Solid dosage form production

Abstract

This application relates to the production of solid dosage forms. The invention utilizes 3D printing technology, particularly fused filament manufacturing (FFF) 3D printing, to produce solid dosage forms, such as pharmaceutical tablets. The production process utilizes novel printing filaments containing active ingredients, typically on a spool. Such active ingredient-containing filaments have proven to be very robust, and the principles outlined in this disclosure provide a variety of viable formulations directly from the 3D printer. This provides, for the first time, a feasible means for on-site (e.g., in-pharmacy) 3D printing of personalized medicines tailored to patient needs. The invention also relates to specialized software for operating printing devices and for monitoring the real-time operation of multiple printing devices to enable easy detection of malfunctions, thereby facilitating regulatory approval and establishing a local, national, and global system conducive to regulatory compliance.

Description

[0001] This application is a divisional application of the application filed on September 8, 2015, with application number 201910912296.7 and invention title "Production of Solid Dosage Forms".

[0002] The application filed on September 8, 2015, with application number 201910912296.7 and entitled "Production of Solid Dosage Forms", is a divisional application of the application filed on September 8, 2015, with application number 201580060637.2 and entitled "Production of Solid Dosage Forms".

[0003] introduce

[0004] This invention relates to a solid dosage form printing apparatus (and its method of use) in the production of solid dosage forms such as tablets. The invention also relates to solid dosage forms, solid dosage form packages, associated active ingredient-containing printing elements and other printing elements (and their manufacturing processes), kits of parts, computers for controlling the associated printing processes (and software and computer-implemented methods related to the printing processes), and systems for collecting data related to the solid dosage form production process (and databases associated with the solid dosage form production process). background

[0005] The production and consumption of pharmaceuticals, nutraceuticals, and food supplements in solid dosage forms (e.g., tablets, implants, etc.) (collectively referred to herein as "healthcare dosage forms") are increasing, particularly due to growing reliance on such products in increasingly health-conscious societies, such as the UK's National Health Service. Where possible, solid dosage forms tend to be the preferred choice over other dosage forms (e.g., injectable liquid formulations) due to their ease of administration (i.e., typically oral), resulting in better patient compliance, storability and transportability (low space requirements and ease of packaging), and high stability (longer shelf life – less degradation). However, despite these significant advantages over other dosage forms, solid dosage forms are generally more cumbersome to manufacture (in terms of both the number of ingredients and processing steps) and are typically only cost-effective at large-scale production, meaning they usually require large manufacturing facilities with sophisticated equipment. These manufacturing limitations have a detrimental impact on consumer choice and / or the customizability of healthcare dosage forms because, for example, it is impractical and cost-inefficient to mass-produce various different dosages for a given drug using conventional manufacturing techniques. Therefore, consumers (e.g., patients) and healthcare professionals (e.g., doctors, pharmacists) must make full use of the limited variety of dosages available, prescribed by the supplier rather than according to the consumer's needs.

[0006] Since the advent of 3D printing in the early 1980s, many researchers have attempted to make 3D printing technology viable for manufacturing solid dosage forms in healthcare. For example, for over a decade, MIT and Therics Inc. have collaborated to develop a viable pill printer that uses a 3D printer to print solid drug dosage forms on-site. This technology forms pills via a multi-layer 3D printing process that involves precisely printing a dose of liquid drug solution onto a thin layer of fine powder, followed by the application of additional layers (e.g., additional powder, binder, etc.). Examples of such processes are disclosed in earlier publications such as WO95 / 11007 (MASSACHUSETTS INSTITUTE OF TECHNOLOGY) and WO03 / 092633 (THERICS, INC.), which specifically describe the production of solid dosage forms with various structures and drug release profiles. However, regulatory approval for such 3D drug printing systems (e.g., by the FDA or MHRA) remains elusive, and currently they are only applicable to low-dose drug products, partly due to the limited solubility of many drugs in the relevant ink solutions. Therefore, patients' choices will remain very limited, much like the choices doctors or pharmacists have when providing specific, customized treatments. Furthermore, the resolution and shape of solid dosage forms remain problematic. However, specific issues with existing 3D printing systems, such as the large number of different components required to produce viable dosage forms (and therefore different printing barrels), create high complexity and user-unfriendly characteristics. This, in turn, increases the likelihood of manufacturing errors, machine malfunctions and failures, quality control variations, and regulatory feasibility (i.e., the FDA is unlikely to approve drug printing systems prone to too many variables that could affect the quality of the drug product). Another issue is the poor stability of some drug substances in liquid ink formulations. This can severely limit the shelf life of the drug source, thus creating significant regulatory and cost problems. Invention Overview

[0007] Therefore, the object of the present invention is to provide an improved method for producing solid dosage forms and to appropriately solve at least one problem inherent in the prior art.

