output opening (from which the molten extrudable composition is deposited). Suitably, the output opening is smaller than the input opening. Suitably, the input opening is sized so as to receive an extrudable composition (e.g., an extrudable element, a blend, an extrudable fluid, or an extrudable compressed form) therethrough. Suitably, the diameter of the input opening is 0.1 to 100 mm, 0.2 to 10 mm, 0.3 to 5 mm, 0.3 to 3 mm, 0.3 to 2 mm, 0.4 to 1.5 mm, 1.5 to 2.0 mm, 1.5 to 2.0 mm, 0.75 to 1.25 mm, about 1 mm, 0.2 to 0.6 mm, about 1.75 mm, or about 0.4 mm. The size of the output opening is suitable for the properties of the corresponding extruded article to allow the extrudable composition to be deposited therefrom (e.g., onto a build platform). Suitably, the output opening has a diameter of 0.01 to 10 mm, 0.05 to 5 mm, 0.1 to 1 mm, 0.1 to 0.8 mm, 0.2 to 0.6 mm or about 0.4 mm. In one embodiment, the nozzle has an output opening having a diameter of 0.3 to 0.5 mm.

[0375] Suitably, the or each nozzle is movable (suitably in an automated manner, or in a manner controlled by a computer or by an extruder according to computer instructions) to extrude the extrudable composition at different locations on the build platform (or on a partially formed extruded article extruded thereon). The nozzle may be movable in any or all of the X, Y and Z directions, although in some embodiments (e.g. the build platform is movable in the Z direction, i.e. up and down relative to the nozzle) the nozzle is constrained to move only in the X and Y directions.

[0376] Suitably, when extruding (i.e. when the nozzle is "on" - this may be the nozzle extrusion speed), the or each extrusion nozzle is operable to move at a speed of between 1 mm / s and 150 mm / s, suitably between 70 mm / s and 110 mm / s, more suitably between 80 mm / s and 100 mm / s, suitably between 1 and 10 mm / s, suitably about 4 mm / s. Suitably, when not extruding (i.e. when the nozzle is "off" - this may be the travel speed of the nozzle), the or each extrusion nozzle is operable to move at a speed of between 100 mm / s and 200 mm / s, more suitably between 120 mm / s and 180 mm / s, more suitably between 140 mm / s and 160 mm / s.

[0377] Suitably, the extrusion speed is constant during extrusion (ie the material flow rate is constant).

[0378] Those skilled in the art will appreciate that each or any nozzle may be adjusted to suit the properties of the extrudable composition (e.g., filament) configured to be extruded thereon. The properties / design of the nozzle and the properties of the extrudable composition are suitably complementary to facilitate controlled extrusion of the composition (continuous or discontinuous, such as where more than one extrudable composition is used in the extrusion of an extruded article), suitably without any nozzle blockage or impedance, and suitably without any unacceptable degradation of components in the extrudable composition during extrusion.

[0379] Build the platform

[0380] The extrusion apparatus suitably comprises a build platform (or build plate) on which the extrudable composition can be extruded (i.e., on which the extruded article can be built). The build platform suitably provides a (substantially flat) surface that supports the forming and already formed extruded article throughout the extrusion process. In a particular embodiment, the build platform comprises a surface, a tape layer (i.e., there is a layer of tape on the surface) or a surface coating that promotes adhesion of the extruded article to the build platform during the extrusion process (i.e., promotes adhesion of the first layer of the extruded article to be extruded to the build plate, suitably after the first layer cools and hardens), although suitably, the extruded article can be (conveniently) removed from the build platform after production.

[0381] Suitably, during extrusion (e.g. at the relevant extrusion operating temperature), the surface of the build platform is adhered to the extruded article (or at least to the layer thereof in contact with the build platform) sufficiently to prevent movement of the article exhibited during the extrusion process. However, suitably, after extrusion (e.g., optionally at a temperature different from the extrusion operating temperature), the (one or more) extruded articles can be removed from the build platform without being damaged (e.g., the adhesion of the build platform is insufficient to allow removal of the (one or more) extruded articles, or it can be selectively adjusted, e.g., by changing the operating temperature, to allow removal of the (one or more) extruded articles therefrom). Thus, the surface of the build platform may include a surface coating or surface tape that imparts desired surface properties (e.g., adhesive but not so adhesive that the extruded article does not permanently adhere).

[0382] The building platform is suitably configured or operable to maintain a surface temperature (i.e., a surface for contacting the extruded article) of less than or equal to 150°C, 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, or 30°C during extrusion. Suitably, the surface temperature is greater than or equal to 5°C, 15°C, 30°C, or 40°C. This can be achieved by selectively operating a heating and / or cooling element associated with the surface of the building platform (e.g., located below it). In a specific embodiment, the building platform is operable and is preferably operated to maintain a surface temperature of 5 to 150°C, 20 to 110°C, 20 to 100°C, about 90°C, or about 40°C. Advantageously, the building platform is suitably configured or operated to maintain a surface temperature that is conducive to the removal or partial removal of the temporary plasticizer. Suitably, the surface temperature is about the boiling point of the temporary plasticizer, such as about 80°C or about 100°C. Suitably, the surface temperature is less than the extrusion temperature. Suitably, the surface temperature is less than or equal to the boiling point of the temporary plasticizer.

[0383] The build platform may be movable (suitably in an automated manner, or in a manner controlled by a computer or by an extruder according to computer instructions) to control the position or height of extrusion on the build platform. Although in some embodiments, the build platform is movable only in the Z direction, i.e., up and down, the build platform may be movable in any or all of the X, Y, and Z directions. Movement in the Z direction allows the gap (or height) between the nozzle and the extrusion point to remain substantially constant throughout the extrusion process to maintain layer-by-layer consistency.

[0384] Allocator

[0385] The extrusion device suitably comprises a dispenser. Suitably, the dispenser comprises a storage container, such as a hopper. The storage container suitably comprises an extrudable composition or a precursor thereof. Suitably, the storage container comprises an extrudable element. Suitably, the storage container comprises an extrudable fluid. Suitably, the storage container comprises an extrudable compressed form. The storage container is suitably sealed. The storage container can be in the form of a container (as defined herein, for example, a cartridge or a syringe) that is particularly suitable for compatibility with the apparatus of the present invention. The storage container suitably has an outlet (e.g., a valve-operated tap, optionally used in combination with a forced dispensing device (e.g., a supercharger or agitator)), through which its contents can be dispensed, or has a sampling port, from which the contents can be extracted by an external sampling element.

[0386] The dispenser suitably comprises one or more dispensing containers. Suitably, such dispensing containers are configured to receive a certain amount of the extrudable composition (or its precursor) from a storage container, suitably directly or via a delivery device. Suitably, the one or more dispensing containers can receive a predetermined dose of the extrudable composition (or its precursor).

[0387] Distributor suitably comprises quantitative assembly, for example gravimetric or volumetric assembly.This quantitative assembly suitably weighs or otherwise quantitatively each dosage of the extrudable composition (or its precursor) to be distributed.Suitably, distributor is operable to be transported to a certain amount of extrudable composition (or its precursor) from storage container to quantitative component or the distribution container interactive with quantitative component.Suitably, place one or more distribution containers so that (one or more) quantitative assembly can quantitatively be received by (one or more) distribution container The amount of the extrudable composition.As an alternative, quantitative assembly can be associated with storage container, and thus when distributing extrudable composition (or its precursor) therefrom, measures quality reduction.Can be quantitative by weight and / or by volume.

[0388] Distributor suitably comprises flow control assembly, and it suitably controls and measures the distribution of the extrudable composition (or its precursor) from storage container to one or more distribution containers.Flow control assembly can for example comprise controlled feed mechanism, and can suitably comprise Archimedean screw, valve, agitator (for example, vibrator, faucet or rocker).Alternatively or additionally, flow control assembly can comprise sampling probe, and this sampling probe is operable to sample (estimate) amount of extrudable composition (or its precursor) from storage container.

[0389] The dispenser suitably includes a discharge mechanism for discharging a quantitative amount of the extrudable composition (or its precursor) from the sampling probe or the dispensing container. Such a discharge mechanism may suitably include a release device (e.g., a tap, a valve, a vacuum release or other such mechanism, for example, which can tilt the contents from the dispensing container toward the target dispensing point). Alternatively or additionally, the discharge mechanism may include a discharge device, for example, a pressurizer, a stirrer, a screw, a piston or a plunger, which presses the extrudable composition (or its precursor) out of the (one or more) dispensing container, thereby dispensing the extrudable composition.

[0390] In one embodiment, the dispenser includes a hopper and a movable metering element (e.g., a reciprocating plate) that is movable relative to the hopper and includes a metering cavity / container of fixed or adjustable size. The size of the metering cavity determines the size of each dose. The movable metering element can be operated to receive a certain amount of extrudable composition from the hopper, then encapsulate its metered amount in the cavity, move to the dispensing point, and dispense the extrudable composition from the metering cavity.

[0391] The skilled person will appreciate that there are certain challenges in the metered dispensing of materials, particularly solids such as granular solids. Forces that favor outflow (e.g., gravity, pressure, and / or helical forces, such as the forces of an Archimedean screw) are often offset by forces that are not favorable to outflow, such as: adhesion between particles, adhesion to dispenser components (e.g., the walls of the dispenser and / or the dispensing outlet), wear, friction, unstable flow (e.g., formation of ratholes or arched profiles when funneling), compressibility (incompressible solids flow better), outlet restrictions (e.g., the caliber of the outlet), the repose angle of funneling (preferably less than or equal to an angle of 35°), external pressure (external vacuum helps), etc. The outflow of particles is particularly affected by the particles themselves, in terms of particle shape, particle size, particle density, chemical properties of the particles, surface roughness, and moisture content. The flowability of particles can be improved by judicious particle engineering, including techniques such as particle enlargement (e.g., granulation), reduction of cohesion, smoothing / rounding, optimization of moisture content, co-grinding (e.g., formation of a nano-coating that enhances flowability), etc. To ensure better particle flowability, the compressibility index is between 0-25%, suitably less than or equal to 25%, preferably less than or equal to 15%, preferably 10%. In addition, particle sizes between 10 and 200 μm, suitably greater than or equal to 10 μm, 50 μm or 100 μm are generally preferred for optimal particle flow. Therefore, small particle sizes, including nanoparticles (e.g. less than or equal to 100 nm), may be better distributed in the form of suspensions, such as nanosuspensions.

[0392] Suitably, components of the dispenser are computer controlled and suitably any valves or pressure intensifiers are electronically controlled.

[0393] Suitably, a pinch valve may be incorporated into the dispenser to control the dispensing flow of particles such as granules.

[0394] Suitably, the distributor may further include a mixer. Suitably, the mixer is a shear mixer. Suitably, the mixer may be configured to operate at a mixing rate greater than or equal to 10rpm, 25rpm, 50rpm, 75rpm, 100rpm, 125rpm, 150rpm, 175rpm, 200rpm, 250rpm, 300rpm, 400rpm or 500rpm. Suitably, the mixing rate is less than or equal to 500rpm, 400rpm, 300rpm, 200rpm or 100rpm. Suitably, the mixer may be configured to operate at a mixing rate of 10 to 500rpm.

[0395] Computer interfaces and computers

[0396] The extrusion apparatus, including the extruder (and optionally the build platform), may suitably be operated by a computer, suitably running according to specialist extrusion software, and optionally also running according to one or more databases, to extrude the extrudable composition and thereby form an extruded article on the build platform, suitably by a method involving extruding the extrudable composition.

[0397] Those skilled in the art will readily appreciate that any one or more of the build platform, extrudable composition and / or computer and / or any part thereof may be suitably integrated in the embedder or form part of the extruder. In one embodiment, the extrusion device is substantially an extruder, a 3D printer (including FFF 3D printing) or a printing device.

[0398] Suitably, the extrusion apparatus comprises a computer interface (for wired or wireless connection to a computer operable to control the extruder).

[0399] The extrusion device suitably includes a computer for controlling the extruder. The computer can optionally control the build platform (e.g., its position, height, etc.). Therefore, the computer can be configured to operate the extruder (e.g., 3D printer) according to a predetermined extruded product design pattern.

[0400] The extruder suitably includes a computer or is otherwise connected to a computer. The extruder is suitably connected to the computer via an interface (suitably a digital interface), which may be wired (e.g., port-to-port connection via an appropriate data conductor, such as a USB cable), or wireless. The computer may be located at the location of the extruder (i.e., a local computer). However, the present invention is equally applicable to situations where the associated computer (or multiple computers) is away from the location of the associated extruder, but the extruder and the remote computer all include or are otherwise connected to respective communicators, thereby allowing the remote computer and the extruder to communicate with each other. In this way, the remote computer may be made to operate the extruder. In a particular embodiment, the extruder may be connected to a network so that multiple remote computers (and / or local computers) may communicate with it to cause the operation of the extruder.

[0401] A computer associated with or otherwise connected to the extruder suitably controls the extrusion of the relevant extrudable composition(s) in accordance with the extrusion article design and / or extrusion article parameters (e.g., relative amounts and juxtaposition of ingredients) set forth in a given extrusion article data file (e.g., a CAD or .STL file), suitably the given extrusion article data file being interpreted by associated software upon which the computer operates.

[0402] In certain embodiments, the extrusion device comprises or is connected to a local computer, and both the extrusion device and the local computer are located on-site at the pharmacy, most suitably in a purpose built extrusion area or room (suitably with regulatory approval).

[0403] Suitably, the method and / or extrusion apparatus comprises a computer operating in accordance with extrusion software (and optionally one or more internal and / or external databases).

[0404] Suitably, the computer operating in accordance with the extrusion software is configured to obtain information (e.g., information manually input from a user, or information automatically obtained from other data sources) about one or more parameters related to the extruded article to be extruded (optionally including physical design parameters such as shape). Suitably, the computer operating in accordance with the extrusion software is configured to request manual user input via a user interface (e.g., keyboard / screen) about one or more parameters related to the extruded article to be extruded. For example, the user (who may be a pharmacist acting on the instructions of a patient and / or a doctor) may be asked to enter information about the patient's name, patient reference number (e.g., medical care number) and / or other reference names or numbers, after which the computer may (via an associated communicator associated therewith) communicate with one or more databases (local or remote, wired or wireless, for example, via a network such as the Internet) to automatically call up other information and / or options corresponding to the name or reference (e.g., personal patient data, medication history, repeat prescriptions, data or partial data related to the extruded article to be extruded, such as an extruded article data file containing design and / or other relevant parameters). Thereafter, the user may be asked to manually input or manually select other information (e.g., drug, drug dosage, release profile, etc.) and / or options to enable the computer to obtain all relevant information related to the printed extruded article form. Alternatively or additionally, the user may be asked to manually input or call up information related to one or more specific parameters related to the extruded article (e.g., drug name / reference, drug dosage, drug release requirements, color, size, shape, solubility, package label information, etc.). Suitably, any user input may be recorded and / or stored for future reference or repeat prescriptions, etc.

[0405] There are many ways in which the computer can be configured to obtain the relevant information to allow extrusion of the extruded product, but it is likely that a variety of preset information can be used (e.g., certain approved recipes / filament combinations for producing a given extruded product). In this way, the computer can be suitably associated with or connected / connectable to an extruded product database (suitably a central database accessible via a network such as the Internet) that provides all necessary preset information (e.g., data files related to the extruded product, and details of variable parameters (e.g., drug dosage levels / limits)).

[0406] Suitably, the extrusion article design (and optionally parameters associated therewith) for extrusion may be recorded in an extrusion article data file which may be read by a computer operating in accordance with the extrusion software.

[0407] Suitably, the computer according to the extrusion software operation is configured to calculate the mass and / or volume of the extruded product to be extruded based on the information obtained. Suitably, once the computer has obtained all required information (information manually input by the user, information automatically input or a combination of the two), it is configured to calculate to allow final confirmation of the extrusion instruction before the computer controls the extrusion. At this stage, it may be necessary or requested to input other (e.g., by a user interface), such as one or more sizes and / or shape modifications may be optionally selected. Calculations are generally related to providing the mass and / or volume of a given extruded product required for a given active dose for each extruded product (e.g., in the case of an extruded product). Although it is possible to increase the concentration of a given active ingredient relative to other ingredients (e.g., excipients), typically formulations are optimized and the relative proportions are fixed / preset, and the total mass / volume may vary while maintaining the same relative proportion of the ingredient.

[0408] Suitably, the computer running according to said extrusion software is configured to control the extrusion of the relative proportions of the ingredients within the extruded article, suitably based on the information obtained and suitably based on the calculations performed. Suitably, "controlling extrusion" includes starting extrusion and terminating extrusion and any or all extrusion operations therebetween.

[0409] Suitably, during extrusion, operational data is collected (optionally by one or more local and / or remote computers and / or databases) and suitably stored (most suitably at a central computer where such data can be analyzed, for example for quality control monitoring, monitoring for failures, monitoring batches, monitoring dosage forms distributed to a given patient, etc.). Suitably, the extrusion apparatus comprises or is otherwise associated with one or more operational sensors (e.g., nozzle temperature sensors, extrudable composition feed rate sensors or conveyor sensors, integral temperature sensors, build platform sensors, etc., which build platform sensors can, for example, monitor surface temperature and / or rate of post-extrusion cooling) that feed back operational parameters / information relating to the operation of the extrusion apparatus and its associated elements to a computer, database or data storage device during extrusion of each extruded article. Most preferably, such operational data is collected, stored and / or otherwise transmitted to a central computer or database to enable independent audit of any given extrusion apparatus. This may be important for maintaining quality control and maintaining appropriate records to maintain regulatory approval of any given extrusion system.

[0410] Suitably, the computer operating in accordance with said extrusion software is configured to control the execution of one or more further processing steps.

[0411] Software and Data Files

[0412] The computer operating the extrusion device suitably runs according to the extrusion software (and optionally also runs according to one or more databases). As described herein, the software can configure the computer to obtain information and perform calculations, and then configure the computer to control extrusion via an interface with the extrusion device.

