Solid formulation production method

Abstract

To provide methods of preparing a solid dosage form, particularly a pharmaceutical formulation, using extrusion and 3D printing; the solid dosage form itself; compositions used to make items; uses of the solid dosage form; and containers used in the preparation thereof.SOLUTION: A method of preparing an extruded item comprises: i. providing an extrudable composition comprising an extrudable carrier; and ii. extruding the extrudable composition into a desired form optionally together with one or more supplementary elements. Preferably, the extrudable composition is extruded via 3D printing.SELECTED DRAWING: None

Description

[Technical field]

[0001] Introduction The present invention relates to methods for producing solid dosage forms (and in some cases more generally solid products), particularly methods using extrusion and / or deposition. The invention also relates to the solid dosage forms (or solid products) themselves, precursor compositions used to produce the solid dosage forms, and apparatus for use in producing the solid dosage forms and methods of operating the same. The invention also relates to solid dosage forms obtained by such methods and apparatus, solid dosage form packaging, associated materials and compositions used to produce the solid dosage forms (and the manufacturing processes therefor), computers for controlling the associated manufacturing processes (and associated software and computer implemented methods therefor), and systems for collecting data associated with the solid dosage form manufacturing process (and associated databases therefor).

[0002] background The production and consumption of pharmaceuticals, nutraceuticals, and food supplements (collectively referred to herein as "healthcare dosage forms") in solid dosage forms (e.g., tablets, implants, etc.) is constantly increasing, especially due to the increasing reliance on such products by national health services and the like in an increasingly health-conscious society. Whenever possible, solid dosage forms tend to be the most preferred compared to other formulations (e.g., injectable liquid formulations). This is because of the ease of administration (i.e., usually oral administration) that improves patient compliance, storage and transportability (low space requirements and ease of packaging), and high stability (longer shelf life - less deterioration). However, despite the significant advantages of solid dosage forms over other dosage forms, solid dosage forms are often more difficult to manufacture (in terms of both the number of ingredients and processing steps) and are generally only cost-effective to manufacture on a large scale, usually requiring large manufacturing facilities with sophisticated equipment. These manufacturing limitations have a detrimental effect on consumer choice and / or customizability of medical dosage forms. For example, it is impractical and cost-effective to mass-produce a wide variety of different dosage forms of a given drug via conventional manufacturing techniques, and therefore consumers (e.g., patients) and healthcare professionals (e.g., physicians, pharmacists) must make the most of the limited variety of dosages available, as dictated by suppliers, not by consumer need.

[0003] Since the advent of three-dimensional (3D) printing in the early 1980s, many researchers have attempted to utilize 3D printing technology to manufacture medical solid dosage forms. For example, MIT and Therics, Inc. have collaborated for over a decade on the development of a tablet printer that can be used to print pharmaceutical solid dosage forms in situ using a 3D printer. This technology forms tablets through a multi-layer 3D printing process that involves precisely printing a dose of a liquid drug solution into a thin layer of fine powder before additional layers (e.g., additional powders, binders, etc.) are applied. Examples of such processes are disclosed in prior publications such as WO95 / 11007 (MASSACHUSETTS INSTITUTE OF TECHNOLOGY) and WO03 / 092633 (THERICS, INC.), which, among other things, describe the production of solid dosage forms with various structures and drug release profiles. However, regulatory approval (e.g., by the FDA or MHRA) for such 3D drug printing systems remains elusive, and so far, they are only suitable for low-dose drug products due to the limited solubility of many drugs in the associated ink solutions. Patient choice is therefore very limited, as are physicians and pharmacists' options in providing specialized treatments. Furthermore, the resolution and morphology of the solid dosage forms remain problematic. A particular problem with prior art 3D printing systems is the use of high temperatures in the printing of the solid dosage form itself and / or in the manufacture of the filaments used in the printing process. The use of high temperatures in the manufacture of the printed solid dosage form can thermally degrade some of the components of the solid dosage form. Thus, printing processes that utilize high temperatures are not suitable for use with heat-sensitive ingredients, e.g., heat-sensitive active ingredients, and / or with high loading levels of heat-sensitive ingredients. This can significantly limit the applications of 3D printed solid formulations, as only thermally stable ingredients can be used and / or only low-dose formulations can be produced. Biologically active ingredients, such as monoclonal antibodies, are particularly susceptible to thermal degradation.

[0004] Applicant's previous work outlined in WO2016 / 038356 (University of Central Lancashire), which focused primarily on the use of drug-containing FDM filaments in 3D printing, aims to solve one or more of the aforementioned problems. However, there remains a need for alternative solutions. For example, WO2016 / 038356 provides various innovative options for lowering the melting / softening temperature of drug-containing filaments, but for some drugs (especially those with low decomposition temperatures), the printing temperature of the filament may still be too high and degradation may occur during printing. Decomposition of such drugs may also occur during the manufacture of the filament itself, especially in the case of filaments manufactured via hot melt extrusion, which involves batch-wise heating of a pre-extruded composition prior to extrusion. Furthermore, the technology described in WO2016 / 038356 deploys a significant proportion of thermoplastics in the formation of the dosage form, which is undesirable and can limit the maximum drug loading. It would be desirable to extend 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 including polypeptides, proteins and other biopharmaceuticals would be desirable despite their inherent stability challenges. It would be further desirable to be able to provide such solid dosage forms with immediate release, enteric, and / or sustained release properties. It is therefore an object of the present invention to provide an improved and / or alternative method for producing solid dosage forms, which preferably overcomes at least one problem inherent in the prior art. SUMMARY OF THE PRESENT APPLICATION Summary of the Invention

[0005] According to a first aspect of the present invention there is provided a method of producing an extruded article, the method comprising: i. providing an extrudable composition comprising an extrudable carrier; and ii. extruding the extrudable composition, optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form; where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0006] In one aspect, there is provided a method of producing a pharmaceutical, nutraceutical, or food supplement solid dosage form, the method comprising: i) providing an extrudable composition comprising an extrudable carrier; and ii) extruding the extrudable composition, optionally with one or more auxiliary components (eg, shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0007] According to a further aspect of the present invention there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition (wherein extrudable composition is as defined herein) into a desired form.

[0008] According to a further aspect of the present invention there is provided a method of producing an extruded article, the method comprising: i. providing an extrudable composition as defined herein; ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. an extrudable element; and iii. extruding the extrudable composition of step i (or step ii, if applicable) into a desired form.

[0009] According to a further aspect of the present invention there is provided a method of producing an extruded article, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element; iii. extruding the extrudable composition obtained in step i (and, if applicable, step ii) into a desired form.

[0010] According to a further aspect of the present invention there is provided an extruded article obtained, obtained or directly obtained by a method for producing an extruded article as defined herein.

[0011] According to a further aspect of the present invention there is provided an extruded article comprising: i. an extrudable carrier; and ii. Optionally, a temporary plasticizer.

[0012] According to a further aspect of the present invention there is provided an extruded article, suitably as defined herein, for use in therapy (or for use in the manufacture of a medicament).

[0013] According to a further aspect of the present invention there is preferably provided a use of an extruded article as defined herein.

[0014] In another aspect, a method of making an extrudable composition is provided, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element.

[0015] According to a further aspect of the present invention there is provided an extrudable composition obtained, obtained or directly obtained by a process for producing an extrudable composition as defined herein.

[0016] According to a further aspect of the present invention there is provided an extrudable composition comprising: i. an extrudable carrier; and optionally ii. Transient Plasticizers

[0017] As discussed above, the extrudable composition may 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). Any form of the extrudable composition may be converted into another form, but the resulting product may still be considered an extrudable composition.

[0018] According to a further aspect of the invention, there is provided a method of processing an extrudable composition to produce an extrudable fluid, the method comprising melting or softening (preferably via heating) the extrudable composition.

[0019] According to a further aspect of the invention there is provided a method of processing an extrudable composition to produce an extrudable compressed form, the method comprising compressing the extrudable composition.

[0020] According to a further aspect of the invention there is provided a method of processing an extrudable composition to produce an extrudable element, the method comprising extruding the extrudable composition into the extrudable element.

[0021] According to a further aspect of the invention, there is provided a method for converting an extrudable fluid into an extrudable compressed form.

[0022] According to a further aspect of the invention, a method is provided for converting an extrudable fluid into an extrudable element.

[0023] According to a further aspect of the invention, there is provided a method for converting an extrudable compressed form into an extrudable fluid.

[0024] According to a further aspect of the invention, a method is provided for converting an extrudable compressed form into an extrudable element.

[0025] According to a further aspect of the invention, a method is provided for converting an extrudable element into an extrudable compressed form.

[0026] According to a further aspect of the invention, there is provided a method for converting an extrudable element into an extrudable fluid.

[0027] According to a further aspect of the present invention there is provided an extrusion apparatus comprising an extruder, and suitably also an extrudable composition as defined herein.

[0028] According to a further aspect of the present invention there is provided a method of manufacturing an extruded article package, 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.

[0029] According to a further aspect of the present invention there is provided an extruded article package obtained, obtained or directly obtained by a method for producing an extruded article package as defined herein.

[0030] According to a further aspect of the present invention, there is provided an extruded article package 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.

[0031] According to a further 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.

[0032] According to a further aspect of the present invention there is provided an extrudable composition package obtained, obtained or directly obtained by a process for producing an extrudable composition package as defined herein.

[0033] According to a further aspect of the present invention there is provided an extrudable composition package comprising: i. an extrudable composition as defined herein; and ii. a container (eg, a cartridge or syringe), where the container contains an extrudable composition.

[0034] According to a further 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.

[0035] The method of using an extrusion apparatus and suitable variations thereof may be applied to any of the extrusion apparatus defined herein (as appropriate), and further, aspects of operating an extrusion apparatus may be applied to the method of the present invention defined herein.

[0036] In another aspect of the invention, there is provided a method of manufacturing an implantable article, the method comprising: i. providing a solidifiable body material in a fluid or semi-fluid form; ii. embedding an embeddable material within a solidifiable body material; iii. solidifying the solidifiable body material with the implantable material embedded therein;

[0037] In another aspect of the invention there is provided an implant article obtained by, obtained by or directly obtained by a method for producing an implant article as defined herein.

[0038] According to a further aspect of the present invention, there is provided an implantation article comprising an implantable material embedded within a solidifiable body material.

[0039] According to a further aspect of the present invention there is provided an implantable article, preferably as defined herein, for use in therapy (or for use in the manufacture of a medicament).

[0040] According to a further aspect of the present invention there is preferably provided the use of an implantable article as defined herein.

[0041] According to a further aspect of the present invention there is provided an implantation device including an embedder, preferably also including an implantable material and a solidifiable body material.

[0042] According to a further aspect of the present invention, there is provided a method of manufacturing an embedded article package, the method comprising packaging one or more embedded articles as defined herein, where the one or more embedded articles are, optionally, the same or different.

[0043] According to a further aspect of the present invention there is provided an embedded article package obtained, obtained or directly obtained by a method for producing an embedded article package as defined herein.

[0044] According to a further aspect of the present invention, there is provided an implantable article package comprising one or more implantable articles as defined herein, wherein the one or more implantable articles are optionally the same or different within the package.

[0045] According to a further aspect of the present invention there is provided a solidifiable body material kit comprising a cartridge filled with a solidifiable body material as defined herein.

[0046] According to a further aspect of the invention there is provided an implantable material kit comprising a cartridge filled with an implantable material as defined herein.

[0047] According to a further aspect of the present invention there is provided an implantable and solidifiable body material kit comprising a cartridge loaded with an implantable material and a solidifiable body material as defined herein, the kit comprising a cartridge loaded with an implantable material and a solidifiable body material.

[0048] According to a further aspect of the present invention there is provided an implantable solidifiable body material kit comprising a cartridge filled with an implantable material as defined herein and a cartridge filled with a solidifiable body material as defined herein.

[0049] The methods of using the implantation device and suitable variations thereof may be applied to any of the implantation devices defined herein (as appropriate), and further, aspects of operating the implantation device may be applied to the methods of the invention defined herein.

[0050] Any feature, including any suitable or preferred feature, described in connection with any particular aspect of the invention may be a feature, including any suitable or preferred feature, of any other aspect of the invention. [Brief description of the drawings]

[0051] For a better understanding of the present invention, and to show how the same may be carried into effect, reference will now be made, by way of example, to the following illustrative drawings in which: [Figure 1]DSC thermograms of extruded filament, 3D printable filament (1 hour dry), and 3D printable filament (4 hour dry) [Diagram 2] Moisture content of the powder mixture (control), the extruded filament, the extruded filament dried at 100 °C for 1 h, and the 3D printed tablet. [Diagram 3] Photographs of theophylline-loaded PVA tablets printed a) without water at 210°C, b) with water at 150°C, and hydrocortisone-loaded PVA tablets printed c) without water at 210°C and d) with water at 150°C. [Figure 4] Photograph of a 3D printed tablet and polypill (Unimatrix) loaded with lisinopril dihydrate, indapamide, rosuvastatin calcium, and amlodipine. [Diagram 5] In vitro drug release analysis in gastric fluid of individual tablets containing lisinopril, indapamide, rosuvastatin and amlodipine. [Figure 6] Photo of filament produced by TASFEX 3D printing [Figure 7] Photo of a tablet made using TASFEX 3D printing [Figure 8] In vitro drug release analysis from caplets produced by TASFEX printing [Figure 9] Photographs and SEM images of theophylline-loaded PVA cylindrical tablets produced by TASFEX 3D printing [Figure 10] In vitro release analysis of theophylline-loaded PVA cylindrical tablets prepared by TASFEX printing [Figure 11] In vitro release analysis of 10% hydrocortisone loaded tablets in pH 1.2 medium. [Figure 12] 1 is a schematic diagram of one embodiment of an implantation device of the present invention. [Figure 13] In vitro release analysis of chewable tablets containing ibuprofen in intestinal medium. [Figure 14]Schematic illustrating potential applications of implantable 3D printing: use for dose titration (1), dose personalization (2), combination of two active ingredients (3), and sequential drug release in multiple drug modified release systems. [Figure 15] Photo showing a dual FDM 3D printer modified to accommodate a liquid dispenser (right) in combination with an FDM 3D printer head (left). [Figure 16] This is a photograph of a mold for gelatin casting. [Figure 17] Graph showing paracetamol dosage of implanted articles versus percentage of printed design. [Figure 18] A photo showing the printing ratio of the pattern. [Figure 19] Photograph showing an embedding article with a 300% pattern printed (embedded) within the solidifiable body material. [Figure 20] Photographs showing embedded articles produced using printing speeds of 50.00 mm / min, 60.00 mm / min, 65.00 mm / min, and 70 mm / min. [Figure 21] FIG. 1 is a perspective view of a printing press used for direct ink printing. [Figure 22] Time course drug (theophylline) release profile using various different fillers (lactose, mannitol, and sorbitol). [Figure 23] Release profile of drug (theophylline) over time using various different concentrations of filler / plasticizer (sorbitol). [Figure 24] Drug (theophylline) release profile over time using various different grades of PVA polymer. [Diagram 25] Time course drug (theophylline) release profile using different types of PVA polymers (PVP K29-32). Detailed Description of the Invention Definitions

[0052] Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.

[0053] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations thereof mean "including, but not limited to," and are not intended to (and do not) exclude other moieties, additives, ingredients, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, when the indefinite article is used, the specification is understood to contemplate the plural as well as the singular, unless the context otherwise requires.

[0054] It should be understood that features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed herein (including the accompanying claims, summary and drawings), and / or all steps of the methods or processes so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention also applies to any novel one or any novel combination of features disclosed herein (including the accompanying claims, summary and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0055] The reader's attention is directed to all papers and documents related to this application that have been filed contemporaneously or prior to and are published herewith, and the contents of all such papers and documents are incorporated herein by reference.

[0056] For the avoidance of doubt, it is hereby expressly stated that the information disclosed herein above under the heading "Background" is relevant to the present invention and is to be read as part of the disclosure of the present invention.

[0057] Unless otherwise indicated, reference herein to the term "melt" (or derivatives thereof), particularly in the context of melting an extrudable composition (e.g., filaments, minitablets, blends), preferably includes the glass transition or softening of a given material to allow its extrusion (e.g., through a nozzle). However, the term "melt" in the context of a defined "melting point" of a substance is, as defined in the art, a phase transition - from solid to liquid.

[0058] Here, the "glass transition temperature" or "T gReferences to "preferably refers to the temperature at which the material softens (e.g., to allow its extrusion). Suitably, the glass transition temperature (Tg) of the materials described herein may be determined by standard test methods, suitably using dynamic mechanical analysis - suitable tests include the test protocols defined by ASTM E1640. Differential scanning calorimetry (DSC) may also be utilized. For example, glass transition temperatures may be identified using protocols set forth in ASTM E1356 and ASTM D7426. Those skilled in the art will appreciate that references herein to the glass transition temperature of a particular material being within a particular temperature range are intended to mean that at least one glass transition temperature of that material (which may or may not have multiple glass transition temperatures) is within that temperature range. Suitably, non-limiting references to "glass transition temperature" may mean at least one glass transition temperature, suitably the lowest glass transition temperature, suitably the most heat energy absorbing (or most endothermic) glass transition temperature. As will be apparent to those skilled in the art, what is important is that sufficient softening of the material occurs under a specific set of circumstances (e.g., at the print nozzle, the filament needs to be softened in order to be extruded during the printing process, and then may be re-solidified or re-hardened).

[0059] Unless otherwise specified, the term "viscosity" as used herein shall mean viscosity as defined by Ph.Eur. 2.2.10 or USP <912> The viscosity refers to the viscosity measured using a Brookfield viscometer (UL adapter / 30 rpm / 20°C) according to the test protocol defined in method II.

[0060] Unless otherwise stated, references herein to an "average" are intended to relate to the mean value.

[0061] When a composition / article is said to comprise a specified number of specified components (optionally in a specified amount or concentration), the composition / article may optionally comprise additional components other than the specified components, however, in certain embodiments, a composition / article said to comprise a number of specified components may actually consist essentially of or consist of all of the specified components.

[0062] As used herein, when a composition is described as "consisting essentially of" a particular component, the composition preferably comprises at least 70 wt%, preferably at least 90 wt%, preferably at least 95 wt%, and most preferably at least 99 wt% of the component. Preferably, a composition described as "consisting essentially of" a particular component comprises the component except for one or more trace impurities.

[0063] When the amount or concentration of a particular component of a given composition is specified as weight % (weight %, wt% or %w / w), said weight % refers to the weight % of said component relative to the total weight of the entire composition. Those skilled in the art will understand that the weight percentages of all components of a composition sum to 100wt%. However, if not all components are listed (e.g., if a composition is described as "comprising" one or more particular components), the weight percentage balance can be optionally made up to 100wt% by unspecified components (e.g., diluents such as water, or other non-essential but suitable additives).

[0064] Herein, unless otherwise indicated, the term "portions" (e.g., parts by weight, pbw) when used in connection with a plurality of components / components, refers to the relative proportions between said plurality of components / components. Expressing molar or weight ratios of two, three or more components has the same effect (e.g., the molar ratios of x, y and z are x, y and z, respectively). 1 :y 1 :z 1 or in the range x 1-x2 :y1-y 2 :z 1- z 2でIn many embodiments, the amounts of individual components in a composition may be given as "wt%" values, but in alternative embodiments, any or all such wt% values ​​may be converted to parts by weight (or relative ratios) to define a multi-component composition. This is because the relative ratios between components are often more important than their absolute concentrations in the compositions of the invention (i.e., solid dosage forms such as extrudates / embedded bodies, and / or mixtures used to manufacture said solid dosage forms such as extrudable compositions / embedded bodies / solidifiable bodies). When a composition comprising multiple components is described only in parts by weight (i.e., when only the relative proportions of the components are given), it is not necessary to specify the absolute amounts or concentrations of said components (either in total or individually), since the benefits of the invention can be derived from the relative proportions of each component rather than its absolute amounts or concentrations. However, in certain embodiments, such compositions consist essentially of or consist of the specified components and a diluent (e.g., water).

[0065] The term "mole %" (i.e., mol%) is well understood by those skilled in the art, and 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) converted to a percentage (i.e., multiplied by 100). The concept of mole% is directly related to mole fraction.

[0066] 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 that is substantially free of said component. When a composition is "substantially free" of a given component, said composition preferably contains 0.001 wt% or less of said component, preferably 0.0001 wt% or less of said component, preferably 0.00001 wt% or less, preferably 0.000001 wt% or less, preferably 0.0000001 wt% or less, and most preferably 0.0001 parts per billion (by weight) or less of said component.

[0067] When used in reference to a given component of a composition (e.g., "a liquid pharmaceutical composition that is completely free of compound X"), the term "completely free" refers to a composition that is completely free of any of said components.

[0068] Preferably, unless otherwise stated, when referring to a parameter (e.g., pH, pKa, etc.) or state of a material (e.g., liquid, gas, etc.) that may be pressure and / or temperature dependent, preferably, in the absence of further clarification, such reference refers to said parameter at standard ambient temperature and pressure (SATP), which is a temperature of 298.15 K (25° C., 77° F.) and an absolute pressure of 100 kPa (14.504 psi, 0.987 atm).

[0069] Preferably, unless otherwise stated, when referring to the boiling point, melting point, or glass transition (softening) temperature of a component, such reference refers to said parameters measured at standard ambient pressure, which is a pressure of 100 kPa (14.504 psi, 0.978 atm) absolute. General aspects and advantages of the present invention

[0070] The present invention uses a temporary plasticizer in an extrudable composition, which is used to produce an extruded article and / or another form of the extrudable composition. The temporary plasticizer (temporarily) reduces the temperature required to extrude the extrudable composition compared to the absence of the temporary plasticizer. Advantageously, the use of a temporary plasticizer is particularly suitable for components of the extrudable composition that are heat sensitive, such as active ingredients of pharmaceuticals, nutraceuticals, and / or food supplements that are prone to degradation upon heating. It is therefore possible to have a higher loading of heat sensitive ingredients in the extrudable composition and the corresponding extrudate.

[0071] The use of a temporary plasticizer allows the extrudable composition to be extruded at a lower temperature compared to an equivalent composition that does not include (or includes a lower level of) a temporary plasticizer. Since the temporary plasticizer can be removed (or partially removed) after extrusion, the composition of the extruded article (or an alternative form of the extrudable composition, such as a 3D printable filament) is similar to the extruded equivalent composition, although a lower level of thermal degradation may be observed in the extruded article as a result of the ability to use lower extrusion temperatures.

[0072] Advantageously, the temporary plasticizer reduces the glass transition (or softening) temperature of the extrudable composition. Furthermore, after or during extrusion, the temporary plasticizer is removed or partially removed. This increases the glass transition (or softening) temperature of the resulting product, thereby changing the physical properties of the resulting product. For example, it reduces the flexibility of the extruded article.

[0073] Although the present invention deploys extrusion to produce extrudates, particularly pharmaceutical dosage forms, those skilled in the art will readily appreciate that the principles of the present invention are readily applicable to nutraceuticals and food supplements. Types of extrudates include 3D printing machines, including fused filament fabrication (FFF) 3D printing.

[0074] Standard extrusion components may include an extrusion nozzle (e.g., a nozzle such as those used in 3D printing, such as fused FFF 3D printing, together with any associated conveying and / or heating means, that allows the extrudable composition to be printed onto a surface, typically in a sequential, layered manner).

[0075] The method of the present invention overcomes many of the shortcomings of the extrusion process. For example, polyvinyl alcohol (PVA), a commonly used extrudable carrier, can only be extruded at temperatures above 180°C. The use of a permanent plasticizer such as 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 a mixture of PVA and sorbitol to about 90°C. Advantageously, the temporary plasticizer can be removed or partially removed after or during extrusion of the extruded product (e.g., extruded article and / or extrudable element). This means that the level of the temporary plasticizer can be reduced to a level suitable for the intended use of the extruded article, for example, a level suitable for use in a pharmaceutical, nutraceutical or food supplement product. Alternatively 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 will react with the temporary plasticizer. Finally, the removal or partial removal of the transient plasticizer changes the physical properties of the extruded product (e.g., extruded article and / or extrudable element), e.g., increasing the glass transition (softening) temperature of said article. This changes the physical properties, e.g., the brittleness / flexibility of the extruded article. Thus, the physical and chemical properties of the extruded product can be optimized depending on the intended use of said article (e.g., use as a pharmaceutical product (e.g., extruded article) or use in the manufacture of extruded articles (e.g., extrudable elements)).

[0076] The present invention extends the applicability of extrusion (including 3D printing) to a wider range of physical forms, allowing components (including extrudable carriers and / or active ingredients) to be extruded with minimal thermal degradation of said components.

[0077] The chemical and physical compatibility between the temporary plasticizer and other components of the extrudable composition (e.g., the extrudable carrier, active ingredients, if any, permanent plasticizers, if any, other ingredients, if any) must be considered when developing an extruded article.

[0078] The present invention embeds an implantable substance within a solidifiable body material. Advantageously, the method for producing the implantable article is carried out at ambient temperature or requires heating to a relatively low temperature, for example up to 40° C. As such, the method for producing the implantable article is particularly suitable for use with heat-sensitive components, including heat-sensitive active components such as biologically active components (i.e. proteins, amino acids, peptides, etc.). Advantageously, the implantable substance may be in a liquid-like state (e.g. liquid, solution, semi-solid (preferably a gel or gellable material), emulsion, solid, or suspension) within the solidifiable body material. This allows the implantable article to have a wide range of applicability with multiple active components.

[0079] Preferably, the implantation steps of each portion of implantable material are digitally controlled, i.e., by computer, resulting in less variation in the amount of implantable material dispensed during the process, resulting in a more accurate dosage of the implantable material within the implant article.

[0080] Although the present invention develops an implant for producing implantable articles (preferably using a 3D printer), particularly pharmaceutical dosage forms, those skilled in the art will readily appreciate that the principles of the present invention are readily applicable to nutritional and food supplements.

[0081] The extruded and implantable articles of the present invention can be manufactured "on demand" in an individualized, customized manner to meet the needs of a particular consumer (i.e., patient), thereby avoiding certain undesirable medical compromises (e.g., a patient receiving an incomplete dose due to the limited range of sizes of mass-produced dosage forms offered).