[0008] Another objective is to provide a method for producing dose-customizable solid dosage forms as needed, and a system suitable for regulatory approval and usable in pharmacies (and reducing pharmacy workload or manual operation) or other approved custom pharmaceutical manufacturing facilities, said method having one or more advantages selected from the following: high doses of active ingredient (or higher concentrations in solid dosage forms), minimal input and output variables, minimal input ingredients or elements, minimal complexity, customizable drug release profiles, and maximum storage stability for both input materials (particularly any substance containing an active ingredient, such as a drug) and the product.

[0009] Another object of the present invention is to provide a means to allow for more aesthetically pleasing customization of solid dosage forms (e.g., color and shape) without loss of resolution or functional and structural integrity (e.g., novel shapes for children can promote patient compliance).

[0010] Another objective is to provide a method for producing solid dosage forms to facilitate prototyping and formulation research and development (e.g., as a development tool in the pharmaceutical industry).

[0011] According to a first aspect of the present invention, a solid dosage form printing apparatus is provided for printing solid dosage forms containing active ingredients, the apparatus comprising:

[0012] Fused Filament Fabrication (FFF) 3D Printer;

[0013] The platform allows solid dosage forms to be printed (i.e., solid dosage forms can be built on the platform).

[0014] Printing filaments containing active ingredients, wherein the printing filaments containing active ingredients consist of, are substantially composed of, or contain a filament composition containing active ingredients, the filament composition containing active ingredients comprising an active ingredient (or a precursor thereof, such as a precursor converted to an active ingredient during 3D printing and / or further processing) and optionally (and most appropriately) an active ingredient carrier;

[0015] Optionally, one or more additional printing filaments, each additional printing filament suitably and independently composed of, substantially composed of, or containing an additional filament composition; and

[0016] A computer for controlling an FFF 3D printer and optionally also for controlling a build platform.

[0017] (The FFF 3D printer is suitably computer-operable, operating via a computer, specifically specialist solid dosage form printing software, and optionally one or more databases, to print solid dosage forms on a build platform, the printing being suitably via a process involving the printing and / or extrusion of a filament containing active ingredients and optionally also involving the printing and / or extrusion of one or more additional filaments.) Any or more of the build platform, the filament containing active ingredients, the additional filaments, and / or the computer, and / or any part thereof, may suitably be integrated within or formed part of the FFF 3D printer.

[0018] According to another aspect of the invention, a method for printing a solid dosage form containing an active ingredient (or a method using an apparatus as defined herein) is provided, the method comprising:

[0019] a) Provide a solid dosage form printing apparatus (suitably as defined herein, or suitable variations thereof) for printing solid dosage forms containing an active ingredient, the apparatus comprising:

[0020] Fused Filament Fabrication (FFF) 3D Printer;

[0021] The platform is designed to be printable for solid dosage forms;

[0022] Printing filaments containing active ingredients, wherein the printing filaments containing active ingredients consist of, are substantially composed of, or contain a filament composition containing active ingredients, the filament composition containing active ingredients comprising an active ingredient (or a precursor thereof, such as a precursor converted to an active ingredient during 3D printing and / or further processing) and optionally (and most appropriately) an active ingredient carrier;

[0023] Optionally, one or more additional printing filaments, each additional printing filament suitably and independently consisting of, substantially consisting of, or containing an additional filament composition.

[0024] A computer for controlling an FFF 3D printer and optionally also for controlling a build platform;

[0025] b) Operate the FFF 3D printer to print a solid dosage form (or its precursor) onto the build platform via a process (appropriately computer-implemented), said process comprising:

[0026] i) Printing (and / or extruding) active ingredient-containing filaments (or printing / extruding active ingredient-containing filament compositions derived from active ingredient-containing filaments); and

[0027] ii) Optionally print (and / or extrude) one or more additional printing filaments (or print / extrude one or more additional filament compositions derived from one or more additional printing filaments);

[0028] c) Optionally perform one or more additional processing steps (with or without an FFF 3D printer; for example, coating or otherwise modifying the surface, shape, or properties of a solid form).

[0029] According to another aspect of the invention, solid dosage forms are provided that are obtainable, acquired, or directly obtained by methods of printing solid dosage forms as defined herein.

[0030] According to another aspect of the invention, a solid dosage form comprising a filament composition containing an active ingredient and optionally one or more other filament compositions is provided.

[0031] According to another aspect of the invention, a multilayer solid dosage form is provided comprising one or more layers of a filament composition containing an active ingredient and optionally one or more layers of one or more other filament compositions.

[0032] According to another aspect of the invention, a solid formulation comprising an extruded printing filament containing an active ingredient and optionally one or more other extruded printing filaments is provided.

[0033] According to another aspect of the invention, a solid formulation comprising one or more layers of extruded printing filament containing active ingredients and optionally one or more layers of extruded one or more other types of printing filaments is provided.

[0034] According to another aspect of the invention, a method for producing solid dosage form packages is provided, the method comprising packaging one or more solid dosage forms as defined herein, wherein the one or more solid dosage forms are optionally the same or different.