[0413] Once the computer has obtained the relevant information and performed the relevant calculations, the software will configure the computer to control the extrusion of the extrudable composition to form an extruded article, preferably based on the design (shape and size, texture, layer structure, internal structure, porosity, color, etc.) and / or parameters (relative amounts of ingredients, such as drug dosage) related to the extruded article contained in one or more extruded article data files. The extruded article data files may include design files (e.g., containing data and / or images related to the physical design of the extruded article, including its size, shape, layered structure, core-shell structure, etc.) and / or parameter files (e.g., containing data related to the chemical composition of the extruded article, including drug type, (one or more) excipient types, drug dosage levels, excipients that control drug release, etc.). A single extruded article data file may contain all data related to the physical design and chemical composition. However, the physical design and chemical composition may be modified according to information obtained after user input.

[0414] In some embodiments, the design file may be a CAD file that depicts the extruded article. However, this file format may need to be converted to a file format that is compatible with the extrusion device. In particular, 3D printers typically read design files in .STL format. Thus, the design file is suitably a .STL design file that describes the extruded article (or at least its physical design).

[0415] The design file may include or be linked to a parameter file containing chemical composition details, or the two may be independent. Alternatively, there may be no such parameter file, but relevant parameter information may be called from a database, for example, in response to user input (e.g., patient reference or drug reference, etc.).

[0416] The software may additionally configure the computer to collect, store and / or transmit (e.g., to a central database) operational data fed back to the computer from the extrusion device (e.g., 3D printer) during extrusion. The software may configure the computer to detect and / or respond to any (or preset level) deviations in expected operational data (e.g., if the nozzle temperature exceeds a maximum preset temperature level), such as alerting a user / operator or any other interested party that a fault has occurred and that the extruded article produced during the faulty extrusion should be handled or otherwise tested.

[0417] database

[0418] The extrusion apparatus and / or the computer(s) associated therewith may be configured (e.g., by extrusion software) to communicate (suitably, via (one or more) associated communicators and, suitably, via a network such as the Internet) with one or more extrusion product databases and / or patient databases to obtain information about one or more parameters related to the extruded product to be produced. For example, such database(s) may be queried in response to user input (e.g., a patient reference number) to provide relevant information to the computer (or relevant information supplemented by further user input) to enable calculation and extrusion.

[0419] By way of example, a patient database comprising patient records for a plurality of patients (which records may include, for example, patient name, patient reference number, medical data, medical history, etc.) suitably contains information about the extruded article to be extruded for each patient (which may simply be a cross-reference or reference number to information residing in another database (e.g., an extruded article database)). If the "information" is a cross-reference to an extruded article database, the extruded article database may be queried for more information about the extruded article. The information may be any information as defined herein, but may optionally instruct an extrusion device or computer(s) associated therewith (e.g., via a user interface) to modify the information (e.g., drug dosage level) prior to calculation and / or extrusion. Any of these databases may be accessed by interested parties, preferably securely (to maintain confidentiality of certain data), so that relevant information (residing in the patient database, the extruded article database, or both) may be retrieved and / or modified as required (e.g., if a patient requires an increased dose or a different active release profile in an extruded article). Suitably, such database(s) may be accessed wirelessly via a network such as the Internet. Such database architectures are well known in the art.

[0420] The or each extrusion device or the computer(s) associated therewith may be configured (e.g. by extrusion software) to communicate (suitably via (one or more) associated communicators and suitably via a network such as the Internet) with one or more extrusion device monitoring databases configured to transmit and store operational data collected during each extrusion operation (i.e. each time the extrusion device extrudes) in said database. As described herein, such operational data is suitably obtained / transmitted by sensors associated with each given extrusion device, suitably the sensors being associated with key components of the extrusion device which may affect the quality of the final extruded product. The operational data may be transmitted to said database in real time after extrusion, or at any suitable time (e.g. at night to avoid unnecessary overloading of the communication network during operation). Such an extrusion device monitoring database may be organized using records for each extrusion device, and a log of operational data may be suitably maintained each time said extrusion device is operated. Suitably, each set of operational data is cross-referenced with a given patient extruded product, suitably so that if any operational data is considered to be faulty, the relevant interested parties may be alerted. In this manner, each extrusion device can be monitored (whether in real time or otherwise, whether automatically or otherwise) and data submitted periodically to meet regulatory requirements. Moreover, the central extrusion device monitoring database can trigger a response to any perceived failure of a given extrusion device. Furthermore, a response can be triggered that prevents the associated faulty extrusion device from being used until its performance can be revalidated.

[0421] Again, any of one or more extrusion equipment monitoring databases may be accessed by interested parties, preferably securely (to maintain confidentiality of certain data) to enable relevant information to be retrieved and / or analyzed as needed (e.g., whether a regulatory agency wishes to check whether a given extrusion equipment is in good condition at a given time, or whether a machine maintenance professional needs to use the data to diagnose a problem to restore performance of a given extrusion equipment). Suitably, such database(s) may be accessed wirelessly via a network such as the Internet. Such database architectures are well known in the art.

[0422] Extrudable composition

[0423] The present invention provides an extrudable composition. The extrudable composition may be an extrudable composition obtainable by, obtained by or directly obtained from a method for preparing an extrudable composition as defined herein.

[0424] The present invention provides an extrudable composition comprising:

[0425] i. an extrudable carrier; and optionally

[0426] ii. Temporary plasticizer.

[0427] The present invention provides an extrudable composition comprising:

[0428] i. an extrudable carrier; and

[0429] ii. Temporary plasticizer.

[0430] Suitably, the extrudable composition is a blend of the temporary plasticizer and the extrudable carrier, the active ingredient (if present), the permanent plasticizer (if present) and other components (if present).

[0431] Suitably, most of the extrudable composition is in a molten state at the extrusion temperature. Molten state means that the extrudable composition can be extruded at the extrusion temperature; it does not necessarily mean that all components of the extrudable composition must be in a molten state. For example, a mixture of an extrudable carrier and a temporary plasticizer is in a molten state at the extrusion temperature.

[0432] In one embodiment, the extrudable composition is a free flowing blend. Advantageously, the free flowing blend is prepared by blending the components of the extrudable composition by mixing, such as shear mixing.

[0433] In one embodiment, extrudable composition is a kind of extrudable compressed form (or multiple extrudable compressed forms), for example (one or more) tablets, for example (one or more) mini tablets. Advantageously, compression of extrudable composition allows the preparation of extrudable compressed form before preparing extruded products. For example, extrudable compressed form can be prepared in advance at the same or different position as the extruder site, and / or stored for a period of time until it is needed. In addition, by making the extrudable composition in compressed form, it is possible to prevent that each component of the extrudable composition is physically separated over time, thereby potentially reducing any variability in the extrusion process. In addition, in the extrusion process, using extrudable compressed form, for example mini tablets, advantageously means that the process can be continuously operated (that is, by providing the continuous feeding of extrudable compressed form to the extruder), so that the process can be operated more in time and cost-effectively.

[0434] Suitably, each extrudable compressed form weighs from 10 to 1000 mg, from 20 to 800 mg, from 20 to 500 mg, from 40 to 300 mg, from 50 to 250 mg, from 100 to 200 mg, from 20 to 80 mg, from 30 to 70 mg, from 40 to 60 mg or about 50 mg.

[0435] Suitably, the diameter of each extrudable compressed form is from 1 to 10 mm, from 2 to 8 mm, from 4 to 7 mm, from 5 to 7 mm or about 6 mm.

[0436] In one embodiment, the extrudable composition is an extrudable fluid, suitably an extrudable semi-fluid, such as a molten composition. Suitably, the extrudable fluid is a fluid at room temperature. Suitably, the extrudable fluid is a fluid at ambient temperature, or is a fluid at a temperature greater than or equal to 30°C, 40°C, 50°C, 60°C, 70°C, 80°C or 90°C. Suitably, the extrudable composition can be extruded at a temperature less than or equal to 200°C, 180°C, 150°C, 120°C or 100°C. Suitably, the extrudable composition can be extruded at a temperature of 30 to 200°C, suitably 30 to 150°C. It should be understood that fluid means that the extrudable composition can be extruded at the temperature (i.e., a suitable viscosity to be extruded).

[0437] In one embodiment, the extrudable composition is an extrudable element. Suitably, the extrudable element is a filament. Advantageously, the extrudable composition can be extruded for the first time before being extruded (forming an extrudable element, such as a filament), and extruded for the second time in the process of preparing an extruded product. In particular, the use of filaments in 3D printing technology is mature, such as in molten filament manufacturing (FFF) technology. The temporary plasticizer makes the extrusion temperature in the process of forming an extrudable element (such as a filament) lower than the temperature when there is no temporary plasticizer, so that the process is very suitable for heat-sensitive extrudable compositions. Subsequently, the temporary plasticizer is partially or completely removed from the extrudable element, and an extrudable composition with physical properties suitable for use in the process of preparing an extruded product can be produced. For example, a temporary plasticizer can be used initially to reduce the extrusion temperature for forming an extrudable element by reducing the glass transition (softening) temperature of the extrudable composition for preparing an extrudable element. Due to the low glass transition (softening) temperature, the physical property may not be the best state for subsequent processing, for example, the extrudable element produced may be too flexible and cannot be used for FFF3D printing. Partial removal of the transient plasticizer results in an increase in the glass transition (softening) temperature of the extrudable element, which in turn reduces the flexibility of the extrudable composition. The amount of transient plasticizer removed (thereby increasing the glass transition (softening) temperature) can be optimized to provide the extrudable element with optimal physical properties (e.g., flexibility) for use in the process of forming an extruded article.

[0438] The skilled person will appreciate that the extrudable element may also be an extruded article. Therefore, features applicable to extruded articles may be applicable to the extrudable element.

[0439] The process of forming an extrudable element exposes the components of the extrudable element to the time at an elevated temperature longer than the process of forming an extruded product from the extrudable element. This is due to the longer residence time in the extruder compared to when extruding (e.g., 3D printing) an extrudable element (e.g., filament). Advantageously, the level of a temporary plasticizer causes a lower extrusion temperature for preparing an extrudable element and / or an extruded product. Advantageously, the first extrusion temperature (i.e., the temperature for preparing an extrudable element) can be made lower than (i.e., when the temporary plasticizer content is at the highest) the temperature for preparing an extruded product from an extrudable element (i.e., wherein the temporary plasticizer has been removed or partially removed from the extrudable element during the production process of the extrudable element or in the optimization process of the physical properties (e.g., flexibility / brittleness) of the product, for extruding (i.e., 3D printing) the extruded product). Therefore, the degree of thermal degradation can be minimized by reducing the extrusion temperature for forming an extrudable element, and having a shorter residence time and / or reducing the extrusion temperature for forming an extruded product.

[0440] Suitably, the extrudable element is substantially free of transient plasticizers. Suitably, the filaments are substantially free of transient plasticizers. Suitably, the extrudable element is completely free of transient plasticizers. Suitably, the filaments are completely free of transient plasticizers.

[0441] Suitably, the thickness (i.e., diameter or maximum thickness) of the filament is 0.1 mm to 5 mm, 0.5 mm to 2 mm, 0.5 mm to 1.5 mm, or 0.8 mm to 1.2 mm. In a specific embodiment, the thickness of the filament is about 1 mm. However, the filament thickness can be adjusted to be suitable for the extrusion nozzle (particularly the size / diameter of each opening) to be extruded therethrough.

[0442] Suitably, the filament is capable of being wound (or coiled) around a spool, and suitably, the hub diameter of the spool is about 25 cm, about 20 cm, about 15 cm, about 12 cm, about 10 cm, about 8 cm, about 6 cm, about 5 cm, about 4 cm, about 2.5 cm or about 1 cm. Suitably, the hub diameter allows the filament to be wound (or coiled) around the spool without breaking and / or stretching.

[0443] The extrudable composition suitably has a temporary plasticizer that is less than or equal to 30 % by weight, 25 % by weight, 20 % by weight, 18 % by weight, 16 % by weight, 14 % by weight, 12 % by weight, 10 % by weight, 8 % by weight, 6 % by weight, 5 % by weight, 4 % by weight, 3 % by weight, 2 % by weight or 1 % by weight. Suitably, the extrudable composition comprises a temporary plasticizer that is greater than or equal to 5%, 10%, 15% or 20%. Suitably, the extrudable composition comprises 1 to 25% of a temporary plasticizer.

[0444] Suitably, the glass transition (softening) temperature (Tg) of the extrudable composition is -50°C to 100°C, -40°C to 80°C, -40°C to 75°C, -40°C to 60°C, -40°C to 50°C, -40°C to 30°C, -20°C to 50°C, -35°C to 25°C, -30°C to 25°C, -25°C to 25°C, -20°C to 25°C, -20°C to 20°C, -20°C to 15°C, -20°C to 10°C, -20°C to 5°C, -20°C to 0°C, -20°C to -5°C, -15°C to -5°C, -15°C to -10°C or -12°C to -8°C. Suitably, the glass transition temperature of the extrudable composition is about -15°C or about -10°C. Suitably, the extrudable composition has a glass transition (softening) temperature (Tg) less than or equal to 70°C, 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, 5°C, 0°C, -5°C, -10°C, -15°C or -20°C.

[0445] Suitably, the extrudable composition is suitably tailored to have the appropriate proportions and types of ingredients, wherein the extrusion temperature for preparing the extruded article is minimized.

[0446] Suitably, extrudable carrier, temporary plasticizer, and permanent plasticizer (if present) form part or all of the meltable components of extrudable composition. Extrudable composition may further include infusible components to alleviate the bubbles of nozzle. Suitably, "meltable" component is a component that melts (or undergoes glass transition, thereby softening) at the specified operating temperature of any extrusion equipment nozzle (such as 3D printer) configured to process the extrudable composition, and "infusible" component is suitably a component that does not melt (or does not undergo glass transition) at the same temperature. Suitably, "meltable" component is a mixture of components, which melts together or undergoes glass transition together as a mixture (such as extrudable carrier and temporary plasticizer). However, "infusible" component is more likely to be a single component with different melting points or glass transition temperatures. Suitably, the melting point (or Tg) of the meltable component is equal to or lower than 220°C, 150°C, 100°C, 80°C or 60°C. Suitably, the melting point (or Tg - i.e. at least one Tg) of the meltable component is greater than or equal to 20°C, suitably, greater than or equal to 30°C. Suitably, the melting point (or Tg - i.e. at least one Tg) of the meltable component is 20 to 220°C, 30 to 200°C, 30 to 150°C, 30 to 65°C or 30 to 35°C. Suitably, the melting point (or Tg) of the non-meltable component is equal to or higher than 150°C, 200°C, 500°C or 1000°C.

[0447] Suitably, the glass transition temperature of the meltable component is below the melting point of the active ingredient, suitably at least 20°C below, at least 40°C below, or at least 50°C below.

[0448] As mentioned above, references to "meltable" and "non-meltable" components encompass "softenable" and "non-softenable" components, respectively, where the component "softens" rather than "melts" at a particular temperature, thereby allowing extrusion at that temperature. Thus, references to melting points in this context may additionally or alternatively refer to glass transition temperatures. Such glass transitions apply specifically to one or more thermoplastic components. Thus, a "meltable" component may be a thermoplastic component, suitably having a glass transition temperature (the temperature at which the thermoplastic component softens rather than melts) that is lower than the temperature to which the component is exposed (e.g. during extrusion).

[0449] Each of the various ingredients described herein is suitably a meltable or non-meltable component (not both at the same time). For example, a mixture of an extrudable carrier and a temporary plasticizer is suitably a meltable component, and is suitably selected to undergo melting or glass transition during extrusion. On the contrary, fillers (such as tribasic calcium phosphate, talcum powder, etc.) are suitably non-meltable components, and are suitably selected to remain solid during extrusion. Although various ingredients have different melting / glass transition properties, extrudable compositions (such as filaments) themselves have characteristic glass transition temperatures. Suitably, this characteristic glass transition temperature can be measured using the well-known techniques described herein and elsewhere, and is the result of a combination of ingredients. Meltable component: various concentration (wt%) ratios of non-meltable components can provide feasible extrudable compositions for extrusion (such as 3D printing). Suitably, the ratio of meltable: non-meltable components is between 1:10 and 10:1, more suitably between 3:7 and 7:3, suitably between 4:6 and 6:4, wherein suitably (one or more) meltable components include all relevant meltable components (such as extrudable carriers, temporary plasticizers, permanent plasticizers, etc.), and non-meltable components include all relevant non-meltable components (such as fillers, lubricants, etc.).

[0450] The extrudable composition (e.g., extrudable element) is suitably hard enough to enable it to be feasibly fed (at a constant rate) to and through a corresponding extrusion nozzle in an extrusion device. The extrudable composition is suitably hard enough to avoid stretching of the extrudable composition (e.g., extrudable element) during printing. However, the extrudable composition (e.g., extrudable element) should not be so hard that the nozzle operating temperature required to extrude the filament will degrade the content of the component (e.g., cause a composition change of greater than or equal to 1 wt%).

[0451] In one embodiment, the extrudable composition, such as an extrudable element, such as a filament, has enough flexibility and / or is soft enough to enable it to be extruded (at a constant rate) from a corresponding extrusion nozzle in an extrusion device. In one embodiment, the extrudable element suitably has enough flexibility and / or is soft enough to allow the extrudable composition, such as an extrudable element, such as a filament, to be wound / coiled around a filament bobbin.

[0452] Generally, if the extrudable composition (i.e., extrudable element, such as filament) has a too high glass transition temperature (Tg), then for the extruder, it may be too brittle (e.g., cannot be wound onto the filament spool) and difficult to operate (i.e., do not break the filament), and / or may need such a high extrusion nozzle operating temperature, so that the degradation of the components in the extrudable composition may occur in the process of preparing the extruded product. On the contrary, when the glass transition temperature of the extrudable composition is too low, the extrudable composition (i.e., filament) may be too soft and / or too soft to operate for the extruder, too twisted for consistent extrusion, and in the process of preparing the extruded product, the shape control is poor, and the extruded product is incoherent. The extrudable composition (e.g., filament) is suitably neither too brittle (and not fragile during printing / winding), nor too flexible (so that it cannot be transported by the extrusion device). Using the principle of teaching in the present disclosure, the size of the extrudable composition (e.g., the thickness of the filament) can be judiciously changed to obtain the best structure.

[0453] Suitably, the extrudable composition comprises at least one active ingredient, suitably a pharmaceutical, nutraceutical or food supplement active ingredient as defined herein. Most suitably, the at least one active ingredient is a pharmaceutical active ingredient.

[0454] Suitably, the extrudable composition comprises a permanent plasticiser as defined herein.

[0455] Suitably, the extrudable composition comprises one or more further components as defined herein.