[0082] The present invention is expected to represent a significant technological contribution to the production, formulation and consumption of pharmaceuticals, with positive health impacts for all concerned.

[0083] Although the technology of the present invention is described herein in the context of solid formulations, particularly pharmaceutical formulations, it will be appreciated that the technology is more generally applicable and can be effectively deployed to produce a range of solid articles, extruded or implanted articles, of various forms and sizes. Furthermore, the technology can be utilized beyond 3D printing and / or hot melt extrusion and used on an industrial scale, for example in large-scale manufacturing facilitation, whether in batch production, continuous flow production, or a combination thereof.

[0084] It will be understood that the term solid dosage form includes dosage forms that may be filled with a fluid substance (i.e., a liquid, solution, emulsion, suspension, or a semi-solid such as a gel) within the body of the dosage form, with the body of the dosage form providing the structure of the dosage form. For example, an implantable article containing a liquid implantable substance would be considered a solid dosage form.

[0085] It will be understood that the term solid dosage form also includes semi-solid dosage forms, for example implantable articles comprising gelatin as a solidifiable body material. Methods for Producing Extrudable Compositions

[0086] The present invention suitably provides a method of making an extrudable composition as defined herein.

[0087] The method preferably comprises: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid. b. in an extrudable compressed form; or c. An extrudable element.

[0088] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. Extrudable fluid b. in an extrudable compressed form; or c. An extrudable element. Here, a transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature below 150° C. (preferably at standard ambient pressure, e.g. 100 kPa).

[0089] Preferably, mixing the extrudable carrier and the temporary plasticizer together is done by shear mixing.

[0090] Preferably, the extrudable carrier and temporary plasticizer are mixed at a mixing speed of 10 rpm, 25 rpm, 50 rpm, 75 rpm, 100 rpm, 125 rpm, 150 rpm, 175 rpm, 200 rpm, 250 rpm, 300 rpm, 400 rpm, or 500 rpm or more. Preferably, the extrudable carrier and temporary plasticizer are mixed at a mixing speed of 500 rpm, 400 rpm, 300 rpm, 200 rpm, or 100 rpm or less. Preferably, the extrudable carrier and temporary plasticizer are mixed at a mixing speed of 10 to 500 rpm.

[0091] Preferably, the extrudable carrier and temporary plasticizer are mixed at room temperature. Preferably, the extrudable carrier and temporary plasticizer are mixed at a temperature of 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C or higher. Preferably, the extrudable carrier and temporary plasticizer are mixed at a temperature of 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C, 25°C, 20°C, or 10°C or lower. Preferably, the extrudable carrier and temporary plasticizer are mixed at a temperature of 10-100°C.

[0092] Preferably, the extrudable carrier and the temporary plasticizer are mixed at a temperature below the boiling point of the temporary plasticizer. Preferably, the extrudable carrier and the temporary plasticizer are mixed at a temperature above the melting point of the temporary plasticizer. Preferably, the extrudable carrier and the temporary plasticizer are mixed at a temperature between the boiling point and the melting point of the temporary plasticizer.

[0093] Preferably, the method further comprises spraying a transient plasticizer onto the extrudable carrier during the mixing step.

[0094] Preferably, the method includes further processing the mixture from step i. to form an extrudable fluid. Preferably, the extrudable fluid is an extrudable semi-liquid. Preferably, the extrudable fluid is a molten extrudable composition. Preferably, the extrudable fluid has properties suitable for direct use in extrusion. The composition can be used in a process for producing an extrudate without further processing, i.e., the extrudable fluid can be extruded without the need to manipulate the physical properties of the extrudable composition, for example by (further) heating the extrudable composition.

[0095] Preferably, the extrudable fluid is obtained by heating the mixture from step i. to a temperature above the melting point or glass transition (softening) temperature of the mixture, preferably above 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, or 120°C. Preferably, the extrudable fluid is obtained by heating the mixture from step i. to a temperature below 200°C, 180°C, 160°C, 150°C, 140°C, 130°C, 120°C, 110°C, or 100°C. Preferably, the extrudable fluid is obtained by heating the mixture from step i. to a temperature between 20°C and 200°C.

[0096] Advantageously, a container such as a syringe or cartridge may be filled with the extrudable composition. Suitably, the method further comprises filling a container such as a syringe or cartridge with the extrudable composition. Suitably, the method further comprises filling a container such as a syringe or cartridge with the mixture from step i, and optionally further treating the mixture from step i, for example by heating the container, to form an extrudable fluid in the container. Suitably, the method comprises heating the container (e.g., a syringe) to a temperature at or above the glass transition (softening) temperature of the mixture formed in step i, suitably, the method comprises heating the container (e.g., a syringe) to a temperature at or above 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C. Suit ... between 25°C and 100°C. Preferably, the method further comprises filling the container with the extrudable fluid, for example, preferably, filling a syringe with the extrudable fluid. Preferably, the extrudable fluid is optimized for delivery to the syringe, for example, the viscosity of the extrudable fluid allows the fluid to flow from 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 metallic syringe.

[0097] Preferably, the method includes further processing the mixture from step i to form an extrudable compressed form such as a tablet or multiple tablets, e.g. mini-tablets. Preferably, the extrudable compressed form is formed by compressing the mixture from step i. Preferably, the compression step utilises a punch tool. Preferably, the punch tool has a diameter of 1-10 mm, 2-8 mm, 4-7 mm, 5-7 mm, or about 6 mm. Preferably, the punch tool is circular, oval, square or rectangular.

[0098] Suitably, each extrudable compressed form is formed by compressing 10-100 mg, 20-80 mg, 30-70 mg, 40-60 mg, or about 50 mg of the mixture from step i per extrudable compressed form.

[0099] Suitably, each extrudable compressed form has a weight of between 10 and 100 mg, 20 and 80 mg, 30 and 70 mg, 40 and 60 mg, or about 50 mg.

[0100] Preferably, the method includes further processing the mixture from step i. to form an extrudable element. Preferably, the extrudable element is a filament. Preferably, the method includes extruding the mixture from step i. to form an extrudable element. Preferably, the extrusion temperature is equal to or higher than the glass transition (softening) temperature of the mixture from step i., for example, preferably, equal to or higher than -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. Preferably, the extrusion temperature is equal to or lower than 200°C, equal to or lower than 180°C, equal to or lower than 160°C, equal to or lower than 140°C, equal to or lower than 130°C, equal to or lower than 120°C, equal to or lower than 110°C, equal to or lower than 100°C, or equal to or lower than 90°C. Preferably, the extrusion temperature is from -50°C to 200°C, from 60°C to 100°C, from 65°C to 95°C, or from 70°C to 90°C.

[0101] Preferably, the extrusion step uses a hot melt extruder. Preferably, the hot melt extruder comprises an extrusion nozzle. Preferably, the extrusion nozzle comprises an output opening. It is suitably dimensioned for the properties of the corresponding extrudable composition so that the extrudable composition can be deposited therefrom (e.g., onto a build platform). Preferably, the output opening has a diameter of 50-2000 μm, 100-1500 μm, 200-1500 μm, 500-1500 μm, 750-1250 μm, or about 1000 μm. In one embodiment, the nozzle has an output opening with a diameter of 750-1250 μm.

[0102] Suitably, the extrudable elements (e.g. filaments) have a thickness (i.e. diameter or maximum thickness) of 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 particular embodiment, the filaments have a thickness of about 1 mm. However, the thickness can be tailored to the extrusion nozzles through which they are extruded (particularly the size / diameter of their respective openings).

[0103] Preferably, the mixture from step i. is mixed during the extrusion step at a mixing speed of 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 or more. Preferably, the mixture from step i. is mixed at a mixing speed of 500 rpm, 400 rpm, 300 rpm, 200 rpm, or 100 rpm or less. Preferably, the mixture from step i. is mixed during the extrusion step at a mixing speed of 10 to 500 rpm.

[0104] Preferably, the method further comprises coating the extrudable element with a lubricant and / or a glidant. Suitable lubricants can include silica; fats and oils, such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable lubricants can include fumed silica, talc, magnesium carbonate, and / or colloidal silica. The lubricant facilitates the flow of the extrudable element through the extruder during the production of the extruded article.

[0105] Suitably, the extrusion step to form the extrudable element may optionally further comprise the step of removing or partially removing the transient plasticizer via vaporization. Suitably, the transient plasticizer is removed or partially removed by heating the extrudable element and / or by holding the extrudable element under vacuum. Suitably, the extrudable element is heated and / or held under vacuum until the properties (e.g. flexibility) of the extrudable element are suitable for use in a method for producing an extruded article (e.g. solid dosage form). Suitably, the extrudable element is heated and / or held under vacuum until the glass transition (softening) temperature of the extrudable element is between -50°C and 100°C, -40°C and 80°C, -40°C and 75°C, -40°C and 60°C, -40°C and 50°C, -40°C and 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 held under vacuum until the glass transition (softening) temperature of the extrudable element is below 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. Preferably, the extrudable elements are heated and / or held under vacuum until the glass transition (softening) temperature of the extrudable elements is about -10°C, or about 15°C.

[0106] Suitably, the extrudable element is heated and / or held under vacuum until the temporary plasticizer is less than 20%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% by weight or until the temporary plasticizer is substantially absent. Suitably, the extrudable element is heated and / or held under vacuum until between 0 and 20% by weight of the temporary plasticizer is present.

[0107] Suitably, the extrudable element is heated and / or held under vacuum until the temporary plasticizer content of the extrudable composition is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0108] Suitably, the extrudable element is heated and / or held under vacuum for more than 10, 20, 30, 40, 50, 60, 90, or 120 minutes. Suitably, the extrudable element is heated and / or held under vacuum for less than 120, 100, 80, or 60 minutes. Suitably, the extrudable element is heated and / or held under vacuum for between 10 and 120 minutes.

[0109] Preferably, the extrudable element is heated. Preferably, the extrudable element is heated to a temperature below the melting point of the extrudable element. Preferably, the extrudable element is heated to a temperature of 30°C or more, preferably 40°C or more, 50°C or more, 60°C or more, 70°C or more, 80°C or more, 90°C or more, or 100°C or more. Preferably, the extrudable element is heated to a temperature of 200°C or less, preferably 180°C or less, 160°C or less, 140°C or less, 130°C or less, 120°C or less, 110°C or less, 100°C or less, 90°C or less, or 80°C or less. Preferably, the extrudable element is heated to a temperature between 30 and 200°C.

[0110] Preferably the extrudable element is held under reduced pressure, preferably under vacuum. Preferably the vacuum has a pressure below atmospheric pressure, preferably below 90 kPa, 10 kPa, 5 kPa, 1 kPa, 0.5 kPa, 0.1 kPa, 0.05 kPa, 0.01 kPa, or 0.005 kPa. Preferably the vacuum has a pressure between 0.005 and 90 kPa.

[0111] Preferably, the transient plasticizer is removed or partially removed by exposing the extrudable element to a relative humidity less than ambient relative humidity (RH), preferably less than 60% RH, 50% RH, 40% RH, 30% RH, 20% RH, 10% RH, or about 0% RH. Preferably, the transient plasticizer is removed or partially removed by exposing the extrudable element to a relative humidity between 0 and 60% RH.

[0112] Preferably, there is provided a method of processing an extrudable composition to produce an extrudable fluid, the method comprising melting or softening (preferably by heating) the extrudable composition.

[0113] Suitably, there is provided a method of processing an extrudable composition to produce an extrudable compressed form, the method comprising compressing the extrudable composition.

[0114] Suitably, there is provided a method of processing an extrudable composition to produce an extrudable element, the method comprising extruding the extrudable composition into an extrudable element.

[0115] Preferably, a method is provided for converting an extrudable fluid into an extrudable compressed form.

[0116] Preferably, a method is provided for converting an extrudable fluid into an extrudable element.

[0117] Preferably, a method is provided for converting the extrudable compressed form into an extrudable fluid.

[0118] Preferably, a method is provided for converting the extrudable compressed form into an extrudable element.

[0119] Preferably, a method is provided for converting the extrudable elements into an extrudable compressed form.

[0120] Preferably, a method is provided for converting an extrudable element into an extrudable fluid.

[0121] Preferably, the further processing step comprises converting the extrudable fluid into an extrudable compressed form. Preferably, the further processing step comprises converting the extrudable fluid into an extrudable element. Preferably, the further processing step comprises converting the extrudable compressed form into an extrudable fluid. Preferably, the further processing step comprises converting the extrudable compressed form into an extrudable element. Preferably, the further processing step comprises converting the extrudable element into an extrudable compressed form. Preferably, the further processing step comprises converting the extrudable element into an extrudable fluid.

[0122] Preferably, the further processing step comprises converting the extrudable fluid into an extrudable compressed form and then converting the extrudable compressed form into an extrudable element. Preferably, the further processing step comprises converting the extrudable fluid into an extrudable element and then converting the extrudable element into an extrudable compressed form. Preferably, the further processing step comprises converting the extrudable compressed form into an extrudable fluid and then converting the extrudable fluid into an extrudable element. Preferably, the further processing step comprises converting the extrudable compressed form into an extrudable element and then converting the extrudable element into an extrudable fluid. Preferably, the further processing step comprises converting the extrudable element into an extrudable compressed form and then converting the extrudable compressed form into an extrudable fluid. Preferably, the further processing step comprises converting the extrudable element into an extrudable compressed form and then converting the extrudable compressed form into an extrudable fluid. Preferably, the further processing step comprises converting the extrudable element into an extrudable fluid and then converting the extrudable fluid into an extrudable compressed form.

[0123] Preferably, the converting step comprises heating, compressing, dry pressing, wet pressing, moulding and / or extrusion. Preferably, the extrudable composition is converted into an extrudable fluid form by heating. Preferably, the extrudable composition is converted into an extrudable element form by extrusion. Preferably, the extrudable composition is transformed into an extrudable compact form by compression, dry pressing and / or wet pressing.

[0124] Preferably, the compressed form of the extrudable composition is converted to an extrudable fluid form, preferably via heating.

[0125] Preferably, the extrudable composition in its extrudable compressed form is converted, preferably via extrusion, into the form of an extrudable element, such as a filament for 3D printing.

[0126] Preferably, further processing steps include converting the extrudable compressed form (e.g., a tablet) into an extrudable element (e.g., a filament for 3D printing).

[0127] Suitably, the further processing step involves heating the extrudable compressed form (eg a tablet) to convert the extrudable compressed form into an extrudable fluid.

[0128] Preferably, a further processing step involves converting the extrudable fluid into an extrudable element (e.g., a filament for 3D printing) by extruding.

[0129] Preferably, the further processing step includes converting the extrudable element (e.g., a filament for 3D printing) into an extrudable fluid by heating the extrudable element.

[0130] Suitably, the method includes compressing the extrudable composition to form an extrudable compressed form.

[0131] Suitably, following mixing, the method includes compressing the components of the extrudable composition together to form an extrudable compressed form.

[0132] 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 (e.g., a filament for 3D printing).

[0133] Suitably, following mixing, 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.

[0134] It will be understood that any of the foregoing aspects and embodiments may be accomplished with or without including (or mixing together) a transient plasticizer, and such aspects and embodiments are also contemplated to be within the scope of the invention. For example, the invention provides a method of making an extrudable composition, the method comprising: i. providing an extrudable carrier, optionally mixed with a drug substance or active substance; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element.

[0135] In such aspects, step ii may, for example, comprise softening, melting, or otherwise mobilizing an initial extrudable composition (preferably in an initially solid form), such as an extrudable powder, extrudable granules, extrudable compressed form (whether in monolithic form or in multiple compressed forms such as mini-tablets), to produce an extrudable fluid. Such mobilization of the initial extrudable composition preferably comprises heating said composition in situ in a dispenser (e.g. a syringe, preferably a metal syringe having a heating jacket), which composition may then be extruded into an extrudable element (e.g. a filament) or directly extruded into an extruded article (e.g. a tablet, preferably via direct ink 3D printing).

[0136] Alternatively, in such aspects, step ii may include, for example, compressing the initial extrudable composition (preferably a granular or powder composition) to form a compact extrudable form, which may be fed back into the process, with or without supplementation or admixture of a transient plasticizer, to produce an extrudable fluid, extrudable element, or extrudable article (e.g., by direct ink 3D printing).

[0137] Alternatively, in such aspects, step ii may comprise, for example, extruding the initial extrudable composition (which may be in the form of an extrudable powder, extrudable granules, extrudable compacted form(s)) into an extrudable element.

[0138] Preferably, when practicing the invention without the use of a temporary plasticizer, any extrusion is preferably carried out at a temperature of from 40 to 120°C, preferably from 60 to 100°C.

[0139] All optional features mentioned above and all features described below in relation to aspects or embodiments involving the use of a temporary plasticizer apply equally to aspects or embodiments that do not use a temporary plasticizer, unless otherwise compatible in a given context. Method for Producing Extruded Articles

[0140] The present invention suitably provides a method of producing an extruded article, as defined herein.

[0141] The method preferably includes the following: i. providing an extrudable composition comprising an extrudable carrier; and ii. Extruding the extrudable composition, optionally with one or more auxiliary components (eg, shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0142] The method preferably includes the following: i. providing an extrudable composition comprising an extrudable carrier; and ii. Extruding the extrudable composition, optionally with one or more auxiliary components (eg, shell, coating, core), into a desired form. where the extrudable composition initially comprises 5% by weight or more of a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0143] Preferably, the method preferably includes the following: i. providing an extrudable composition comprising an extrudable carrier; and ii. 3D printing the extrudable composition, optionally with one or more auxiliary elements (e.g., shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0144] Preferably, the desired form is a solid dosage form, preferably a solid oral dosage form. Preferably, the extruded article is a pharmaceutical, nutraceutical, or dietary supplement solid dosage form. Preferably, the extruded article comprises at least one active ingredient, preferably at least one pharmaceutical, nutraceutical, or dietary supplement active ingredient. Most preferably, the active ingredient is a pharmaceutical active ingredient.

[0145] A method for producing a solid dosage form of a pharmaceutical, nutraceutical, or food supplement is provided, the method comprising: i) providing an extrudable composition comprising an extrudable carrier; and ii) extruding the extrudable composition, optionally with one or more auxiliary components (eg, shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0146] Suitably, there is provided a method for producing a pharmaceutical, nutraceutical, or food supplement solid dosage form, the method comprising: i) providing an extrudable composition comprising an extrudable carrier; and ii) extruding the extrudable composition, optionally with one or more auxiliary components (eg, shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0147] Suitably, there is provided a method for producing a pharmaceutical, nutraceutical, or food supplement solid dosage form, the method comprising: i) providing an extrudable composition comprising an extrudable carrier; and ii) extruding the extrudable composition, optionally with one or more auxiliary elements (e.g., shell, coating, core), into a desired form via 3D printing. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0148] Suitably, the extrudable composition is as defined herein. Suitably, the extrudable composition initially comprises 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% or more by weight of the transient plasticizer. Suitably, the extrudable composition initially comprises 0.1-25% by weight of the transient plasticizer.

[0149] Preferably, the method includes producing the extruded article by operating an extrusion apparatus, preferably on a build platform, to extrude the extruded article thereon. Preferably, such production is performed via a computer-implemented process (i.e., extrusion is controlled by a computer connected to or connectable within the apparatus, and preferably initiated in a wired or wireless manner).

[0150] Suitably, the extrusion apparatus comprises a container for containing the extrudable composition prior to the extrusion step, and a nozzle for discharging the extrudable composition during the extrusion step, where the container is heated at a temperature to maintain the extrudable composition in a (substantially) fluid state.

[0151] The method preferably includes extruding an extrudable composition onto a build platform. Such extrusion preferably includes 3D printing, preferably FFF 3D printing. Thus, extruding can include extruding with one or more extrudable compositions. The extrudable composition (or a precursor thereof) is preferably extruded through an extrusion nozzle of an extrusion apparatus of the present invention.

[0152] Extrusion of the extrudable composition onto the build platform is preferably performed by an extruder (e.g., a 3D printer) using one or more extrudable compositions, such as those extruded through an extrusion nozzle, as described herein.

[0153] Initially, the extrudable composition (or a precursor thereof) is preferably present in the device at a storage location, preferably in a cartridge such as a filament spool. The extrudable composition is preferably transported to the extrusion nozzle via one or more conveyors (e.g. rollers). The extrudable composition is then extruded through the extrusion nozzle (preferably while the extrudable composition continues to be transported from the storage location towards the extrusion nozzle). Extrusion through the extrusion nozzle preferably includes melting and / or softening the extrudable composition to allow it to be deposited, preferably in a layer-by-layer manner, on the build platform. Preferably, the associated extrudable composition solidifies after being deposited on the build platform or after being deposited on an already extruded layer on the build platform. Preferably, the 3D form is built up in a layer-by-layer manner by judicious deposition according to a predefined design. Preferably, the temporary plasticizer is removed or partially removed after or during extrusion. Preferably, the temporary plasticizer is removed or partially removed by exposing the extruded extrudable composition to a temperature above ambient temperature and / or to a vacuum.

[0154] The extrusion nozzle is suitably heated to an operating temperature as described herein to facilitate melting and / or softening of the extrudable composition. The extrusion nozzle suitably extrudes the extrudable composition at one or more of the operating speeds described herein.

[0155] The extrusion nozzle is suitably moved in any or all of the X, Y and Z directions during extrusion.

[0156] Once extruded, the extruded article, preferably on the build platform, preferably resembles a solid dosage form.

[0157] Preferably, multiple extruded articles are printed on the build platform.

[0158] As will be appreciated by those skilled in the art, each or any extrusion nozzle may be adapted with characteristics designed to extrude a corresponding extrudable composition. The nozzle characteristics / design and the characteristics of the extrudable compositions are preferably complementary to one another to facilitate controlled extrusion of said compositions (whether continuous or intermittent, e.g., when two or more extrudable compositions are used to extrude an extruded article), preferably without nozzle blockage or impedance, and preferably without unacceptable degradation of the components within the extrudable compositions during the extrusion process.

[0159] In an embodiment, the composition of the extruded article includes less transient plasticizer than the extrudable composition used to make the extruded article. Extrusion Step

[0160] Preferably, the extrusion step is carried out at a temperature above the glass transition temperature of the extrudable composition. Preferably, the extrusion step is carried out at a temperature of -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 or higher. Preferably, the extrusion step is carried out at a temperature of 200°C or lower, 180°C or lower, 160°C or lower, 150°C or lower, 140°C or lower, 130°C or lower, 120°C or lower, 110°C or lower, 100°C or lower, or 90°C or lower. Preferably, the extrusion step is carried out at a temperature between -50°C and 200°C.

[0161] Preferably, the extrusion step uses an extruder. Preferably, the extruder is a 3D printer. Preferably, the 3D printer is a FFF 3D printer. Preferably, the extrusion step uses direct ink printing. Preferably, the extrusion step uses a syringe, preferably a heated syringe. Preferably, the syringe or heated syringe comprises an extrudable composition, preferably the extrudable composition is a blend or an extrudable fluid.

[0162] Suitably, the extruding step includes extruding the extrudable composition to form an initial layer of extrudate and, optionally, extruding the extrudable composition to form subsequent layers. Suitably, each layer has a thickness of 10-1000 μm, 20-800 μm, 30-500 μm, 40-300 μm, 50-200 μm, 100-200 μm, 125-200 μm, 140-190 μm, 155-175 μm, 250-350 μm, 750-850 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 a different thickness. Advantageously, having a thicker first layer (i.e., the layer contacting the build platform) can result in greater adhesion of the extruded article during manufacture of the extruded article.

[0163] Preferably, the extrusion step uses 100% infill. Preferably, the extrusion step uses a concentric fill pattern.

[0164] The method includes removing or partially removing the temporary plasticizer via vaporization. Preferably, the temporary plasticizer is removed or partially removed from the extruded article prior to the step of extrusion (i.e., from the extrudable composition, such as the extrudable element), during and / or after the step of extrusion. Preferably, the temporary plasticizer is removed or partially removed from the extruded article during and / or after the step of extrusion. Preferably, the temporary plasticizer is removed or partially removed from the extruded article after the step of extrusion. Preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the temporary plasticizer is removed. Preferably, between 10% and 90% of the temporary plasticizer is removed. Suitably, the temporary plasticizer is removed or partially removed until no more than 20%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% by weight of temporary plasticizer is present in the extruded article. Suitably, the extruded article is substantially free of temporary plasticizer. Suitably, the extruded article is completely free of temporary plasticizer. Suitably, the temporary plasticizer is removed or partially removed until 0-20% by weight of temporary plasticizer is present in the extruded article.

[0165] Preferably, the step of removing or partially removing the transient plasticizer comprises heating and / or holding the extrudable composition (preferably the extrudable element) and / or the extruded article (during or after the formation of the extruded article) under reduced pressure, such as a vacuum. Preferably, the extrudable composition and / or the extruded article is heated to a temperature of 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C or more. Preferably, the extrudable composition and / or the extruded article is heated to a temperature of 200°C, 180°C, 160°C, 140°C, 130°C, 120°C, 110°C, 100°C, 90°C, or 80°C or less. Preferably, the extrudable composition and / or the extruded article is heated to a temperature of 30°C or more and 200°C or less. Preferably, the extrudable composition and / or the extruded article is held under reduced pressure, such as under a vacuum. Preferably the vacuum has a pressure below atmospheric pressure, preferably below 90 kPa, 10 kPa, 5 kPa, 1 kPa, 0.5 kPa, 0.1 kPa, 0.05 kPa, 0.01 kPa, or 0.005 kPa. Preferably the vacuum has a pressure between 0.005 and 90 kPa.

[0166] Suitably, the extrudable composition is as defined herein.

[0167] Preferably, step i. further comprises extruding the extrudable composition onto a build platform. Preferably, the build platform is held at a temperature lower than the extrusion temperature. Preferably, the build platform is held at a temperature of 100° C. or lower, preferably 90° C. or lower, 80° C. or lower, 70° C. or lower, 60° C. or lower, 50° C. or lower, 40° C. or lower, or 30° C. or lower. Preferably, the build platform is held at a temperature between 0 and 100° C., such as between 30 and 100° C. Advantageously, having a build platform temperature lower than the extrusion temperature helps to solidify the extruded article during molding. Additionally, a build platform temperature higher than ambient temperature facilitates removal or partial removal of the transient plasticizer.