[0035] According to another aspect of the invention, solid dosage form packages that are obtainable, acquired, or directly obtained by means of producing solid dosage form packages as defined herein are provided.

[0036] According to another aspect of the invention, a solid dosage form package is provided, which contains one or more solid dosage forms as defined herein.

[0037] According to another aspect of the invention, there is provided an active ingredient-containing printing filament (suitably for fused filament manufacturing 3D printing), wherein the active ingredient-containing printing filament consists of, substantially consists of, or comprises an active ingredient-containing filament composition, which contains an active ingredient (or a precursor thereof, such as a precursor converted to an active ingredient during 3D printing and / or further processing) and optionally (and most suitably) an active ingredient carrier;

[0038] The active ingredients may be selected from pharmaceuticals, nutritional products, or food supplements.

[0039] Appropriately, the active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers.

[0040] According to another aspect of the invention, a filament composition containing an active ingredient is provided, the filament composition containing an active ingredient comprising an active ingredient (or a precursor thereof, such as a precursor converted to an active ingredient during 3D printing and / or further processing) and optionally (and most suitably) an active ingredient carrier;

[0041] The active ingredients may be selected from pharmaceuticals, nutritional products, or food supplements.

[0042] Appropriately, the active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers.

[0043] According to another aspect of the invention, an active ingredient-containing printing filament (suitably for fused filament fabrication 3D printing) comprising an active ingredient and optionally (and most suitably) an active ingredient carrier is provided;

[0044] The active ingredients may be selected from pharmaceuticals, nutritional products, or food supplements.

[0045] Appropriately, the active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers.

[0046] According to another aspect of the invention, printing filaments, filament compositions, or solid formulations comprising a fusible component and an infusible component are provided. Suitably, the fusible component has a melting point (or glass transition temperature) of 150°C or less, suitably 100°C or less, or suitably 80°C or less. Suitably, the infusible component has a melting point of 150°C or more, suitably 200°C or more, suitably 500°C or more, or suitably 1000°C or more.

[0047] According to another aspect of the invention, an active filament spool (suitably for fused filament manufacturing 3D printing) is provided, comprising a printing filament containing an active ingredient as defined herein.

[0048] According to another aspect of the invention, a method for preparing a filament composition containing an active ingredient is provided, the method comprising mixing the active ingredient and optionally (and most preferably) an active ingredient carrier together (and optionally additionally melting or liquefying them together).

[0049] According to another aspect of the invention, there are provided silk compositions containing active ingredients that can be obtained, acquired, or directly obtained by methods for preparing silk compositions containing active ingredients as defined herein.

[0050] According to another aspect of the invention, a method for preparing a printing filament containing an active ingredient is provided, the method comprising mixing the active ingredient and optionally (and most suitably) an active ingredient carrier together to produce a premix; melting (or liquefying) the premix to produce a molten (or liquefied) premix; and extruding the molten (or liquefied) premix to produce a printing filament containing the active ingredient.

[0051] According to another aspect of the invention, there are provided printing filaments containing active ingredients that can be obtained, acquired, or directly obtained by methods for preparing printing filaments containing active ingredients as defined herein.

[0052] According to another aspect of the invention, a method for preparing an active filament spool is provided, the method comprising providing a printing filament containing an active ingredient as defined herein, or preparing a printing filament containing an active ingredient by a method as defined herein; and winding the printing filament containing the active ingredient around a spool.

[0053] According to another aspect of the invention, active filament spools are provided that can be obtained, acquired, or directly obtained by methods for preparing active filament spools as defined herein.

[0054] According to another aspect of the invention, an additional printing filament (suitably for fused filament manufacturing 3D printing) is provided, wherein the additional printing filament comprises, substantially comprises, or contains an additional filament composition, the additional filament composition comprising an active ingredient carrier for the active ingredient and optionally one or more pharmaceutically or nutritionally acceptable diluents or carriers.

[0055] The active ingredients may be selected from pharmaceuticals, nutritional products, or food supplements.

[0056] Appropriately, the active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers.

[0057] According to another aspect of the invention, a further silk composition is provided, comprising an active ingredient carrier for the active ingredient and optionally one or more pharmaceutically or nutritionally acceptable diluents or carriers.

[0058] The active ingredients may be selected from pharmaceuticals, nutritional products, or food supplements.

[0059] Appropriately, the active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers.

[0060] According to another aspect of the invention, an additional printing filament (suitably for fused filament manufacturing 3D printing) is provided, comprising an active ingredient carrier for the active ingredient and optionally one or more pharmaceutically or nutritionally acceptable diluents or carriers.

[0061] The active ingredients may be selected from pharmaceuticals, nutritional products, or food supplements.

[0062] Appropriately, the active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers.