[0456] Many preferred features of the extrudable composition are described elsewhere herein.For example, features described with respect to the method of producing the extrudable composition may suitably reflect features of the extrudable composition itself (eg, filament diameter).

[0457] Extrusion products

[0458] The present invention provides an extruded article. The extruded article may be an extruded article obtainable by, obtained by or directly obtained from the method for preparing an extruded article as defined herein.

[0459] The extruded article is suitably formed from the extrudable composition and thus the extruded article is suitably or comprises an extrudable composition.As such, any definition herein of an extrudable composition may per se apply equally to the extruded article.

[0460] The present invention provides an extruded article comprising an extrudable carrier and a transient plasticizer.

[0461] Most suitably, compared with the extrudable composition, the composition of extruded article comprises a temporary plasticizer of less amount (including being substantially free of and being completely free of).In one embodiment, extruded article comprises a low level of temporary plasticizer, for example, being less than or equal to 30 % by weight, 20 % by weight, 10 % by weight, 8 % by weight, 6 % by weight, 5 % by weight, 4 % by weight, 3 % by weight, 2 % by weight, 1 % by weight, 0.5 % by weight, 0.2 % by weight or 0.1 % by weight.Suitably, extruded article is substantially free of temporary plasticizer, or is completely free of temporary plasticizer.Suitably, extruded article comprises 0 to 30% temporary plasticizer.Suitably, compared with the extrudable composition for the preparation of the article, the temporary plasticizer of extruded article is less than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98%.

[0462] The (one or more) extruded articles of the present invention can be generally distinguished by chemical and / or microscopic analysis, which will suitably reveal whether the extruded article has been extruded, such as by 3D printing, such as by extruding the extrudable composition in a layer-by-layer manner. Suitably, the extruded article comprises a plurality of layers. Suitably, the thickness of each layer is 10 to 1000 μm, 20 to 800 μm, 30 to 500 μm, 40 to 300 μm, 50 to 200 μm, 100 to 200 μm, 125 to 200 μm, 140 to 190 μm, 155 to 175 μm, 250 to 350 μm or 750 to 850 μm. Suitably, the thickness of each layer is about 166 μm, about 300 μm or about 800 μm. Suitably, each layer of the extruded article can have the same thickness, or each layer can have different thicknesses. Suitably, there is no gap between the layers.

[0463] The extruded article(s) of the invention are suitable for oral administration. Examples of such extruded articles are tablets, capsules, granules, powders, beads and microcapsules. Most suitably, the extruded article is a tablet or an implant, most suitably a pharmaceutical tablet or a medical implant (e.g. an implant allowing sustained and / or controlled release of the active ingredient).

[0464] The extruded article(s) of the present invention may advantageously be customized with respect to: the type / nature of the active ingredient, the dosage of the active ingredient within the extruded article (either as an absolute dosage per extruded article, or as a concentration of the active ingredient within the extruded article), the mass / volume of the extruded article (which is generally suitable for varying the absolute dosage of the active ingredient without varying the concentration of the active ingredient in the extruded article), the active ingredient release profile (which may be varied by judicious use and / or dispensing of appropriate excipients), or the shape and appearance (including novel shapes, colors, and patterns, such as those that may aid in medical compliance for a particular patient).

[0465] Suitably, the extruded article is a filament.

[0466] Suitably, the extruded product is a pharmaceutical, nutraceutical or food supplement solid dosage form, such as a tablet. Suitably, the extruded product is a pharmaceutical solid dosage form, such as a tablet. Suitably, the extruded product is an immediate release dosage form, a delayed release dosage form (e.g. with an enteric coating or shell) or a sustained release dosage form.

[0467] Suitably, the extruded article is a solid oral dosage form, most suitably, an immediate release solid dosage form.

[0468] The immediate release solid dosage form suitably releases at least 75% of the one or more active ingredients within a period of 45 minutes, suitably releases at least 85% of the one or more active ingredients within a period of 30 minutes, and may suitably release at least 85% of the one or more active ingredients within a period of 15 minutes. The skilled person may refer to the European Pharmacopoeia 8.0 Strasbourg, France: Council of Europe; European Directorate for Quality in Medicines; 2014, for further details.

[0469] The longest dimension of the extruded product (D max ) (e.g., in either the X, Y or Z direction) is suitably greater than or equal to 3mm, 5mm, 8mm, 10mm or 12mm. The longest dimension of the extruded article is suitably less than or equal to 30mm, 25mm, 20mm or 15mm.

[0470] The shortest dimension of the extruded product (D min The shortest dimension of the extruded article is suitably less than or equal to 30 mm, 25 mm, 20 mm, 15 mm, 10 mm, 8 mm, 5 mm or 2 mm. Suitably, the shortest dimension of the extruded article (D min ) is between 0.1mm and 30mm.

[0471] The volume of the extruded product is suitably greater than or equal to 3 mm 3 , 5mm 3 , 10mm 3 , 50mm 3 , 100mm 3 or 200mm 3 The volume of the extruded product is suitably less than or equal to 500 mm 3 、300mm 3 , 250mm 3 、150mm 3 or 50mm 3 Suitably, the volume of the extruded product is between 3 and 500 mm 3 between.

[0472] Suitably, the weight of the extruded article is greater than or equal to 1 mg, suitably greater than or equal to 5 mg, 10 mg, 50 mg or 80 mg. Suitably, the weight of the extruded article is less than or equal to 1000 mg, suitably less than or equal to 500 mg, 250 mg or 100 mg. Suitably, the weight of the extruded article is from 1 to 1000 mg.

[0473] Suitably, the extruded article is a pharmaceutical, nutraceutical or food supplement solid dosage form. Suitably, the extruded article comprises at least one active ingredient, suitably a pharmaceutical, nutraceutical or food supplement active ingredient as defined herein. Most suitably, the at least one active ingredient is a pharmaceutical active ingredient.

[0474] Suitably, the extruded article comprises a permanent plasticiser as defined herein.

[0475] Suitably, the extruded article comprises one or more further components as defined herein.

[0476] Many preferred features of the extruded article are described elsewhere herein. For example, features described with respect to the method of producing the extruded article may suitably reflect features of the extruded article itself (e.g., layer height). Suitably, the extruded article comprises ingredients provided by the extrudable composition(s) used in its formation, and may be considered to comprise the associated extrudable composition.

[0477] Components in extrudable compositions and extruded articles

[0478] The components described below are suitable for use in the methods, devices, packages and uses described herein.

[0479] Extrudable carrier

[0480] The extrudable carrier is suitably an extrudable material suitable for extrusion (e.g. 3D printing), and is particularly suitable as a printable (and suitably meltable / softenable) carrier component within a filament for FFF 3D printing. Suitably, any suitable polymer(s) may be used.

[0481] The extrudable carrier(s) are suitably selected from polymers (suitably cationic or neutral polymers or copolymers) having a viscosity of less than or equal to 300 mPa.s, 200 mPa.s, 100 mPa.s, 80 mPa.s, 65 mPa.s, 50 mPa.s, 30 mPa.s or 10 mPa.s, but suitably have a viscosity of at least 1 mPa.s. Suitably, the polymer has a viscosity of 1 to 300 mPa.s.

[0482] The (one or more) extrudable carriers suitably have or comprise one or more compounds having a molecular weight of at least 2,000 g / mol, 5,000 g / mol, 10,000 g / mol, 15,000 g / mol, 20,000 g / mol, 35,000 g / mol, 45,000 g / mol or 100,000 g / mol. Suitably, the molecular weight is from 2,000 to 500,000 g / mol or from 2,000 to 100,000 g / mol. The molecular weight is suitably quoted in g / mol. Suitably, the molecular weight is an average molecular weight, particularly where it may refer to a polymer.

[0483] According to the standard USP definitions (and therefore the standard tests defined in the USP), the one or more extrudable carriers are suitably or comprise one or more compounds that are slightly soluble, sparingly soluble, very sparingly soluble, practically insoluble, or insoluble according to the following table:

[0484] Descriptive terms Number of parts of solvent required for 1 part of solute Very soluble Less than 1 Soluble From 1 to 10 Soluble From 10 to 30 Slightly soluble From 30 to 100 Slightly soluble From 100 to 1000 Very little soluble From 1000 to 10000 Almost insoluble or insoluble Greater than or equal to 10000

[0485] According to the standard USP definition, according to the above table, the one or more extrudable carriers are suitably or comprise one or more compounds, which are very slightly soluble, almost insoluble, or insoluble. Suitably, according to the standard USP definition, according to the above table, the one or more extrudable carriers are suitably or comprise one or more compounds, which are almost insoluble, or insoluble.

[0486] The melting point of the extrudable carrier itself is suitably between 140 and 250°C, suitably between 160 and 250°C, or between 170 and 230°C.

[0487] The melting point (or glass transition temperature) of the extrudable carrier is suitably lower than that of the active ingredient, suitably at least 20°C, 40°C or 50°C lower. The melting point of the extrudable carrier is suitably between 140 and 250°C, between 150 and 200°C or between 155 and 175°C.

[0488] The glass transition temperature of the extrudable carrier itself is suitably greater than or equal to 0° C., 10° C., 20° C., 25° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., 100° C., 120° C., 140° C., 160° C., 180° C., or 200° C. The glass transition temperature of the extrudable carrier itself is from 0° C. to 250° C., suitably from 0° C. to 200° C. In some embodiments, the extrudable carrier itself does not have such a glass transition temperature, although observable softening may still occur.

[0489] Suitably, the glass transition temperature of the extrudable carrier is below the melting point of the active ingredient, suitably at least 20°C below, at least 40°C below, or at least 50°C below.

[0490] Suitably, the extrudable support has a specific heat of from 0.1 to 1 cal / g°C, most suitably from 0.3 to 0.5.

[0491] The density of the extrudable carrier is suitably from 1.1 to 1.6 g / mL, most suitably from 1.2 to 1.4.

[0492] Any suitable extrudable carrier may be used.In the pharmaceutical context, extrudable carriers are commonly used for compounding solid dosage forms such as tablets and capsules.

[0493] The (one or more) extrudable carriers, particularly where an immediate release solid dosage form is desired, are suitably selected from carriers (suitably cationic polymers or neutral polymers or copolymers) having a viscosity of no more than 50 mPa.s, suitably no more than 30 mPa.s, suitably no more than 10 mPa.s, but suitably a viscosity of at least 1 mPa.s - suitably a viscosity of 1 to 50 mPa.s, suitably 1 to 25 mPa.s, suitably 2 to 8 mPa.s. The (one or more) extrudable carriers, particularly where an immediate release solid dosage form is desired, are suitably selected from carriers having a molecular weight of at least 20,000 g / mol, suitably at least 35,000, suitably at least 45,000, but suitably less than 1,000,000 g / mol, suitably less than 100,000 g / mol - suitably a molecular weight of 20,000 to 1,000,000 g / mol, suitably 35,000 to 65,000 g / mol. The extrudable carrier(s), particularly where an immediate release solid dosage form is desired, is suitably selected from carriers having a glass transition temperature (Tg) of up to 100°C, suitably up to 80°C, suitably up to 50°C, but suitably at least -10°C, suitably at least 35°C - suitably, Tg is from -10 to 100°C, suitably from 30 to 60°C. In some embodiments, the extrudable carrier itself may not have such a glass transition temperature, although observable softening may still occur. The extrudable carrier(s), particularly where an immediate release solid dosage form is desired, is suitably a (optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethylacrylate copolymer (suitably comprising amine-containing monomer units), suitably having a viscosity between 2mPa and 8mPa, suitably having a molecular weight between 35,000g / mol and 65,000g / mol, and / or suitably having a Tg between 30°C and 60°C. In a specific embodiment, the relevant copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate), suitably in a molar ratio of 1:2:1 (+ / - 5% for each molar value of this ratio). The extrudable carrier is suitably Eudragit E.

[0494] The (one or more) extrudable carriers, particularly where an extended release solid dosage form is desired, are suitably selected from carriers having a viscosity of no more than 30 mPa.s, 20 mPa.s or 16 mPa.s, but suitably a viscosity of at least 1 mPa.s - suitably a viscosity of 1 to 30 mPa.s, suitably 1 to 15 mPa.s. The (one or more) extrudable carriers, particularly where an extended release solid dosage form is desired, are suitably selected from carriers having a molecular weight of at least 10,000 g / mol, 250000 g / mol or 30,000 g / mol, but suitably less than 100,000 g / mol, suitably less than 40,000 g / mol - suitably a molecular weight of between 10,000 and 100,000 g / mol, suitably between 29,000 and 35,000 g / mol. The extrudable carrier(s), particularly where an extended release solid dosage form is desired, is suitably selected from a carrier having a glass transition temperature (Tg) of up to 100°C, suitably up to 80°C, suitably up to 70°C, but suitably at least 40°C, more suitably at least 50°C - suitably, Tg is between 50 and 100°C, suitably between 55 and 70°C. In some embodiments, although observable softening may still occur, the extrudable carrier itself may not have such a glass transition temperature. The extrudable carrier(s), particularly where an extended release solid dosage form is desired, is suitably a (optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethacrylate copolymer (suitably comprising amine-containing monomer units), suitably having a viscosity of 1 to 15 mPa., suitably having a molecular weight of 29,000 to 35,000 g / mol, and / or suitably having a Tg of 55 to 70°C. In a particular embodiment, the relevant copolymer is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoniumethyl methacrylate chloride), suitably the respective monomer molar ratio is 1:2:0.2 (+ / - 5% for each molar value of this ratio). The extrudable carrier is suitably Eudragit RL.

[0495] The extrudable carrier(s), particularly where a delayed release solid dosage form is desired, is suitably selected from a carrier having a viscosity of at least 20 mPa.s, suitably at least 40 mPa.s, suitably at least 50 mPa.s, but suitably a viscosity of no more than 300 mPa.s, suitably no more than 210 mPa.s - suitably a viscosity of 20 to 300 mPa.s, suitably 40 to 210 mPa.s. The extrudable carrier(s), particularly where a delayed release solid dosage form is desired, is suitably selected from a carrier having a molecular weight of at least 10,000 g / mol, suitably at least 15,000, but suitably less than 400,000 g / mol - in a particular embodiment, the molecular weight is between 10,000 and 400,000 g / mol, suitably 10,000 to 25,000 g / mol, and in other embodiments, the molecular weight is 100,000 to 350,000 g / mol. The (one or more) extrudable carriers, particularly where a delayed release solid dosage form is desired, are suitably selected from carriers having a glass transition temperature (Tg) of at least 80°C, suitably at least 90°C, suitably at least 100°C, although suitably up to 200°C, suitably up to 160°C - suitably, Tg is between 50 and 200°C, suitably between 90 and 160°C. In some embodiments, the (one or more) active ingredient carriers themselves may not have such a glass transition temperature, although observable softening may still occur. The extrudable carrier, particularly where a delayed release solid dosage form is desired, is suitably selected from:

[0496] a (optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethacrylate polymer or copolymer (suitably free of any amine-containing monomer units), suitably having a viscosity between 90 and 210 mPa.s, suitably a molecular weight between 100,000 and 350,000 g / mol, and / or suitably having a glass transition temperature between 90 and 140°C; wherein the relevant polymer or copolymer is suitably selected from: poly(methacrylic acid-co-ethyl acrylate), suitably in a 1:1 molar ratio of the monomers (for each molar value of the ratio, + / - 5%); poly(methacrylic acid-co-methyl methacrylate), suitably in a 1:1 molar ratio of the monomers (for each molar value of the ratio, + / - 5%); poly(methacrylic acid-co-methyl methacrylate), suitably in a 2:1 molar ratio of the monomers (for each molar value of the ratio, + / - 5%); or

[0497] Cellulose or a cellulose derivative, suitably a hydroxypropylmethylcellulose (HPMC) derivative, most suitably hydroxypropylmethylcellulose (HPMC) succinate acetate (HPMCAS), suitably having a molecular weight between 10,000 and 25,000 g / mol, and / or suitably having a glass transition temperature between 100 and 145°C (or suitably between 100 and 165°C); wherein the relevant HPMCAS is suitably selected from Aqoat LG, Aqoat MG, and / or Aqoat HG. However, suitably, the HPMC derivative may also include hydroxypropylmethylcellulose phthalate (HPMCP), for example its HP-50, HP-55 and HP-55S grades.

[0498] In principle, any suitable (one or more) extrudable carriers may be used, including any one or more selected from: (optionally, alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethacrylate copolymers (suitably including amine-containing monomer units); (optionally, alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethacrylate polymers or copolymers (suitably, not containing any amine-containing monomer units); cellulose or a cellulose derivative; polyvinyl alcohol (PVA); poly(lactic-co-glycolic acid) (PLGA); and / or any suitable pharmaceutically acceptable carrier.

[0499] The (optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethylacrylate polymers or copolymers are particularly advantageous in supporting high loadings of active ingredients.

[0500] The extrudable carrier(s) are suitably selected from Eudragit E, Eudragit NE, HPC SSL, Eudragit RS, Eudragit RL, HPC SL, HPC M, HPC H, Eudragit L100-55, Eudragit L100, Eudragit S100, Aqoat LG, Aqoat MG, Aqoat HG and / or polyvinyl alcohol (PVA) or any combination of any of the foregoing.

[0501] In some embodiments, particularly when the active ingredient has limited solubility in the target solubilization medium (e.g., in the body), one or more extrudable carriers (such as polyvinyl pyrrolidone polymers or polyvinyl pyrrolidone-derived polymers) can be used. Such polymers can promote the dissolution of active ingredients that may otherwise exhibit limited solubility. In a specific embodiment, PVP K29-32 (povidone) can be used. When present, suitably, PVP or a PVP-based carrier (e.g., in an extrudable composition) is present at the following concentrations: between 20wt% and 80wt%, suitably at a concentration between 40wt% and 60wt%, suitably 45wt%-55wt%. PVP or a PVP-based carrier polymer can be used with one or more fillers and optionally with other ingredients (such as one or more plasticizers). Mixtures of different PVP or PVP-based carriers (e.g., PVP of different molecular weights) can also or alternatively be used.