[0168] Preferably, the extruded article is heated by the build platform until the extruded article contains no more than 20%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% by weight of temporary plasticizer, or is substantially free of temporary plasticizer, or is completely free of temporary plasticizer. Preferably, the extruded article is heated by the build platform until the extruded article contains between 0 and 20% by weight of temporary plasticizer.

[0169] Preferably, the extruded article is heated by the build 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 extrudable composition. Preferably, the extruded article is heated by the build platform until the extruded article is substantially free or completely free of temporary plasticizer. Preferably, the extruded article is heated by the build platform until the temporary plasticizer content is reduced by 10-100%, for example 10-90%, relative to the temporary plasticizer content of the extrudable composition.

[0170] Preferably, the extruder comprises an extrusion nozzle. Preferably, the extrusion nozzle comprises an input opening (to which the extrudable composition is fed) and an output opening (from which the molten extrudable composition is deposited). The input opening is preferably dimensioned to pass and receive the extrudable composition (e.g., an extrudable element, a blend of extrudable composition components, an extrudable fluid, or an extrudable compressed form). Preferably, the input opening has a diameter of 0.1-100 mm, 0.2-10 mm, 0.5-5 mm, 0.5-1.5 mm, 1.0-2.5 mm, 1.5-2.0 mm, 0.75-1.25 mm, about 1.75 mm, or about 1 mm. The output opening is preferably dimensioned to match the characteristics of the corresponding extruded article so that the molten extrudable composition can 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 with a diameter of 0.3 to 0.5 mm.

[0171] The feeding of the extrudable compositions to and through each of the extrusion nozzles is preferably facilitated by a conveyor (or rollers), as described elsewhere herein, such a conveyor being preferably disposed along the path of the extrudable compositions, preferably between a source of the extrudable composition (e.g., a filament spool or cartridge) and the extrusion nozzle through which a given extrusion composition is assigned to flow.

[0172] Suitably, prior to the extrusion step, the extrudable composition is in that form or is transformed into that form. a. An extrudable fluid. b. in an extrudable compressed form; or c. An extrudable element.

[0173] Preferably, the method comprises extruding an extrudable compressed foam to form the extruded article. Preferably, the method comprises extruding an extrudable fluid to form the extruded article. Preferably, the method comprises extruding an extrudable element to form the extruded article.

[0174] Extrudable fluid, extrudable compressed form, and extrudable element are as defined herein.

[0175] Preferably, prior to the extrusion step, the extrudable composition is in or is converted, preferably via heating, into an extrudable fluid form, and the extrudable composition is then directly extruded in a fluid state.

[0176] Preferably, prior to the extrusion step, the extrudable composition is in or is transformed into an extrudable compacted form, preferably in the form of a plurality of tablets.

[0177] Preferably, prior to the extrusion step, the extrudable compressed form of the extrudable composition is converted, preferably via heating, into an extrudable fluid form, and the extrudable composition is then directly extruded in a fluid state.

[0178] Preferably, prior to the extrusion step, the extrudable compressed form of the extrudable composition is converted, preferably via extrusion, into the form of an extrudable element, such as a 3D printing filament, which is then preferably directly extruded as a filament through a 3D printing nozzle. Extrusion from the dispenser

[0179] Suitably, the method comprises providing a dispenser filled with the extrudable composition and then extruding the extrudable composition into the desired form, where the extrudable composition is as defined herein.

[0180] Preferably, the method includes providing a dispenser filled with an extrudable fluid. Preferably, the method includes providing a dispenser filled with an extrudable compressed foam or a plurality of extrudable compressed foams. Preferably, the method includes providing a dispenser filled with an extrudable element.

[0181] Preferably, the method comprises conveying the extrudable composition from a dispenser through an extruder, preferably from the dispenser and to (and through) an extrusion nozzle.

[0182] Suitably the dispenser is a container, such as a cartridge, suitably a 3D printer cartridge.

[0183] Preferably, the container is a filament spool loaded with filament.

[0184] Preferably the container is a syringe. Preferably the syringe is filled with an extrudable fluid.

[0185] Preferably the method further comprises filling a container with the extrudable fluid, preferably comprising filling a syringe with the extrudable fluid.

[0186] Suitably, the extrudable liquid 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 of 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C or higher. Suitably, the method comprises heating the container (e.g. a syringe) to a temperature of from 25°C to 100°C.

[0187] Preferably, the extrudable fluid is extruded from a syringe (i.e., the syringe functions as an extruder). Preferably, the extrudable fluid is optimized for delivery from a syringe, e.g., the viscosity of the extrudable fluid allows the fluid to flow from the syringe when pressure is applied to the syringe. Advantageously, the extrusion of the extrudable fluid is performed in a single step. For example, the components of the extrudable composition can be added to a syringe, the syringe heated to form an extrudable fluid, and then directly extruded to form an extrudate. This direct extrusion reduces the overall exposure of the extrudable composition to high temperatures, e.g., in comparison, when an extrudable element (e.g., a filament) is used to manufacture an extruded article, the components of the extrudable composition are first exposed to high temperatures during the process of manufacturing the element, and then exposed to high temperatures during the process of manufacturing the extruded article. Additional Method Steps

[0188] The method of the present invention may include further steps either before, during and / or after the above steps. The exterior surface of the extruded article may be pre- or post-treated by extrusion of additional or partial layers, or by alternative coating techniques well known in the art.

[0189] Preferably, the method comprises extruding the extrudable composition into a desired form along with one or more auxiliary components, preferably comprising a shell, coating and / or a core.

[0190] Preferably, the method further comprises the step of incorporating at least one further excipient and / or at least one further active ingredient into the extruded article, preferably surrounding the desired form with the at least one further excipient and / or at least one active ingredient. Preferably, the desired form is an extruded article.

[0191] The extruded article produced by the method of the present invention can then be processed in various ways to obtain a further processed extruded article. Preferably, the method further comprises coating the article obtained from the extrusion process. Preferably, the coating is as described herein. For example, the extruded article may be enteric coated by standard enteric coating processes known in the art. Similarly, other controlled release properties may be imparted to the extruded article by further processing.

[0192] Most preferably, all steps (including further processing steps) are performed by an extrusion apparatus. Preferably, all steps (including further processing steps) are preferably controlled by the same computer. Computer implementation of the method

[0193] The method of producing an extruded article is preferably a computer-implemented method, as defined herein.

[0194] Preferably, the method comprises providing an extrusion apparatus, preferably as defined herein, and operating said apparatus to extrude an extrudable composition, thereby forming an extrudate. Preferably, the extrusion apparatus comprises or is otherwise connected to a computer. Preferably, operating the extrusion apparatus comprises operating a computer connected (wired or wireless) to or within the extrusion apparatus (to enable the computer to control and coordinate other parts of the extrusion apparatus, including the extrusion apparatus) to extrude the extrudable composition to form an extruded article and / or extrudable element.

[0195] A computer included in or otherwise associated with the extrusion apparatus of the present invention may suitably be referred to as an extrusion control computer. The extrusion control computer may perform different functions (and may be separate entities) than other "computers" referred to herein, such as a monitoring computer or an analysis computer, although a single computer may perform one or more functions of any combination 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 article formed after extrusion. Wherever separate computers are used to perform each of these operations, said computers are suitably coordinated and may therefore be considered to be part of one overall computer.

[0196] The extrusion of the extrudable compositions to form extruded articles and / or extrudable elements is preferably controlled by a computer running according to extrusion software based on information provided to the computer by user input (drug type, drug dosage level), databases (e.g., patient database and / or extruded article database), and / or data files (e.g., design files and / or parameter files), as described herein. Preferably, the extrusion apparatus is configured to extrude according to instructions provided by the computer by feeding the extrudable composition(s) to and / or through the respective extrusion nozzle(s) at appropriate intervals and / or at appropriate speeds; heating the associated extrusion nozzle(s) at appropriate temperature(s) for appropriate time; and moving the extrusion nozzle(s) and / or build platform to enable systematic extrusion layer by layer according to relevant information and calculations obtained by the computer.

[0197] The extrusion nozzles are suitably controlled by a computer according to "obtained information" (e.g., design and / or other parameters) regarding the extruded article. The extrusion nozzles are suitably controlled to extrude a given extrudable composition onto the build platform (or onto an extruded article partially built on the build platform) toward a pattern predefined by the "obtained information." As such, or each extrusion nozzle may be controlled to switch "on" and "off" according to a predefined schedule to provide a required pattern in the construction of the extruded article. The extrusion nozzles may be switched "on" by opening an output aperture, by adjusting the operating temperature of the extrusion nozzle (e.g., by increasing it to cause melting of the associated extrudable composition), by operating a conveyor to feed the extrudable composition through the nozzle, or by a combination of any or all of the foregoing. Of course, the extrusion nozzle may be switched off by causing the closing of the output opening, by adjusting the operating temperature of the extrusion nozzle (e.g. by lowering it to a temperature that does not cause melting of the extrudable composition), by operating a conveyor to limit or stop the supply of the extrudable composition through the extrusion nozzle, or by a combination of any or all of the above. The temperature of the extrusion nozzle is preferably set and controlled by a computer depending on the properties of the extrudable composition in question, as described elsewhere herein. Preferably, the operating temperature of the extrusion nozzle through which the extrudable composition passes is between 50°C and 220°C, between 60°C and 150°C, or between 70°C and 120°C. However, the operating temperature of the extrusion nozzle may be lower, for example below 50°C, especially in systems using extrudable compositions with low glass transition temperatures. Preferably, the temperature of the extrusion nozzle is set to at least 65°C, more preferably at least 70°C. In certain embodiments, the extrusion nozzle temperature is 50-130°C, 60-120°C, 70-110°C, or 80-100°C.Preferably, the operating temperature of the extrusion nozzle assigned to a given extrudable composition is lower than a corresponding extrudable composition having a low level (ie, substantially free) of transient plasticizer.

[0198] The build platform is preferably controlled by a computer according to "obtained information" (e.g., design and / or other parameters) regarding the extruded article, as described elsewhere herein. This may include controlling the operating temperature of the build platform, particularly the operating temperature of the surface of the build platform. Preferably, the operating temperature of the build platform or its surface is maintained substantially constant, preferably within ±5°C of the constant temperature, during extrusion. Such temperature control may facilitate removal or partial removal of the fugitive plasticizer, cooling, and / or hardening of the post-deposited extrudable composition, thereby ensuring the structural integrity of the extruded article while it is being extruded. During extrusion, such temperature control may facilitate attachment of the developed extruded article to the surface of the build platform. Such temperature control may facilitate release (i.e., de-attachment) of the extruded article after extrusion (e.g., the surface of the build platform may be heated or cooled as appropriate to reduce sticking of the extruded article). During extrusion, the build platform is preferably configured or operable to maintain a surface temperature (i.e., for surfaces in contact with the extruded article) of no more than 100° C., preferably no more than 90° C., 80° C., 70° C., 60° C., 50° C., 40° C., or 30° C. During extrusion, the build platform is preferably configured or operable to maintain a surface temperature (i.e., for surfaces in contact with the extruded article) of between 30 and 100° C.

[0199] It will be understood that any of the foregoing aspects and embodiments may be accomplished with or without the use or inclusion (or admixture) of a transient plasticizer, and such aspects and embodiments are also considered to be within the scope of the present invention. For example, the present invention provides a method of making an extruded article, the method comprising: i. providing an extrudable composition comprising an extrudable carrier and, optionally, a drug substance or active agent; and ii. Extruding the extrudable composition, optionally with one or more auxiliary components (eg, shell, coating, core), into a desired form.

[0200] In such aspects, providing an extrudable composition preferably includes providing an extrudable fluid, an extrudable compressed form, or an extrudable element as described herein, but may also include providing an extrudable solid form as described herein (e.g., powder, granules, mini-tablets, monoliths). Particularly preferred are extrudable compressed forms, preferably in the form of a plurality of compressed units (e.g., mini-tablets) or compressed monoliths (e.g., as a pre-compressed solid mass).

[0201] In such aspects, extruding the extrudable composition into a desired form (e.g., an oral dosage form) preferably comprises dispensing the extrudable composition from a dispenser (e.g., a syringe), preferably after sufficient mobilization (e.g., melting by heating), preferably in situ within the syringe to enable direct ink 3D printing.

[0202] All optional features mentioned above and all features described below in relation to aspects or embodiments involving the use of a temporary plasticizer apply equally to aspects or embodiments that do not use a temporary plasticizer, unless otherwise compatible in a given context. Methods for Producing Extrudable Compositions and Extruded Articles

[0203] According to a further aspect of the present invention there is provided a method of producing an extruded article, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element; iii. extruding the extrudable composition resulting from step i (or step ii, if applicable), optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0204] In one embodiment, a method of making an extruded article is provided, the method comprising the steps of: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element; iii. 3D printing the extrudable composition resulting from step i (or step ii, if applicable), optionally together with one or more ancillary elements (e.g., shell, coating, core), into a desired form. where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0205] The method step features are described elsewhere herein. For example, method steps i. and ii., and method step iii., are described elsewhere above.

[0206] It will be understood that any of the foregoing aspects and embodiments may be accomplished with or without the use or inclusion (or admixture) of a transient plasticizer, and such aspects and embodiments will also be considered within the scope of the invention. For example, the invention provides a method of making an extruded article, the method comprising: i. providing an extrudable composition comprising an extrudable carrier and, optionally, a drug substance or active agent; and ii. optionally, further processing the mixture from step i to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element; iii. extruding the extrudable composition resulting from step i (or step ii, if applicable), optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form.

[0207] All optional features mentioned above and all features described below in relation to aspects or embodiments involving the use of a temporary plasticizer apply equally to aspects or embodiments that do not use a temporary plasticizer, unless otherwise compatible in a given context. Extrusion apparatus and associated equipment and software for producing extruded articles

[0208] The present invention preferably provides an extrusion apparatus for producing (e.g. printing) an extruded article (e.g. a solid dosage form such as a tablet), preferably comprising an extrudable composition as defined herein. The extrusion apparatus is preferably operable to form the extruded article (e.g. a solid dosage form) via extruding the extrudable composition (preferably layer by layer) and manufacturing the extruded article.

[0209] Preferably, the extrusion device comprises an extrudable element. Preferably, the extrusion device comprises an extrudable fluid. Preferably, the extrusion device comprises an extrudable compressed form.

[0210] The extrusion apparatus is suitable for extruding the extrudable composition to form an extrudate, the extrudable composition and the extrudate comprising at least one active ingredient.

[0211] Preferably, the extrusion apparatus comprises a vessel for containing the extrudable composition and a nozzle for discharging the extrudable composition, wherein the vessel is heatable. Preferably, the vessel is heatable to a temperature of 25 to 300°C, 25 to 250°C, 25 to 200°C, or 25 to 150°C. Extruder

[0212] The extrusion device preferably comprises an extruder. Preferably, the extruder is a 3D printer. Preferably, the 3D printer is a Fused Filament Fabrication (FFF) 3D printer. Such printers are often referred to as fabrication deposition modelling™ (FDM) 3D printers. Preferably, the extrusion device comprises a Fused Filament Fabrication 3D printer (FFF 3D printer).

[0213] Extruders, including conventional 3D printers (including FFF 3D printers), are known in the art and may be judiciously modified based on the principles outlined herein to optimize extrusion of the extrudate, but are generally suitable for use in the present invention. For reference to those skilled in the art, the following research papers describe possible operation of FFF 3D printers - SH Masood, "Application of fused deposition modelling in controlled drug delivery devices", Assembly Automation, 27 / 3 (2007), p.215-221 and Khaled et al, "Desktop 3D printing of controlled release pharmaceutical bilayer tablets", International Journal of Pharmaceutics, 461 (2014), p.105-111 - and describe printing of filaments using FFF 3D printers, even though no active ingredient is included within the printed filament (drug compound is injected at a later stage). Furthermore, PCT Publication WO2016 / 038356, which is incorporated herein by reference, also describes a suitable apparatus for use in accordance with the present invention.

[0214] Extruders suitable for use according to the invention generally include a heated / heatable extruder nozzle that melts / softens and deposits (preferably onto a build platform) a molten extrudable composition layer by layer. The deposited molten composition preferably hardens rapidly following deposition. Maintaining the build platform with a relatively low surface temperature can facilitate such cooling / hardening to improve the final structure of the printed solid dosage form. The extruder also preferably includes one or more nozzle heaters (preferably one nozzle heater associated with each nozzle, but optionally one nozzle heater serving multiple nozzles), and preferably one or more conveyors (preferably one conveyor associated with each filament and / or nozzle), as defined herein. Preferably, the extruder includes one or more filament spool zones (or filament spool attachment points) for holding associated filament spools.

[0215] Suitably, in the present invention, the drug compound is formulated within an extrudable composition(s) and directly extruded as an extrudate.

[0216] Preferably, the extrusion device uses filaments as defined herein. Preferably, the extrusion device uses prefabricated filaments that are selectively extruded and deposited in a layer-by-layer printing process to produce the extruded article.

[0217] The extrusion apparatus of the present invention may optionally include one or more other components that extrude, print, or dispense materials intended to form part of the extruded article. For example, the extruded article may be coated. Extrusion Nozzle

[0218] Preferably, the extrusion device comprises at least one extrusion nozzle through which the extrudable composition (or a part thereof) can pass and be extruded therefrom. Preferably, the or each extrusion nozzle may be a heated extrusion nozzle, preferably a heated extrusion nozzle having variable temperature control (e.g. to allow the extrusion nozzle to be selectively heated at a desired temperature). Thus, the extrusion device may preferably comprise an extrusion nozzle heating element for heating the extrusion nozzle to melt, soften or otherwise liquefy the associated composition or part thereof. Preferably, such an extrusion device may comprise a plurality of said extrusion nozzles, each of which may be assigned to one or more extrudable compositions. Preferably, such an extrusion nozzle is part of the extrusion device.

[0219] The temperature of the nozzle is preferably computer controlled.

[0220] Suitably, the extrusion apparatus includes a conveyor for conveying the extrudable composition to at least one extrusion nozzle.

[0221] Preferably, the conveyor feeds the extrudable composition through itself (e.g., by gripping filaments) toward and / or through an associated extrusion nozzle. Preferably, the conveyor is controlled to deliver the extrudable composition at a suitable rate and / or interval to provide the desired extrudate. The conveyor or a portion thereof (e.g., a "feeder") (preferably the portion en route to the extrusion nozzle) may be preferably heated via a heating element associated therewith, preferably separately and / or via a separately controllable heating element from any heating element associated with the extrusion nozzle. If the extrusion apparatus includes more than one nozzle, preferably, the extrusion apparatus includes more than one feeder associated with each extrusion nozzle.

[0222] The temperature of the extrusion nozzle is preferably computer controlled. Preferably the nozzle is set to operate at a temperature of 60-350°C, 80-300°C, 100-220°C, or 120-190°C.

[0223] Preferably, the operating temperature of the extrusion nozzle through which the relevant extrudable composition(s) pass is high enough to allow extrusion, but low enough to avoid unacceptable degradation of any components, such as active component(s), at the relevant filament feed rate. Preferably, the operating temperature of the extrusion nozzle through which the relevant extrudable composition(s) pass is between 50 and 220°C, between 60 and 150°C, or between 70 and 120°C. However, the operating temperature of the extrusion nozzle may be lower, for example below 50°C, especially in systems using extrudable compositions with low glass transition temperatures. Most preferably, the temperature of the extrusion nozzle is set to at least 65°C, more preferably at least 70°C. In certain embodiments, the nozzle temperature is between 50 and 130°C, between 60 and 120°C, between 70 and 110°C, or between 80 and 100°C.

[0224] Preferably, each extrusion nozzle comprises an input opening (through which the extrudable composition is delivered) and an output opening (through which the molten extrudable composition is deposited). The output opening is preferably smaller than the input opening. The input opening is preferably dimensioned to pass through and receive the extrudable composition (e.g., extrudable elements, blends, extrudable fluids, or extrudable compressed forms). Preferably, the input opening has a diameter of 0.1-100 mm, 0.2-10 mm, 0.3-5 mm, 0.3-3 mm, 0.3-2 mm, 0.4-1.5 mm, 1.5-2.0 mm, 1.5-2.0 mm, 0.75-1.25 mm, about 1 mm, 0.2-0.6 mm, about 1.75 mm, or about 0.4 mm. The output opening is preferably dimensioned to suit the characteristics of the corresponding extruded article so that the molten extrudable composition can 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 an embodiment, the nozzle has an output opening with a diameter of about 0.3 to about 0.5 mm.

[0225] Preferably, the or each nozzle may be movable (preferably in an automated manner or under direction from a computer, in a computer-controlled manner) 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., when 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.

[0226] Preferably, each extrusion nozzle is operable to move at a speed of from 1 to 150 mm / s, more preferably from 70 to 110 mm / s, more preferably from 80 to 100 mm / s, preferably from 1 to 10 mm / s, preferably about 4 mm / s, during extrusion (i.e. when the nozzle is "on" - this may be the extrusion speed of the nozzle). Preferably, the or each extrusion nozzle is operable to move at a speed of from 100 to 200 mm / s, more preferably from 120 to 180 mm / s, more preferably from 140 to 160 mm / s, when not extruding (i.e. when the nozzle is "off" - this may be the nozzle movement speed).

[0227] Preferably, the rate of extrusion is constant during extrusion (ie, the flow of material is constant).

[0228] As will be appreciated by those skilled in the art, each nozzle, or any nozzle, may be adapted to the properties of the extrudable composition (e.g., filaments). The properties / design of the nozzle and the properties of the extrudable composition are preferably complementary to each other to facilitate controlled extrusion of said composition (whether continuous or intermittent, e.g., when more than one extrudable composition is used in extruding an extruded article), preferably without clogging or obstruction of the nozzle, and preferably without unacceptable degradation of the components within the extrudable composition during the extrusion process. Build Platform

[0229] The extrusion apparatus preferably includes a build platform (or build plate) onto which the extrudable composition is extruded (i.e., onto which the extruded article may be constructed). The build platform preferably provides a (substantially flat) surface that supports the shaping and formation of the extruded article throughout the extrusion process. In certain embodiments, the build platform includes a surface, tape layer (i.e., a layer of tape at a surface) or surface coating that facilitates adhesion of the extruded article to the build platform during the extrusion process (i.e., facilitates adhesion of a first layer of the extruded article extruded onto the build plate, preferably after the first layer has hardened upon cooling), but preferably allows the extruded article to be (easily) removed from the build platform after its production.

[0230] Preferably, during extrusion (e.g., at the relevant extrusion operating temperature), the surface of the build platform adheres sufficiently to the extruded article (or at least a layer thereof in contact with the build platform) to prevent movement of the developed article during extrusion. However, preferably, after extrusion (e.g., optionally at a temperature different from the extrusion operating temperature), the extruded article can be removed from the build platform without being damaged (e.g., the build platform is sufficiently non-adhesive to allow the extruded article to be removed, or is selectively adjustable, e.g., by changing the operating temperature, to allow the extruded article to be removed therefrom). Thus, the surface of the build platform may include a surface coating or surface tape that imparts the required surface properties (e.g., adhesive, but not so adhesive that the extruded article is permanently attached).

[0231] The build platform is preferably configured or operable to maintain a surface temperature during extrusion (i.e. for the surface in contact with the extruded article) of 150°C, 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, or 30°C or less. Preferably, the surface temperature is 5°C, 15°C, 30°C, or 40°C or more. This may be achieved by selective operation of heating and / or cooling elements associated with (e.g. underlying) the surface of the build platform. In certain embodiments, the build platform is operable and preferably operable to maintain a surface temperature of 5-150°C, 20-110°C, 20-100°C, about 90°C, or about 40°C. Advantageously, the build platform is preferably configured or operable to maintain a surface temperature that provides for removal or partial removal of the transient plasticizer. Preferably, the surface temperature is about the boiling point of the transient plasticizer, e.g. about 80°C or about 100°C. Preferably, the surface temperature is less than the extrusion temperature. Preferably, the surface temperature is at or below the boiling point of the transient plasticizer.

[0232] The build platform may be movable (preferably in an automated or computer controlled manner, or by the extruder under direction from a computer) to control the position or height of the extrusion on the build platform. The build platform may be movable in any or all of the X, Y, and Z directions, although in some embodiments the build platform is movable only in the Z direction, i.e., up and down. 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-to-layer consistency. dispenser

[0233] The extrusion device preferably comprises a dispenser. Preferably, the dispenser comprises a storage vessel, such as a hopper. The storage vessel preferably comprises an extrudable composition or a precursor thereof. Preferably, the storage vessel comprises an extrudable element. Preferably, the storage vessel comprises an extrudable fluid. Preferably, the storage vessel comprises an extrudable compressed form. The storage vessel is preferably sealed. The storage vessel may be in the form of a container (e.g., a cartridge or a syringe, as defined herein) specifically adapted for compatibility with the device of the present invention. The storage vessel preferably has either an outlet (e.g., such as a valve-activated tap, optionally in combination with a positive dispensing means, such as a pressurizer or agitator) through which its contents may be dispensed, or a sampling port through which the contents may be extracted by an external sampling element.

[0234] The dispenser preferably includes one or more dispensing vessels. Preferably, such dispensing vessels are configured to receive an amount of the extrudable composition (or precursor thereof) from a storage vessel, preferably directly or via a delivery means. Preferably, the one or more dispensing vessels may receive a predetermined amount of the extrudable composition (or precursor thereof).

[0235] The dispenser preferably includes a quantification component, for example a gravimetric or volumetric component. Such a quantification component appropriately meters or otherwise quantifies each dose of the extrudable composition (or precursors thereof) dispensed. Preferably, the dispenser is operable to transfer an amount of the extrudable composition (or precursors thereof) from a storage container to the quantification component or to a dispensing container that interacts with the quantification component. Preferably, the one or more dispensing containers are arranged such that the quantification component can quantify the amount of the extrudable composition received by the dispensing container. Alternatively, the quantification component may be associated with the storage container, thereby measuring the mass loss as the extrudable composition (or precursors thereof) is dispensed from the storage container. Quantification may be by weight and / or volume.