[0063] According to another aspect of the invention, an additional filament spool (suitably for fused filament fabrication 3D printing) is provided, which comprises additional printing filament as defined herein.

[0064] According to another aspect of the invention, a method for preparing another filament composition is provided, the method comprising mixing together an active ingredient carrier for the active ingredient and optionally one or more pharmaceutically or nutritionally acceptable diluents or carriers (and optionally additionally melting or liquefying them together).

[0065] According to another aspect of the invention, additional filament compositions are provided that are obtainable, acquired, or directly obtained by methods for preparing additional filament compositions as defined herein.

[0066] According to another aspect of the invention, a method for preparing additional printing filaments is provided, the method comprising mixing an active ingredient carrier for an active ingredient and optionally one or more pharmaceutically or nutritionally acceptable diluents or carriers together (and optionally additionally melting or liquefying them together) to produce a premix; melting (or liquefying) the premix to produce a molten (or liquefied) premix; and extruding the molten (or liquefied) premix to produce additional printing filaments.

[0067] According to another aspect of the invention, additional printing filaments are provided that can be obtained, acquired, or directly obtained by methods for preparing additional printing filaments as defined herein.

[0068] According to another aspect of the invention, a method for preparing an additional filament spool is provided, the method comprising providing an additional printing filament as defined herein, or preparing the additional printing filament by a method as defined herein; and winding the additional printing filament around the spool.

[0069] According to another aspect of the invention, additional spools are provided that can be obtained, acquired, or directly obtained by methods for preparing additional spools as defined herein.

[0070] According to another aspect of the invention, a component kit is provided comprising a printing filament containing an active ingredient as defined herein and optionally one or more other printing filaments as defined herein.

[0071] According to another aspect of the invention, a component kit is provided comprising an active spool as defined herein and optionally one or more other spools as defined herein.

[0072] According to a first aspect of the present invention, a solid dosage form printing apparatus is provided for printing solid dosage forms containing active ingredients, the apparatus comprising:

[0073] Fuse-forming (FFF) 3D printers with a computer interface (whether for wired or wireless connection to a computer operable to control the FFF 3D printer);

[0074] The platform allows solid dosage forms to be printed (i.e., solid dosage forms can be built on the platform).

[0075] Printing filaments containing active ingredients, wherein the printing filaments containing active ingredients consist of, are substantially composed of, or contain a filament composition containing active ingredients, the filament composition containing active ingredients comprising an active ingredient (or a precursor thereof, such as a precursor converted to an active ingredient during 3D printing and / or further processing) and optionally (and most appropriately) an active ingredient carrier;

[0076] Optionally, one or more additional printing filaments, each of which is suitably composed independently of, substantially composed of, or contains additional filament compositions.

[0077] According to another aspect of the present invention, a fused filament fabrication (FFF) 3D printer or printing apparatus is provided for printing solid formulations containing active ingredients, the FFF 3D printer or printing apparatus comprising:

[0078] Computer interface (whether for wired or wireless connection to a computer that can be operated to control an FFF 3D printer or printing device);

[0079] Active filament spools, which contain printing filaments containing active ingredients as defined herein;

[0080] Optionally, one or more additional filament spools, which independently contain one or more additional printing filaments as defined herein;

[0081] At least one extrusion nozzle through which a filament (or a portion thereof) can be extruded; and

[0082] A conveyor for conveying printing filaments containing active ingredients and any optional one or more other printing filaments to and / or through the at least one extrusion nozzle;

[0083] Extrusion nozzle heating element (for heating the at least one extrusion nozzle to melt (or otherwise liquefy) the active ingredient-containing printing filament and any optional one or more other printing filaments, or a portion thereof);

[0084] The platform is designed to be printable for solid dosage forms (i.e., solid dosage forms can be built on the platform).

[0085] The method of using the apparatus and its sensible variations can be applied (as the case may be) to any apparatus as defined herein.

[0086] According to another aspect of the invention, a computer is provided for operating a solid dosage form printing apparatus, a fused filament fabrication (FFF) 3D printer, or a printing apparatus as defined herein, wherein the computer comprises:

[0087] An interface that connects or enables a computer to connect to (whether wirelessly or wired) a solid-form printing device, a fused filament manufacturing (FFF) 3D printer, or a printing device as defined herein, or connects to it (appropriately to allow the computer to control and / or operate the aforementioned).

[0088] The computer operates based on solid dosage form printing software (and optionally, one or more databases), which configures the computer to perform the following steps:

[0089] i) Obtain information about one or more parameters related to the solid dosage form to be printed (e.g., active ingredient, active ingredient load / dose, shape, release profile, etc.) (e.g., by manual user input or via one or more databases, optionally in response to user-inputted references, such as the patient's name);

[0090] ii) Calculate the mass and / or volume of the solid dosage form to be printed based on the information obtained in step (i);

[0091] iii) Based on the information obtained in step (i) and the calculations performed in step (ii), the printing and relative proportions of the components within the solid dosage form (i.e., constituting the solid dosage form) are controlled by the following:

[0092] a. Controlling the printing, deposition, and / or extrusion of printing filaments (or portions thereof) containing active ingredients;

[0093] b. Optionally control the printing, deposition, and / or extrusion of one or more additional printing filaments (or portions thereof);

[0094] c. Optionally control the execution of one or more additional processing steps.