[0502] In some embodiments, polyalkylene glycol and polyalkylene glycol derived polymer can be used as extrudable carrier.In a specific embodiment, polyalkylene glycol or polyalkylene glycol derived carrier polymer is polyethylene glycol (PEG) or polyethylene glycol derived carrier polymer.Suitably, in the case of deploying PEG or PEG-based carrier polymer, at least part of PEG or PEG-based carrier polymer has a molecular weight of at least 100,000, although suitably at most 1,000,000, suitably between 100,000 to 1,000,000.However, a mixture of different polyalkylene glycols and polyalkylene glycol derived polymers (such as PEG or PEG-based carrier polymers) can be incorporated into long filaments and / or corresponding dosage forms.For example, high molecular weight PEG can be used together with relatively low molecular weight PEG to achieve the optimal balance of performance. Higher molecular weight PEG or PEG-based polymers (e.g., Mw ≥ 80,000) can be used as carrier molecules, while lower molecular weight PEG or PEG-based polymers (e.g., Mw 200-20000) can be used as plasticizers and / or dissolution promoters. Increasing the ratio of lower molecular weight PEG may reduce the Tg of the resulting filament. Moreover, increasing the ratio of lower Mw PEG also helps accelerate drug release. Suitably, any PEG or PEG-based carrier polymer is used together with one or more fillers, although such polymers may be used with or without non-melting components.

[0503] Suitably, the extrudable carrier is a pharmaceutically acceptable polymer (or a GRAS approved polymer). The extrudable carrier may include one or more thermoplastics. The extrudable carrier may include one or more pharmaceutically acceptable polymers selected from: (optionally alkyl-) acrylate, methacrylate or ethacrylate polymers or copolymers, optionally including amine-containing monomer units, silicones, polyurethanes, polyolefins (e.g., polystyrene), polyalkylene glycols, polymers or copolymers derived from polyalkylene glycols, polyvinyl pyrrolidone or polyvinyl pyrrolidone derived polymers or copolymers, polyvinyl alcohol, polyamide, acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polyglycolide, nylon and / or copolymers or mixtures thereof. This list is by no means exhaustive. Suitably, the extrudable carrier is polyvinyl alcohol.

[0504] Suitably, the extrudable composition of the invention comprises greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% by weight of an extrudable carrier. Suitably, the extrudable composition comprises less than or equal to 99%, 95%, 90%, 80% or 60% by weight of an extrudable carrier. Suitably, the extrudable composition comprises from 10 to 95% by weight of an extrudable carrier.

[0505] Suitably, the extruded article of the invention comprises greater than or equal to 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt% or 80 wt% of the extrudable carrier. Suitably, the extruded article comprises less than or equal to 99 wt%, 95 wt%, 90 wt%, 80 wt% or 60 wt% of the extrudable carrier. Suitably, the extruded article comprises 10 to 95 wt% of the extrudable carrier.

[0506] More than one extrudable carrier (optionally as defined herein) may be used.

[0507] Temporary plasticizer

[0508] Temporary plasticizers allow extrudable compositions to be extruded at lower temperatures by lowering the glass transition (or softening) temperature of the extrudable composition (i.e., lowering the extrusion temperature required to form an extruded article and / or an extrudable element). Advantageously, this allows heat-sensitive components and / or components to be used in extrudable compositions and extruded articles. For example, heat-sensitive active ingredients. In addition, this allows the use of active ingredients and / or other components with low melting points, such as those with lower melting points relative to the extrudable carrier.

[0509] Suitably, temporary plasticizer can cause the physical property of extruded article and / or extrudable element to be changed, for example, reduce the glass transition temperature of extruded article and / or extrudable element. This may cause the physical property of extruded article and / or extrudable element to be not optimal for subsequent processing, for example, if the glass transition temperature of extruded article and / or extrudable element is too low, then extruded article and / or extrudable element can be very flexible. Advantageously, temporary plasticizer can be removed or partially removed during the method for preparing extruded article and / or extrudable element, for example, during or after extrusion. This may cause the physical property of extruded article and / or extrudable element to be changed, depending on how many temporary plasticizers are removed, for example, the glass transition temperature of extruded article and / or extrudable element increases, thereby causing the flexibility of extruded article and / or extrudable element to be lower. Therefore, the physical property of extrudable element and / or extruded article can be controlled by changing the content of temporary plasticizer contained therein.

[0510] Suitably, the temporary plasticizer is a vaporizable substance (or a combination of vaporizable substances) that can be vaporized at a temperature of 150°C or less (suitably, at standard ambient pressure, such as 100kPa). Suitably, the or each vaporizable substance is a liquid, suitably a solvent or water. Suitably, the solvent is a solvent of acceptable grade for pharmacy, nutraceuticals or food supplements. Suitably, the boiling point of the temporary plasticizer is less than or equal to 150°C, for example, less than or equal to 140°C, 130°C, 120°C, 110°C, 105°C or 100°C (suitably, at standard ambient pressure, such as 100kPa). Suitably, the boiling point of the temporary plasticizer is between 25 and 150°C (suitably, at standard ambient pressure, such as 100kPa). In one embodiment, the temporary plasticizer is a pharmaceutically acceptable grade solvent or water (e.g., distilled water). Suitably, the pharmaceutical grade solvent is an ICH Class 3 solvent (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH Harmonised Guideline; Impurities: Guideline for Residual Solvents Q3C (R6)). Suitably, the temporary plasticizer is ethanol. Suitably, the temporary plasticizer is water.

[0511] Other components of the extrudable composition and / or extruded article may contain residual levels of transient plasticizer, such as residual water in the extrudable carrier. It should be understood that the amount of transient plasticizer present in the extrudable composition and extruded article defined herein may include any contribution from other components present.

[0512] Suitably, the extrudable composition comprises a temporary plasticizer greater than or equal to 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 18%, 20%, 25% or 30% by weight. Suitably, the extrudable composition comprises a temporary plasticizer less than or equal to 50%, 40%, 30%, 20%, 15%, 10%, 5%, 4%, 3% or 2% by weight. Suitably, the extrudable composition comprises a temporary plasticizer of 0.1 to 50%.

[0513] Suitably, the extruded article comprises greater than or equal to 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or 30% by weight of a temporary plasticizer. Suitably, the extruded article comprises less than or equal to 50%, 40%, 30%, 20%, 15%, 10%, 5%, 4%, 3% or 2% by weight of a temporary plasticizer. Suitably, the extruded article comprises 0.1 to 50% of a temporary plasticizer.

[0514] Suitably, the extruded article has a lower content of transient plasticizer than the extrudable composition used to prepare the extruded article, suitably 10%, 20%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% lower.

[0515] More than one temporary plasticizer (optionally as defined herein) may be used.

[0516] In a particular embodiment, the extrudable composition can be used to form an extrudable element, such as a 3D printable filament. Although the composition of such an extrudable element can be consistent with the composition of the extrudable composition herein, in some embodiments, such an extrudable element can include a lower temporary plasticizer concentration than the extrudable composition used to produce the extrudable element, and in some embodiments can be substantially free of or free of temporary plasticizer. Suitably, the extrudable element still obtains the benefits of the present invention, for example, by forming at a lower temperature than the case where a temporary plasticizer is not present in the precursor extrudable composition used to prepare the extrudable element.

[0517] Permanent plasticizer

[0518] In one embodiment, the extrudable composition and / or the extruded article also comprise a permanent plasticizer. A permanent plasticizer is a plasticizer that is not removed during the manufacture of the extruded article and / or the extrudable composition. A permanent plasticizer can reduce the glass transition (or softening) temperature of the extrudable composition, thereby causing the use of a lower extrusion temperature when forming an extruded article or forming an extrudable element. Relative to being used alone, using a permanent plasticizer and a temporary plasticizer simultaneously allows the use of a lower extrusion temperature. In these cases, the extrudable composition of the present invention and the extruded article can be used in combination with other components that are particularly sensitive to heat, for example, active ingredients.

[0519] Suitably, the permanent plasticizer is a pharmaceutically acceptable plasticizer.Many pharmaceutically acceptable plasticizers are known in the art for use in forming pharmaceutical extruded articles (ie, solid dosage forms).

[0520] Suitably, the permanent plasticizer has a melting point lower than the molten melt of the extrudable carrier. Suitably, the permanent plasticizer has a melting point less than or equal to 140°C, suitably less than or equal to 130°C, 120°C, 110°C or 100°C. Suitably, the permanent plasticizer has a melting point between 0 and 140°C, suitably between 50 and 140°C.

[0521] Suitably, the glass transition (softening) temperature of the permanent plasticizer is lower than the glass transition (softening) temperature of the extrudable carrier. Suitably, the glass transition (softening) temperature of the permanent plasticizer is less than or equal to 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, 0°C or -10°C. Suitably, the glass transition (softening) temperature of the permanent plasticizer is from -10 to 100°C.

[0522] Suitably, the permanent plasticizer is a pharmaceutically, nutraceutical or food supplement acceptable grade excipient.

[0523] Suitably, the permanent plasticizer may be selected from one or more of the following: triethyl citrate (TEC), glycerol, castor oil, oleic acid, glycerol, tryacetin, polyalkylene glycol (e.g. polyethylene glycol or polypropylene glycol, e.g. PEG400) and a general formula of HOCH 2 (CHOH) n CH 2 OH, wherein n is 2 to 12. Suitably, the sugar alcohol is selected from ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fructitol, iditol, inositol, heptyl alcohol, isomalt, maltitol and maltotriitol. Suitably, the permanent plasticizer is sorbitol or triethyl citrate.

[0524] Certain permanent plasticizers may be more suitable than other permanent plasticizers, depending on the particular extrudable carrier, temporary plasticizer, active ingredient (if present), and other components (if present).

[0525] Suitably, the extrudable composition and / or the extruded article comprises at least or equal to 1%, 2%, 4%, 5%, 8% or 10% by weight of a permanent plasticizer. Suitably, the extrudable composition and / or the extruded article comprises from 1% to 50%, suitably from 1% to 25%, suitably from 1% to 10% of a permanent plasticizer, based on the total weight of the extrudable composition and / or the extruded article.

[0526] More than one permanent plasticizer (optionally as defined herein) may be used.

[0527] Active ingredients

[0528] The at least one active ingredient is suitably a pharmaceutical drug (which may be any suitable pharmaceutical compound or a pharmaceutically acceptable salt, solvate (including hydrate), prodrug or polymorph thereof). Therefore, any extrudable carrier, temporary plasticizer, permanent plasticizer and / or other component in the extrudable composition is a pharmaceutically acceptable extrudable carrier, temporary plasticizer, permanent plasticizer and / or other component.

[0529] The at least one active ingredient is suitably in the same form (and has substantially the same purity) as the active ingredient in the approved pharmaceutical product.

[0530] In a specific embodiment, the at least one active ingredient is very soluble, freely soluble, or soluble according to the standard USP (United States Pharmacopeia) definition of solubility. In another embodiment, the at least one active ingredient is slightly soluble, slightly soluble, or very slightly soluble according to the standard USP definition of solubility.

[0531] In a specific embodiment, the at least one active ingredient is very soluble according to the standard USP definition for solubility.

[0532] In specific embodiments, the at least one active ingredient is freely soluble according to the standard USP definition of solubility.

[0533] In specific embodiments, the at least one active ingredient is soluble according to the standard USP definition of solubility.

[0534] In specific embodiments, the at least one active ingredient is slightly soluble according to the standard USP definition of solubility.

[0535] In a specific embodiment, the at least one active ingredient is slightly soluble according to the standard USP definition for solubility.

[0536] In specific embodiments, the at least one active ingredient is very slightly soluble according to the standard USP definition for solubility.

[0537] In specific embodiments, the at least one active ingredient is substantially insoluble according to the standard USP definition of solubility.

[0538] In a particular embodiment, the at least one active ingredient is heat sensitive. In one embodiment, during the method for preparing an extruded article and / or an extrudable element as defined herein, the at least one active ingredient is susceptible to thermal degradation at a temperature higher than the temperature to which the extrudable composition will be exposed. In one embodiment, the at least one active ingredient is susceptible to thermal degradation at a temperature greater than or equal to 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 180°C or 200°C. Suitably, the at least one active ingredient is susceptible to thermal degradation at a temperature of 90 to 200°C. Such thermal degradation can be suitably discerned by techniques known in the art, such as DSC.

[0539] Suitably, the active ingredient is a small molecule active ingredient. Suitably, the active ingredient is a biologically active ingredient, such as a protein or peptide.

[0540] In a particular embodiment, the extrudable composition and / or extruded article comprises one active ingredient. In another embodiment, the extrudable composition and / or extruded article comprises two active ingredients.

[0541] Suitably, the extruded article of the present invention comprises greater than or equal to 0.5wt%, 1wt%, 5wt%, 10wt%, 20wt% or 40wt% of the active ingredient. Suitably, the extruded article of the present invention comprises less than or equal to 60wt%, 50%wt or 30%wt of the active ingredient. Suitably, the extruded article of the present invention comprises 0.5 to 50%wt of the active ingredient.

[0542] Suitably, the extrudable composition(s) of the present invention comprises greater than or equal to 0.5wt%, 1wt%, 5wt%, 10wt%, 20wt% or 40wt% of the active ingredient. Suitably, the extrudable composition(s) of the present invention comprises less than or equal to 60wt%, 50%wt or 30%wt of the active ingredient. Suitably, the extrudable composition(s) of the present invention comprises from 0.5%wt to 60wt% of the active ingredient.

[0543] Other components

[0544] In a particular embodiment, the extrudable composition and / or extruded article further comprises one or more other components. Other components may suitably include one or more excipients, excipient carriers and / or diluents, all of which may be included in the extruded article.

[0545] In particular, one or more other components of the extrudable composition and / or extruded article may be selected from one or more fillers / diluents, anti-adherents, binders, disintegrants, lubricants, glidants, flavoring agents, preservatives, sweeteners, colorants and coatings.

[0546] Fillers / diluents, anti-adherents, binders, disintegrants, lubricants, glidants, flavoring agents, preservatives, sweeteners, coloring agents and coatings are known in the pharmaceutical, nutraceutical and dietary supplement arts, and any of them may be used where appropriate or desired in the pharmaceutical, nutraceutical and dietary supplement formulation.

[0547] Suitably, fillers / diluents, anti-adherents, binders, disintegrants, lubricants, glidants, flavorings, preservatives, sweeteners, colorants and coatings are substantially inert and / or suitably have minimal or no interaction with the other component(s) of the extruded article and / or extrudable composition.

[0548] Suitable anti-adhesives may include magnesium stearate. Suitable diluents / fillers may include vegetable cellulose, dibasic calcium phosphate, vegetable oils and fats, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate and / or microcrystalline cellulose. Suitable binders may include sugars; polysaccharides / derivatives thereof, such as starch, cellulose or modified cellulose, such as microcrystalline cellulose and cellulose ethers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose and derivatives thereof; sugar alcohols, such as xylitol, sorbitol or maltitol; synthetic polymers, such as polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG)). Suitable disintegrants may include cross-linked polyvinyl pyrrolidone (crosslinked vinone), crosslinked sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, modified starch sodium and / or starch glycolate. Suitable lubricants may include silicon dioxide; sodium stearyl fumarate; fats, such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable glidants may include fumed silicon dioxide, talc, magnesium carbonate and / or colloidal silicon dioxide. Suitable coatings may include tablet coatings to protect tablet ingredients from moisture in the air and to make bulky or unpalatable tablets easier to swallow (e.g., cellulose ether hydroxypropyl methylcellulose (HPMC) film coatings; synthetic polymers, shellac, corn zein or other polysaccharides, gelatin; enteric coatings, e.g., including fatty acids, waxes, shellac, plastics, plant fibers). Suitable coloring agents may include curcumin, riboflavin, 5'-phosphoric acid riboflavin, tartrazine, quinoline yellow, sunset yellow FCF, carmine, azorubine, amaranth, Ponceau 4R, erythrosine, allure red AC, patent blue V, indigo, brilliant blue FCF, chlorophyll, copper complex of chlorophyll, green S, ordinary caramel, caustic sulfite caramel, ammonia caramel, ammonia sulfite caramel, brilliant black BN, vegetable carbon, brown HT, carotene, fruit red, paprika extract, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, beetroot red, anthocyanin, calcium carbonate, titanium dioxide, iron oxide and iron hydroxide, aluminum, silver, gold and / or litholrubine BK. The general categories of excipients are well known to those skilled in the art.

[0549] Solid oral dosage forms can be designed to release the active portion of the formulation in the gastrointestinal tract where bioavailability is maximized and degradation prior to systemic circulation is minimized.At least one additional agent can be included to promote absorption of the active of the present disclosure and / or any additional therapeutic agent. In such solid dosage forms, the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., lactose, sodium citrate or dicalcium phosphate) and / or one or more of the following: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapak starch, alginic acid, certain silicates and sodium carbonate; e) solubilizers such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, such excipients as lactose or high molecular weight polyethylene glycols.

[0550] Such excipients may be selected to suit the properties of the extruded article, the properties of the extrudable composition, or both, or a judicious compromise between the two. For example, in the case of an extruded article (i.e., a solid dosage form), the excipient(s) may be selected to facilitate administration to the target patient population(s) by the intended route; improve dosage compliance; consistency and control of drug bioavailability; increase bioavailability; improve stability of the active ingredient, including protection against degradation; ensure a robust and reproducible physical product. In the case of an extrudable composition (e.g., a filament for 3D printing), the excipient(s) may be selected to optimize the physical form and / or stability of the extrudable composition; ensure a robust and reproducible physical product; the flexibility and stiffness of the extrudable composition (it is desirable to have an optimal balance between the flexibility and stiffness of the filament to ensure that the filament can be successfully delivered to the extrusion nozzle and then easily extruded from the nozzle); produce an optimal extruded article (e.g., in accordance with the above points).

[0551] Suitably, the extruded article comprises a coating. Suitably, the coating protects the inner contents of the extrudate from light, moisture and / or air (ie oxygen). Suitably, the coating is a lubricant as defined herein.

[0552] Application of extruded products

[0553] The extruded article of the invention may take a variety of forms, although most suitably the extruded article is a solid dosage form, most suitably a pharmaceutical, nutraceutical and / or food supplement solid dosage form.

[0554] In a particular embodiment, the extruded article is a pharmaceutical solid dosage form.

[0555] In a particular embodiment, the extruded article is an extruded article for use in the manufacture of a medicament.

[0556] The present invention also provides a method of treating and / or preventing a disease, condition, or disorder in a subject in need of such treatment. The method suitably comprises administering to the subject a therapeutically effective amount of the extruded article. Suitably, the subject is an animal or human subject, most suitably a human subject. Suitably, an extruded article for use as a medicament is provided.