[0236] The dispenser preferably includes a flow control component, which preferably controls and measures the dispensing of the extrudable composition (or precursors thereof) from the storage vessel to one or more dispenser vessels. The flow control component may, for example, include a controlled feed mechanism, and may preferably include an Archimedes screw, a valve, an agitator (e.g., a vibrator, a tap, or a shaker). Alternatively or additionally, the flow control component may include a sampling probe operable to sample an (estimated) amount of the extrudable composition (or precursors thereof) from the storage vessel.

[0237] The dispenser preferably includes a discharge mechanism for discharging a quantified amount of the extrudable composition (or precursor thereof) from either the sampling probe or the dispensing vessel. Such a discharge mechanism may preferably include a discharge means (e.g., a tap, a valve, a vacuum discharge, or other such mechanism that can tip the contents of the dispensing vessel towards a targeted dispensing point). Alternatively or additionally, the discharge mechanism may include a discharge means, such as, for example, a pressurizer, an agitator, a screw, a piston, or a plunger, which can force the extrudable composition (or precursor thereof) out of the dispensing vessel, thereby discharging the extrudable composition.

[0238] In one embodiment, the dispenser includes a hopper and a movable metering element (e.g., a shuttle plate) that is movable relative to the hopper and includes fixed or adjustable sized metering cavities / containers. The size of the metered cavities determines the size of each dose. The movable metering element may be operable to receive a quantity of the extrudable composition from the hopper, move to a dispensing point, and dispense the extrudable composition from the metered cavities before encapsulating a metered amount of the extrudable composition in the cavities.

[0239] The skilled artisan will be aware of certain challenges faced in the quantitative dispensing of materials, especially solids such as particulate solids. The forces favoring the outflow (e.g., gravity, pressure, screw forces such as Archimedes screw) are often countered by forces opposing the flow (e.g., adhesion between particles, adhesion to parts of the dispenser (e.g., dispenser walls or dispenser outlet), wear, friction, irregular flow (e.g., ratholes or arching in the funnel), compressibility (non-compressible solids flow better), outlet restrictions (e.g., holes in the outlet), angle of repose in the funnel (preferably an angle of 35° or less), external pressure (external vacuum can also be utilized), etc. Particle flow is particularly influenced by the particle itself in terms of particle morphology, particle size, particle density, particle chemistry, surface roughness, moisture content, etc. Particle flowability can be improved by judicious particle engineering, including techniques such as particle enlargement (e.g., granulation), reduction of cohesion, smoothing / rounding, moisture content optimization, co-grinding (e.g., to form nanocoatings that enhance flowability), etc. A compressibility index of preferably 0-25%, more preferably 25% or less, more preferably 15% or less, more preferably 10% or less is encouraging for better particle flowability. Furthermore, particle sizes preferably between 10 and 200 μm, preferably 10 μm or more, 50 μm or more, or 100 μm or more are often preferred for optimal particle flow. Thus, small particle sizes, including nanoparticles (e.g., 100 nm or less), may be more preferably dispensed in the form of a suspension, such as a nanosuspension.

[0240] Preferably the components of the dispenser are computer controlled and preferably any valves or pressurizers are electronically controlled.

[0241] Suitably, a clench valve may be incorporated into the dispenser to control the dispensing flow of particulates such as granules.

[0242] Preferably, the dispenser may further comprise a mixer. Preferably, the mixer is shear mixing. Preferably, the mixer is set to operate at a mixing speed of 10 rpm, 25 rpm, 50 rpm, 75 rpm, 100 rpm, 125 rpm, 150 rpm, 175 rpm, 200 rpm, 250 rpm, 300 rpm, 400 rpm, or 500 rpm or more. Preferably, the mixing speed is 500 rpm, 400 rpm, 300 rpm, 200 rpm, or 100 rpm or less. Preferably, the mixer can be set to operate at a mixing speed of 10 to 500 rpm. Computer Interface and Computer

[0243] The extrusion apparatus, including the extruder (and optionally the build platform), is preferably operable via a computer running in accordance with specialized extrusion software, preferably to extrude an extrudable composition, thereby forming an extruded article on the build platform, preferably via a process including extruding the extrudable composition, thereby forming an extruded article on the build platform, and optionally one or more databases.

[0244] It will be readily appreciated by those skilled in the art that any one or more of the build platform, extrudable composition, and / or computer, and / or portions thereof may suitably be incorporated within or form part of an extrusion device. In one embodiment, the extrusion device is essentially an extruder, 3D printer (including FFF3D-printing) or printing device.

[0245] Suitably the extrusion apparatus includes a computer interface, whether for wired or wireless connection to a computer operable to control the extruder.

[0246] The extrusion apparatus preferably includes a computer for controlling the extruder. The computer may optionally control the build platform (e.g., its position, height, etc.). The computer may thus be configured to operate the extruder (e.g., a 3D printer) according to a predetermined extruded article design pattern.

[0247] The extruder preferably includes a computer or is otherwise connected to a computer. The extruder is preferably connected to the computer via an interface (preferably a digital interface), which may be wired (e.g., a port-to-port connection via a suitable data lead, e.g., a USB lead) or wireless. The computer may be located at the site of the extruder (i.e., a local computer). However, the invention is equally applicable when the associated computer (or computers) are located remotely from the site of the associated extruder, but both the extruder and the remote computer include or are otherwise connected to respective communicators that allow the remote computer and the extruder to communicate with each other. In this way, the remote computer may be caused to operate the extruder. In certain embodiments, the extruder may be connected to a network such that multiple remote computers (and / or local computers) may communicate thereto to cause the operation of the extruder.

[0248] A computer associated with or otherwise connected to the extruder suitably controls the extrusion of an associated extrudable composition in accordance with extrusion article design and / or extrusion article parameters (e.g., relative amounts and juxtaposition of components) defined in a given extrusion article data file (e.g., in a CAD or .STL file), as interpreted by associated software executed by the computer.

[0249] In certain embodiments, the extrusion device includes or is connected to a local computer, and both the extrusion device and the local computer are located at the pharmacy site, most preferably in a dedicated extrusion area or room (which may preferably be approved by regulatory authorities).

[0250] Suitably the method and / or extrusion apparatus includes a computer running in accordance with extrusion software (and optionally one or more internal and / or external databases).

[0251] Preferably, the computer running according to the extrusion software is configured to obtain information regarding one or more parameters (optionally including physical design parameters such as morphology) of the extruded article to be extruded (e.g., from information manually entered by a user or information automatically obtained from other data sources). Preferably, the computer running according to the extrusion software is configured to request manual input of the user via a user interface (e.g., keyboard / screen) regarding one or more parameters of the extruded article to be extruded. For example, the user (which may be a pharmacist acting on instructions from the patient and / or doctor) is requested to enter information regarding the patient name, patient reference number (e.g., health care number), and / or another reference name or number, and the computer may then communicate (through associated communicators) with one or more databases (local or remote, wired or wireless, e.g., via a network such as the Internet) to automatically call up further information and / or options corresponding to said name or reference (e.g., including individual patient data, medical history, repeat prescriptions, data or partial data related to the extruded article to be extruded, extruded article data files including design and / or other related parameters). The user may then be requested to manually enter or select further information (e.g., drug, drug dosage, release profile, etc.) and / or options to enable the computer to obtain all relevant information related to printing the extruded article form. Alternatively, or additionally, the user may be requested to manually enter or recall information related to one or more specific parameters associated with the extruded article (e.g., drug name / reference, drug dosage, drug release requirements, color, size, form, solubility, package label information, etc.). Suitably, any user input may be recorded and / or stored for future reference or to repeat the formulation.

[0252] Although the computer may be configured to obtain the relevant information to render the extruded article extrudable, it is envisaged that various pre-configured information may be used (e.g., specific approved formula / filament combinations for producing a given extruded article).As such, the computer may be preferably associated with or connected to or connectable to an extrusion article database (preferably a central database accessible via a network such as the Internet) that provides all the necessary pre-configured information (e.g., data files relating to the extruded article and details of variable parameters such as drug dosage levels / limits).

[0253] Suitably, the design of the extrusion article for extrusion (and optionally its associated parameters) may be recorded in an extrusion article data file, which may be read by a computer running in accordance with the extrusion software.

[0254] Preferably, the computer running according to said extrusion software is configured to calculate the mass and / or volume of the extrudate to be extruded based on the obtained information. Preferably, once the computer has all the necessary information (which may be manually entered by the user, automatically imported, or a combination of both), it is configured to perform calculations to allow the finalization of the extrusion instructions before the computer controls the extrusion. At this stage, further inputs may be required or requested (e.g. via the user interface), e.g., optional selection of dimensions, morphology, etc. The calculations typically relate to the mass and / or volume of a given extrudate (e.g., in the case of extrudates) required to provide a given active dose per extrudate. Although it may be possible to increase the concentration of a given active ingredient compared to other ingredients (e.g., excipients), typically the formulation is optimized and the relative proportions are fixed / pre-set, while the overall mass / volume may be varied while maintaining the same relative proportions of the ingredients.

[0255] Preferably, a computer running in accordance with said extrusion software is configured to control the extrusion and relative proportions of components within the extruded article based on the information obtained, preferably based on the calculations performed. Preferably, "controlling extrusion" includes initiating extrusion, terminating extrusion, and any or all extrusion operations in between.

[0256] Preferably, during extrusion, operational data is collected (optionally by one or more local and / or remote computers and / or databases) and preferably stored (most preferably at a central computer where such data can be analyzed, e.g., for quality control monitoring, fault monitoring, batch monitoring, monitoring of dosage forms dispensed to a given patient, etc.). Preferably, the extrusion apparatus includes or is otherwise associated with one or more operational sensors (e.g., nozzle temperature sensor, extrudable composition feed rate sensor or conveyor sensor, overall temperature sensor, build platform sensor that can monitor, e.g., surface temperature and / or post-extrusion cooling rate, etc.) that feed back operational parameters / information to a computer, database, or data storage device related to the operation of the extrusion apparatus and its associated elements during the extrusion of each extrudate. Most preferably, such operational data is collected, stored, and / or otherwise transmitted to a central computer or database to allow for an independent audit of any given extrusion apparatus. This may be important for maintaining quality control and for maintaining proper records to retain regulatory approval of any given extrusion system.

[0257] Preferably, a computer running in accordance with the extrusion software is configured to control the performance of one or more further processing steps. Software and Data Files

[0258] The computer that operates the extrusion device is preferably run in accordance with extrusion software (and optionally one or more databases), which may configure the computer to obtain information and perform calculations, as described herein, and then configure the computer to control extrusion via an interface with the extrusion device.

[0259] Once the computer has obtained the relevant information and performed the relevant calculations, the software configures the computer to control the extrusion of the extrudable composition, thereby forming the extruded article, preferably based on the design (morphology and dimensions, texture, layer structure, internal structure, porosity, color, etc.) and / or parameters (relative amounts of components, such as drug dosage) related to said 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 dimensions, morphology, layer 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, excipient type, drug dosage level, excipients for controlling drug release, etc.). An extruded article data file may contain all data related to the physical design and chemical composition, although the physical design and chemical composition may be changed depending on information obtained following user input.

[0260] In some embodiments, the design file may be a CAD file depicting the extruded article. However, such a file format will likely require conversion to a file format compatible with the extrusion device. In particular, 3D printers typically read design files in .STL format. Thus, the design file is preferably an .STL design file depicting the extruded article (or at least its physical design).

[0261] The design file may include or be linked to a parameter file containing details of the chemical composition, or the two may be independent, or there may be no such parameter file and instead the relevant parameter information may be recalled from a database, for example in response to user input (e.g., a patient reference, or a drug reference, etc.).

[0262] The software may further 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., a 3D printing machine) during extrusion. The software may configure the computer to detect and / or respond to any (or preset levels of) deviations from expected operational data (e.g., if the nozzle temperature exceeds a preset maximum temperature level), e.g., alerting a user / operator or other interested party that a malfunction has occurred and that extruded articles produced during the malfunctioning extrusion should be discarded or otherwise tested. Database

[0263] The extrusion device and / or its associated computer may be configured (e.g., by extrusion software) to communicate (preferably via an associated communications device, preferably via a network such as the Internet) with one or more extruded article databases and / or patient databases to obtain information regarding one or more parameters related to the extruded articles to be produced. For example, such databases may be consulted in response to user input (e.g., a patient reference number) to provide the computer with relevant information (or relevant information supplemented by further user input) to enable calculations and extrusion to be performed.

[0264] For example, a patient database containing patient records of multiple patients (which records may include, for example, patient name, patient reference number, medical data, medical history, etc.) preferably contains information (which may simply be a cross-reference or reference number to information present in another database, such as an extruded article database) regarding the extruded article to be extruded for each patient. If the "information" is a cross-reference to an extruded article database, this extruded article database may then be referenced to obtain further information regarding the extruded article. This information may be any of the information defined herein, but optionally the extrusion device or its associated computer may be instructed (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 accessible, and preferably securely accessible (to maintain confidentiality of certain data), to interested parties so that relevant information (be it the patient database, the extrudate database, or both) can be searched and / or modified as necessary (e.g., if a patient requires an increased dose or a different active release profile in the extrudate). Preferably, such databases may be wirelessly accessible via a network such as the Internet. Such database architectures are well known in the art.

[0265] The extrusion device and / or each extrusion device and / or computer associated therewith may be configured (e.g., by extrusion software) to communicate (preferably via an associated communication device, preferably via a network such as the Internet) with one or more extrusion device monitoring databases configured to transmit to and store in said databases operational data collected (preferably by one or more local and / or remote computers and / or databases) during each extrusion operation (i.e., each time the extrusion device performs an extrusion). As described herein, such operational data is preferably obtained / delivered by sensors associated with each given extrusion device, preferably sensors associated with key parts of the extrusion device that may affect the quality of the final extruded article. The operational data may be transmitted to said databases in real time, after extrusion, or at any suitable time (e.g., overnight to avoid unnecessary overloading of the communication network during working hours). Such extrusion device monitoring databases may be organized to have a record for each extrusion device, and preferably maintain a log of operational data each time said extrusion device is operated. Preferably, each set of operational data is preferably cross-referenced to a given patient and extrusion article such that relevant stakeholders can be alerted if any of the operational data is deemed to be malfunctioning. In this manner, each extrusion device may be monitored (whether in real-time, automatically, or otherwise) and data submitted periodically to meet regulatory requirements. Additionally, the central extrusion device monitoring database may trigger a response to a sensed malfunction of a given extrusion device. Additionally, a response may be triggered that prevents use of the associated malfunctioning extrusion device until its performance has been re-verified.

[0266] Again, any of the one or more extrusion equipment monitoring databases are accessible, and preferably securely accessible (so as to maintain confidentiality of certain data), to interested parties to enable retrieval and / or analysis of relevant information as required. Suitably, such databases may be wirelessly accessible over a network such as the Internet. Such database architectures are well known in the art. Extrudable Composition

[0267] The present invention provides an extrudable composition, which may be an extrudable composition obtained, obtained or directly obtained by a process for producing an extrudable composition as defined herein.

[0268] The present invention provides an extrudable composition comprising: i. an extrudable carrier; and optionally ii. It is a temporary plasticizer.

[0269] The present invention provides an extrudable composition comprising: i. an extrudable carrier; and ii. It is a temporary plasticizer.

[0270] Preferably, the extrudable composition is a blend of a temporary plasticizer, an extrudable carrier, if present, an active ingredient, if present, a permanent plasticizer, if present, and other ingredients, if present.

[0271] Preferably, a majority of the extrudable composition is in a molten state at the extrusion temperature. By molten state, it is meant that the extrudable composition is extrudable at the extrusion temperature, but does not mean that all components of the extrudable composition must be in a molten state. For example, a mixture of an extrudable carrier and a transient plasticizer is in a molten state at the extrusion temperature.

[0272] In one embodiment, the extrudable composition is a free-flowing blend. Advantageously, the free-flowing blend is prepared by combining the components of the extrudable composition by mixing, such as shear mixing.

[0273] In one embodiment, the extrudable composition is in an extrudable compressed form (or multiple extrudable compressed forms), such as tablet(s), e.g. mini-tablet(s). Advantageously, the extrudable compressed form can be produced prior to the process of producing the extruded article by compressing the extrudable composition. For example, the extrudable compressed form can be pre-produced at the same or a different location as the extruder site and / or stored for a period of time until needed. Furthermore, having the extrudable composition in a compressed form can prevent physical separation of the various components of the extrudable composition over time, thereby potentially reducing variability during the extrusion process. Also, using extrudable compressed forms, such as mini-tablets, in the extrusion process advantageously means that the process can be run continuously (i.e., by providing a continuous supply of extrudable compressed forms to the extruder), thereby allowing the process to be run more time- and cost-efficiently.

[0274] Suitably, each extrudable compressed form has a weight of 10-1000 mg, 20-800 mg, 20-500 mg, 40-300 mg, 50-250 mg, 100-200 mg, 20-80 mg, 30-70 mg, 40-60 mg, or about 50 mg.

[0275] Suitably, each extrudable compressed foam has a diameter of 1-10mm, 2-8mm, 4-7mm, 5-7mm, or about 6mm.

[0276] In one embodiment, the extrudable composition is an extrudable fluid, preferably an extrudable semi-fluid, such as a molten composition. Preferably, the extrudable fluid is a fluid at room temperature. Preferably, the extrudable fluid is a fluid at room temperature or at a temperature of 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C or higher. Preferably, the extrudable composition can be extruded at a temperature of 200°C, 180°C, 150°C, 120°C, or 100°C or lower. Preferably, the extrudable composition can be extruded at a temperature of 30°C or higher and 200°C or lower, preferably 30°C or higher and 150°C or lower. Fluid is understood to mean that the extrudable composition can be extruded (i.e. preferably has a viscosity that allows it to be extruded) at said temperatures.

[0277] In one embodiment, the extrudable composition is an extrudable element. Suitably, the extrudable element is a filament. Advantageously, the extrudable composition can be extruded a first time (to form an extrudable element, such as a filament) before being extruded a second time during the process for producing an extruded article. In particular, the use of filaments in 3D printing technology is well established, for example in fused filament fabrication (FFF) technology. The temporary plasticizer allows the extrusion temperature in the process for forming the extrudable element (e.g., filament) to be lower than in the absence of the temporary plasticizer, making the process suitable for use with components of the extrudable composition that are thermally sensitive. By partially or completely removing the temporary plasticizer from the extrudable element, an extrudable composition can be obtained that has physical properties suitable for use in the process for producing an extruded article. For example, the temporary plasticizer can be used initially to reduce the glass transition (softening) temperature of the extrudable composition used to produce the extrudable element, thereby reducing the extrusion temperature used to form the extrudable element. Due to the low glass transition (softening) temperature, the physical properties may not be optimal for further processing, for example, the resulting extrudable element may be too flexible for use in FFF 3D printing. Partial removal of the temporary plasticizer increases the glass transition (softening) temperature of the extrudable element, thereby decreasing the flexibility of the extrudable composition. The amount of temporary plasticizer that is removed (thereby increasing the glass transition (softening) temperature) can be optimized so that the extrudable element has optimal physical properties (e.g., flexibility) for use in the extruded article to extruded article process.

[0278] It will be appreciated by those skilled in the art that the extrudable element may be an extruded article, and thus features applicable to extruded articles may also be applicable to the extrudable element.

[0279] The process of forming the extrudable element exposes the components of the extrudable element to high temperatures for a longer period of time than the process of forming an extrudate from the extrudable element. This is because the extrusion of a bulk material involves a longer residence time in the extruder compared to the extrusion of an extrudable element (e.g., 3D printing) (e.g., filament). Advantageously, the level of temporary plasticizer leads to a lower extrusion temperature for producing the extrudable element and / or the extruded article. Advantageously, it is possible for the first extrusion temperature (i.e., the temperature used to produce the extrudable element) to be lower (i.e., when the content of temporary plasticizer is highest) than the temperature for producing the extrudable article from the extrudable element (wherein the temporary plasticizer has been removed or partially removed from the extrudable element during the production of the extrudable element or during the extrusion of the extrudated article, i.e., optimization of physical properties such as flexibility / brittleness for use in 3D printing). Thus, the extent of thermal degradation can be minimized by lowering the extrusion temperature used to form the extrudable element, having a shorter residence time, and / or by lowering the extrusion temperature used to form the extruded article.

[0280] Preferably, the extrudable element is substantially free of temporary plasticizers. Preferably, the filaments are substantially free of temporary plasticizers. Preferably, the extrudable element is completely free of temporary plasticizers. Preferably, the filaments are completely free of temporary plasticizers.

[0281] Suitably, the filaments have a thickness (i.e. diameter or maximum thickness) of 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 certain embodiments, the filaments have a thickness of about 1 mm. However, the thickness of the filaments can be tailored to the extrusion nozzles through which they are extruded (particularly the size / diameter of their respective openings).

[0282] Preferably, the filament is wound on a spool having a hub diameter of 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, preferably the hub diameter allows the filament to be coiled (or spooled) around the spool without breaking and / or stretching.

[0283] The extrudable composition preferably contains less than 30%, 25%, 20%, 18%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1% by weight of temporary plasticizer. Preferably, the extrudable composition contains more than 5%, 10%, 15%, or 20% by weight of temporary plasticizer. Preferably, the extrudable composition contains 1-25% of temporary plasticizer.

[0284] The extrudable composition preferably has a glass transition (softening) temperature (T g Preferably, the extrudable composition has a glass transition temperature of about -15°C or about -10°C. Preferably, the extrudable composition has a glass transition (softening) temperature (T g ).

[0285] Preferably, the extrudable composition is prepared by determining the appropriate proportions and types of components so that the extrusion temperature used to produce the extrudate is minimized.

[0286] Preferably, the extrudable carrier, the temporary plasticizer, and the permanent plasticizer, if present, form part or all of the meltable components of the extrudable composition. The extrudable composition may further comprise a non-meltable component to mitigate nozzle blockage. Preferably, a "meltable" component is one that melts (or undergoes a glass transition to soften) at a given operating temperature of the nozzle of any extrusion device (e.g., a 3D printer) configured to process said extrudable composition, while a "non-meltable" component is one that does not melt (or undergoes a glass transition) at the same temperature. Preferably, a "meltable" component is a mixture of components that collectively melt or undergo a glass transition, e.g., an extrudable carrier and a temporary plasticizer. However, a "non-meltable" component is more likely to be an individual component with different melting or glass transition temperatures. Preferably, a meltable component has a melting point (or T) of 220°C, 150°C, 100°C, 80°C, or 60°C or less. g Preferably, the meltable component has a melting point (or T g - i.e. at least one T g Preferably, the meltable component has a melting point (or Tg-i.e., at least one T) of 20°C to 220°C, 30°C to 200°C, 30°C to 150°C, 30°C to 65°C, or 30°C to 35°C. g Suitably, the non-meltable component has a melting point (or Tg) of 150° C. or more, 200° C. or more, 500° C. or more, or 1000° C. or more.

[0287] The meltable component preferably has a glass transition temperature lower than the melting point of the active ingredient, preferably at least 20°C lower, at least 40°C lower, or at least 50°C lower.

[0288] As explained above, references to "meltable" and "non-meltable" components encompass "softenable" and "non-softenable" components, respectively, where instead of "melting" at a particular temperature, the component "softens" thereby allowing extrusion at that temperature. Thus, references to melting point in this context can additionally or alternatively relate to glass transition temperature. Such glass transition is particularly applicable to thermoplastic components. Thus, a "meltable" component may suitably be a thermoplastic component whose glass transition temperature (the temperature at which the thermoplastic component softens rather than melts) is lower than the temperature to which said component is exposed (e.g., during extrusion).

[0289] Each of the various components described herein is preferably either a meltable component or a non-meltable component (but not both). For example, the mixture of extrudable carrier and temporary plasticizer is preferably a meltable component and is selected to melt or undergo a glass transition during extrusion. In contrast, the filler (e.g., tribasic calcium phosphate, talc, etc.) is preferably a non-meltable component and is preferably selected to remain solid during extrusion. Regardless of the contrasting melting / glass transition properties of the various components, the extrudable composition (e.g., filament) itself preferably has a characteristic glass transition temperature. Preferably, this characteristic glass transition temperature is measurable using well-known techniques described herein and elsewhere and is a result of the combination of components. Various concentration (wt%) ratios of meltable:non-meltable components may enable a viable extrudable composition for extrusion such as 3D printing. Preferably, the ratio of meltable components:non-meltable components is between 1:10 and 10:1, more preferably between 3:7 and 7:3, more preferably between 4:6 and 6:4, where preferably the meltable components include all meltable components collectively associated (e.g., extrudable carriers, temporary plasticizers, permanent plasticizers, etc.) and the non-meltable components include all non-meltable components collectively associated (e.g., fillers, lubricants, etc.).

[0290] The extrudable composition (e.g., extrudable element) is preferably sufficiently rigid to allow it to be feasibly fed (at a consistent rate) to and passed through a corresponding extrusion nozzle in an extrusion apparatus. The extrudable composition is suitably sufficiently rigid to avoid stretching of the extrudable composition (e.g., extrudable element) during printing. However, the extrudable composition (e.g., extrudable element) is preferably not so rigid that the nozzle operating temperatures required to extrude the filament degrade the component content (e.g., cause a change in composition of 1 wt % or more).

[0291] In one embodiment, the extrudable composition, e.g., the extrudable element, such as a filament, is preferably sufficiently flexible and / or soft to allow it to be extruded (at a consistent rate) from a corresponding extrusion nozzle in an extrusion apparatus. In one embodiment, the extrudable element, e.g., the extrudable composition, e.g., the extrudable element, such as a filament, is preferably sufficiently flexible and / or soft to allow it to be operably spooled / coiled around a filament spool.

[0292] In general, if the extrudable composition (i.e., the extrudable elements such as filaments) has a glass transition temperature (Tg) that is too high, it may be too brittle (e.g., to coil into a filament spool) for the extruder to handle (i.e., without breaking the filament) and / or may require high extrusion nozzle operating temperatures that may result in degradation of components within the extrudable composition during the process of making the extruded article. Conversely, if the extrudable composition has a glass transition temperature that is too low, the extrudable composition (i.e., the filament) may be too soft and / or flexible for the extruder to handle and may be too distorted for consistent extrusion, resulting in poor morphology control and incoherent extruded articles during the process of making the extruded article. The extrudable composition (e.g., the filament) is preferably not too brittle (breakable during printing / spooling) and not too flexible (preventing its viable transport through the extrusion device). The dimensions of the extrudable composition (e.g., the thickness of the filament) may be carefully varied using the principles taught in this disclosure to obtain optimal structures.