[0095] According to another aspect of the invention, a computer-implemented method for operating a solid dosage form printing apparatus, a fused filament fabrication (FFF) 3D printer, or a printing apparatus as defined herein is provided, the method comprising:

[0096] A computer (with a suitable data connection to the relevant printing device, whether wired or wireless) that operates based on solid dosage form printing software (and optionally also based on one or more databases) to:

[0097] i) Obtain information about one or more parameters related to the solid dosage form to be printed (e.g., active ingredient, active ingredient load / dose, shape, release profile, shape, color, etc.) (e.g., by manual user input or via one or more databases, optionally in response to user input references, such as the patient's name);

[0098] ii) Calculate the mass and / or volume of the solid dosage form to be printed based on the information obtained in step (i);

[0099] iii) Based on the information obtained in step (i) and the calculations performed in step (ii), the printing and relative proportions of the components within the solid dosage form (i.e., constituting the solid dosage form) are controlled by the following:

[0100] a. Controlling the printing, deposition, and / or extrusion of printing filaments (or portions thereof) containing active ingredients;

[0101] b. Optionally control the printing, deposition, and / or extrusion of one or more additional printing filaments (or portions thereof);

[0102] c. Optionally control the execution of one or more additional processing steps.

[0103] According to another aspect of the invention, a computer program is provided that includes solid dosage form printing software code for performing, when the computer program is run on a computer, a computer-implemented method as defined herein (i.e., a method for operating a solid dosage form printing apparatus, a fused filament fabrication (FFF) 3D printer, or a printing apparatus as defined herein).

[0104] According to another aspect of the invention, a computer-readable medium is provided that contains solid dosage form printing software code, which, when run on a computer, is executable to cause the computer to perform computer-implemented methods as defined herein (i.e., methods of operating a solid dosage form printing apparatus, a fused filament fabrication (FFF) 3D printer, or a printing apparatus as defined herein).

[0105] According to another aspect of the invention, a system for collecting data related to solid dosage form production is provided (suitably having a solid dosage form printing apparatus, a fused filament fabrication (FFF) 3D printer, or a printing apparatus as defined herein), the system comprising:

[0106] Networked computer systems;

[0107] A central production database associated with a networked computer system;

[0108] One or more monitoring computers (whether they correspond to or are different from computers associated with and regulating the operation of the respective printing devices, and whether they are local or remote to the associated printing devices) communicate with one or more solid dosage form printing devices (or their FFF 3D printers), each of which is configured to collect production data relating to the operation of the one or more solid dosage form printing devices (or FFF 3D printers) (optionally via sensors associated with the associated printing device or FFF 3D printer, which are configured to detect operating parameters and feed them back (or send them) to the associated monitoring computer) in order to monitor the production of the respective solid dosage form;

[0109] A communicator associated with each of one or more monitoring computers, used to communicate (or send / receive) with a central production database via the network computer system, so that the central production database can record (or collect and / or store) collected production data (from the monitoring computer or each monitoring computer) relating to some or all of the operations of one or more solid dosage form printing devices (or FFF 3D printers), so as to enable centralized monitoring of the production of some or all solid dosage forms;

[0110] Optionally, one or more analysis computers (optionally the same as one or more monitoring computers) are configured or operable to analyze data transmitted to a central production database and optionally trigger responses (e.g., data transmission and / or actions) based on the analysis of the data (e.g., alarms when operational failures are identified).

[0111] Any feature described with respect to any particular aspect of the invention, including optional, suitable, and preferred features, may also be a feature of any other aspect of the invention, including optional, suitable, and preferred features. Brief description of the attached diagram

[0112] To better understand the present invention and to show how embodiments of the invention can be put into practice, reference is now made to the following schematic diagram by way of example, wherein:

[0113] Figure 1 (a) and Figure 1 (b) shows top and bottom projections of ABS-based model tablets produced using ABS filaments.

[0114] Figure 2 (a) and Figure 2 (b) shows top and bottom projections of ABS-based core-shell model tablets produced using white and red ABS filaments.

[0115] Figure 3 Top projections of several PVA-based disc-shaped homogeneous model tablets produced using PVA filaments are shown.

[0116] Figure 4 A top projection of a PVA-based disc-shaped core-shell model tablet produced using PVA filaments and its open cross-section is shown.

[0117] Figure 5 (a) Figure 5 (b) and Figure 5 (c) Projection diagrams of PVA filaments treated with methanol, PVA filaments loaded with prednisolone, and PVA filaments loaded with dipyridamole are shown respectively.