[0557] Suitably, the extruded article is an immediate release pharmaceutical solid dosage form for oral administration.

[0558] Packaging of extrudable composition(s)

[0559] The (one or more) extrudable compositions of the present invention can be packaged by any of a variety of methods well known in the art. For example, the (one or more) extrudable compositions can be preloaded in a cartridge for an extruder. Advantageously, the cartridge can be prepared at a position different from the position of the extruder, and can be inserted into the extruder when necessary. Therefore, when the extruder is located at different positions, the user of the extrusion device, such as a pharmacist, can select suitable (one or more) extrudable composition packaging, insert the (one or more) packaging into the extrusion device, and use the extrudable composition and the extruder to prepare the extruded product.

[0560] Suitably, there is provided a package of an extrudable composition comprising:

[0561] i. an extrudable composition comprising an extrudable carrier and a temporary plasticizer; and

[0562] ii. a container, wherein said container comprises said extrudable composition.

[0563] Suitably, there is provided a package of an extrudable composition comprising:

[0564] i. an extrudable composition comprising an extrudable carrier and a temporary plasticizer; and

[0565] ii. A syringe, wherein said syringe comprises said extrudable composition.

[0566] Suitably, there is provided a package of an extrudable composition comprising:

[0567] i. an extrudable composition comprising an extrudable carrier and a temporary plasticizer; and

[0568] ii. An ink cartridge, wherein the ink cartridge comprises the extrudable composition.

[0569] Suitably, the container is adapted to be fitted into an extrusion device, suitably so that the contents of the container (e.g., extrudable composition) can be conveyed through the extruder. In one embodiment, the container is adjusted so that the contents of the container (e.g., extrudable composition) can be conveyed to the extrusion nozzle of the extruder.

[0570] In one embodiment, the container comprises an extrusion nozzle.

[0571] Suitably, the container is an ink cartridge, suitably a 3D printer ink cartridge. Suitably, the ink cartridge contains an extrudable composition, wherein the extrudable composition is in the form of a filament. Suitably, the ink cartridge contains an extrudable composition, wherein the extrudable composition is in the form of a plurality of mini tablets. Suitably, the ink cartridge contains an extrudable composition, wherein the extrudable composition is in the form of an extrudable fluid.

[0572] Suitably, the container is a syringe and the extrudable composition is an extrudable fluid.

[0573] Suitably, the container is a heatable syringe. Advantageously, the syringe can be heated to form the extrudable fluid in situ.

[0574] Advantageously, when the container is a syringe and is filled with an extrudable fluid (either added directly to the syringe or formed in situ by heating), the syringe can be used as an extruder, for example, the syringe can be used for direct ink writing.

[0575] Suitably, there is provided a package of extrudable compositions comprising: one or more extrudable compositions as defined herein, wherein the one or more extrudable compositions are optionally the same or different within the package.

[0576] Suitably, there is provided a method of producing a package of an extrudable composition, the method comprising: packaging one or more extrudable compositions as defined herein, wherein the one or more extrudable compositions are optionally the same or different.

[0577] Suitably, there is provided an extrudable composition package obtainable by, obtained by or directly obtained by a method of producing an extrudable composition package as defined herein.

[0578] Packaging of (one or more) extruded products

[0579] The extruded product(s) of the present invention may be packaged by any of a variety of methods well known in the art. For example, when a pharmaceutical solid dosage form according to the present invention is produced by an extrusion device located in a pharmacy (e.g., to provide a patient with a customized medication on demand), the pharmacist may package the extruded product (e.g., solid dosage form) in a variety of ways, including in a tablet bottle, or even in a monitored dosing system, which may then be distributed to hospitals, nursing homes, etc., for ultimate distribution to patients.

[0580] Suitably, there is provided a method of producing a package of extruded articles, the method comprising: packaging one or more extruded articles as defined herein, wherein the one or more extruded articles are optionally the same or different.

[0581] Suitably, there is provided an extruded article package obtainable by, obtained by or directly obtained by a method of producing an extruded article package as defined herein.

[0582] Suitably, there is provided a package of extruded articles comprising: one or more extruded articles as defined herein, wherein the one or more extruded articles are optionally the same or different within the package.

[0583] In some embodiments, packaging can be formed by identical or different extrusion equipment. In some embodiments, packaging and extruded articles can be produced simultaneously, and thus extrusion operation utilizes one or more extrudable compositions relevant to extruded articles, and one or more extrudable compositions relevant to packaging, and packaging can be constructed around (one or more) extruded articles in the extrusion process.

[0584] Preparation of filaments

[0585] The filaments are suitably prepared by any of the methods described in WO2016 / 038356 (Applicant). However, since lower temperatures can be used, for example, during hot melt extrusion of the filaments, this method obtains the benefits of the present invention by utilizing an extrudable composition containing a temporary plasticizer in the production of the filaments.

[0586] Specific embodiments of extruded products

[0587] Suitably, there is provided an extrudable composition comprising:

[0588] i. an extrudable carrier; and

[0589] ii. Temporary plasticizer.

[0590] Suitably, there is provided an extrudable composition comprising:

[0591] i. an extrudable carrier; and

[0592] ii. a temporary plasticizer, wherein the boiling point of the temporary plasticizer is less than or equal to 120°C.

[0593] Suitably, there is provided an extrudable composition comprising:

[0594] i. an extrudable carrier; and

[0595] ii. Temporary plasticizer;

[0596] The content of the temporary plasticizer is greater than or equal to 5 weight % of the total weight of the extrudable composition.

[0597] Suitably, there is provided an extrudable composition comprising:

[0598] i. an extrudable carrier; and

[0599] ii. Temporary plasticizer;

[0600] The content of the temporary plasticizer is greater than or equal to 10 weight % of the total weight of the extrudable composition.

[0601] Suitably, there is provided an extrudable composition comprising:

[0602] i. an extrudable carrier; and

[0603] ii. Temporary plasticizer;

[0604] The content of the temporary plasticizer is greater than or equal to 15 weight % of the total weight of the extrudable composition.

[0605] Suitably, there is provided an extrudable composition comprising:

[0606] i. Extrudable carrier;

[0607] ii. Temporary plasticizers; and

[0608] iii. at least one active ingredient.

[0609] Suitably, there is provided an extrudable composition comprising:

[0610] i. Extrudable carrier;

[0611] ii. Temporary plasticizer;

[0612] iii. at least one active ingredient; and

[0613] iv. Permanent plasticizers.

[0614] Suitably, there is provided an extrudable composition comprising:

[0615] i. Extrudable carrier;

[0616] ii. Temporary plasticizer;

[0617] iii. at least one active ingredient;

[0618] iv. permanent plasticizers; and

[0619] v. One or more further components, suitably an excipient, excipient carrier and / or diluent.

[0620] Suitably, there is provided an extrudable composition comprising:

[0621] i. Extrudable carrier;

[0622] ii. Temporary plasticizer;

[0623] iii. at least one active ingredient;

[0624] iv. permanent plasticizers; and

[0625] v. Colorant.

[0626] Suitably, there is provided an extrudable composition comprising:

[0627] i. at least 20% by weight of an extrudable carrier;

[0628] ii. greater than or equal to 1% by weight of a temporary plasticizer; and

[0629] iii. at least one active ingredient;

[0630] The weights herein are relative to the total weight of the extrudable composition.

[0631] Suitably, there is provided an extrudable composition comprising:

[0632] i. at least 20% by weight of an extrudable carrier;

[0633] ii. greater than or equal to 1% by weight of a temporary plasticizer;

[0634] iii. at least one active ingredient; and

[0635] iv. at least 1% by weight of a permanent plasticizer;

[0636] The weights herein are relative to the total weight of the extrudable composition.

[0637] Suitably, there is provided an extrudable composition comprising:

[0638] i. at least 20% by weight of an extrudable carrier;

[0639] ii. greater than or equal to 1% by weight of a temporary plasticizer;

[0640] iii. at least one active ingredient; and

[0641] iv. at least 10% by weight of a permanent plasticizer;

[0642] The weights herein are relative to the total weight of the extrudable composition.

[0643] Suitably, there is provided an extrudable composition comprising:

[0644] i. at least 20% by weight of an extrudable carrier;

[0645] ii. greater than or equal to 1% by weight of a temporary plasticizer;

[0646] iii. at least one active ingredient;

[0647] iv. at least 10% by weight of a permanent plasticizer; and

[0648] v. one or more other components, suitably excipients, excipient carriers and / or diluents;

[0649] The weights herein are relative to the total weight of the extrudable composition.

[0650] Suitably, there is provided an extrudable composition comprising:

[0651] i. an extrudable carrier selected from: (optionally alkyl-)acrylate, methacrylate or ethacrylate polymers or copolymers, optionally comprising amine-containing monomer units, silicones, polyurethanes, polyolefins (e.g. polystyrene), polyalkylene glycols, polyalkylene glycol-derived polymers or copolymers, polyvinyl pyrrolidone or polyvinyl pyrrolidone-derived polymers or copolymers, polyvinyl alcohol, polyamides, acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polyglycolide, nylon and / or copolymers or mixtures thereof;

[0652] ii. a temporary plasticizer having a boiling point of less than or equal to 120°C;

[0653] iii. at least one active ingredient; and

[0654] iv. Permanent plasticizers.

[0655] Suitably, there is provided an extrudable composition comprising:

[0656] i. Polyvinyl alcohol;

[0657] ii. a temporary plasticizer selected from ethanol or water;

[0658] iii. at least one active ingredient; and

[0659] iv. Sorbitol.

[0660] Suitably, there is provided an extrudable element comprising:

[0661] i. an extrudable carrier; and

[0662] ii. Temporary plasticizer.

[0663] Suitably, there is provided an extrudable element comprising:

[0664] i. an extrudable carrier; and

[0665] ii. Temporary plasticizer;

[0666] The content of the temporary plasticizer is greater than or equal to 1 weight % of the total weight of the extrudable composition.

[0667] Suitably, there is provided an extrudable element comprising:

[0668] i. an extrudable carrier; and

[0669] ii. Temporary plasticizer;

[0670] The glass transition temperature of the extrudable element is between -50°C and 100°C.

[0671] Suitably, there is provided an extrudable element comprising:

[0672] i. an extrudable carrier; and

[0673] ii. Temporary plasticizer;

[0674] The glass transition temperature of the extrudable element is between -15°C and -10°C.

[0675] Suitably, there is provided an extrudable element comprising:

[0676] i. an extrudable carrier; and

[0677] ii. Temporary plasticizer;

[0678] The extrudable element is a filament.

[0679] Suitably, there is provided an extrudable element comprising:

[0680] i. Extrudable carrier;

[0681] ii. Temporary plasticizers; and

[0682] iii. at least one active ingredient;

[0683] The extrudable element is a filament.

[0684] Suitably, there is provided an extrudable element comprising:

[0685] i. Extrudable carrier;

[0686] ii. Temporary plasticizer;

[0687] iii. at least one active ingredient; and

[0688] iv. Permanent plasticizer

[0689] The extrudable element is a filament.

[0690] Suitably, there is provided an extrudable compressed form comprising:

[0691] i. an extrudable carrier; and

[0692] ii. Temporary plasticizer.

[0693] Suitably, there is provided an extrudable compressed form comprising:

[0694] i. an extrudable carrier; and

[0695] ii. Temporary plasticizer;

[0696] Among the extrudable compressed forms are a tablet or tablets.

[0697] Suitably, there is provided an extrudable compressed form comprising:

[0698] i. Extrudable carrier;

[0699] ii. Temporary plasticizers; and

[0700] iii. at least one active ingredient;

[0701] Among the extrudable compressed forms are a tablet or tablets.

[0702] Suitably, there is provided an extrudable compressed form comprising:

[0703] i. Extrudable carrier;

[0704] ii. Temporary plasticizer;

[0705] iii. at least one active ingredient; and

[0706] iv. Permanent plasticizer;

[0707] Among the extrudable compressed forms are a tablet or tablets.

[0708] Suitably, there is provided an extrudable compressed form comprising:

[0709] i. an extrudable carrier; and

[0710] ii. Temporary plasticizer;

[0711] The weight of the extrudable compressed form is 10 to 100 mg.

[0712] Suitably, there is provided an extrudable fluid comprising:

[0713] i. an extrudable carrier; and

[0714] ii. Temporary plasticizer.

[0715] Suitably, there is provided an extrudable fluid comprising:

[0716] i. Extrudable carrier;

[0717] ii. Temporary plasticizers; and

[0718] iii. at least one active ingredient.

[0719] Suitably, there is provided an extrudable fluid comprising:

[0720] i. Extrudable carrier;

[0721] ii. Temporary plasticizer;

[0722] iii. at least one active ingredient; and

[0723] iv. Permanent plasticizers.

[0724] Suitably, there is provided an extrudable fluid comprising:

[0725] v. an extrudable carrier; and

[0726] vi. Temporary plasticizer;

[0727] The extrudable fluid is fluid at ambient temperature.

[0728] Suitably, there is provided an extrudable fluid comprising:

[0729] i. an extrudable carrier; and

[0730] ii. Temporary plasticizer;

[0731] Wherein the extrudable fluid is fluid at an elevated temperature.

[0732] Suitably, there is provided an extrudable fluid comprising:

[0733] i. an extrudable carrier; and

[0734] ii. Temporary plasticizer;

[0735] Wherein the extrudable fluid is fluid at a temperature greater than or equal to 80°C.

[0736] Suitably, there is provided an extruded article comprising:

[0737] i. an extrudable carrier; and

[0738] ii. Temporary plasticizer.

[0739] Suitably, there is provided an extruded article comprising:

[0740] i. Extrudable carrier;

[0741] ii. Temporary plasticizers; and

[0742] iii. at least one active ingredient.

[0743] Suitably, there is provided an extruded article comprising:

[0744] i. an extrudable carrier; and

[0745] ii. Temporary plasticizer;

[0746] The content of the temporary plasticizer is greater than or equal to 1 weight % of the total weight of the extruded product.

[0747] Suitably, there is provided an extruded article comprising:

[0748] i. Extrudable carrier;

[0749] ii. Temporary plasticizers; and

[0750] iii. at least one active ingredient;

[0751] The content of the temporary plasticizer is greater than or equal to 1 weight % of the total weight of the extruded product.

[0752] Suitably, there is provided an extruded article comprising:

[0753] i. Extrudable carrier;

[0754] ii. Temporary plasticizer;

[0755] iii. at least one active ingredient; and

[0756] iv. Permanent plasticizer;

[0757] The content of the temporary plasticizer is greater than or equal to 1 weight % of the total weight of the extruded product.

[0758] Suitably, there is provided a pharmaceutical, nutraceutical or food supplement solid dosage form comprising:

[0759] i. Extrudable carrier;

[0760] ii. Temporary plasticizers; and

[0761] The content of the temporary plasticizer is greater than or equal to 1 weight % of the total weight of the extruded product.

[0762] Suitably, there is provided a pharmaceutical, nutraceutical or food supplement solid dosage form comprising:

[0763] i. an extrudable carrier; and

[0764] ii. Temporary plasticizer;

[0765] Suitably, there is provided a pharmaceutical, nutraceutical or food supplement solid dosage form comprising:

[0766] i. Extrudable carrier;

[0767] ii. Temporary plasticizer;

[0768] iii. at least one active ingredient; and

[0769] iv. Permanent plasticizer;

[0770] The content of the temporary plasticizer is greater than or equal to 1 weight % of the total weight of the extruded product.

[0771] Suitably, there is provided an extruded article comprising:

[0772] i. Extrudable carrier;

[0773] ii. Temporary plasticizer;

[0774] iii. at least one active ingredient; and

[0775] iv. Permanent plasticizer;

[0776] wherein the content of the temporary plasticizer is greater than or equal to 5 weight % of the total weight of the extruded product; and wherein the extruded product is a solid dosage form.

[0777] Suitably, there is provided an extruded article comprising:

[0778] i. at least 20% by weight of an extrudable carrier;

[0779] ii. greater than or equal to 1% by weight of a temporary plasticizer;

[0780] iii. at least one active ingredient; and

[0781] iv. at least 10% by weight of a permanent plasticizer;

[0782] The weights are relative to the total weight of the extruded article.

[0783] Suitably, there is provided an extruded article comprising:

[0784] i. at least 20% by weight of an extrudable carrier;

[0785] ii. greater than or equal to 5% by weight of a temporary plasticizer;

[0786] iii. at least one active ingredient; and

[0787] iv. at least 10% by weight of a permanent plasticizer;

[0788] The weights are relative to the total weight of the extruded article.

[0789] Suitably, there is provided an extruded article comprising:

[0790] i. Extrudable carrier;

[0791] ii. Temporary plasticizer;

[0792] iii. at least one active ingredient; and

[0793] iv. Permanent plasticizer;

[0794] wherein the content of the temporary plasticizer is greater than or equal to 1 wt% of the total weight of the extruded article; and wherein the extruded article is a solid dosage form comprising a plurality of layers, wherein the thickness of each layer is 10 to 1000 μm.

[0795] Suitably, there is provided an extruded article comprising:

[0796] i. Extrudable carrier;

[0797] ii. Temporary plasticizer;

[0798] iii. at least one active ingredient;

[0799] iv. permanent plasticizers; and

[0800] v.Paint

[0801] wherein the content of the temporary plasticizer is greater than or equal to 1 wt % of the total weight of the extruded product; and wherein the extruded product is a solid dosage form.

[0802] Suitably, there is provided an extruded article comprising:

[0803] i. an extrudable carrier selected from: (optionally alkyl-)acrylate, methacrylate or ethacrylate polymers or copolymers, optionally comprising amine-containing monomer units, silicones, polyurethanes, polyolefins (e.g. polystyrene), polyalkylene glycols, polyalkylene glycol-derived polymers or copolymers, polyvinyl pyrrolidone or polyvinyl pyrrolidone-derived polymers or copolymers, polyvinyl alcohol, polyamides, acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polyglycolide, nylon and / or copolymers or mixtures thereof;

[0804] ii. a temporary plasticizer having a boiling point of less than or equal to 120°C;

[0805] iii. at least one active ingredient; and

[0806] iv. Permanent plasticizer;

[0807] wherein the content of the temporary plasticizer is greater than or equal to 1 wt % of the total weight of the extruded product; and wherein the extruded product is a solid dosage form.