[0293] Preferably, the extrudable composition comprises at least one active ingredient, preferably a pharmaceutical, nutritional or food supplement active ingredient as defined herein, and most preferably, the at least one active ingredient is a pharma- ceutical active ingredient.

[0294] Suitably, the extrudable composition comprises a permanent plasticizer as defined herein.

[0295] Suitably, the extrudable composition comprises one or more other components, as defined herein.

[0296] Many of the preferred characteristics of the extrudable composition are described elsewhere herein, for example, characteristics described in connection with the method of making the extrudable composition may suitably reflect characteristics of the extrudable composition itself (e.g., filament diameter). Extruded Articles

[0297] The present invention provides an extruded article, which may be an extruded article obtained, obtained or directly obtained by a method for producing an extruded article as defined herein.

[0298] The extruded article is preferably formed from, and thus preferably is, or comprises, an extrudable composition, and as such, any definition herein relating to an extrudable composition is equally applicable to the extruded article.

[0299] The present invention provides an extruded article that includes an extrudable carrier and a transient plasticizer.

[0300] Most preferably, the composition of the extruded article contains a lower amount of temporary plasticizer (including substantially free and completely free) than the extrudable composition. In one embodiment, the extruded article contains low levels of temporary plasticizer, including amounts of 30%, 20%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, or 0.1% or less by weight. Preferably, the extruded article is substantially free of temporary plasticizer or completely free of temporary plasticizer. Preferably, the extruded article contains 0-30% of temporary plasticizer. Preferably, the extruded article has 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98% less temporary plasticizer than the extrudable composition used to make the article.

[0301] The extruded articles of the present invention are generally identifiable by chemical and / or microscopic analysis, which will suitably reveal whether the extruded article has been extruded, e.g. 3D printed, e.g. by extruding an extrudable composition layer by layer. Suitably, the extruded article comprises a plurality of layers. Suitably, each layer has a thickness of 10-1000 μm, 20-800 μm, 30-500 μm, 40-300 μm, 50-200 μm, 100-200 μm, 125-200 μm, 140-190 μm, 155-175 μm, 250-350 μm, or 750-850 μm. Suitably, each layer of the extruded article can have the same thickness, or each layer can have a different thickness. Suitably, there are no gaps between the layers.

[0302] The extrudate of the present invention is suitable for oral administration. Examples of such extrudates are tablets, capsules, granules, powders, beads and microcapsules. Most preferably, the extruded article is a tablet or an implant, most preferably a pharmaceutical tablet or a medical implant (e.g., an implant that allows sustained and / or controlled release of the active ingredient).

[0303] The extruded articles of the present invention are advantageously customizable in terms of the type / nature of the active ingredient, the dosage of the active ingredient in the extruded article (which may be the absolute dosage per extruded article or the concentration of the active ingredient with the extruded article), the mass / volume of the extrudate (which is typically adaptable to change the absolute amount of the active ingredient without changing the concentration of the active ingredient in the extrudate), the active ingredient release profile (which can be altered by the judicious use and / or distribution of appropriate excipients), or the form and appearance (including novel forms, colors, and patterns that may aid in medical compliance for a particular patient), etc.

[0304] Preferably, the extruded article is a filament.

[0305] Preferably, the extruded article is a pharmaceutical, nutraceutical, or food supplement solid dosage form, such as a tablet. Preferably, the extruded article is a pharmaceutical solid dosage form, such as a tablet. Preferably, the extruded article 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.

[0306] Preferably, the extruded article is a solid oral dosage form, most preferably an immediate release solid dosage form.

[0307] The immediate release solid dosage form may preferably release at least 75% of the active ingredient within a 45 minute period, preferably release at least 85% of the active ingredient within a 30 minute period, and preferably release at least 85% of the active ingredient within a 15 minute period. The skilled person may refer to the European Pharmacopoeia 8.0. Strasbourg, France; Council of Europe; European Directorate for the Quality of Medicine; 2014.

[0308] The longest dimension of the extruded article (e.g., in either the X, Y or Z direction) (Dmax) is preferably 3 mm, 5 mm, 8 mm, 10 mm or 12 mm or more. The longest dimension of the extruded article is preferably 30 mm, 25 mm, 20 mm, or 15 mm or less.

[0309] The shortest dimension of the extruded article (i.e. not necessarily the thinnest part, but the maximum length of the thinnest dimension, or the shortest dimension of X, Y, or Z) Dmin is preferably 0.1 mm, 0.5 mm, 1 mm, 3 mm, 5 mm, 8 mm, 10 mm, or 12 mm or more. Preferably, the shortest dimension of the extruded article is 30 mm, 25 mm, 20 mm, 15 mm, 10 mm, 8 mm, 5 mm, or 2 mm or less. Preferably, the shortest dimension of the extruded article (Dmin) is 0.1 to 30 mm.

[0310] The volume of the extrudate is preferably less than 3 mm 3 , 5mm 3、10mm 3 , 50mm 3、 100mm 3 , or 200mm 3 The volume of the extruded article is preferably 500 mm 3 , 300mm 3 , 250mm 3 , 150mm 3 , or 50mm 3 Preferably, the volume of the extruded article is between 3 and 500 mm 3 It is.

[0311] Preferably, the extrudate has a weight of 1 mg or more, preferably 5 mg, 10 mg, 50 mg, or 80 mg or more. Preferably, the extrudate has a weight of 1000 mg or less, preferably 500 mg or less, 250 mg or less, or 100 mg or less. Preferably, the extrudate has a weight of between 1 and 1000 mg.

[0312] Preferably, the extruded article is a pharmaceutical, nutraceutical, or dietary supplement solid dosage form. Preferably, the extruded article comprises at least one active ingredient, preferably a pharmaceutical, nutraceutical, or dietary supplement active ingredient, as defined herein. Most preferably, the at least one active ingredient is a pharma- ceutical active ingredient.

[0313] Suitably, the extruded article includes a permanent plasticizer as defined herein.

[0314] Suitably, the extruded article comprises one or more other components, as defined herein.

[0315] Many of the preferred features of the extruded article are described elsewhere herein. For example, features described in connection with the method of making the extruded article may suitably reflect features of the extruded article itself (e.g., layer height). Suitably, the extruded article includes components provided by the extrudable composition(s) used to form it, and may be considered to include the associated extrudable composition. Components of extrudable compositions and extruded articles

[0316] The components described below apply to the methods, apparatus, packages, and applications described herein. Extrudable Carrier

[0317] The extrudable carrier is preferably an extrudable material suitable for use in extrusion, such as 3D printing, and in particular as a printable (and preferably meltable / softenable) carrier component in a filament for FFF 3D printing. Suitably, any suitable polymer(s) may be used.

[0318] The extrudable carrier is preferably selected from polymers (preferably cationic or neutral polymers or copolymers) having a viscosity of less than 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 preferably has a viscosity of at least 1 mPa.s. Preferably the polymer has a viscosity of 1 to 300 mPa.s.

[0319] The extrudable carrier(s) preferably comprises or comprises one or a compound 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. Preferably, the molecular weight is between 2,000 and 500,000 g / mol, or between 2,000 and 100,000 g / mol. Preferably, the molecular weights are stated in g / mol. Preferably, the molecular weights are average molecular weights, especially when they refer to polymers.

[0320] The extrudable carrier preferably comprises one or more compounds that are somewhat soluble, slightly soluble, very slightly soluble, substantially insoluble, or insoluble according to the standard USP definitions (and standard tests defined by the USP), as shown in the table below. JPEG2025061315000001.jpg49150

[0321] Preferably, the extrudable carrier(s) comprises one or more compounds that are very slightly soluble, substantially insoluble, or insoluble according to the standard USP definition as per the table above. Preferably, the extrudable carrier(s) comprises one or more compounds that are substantially insoluble or insoluble according to the standard USP definition as per the table above.

[0322] The extrudable carrier itself preferably has a melting point of from 140 to 250°C, preferably from 160 to 250°C, or from 170 to 230°C.

[0323] The melting point (or glass transition temperature) of the extrudable carrier is preferably less than that of the active ingredient, preferably at least 20° C., 40° C., or 50° C. The extrudable carrier preferably has a melting point of from 140° C. to 250° C., from 150° C. to 200° C., or from 155° C. to 175° C.

[0324] The extrudable carrier itself preferably has a glass transition temperature of 0° C. or higher, 10° C. or higher, 20° C. or higher, 25° C. or higher, 40° C. or higher, 50° C. or higher, 60° C. or higher, 70° C. or higher, 80° C. or higher, 90° C. or higher, 100° C. or higher, 120° C. or higher, 140° C. or higher, 160° C. or higher, 180° C. or higher, or 200° C. The extrudable carrier itself preferably has a glass transition temperature of 0° C. to 250° C., preferably 0° C. to 200° C. In some embodiments, the extrudable carrier does not have such a glass transition temperature, although observed softening may still occur.

[0325] The extrudable carrier preferably has a glass transition temperature lower than the melting point of the active ingredient, preferably at least 20°C lower, at least 40°C lower, or at least 50°C lower.

[0326] Preferably, the extrudable carrier has a specific heat of 0.1 to 1 cal / g° C., most preferably 0.3 to 0.5.

[0327] The extrudable carrier preferably has a density of 1.1 to 1.6 g / mL, most preferably 1.2 to 1.4.

[0328] Any suitable extrudable carrier may be used. In the pharmaceutical context, extrudable carriers are routinely used in the formulation of solid dosage forms such as tablets and capsules.

[0329] The extrudable carrier(s), particularly where an immediate release solid dosage form is desired, is preferably selected from carriers (preferably cationic or neutral polymers or copolymers) having a viscosity of at least 1 mPa·s but not more than 50 mPa·s, preferably not more than 30 mPa·s, preferably not more than 10 mPa·s - preferably having a viscosity of 1 to 50 mPa·s, preferably of 1 to 25 mPa·s, preferably between 2 to 8 mPa·s. The extrudable carrier(s) are preferably selected from carriers having a molecular weight of at least 20,0000 g / mol, preferably at least 35,000, preferably at least 45,000 but preferably less than 1,000,000 g / mol, preferably less than 100,000 g / mol - preferably with a molecular weight of 20,000 to 1,000,000 g / mol, preferably 35,000 to 65,000 g / mol, particularly when an immediate release solid dosage form is desired. The extrudable carrier, particularly where an immediate release solid dosage form is desired, is preferably selected from carriers having a glass transition temperature (Tg) of at most 100° C., preferably having a glass transition temperature of at most 80° C., preferably having a glass transition temperature of at most 50° C., preferably having a glass transition temperature of at least −10° C., preferably having a glass transition temperature of at least 35° C., preferably having a Tg of −10° C. to 100° C., preferably having a Tg of 30° C. to 60° C. In some embodiments, the extrudable carrier(s) may not have such a glass transition temperature, although the observed softening may still occur. The extrudable carrier(s), particularly where an immediate release solid dosage form is desired, is preferably an (optionally alkyl-, preferably methyl- or ethyl-) acrylate, methacrylate and / or ethacrylate copolymer (preferably comprising amine-containing monomer units), preferably having a viscosity of 2 to 8 mPa., preferably having a molecular weight of 35,000 to 65,000 g / mol, and / or preferably having a Tg of 30 to 60° C.In a particular embodiment, the copolymer involved is preferably poly(butyl methacrylate-co-(2-demethylaminoethyl) methacrylate-co-methyl methacrylate), preferably with a molar ratio of the respective monomers of 1:2:1 (±5% for each molar value of the molar ratio). The extrudable carrier is preferably Eudragit E.

[0330] The extrudable carrier(s), particularly where a sustained release solid dosage form is desired, is preferably selected from carriers having a viscosity of at least 1 mPa·s but not more than 30 mPa·s, 20 mPa·s, or 16 mPa·s, preferably from 1 to 30 mPa·s, preferably from 1 to 15 mPa·s. The extrudable carrier(s), particularly where a sustained release solid dosage form is desired, is preferably selected from carriers having a molecular weight of at least 10,000 g / mol, 250000 g / mol, or 30,000 g / mol, but preferably from carriers having a molecular weight of less than 100,000 g / mol, more preferably less than 40,000 g / mol - preferably from 10,000 to 100,000 g / mol, preferably from 29,000 to 35,000 g / mol. The extrudable carrier is preferably selected from carriers having a glass transition temperature (Tg) of at most 100°C, preferably at most 80°C, preferably at most 70°C, but preferably at least 40°C, more preferably at least 50°C, preferably a Tg of 50°C to 100°C, preferably 55°C to 70°C, particularly when a sustained release solid dosage form is desired. In some embodiments, the extrudable carrier(s) may not have such a glass transition temperature, although the observed softening may still occur. The extrudable carrier is preferably an (optionally alkyl-, preferably methyl- or ethyl-) acrylate, methacrylate and / or ethacrylate copolymer (preferably containing amine-containing monomer units), particularly when a sustained release solid dosage form is desired, preferably having a viscosity of 1 to 15 mPa., preferably having a molecular weight of 29,000 to 35,000 g / mol, and / or preferably having a Tg of 55 to 70°C. In a particular embodiment, the copolymer involved is preferably poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), preferably in a molar ratio of the respective monomers of 1:2:0.2 (±5% for each molar value of that ratio).The extrudable carrier is preferably Eudragit RL.

[0331] The extrudable carrier(s), particularly where a delayed release solid dosage form is desired, is preferably selected from carriers having a viscosity of at least 20 mPa.s, preferably at least 40 mPa.s, preferably at least 50 mPa.s, but preferably has a viscosity of 300 mPa.s or less, preferably 210 mPa.s or less - preferably from carriers having a viscosity of 20-300 mPa.s, preferably 40-210 mPa.s. The extrudable carrier(s) are preferably selected from carriers having a molecular weight of at least 10,000 g / mol, preferably at least 15,000, but preferably less than 400,000 g / mol - in certain embodiments the molecular weight is between 10,000 and 400,000 g / mol, preferably between 10,000 and 25,000 g / mol, while in other embodiments the molecular weight is between 100,000 and 350,000 g / mol. The extrudable carrier(s) are preferably selected from carriers having a glass transition temperature (Tg) of at least 80°C, preferably at least 90°C, preferably at least 100°C, but preferably at most 200°C, preferably at most 160°C, preferably between 50°C and 200°C, preferably between 90°C and 160°C, especially when a delayed release solid dosage form is desired. In some embodiments, the observed softening may still occur, but the active ingredient carrier(s) may not have such a glass transition temperature. The extrudable carrier(s) is preferably selected from among the following, especially when a delayed release solid dosage form is desired: optionally alkyl-, preferably methyl- or ethyl-) acrylate, methacrylate and / or ethacrylate polymers or copolymers (preferably free of amine-containing monomeric units), preferably having a viscosity between 90 and 210 mPa.s, preferably having a molecular weight between 100,000 and 350,000 g / mol, and / or preferably having a glass transition temperature between 90 and 140° C.; where the relevant polymer or copolymer is preferably selected from: poly(methacrylic acid-co-ethyl acrylate), preferably with a molar ratio of the respective monomers of 1:1 (±5% for each molar value of the ratio); poly(methacrylic acid-co-methyl methacrylate), preferably with a respective monomeric molar ratio of 1:1 (±5% for each molar value of the ratio); poly(methacrylic acid-co-methyl methacrylate), preferably with a respective monomeric molar ratio of 1:2 (±5% for each molar value of the ratio); or The cellulose or cellulose derivative, preferably a hydroxypropyl methylcellulose (HPMC) derivative, most preferably a hydroxypropyl methylcellulose (HPMC) acetate succinate (HPMCAS), preferably having a molecular weight of 10,000 to 25,000 g / mol and / or preferably having a glass transition temperature of 100 to 145° C. (or preferably 100 to 165° C.); wherein the HPMCAS is preferably selected from Aqoat LG, Aqoat MG, and / or Aqoat HG. Preferably, the HPMC derivative may however also include hydroxypropyl methylcellulose phthalate (HPMCP), such as grades thereof, such as HP-50, HP-55 and HP-55S grades.

[0332] In principle, any suitable extrudable carrier can be used, including one or more selected from (optionally alkyl-, preferably methyl- or ethyl-) acrylate, methacrylate and / or ethacrylate copolymers (preferably comprising amine-containing monomer units); optionally alkyl-, preferably methyl- or ethyl-) acrylate, methacrylate and / or ethacrylate polymers or copolymers (preferably not comprising any amine-containing monomer units); cellulose or cellulose derivatives; polyvinyl alcohol (PVA); polylactic-co-glycolic acid (PLGA); and / or any suitable pharma- ceutically acceptable carrier.

[0333] Optionally alkyl-, preferably methyl- or ethyl-) acrylate, methacrylate and / or ethacrylate polymers or copolymers are particularly advantageous for supporting high loadings of active ingredients.

[0334] Suitably, the extrudable carrier is 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 thereof.

[0335] In some embodiments, extrudable carriers such as polyvinylpyrrolidone polymers or polyvinylpyrrolidone-derived polymers may be employed, especially when the active ingredient has limited solubility in the target solubilization medium (e.g., in the body). Such polymers can facilitate dissolution of active ingredients that may otherwise exhibit limited solubility. In certain embodiments, PVP K29-32 (povidone) may be used. When present, preferably, the PVP or PVP-based carrier is present (e.g., in the extrudable composition) at a concentration of 20-80 wt%, preferably at a concentration of 40-60 wt%, preferably at a concentration of 45-55 wt%. PVP and PVP-based carrier polymers may be used together with one or more filler(s) and, optionally, together with other ingredients such as plasticizer(s). Mixtures of different PVPs or PVP-based carriers may also or alternatively be used (e.g., PVPs of different molecular weights).

[0336] In some embodiments, polyalkylene glycols or polyalkylene glycol-derived polymers may be employed as extrudable carriers. In certain embodiments, the polyalkylene glycol or polyalkylene glycol-derived carrier polymer is a polyethylene glycol (PEG) or polyethylene glycol-derived carrier polymer. Preferably, wherever the PEG or PEG-derived carrier polymer is deployed, at least a portion of the PEG or PEG-derived carrier polymer has a molecular weight of at least 100,000, preferably at most 1,000,0000, preferably between 100,0000 and 1,000,0000. However, mixtures of different polyalkylene glycols and polyalkylene glycol-derived polymers (e.g., PEG or PEG-based carrier polymers) may be incorporated within the filaments and / or corresponding dosage forms. For example, a high molecular weight PEG may be used together with a relatively low molecular weight PEG to achieve an optimal balance of properties. Higher molecular weight PEG and PEG-based polymers (e.g., Mw ≥ 80,0000) may function as carrier molecules, while lower molecular weight PEG and PEG-based polymers (e.g., Mw 200-20000) may function as plasticizers and / or solubility enhancers. Increasing the proportion of low molecular weight PEG may decrease the Tg of the resulting filaments. In addition, increasing the proportion of low molecular weight PEG is also advantageous for enhancing drug release. Suitably, any PEG or PEG-based carrier polymer may be used with one or more fillers, although such polymers may be used with or without non-melting components.

[0337] Preferably, the extrudable carrier is a pharma- ceutically acceptable polymer (or a GRAS approved polymer). The extrudable carrier may comprise one or more thermoplastics. The extrudable carrier may comprise one or more pharma- ceutically acceptable polymers selected from the group comprising: optionally alkyl-)acrylate, methacrylate or ethacrylate polymers or copolymers, optionally polymers or copolymers containing amine-containing monomer units, silicones, polyurethanes, polyolefins (e.g., polystyrene), polyalkylenes (e.g., polystyrene), polyalkylene glycols, polymers or copolymers derived from polyalkylene glycols, polyvinylpyrrolidone or polymers or copolymers derived from polyvinylpyrrolidone, polyvinyl alcohol, polyamides, acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polyglycolide, nylon, and / or copolymers or mixtures thereof. The list is by no means exhaustive. Preferably, the extrudable carrier is polyvinyl alcohol.

[0338] Preferably, the extrudable composition of the present invention comprises more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% by weight of the extrudable carrier. Preferably, the extrudable composition comprises up to 99%, 95%, 90%, 80%, or 60% by weight of the extrudable carrier. Preferably, the extrudable composition comprises from 10% to 95% by weight of the extrudable carrier.

[0339] Preferably, the extruded article of the present invention comprises more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% by weight of the extrudable carrier. Preferably, the extruded article of the present invention comprises less than 99%, 95%, 90%, 80%, or 60% by weight of the extrudable carrier. Preferably, the extruded article comprises more than 10% and less than 95% by weight of the extrudable carrier.

[0340] One or more extrudable carriers (as optionally defined herein) may be used. Temporary Plasticizer

[0341] Transient plasticizers allow the extrudable composition 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 the extruded article and / or extrudable element). Advantageously, this allows heat sensitive ingredients and / or components to be used in the extrudable composition and / or extrudable article, including heat sensitive active ingredients. Additionally, this allows the use of active ingredients and / or other ingredients with low melting points, for example, with respect to the extrudable carrier.

[0342] Suitably, the temporary plasticizer may result in a change in the physical properties of the extruded article and / or extrudable element, for example a decrease in the glass transition temperature of the extruded article and / or extrudable element. This may result in the physical properties of the extruded article and / or extrudable element not being optimal for subsequent handling, for example if the glass transition temperature of the extruded article and / or extrudable element is too low, the extruded article and / or extrudable element may be very flexible. Advantageously, the temporary plasticizer may be removed or partially removed during the process for producing the extruded article and / or extrudable element, for example during or after extrusion. This may result in a change in the physical properties of the extruded article and / or extrudable element, for example an increase in the glass transition temperature of the extruded article and / or extrudable element, thereby decreasing the flexibility of the extruded article and / or extrudable element, depending on the amount of temporary plasticizer removed. Thus, the physical properties of the extrudable element and / or extruded article may be controlled by varying the level of temporary plasticizer contained therein.

[0343] Preferably, the temporary plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g. 100 kPa). Preferably, the or each vaporizable substance is a liquid, preferably a solvent or water. Preferably, the solvent is a pharma- ceutically, nutritionally, or food supplement acceptable grade solvent. Preferably, the temporary plasticizer has a boiling point of 150° C. or less, e.g. 140° C. or less, 130° C. or less, 120° C. or less, 110° C. or less, 105° C. or less, or 100° C. or less (preferably at standard ambient pressure, e.g. 100 kPa). Preferably, the temporary plasticizer has a boiling point of 25° C. or more and 150° C. or less (preferably at standard ambient pressure, e.g. 100 kPa). In one embodiment, the temporary plasticizer is a pharma-ceutically acceptable grade solvent or water (e.g. distilled water). Preferably, the pharma- ceutically acceptable grade solvent is an ICH Class 3 solvent (International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use, ICH Harmonised Guideline; Impurities. Residual Solvents Guideline Q3C(R6)). Preferably, the temporary plasticiser is ethanol. Preferably, the temporary plasticiser is water.

[0344] Other components of the extrudable composition and / or extruded article may include residual levels of temporary plasticizer, e.g., residual water in the extrudable carrier. It is understood that the amounts of temporary plasticizer present in the extrudable composition and extruded article defined herein may include contributions from other components present.

[0345] Preferably, the extrudable composition comprises 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% or more by weight of the temporary plasticizer. Preferably, the extrudable composition comprises 50% or less, 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, or 2% or less by weight of the temporary plasticizer. Preferably, the extrudable composition comprises 0.1 to 50% of the temporary plasticizer.

[0346] Preferably, the extruded article comprises 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or 30% or more by weight of temporary plasticizer. Preferably, the extruded article comprises 50% or less, 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, or 2% or less by weight of temporary plasticizer. Preferably, the extruded article comprises 0.1 to 50% temporary plasticizer.

[0347] Preferably, the extruded article has a lower level of temporary plasticizer than the extrudable composition used to make the extruded article, preferably 10%, 20%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% lower.

[0348] One or more transient plasticizers (optionally defined herein) may be used.

[0349] In certain embodiments, the extrudable composition may be used to form an extrudable element, such as a 3D printable filament. The composition of such an extrudable element may conform to that described herein in connection with the extrudable composition, but in some embodiments, such an extrudable element may include a lower concentration of temporary plasticizer than the extrudable composition used to make the extrudable element, and in some embodiments may be substantially free or free of temporary plasticizer. Suitably, the extrudable element still enjoys the benefits of the present invention, for example, by being formed at a lower temperature than would have to be the case if the temporary plasticizer had not been present in the precursor extrudable composition used to make the extrudable element. Permanent Plasticizer

[0350] In one embodiment, the extrudable composition and / or extruded article further comprises a permanent plasticizer. A permanent plasticizer is a plasticizer that is not removed during the manufacturing process to produce the extruded article and / or extrudable composition. The permanent plasticizer reduces the glass transition (or softening) temperature of the extrudable composition, thereby reducing the extrusion temperature used to form the extruded article or to form the extrudable element. The use of both a permanent plasticizer and a temporary plasticizer allows for even lower extrusion temperatures to be utilized compared to the use of either one alone. In these examples, the extrudable compositions and extruded articles of the present invention can be used in combination with other ingredients, particularly heat-sensitive active ingredients.

[0351] Suitably, the permanent plasticizer is a pharma- ceutically acceptable plasticizer. Many pharma-ceutically acceptable plasticizers are known in the art for use in forming pharmaceutical extruded articles (i.e., solid dosage forms).

[0352] Preferably, the melting point of the permanent plasticizer is lower than the melting point of the extrudable carrier. Preferably, the melting point of the permanent plasticizer is 140° C. or less, preferably 130° C. or less, 120° C. or less, 110° C. or less, or 100° C. or less. Preferably, the melting point of the permanent plasticizer is 0° C. or more and 140° C. or less, preferably 50° C. or more and 140° C. or less.