[0118] Figure 6 A top projection of a PVA model tablet loaded with prednisolone is shown.

[0119] Figure 7 (a) and Figure 7 (b) shows a special cap (or plasticizing station) that dispenses plasticizer from the fabric pre-soaked in plasticizer onto the filament as it passes through the printing nozzles inside the 3D printer.

[0120] Figure 8 (a) Figure 8 (b) and Figure 8 (c) Schematic top projection, side view and plan view of the tablet design are shown respectively.

[0121] Figure 9Top projection diagrams of several tablets are shown, with the top row showing PVA tablets loaded with prednisolone at the corresponding prednisolone doses of 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, and 10 mg; and the bottom row showing blank PVA-only tablets of the same size as the tablets corresponding to the 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, and 10 mg doses in the top row.

[0122] Figure 10 A graph illustrating the linear correlation between theoretical volume and the mass of a printed default (drug-free) PVA tablet is shown.

[0123] Figure 11 A graph illustrating the linear correlation between theoretical volume and the mass of printed PVA tablets loaded with prednisolone is shown.

[0124] Figure 12 A graph illustrating the relationship between the target dose and the dose achieved in a prednisolone-loaded tablet is shown.

[0125] Figure 13 SEM images of a) surface view and b) cross-sectional view of default PVA filament (PVA only) are shown; and SEM images of c) surface view and d) cross-sectional view of PVA filament loaded with prednisolone are shown.

[0126] Figure 14 SEM images of PVA after extrusion from the nozzle of a fused deposition modeling 3D printer are shown at a magnification of a) 1000 μm and b) 50 μm.

[0127] Figure 15 SEM images of the sides of PVA tablets loaded with prednisolone are shown at different magnifications: a) at 2000 μm; b) at 200 μm; c) at 20 μm.

[0128] Figure 16 SEM images of the top surface of a PVA tablet loaded with prednisolone are shown at different magnifications: a) at 1000 μm; and b) at 100 μm.

[0129] Figure 17 SEM images of cross-sections of PVA tablets loaded with prednisolone are shown: a) overall view; b) magnified view of the peripheral domain; and c) magnified view of the central domain.

[0130] Figure 18The spectra obtained from powder X-ray diffraction are shown for default prednisolone (top spectrum), PVA filament (middle spectrum), and PVA filament and tablet loaded with prednisolone (bottom spectrum).

[0131] Figure 19 The DSC thermographs of prednisolone (top spectrum), default PVA filament (middle spectrum), and PVA tablet loaded with prednisolone (bottom spectrum) are shown.

[0132] Figure 20 This is a graph showing the time versus prednisolone concentration for 3D-printed PVA tablets during a pH change flow-through dissolution test.

[0133] Figure 21 This is a diagram illustrating the in vitro release pattern of prednisolone from 3D-printed PVA tablets using a pH-varying flow dissolution system.

[0134] Figures 22 to 44 The diagram shows the filaments and / or solid dosage forms prepared in Examples 3.1 to 3.28 as described in Table 5 below.

[0135] Figure 45 It is a schematic diagram illustrating an example of a system for generating and collecting production data related to solid dosage forms, and it describes in detail the flow of data and information within the system.

[0136] Figure 46 This is a graph showing the linear relationship between the theoretical printed volume and the retrieved mass.

[0137] Figure 47 An array of 3D-printed theophylline tablets with increased size and strength is shown.

[0138] Figure 48 This is a graph showing the linear relationship between the achieved dose and the expected dose of theophylline tablets.

[0139] Figure 49 This is a graph showing the in vitro release curves of theophylline from 3D tablets of different strengths.

[0140] Figure 50 This is a graph illustrating the effect of 3D printing resolution on drug release patterns.

[0141] Figure 51 The image shows a low-resolution SEM image of a 3D-printed tablet of theophylline Eudragit RL.

[0142] Figure 52 SEM images of a theophylline Eudragit RL 3D-printed tablet are shown at standard resolution.

[0143] Figure 53 SEM images of a theophylline Eudragit RL 3D-printed tablet are shown at high resolution.

[0144] Figure 54 This is a graph showing the drug release curves of Eudragit E filament (hollow rhombus), Eudragit E 3D printed tablet (solid rhombus), HPC SSL filament (hollow circle), and HPC SSL 3D printed tablet (solid circle).

[0145] Figure 55 The diagrams shown are derived from the drug release profiles of: a) Eudragit RL:E filaments (hollow square), Eudragit RL:RS 1:1 (hollow rhombus), Eudragit RL (hollow triangle), and Eudragit RS (hollow circle); and b) 3D-printed tablets of the drug formulated with Eudragit RL:E (solid square), Eudragit RL:RS 1:1 (solid rhombus), Eudragit RL (solid triangle), and Eudragit RS (solid circle).

[0146] Figure 56 This is a graph showing the effect of infill setting on the quality of 3D printed tablets.