[0808] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0809] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0810] ii. further treating the mixture from step i to form:

[0811] a. Extrudable fluid;

[0812] b. Extrudable compressed form; or

[0813] c. Extrudable components.

[0814] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0815] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0816] ii. Optionally, further treating the mixture from step i to form:

[0817] a. Extrudable fluid;

[0818] b. Extrudable compressed form; or

[0819] c. Extrudable components;

[0820] wherein the extrudable composition has at least 20 weight percent of an extrudable carrier; less than or equal to 30 weight percent of a transient plasticizer; and wherein the weights are relative to the total weight of the extrudable composition.

[0821] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0822] i. mixing an extrudable carrier, a temporary plasticizer and at least one active ingredient; and

[0823] ii. Optionally, further treating the mixture from step i to form:

[0824] a. Extrudable fluid;

[0825] b. Extrudable compressed form; or

[0826] c. Extrudable components;

[0827] wherein the extrudable composition has at least 20 weight percent of an extrudable carrier; less than or equal to 30 weight percent of a transient plasticizer; and wherein the weights are relative to the total weight of the extrudable composition.

[0828] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0829] i. mixing an extrudable carrier, a temporary plasticizer, at least one active ingredient and a permanent plasticizer; and ii. optionally, further processing the mixture from step i to form:

[0830] a. Extrudable fluid;

[0831] b. Extrudable compressed form; or

[0832] c. Extrudable components.

[0833] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0834] i. mixing an extrudable carrier, a temporary plasticizer, at least one active ingredient and a permanent plasticizer; and ii. optionally, further processing the mixture from step i to form:

[0835] a. Extrudable fluid;

[0836] b. Extrudable compressed form; or

[0837] c. Extrudable components;

[0838] wherein the extrudable composition has at least 20 weight percent of an extrudable carrier; less than or equal to 30 weight percent of a temporary plasticizer; at least 10 weight percent of a permanent plasticizer; and wherein the weights are relative to the total weight of the extrudable composition.

[0839] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0840] i. Mix the extrudable carrier and the temporary plasticizer together.

[0841] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0842] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0843] ii. further treating the mixture from step i to form:

[0844] a. Extrudable fluid.

[0845] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0846] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0847] ii. further treating the mixture from step i to form:

[0848] a. Can be extruded and compressed.

[0849] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0850] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0851] ii. further treating the mixture from step i to form:

[0852] a. Extrudable components.

[0853] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0854] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0855] ii. Optionally, further treating the mixture from step i to form:

[0856] a. Extrudable fluid;

[0857] b. Extrudable compressed form; or

[0858] c. Extrudable components;

[0859] The mixing is shear mixing.

[0860] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0861] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0862] ii. Optionally, further treating the mixture from step i to form:

[0863] a. Extrudable fluid;

[0864] b. Extrudable compressed form; or

[0865] c. Extrudable components;

[0866] The mixing is shear mixing, wherein the mixing is performed at a temperature greater than or equal to 10°C.

[0867] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0868] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0869] ii. Optionally, further treating the mixture from step i to form:

[0870] a. Extrudable fluid;

[0871] b. Extrudable compressed form; or

[0872] c. Extrudable components;

[0873] Wherein the mixing is shear mixing, and during the mixing step the temporary plasticizer is sprayed onto the extrudable carrier. Suitably, there is provided a method for preparing an extrudable composition, the method comprising:

[0874] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0875] ii. further treating the mixture from step i to form:

[0876] a. Extrudable fluid;

[0877] The extrudable fluid is fluid at ambient temperature.

[0878] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0879] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0880] ii. further treating the mixture from step i to form:

[0881] b. Extrudable fluid;

[0882] Wherein the extrudable fluid is fluid at an elevated temperature.

[0883] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0884] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0885] ii. Fill a container with the mixture from step i.

[0886] Suitably, there is provided a method of preparing an extrudable fluid, the method comprising:

[0887] i. mixing the extrudable carrier and the temporary plasticizer together;

[0888] ii. filling a container with the mixture in step i; and

[0889] iii. Heating container.

[0890] Suitably, there is provided a method of preparing an extrudable fluid, the method comprising:

[0891] i. mixing the extrudable carrier and the temporary plasticizer together;

[0892] ii. filling a container with the mixture in step i; and

[0893] iii. Heating container;

[0894] The container is a syringe.

[0895] Suitably, there is provided a method of preparing an extrudable fluid, the method comprising:

[0896] i. mixing the extrudable carrier and the temporary plasticizer together;

[0897] ii. filling a container with the mixture in step i; and

[0898] iii. heating the container to a temperature above the glass transition (or softening) temperature of the mixture formed in step i. Suitably, there is provided a method for preparing an extrudable fluid, the method comprising:

[0899] i. mixing the extrudable carrier and the temporary plasticizer together;

[0900] ii. filling a container with the mixture in step i; and

[0901] iii. heating the container to a temperature above the glass transition (or softening) temperature of the mixture formed in step i; wherein the container is a syringe.

[0902] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0903] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0904] ii. further treating the mixture from step i to form:

[0905] a. Can be extruded and compressed.

[0906] Suitably, there is provided a method of preparing an extrudable composition, the method comprising:

[0907] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0908] ii. further treating the mixture from step i to form:

[0909] a. Can be extruded and compressed;

[0910] The compressed form is a tablet or tablets.

[0911] Suitably, there is provided a method of preparing an extrudable element, the method comprising:

[0912] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0913] ii. extruding the mixture of step i.; and

[0914] iii. Removing or partially removing the transient plasticizer from the product of step ii.

[0915] Suitably, there is provided a method of preparing an extrudable element, the method comprising:

[0916] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0917] ii. extruding the mixture of step i.; and

[0918] iii. removing or partially removing the temporary plasticizer from the product of step ii;

[0919] The extrudable element is a filament.

[0920] Suitably, there is provided a method of preparing an extrudable element, the method comprising:

[0921] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0922] ii. extruding the mixture of step i.; and

[0923] iii. Removing or partially removing the temporary plasticizer from the product of step ii, so that the glass transition (softening) temperature of the extruded element is between -50°C and 100°C.

[0924] Suitably, there is provided a method of preparing an extrudable element, the method comprising:

[0925] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0926] ii. extruding the mixture of step i.; and

[0927] iii. Removing or partially removing the temporary plasticizer from the product of step ii, so that the glass transition (softening) temperature of the extruded element is between -15°C and -10°C.

[0928] Suitably, there is provided a method of preparing an extrudable element, the method comprising:

[0929] i. mixing the extrudable carrier and the temporary plasticizer together; and

[0930] ii. extruding the mixture of step i.; and

[0931] iii. removing or partially removing the temporary plasticizer by heating the product of step ii and / or keeping the product of step ii under reduced pressure until the glass transition (softening) temperature of the extruded element is within -15°C

[0932] to -10℃.

[0933] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0934] i. extruding an extrudable composition into a desired form, wherein the extrudable composition is as defined herein, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0935] in:

[0936] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[0937] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0938] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0939] i. Extruding the extrudable composition into a desired form, wherein the extrudable composition comprises an extrudable carrier

[0940] and a transient plasticizer, optionally associated with one or more auxiliary elements (e.g., shell, coating, core); wherein:

[0941] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0942] The method further comprises removing or partially removing the transient plasticizer.

[0943] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0944] i. Extruding the extrudable composition into a desired form, wherein the extrudable composition comprises an extrudable carrier

[0945] and a transient plasticizer, optionally associated with one or more auxiliary elements (e.g., shell, coating, core); wherein:

[0946] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0947] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0948] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0949] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20 wt. % of an extrudable carrier and less than or equal to 30 wt. % of a transient plasticizer, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0950] in:

[0951] The weight is relative to the total weight of the extrudable composition;

[0952] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0953] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0954] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0955] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises an extrudable carrier, a transient plasticizer and at least one active ingredient, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0956] in:

[0957] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0958] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0959] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0960] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, less than or equal to 30% by weight of a transient plasticizer and at least one active ingredient, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0961] in:

[0962] The weight is relative to the total weight of the extrudable composition;

[0963] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0964] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0965] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0966] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, less than or equal to 30% by weight of a transient plasticizer and at least one active ingredient, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0967] in:

[0968] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[0969] The weight is relative to the total weight of the extrudable composition;

[0970] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0971] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0972] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0973] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises an extrudable carrier, a temporary plasticizer, at least one active ingredient and a permanent plasticizer, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0974] in:

[0975] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0976] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0977] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0978] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, less than or equal to 30% by weight of a temporary plasticizer, at least one active ingredient and at least 10% by weight of a permanent plasticizer, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0979] in:

[0980] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[0981] The weight is relative to the total weight of the extrudable composition;

[0982] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0983] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0984] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0985] i. Extruding the extrudable composition into a desired form, wherein the extrudable composition comprises an extrudable carrier

[0986] and a transient plasticizer, optionally associated with one or more auxiliary elements (e.g., shell, coating, core); wherein:

[0987] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[0988] The extruded article contains a lower amount of transient plasticizer than the extrudable composition;

[0989] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[0990] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0991] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0992] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20 wt. % of an extrudable carrier and less than or equal to 30 wt. % of a transient plasticizer, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[0993] in:

[0994] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[0995] The extruded article contains a lower amount of transient plasticizer than the extrudable composition;

[0996] The weight is relative to the total weight of the extrudable composition, and wherein the temporary plasticizer is a vaporizable substance (or a combination of vaporizable substances) capable of vaporizing at a temperature of 150° C. or below (suitably, at standard ambient pressure, such as 100 kPa); and

[0997] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[0998] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[0999] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, less than or equal to 30% by weight of a transient plasticizer and at least one active ingredient, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[1000] in:

[1001] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[1002] The extruded article contains a lower amount of transient plasticizer than the extrudable composition;

[1003] The weight is relative to the total weight of the extrudable composition;

[1004] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[1005] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1006] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1007] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, less than or equal to 30% by weight of a temporary plasticizer, at least one active ingredient and at least 10% by weight of a permanent plasticizer, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[1008] in:

[1009] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[1010] The extruded article contains a lower amount of transient plasticizer than the extrudable composition;

[1011] The weight is relative to the total weight of the extrudable composition;

[1012] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[1013] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1014] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1015] i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, less than or equal to 30% by weight of a temporary plasticizer, at least one active ingredient and at least 10% by weight of a permanent plasticizer, optionally associated with one or more auxiliary elements (e.g., a shell, a coating, a core);

[1016] in:

[1017] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[1018] The content of temporary plasticizer in the extruded article is 10% less than that of the extrudable composition;

[1019] The weight is relative to the total weight;

[1020] The temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[1021] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1022] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1023] i. extruding the extrudable composition into a desired form, wherein the extrudable composition is as defined herein; wherein:

[1024] The extruded product is a solid dosage form of a drug, a nutraceutical, or a food supplement;

[1025] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1026] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1027] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1028] i. extruding an extrudable element (optionally associated with one or more auxiliary elements (e.g., shell, coating, core)) into a desired form, wherein the extrudable element is as defined herein;

[1029] in:

[1030] the extrudable element initially comprises a temporary plasticizer, the temporary plasticizer being a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1031] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1032] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1033] i. extruding the extrudable compressed form into a desired form, wherein the extrudable compressed form is as defined herein;

[1034] in:

[1035] The extrudable compressed form initially comprises a temporary plasticizer, the temporary plasticizer being a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1036] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1037] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1038] i. extruding an extrudable fluid into a desired form, wherein the extrudable fluid is as defined herein;

[1039] in:

[1040] The extrudable fluid initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, such as 100 kPa); and

[1041] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1042] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1043] i. extruding an extrudable composition into a desired form onto a build platform, wherein the extrudable composition is as defined herein;

[1044] in:

[1045] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1046] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1047] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1048] i. extruding the extrudable composition into a desired form, wherein the extrudable composition is as defined herein; and

[1049] ii. heating the desired form of step i and / or maintaining the desired form of step i under reduced pressure to remove or partially remove the temporary plasticizer;

[1050] in:

[1051] The extrudable composition initially comprises a temporary plasticiser which is a vaporisable substance (or combination of vaporisable substances) capable of vaporising at a temperature at or below 150°C (suitably at standard ambient pressure, for example 100 kPa).

[1052] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1053] i. extruding the extrudable composition into a desired form, wherein the extrudable composition is as defined herein; and

[1054] ii. heating the desired form of step i and / or maintaining the desired form of step i under reduced pressure to remove at least 10 wt % of the temporary plasticizer;

[1055] in:

[1056] The extrudable composition initially comprises a temporary plasticiser which is a vaporisable substance (or combination of vaporisable substances) capable of vaporising at a temperature at or below 150°C (suitably at standard ambient pressure, for example 100 kPa).

[1057] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1058] i. extruding an extrudable composition into a desired form, wherein the extrudable composition is as defined herein, and wherein the desired form is built up layer by layer;

[1059] in:

[1060] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1061] The method further comprises removing or partially removing the temporary plasticizer by vaporization.

[1062] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1063] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier; and

[1064] ii. extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core);

[1065] in:

[1066] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1067] The method further comprises removing or partially removing the transient plasticizer from the extruded article by vaporization before, during or after the extrusion step.

[1068] Suitably, there is provided a method of preparing a pharmaceutical, nutraceutical or food supplement solid dosage form, the method comprising:

[1069] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier; and

[1070] ii. extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core);

[1071] in:

[1072] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa); and

[1073] The method further comprises removing or partially removing the transient plasticizer from the extruded article by vaporization before, during or after the extrusion step.

[1074] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1075] i. providing a container filled with an extrudable composition, the extrudable composition comprising an extrudable carrier;

[1076] ii. extruding the extrudable composition into a desired form, optionally in association with one or more auxiliary elements (eg, shell, coating, core);

[1077] in:

[1078] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa);

[1079] Suitably, the extrudable composition is converted in situ by heating the container, or provided in the form of an extrudable fluid; and the method further comprises removing or partially removing the transient plasticizer from the extruded article by vaporization before, during or after the extrusion step.

[1080] Suitably, there is provided a method of preparing an extruded article, the method comprising:

[1081] i. providing an extrudable composition, the extrudable composition comprising an extrudable carrier;

[1082] ii. extruding the extrudable composition into the desired form through an extruder, optionally associated with one or more auxiliary elements (eg, shell, coating, core);

[1083] in:

[1084] The extrudable composition initially comprises a temporary plasticizer, which is a vaporizable substance (or combination of vaporizable substances) capable of vaporizing at a temperature at or below 150°C (suitably at standard ambient pressure, e.g. 100 kPa);

[1085] The extruder includes a heated build platform;

[1086] The method further comprises removing or partially removing the transient plasticizer from the extruded article by vaporization during or after the extrusion step by heating the build platform to above ambient temperature.

[1087] In one embodiment, extrudable articles are produced by direct writing 3D printing of ink extrudable compressed forms, wherein the extrudable compressed forms are suitably multiple compression units (e.g., mini tablets) or compressed monoliths (e.g., compressed powders or compressed granule compositions). Extrudable compositions may optionally include or be mixed with a temporary plasticizer before 3D printing, but in certain embodiments, extrudable compositions do not contain or are not mixed with a temporary plasticizer. Suitably, in such embodiments, the longest dimension of each mini tablet is between 0.5mm and 10mm, suitably between 1mm and 8mm, suitably between 3mm and 7mm, and most suitably between 5mm and 7mm. Suitably, each extrudable compressed form weighs 10 to 100mg, 20 to 80mg, 30 to 70mg, 40 to 60mg or about 50mg. Suitably, each extrudable compressed form is formed by compressing 10 to 100 mg, 20 to 80 mg, 30 to 70 mg, 40 to 60 mg or about 50 mg of the otherwise powdered or granular extrudable composition.

[1088] Suitably, any extrudable composition defined herein comprises any one or both of a temporary and / or permanent plasticizer, suitably as defined herein. Whenever a temporary plasticizer is used, suitably, it is eventually removed or partially removed after processing into the desired form (e.g., extruded article). Whenever a permanent plasticizer is used, suitably, it remains in the final desired form into which it is processed.

[1089] Embedded products

[1090] Method for preparing embedded article

[1091] The present invention provides a method of preparing an embedded article, suitably as defined herein.

[1092] A method for preparing an embedded article is provided, the method comprising:

[1093] i. Providing a curable body material in the form of a fluid or semi-fluid;

[1094] ii. embedding an embeddable substance in the curable body material;

[1095] iii. curing the curable body material having the embeddable material therein.

[1096] Suitably, the embedment article is as defined herein.

[1097] The method suitably comprises operating the embedding apparatus to produce an embedded solid on the embedding apparatus, suitably on the build platform, by embedding an embeddable substance within the curable body substance.

[1098] Suitably, such production is carried out by a computer-implemented process (ie embedding is controlled and suitably initiated by a computer connected or connectable to or within the device, either by wire or wirelessly).

[1099] Embeddable material suitably resides in the storage position in the equipment, suitably resides in the container, such as ink cartridge.Suitably embeddable material is transported to the deposition nozzle, suitably, by one or more conveyors (such as pumps or syringes).Deposition nozzle suitably penetrates the solidifiable material provided or passes the surface of a part of the solidifiable material, then makes embeddable material enter the solidifiable material by deposition nozzle or on the surface of a part of the solidifiable material (suitably, when embeddable material continues to be transported towards the deposition nozzle from the storage position).Embeddable material is deposited at least one layer in / on the solidifiable material, suitably in a single layer or multilayer.If embeddable material is deposited on the surface of the solidifiable material, another part of the solidifiable material is placed on the first part, thereby embeddable material is embedded in the solidifiable material.Suitably, embeddable material is deposited in a continuous manner (such as, line) or a discontinuous manner (such as, the connectable or separate part of a point or pattern) per layer.Suitably, the pattern of embeddable material is formed on each layer in the solidifiable material. Due to the immiscibility of embeddable material and curable body material, embeddable material is retained in the position deposited in the curable body material, that is to say, in the process of manufacturing embedded article, embeddable material does not have obvious migration in the curable body material. Suitably, within the shelf life of embedded article, embeddable material does not have obvious migration in the curable body material. Suitably, at least 1 hour after producing embedded article, suitably at least 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 6 months, 8 months, 10 months, 12 months, 18 months or 24 months, embeddable material does not have obvious migration in the curable body material. Suitably, within 1 hour to 24 months after producing embedded article, embeddable material does not have obvious migration in the curable body material. The term "no obvious migration" should be construed as no migration, or migration will not affect the suitability of embedded article for its intended use (i.e. as dosage form). The skilled person will be aware of techniques in the art which can determine the level of migration of the embeddable species in the curable species, for example, by visual or microscopic observation, using spectroscopy to monitor the concentration profile of the embeddable species in the embedded article.