[0353] Preferably, the permanent plasticizer has a glass transition (softening) temperature lower than the glass transition (softening) temperature of the extrudable carrier. Preferably, the glass transition (softening) temperature of the permanent plasticizer is 100° C. or less, 90° C. or less, 80° C. or less, 70° C. or less, 60° C. or less, 50° C. or less, 40° C. or less, 30° C. or less, 20° C. or less, 10° C. or less, 0° C. or less, or −10° C. or less. Preferably, the glass transition (softening) temperature of the permanent plasticizer is −10 to 100° C.

[0354] Preferably, the permanent plasticizer is a pharma- ceutical, nutritional, or food supplement acceptable grade excipient.

[0355] Suitably, the permanent plasticizer is selected from the group consisting of triethyl citrate (TEC), glycerol, castor oil, oleic acid, glycerol, triacetin, polyalkylene glycols (e.g., polyethylene glycol or polypropylene glycol, e.g., PEG 400), and HOCH. 2 (CHOH)nCH 2 The permanent plasticizer is selected from one or more of the sugar alcohols having the general formula: OH, where n is from 2 to 12. Preferably, the sugar alcohol is selected from ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, and maltotritol. Preferably, the permanent plasticizer is sorbitol or triethyl citrate.

[0356] Certain permanent plasticizers may be more suitable than others depending on the particular extrudable carrier, temporary plasticizer, active ingredient, if present, and other ingredients, if present.

[0357] Preferably the extrudable composition and / or extruded article comprises at least 1% by weight of 2%, 4%, 5%, 8% or 10% by weight of permanent plasticizer. Preferably the extrudable composition and / or extrudate comprises from 1% to 50% by weight of permanent plasticizer, preferably from 1% to 25% by weight, preferably from 1% to 10% by weight of the total weight of the extrudable composition and / or extrudate.

[0358] More than one permanent plasticizer (optionally defined herein) may be used. active ingredient

[0359] The at least one active ingredient is preferably a pharma- ceutically acceptable drug substance, which may be any suitable pharmaceutical compound or a pharma- ceutically acceptable salt, solvate (including hydrate), prodrug, or polymorph thereof. Thus, any extrudable carriers, temporary plasticizers, permanent plasticizers, and / or other ingredients in the extrudable composition are preferably pharma- ceutically acceptable extrudable carriers, temporary plasticizers, permanent plasticizers, and / or other ingredients.

[0360] At least one active ingredient is preferably in the same form (and has substantially the same purity) as the active ingredient is present in the approved pharmaceutical agent.

[0361] In certain embodiments, at least one active ingredient is highly soluble, freely soluble, or soluble according to the standard USP (United States Pharmacopeia) definition of solubility. In other embodiments, at least one active ingredient is partially soluble, slightly soluble, or very slightly soluble according to the standard USP definition of solubility.

[0362] In certain embodiments, at least one active ingredient is highly soluble according to the standard USP definition for solubility.

[0363] In certain embodiments, at least one active ingredient is freely soluble according to the standard USP definition for solubility.

[0364] In certain embodiments, at least one active ingredient is soluble according to the standard USP definition for solubility.

[0365] In certain embodiments, at least one active ingredient is soluble to some extent according to the standard USP definition of solubility.

[0366] In certain embodiments, at least one active ingredient is slightly soluble according to the standard USP definition of solubility.

[0367] In certain embodiments, at least one active ingredient is very slightly soluble according to the standard USP definition of solubility.

[0368] In certain embodiments, at least one active ingredient is substantially insoluble according to the standard USP definition of solubility.

[0369] In certain embodiments, at least one active ingredient is susceptible to thermal degradation. In some embodiments, at least one active ingredient is susceptible to thermal degradation at temperatures greater than the temperatures to which the extrudable composition is exposed during the method of producing the extruded article and / or extrudable element as defined herein. In one embodiment, at least one active ingredient is susceptible to thermal degradation at temperatures greater than 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 180°C, or 200°C. Suitably, at least one active ingredient is susceptible to thermal decomposition at temperatures between 90 and 200°C or less. Such thermal degradation is suitably identifiable by techniques known in the art, such as DSC.

[0370] Preferably, the active ingredient is a small molecule active ingredient. Preferably, the active ingredient is a biologically active ingredient, such as a protein or a peptide.

[0371] In certain embodiments, the extrudable composition and / or extruded article comprises one active ingredient, hi other embodiments, the extrudable composition and / or extruded article comprises two active ingredients.

[0372] Suitably, the extruded articles of the invention comprise 0.5 wt%, 1 wt%, 5 wt%, 10 wt%, 20 wt%, or 40 wt% or more of the active ingredient. Suitably, the extrudates of the invention comprise 60 wt%, 50 wt%, or 30 wt% or less of the active ingredient. Suitably, the extruded articles of the invention comprise 0.5 to 50 wt% of the active ingredient.

[0373] Suitably, the extrudable composition of the invention comprises 0.5 wt%, 1 wt%, 5 wt%, 10 wt%, 20 wt%, or 40 wt% or more of the active ingredient. Suitably, the extrudable composition of the invention comprises 60 wt%, 50 wt%, or 30 wt% or less of the active ingredient. Suitably, the extrudable composition(s) of the invention comprise between 0.5 wt% and 60 wt% of the active ingredient. Other parts

[0374] In certain embodiments, the extrudable composition and / or the extruded article further comprises one or more other ingredients, which may suitably include one or more excipients, excipient carriers, and / or diluents, all of which may be included in the extruded article.

[0375] In particular, one or more other ingredients in the extrudable composition and / or extruded article may be selected from one or more fillers / diluents, anti-adherents, binders, disintegrants, glidants, lubricants, flavors, preservatives, sweeteners, colorants, and coating agents.

[0376] Fillers / diluents, anti-adherents, binders, disintegrants, glidants, lubricants, flavorings, preservatives, sweeteners, coloring agents, and coating agents are known in the pharmaceutical, nutraceutical and food supplement arts, and any of these may be located where appropriate or desired for a particular pharmaceutical, nutraceutical or food supplement formulation.

[0377] Preferably, the fillers / diluents, anti-adherents, binders, disintegrants, glidants, lubricants, flavours, preservatives, sweeteners, colourants and coating agents are substantially inert and / or preferably have minimal or no interaction with other components of the extruded article and / or extrudable composition.

[0378] Suitable anti-adherents may include magnesium stearate. Suitable diluents / fillers may include vegetable cellulose, dibasic calcium phosphate, vegetable fats and oils, 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, cellulose ethers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, and derivatives thereof; sugar alcohols, such as xylitol, sorbitol, or maltitol; synthetic polymers, such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). Suitable disintegrants may include cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose, croscamellose sodium, modified sodium starch, and / or starch glycolate. Suitable lubricants may include silica; sodium stearyl fumarate; fats and oils, such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable lubricants may include fumed silica, talc, magnesium carbonate, and / or colloidal silica. Suitable coatings may include tablet coatings (e.g., cellulose ether hydroxypropyl methylcellulose (HPMC) film coatings; synthetic polymers, shellac, corn protein zein or other polysaccharides, gelatin; enteric coatings, including fatty acids, waxes, shellac, plastics, vegetable fibers) to protect tablet ingredients from deterioration due to moisture in the air and to make large or unpleasant tasting tablets easier to swallow. Suitable colorants include curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, quinoline yellow, sunset yellow FCF, cochineal, azorubin, amaranth, poncelo 4R, erythrosine, allura red AC, patent blue V, indigotine, brilliant blue FCF, chlorophyll, copper complex of chlorophyll, green S, plain caramel, caustic sulfite caramel.They may include ammoniacal caramel, ammoniacal caramel sulfite, brilliant black BN, vegetable carbon, brown HT, carotene, annatto, paprika extract, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, beet red, anthrocyanin, calcium carbonate, titanium dioxide, iron oxides and hydroxides, aluminum, silver, gold and / or resolvin BK. General classes of excipients are well understood to those of skill in the art.

[0379] Solid oral dosage forms may be designed to release the active portion of the formulation at a point in the digestive tract where bioavailability is maximized and pre-systemic degradation is minimized. At least one additional agent may be included to facilitate absorption of the active portion 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, pharma- ceutically acceptable excipient or carrier, such as lactose, sodium citrate, or dicalcium phosphate, and / or one or more of: a) fillers or extenders, such as starch, 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-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate. e) solution retarding agents such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; 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 such excipients as lactose or high molecular weight polyethylene glycols.

[0380] Such excipients may be selected to match the properties of the extrudate, the properties of the extrudable composition, or both, or to match a sensible compromise between both. For example, with respect to extrudates (i.e., solid dosage forms), excipients may be selected to: facilitate ease of administration to the target patient population by the intended route; improve dosing compliance; provide consistency and control of the drug's bioavailability; enable bioavailability; improve the stability of the active ingredient, including protection from degradation; ensure a robust and reproducible physical product. With respect to extrudable compositions (e.g., filaments for use in 3D printing), excipients 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 (an optimal balance between the flexibility and stiffness of the filament is desirable to ensure that the filament is successfully transported to the extrusion nozzle, but can then be easily extruded from the nozzle); and enable the production of optimal extruded articles (e.g., following the points above).

[0381] Preferably, the extruded article includes a coating. Preferably, the coating protects the internal contents of the extruded article from light, moisture and / or air (i.e., oxygen). Preferably, the coating is a lubricant as defined herein. Uses of extruded articles

[0382] The extruded articles of the present invention can take a variety of forms, but most preferably the extruded articles are pharmaceutical, nutraceutical and / or food supplement solid dosage forms, but most preferably are solid dosage forms.

[0383] In certain embodiments, the extruded article is a pharmaceutical solid dosage form.

[0384] In certain embodiments, the extruded article is an extruded article for use in the manufacture of a pharmaceutical product.

[0385] The present invention also provides a method for treating and / or preventing a disease, condition, or disorder in a subject in need of such treatment. Preferably, the method comprises administering a therapeutically effective amount of the extrudate to the subject. Preferably, the subject is an animal or human subject, most preferably a human subject. Preferably, the extrudate is provided for use as a medicament.

[0386] Preferably, the extruded article is an immediate release pharmaceutical solid dosage form for oral administration. Packaging of extrudable compositions

[0387] The extrudable composition(s) of the present invention may be packaged by any one of several methods well known in the art. For example, cartridges for use with an extruder can be pre-loaded with the extrudable composition. Advantageously, the cartridges can be manufactured at a location different from where the extruder is located and inserted into the extruder as needed. Thus, if the extruder is located at a different site, a user of the extrusion device, e.g., a pharmacist, can select a suitable package of extrudable composition, insert said package into the extrusion device, and use said extrudable composition and extruder to produce the extrudate.

[0388] Suitably, there is provided an extrudable composition package comprising: i. an extrudable composition comprising an extrudable carrier and a temporary plasticizer; ii. a container, said container comprising an extrudable composition.

[0389] Suitably, there is provided an extrudable composition package comprising: i. an extrudable composition comprising an extrudable carrier and a temporary plasticizer; ii. a syringe, said syringe comprising an extrudable composition.

[0390] Suitably, there is provided an extrudable composition package comprising: i. an extrudable composition comprising an extrudable carrier and a temporary plasticizer; ii. A cartridge, said cartridge comprising an extrudable composition.

[0391] The container is preferably adapted to an extrusion apparatus such that the contents of the container (e.g., an extrudable composition) can be conveyed through the extruder. In one embodiment, the container is adapted to allow the contents of the container (e.g., an extrudable composition) to be conveyed to the extrusion nozzle of the extruder.

[0392] In one embodiment, the container includes an extrusion nozzle.

[0393] Preferably, the container is a cartridge, preferably a 3D printer cartridge. Preferably, the cartridge comprises an extrudable composition, wherein the extrudable composition is in the form of a filament. Preferably, the cartridge comprises an extrudable composition, wherein the extrudable composition is in the form of a plurality of mini-tablets. Preferably, the cartridge comprises an extrudable composition, wherein the extrudable composition is in the form of an extrudable fluid.

[0394] Preferably, the container is a syringe and the extrudable composition is an extrudable fluid.

[0395] Preferably, the container is a heatable syringe. Advantageously, the syringe can be heated to form the extrudable fluid in situ.

[0396] Advantageously, if 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 function as an extruder, e.g., it is possible to write ink directly using the syringe.

[0397] Suitably, an extrudable composition package is provided comprising one or more extrudable compositions as defined herein, where the one or more extrudable compositions are optionally the same or different within the package.

[0398] 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, where the one or more extrudable compositions are optionally the same or different.

[0399] Suitably there is provided an extrudable composition package obtained by, obtained by or directly obtained by a process for producing an extrudable composition package as defined herein. Extrusion Product Packaging

[0400] The extruded articles of the present invention may be packaged by any one of several methods known in the art. For example, when pharmaceutical solid dosage forms according to the present invention are produced via extrusion equipment located in a pharmacy (e.g., to provide patients with customized medications on demand), the pharmacist can package the extruded article (e.g., solid dosage form) in a number of ways, including into a tablet bottle or into a monitored dosing system that can then be dispatched to a hospital, nursing home, etc. for ultimate dispensing to the patient.

[0401] Suitably, there is provided a method of producing an extruded article package, the method comprising packaging one or more extruded articles as defined herein, optionally the one or more extruded articles being the same or different.

[0402] Suitably there is provided an extruded article package obtained, obtained or directly obtained by a method of producing an extruded article package as defined herein.

[0403] Suitably, there is provided an extruded article package 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.

[0404] In some embodiments, the package may be formed by the same or different extrusion equipment. In some instances, the package and the extruded article may be produced simultaneously, whereby the extrusion operation utilizes one or more extrudable compositions of the extruded article and one or more extrudable compositions of the package, and the package may be formed around the extruded article during extrusion. Filament Production

[0405] The filaments are suitably manufactured by any one of the methods described in WO2016 / 038356 (by the applicant). However, such methods may incorporate the advantages of the present invention by utilizing an extrudable composition containing a transient plasticizer in the manufacture of the filaments, for example, since lower temperatures may be employed during hot melt extrusion of the filaments. Specific Embodiments of Extruded Articles

[0406] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; and ii. Transient plasticizers.

[0407] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; and ii. Temporary plasticizers with a boiling point below 120°C.

[0408] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; and ii. Transient plasticizers. wherein the transient plasticizer is present at a level of 5% by weight or greater of the total weight of the extrudable composition.

[0409] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the transient plasticizer is present at a level of 10% by weight or greater of the total weight of the extrudable composition.

[0410] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the transient plasticizer is present at a level of 15% or greater by weight of the total weight of the extrudable composition.

[0411] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; ii. Transient plasticizers; and iii. at least one active ingredient

[0412] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers.

[0413] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient iv. Permanent plasticizers; and v. one or more other ingredients, preferably an excipient, excipient carrier, and / or diluent.

[0414] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient iv. Permanent plasticizers; and v. Coloring agent.

[0415] Suitably, there is provided an extrudable composition comprising: i. at least 20% by weight of an extrudable carrier; ii. 1% by weight or more of a temporary plasticizer; iii. at least one active ingredient Here, the weights are relative to the total weight of the extrudable composition.

[0416] Suitably, there is provided an extrudable composition comprising: i. at least 20% by weight of an extrudable carrier; ii. 1% by weight or more of a temporary plasticizer; iii. at least one active ingredient; and iv. At least 1% by weight of a permanent plasticizer. Here, the weights are relative to the total weight of the extrudable composition.

[0417] Suitably, there is provided an extrudable composition comprising: i. at least 20% by weight of an extrudable carrier; ii. 1% by weight or more of a temporary plasticizer; iii. at least one active ingredient; and iv. at least 10% by weight of a permanent plasticizer. Here, the weights are relative to the total weight of the extrudable composition.

[0418] Suitably, there is provided an extrudable composition comprising: i. at least 20% by weight of an extrudable carrier; ii. 1% by weight or more of a temporary plasticizer; iii. at least one active ingredient iv. at least 10% by weight of a permanent plasticizer; and v. one or more other ingredients, preferably an excipient, excipient carrier, and / or diluent. Here, the weights are relative to the total weight of the extrudable composition.

[0419] Suitably, there is provided an extrudable composition comprising: i. an extrudable carrier selected from (optionally alkyl-)acrylate, methacrylate or ethacrylate polymers or copolymers, optionally amine-containing monomer units, silicones, polyurethanes, polyolefins (e.g., polystyrene), polyalkylene glycols, polymers or copolymers derived from polyalkylene glycols, polyalkylene glycol or polyalkylene glycol derived polymers or copolymers, polyvinylpyrrolidone or polyvinylpyrrolidone-derived polymers or copolymers, polyvinyl alcohol, polyamides, acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polyglycolide, nylon, and / or copolymers or mixtures thereof; ii. Temporary plasticizers with a boiling point below 120°C; iii. at least one active ingredient; and iv. Permanent plasticizers.

[0420] Suitably, there is provided an extrudable composition comprising: i. polyvinyl alcohol; ii. a temporary plasticizer selected from ethanol or water; iii. at least one active ingredient; and iv. Sorbitol.

[0421] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; and ii. Transient plasticizers.

[0422] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; and ii. Transient plasticizers. wherein the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extrudable composition.

[0423] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable element has a glass transition temperature of -50°C to 100°C.

[0424] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable element has a glass transition temperature of -15°C to -10°C.

[0425] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable element is a filament.

[0426] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; ii. Transient plasticizers; and iii. at least one active ingredient Here, the extrudable element is a filament.

[0427] Preferably, there is provided an extrudable element comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers Here, the extrudable element is a filament.

[0428] Suitably there is provided an extrudable compact comprising: i. an extrudable carrier; and ii. Transient plasticizers.

[0429] Suitably there is provided an extrudable compact comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable compressed form is a tablet or multiple tablets.

[0430] Suitably there is provided an extrudable compact comprising: i. an extrudable carrier; ii. Transient plasticizers; and iii. at least one active ingredient Here, the extrudable compressed form is a tablet or multiple tablets.

[0431] Suitably there is provided an extrudable compact comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers. Here, the extrudable compressed form is a tablet or multiple tablets.

[0432] Suitably there is provided an extrudable compact comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable compressed form has a weight of 10 to 100 mg.

[0433] Preferably, there is provided an extrudable fluid comprising: i. an extrudable carrier; and ii. Transient plasticizers.

[0434] Preferably, there is provided an extrudable fluid comprising: i. an extrudable carrier; ii. Transient plasticizers; and iii. at least one active ingredient

[0435] Preferably, there is provided an extrudable fluid comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers.

[0436] Preferably, there is provided an extrudable fluid comprising: v. an extrudable carrier; and vi. Temporary plasticizers. Here, the extrudable fluid is a fluid at ambient temperature.

[0437] Preferably, there is provided an extrudable fluid comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable fluid is a hot fluid.

[0438] Preferably, there is provided an extrudable fluid comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the extrudable fluid is a fluid at a temperature of 80° C. or higher.

[0439] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; and ii. Transient plasticizers.

[0440] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; ii. Transient plasticizers; and iii. at least one active ingredient

[0441] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; and ii. Transient plasticizers. Here, the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article.

[0442] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; ii. Transient plasticizers; and iii. at least one active ingredient Here, the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article.

[0443] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers. Here, the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article.

[0444] Suitably, a solid pharmaceutical, nutraceutical or food supplement dosage form is provided. i. an extrudable carrier; ii. Temporary plasticizers and Here, the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article.

[0445] Suitably, a solid pharmaceutical, nutraceutical or food supplement dosage form is provided. i. an extrudable carrier; and ii. Transient plasticizers.

[0446] Suitably, a solid pharmaceutical, nutraceutical or food supplement dosage form is provided. i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers. Here, the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article.

[0447] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers. wherein the transient plasticizer is present at a level of 5% by weight or greater of the total weight of the extruded article, and wherein the extruded article is a solid dosage form.

[0448] Suitably, there is provided an extruded article comprising: i. at least 20% by weight of an extrudable carrier; ii. 1% by weight or more of temporary plasticizer; iii. at least one active ingredient; and iv. at least 10% by weight of a permanent plasticizer. Here, the weights are relative to the total weight of the extruded article.

[0449] Suitably, there is provided an extruded article comprising: i. at least 20% by weight of an extrudable carrier; ii. 5% by weight or more of temporary plasticizers; iii. at least one active ingredient; and iv. at least 10% by weight of a permanent plasticizer. Here, the weights are relative to the total weight of the extruded article.

[0450] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient; and iv. Permanent plasticizers. wherein the transient plasticizer is present at a level of 1 wt % or greater of the total weight of the extruded article, and wherein the extruded article is a solid dosage form comprising multiple layers, each layer having a thickness of 10-1000 μm.

[0451] Suitably, there is provided an extruded article comprising: i. an extrudable carrier; ii. Transient plasticizers; iii. at least one active ingredient iv. Permanent plasticizers; and v. Lacquerware wherein the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article, and wherein the extruded article is a solid dosage form.

[0452] Suitably, there is provided an extruded article comprising: i. an extrudable carrier selected from (optionally alkyl-)acrylate, methacrylate or ethacrylate polymers or copolymers, optionally amine-containing monomer units, silicones, polyurethanes, polyolefins (e.g., polystyrene), polyalkylene glycols, polyalkylene glycol-derived polymers or copolymers, polyalkylene glycols or polyalkylene glycol-derived polymers or copolymers, polyvinylpyrrolidone or polyvinylpyrrolidone-derived polymers or copolymers, polyvinyl alcohol, polyamides, acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), polyglycolide, nylon, and / or copolymers or mixtures thereof; ii. Temporary plasticizers with a boiling point below 120°C; iii. at least one active ingredient; and iv. Permanent plasticizers. wherein the transient plasticizer is present at a level of 1 weight percent or greater of the total weight of the extruded article, and wherein the extruded article is a solid dosage form.

[0453] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element.

[0454] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element. An extrudable composition, wherein the extrudable composition is at least 20% by weight of an extrudable carrier; no more than 30% by weight of a temporary plasticizer; and the weights are relative to the total weight of the extrudable composition.

[0455] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier, a temporary plasticizer, and at least one active ingredient; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element. An extrudable composition, wherein the extrudable composition is at least 20% by weight of an extrudable carrier; no more than 30% by weight of a temporary plasticizer; and the weights are relative to the total weight of the extrudable composition.

[0456] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together 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: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element.

[0457] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together 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: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element. 13. An extrudable composition, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier; no more than 30% by weight of a temporary plasticizer; at least 10% by weight of a permanent plasticizer; and the weights are relative to the total weight of the extrudable composition.

[0458] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. Mix together the extrudable carrier and the temporary plasticizer.

[0459] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. An extrudable fluid.

[0460] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. An extrudable compressed form.

[0461] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. Extrudable element.

[0462] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element. Here, the mixing is shear mixing.

[0463] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element. Here, the mixing is shear mixing and the mixing is carried out at a temperature of 10° C. or higher.

[0464] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. optionally, further processing the mixture from step i. to form: a. An extrudable fluid; b. in an extrudable compressed form; or c. An extrudable element. Here, the mixing is shear mixing and the temporary plasticizer is sprayed onto the extrudable carrier during the mixing step.

[0465] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. An extrudable fluid. Here, the extrudable fluid is a fluid at ambient temperature.

[0466] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: b. An extrudable fluid. Here, the extrudable fluid is a hot fluid.

[0467] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. filling a container with the mixture from step i.

[0468] Preferably, there is provided a method of producing an extrudable fluid, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; ii. filling the mixture from step i into a container; and iii. Heating the container.

[0469] Preferably, there is provided a method of producing an extrudable fluid, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; ii. filling the mixture from step i into a container; and iii. Heating the container. Here, the container is a syringe.

[0470] Preferably, there is provided a method of producing an extrudable fluid, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; ii. filling the mixture from step i into a container; and iii. heating the vessel to a temperature above the glass transition temperature (or softening temperature) of the mixture formed from step i.

[0471] Preferably, there is provided a method of producing an extrudable fluid, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; ii. filling the mixture from step i into a container; and iii. heating the vessel to a temperature above the glass transition temperature (or softening temperature) of the mixture formed from step i. Here, the container is a syringe.

[0472] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. An extrudable compressed form.

[0473] Suitably, there is provided a method of making an extrudable composition, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. further processing the mixture from step i to form: a. An extrudable compressed form. Here, the compressed form is a tablet or multiple tablets.

[0474] Preferably, there is provided a method of manufacturing an extrudable element, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. extruding the mixture from step i; and iii. Removing or partially removing the transient plasticizer from the product from step ii.

[0475] Preferably, there is provided a method of manufacturing an extrudable element, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. extruding the mixture from step i; and iii. Removing or partially removing the transient plasticizer from the product from step ii; Here, the extrudable element is a filament.

[0476] Preferably, there is provided a method of manufacturing an extrudable element, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. extruding the mixture from step i; and iii. Removing or partially removing the transient plasticizer from the product from step ii. so that the extruded element has a glass transition (softening) temperature of -50°C to 100°C.

[0477] Preferably, there is provided a method of manufacturing an extrudable element, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. extruding the mixture from step i; and iii. Removing or partially removing the transient plasticizer from the product from step ii. so that the extruded element has a glass transition (softening) temperature of -15°C to -10°C.

[0478] Preferably, there is provided a method of manufacturing an extrudable element, the method comprising: i. mixing together an extrudable carrier and a temporary plasticizer; and ii. extruding the mixture from step i; and iii. removing or partially removing the transient plasticizer by heating the product from step ii and / or holding the product from step ii under reduced pressure until the extruded element has a glass transition (softening) temperature of -15°C to -10°C.

[0479] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable composition into a desired form, where the extrudable composition is as defined herein, and where the extrudable composition is with one or more auxiliary components (e.g., shell, coating, core); where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0480] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition includes an extrudable carrier and a transient plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer.