[0147] Figure 57 This is a graph showing the effect of filling settings on theophylline release from 3D-printed HPC SSL tablets.

[0148] Figure 58 This is a graph showing the thermal degradation curves of theophylline, Eudragit RL, a physical mixture of theophylline and Eudragit RL, extruded filaments of theophylline and Eudragit RL, and tablets of theophylline and Eudragit RL.

[0149] Figure 59 The glass transition temperature for Eudragit in the first heating step in the following forms: pure polymer, physical mixture with theophylline, extruded filament, and printed tablets.

[0150] Figure 60 DSC scans of a physical mixture of theophylline, theophylline, and Eudragit, extruded filaments of theophylline and Eudragit RL, and printed tablets are shown.

[0151] Figure 61 The following X-ray diffraction patterns are shown: pure theophylline, pure Eudragit RL, a physical mixture of the two, extruded filaments, and printed tablets.

[0152] Figure 62 The following thermal degradation curves are shown: pure theophylline, pure HPC SSL, physical mixtures, extruded filaments, and printed tablets.

[0153] Figure 63 DSC scans showing the glass transition temperatures of a physical mixture of pure HPC SSL, theophylline, and HPC SSL, extruded filaments, and printed tablets are presented.

[0154] Figure 64 The DSC scans show the endothermic melting of pure theophylline, HPC SSL, physical mixtures, extruded filaments, and printed tablets.

[0155] Figure 65 The following X-ray diffraction patterns are shown: pure theophylline, HPC SSL, physical mixture, extruded filament, and printed tablet.

[0156] Figure 66 A filament spool with nozzles is shown that can be releasably fixed inside a 3D printer.

[0157] Figure 67 A photograph shows filaments formed using spray-dried lactose filler.

[0158] Figure 68 A photograph shows filaments formed using a compressible lactose filler.

[0159] Figure 69 A photograph of a filament formed using tricalcium phosphate filler is shown.

[0160] Figure 70 This is a DSC temperature record graph showing the thermal analysis of various filaments containing tricalcium phosphate filler.

[0161] Figure 71 Photographs show filaments and tablets formed with different levels of plasticizer.

[0162] Figure 72 This is a DSC temperature record graph showing the thermal analysis of various filaments containing different levels of plasticizer.

[0163] Figure 73 Photographs show tablets formed with different levels of plasticizer.

[0164] Figure 74 TGA diagrams of different filler combinations used with Eudragit E are shown.

[0165] Figure 75 DSC temperature recordings of different filler combinations used with Eudragit E are shown.

[0166] Figure 76 Photographs show filaments and tablets formed with different levels of disintegrants.

[0167] Figure 77 The diagram shows drug release profiles for tablets containing different amounts of polyplasdone.

[0168] Figure 78 This is a graph showing the in vitro drug release curves of the drug formulations in Table 21.

[0169] Figure 79 This is a diagram of the tablet structure that was designed and imported into the MakerBot desktop software.

[0170] Figure 80 This is an illustration of the geometry of a 3D-printed tablet.

[0171] Figure 81 Images of all successfully printed PVP-based tablets with uniform design are shown.

[0172] Figure 82 The drug release profiles for PVP-based tablets loaded with theophylline are shown.

[0173] Figure 83 The drug release profile for a PVP-based tablet loaded with aspirin is shown.

[0174] Figure 84 The drug release profiles for PVP-based tablets loaded with diclofenac are shown.

[0175] Figure 85 The theophylline release profiles of the successfully printed filament compositions shown in Table 37, which contain PEG 200,000:talc:theo in a ratio of 70%:20%:10%, are illustrated.

[0176] Figure 86 and Figure 87 This is a photographic image of a successfully printed PEG 200,000-based tablet.

[0177] Figure 88 , Figure 89 and Figure 90 The illustration shows an array of designs representing the core (red) and shell (white) using 3D Max software.

[0178] Figure 91 Photographs show 3D-printed PVA-based cores (left) and shell-core structures loaded with theophylline, the shell-core structures having increased shell thicknesses of Eudragit L100-55 shells of 0.3 mm, 0.6 mm, 0.9 mm, 1.2 mm and 1.5 mm.

[0179] Figure 92 The image shows a sectioned core-shell tablet (left) and a 100% finished tablet (middle and right).

[0180] Figure 93 Drug release profiles based on core-only and shell-core structures with increased thickness of the enteric shell are shown.

[0181] Figure 94 The image shows a PVP-based core (leftmost) theophylline tablet and a series of core-shell structures with increased shell diameter (from right to left).

[0182] Figure 95 The corresponding drug release profiles for dosage forms, with and without oil (in this case, olive oil BP), applied to the surface of the filament before printing are shown.

[0183] Figure 96 It shows Figure 94 The drug release curves for each drug described herein illustrate that zero-order kinetics can be achieved using the 3D printing filaments of this invention.