[1100] During the embedding step, the deposition nozzle is suitably moved in any one or all of the X, Y, and Z directions.

[1101] The curable body material is suitably resident in a storage location within the apparatus, suitably resident in a container, such as an ink cartridge. The curable body material is suitably delivered to the deposition nozzle, suitably by one or more conveyors (such as pumps or syringes). The deposition nozzle suitably provides the curable body material by filling the mold with the curable body material.

[1102] Those skilled in the art will appreciate that the, each or any deposition nozzle may be adjusted so that the characteristics are suitable for the corresponding embeddable substance / curable body substance configured to be embedded / provided thereon. The nozzle characteristics / design and the embeddable substance characteristics / curable body substance suitably complement each other to facilitate controlled embedding / providing of the composition (continuously or intermittently, e.g., where more than one embeddable substance / curable body substance is used), suitably without any deposition nozzle clogging or impedance, and suitably without any unacceptable degradation of the components in the embeddable substance / curable body substance during the embedding / providing step.

[1103] Suitably, the method comprises embedding the embeddable substance into the solidifiable body substance after the solidifiable body substance has been solidified. For example, the solidifiable body substance is solidified and then the embeddable body substance is embedded (i.e., printed using a needle that cuts the solidifiable body substance into pieces) into the solidified body substance, thereby incorporating the embeddable body substance into the solidified body substance.

[1104] Suitably, the method comprises embedding an embeddable substance into a curable body substance by curing a portion of the curable body substance, providing the embeddable substance onto a surface of the curable body substance (i.e. by printing directly on the top surface), providing the remaining curable body substance on top of the curable body substance, and curing the remaining portion of the curable body substance, thereby embedding the embeddable substance between the two portions of the body substance.

[1105] Providing a curable substance

[1106] Suitably, the curable body material is as defined herein.

[1107] Suitably, the providing step is carried out at an elevated temperature, suitably at a temperature greater than or equal to ambient temperature. Suitably, at a temperature greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C or 80°C. Suitably, the providing step is carried out at 25 to 80°C.

[1108] Suitably the curable mass is at a temperature greater than or equal to ambient temperature, suitably greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C or 80°C. Suitably the curable mass is at a temperature of 25 to 80°C.

[1109] Suitably, the curable body material is heated in step i. Suitably, the curable body material is heated to a temperature greater than or equal to ambient temperature. Suitably, at a temperature greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C or 80°C. Suitably, the curable body material is heated in step i to a temperature of 25 to 80°C.

[1110] Suitably, the providing step comprises filling or partially filling the mould with the curable body substance. Suitably, the mould is sized and shaped to produce an embedded article of size and shape as defined herein. Suitably, the curable body substance is poured into the mould.

[1111] Suitably the mould is maintained at a temperature greater than or equal to ambient temperature, suitably greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C or 80°C. Suitably the mould is maintained at a temperature of 25 to 80°C.

[1112] Suitably, the curable mass is provided at a temperature above the temperature of the mould. Suitably, the curable mass is provided at a temperature at least 10°C above the temperature of the mould, suitably at least 15°C, 20°C, 25°C or 30°C above the temperature of the mould.

[1113] Suitably, in the step of providing a curable body substance, more than one curable body substance is used.

[1114] Embedding steps

[1115] Suitably, the embeddable substance is as defined herein.

[1116] Suitably, during the embedding step, more than one embeddable substance is used.

[1117] Suitably, the embedding step comprises embedding the embeddable substance in at least one layer or part of a layer within the curable body substance. Suitably, there is one layer of the embeddable substance, suitably multiple layers, suitably two layers.

[1118] Suitably, the embeddable material comprises at least one active ingredient. Suitably, each layer may comprise one or more active ingredients. Suitably, if more than one layer is present, each layer may comprise a different active ingredient. Suitably, if more than one layer is present, each layer may be the same or different.

[1119] Suitably, each layer is a continuous layer or a discontinuous layer. Suitably, each layer may be in the form of a straight, curved or interrupted layer (e.g. a dashed layer). Suitably, each layer may be in the form of a continuous line, suitably a continuous straight line, suitably a continuous line including a bend and / or curvature.

[1120] Suitably, the embedding step uses a printer, suitably a 3D printer, suitably an embedded 3D printer. Suitably, the printer comprises a printing plate. Suitably, the embedded article is formed on the printing plate, suitably in a mould on the printing plate.

[1121] Suitably, the embedding step uses at least one syringe. Suitably, the syringe is filled with the embeddable substance.

[1122] Suitably, the embedding step is carried out at a temperature of less than or equal to 60°C, suitably less than or equal to 50°C, 40°C, 30°C or 25°C. Suitably, the embedding step is carried out at a temperature of 0 to 50°C, such as 25 to 50°C. Advantageously, during the embedding step, the embeddable material is not exposed to very high temperatures. This is particularly useful for embeddable materials comprising heat-sensitive components, such as heat-sensitive active ingredients, such as biologically active ingredients, i.e. proteins or peptides.

[1123] Suitably, each embedding step is sequential.

[1124] Suitably, the embeddable substance is present in the curable body substance as at least one layer or at least part of a layer.

[1125] Suitably, the method comprises two or more embedding steps, each embedding step comprising: embedding an embeddable substance in the solidifiable body substance, wherein the embeddable substances used in each embedding step are the same or different. Suitably, each embedding step forms different layers of embeddable substances in the solidifiable body substance. Suitably, each embedding step forms part of the same layer of embeddable substances in the solidifiable body substance.

[1126] Suitably, each embedding step embeds a part of embeddable material in the curable body material. Suitably, the embedding step comprises embedding a part of embeddable material in the curable body material, then embeds at least another part of the embeddable material. Suitably, these parts are identical or different. Suitably, the embedding step comprises embedding a part of embeddable material in the curable body material, then embeds other three parts. Suitably, each part embeds about 25% of the embeddable material in the curable body material. For example, about 25% of the embeddable material is embedded in the curable body material, followed by another part about 25%, followed by another part about 25%, and finally another part about 25%. These parts of the embeddable material can be combined or not combined in the curable body material. Suitably, the embedding step comprises embedding the first layer or its part of the embeddable material in the curable body material, then the second layer or its part of the embeddable material is embedded in the curable body material. Suitably, the first layer and the second layer are different from the curable body material (that is, each layer is separated by the curable body material) or contact each other.

[1127] Suitably, the embedding step of each portion of the embeddable substance is digitally controlled, ie by a computer. Advantageously, embedding the embeddable substance in portions results in less variation in the amount of the embeddable substance dispensed during the embedding process, thus resulting in a more precise dosing of the embeddable substance within the embedded article.

[1128] Suitably, the embedding step uses a needle. Suitably, the size of the needle controls the amount of embeddable material embedded in the curable body material. Suitably, the size of the needle is from 1 to 1.6 mm.

[1129] Suitably, the amount of the embeddable substance embedded in the curable body substance is controlled by the embedding speed of the embedder. Suitably, the embedding speed is between 40 and 80 mm / min, such as between 50 and 70 mm / min, suitably about 50 mm / min, suitably about 60 mm / min, suitably about 65 mm / min, suitably about 70 mm / min.

[1130] Suitably, the embeddable substance is embedded in the curable body substance to produce a pattern, suitably a pattern personalised to the patient.

[1131] Suitably, the embeddable substance is embedded in the solidifiable body substance to allow sequential release of the embeddable substances from the embedding article when the embedding article is administered, suitably orally. Suitably, two embeddable substances are embedded to allow sequential release of the embeddable substances.

[1132] Suitably, the embeddable substance is embedded in the solidifiable body substance, thereby allowing dose titration of the embeddable substance from the embeddable article when the embeddable article is administered, suitably orally.

[1133] Curing steps

[1134] Suitably, the curing step comprises UV curing, heating, cooling and / or providing a cross-linking agent.

[1135] Suitably, the curing step comprises heating the curable body substance, suitably heating the curable body substance to above ambient temperature, suitably heating the curable body substance to greater than or equal to 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Suitably, the curing step comprises heating the curable body substance to less than or equal to 200°C, 150°C, 120°C or 100°C. Suitably, the curing step comprises heating the curable body substance to 25 to 200°C.

[1136] Suitably, the curing step comprises cooling the curable body substance, suitably cooling the curable body substance to a temperature lower than the temperature used in the previous step. Suitably, the curing step comprises cooling the curable body substance to a temperature below ambient temperature, suitably cooling to a temperature greater than or equal to -20°C, -10°C, 0°C, 10°C or 20°C. Suitably, the curing step comprises cooling the curable body substance to a temperature less than or equal to 40°C, 30°C, 20°C or 10°C. Suitably, the curing step comprises cooling the curable body substance to a temperature between -20 and 40°C.

[1137] Suitably, the curing step comprises UV curing, suitably by exposing the curable body material to a UV light source. Suitably, the exposure time is at least 1 minute, suitably at least 5 minutes, 10 minutes, 20 minutes, 30 minutes or 60 minutes. Suitably, the curing step comprises exposing the curable body material to ultraviolet light for 1 to 60 minutes. Suitably, the ultraviolet light source is an ultraviolet lamp.

[1138] Suitably, the curing step also includes providing a crosslinking agent as defined herein. Suitably, the crosslinking agent solidifies the curable body material. The technician will appreciate that there are many reagents that can serve as crosslinking agents and many reagents that can serve as curable body materials. The selection of two kinds of reagents will depend on the compatibility of reagents with each other and other components in the embedded article, and the suitability and the desired attributes of the embedded article used in the method for preparing the embedded article.

[1139] Suitably, the curable body composition comprises at least one active ingredient.

[1140] Other methods and steps

[1141] The method may include one or more further steps before, during and / or after any of the aforementioned steps. The surface(s) of the embedded article may be pre-treated or post-treated by embedding additional layers or partial layers, or by other coating techniques known in the art.

[1142] The embedded article produced by the method of the present invention can then be treated in various ways to provide a further processed embedded article. Suitably, the method also includes coating the product obtained by the embedding step. Suitably, the coating is described herein. For example, the embedded article can be enteric coated by standard enteric coating treatments known in the art. Similarly, other controlled release properties can be imparted to the embedded article by further processing.

[1143] Most suitably, all steps (including any further processing steps) are performed by the embedded device. Suitably, all steps (including further processing steps) are controlled by the same computer.

[1144] Computer implementation of the method

[1145] The method of preparing an embedded article is suitably a computer implemented method, suitably as defined herein.

[1146] The method suitably comprises providing an embedding device, suitably an extrusion device as defined herein, and operating said device to prepare an embedded article. Suitably, the embedding device comprises a computer or is otherwise connected to a computer. Operating the embedding device suitably comprises operating a computer, which is suitably connected to or within the relevant embedding device (in a wired or wireless manner) (so that the computer can control and coordinate other parts of the embedding device, including the printer).

[1147] The computer consisting of or associated with the embedding device of the present invention may be appropriately referred to as an embedding control computer. The embedding control computer may function differently from other "computers" mentioned herein, such as monitoring computers and analysis computers (and may be different entities), but a single computer may perform the (one or more) functions of any one or more combinations of these computers. The embedding control computer appropriately controls the preparation of the embedded article, for example, embedding the embeddable substance in the curable body substance by a deposition nozzle, and optionally controls other processing steps, such as coating the formed article. As long as different computers are used to implement each of these operations, the computers will be appropriately coordinated and therefore can be considered as part of an integral computer.

[1148] The preparation of the embedded article is suitably controlled by a computer running according to software, suitably based on information provided to the computer by user input (drug type, drug dosage level), databases (e.g., patient databases and / or extruded article databases) and / or data files (e.g., design and / or parameter files), as described herein. Suitably, the embedding device is configured according to instructions provided by the computer: feeding (one or more) embeddable substances and / or feeding (one or more) solidifiable substances to their respective (one or more) deposition nozzles and through them at appropriate intervals and / or appropriate rates; and moving (one or more) deposition nozzles and / or building platforms to systematically embed the embeddable substances into the solidifiable substances according to the relevant information obtained and the calculations performed by the computer.

[1149] The deposition nozzle(s) are suitably controlled by a computer based on "obtained information" (e.g., design and / or other parameters) related to the embedded article. The deposition nozzle is suitably controlled so that a given embeddable substance is embedded into the curable body substance by means of the "obtained information" to form a predefined pattern. In this way, the or each deposition nozzle can be controlled "on" and "off" according to a predefined plan to deliver the desired pattern in the construction of the embedded article. The deposition nozzle can be turned "on" by leaving the output opening open.

[1150] The building platform is suitably controlled by a computer according to "obtained information" (e.g., design and / or other parameters) related to the embedded product, suitably as described elsewhere herein. This may include controlling the operating temperature of the building platform, in particular the operating temperature of the surface of the building platform. Suitably, in the process of preparing the embedded product, the operating temperature of the building platform or its surface remains substantially constant, suitably maintained at a constant temperature of + / -5°C, according to the requirements of the specific stage of the process. For example, during the filling or partial filling of the mold with a curable substance, the building platform can be maintained at a first temperature. In the curing stage, the building platform can be maintained at a second temperature. In the embedding stage, the building platform can be maintained at a third temperature. Depending on the curing mode of the curable body material, the first temperature can be higher than the second temperature and / or the third temperature (e.g., cured by cooling), and vice versa (e.g., cured by heating). Suitably, the first, second and third temperatures can be the same, for example when cured by exposure to ultraviolet rays and / or crosslinking. In addition, such temperature control can promote the adhesion of the embedded product imaged during its formation to the surface of the building platform. Such temperature control can promote the release (i.e., non-stickiness) of the embedded article after its formation (e.g., the surface of the build platform can be suitably heated or cooled to reduce the adhesion of (one or more) embedded articles thereon). During the preparation of the embedded article, the build platform is suitably configured or operable to maintain a surface temperature (i.e., the surface in contact with the embedded article, or the mold in which the embedded article is formed) less than or equal to 100°C, suitably less than or equal to 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C or 25°C. Suitably, the surface temperature is greater than or equal to 0°C, suitably greater than or equal to 0°C, 20°C, 25°C, 30°C, 40°C, 50°C or 60°C. Suitably, the surface temperature is between 10 and 100°C.

[1151] Embedded products

[1152] The present invention provides an embedded article obtainable by, obtained by or directly obtained from a method for preparing an embedded article as defined herein.

[1153] The embedding article is suitably formed of a curable substance and an embeddable substance. Thus, any definition of a curable substance and an embeddable substance herein may itself be equally applicable to the embedding article.

[1154] Provided is an embedding article comprising an embeddable substance in a curable substance. Suitably, the embedding article comprises one or more embeddable substances, suitably one embeddable substance, suitably two embeddable substances. Suitably, each embeddable substance may comprise the same or different components, i.e., each embeddable substance may comprise the same or different active ingredients. Suitably, the embedding article may comprise a plurality of curable substances, suitably, comprising two curable substances. Suitably, each curable substance may be the same or different.

[1155] Suitably, the embedded article comprises greater than or equal to 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25% or 30% by weight of the embeddable substance, suitably 1 to 30% by weight. Suitably, the embedded article comprises greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the curable body substance, suitably 0.1 to 90%.

[1156] Suitably, the embedding article is a solid. Suitably, the embedding article is a semi-solid. Suitably, the embedding article is a solid or semi-solid, suitably including a solid or semi-solid (formed from a solidifiable body substance) and an embeddable substance in vivo. Suitably, the embeddable substance is a liquid, a solution, an emulsion, a suspension, a solid or a semi-solid (suitably, a gel). Suitably, the embeddable substance is a gel.

[1157] The (one or more) embedded articles of the present invention can be advantageously customized according to: the type / nature of the active ingredient, the dosage of the active ingredient within the embedded article (either the absolute dosage per embedded article, or the concentration of the active ingredient within the embedded article), the mass / volume of the embedded article (which is generally suitable for varying the absolute dosage of the active ingredient without varying the concentration of the active ingredient in the embedded article), the active ingredient release profile (which can be varied by judicious use and / or dispensing of appropriate excipients), or the shape and appearance (including novel shapes, colors, and patterns, such as those that may aid in medical compliance for a particular patient).

[1158] Suitably, the embedding article comprises at least one active ingredient, suitably one active ingredient, suitably a plurality of active ingredients, suitably two active ingredients.

[1159] Suitably, the embeddable material comprises at least one active ingredient. Suitably, the curable body material comprises at least one active ingredient. Suitably, the curable body material comprises at least one active ingredient, and the embeddable material comprises at least one active ingredient, wherein the active ingredients in the embeddable body material and the curable body material are the same or different.

[1160] Suitably, the embedded article is a solid dosage form, suitably a pharmaceutical, nutraceutical or food supplement solid dosage form, suitably a tablet. Suitably, the tablet is a chewable tablet. Suitably, the embedded article is a solid oral dosage form, most suitably, an immediate release solid dosage form. Suitably, the embedded article is an extended release dosage form or a delayed release dosage form. Suitably, the embedded article of the present invention is for oral administration.

[1161] Suitably, upon oral administration, the insert has immediate, extended or delayed release characteristics.

[1162] Suitably, the solidifiable body material provides gastric protection to the embeddable material when the embeddable article is administered orally.

[1163] The immediate release solid dosage form suitably releases at least 75% of the one or more active ingredients within a period of 45 minutes, suitably releases at least 85% of the one or more active ingredients within a period of 30 minutes, and may suitably release at least 85% of the one or more active ingredients within a period of 15 minutes. The skilled person may refer to the European Pharmacopoeia 8.0 Strasbourg, France: Council of Europe; European Directorate for Quality in Medicines; 2014, for further details.

[1164] Suitably, embeddable material is completely in curable body material.Suitably, this (one or more) embeddable material is the layer in curable body material or the part of layer, suitably is monolayer (or its part), suitably is multilayer (or its part), suitably is two layers (or its part).Suitably, this layer (or its part) is continuous or discontinuous.Suitably, embeddable material exists with straight line, curve and / or interruption (i.e. discontinuous) in layer.Suitably, each layer can comprise a kind of embeddable material or multiple embedding material.Suitably, each layer can comprise at least a portion.Suitably, if there are two or more layers, these layers are contacting or non-contacting, that is, the part of layer or layer is separated by curable body material.