[0481] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition includes an extrudable carrier and a transient plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0482] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition comprises at least 20% by weight of an extrudable carrier and up to 30% by weight of a transient plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where The weights are relative to the total weight of the extrudable composition; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0483] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition includes an extrudable carrier, a transient plasticizer, and at least one active ingredient, optionally with one or more accessory components (e.g., shell, coating, core); where The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0484] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, up to 30% by weight of a transient plasticizer, and at least one active ingredient, optionally with one or more accessory components (e.g., shell, coating, core); where The weights are relative to the total weight of the extrudable composition; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0485] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition comprises at least 20% by weight of an extrudable carrier, up to 30% by weight of a transient plasticizer, and at least an active ingredient, optionally together with one or more auxiliary components (e.g., shell, coating, core); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; The weights are relative to the total weight of the extrudable composition; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0486] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition includes an extrudable carrier, a temporary plasticizer, at least one active ingredient, and a permanent plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0487] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable composition into a desired form (the extrudable composition comprises at least 20% by weight of an extrudable carrier, up to 30% by weight of a temporary plasticizer, at least one active ingredient, and at least 10% by weight of a permanent plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core)); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; Weights are relative to the total weight of the extrudable composition: The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0488] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition includes an extrudable carrier, and a transient plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; The extruded article comprises a lower amount of temporary plasticizer than the extrudable composition; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0489] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, where the extrudable composition comprises at least 20% by weight of an extrudable carrier and up to 30% by weight of a transient plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; The extruded article comprises a lower amount of temporary plasticizer than the extrudable composition; The weights are relative to the total weight of the extrudable composition, where the transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0490] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, up to 30% by weight of a transient plasticizer, and at least one active ingredient, optionally together with one or more accessory components (e.g., shell, coating, core); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; The extruded article comprises a lower amount of temporary plasticizer than the extrudable composition; The weights are relative to the total weight of the extrudable composition; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0491] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, up to 30% by weight of a temporary plasticizer, at least one active ingredient, and at least 10% by weight of a permanent plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; The extruded article comprises a lower amount of temporary plasticizer than the extrudable composition; The weights are relative to the total weight of the extrudable composition; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0492] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition into a desired form, wherein the extrudable composition comprises at least 20% by weight of an extrudable carrier, up to 30% by weight of a temporary plasticizer, at least one active ingredient, and at least 10% by weight of a permanent plasticizer, optionally with one or more auxiliary components (e.g., shell, coating, core); where the extruded article is a solid dosage form of a pharmaceutical, nutraceutical or food supplement; the extruded article has 10% less transient plasticizer than the extrudable composition; The weights of are relative to the total weight; The transient plasticizer is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0493] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable composition into a desired form, where extrudable composition is as defined herein; where the extruded article is a solid dosage form of a pharmaceutical, dietary supplement, or food supplement; the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0494] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable element into a desired form, optionally with one or more auxiliary elements (e.g., shell, coating, core), where the extrudable element is as defined herein; where the extrudable element initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0495] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable compressed form into a desired form, where extrudable compressed form is as defined herein; where the extrudable compressed foam initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (suitably at standard ambient pressure, e.g., 100 kPa); The method further includes removing or partially removing the transient plasticizer via vaporization.

[0496] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable fluid into a desired form (wherein extrudable fluid is as defined herein); where the extrudable fluid initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0497] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding an extrudable composition onto a build platform into a desired form, where extrudable composition is as defined herein; where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0498] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable composition into a desired form, where extrudable composition is a form as defined herein; and ii. heating the desired form from step i and / or holding the desired form from step i under reduced pressure to remove or partially remove the transient plasticizer; where The extrudable composition initially comprises a transient plasticizer, which is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa).

[0499] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable composition into a desired form, where the extrudable composition is a form as defined herein; and ii. heating the desired form from step i and / or holding the desired form from step i under reduced pressure such that at least 10% by weight of the transient plasticizer is removed; where The extrudable composition initially comprises a transient plasticizer, which is a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa).

[0500] Preferably, there is provided a method of producing an extruded article, the method comprising: i. extruding the extrudable composition into a desired form, where the extrudable composition is as defined herein and the desired form is built up layer by layer; where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer via vaporization.

[0501] Preferably, there is provided a method of producing an extruded article, the method comprising: i. providing an extrudable composition comprising an extrudable carrier; and ii. extruding the extrudable composition, optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form; where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer from the extruded article via vaporization before, during, or after the extrusion step.

[0502] Suitably, there is provided a method for producing a pharmaceutical, nutraceutical, or food supplement solid dosage form, the method comprising: i. providing an extrudable composition comprising an extrudable carrier; and ii. extruding the extrudable composition, optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form; where the extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); and The method further includes removing or partially removing the transient plasticizer from the extruded article via vaporization before, during, or after the extrusion step.

[0503] Preferably, there is provided a method of producing an extruded article, the method comprising: i. providing a container filled with an extrudable composition comprising an extrudable carrier; ii. extruding the extrudable composition, optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form; where: The extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); The extrudable composition is preferably converted in situ via heating of the vessel or provided as an extrudable fluid; and The method further includes removing or partially removing the transient plasticizer from the extruded article via vaporization before, during, or after the extrusion step.

[0504] Preferably, there is provided a method of producing an extruded article, the method comprising: i. providing an extrudable composition comprising an extrudable carrier; ii. extruding the extrudable composition, optionally with one or more auxiliary components (e.g., shell, coating, core), through an extruder into a desired form; where The extrudable composition initially comprises a transient plasticizer, the transient plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150° C. or less (preferably at standard ambient pressure, e.g., 100 kPa); The extruder includes a heatable build platform; The method further includes removing or partially removing the transient plasticizer from the extruded article via vaporization during or after the extrusion step by heating the build platform to a temperature greater than ambient temperature.

[0505] In one embodiment, the extrudable article is produced by direct ink 3D printing of an extrudable compressed form, where the extrudable compressed form is preferably a plurality of compressed units (e.g., mini-tablets) or compressed monoliths (e.g., compressed powders or compressed granular compositions). The extrudable composition may optionally include or be mixed with a temporary plasticizer prior to 3D printing, although in certain embodiments, the extrudable composition does not include or is not mixed with a temporary plasticizer. Preferably, in such embodiments, each mini-tablet has a longest dimension between 0.5 mm and 10 mm, preferably between 1 mm and 8 mm, preferably between 3 mm and 7 mm, and most preferably between 5 mm and 7 mm. Preferably, each extrudable compressed form weighs between 10 and 100 mg, 20 and 80 mg, 30 and 70 mg, 40 and 60 mg, or about 50 mg. Suitably, each compressed extrudable form is formed by compressing 10-100 mg, 20-80 mg, 30-70 mg, 40-60 mg, or about 50 mg of another powdered or granular extrudable composition.

[0506] Preferably, any extrudable composition defined herein comprises either or both a temporary plasticizer and / or a permanent plasticizer. Whenever a temporary plasticizer is used, it is preferably ultimately removed or partially removed after processing into the desired form (e.g., an extruded article). Whenever a permanent plasticizer is used, it is preferably left in the final desired form in which it is processed. Embedded items How to create embedded items

[0507] The present invention preferably provides a method for producing an implantable article as defined herein.

[0508] A method of manufacturing an implantable article is provided, the method including: i. providing a solidifiable body material in a fluid or semi-fluid form; ii. embedding an embeddable material within a solidifiable body material; iii. solidifying the solidifiable body material with the implantable material embedded therein;

[0509] Preferably, the embedded article is as defined herein.

[0510] A suitable method includes operating an embedding device, preferably on a build platform, to generate an embedded solid thereon through embedding of an embeddable material within a solidifiable body material.

[0511] Preferably, such manufacturing is performed via a computer-implemented process (i.e., embedding is controlled and preferably initiated in a wired or wireless manner by a computer connected to or within the device).

[0512] The embeddable material is present in the device, preferably in a storage location in a container such as a cartridge. The embeddable material is preferably transported to the deposition nozzle by one or more conveyors (e.g. pumps or syringes). The deposition nozzle preferably passes through the provided solidifiable body material or over the surface of a portion of the solidifiable body material, and the embeddable material is then passed through the deposition nozzle into the solidifiable body material or over the surface of a portion of the solidifiable body material (preferably while the embeddable material continues to be transported from the storage location towards the deposition nozzle). The embeddable material is deposited in / on the solidifiable body material in at least one layer, preferably in a single layer or multiple layers. When the embeddable material is deposited on the surface of the solidifiable body material, another portion of the solidifiable body material is placed on top of the initial portion, thereby embedding the embeddable material in the solidifiable body material. Preferably, the implantable material is deposited layer by layer in a continuous manner (e.g. lines) or in a discontinuous manner (e.g. dots or parts of a pattern which may be connected or separated). Preferably, a pattern of the implantable material is formed layer by layer in the solidifiable body material. Due to the miscibility of the implantable material with the solidifiable body material, the implantable material remains in the solidifiable body material where it was deposited, i.e. there is no appreciable migration of the implantable material within the solidifiable body material during the process of making the implantable article. Preferably, there is no appreciable migration of the implantable material within the solidifiable body material during the shelf life of the implantable article. Preferably, there is no appreciable migration of the implantable substance within the solidifiable body material for at least 1 hour, preferably 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 after the manufacture of the implantable article. Preferably, there is no appreciable migration of the implant quality within the solidifiable body material for between 1 hour and 24 months after the manufacture of the implantable article. The term no appreciable migration should be understood as no migration or migration that does not affect the suitability of the implantable article for its intended use, i.e. as a dosage form.Those skilled in the art will be aware of techniques by which the level of migration of an implantable substance within a solidifiable substance can be determined, such as by visual monitoring by eye or by microscope, monitoring the concentration profile of the implantable substance within the implantable article using spectroscopy, etc.

[0513] The deposition nozzle is preferably moved in any or all of the X, Y and Z directions during the filling step.

[0514] The solidifiable body material is preferably present in the apparatus in a storage location in a container such as a cartridge. The solidifiable body material is preferably conveyed by one or more conveyors (e.g., pumps or syringes) to the deposition nozzle. The deposition nozzle preferably provides the solidifiable body material by filling a mold with the solidifiable body material.

[0515] As will be appreciated by those skilled in the art, each or any deposition nozzle may be adapted to match the properties of, and configured to embed / provide, a corresponding embeddable / solidifiable body material, where the nozzle properties / design and embeddable / solidifiable body material properties suitably complement each other to facilitate controlled embedding / delivery of said composition (whether continuous or intermittent, e.g., when multiple embeddable / solidifiable body materials are used), without clogging or impedance of the deposition nozzle, and without unacceptable degradation of components within the embeddable / solidifiable body materials during the embedding / delivery step.

[0516] Preferably, the method includes embedding the embeddable body material in the solidifiable body material after the solidifiable body material has solidified, for example, the solidifiable body material may be solidified and then embedded in the solidified body material (e.g., by printing the solidified body material with a needle that has broken the solidified body material into pieces) to incorporate the embeddable body material within the solidified body material.

[0517] Preferably, the method comprises solidifying a portion of the solidifiable body material, thereby embedding the embeddable material within the solidifiable body material, providing the embeddable material on a surface of the solidified body material (i.e., by printing directly on top), providing a remaining portion of the solidifiable body material on top of the solidified body material, and solidifying the remaining portion of the solidifiable body material, thereby embedding the embeddable material between the two portions of the body material. Providing a solidifiable body material

[0518] Suitably the solidifiable body material is as defined herein.

[0519] Preferably, the providing step is carried out at an elevated temperature, preferably at or above ambient temperature, preferably at a temperature greater than 25° C., 30° C., 40° C., 50° C., 60° C., 70° C., or 80° C. Preferably, the providing step is carried out at a temperature greater than or equal to 25° C. and less than or equal to 80° C.

[0520] Preferably, the solidifiable body material is at a temperature above ambient temperature, preferably at a temperature above 25° C., 30° C., 40° C., 50° C., 60° C., 70° C., or 80° C. Preferably, the solidifiable body material is at a temperature above 25° C. and below 80° C.

[0521] Preferably, in step i, the solidifiable body material is heated to a temperature above ambient temperature, preferably greater than 25° C., 30° C., 40° C., 50° C., 60° C., 70° C. or 80° C. Preferably, the solidifiable body material is heated in step i to a temperature between 25° C. and 80° C.

[0522] Preferably, the providing step comprises filling or partially filling a mould with the solidifiable body material. Preferably, the mould has a size and shape for producing an implant article of a size and shape as defined herein. Preferably, the solidifiable body material is poured into the mould.

[0523] Preferably the mould is maintained at a temperature above ambient temperature, preferably above 25° C., above 30° C., above 40° C., above 50° C., above 60° C., above 70° C. or above 80° C. Preferably the mould is maintained at a temperature between 25° C. and 80° C.

[0524] Preferably the solidifiable body material is provided at a temperature higher than the temperature of the mould. Preferably the solidifiable body material is provided at a temperature at least 10°C higher than the temperature of the mould, preferably at least 15°C, 20°C, 25°C or 30°C higher.

[0525] Suitably, one or more solidifiable body materials are used in providing the solidifiable body material step. Mounting Step

[0526] Preferably, the implantable material is as defined herein.

[0527] Preferably, one or more implantable substances are used in the implanting step.

[0528] Preferably, the embedding step comprises embedding the embeddable material in at least one layer or partial layer within the solidifiable body material, preferably there is one layer of the embeddable material, preferably there are multiple layers, preferably there are two layers.

[0529] Preferably, the implantable material comprises at least one active ingredient. Preferably, each layer may comprise one or more active ingredients. Preferably, if there is more than one layer, each layer may comprise a different active ingredient. Preferably, if there is more than one layer, each layer may be the same or different.

[0530] Preferably, each layer is a continuous layer or a discontinuous layer. Preferably, each layer may be in the form of a straight line, a curved line, or an interrupted layer (e.g., a dotted line layer). Preferably, each layer may be in the form of a continuous line, preferably in the form of a continuous straight line, preferably in the form of a continuous line that includes bends and / or curves.

[0531] Preferably, the embedding step uses a printer, preferably a 3D printer, preferably an embedded 3D printer. Preferably, the printer includes a printing plate. Preferably, the embedded article is formed on the printing plate, preferably in a mould on the printing plate.

[0532] Preferably, the implanting step uses at least one syringe. Preferably, the syringe is filled with the implantable substance.

[0533] Preferably, the embedding step is performed at a temperature below 60° C., preferably below 50° C., below 40° C., below 30° C., or below 25° C. Preferably, the embedding step is performed at a temperature between 0° C. and 50° C., preferably between 25° C. and 50° C. Advantageously, during the embedding step the implantable material is not exposed to very high temperatures. This is particularly useful for implantable materials which contain a heat sensitive component, e.g. a heat sensitive active component such as a biologically active component, i.e. a protein or a peptide.

[0534] Preferably, each embedding step is consecutive.

[0535] Preferably, the implantable material is present within the solidifiable body material in at least one layer or at least one partial layer.

[0536] Preferably, the method comprises two or more embedding steps, each embedding step comprising embedding an embeddable material within the solidifiable body material, wherein the embeddable materials used in each embedding step are the same or different, forming different layers of embeddable material within the solidifiable body material, preferably each embedding step forms part of the same layer of embeddable material within the solidifiable body material.

[0537] Preferably, each embedding step embeds a portion of the embeddable material within the solidifiable body material. Preferably, the embedding step includes embedding a portion of the embeddable material within the solidifiable body material and then embedding at least another portion of the embeddable material. Preferably, the portions may be the same or different. Preferably, the embedding step includes embedding a portion of the embeddable material within the solidifiable body material and then embedding three other portions. Preferably, each portion embeds about 25% of the embeddable material within the solidifiable body material. For example, about 25% of the embeddable material is embedded within the solidifiable body material, followed by another about 25% portion, then another about 25% portion, and finally another about 25% portion. The portions of the embeddable material may or may not be joined within the solidifiable body material. Preferably, the embedding step comprises embedding a first layer of embeddable material, or a portion thereof, within the solidifiable body material, and then embedding a second layer of embeddable material, or a portion thereof, within the solidifiable body material. Preferably, the first and second layers are distinct from the solidifiable body material (i.e., the layers are separated by the solidifiable body material) or in contact with each other.

[0538] Preferably, the implantation steps of each portion of the implantable material are digitally, i.e., computer controlled. Advantageously, implanting a partial implantable material results in less variability in the amount of implantable material dispensed during the implantation process, resulting in a more accurate dosage of the implantable material within the implanted article.

[0539] Preferably, the embedding step uses a needle. Preferably, the size of the needle controls the amount of embeddable material embedded in the solidifiable body material. Preferably, the size of the needle is between 1 and 1.6 mm.

[0540] Preferably, the amount of embeddable material embedded in the solidifiable body material is controlled by the embedding speed of the embedder, preferably the embedding speed is 40-80 mm / min, for example, preferably about 50-70 mm / min, preferably about 50 mm / min, preferably about 60 mm / min, preferably about 65 mm / min, preferably about 70 mm / min.

[0541] Preferably, the implantable material is embedded in the solidifiable body material to create a pattern, preferably a patient-personalized pattern.

[0542] Preferably, the implant is embedded in a solidifiable body material, preferably administered orally, to allow for sequential release of the implant from the implant when the implant is administered. Preferably, two implantable materials are embedded in the implantable material to allow for sequential release of the implantable materials.

[0543] Preferably, the implantable substance is embedded in a solidifiable body material, preferably administered orally, to allow titration of the dose of implantable substance from the implantable article when the implantable article is administered. Solidify the steps

[0544] Suitably the solidifying step comprises UV curing, heating, cooling and / or providing a cross-linking agent.

[0545] Preferably the solidifying step comprises heating the solidifiable body material, preferably heating the solidifiable body material to above ambient temperature, preferably heating the solidifiable body material to above 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Preferably the solidifying step comprises heating the solidifiable body material to below 200°C, below 150°C, below 120°C or below 100°C. Preferably the solidifying step comprises heating the solidifiable body material to between 25 and 200°C.

[0546] Preferably, the solidifying step comprises cooling the solidifiable body material, preferably cooling the solidifiable body material to a temperature lower than that used in the previous step. Preferably, the solidifying step comprises cooling the solidifiable body material to a temperature below ambient temperature, preferably above -20°C, -10°C, 0°C, 10°C or 20°C. Preferably, the solidifying step comprises cooling the solidifiable body material to a temperature below 40°C, 30°C, 20°C or 10°C. Preferably, the solidifying step comprises cooling the solidifiable body material to a temperature between -20°C and 40°C.

[0547] Preferably, the solidifying step comprises UV light curing, preferably by exposing the solidifiable body material to a UV light source. Preferably, the exposure time is at least 1 minute, preferably at least 5 minutes, 10 minutes, 20 minutes, 30 minutes, or 60 minutes. Preferably, the solidifying step comprises exposing the solidifiable body material to UV light for between 1 minute and 60 minutes. Preferably, the UV light source is a UV lamp.

[0548] Preferably, the solidification step further comprises providing a cross-linking agent as defined herein. Preferably, the cross-linking agent solidifies the solidifiable body material. Those skilled in the art will understand that there are many agents that may act as cross-linking agents and as solidifiable body materials. The choice of both agents will depend on their compatibility with each other and with other components in the implantable article, as well as their suitability for use in the method for producing the implantable article, and the desired attributes of the implantable article.

[0549] Suitably, the solidifiable body material comprises at least one active ingredient. Additional method steps

[0550] The method of the present invention may further include one or more steps either before, during and / or after the above steps. The exterior surface of the implanted article may be pre- or post-treated via the implantation of additional or partial layers, or via alternative coating techniques well known in the art.

[0551] The implantable article produced by the method of the present invention can then be treated in various ways to obtain a further treated implantable article. Preferably, the method further comprises coating the product obtained from the implantation step. Preferably, the coating is as described herein. For example, the implantable article may be enteric coated by standard enteric coating processes known in the art. Similarly, other controlled release properties may be imparted to the implantable article by further treatment.

[0552] Most preferably, all steps (including any further processing steps) are performed by an embedded device. Preferably, all steps (including any further processing steps) are preferably controlled by the same computer. Computer implementation of the method

[0553] The method of manufacturing an embedded article is preferably a computer-implemented method, as defined herein, and is preferably a method of manufacturing an embedded article.

[0554] Preferably, the method includes providing an embedding apparatus, preferably as defined herein, and operating said apparatus to manufacture the embedded article. Preferably, the embedding apparatus includes or is otherwise connected to a computer. Preferably, operating the embedding apparatus includes operating a computer, preferably connected (whether by wired or wireless means) to or within the associated embedding apparatus (so that the computer can control and coordinate other parts of the embedding apparatus, including the printing press).

[0555] A computer that includes or is otherwise associated with the embedding device of the present invention may preferably be referred to as an embedded control computer. The embedded control computer may perform different functions (and may be a separate entity) than other "computers" referred to herein, such as a monitoring computer or an analysis computer, although a single computer may perform one or more functions of any combination of these computers. The embedded control computer preferably controls the manufacture of the embedded article, e.g., embedding of the embeddable material in the solidifiable body material via a deposition nozzle, and optionally further processing steps, e.g., coating of the formed article. Wherever separate computers are used to perform each of these operations, the computers are appropriately coordinated and may therefore be considered to be part of one overall computer.

[0556] The production of the implantable articles is preferably controlled by a computer running according to software based on information provided to the computer by user input (drug type, drug dosage level), databases (e.g., patient database and / or extrusion article database), and / or data files (e.g., design files and / or parameter files) as described herein. Preferably, the implantation apparatus is set according to instructions provided by the computer: by feeding the implantable material and / or solidifiable body material to and / or through the respective deposition nozzles at appropriate intervals and / or at appropriate speeds; and by moving the deposition nozzles and / or build platform to allow systematic embedding of the implantable material within the solidifiable body material according to relevant information and calculations obtained by the computer.

[0557] The deposition nozzles are preferably controlled by a computer according to "obtained information" (e.g., design and / or other parameters) regarding the embedded article. The deposition nozzles are preferably controlled to embed a given embeddable material within the solidifiable body material in a pattern predefined by the "obtained information." As such, or each deposition nozzle may be controlled to be switched "on" and "off" according to a predefined schedule to provide a required pattern in the construction of the embedded article. The deposition nozzles may be switched "on" by having an output aperture open.

[0558] The build platform is preferably controlled by a computer according to "obtained information" regarding the embedded article (e.g., design and / or other parameters), as described elsewhere herein. This may include controlling the operating temperature of the build platform, in particular the operating temperature of the surface of the build platform. Preferably, during the manufacture of the embedded article, the operating temperature of the build platform or its surface is maintained at a substantially constant temperature, preferably at a constant temperature ±5°C, as required for that particular stage of the process. For example, during the filling or partial filling of the mould with the solidifiable material, the build platform may be held at an initial temperature. During the solidification stage, the build platform may be held at a second temperature. During the embedding stage, the build platform may be held at a third temperature. Depending on how the solidification of the solidifiable body material is performed, the first temperature may be higher than the second temperature and / or the third temperature (e.g., solidification is performed by cooling) or vice versa (e.g., solidification is performed by heating), the first temperature may be higher than the second temperature and / or the third temperature. Preferably, the first temperature, the second temperature and / or the third temperature may be the same, for example, when the solidification is by exposure to UV light and / or crosslinking. Furthermore, such temperature control may facilitate the adhesion of the developed embedded article to the surface of the build platform during its formation. Such temperature control may facilitate the release (i.e., de-adhesion) of the embedded article after its formation (e.g., the surface of the build platform may be heated or cooled as appropriate to reduce adhesion of the embedded article). During the process of manufacturing the embedded article, the build platform is preferably 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) of 100° C. or less, preferably 90° C., 80° C., 70° C., 60° C., 50° C., 40° C., 30° C., or 25° C. or less. Preferably, the surface temperature is 0° C. or more, preferably 10° C. or more, 20° C. or more, 25° C. or more, 30° C. or more, 40° C. or more, 50° C. or more, or 60° C. or more.Preferably, the surface temperature is 10°C or higher and 100°C or lower. Embedded items

[0559] The present invention provides an implantable article obtained, obtained or directly obtained by a method for producing an implantable article as defined herein.

[0560] The implantable article is preferably formed from a solidifiable material and an implantable material, and as such, the definitions herein relating to solidifiable material and implantable material are equally applicable to the implantable article.

[0561] There is provided an implantable article comprising an implantable substance within a solidifiable body substance. Preferably, the implantable article comprises one or more implantable substances, preferably one implantable substance, preferably two implantable substances. Preferably, each implantable substance may comprise the same or different components, i.e. each implantable substance may comprise the same or different active ingredient. Alternatively, the implantable article may comprise a plurality of solidifiable body substances, preferably two solidifiable body substances. Preferably, each solidifiable body substance may be the same or different.

[0562] Preferably the implantable article comprises more than 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25% or 30% by weight of the implantable material, preferably 1-30%. Preferably the implantable article comprises more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the solidifiable body material, preferably between 0.1% and 90% by weight.

[0563] Preferably, the implantable article is a solid. Preferably, the implantable article is a semi-solid. Preferably, the implantable article is a solid or semi-solid, preferably comprising a solid or semi-solid body (formed from a solidifiable body material) and an implantable material within the body. Preferably, the implantable material is a liquid, solution, emulsion, suspension, solid or semi-solid (preferably a gel). Preferably, the implantable material is a gel.

[0564] The implantable articles of the present invention are advantageously customizable in terms of the type / nature of the active ingredient, the dosage of the active ingredient within the implantable article (which may be the absolute dosage per implantable article or the concentration of the active ingredient with the implantable article), the mass / volume of the implantable article (which may be adaptable to change the absolute amount of the active ingredient, typically without changing the concentration of the active ingredient within the implantable article), the active ingredient release profile (which may be altered by the judicious use and / or distribution of appropriate excipients), or the form and appearance (including novel forms, colors, and patterns that may aid medical compliance for a particular patient).

[0565] Preferably, the implanted article comprises at least one active ingredient, preferably one active ingredient, preferably a plurality of active ingredients, preferably two active ingredients.

[0566] Preferably, the solidifiable body material comprises at least one active ingredient. Preferably, the solidifiable body material comprises at least one active ingredient. Preferably, said solidifiable body material comprises at least one active ingredient and said implantable body material comprises at least one active ingredient, wherein the active ingredients of said implantable body material and said solidifiable body material are the same or different.

[0567] Preferably, the implanted article is a solid dosage form, preferably a pharmaceutical, nutraceutical or food supplement solid dosage form, preferably a tablet. Preferably, the tablet is a chewable tablet. Preferably, the implanted article is a solid oral dosage form, most preferably an immediate release solid dosage form. Preferably, the implanted article is a sustained release dosage form or a delayed release dosage form. Preferably, the implanted article of the present invention is for oral administration.

[0568] Suitably, the implantable article upon oral administration has an immediate, sustained or delayed release profile.