[1165] Suitably, each layer of the embeddable substance has a thickness of between 10 and 1000 μm, suitably between 20 and 800 μm, between 30 and 600 μm, between 40 and 500 μm, between 50 and 400 μm, or between 60 and 300 μm. Suitably, if there is more than one layer, each layer of the embeddable substance embedded in the article may have the same thickness, or each layer may have a different thickness.

[1166] Suitably, the shape of the embedded article is a cuboid, a cube or a cylinder.

[1167] Suitably, the volume of the embedded article is suitably greater than or equal to 3 mm 3 , 5mm 3 , 10mm 3, 50mm 3 , 100mm 3 or 200mm 3 The volume of the embedded solid is suitably less than or equal to 500 mm 3 、300mm 3 , 250mm 3 、150mm 3 or 50mm 3 Suitably, the volume of the embedded article is between 5 and 500 mm 3 between.

[1168] The longest dimension of the embedded product (D max The longest dimension of the embedded article is suitably less than or equal to 3 mm, 25 mm, 20 mm or 15 mm. The longest dimension of the embedded article is suitably between 3 and 30 mm.

[1169] The shortest dimension of the embedded product (D min The shortest dimension of the embedded article is suitably less than or equal to 30 mm, 25 mm, 20 mm, 15 mm, 10 mm, 8 mm, 5 mm or 2 mm. The shortest dimension of the embedded article is suitably between 0.1 and 30 mm.

[1170] Suitably, the weight of the embedded article is greater than or equal to 1 mg, suitably greater than or equal to 5 mg, 10 mg, 50 mg or 80 mg. Suitably, the weight of the embedded article is less than or equal to 1000 mg, suitably less than or equal to 500 mg, 250 mg or 100 mg. Suitably, the weight of the embedded article is 1-1000 mg.

[1171] Many preferred features of the embedded article are described elsewhere herein. For example, features described with respect to the method of producing the embedded article may suitably reflect features of the embedded article itself (e.g., the number of layers of the embeddable substance). Suitably, the embedded article includes components provided by (one or more) curable substances and (one or more) embeddable substances used in its formation, and may be considered to include the associated curable body substance and the embeddable substance.

[1172] Suitably, the embeddable substance does not migrate into the curable body substance. Suitably, it does not migrate at least during the process of embedding the article into the article, and suitably, it does not migrate at least until the embedded article is used by an end user (eg, a patient applies the embedded article).

[1173] Suitably, the insert comprises at least one active ingredient, suitably two active ingredients.

[1174] Suitably, the embedded article comprises 0.01 to 50%, 0.1 to 50%, 0.1-40%, 1-30%, 5-25%, 5-20%, 5-15%, 8-12%, or about 10% active ingredient by weight. Suitably, the embedded article comprises less than or equal to 80%, 60%, or 50% active ingredient by weight. Suitably, the embedded article comprises greater than or equal to 1%, 2%, or 5% active ingredient by weight.

[1175] Suitably, the insertable substance is arranged in the insert article so as to allow for sequential release of the insertable substance when the insert article is administered to a patient, suitably orally.

[1176] Suitably, the insertable substance is arranged in the insert article so as to allow for titration of the dose of the insertable substance when the insert article is administered to a patient, suitably orally. Suitably, the insertable substance is arranged in the insert article so as to allow for titration of the dose of the insertable substance when the insert article is administered to a patient, suitably orally.

[1177] Curable material

[1178] A curable substance is provided. Suitably, the curable substance is a substance that cures when exposed to elevated temperature, subambient temperature, ultraviolet light and / or a cross-linking agent.

[1179] Suitably, the curable mass is in fluid or semi-fluid form at ambient and / or elevated temperature, suitably at a temperature greater than or equal to 25° C., 30° C., 40° C., 50° C., 60° C. or 70° C. Suitably, the curable mass is in fluid or semi-fluid form at a temperature of 25 to 70° C.

[1180] Suitably, the curable mass cures when exposed to elevated temperatures, suitably when exposed to temperatures above ambient temperature, suitably when exposed to temperatures greater than or equal to 25°C, suitably when exposed to 30°C, 35°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Suitably, the curable mass cures when exposed to temperatures less than or equal to 200°C, 150°C, 120°C or 100°C. Suitably, the curable mass cures when exposed to temperatures between 25 and 200°C.

[1181] Suitably, the curable substance cures when exposed to a temperature below ambient temperature, suitably a temperature greater than or equal to -20°C, -10°C, 0°C, 10°C or 20°C. Suitably, the curable substance cures when exposed to a temperature less than or equal to 40°C, 30°C, 20°C or 10°C. Suitably, the curable substance cures when exposed to a temperature of -20 to 40°C.

[1182] Suitably, the curable substance cures when exposed to ultraviolet light.

[1183] Suitably, there is a cross-linking agent for curing of the curable body material. Suitable cross-linking agents are selected from ethylene glycol diacrylate, di(ethylene glycol) diacrylate, tetra(ethylene glycol) diacrylate, ethylene glycol dimethacrylate, di(ethylene glycol) dimethacrylate, tri(ethylene glycol) dimethacrylate, N,N'-methylenebisacrylamide, N,N'-(1,2-dihydroxyethylene)bisacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)acrylamide and divinylbenzene. This list is not exhaustive. The technician will understand that other cross-linking agents are available, and the selection of reagents depends on the compatibility of the selected curable body material and the material with other components present in the embedded article.

[1184] Suitably, the curable body material is a gel. Suitably, the curable body material is a gelatin matrix. Suitably, the gelatin matrix includes gelatin, glycerol and / or water. Suitably, the curable body material includes gelatin, glycerol and water. Suitably, the curable body material includes 10-40% w / v, suitably 20-30% w / v, suitably about 25% w / v of gelatin. Suitably, the curable body material includes 15-45% w / v, suitably 25-35% w / v, suitably about 30% w / v of glycerol. Suitably, the curable body material includes 30-60% w / v, suitably 40-50% w / v, suitably about 45% w / v of water. Suitably, the curable body material includes 10-40% w / v of gelatin, 15-45% w / v of glycerol and 30-60% w / v of water.

[1185] Suitably, the curable body material comprises at least one active ingredient. Suitably, the curable body material comprises one active ingredient. Suitably, the curable body material comprises multiple active ingredients. Suitably, the active ingredient is a drug, a nutraceutical or a food supplement active ingredient. Suitably, the active ingredient is heat-sensitive, for example, suitably, the active ingredient is a biological agent, suitably a pharmaceutical biological agent. Suitably, the biological agent is a protein or peptide. Suitably, the active ingredient is a small molecule, suitably a pharmaceutically active small molecule. Suitably, the active ingredient is stable in the curable body material, for example, from the time when the curable body material is prepared, in the process of preparing the embedded article, at least until the embedded article is used, the active ingredient is stable in the curable body material. Suitably, stable means that within the above time range, for example, 1 hour, 1 day, 1 week, 1 month, 3 months, 6 months or more than 6 months, the change of the active ingredient is less than or equal to 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4% or 5%.

[1186] Suitably, the curable body material comprises 0.01 to 50%, 0.1 to 50%, 0.1-40%, 1-30%, 5-25%, 5-20%, 5-15%, 8-12% or about 10% active ingredient by weight. Suitably, the curable body material comprises less than or equal to 80%, 60% or 50% active ingredient by weight. Suitably, the curable body material comprises greater than or equal to 1%, 2% or 5% active ingredient by weight.

[1187] Suitably the curable mass also comprises one or more other components. Other components may suitably include one or more excipients, excipient carriers and / or diluents, all of which may be contained in the curable mass.

[1188] Fillers / diluents, anti-adherents, binders, disintegrants, lubricants, glidants, flavoring agents, preservatives, sweeteners, coloring agents and coatings are known in the pharmaceutical, nutraceutical and dietary supplement arts, and any of them may be used where appropriate or desired in the pharmaceutical, nutraceutical and dietary supplement formulation.

[1189] Suitably, fillers / diluents, anti-adherents, binders, disintegrants, lubricants, glidants, flavoring agents, preservatives, sweeteners, colorants and coatings are substantially inert and / or have minimal or no interaction with the other component(s) of the embedded article.

[1190] Suitable anti-adhesives may include magnesium stearate. Suitable diluents / fillers may include vegetable cellulose, dibasic calcium phosphate, vegetable oils and fats, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate and / or microcrystalline cellulose. Suitable binders may include sugars; polysaccharides / derivatives thereof, such as starch, cellulose or modified cellulose, such as microcrystalline cellulose and cellulose ethers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose and derivatives thereof; sugar alcohols, such as xylitol, sorbitol or maltitol; synthetic polymers, such as polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG)). Suitable disintegrants may include cross-linked polyvinyl pyrrolidone (crosslinked vinone), crosslinked sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, modified starch sodium and / or starch glycolate. Suitable lubricants may include silicon dioxide; sodium stearyl fumarate; fats, such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable glidants may include fumed silicon dioxide, talc, magnesium carbonate and / or colloidal silicon dioxide. Suitable coatings may include tablet coatings to protect tablet ingredients from moisture in the air and to make bulky or unpalatable tablets easier to swallow (e.g., cellulose ether hydroxypropyl methylcellulose (HPMC) film coatings; synthetic polymers, shellac, corn zein or other polysaccharides, gelatin; enteric coatings, e.g., including fatty acids, waxes, shellac, plastics, plant fibers). Suitable coloring agents may include curcumin, riboflavin, 5'-phosphoric acid riboflavin, tartrazine, quinoline yellow, sunset yellow FCF, carmine, azorubine, amaranth, Ponceau 4R, erythrosine, allure red AC, patent blue V, indigo, brilliant blue FCF, chlorophyll, copper complex of chlorophyll, green S, ordinary caramel, caustic sulfite caramel, ammonia caramel, ammonia sulfite caramel, brilliant black BN, vegetable carbon, brown HT, carotene, fruit red, paprika extract, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, beetroot red, anthocyanin, calcium carbonate, titanium dioxide, iron oxide and iron hydroxide, aluminum, silver, gold and / or litholrubine BK. The general categories of excipients are well known to those skilled in the art.

[1191] Embeddable substances

[1192] Suitably, the embeddable substance is a liquid, a solution, a semi-solid (suitably a gel), an emulsion, a solid or a suspension. Suitably, the semi-solid is a gel.

[1193] Advantageously, this results in that embedded articles can be prepared using embedded 3D printing. In particular, embedded articles can be prepared without exposing the embeddable substance to high temperatures. This is particularly useful when the embeddable substance contains heat-sensitive ingredients, such as heat-sensitive active ingredients, such as bioactive ingredients, such as proteins or peptides.

[1194] Suitably, the embeddable material comprises at least one active ingredient. Suitably, the embeddable material comprises one active ingredient. Suitably, the embeddable material comprises multiple active ingredients. Suitably, the active ingredient is a drug, a nutraceutical or a food supplement active ingredient. Suitably, the active ingredient is heat-sensitive, for example, suitably, the active ingredient is a biological agent, suitably a pharmaceutical biological agent. Suitably, the biological agent is a protein or peptide. Suitably, the active ingredient is a small molecule, suitably a pharmaceutically active small molecule. Suitably, the active ingredient is stable in the embeddable material, for example, from the time of preparing the embeddable material, in the process of preparing the embedded article, at least until the embedded article is used, the active ingredient is stable in the embeddable material. Suitably, stable means that within the above time range, for example, 1 hour, 1 day, 1 week, 1 month, 3 months, 6 months or more than 6 months, the change of the active ingredient is less than or equal to 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4% or 5%.

[1195] Suitably, the embeddable material comprises 0.01 to 50%, 0.1 to 50%, 0.1-40%, 1-30%, 5-25%, 5-20%, 5-15%, 8-12%, or about 10% active ingredient by weight. Suitably, the embeddable material comprises less than or equal to 80%, 60%, or 50% active ingredient by weight. Suitably, the embeddable material comprises greater than or equal to 1%, 2%, or 5% active ingredient by weight.

[1196] Suitably, the embeddable substance comprises a gel-forming agent, a suspension-forming agent, an emulsion-forming agent or a solution-forming agent.

[1197] The suspension former is a liquid in which the active ingredient has poor solubility, for example the solubility of the active ingredient is less than 0.5 mg / mL, suitably less than 0.1 mg / mL, 0.05 mg / mL or 0.01 mg / mL.

[1198] The solution former is a liquid in which the active ingredient is soluble, for example, the solubility of the active ingredient in the solution former is greater than or equal to 0.5 mg / mL, suitably greater than or equal to 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 50 mg / mL or 100 mg / mL. Suitably, the solubility of the active ingredient in the solution former is 0.5 to 10 mg / mL.

[1199] The emulsion former comprises two liquids, wherein the two liquids are immiscible with each other. Suitably, one liquid is a hydrophobic liquid and the other liquid is a hydrophilic liquid. Suitably, the hydrophobic liquid is an oil of plant origin, such as soybean oil. Suitably, the hydrophilic liquid is an aqueous system, such as water.

[1200] The gel forming agent used herein can be any gelling agent commonly used in the field of medicine, nutraceutical or food supplements commonly used for oral delivery. As used herein, the term "gelling agent" means a compound used to turn a liquid solvent into a jelly-like solvent. By way of example but not limited thereto, exemplary gelling agents include synthetic polymers, cellulose derivatives (e.g., carboxymethyl cellulose and hydroxypropyl methylcellulose) and natural colloids (e.g., tragacanth, sodium alginate or xanthan gum). Synthetic polymers include carbomers (e.g., carbomers 910, 934, 934P, 940, 941 and 1342), which are high molecular weight water-soluble polymers of acrylic acid cross-linked with allyl ethers of sucrose and / or pentaerythritol. Carbomers have different viscosities depending on their polymer components. The gelling agent of the present invention can be selected from any one of synthetic or semi-synthetic polymer materials, polyacrylate copolymers, cellulose derivatives and polymethyl vinyl ether / maleic anhydride copolymers. The present invention preferably uses natural colloids. Suitably, the gelling agent is sodium alginate or xanthan gum.

[1201] Suitably, the intercalable substance further comprises water. Suitably, the intercalable substance further comprises a base. Suitably, the base is sodium hydroxide.

[1202] Suitably, the embeddable material comprises sodium alginate, water and sodium hydroxide. Suitably, the embeddable material comprises 1-20% w / v sodium alginate, suitably 2-15% w / v, 6-10% w / v or about 8% w / v. Suitably, the embeddable material comprises 0.1-5% w / v, suitably 0.5-5% w / v, 1-3% w / v or about 2% w / v.

[1203] Suitably, the embeddable material further comprises one or more other components. Other components may suitably include one or more excipients, excipient carriers and / or diluents, all of which may be contained in the embeddable material.

[1204] Flavoring agents, preservatives, sweetening agents and coloring agents are known in the pharmaceutical, nutraceutical and dietary supplement arts, and any of them may be used where appropriate or desired in the pharmaceutical, nutraceutical and dietary supplement formulation.

[1205] Suitably, the flavouring agents, preservatives, sweeteners and colouring agents are substantially inert and / or suitably have minimal or no interaction with the other component(s) of the embedded article.

[1206] Suitable coloring agents may include curcumin, riboflavin, 5'-riboflavin phosphate, tartrazine, quinoline yellow, sunset yellow FCF, carmine, azorubine, amaranth, Ponceau 4R, erythrosine, allure red AC, patent blue V, indigo, brilliant blue FCF, chlorophyll, copper complex of chlorophyll, green S, ordinary caramel, caustic sulfite caramel, ammonia caramel, ammonia sulfite caramel, brilliant bla...

Claims

1. A method for preparing a pharmaceutical, nutraceutical or food supplement tablet capable of being administered orally, the method comprising: i. Providing an apparatus comprising a container and an extrusion nozzle; ii. providing a solid extrudable composition in said container, said solid extrudable composition comprising: an extrudable carrier; and at least one pharmaceutical, nutraceutical or food supplement active ingredient; iii. mixing the solid extrudable composition with water in the container and heating the mixture to provide an extrudable fluid, the extrudable fluid comprising: at least 20 wt. % of an extrudable carrier; At least one pharmaceutical, nutraceutical or food supplement active ingredient; and 5-30% by weight of water; iv. before extrusion, heating the container to a certain temperature so that the extrudable fluid is maintained in a fluid state in the container; v. extruding the extrudable fluid through the extrusion nozzle to form the tablet by direct 3D printing, optionally in association with one or more auxiliary elements; vi. removing at least 50% by weight of water from the tablet; wherein removing or partially removing water comprises heating and / or maintaining the tablet under reduced pressure; in: The solid extrudable composition is provided in the form of a powder, granules or various extrudable compressed forms, or a compressed monolith, with the proviso that the solid extrudable composition is not in the form of a filament.

2. The method of claim 1, wherein the extrudable fluid is printed from a syringe, wherein when pressure is applied to the syringe, the extrudable fluid is caused to flow out of the syringe.

3. The method of claim 1, wherein the extrudable fluid is dispensed from a container via a piston or plunger.

4. The method of claim 1, wherein forming the extrudable fluid comprises heating the mixture to a temperature of 60°C to 140°C.

5. The method of claim 1, wherein extruding the extrudable fluid is performed at an extrusion temperature of 60°C to 140°C. The method according to claim 1 , wherein the extrusion is carried out in a layer-by-layer manner.

7. The method of claim 1, wherein the extrudable fluid is provided in a heated syringe.

8. The method of claim 1, wherein the extrudable composition is provided in a plurality of extrudable compressed forms, wherein the plurality of compressed forms are mini-tablets.

9. The method of claim 8, wherein the longest dimension of each microtablet is 0.5 mm to 10 mm.

10. The method according to claim 8 or 9, wherein each microtablet has a weight of 10 to 100 mg.

11. A method according to claim 1, wherein the extrudable composition is provided in a monolithic extrudable compressed form, suitably in the form of a monolith of compressed powder or compressed granules.

12. The method according to claim 1, further comprising the steps of: At least one further excipient and / or at least one further active ingredient is incorporated into the tablet, suitably the tablet is surrounded by the at least one further excipient and / or the at least one active ingredient.

13. The method of claim 1, wherein the auxiliary element is selected from a shell, a coating or a core.

14. A tablet obtainable by the process according to any one of the preceding claims.

15. Use of the tablet according to claim 14 in the preparation of medicines.

Images