[0569] Preferably, the solidifiable body material provides gastroprotection for the implant when the implant is administered orally.

[0570] The immediate release solid dosage form may preferably release at least 75% of the active ingredient within a 45 minute period, preferably release at least 85% of the active ingredient within a 30 minute period, and preferably release at least 85% of the active ingredient within a 15 minute period. Those skilled in the art may refer to the European Pharmacopoeia 8. Strasbourg, France. Council of Europe; European Directorate for the Quality of Medicine; 2014.

[0571] Preferably, the implantable material is entirely within the solidifiable body material. Preferably, the implantable material is a layer or part of a layer within the solidifiable body material, preferably a single layer (or part thereof), preferably multiple layers (or parts thereof), preferably two layers (or parts thereof). Preferably, the layer (or part thereof) is continuous or discontinuous. Preferably, the implantable material is present within a layer in a linear, curvilinear and / or intermittent (i.e. non-continuous) manner. Preferably, each layer may comprise one implantable material or multiple implantable materials. Preferably, each layer may comprise at least one portion. Preferably, if there is more than one layer, the layers may be contiguous or non-contiguous, i.e. the solidifiable body material separates the layers or parts of the layers.

[0572] Preferably, each layer of implantable material has a thickness of 10 to 1000 μm, preferably 20 to 800 μm, 30 to 600 μm, 40 to 500 μm, 50 to 400 μm, or 60 to 300 μm. Preferably, if there is more than one layer, each layer of implantable material in the implantable article may have the same thickness or each layer may have a different thickness.

[0573] Preferably, the shape of the embedded article is a cube, a cuboid, or a cylinder.

[0574] Preferably, the volume of the embedded article is less than 3 mm 3 , 5mm 3、 10mm 3 , 50mm 3、 100mm 3 , or 200mm 3 Preferably, the volume of the embedded article is 500 mm 3、 300mm 3 , 250mm 3 , 150mm 3 , or 50mm 3 Preferably, the volume of the embedded article is between 5 and 500 mm 3 The following is the result.

[0575] The longest dimension of the embedded item (D max ) (e.g. whether in the X, Y or Z direction) is preferably 3mm, 5mm, 8mm, 10mm, or 12mm or more. The longest dimension of the embedded article is preferably 30mm, 25mm, 20mm, or 15mm or less. The longest dimension of the embedded article is preferably between 3 and 30mm.

[0576] The shortest dimension of the embedded item (D min ) (i.e., not necessarily the thinnest part, but the maximum length of the thinnest dimension, or the shortest dimension of X, Y, or Z) is preferably 0.1 mm, 0.5 mm, 1 mm, 3 mm, 5 mm, 8 mm, 10 mm, or 12 mm or more. The shortest dimension of the embedded article is preferably 30 mm, 25 mm, 20 mm, 15 mm, 10 mm, 8 mm, 5 mm, or 2 mm or less. The shortest dimension of the embedded article is preferably 0.1 to 30 mm.

[0577] Preferably, the implanted article has a weight of 1 mg or more, preferably 5 mg, 10 mg, 50 mg, or 80 mg or more. Preferably, the implanted article has a weight of 1000 mg or less, preferably 500 mg or less, 250 mg or less, or 100 mg or less. Preferably, the implanted article has a weight of 1 to 1000 mg.

[0578] Many of the preferred features of the implantable article are described elsewhere herein. For example, features described in relation to the method of making the implantable article may suitably reflect features of the implantable article itself (e.g., the number of layers of implantable material). Suitably, the implantable article may be considered to include the solidifiable body material and the implantable material involved, including the components provided by the solidifiable material(s) and the implantable material(s) used in its formation.

[0579] Preferably, there is no migration of the implantable material to the solidifiable body material, preferably at least during the process of manufacturing the implantable article, and preferably at least until the implantable article is used by an end user (e.g., a patient administers the implantable article).

[0580] Preferably, the implanted article contains at least one active ingredient, preferably two active ingredients.

[0581] Preferably, the implanted article comprises 0.01-50%, 0.1-50%, 0.1-40%, 1-30%, 5-25%, 5-20%, 5-15%, 8-12%, or about 10% by weight of the active ingredient. Preferably, the implanted article comprises less than 80%, 60%, or 50% by weight of the active ingredient. Preferably, the implanted article comprises more than 1%, 2%, or 5% by weight of the active ingredient.

[0582] Preferably, the implant is positioned within the implant to allow for sequential release of the implant when the implant is administered to a patient, preferably orally.

[0583] Preferably, the implant is positioned within the implant to allow for dose titration of the implant when the implant is administered to a patient, preferably administered orally. Solidifiable body material

[0584] A solidifiable body material is provided. Preferably, the solidifiable body material is a material that solidifies when exposed to elevated temperatures, sub-ambient temperatures, UV light, and / or a cross-linking agent.

[0585] Preferably, the solidifiable body material is in a fluid or semi-fluid form at ambient and / or elevated temperatures, preferably at temperatures above 25° C., 30° C., 40° C., 50° C., 60° C., or 70° C. Preferably, the solidifiable body material is in a fluid or semi-fluid form at temperatures between 25° C. and 70° C.

[0586] Preferably, the solidifiable body material solidifies when exposed to an elevated temperature, preferably a temperature above ambient temperature, preferably above 25° C., preferably 30° C., 35° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., or 100° C. Preferably, the solidifiable body material solidifies when exposed to a temperature below 200° C., preferably below 150° C., preferably below 120° C., preferably below 100° C. Preferably, the solidifiable body material solidifies when exposed to a temperature above 25° C. and below 200° C.

[0587] Preferably, the solidifiable body material solidifies when exposed to a temperature below ambient temperature, preferably above -20°C, -10°C, 0°C, 10°C, or 20°C. Preferably, the solidifiable body material solidifies when exposed to a temperature below 40°C, 30°C, 20°C, or 10°C. Preferably, the solidifiable body solidifies when exposed to a temperature between -20°C and 40°C.

[0588] Preferably, the solidifiable body material solidifies upon exposure to UV light.

[0589] Preferably, the solidifiable body material has a crosslinking agent present. Preferably, the crosslinking agent is 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. Those skilled in the art will understand that other crosslinking agents are available and the choice of agent will depend on the compatibility with the selected solidifiable body material and other components present in the implanted article.

[0590] Preferably, the solidifiable body substance is a gel. Preferably, the solidifiable body substance is a gelatin matrix. Preferably, the gelatin matrix comprises gelatin, glycerol and / or water. Preferably, the solidifiable body substance comprises gelatin, glycerol and water. Preferably, the solidifiable body substance comprises gelatin at 10-40% / v, preferably 20-30% / v, preferably about 25% / v. Preferably, the solidifiable body substance comprises glycerol at 15-45% w / v, preferably 25-35% w / v, preferably about 30% w / v. Preferably, the solidifiable body substance comprises 30-60%, preferably 40-50%, more preferably about 45% water. Suitably the solidifiable body material comprises 10-40% w / v gelatin, 15-45% w / v glycerol and 30-60% w / v water.

[0591] Preferably, the solidifiable body material comprises at least one active ingredient. Preferably, the solidifiable body material comprises one active ingredient. Preferably, the solidifiable body material comprises multiple active ingredients. Preferably, the active ingredient is a pharmaceutical, nutraceutical or food supplement active ingredient. Preferably, the active ingredient is heat sensitive, for example, preferably, the active ingredient is a biological, preferably a pharmaceutical biological. Preferably, the biological ingredient is a protein or peptide. Preferably, the active ingredient is a small molecule, preferably a pharma-ceutical active small molecule. Preferably, the active ingredient is stable in the solidifiable body material, for example, the active ingredient is stable in the solidifiable body material from the time the solidifiable body material is manufactured, during the process of manufacturing the implantable article, and at least until the time of use of the implantable article. Suitably, stable means less than 0.05%, less than 0.1%, less than 0.5%, less than 1%, less than 2%, less than 3%, less than 4%, or less than 5% change in the active ingredient over the time frames specified above, such as over an hour, a day, a week, a month, three months, six months, or over six months or more.

[0592] Preferably, the solidifiable body material comprises 0.01-50%, 0.1-50%, 0.1-40%, 1-30%, 5-25%, 5-20%, 5-15%, 8-12%, or about 10% by weight of the active ingredient. Preferably, the solidifiable body material comprises less than 80%, 60%, or 50% by weight of the active ingredient. Preferably, the solidifiable body material comprises more than 1%, 2%, or 5% by weight of the active ingredient.

[0593] Preferably, the solidifiable body material further comprises one or more other ingredients, which may preferably comprise one or more excipients, excipient carriers, and / or diluents, all of which may be included in the solidifiable body material.

[0594] Fillers / diluents, anti-adherents, binders, disintegrants, glidants, lubricants, flavorings, preservatives, sweeteners, coloring agents, and coating agents are known in the pharmaceutical, nutraceutical and food supplement arts, and any of these may be located where appropriate or desired for a particular pharmaceutical, nutraceutical or food supplement formulation.

[0595] Preferably, the fillers / diluents, anti-adherents, binders, disintegrants, glidants, lubricants, flavours, preservatives, sweeteners, colouring agents and coating agents are substantially inert and / or preferably have minimal or no interaction with other components of the implanted article.

[0596] Suitable anti-adherents may include magnesium stearate. Suitable diluents / fillers may include vegetable cellulose, dibasic calcium phosphate, vegetable fats and oils, 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, cellulose ethers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, and derivatives thereof; sugar alcohols, such as xylitol, sorbitol, or maltitol; synthetic polymers, such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). Suitable disintegrants may include cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose, croscamellose sodium, modified sodium starch, and / or starch glycolate. Suitable lubricants may include silica; sodium stearyl fumarate; fats and oils, such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable lubricants may include fumed silica, talc, magnesium carbonate, and / or colloidal silica. Suitable coatings may include tablet coatings (e.g., cellulose ether hydroxypropyl methylcellulose (HPMC) film coatings; synthetic polymers, shellac, corn protein zein or other polysaccharides, gelatin; enteric coatings, including fatty acids, waxes, shellac, plastics, vegetable fibers) to protect tablet ingredients from deterioration due to moisture in the air and to make large or unpleasant tasting tablets easier to swallow. Suitable colorants include curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, quinoline yellow, sunset yellow FCF, cochineal, azorubin, amaranth, poncelo 4R, erythrosine, allura red AC, patent blue V, indigotine, brilliant blue FCF, chlorophyll, copper complex of chlorophyll, green S, plain caramel, caustic sulfite caramel.Ammoniacal caramel, ammoniacal caramel sulfite, brilliant black BN, vegetable carbon, brown HT, carotene, annatto, paprika extract, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, beet red, anthrocyanin, calcium carbonate, titanium dioxide, iron oxides and hydroxides, aluminum, silver, gold and / or resolvin BK. General classes of excipients are well understood by those skilled in the art. Implantable materials

[0597] Preferably, the implantable material is a liquid, a solution, a semi-solid (preferably a gel), an emulsion, a solid, or a suspension. Preferably, the semi-solid is a gel.

[0598] Advantageously, this allows for the manufacture of implantable articles using embedded 3D printing. In particular, it is possible to manufacture implantable articles without exposing the implantable material to high temperatures. This is particularly useful when the implantable material includes a heat-sensitive component, such as a biologically active component, such as a heat-sensitive active component, such as a protein or peptide.

[0599] Preferably, the implantable material comprises at least one active ingredient. Preferably, the implantable material comprises one active ingredient. Preferably, the implantable material comprises multiple active ingredients. Preferably, the active ingredient is a pharmaceutical, nutraceutical or food supplement active ingredient. Preferably, the active ingredient is heat sensitive, for example, preferably, the active ingredient is a biological, preferably a pharmaceutical biological. Preferably, the biological ingredient is a protein or peptide. Preferably, the active ingredient is a small molecule, preferably a pharmaceutical active small molecule. Preferably, the active ingredient is stable in the implantable material, for example, the active ingredient is stable in the implantable material from the time the implantable material is manufactured, during the process of manufacturing the implantable article, and at least until the time of use of the implantable article. Suitably, stable means no more than 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5% change in the active ingredient over the time frames specified above, e.g., over one hour, one day, one week, one month, three months, six months, or over six months or more.

[0600] Preferably, the implantable material comprises 0.01-50%, 0.1-50%, 0.1-40%, 1-30%, 5-25%, 5-20%, 5-15%, 8-12%, or about 10% by weight of the active ingredient. Preferably, the implantable material comprises less than 80%, 60%, or 50% by weight of the active ingredient. Preferably, the implantable material comprises more than 1%, 2%, or 5% by weight of the active ingredient.

[0601] Suitably, the implantable material comprises a gelling agent, a suspension-forming agent, an emulsion-forming agent or a solution-forming agent.

[0602] Suspension forming agents are liquids in which the active ingredient is poorly soluble, for example the solubility of the active ingredient is less than 0.5 mg / mL, preferably less than 0.1 mg / mL, less than 0.05 mg / mL or less than 0.01 mg / mL.

[0603] The solution-forming agent is a liquid in which the active ingredient dissolves, for example, the active ingredient has a solubility of 0.5 mg / mL or more, preferably 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 50 mg / mL, or 100 mg / mL or more in the solution-forming agent. Preferably, the active ingredient has a solubility of 0.5 to 10 mg / mL in the solution-forming agent.

[0604] The emulsion former comprises two liquids, and the two liquids are not miscible with each other.Preferably, one liquid is a hydrophobic liquid, and the other liquid is a hydrophilic liquid.Preferably, the hydrophobic liquid is a vegetable oil, such as soybean oil.Preferably, the hydrophilic liquid is water-based, such as water.

[0605] A gelling agent for use herein may be any gelling agent typically used in the pharmaceutical, nutritional, or food supplement fields for oral delivery. As used herein, the term "gelling agent" is intended to mean a compound used to make a liquid vehicle into a jelly-like vehicle. Exemplary gelling agents include, by way of example and without limitation, synthetic polymers, cellulose derivatives (e.g., carboxymethylcellulose and hydroxypropylmethylcellulose), and natural gums (e.g., tragacanth, sodium alginate, or xanthan gum). Synthetic polymers include carbomers (e.g., carbomer 910, 934, 934P, 940, 941, 1342), which are high molecular weight water-soluble polymers of acrylic acid crosslinked with allyl ethers of sucrose and / or pentaerythritol. Carbomers vary in viscosity depending on their polymer composition. The gelling agent of the present invention may be selected from any of synthetic or semi-synthetic polymeric materials, polyacrylate copolymers, cellulose derivatives, and polymethylvinylether / maleic anhydride copolymers. In the present invention, natural gums are preferably used, preferably the gelling agent is sodium alginate or xanthan gum.

[0606] Preferably, the implantable material further comprises water. Preferably, the implantable material further comprises an alkali. Preferably, the alkali is sodium hydroxide.

[0607] Preferably, the implantable material comprises sodium alginate, water and sodium hydroxide. Preferably, the implantable material comprises 1-20% w / v sodium alginate, preferably 2-15% w / v, 6-10% w / v or about 8% w / v. Preferably, the implantable material comprises 0.1-5% w / v, preferably 0.5-5% w / v, 1-3% w / v or about 2% w / v.

[0608] Preferably, the implantable material further comprises one or more other ingredients, which may preferably include one or more excipients, excipient carriers, and / or diluents, all of which may be included in the implantable material.

[0609] Flavoring agents, preservatives, sweeteners, and coloring agents are known in the pharmaceutical, nutraceutical, and food supplement arts, and any of these may be placed where appropriate or desired for a particular pharmaceutical, nutraceutical, or food supplement formulation.

[0610] Preferably, the flavourings, preservatives, sweeteners and colouring agents are substantially inert and / or preferably have minimal or no interaction with other components of the embedded article.

[0611] Suitable colorants may include curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, quinoline yellow, sunset yellow FCF, cochineal, azorubine, amaranth, poncelo 4R, erythrosine, allura red AC, patent blue V, indigotine, brilliant blue FCF, chlorophyll, copper complex of chlorophyll, green S, plain caramel, caustic sulfite caramel, ammoniacal caramel, ammoniacal sulfite caramel, brilliant black BN, vegetable carbon, brown HT, carotene, annatto, paprika extract, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, beet red, anthrocyanin, calcium carbonate, titanium dioxide, iron oxides and hydroxides, aluminum, silver, gold and / or resolvin BK. The general classes of excipients are well understood by those skilled in the art.

[0612] Preferably, the implantable material is miscible with the solidifiable body material. Preferably, the implantable material is miscible with the solidifiable body material during the process of manufacturing the implantable article, and preferably during the life of the implantable article (e.g., until it is used by the end user, e.g., a patient), for example, for a period of 1 hour, 1 day, 1 week, 1 month, 3 months, 6 months, or more than 6 months. Embedding device for manufacturing an embedded article

[0613] There is provided an embedding device comprising an embedder, preferably a solidifiable body material as defined herein, and / or an embeddable material as defined herein, the embedding device being preferably operable to form an embedded article via a method as described herein.

[0614] Preferably, the implant device comprises an implantable material.

[0615] Preferably, the implant device comprises a solidifiable body material.

[0616] Preferably, the implantation device comprises a solidifiable body material and an implantable body material.

[0617] Preferably, the implantation device includes a mold, which may be a removable or replaceable mold.

[0618] The embedding device is adapted to form an embedding solid of embeddable quality within a solidifiable body material, the embeddable body material and the embedding solid comprising at least one active ingredient. Embedder

[0619] The embedding device preferably includes an embedder. Preferably, the embedder is a 3D printer. Preferably, the 3D printer is an embedded 3D printer. Embedded 3D printers are known in the art and are generally suitable for use with the present invention, but may be judiciously modified based on the principles outlined herein to optimize the production of embedded articles.

[0620] An embedder suitable for use with the present invention will typically have a deposition nozzle (optionally heated / heatable) which deposits embeddable material into (and within) or onto a surface of a portion of the solidifiable body material. Suitably the deposition nozzle may also deposit the solidifiable body material onto a build platform or into a mould where the mould is on the build platform.

[0621] The embedder also preferably includes one or more deposition nozzle heaters, as defined herein (preferably one associated with each deposition nozzle, but optionally one servicing multiple deposition nozzles), and preferably one or more conveyors (preferably one associated with each deposition nozzle and / or each embeddable material / solidified body material).

[0622] Preferably, the embedder includes a heated / heatable build platform. Preferably, the solidifiable body material is in contact with the build platform, either directly or indirectly via the mould. Preferably, the mould is in direct contact with the build platform.

[0623] Preferably, the embedder uses a container as defined herein. Preferably, the embedding device uses a pre-filled container.

[0624] The embedding device of the present invention may optionally include one or more other components of the embedding material, the printing material, or the ejection material that are intended to form part of the embedded article. For example, the embedded article may be coated. Deposition Nozzle

[0625] Preferably, the embedding device comprises at least one deposition nozzle through which and from which the embeddable material (or part thereof) and / or the solidified body material (or part thereof) may be deposited. Preferably, the or each deposition nozzle may be a heated deposition nozzle, preferably a deposition heated nozzle having variable temperature control (e.g. to allow the deposition nozzle to be selectively heated at a desired temperature). Thus, the embedding device may preferably comprise a deposition nozzle heating element for heating the deposition nozzle to melt, soften or otherwise liquefy the relevant material or parts thereof. Preferably, said embedding device may comprise a plurality of said deposition nozzles, each of which may be assigned to one or more materials. Preferably, such deposition nozzles are part of an embedder.

[0626] The temperature of the deposition nozzle is preferably computer controlled.

[0627] Preferably, the embedding apparatus includes a con...

Claims

1. i. providing an extrudable composition comprising an extrudable carrier; and ii. extruding the extrudable composition, optionally with one or more auxiliary components (e.g., shell, coating, core), into a desired form; A method for producing an extruded article comprising:

2. i) providing an extrudable composition comprising an extrudable carrier; and ii) extruding the extrudable composition, optionally with one or more auxiliary elements (e.g., shell, coating, core), into a desired form via 3D printing.

1. A method for producing a solid dosage form of a pharmaceutical, dietary supplement, or food supplement, comprising:

3. 10. The method of any one of the preceding claims, wherein the extrudable composition is provided as an initially solid extrudable composition.

4. 4. The method of claim 3, wherein the solid extrudable composition is provided as a filament (e.g., suitable for 3D printing), as a powder, as granules, or as an extrudable compressed form (e.g., mini-tablets or compressed monoliths).

5. 5. The method of claim 4, wherein the solid extrudable composition is provided as a powder, as granules, or as an extrudable compressed form (e.g., mini-tablets or compressed monoliths).

6. 6. The method of claim 5, wherein the solid extrudable composition is provided as granules or as an extrudable compressed form (e.g., mini-tablets or compressed monoliths).

7. The method of claim 6 , wherein the solid extrudable composition is provided as an extrudable compressed form (e.g., mini-tablets or compressed monoliths).

8. 8. The method of claim 7, wherein the solid extrudable composition is provided in a heatable or heated syringe and mobilized (or converted to an extrudable fluid) by heating prior to extrusion into the extruded article.

9. 9. The method of claim 7 or 8, wherein the solid extrudable composition is provided as a plurality of extrudable compressed forms, preferably as mini-tablets.

10. 10. The method of claim 9, wherein the solid extrudable composition is provided as a plurality of extrudable compressed mini-tablets, each mini-tablet having a longest dimension of from 0.5 mm to 10 mm.

11. 11. The method of claim 9 or 10, wherein the solid extrudable composition is provided as a plurality of extrudable compressed mini-tablets, each mini-tablet having a weight of 10-100 mg.

12. 9. A method according to claim 7 or 8, wherein the solid extrudable composition is provided as a monolithic extrudable compressed form, preferably as a monolith of compressed powder or compressed granules.

13. 10. The method of any one of the preceding claims, wherein the extrudable composition is initially prepared as an extrudable composition comprising either or both of a temporary and / or permanent plasticizer.

14. 14. The method according to any one of claims 7 to 13, wherein the extrudable composition initially comprises 5% by weight or more of a temporary plasticizer, the temporary plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150°C or less (preferably at standard ambient pressure, e.g. 100 kPa); and the method further comprises removing or partially removing the temporary plasticizer by vaporization during or after the step of extrusion.

15. 14. The method of claim 13, wherein the extrudable composition initially comprises 5% by weight or more of a temporary plasticizer, the temporary plasticizer being a vaporizable substance (or combination of vaporizable substances) that can be vaporized at a temperature of 150°C or less (preferably at standard ambient pressure, e.g. 100 kPa); and the method further comprises removing or partially removing the temporary plasticizer by vaporization during or after the step of extrusion.

16. 16. The method of claim 14 or 15, wherein at least 50% by weight of the temporary plasticizer is removed.

17. 13. The method of any one of the preceding claims, wherein prior to the extrusion step, the extrudable composition is in or has been converted to the following form: a. an extrudable fluid; b. an extrudable compressed form; or c. Extrudable elements

18. 18. The method of claim 17, wherein prior to the extrusion step, the extrudable composition is in or is converted into an extrudable fluid form, preferably via heating; the extrudable composition is then directly extruded in a fluid state.

19. 10. The method of any one of the preceding claims, wherein the extrudable composition comprises at least one active ingredient.

20. 10. The method of any one of the preceding claims, wherein the temporary plasticizer is a pharmaceutical, nutritional, or food supplement acceptable grade solvent.

21. 13. The method of any one of the preceding claims, wherein removing or partially removing the transient plasticizer comprises heating and / or holding the extruded article under reduced pressure, such as under vacuum.

22. 10. The method according to any one of the preceding claims, wherein the extrusion step is carried out by an extrusion apparatus.

23. 23. The method of claim 22, wherein the extrusion apparatus has a container for containing the extrudable composition prior to the extrusion step and a nozzle for discharging the extrudable composition during the extrusion step, the container being heated at a temperature that maintains the extrudable composition in a (substantially) fluid state.

24. The method according to any one of claims 22 to 23, wherein the extrusion device is a 3D printing machine.

25. 13. The method of any of the preceding claims, further comprising the step of incorporating at least one further excipient and / or at least one further active ingredient into the extruded article, preferably surrounding the desired morphology with the at least one further excipient and / or the at least one active ingredient.

26. 10. The method of any preceding claim, wherein the desired form is an extruded article.

27. 13. An extruded article obtainable, obtained or directly obtained by a method for producing an extruded article according to any of the preceding claims.

28. 22. The extruded article of claim 21 for use as a medicament.

29. i. Providing a solidifiable body material in a fluid or semi-fluid form; ii. Embedding an embeddable material within a solidifiable body material; iii. Solidifying the solidifiable body material with the implantable material. A method for manufacturing an implantable article, comprising:

30. 30. The method of claim 29, wherein the implantable material comprises at least one active ingredient.

31. The method according to any one of claims 29 to 30, wherein the implantable material is a liquid, solution, emulsion, suspension, solid or semi-solid.

32. 32. The method of claim 31 , wherein the semi-solid is a gel or a gellable material.

33. The method of any one of claims 29 to 32, wherein the method is performed by an implanted device.

34. The method according to any one of claims 29 to 33, wherein the solidifying step comprises UV curing, heating, cooling and / or providing a cross-linking agent.

35. A method according to any one of claims 29 to 34, wherein the implantable material is present within the solidifiable body material in at least one layer or at least one partial layer.

36. 36. The method of any one of claims 29 to 35, wherein the method comprises two or more embedding steps, each embedding step comprising embedding an embeddable material within the solidifiable body material, and wherein the embeddable materials used in each embedding step are the same or different.

37. 37. The method of claim 36, wherein each embedding step forms a different layer of the embeddable material within the solidifiable body material.

38. A method according to any one of claims 36 to 37, wherein each of the two or more embedding steps embeds a portion of the layer of embeddable material within the solidifiable body material.

39. An implantable article obtainable, obtained or directly obtained by a method for manufacturing an implantable article according to any one of claims 20 to 38.

40. 40. An implantable article according to claim 39 for use as a medicament.

41. 41. The implantable article of claim 40, wherein the implantable article upon oral administration has an immediate, sustained or delayed release profile.

42. 42. An implantable article according to any one of claims 39 to 41, wherein the solidifiable body material provides gastroprotection for the implantable article when the implantable article is administered orally.

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