[0184] Figure 97 The image shows a shell-to-chip formulation after 24 dissolution tests on the tablet. Invention Details

[0185] definition

[0186] Unless otherwise stated, the following terms used in the specification and claims have the following meanings as given below.

[0187] Throughout the description and claims of this specification, the terms "comprise" and "contain," and their variations, mean "including but not limited to," and are not intended to exclude other parts, additives, components, wholes, or steps. Throughout the description and claims of this specification, the singular includes the plural unless the context requires otherwise. In particular, where the indefinite article is used, this specification should be understood to consider both the plural and the singular unless the context requires otherwise.

[0188] Features, integrals, properties, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except where at least some of such features and / or steps are mutually exclusive combinations. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel one or any novel combination of steps in any method or process so disclosed.

[0189] The reader’s attention is directed to all papers and documents related to this application that were submitted concurrently with or prior to this specification and that are publicly available for review, and the contents of all such papers and documents are incorporated herein by reference.

[0190] To avoid any doubt, it is hereby stated that the information previously disclosed in this specification under the heading "Background" is relevant to this invention and should be considered part of the disclosure of this invention.

[0191] Unless otherwise stated, any reference to the term “melting” (or its derivatives) herein, particularly in the context of melting wire, appropriately includes the glass transition or softening of a given material, appropriately to allow it to be extruded (e.g., through a nozzle). However, in the context of the definition of “melting point” of a substance, the term “melting” is according to the definition in the art—a phase transition from solid to liquid.

[0192] In this article, "glass transition temperature" or "T" is mentioned. g "Suitably refers to the temperature at which the material softens (e.g., to allow it to be extruded). Suitablely, the glass transition temperature (T0) of the material described herein..." gThe glass transition temperature (GLT) can be determined using standard test methods, appropriately employing dynamic mechanical analysis—appropriate tests include test protocols defined by ASTM E1640. Differential scanning calorimetry (DSC) can also be used. For example, protocols described in ASTM E1356 and ASTM D7426 can be used to identify the GLT. Those skilled in the art will understand that references herein to the GLT of a particular material falling within a certain temperature range are intended to mean that at least one GLT of the material (which may or may not have multiple GLTs) falls within that temperature range. Appropriately, an unqualified reference to “glass transition temperature” means at least one, appropriately means the lowest GLT, and may appropriately mean the GLT that absorbs the most heat (or is the most endothermic). It is self-evident to those skilled in the art that the material is sufficiently softened under a specific set of conditions (e.g., at the print nozzle, where the filament needs to be softened for extrusion during printing, and subsequently can be recured or rehardened).

[0193] Unless otherwise stated, the term "viscosity" as used herein refers to the viscosity as defined in Ph.Eur.2.2.10 or USP. <912> Viscosity measured using the test protocol defined in Method II, via a Brookfield viscometer (UL adapter / 30 rpm / 20 °C).

[0194] Unless otherwise stated, any reference to “average” in this document is intended to refer to the mean value.

[0195] When a composition is said to contain a plurality of specified ingredients (optionally at specified concentrations), the composition may optionally include additional ingredients in addition to those specified. However, in some embodiments, a composition said to contain a plurality of specified ingredients may actually consist substantially of all of the specified ingredients or consist of all of the specified ingredients.

[0196] In this document, when a composition is described as "consistently composed of" a specific component, the composition suitably contains at least 70 wt% of the component, suitably at least 90 wt% of the component, suitably at least 95 wt% of the component, and most suitably at least 99 wt% of the component. Suitably, a composition described as "consistently composed of" a specific component consists of the component except for one or more trace impurities.

[0197] When the amount or concentration of a particular component of a given composition is specified as a weight percentage (wt% or %w / w), the weight percentage refers to the percentage of that component by weight relative to the total weight of the composition as a whole. Those skilled in the art will understand that the sum of the weight percentages of all components of the composition will total 100 wt%. However, in cases where not all components are listed (e.g., where the composition is stated to "contain" one or more particular components), the remaining weight percentage may optionally be made up to 100 wt% by unspecified ingredients (e.g., diluents, such as water, or other non-essential but appropriate additives).

[0198] In this document, unless otherwise stated, when referring to multiple ingredients / components, the term "part" (e.g., parts by weight, pbw) refers to the relative ratio between the multiple ingredients / components. It indicates that the molar ratio or weight ratio of two, three, or more components produces the same effect (e.g., the molar ratio of x, y, and z is x1:y1:z1 or the range x1-x2:y1-y2:z1-z2, respectively). While in many embodiments the amount of a single component in the composition may be given as a "wt%" value, 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 in the liquid pharmaceutical compositions of the present invention, the relative ratio between components is generally more important than their absolute concentration. When a composition containing multiple ingredients is described individually in parts by weight (i.e., only indicating the relative ratio of the ingredients), it is not necessary to specify the absolute amount or concentration of the ingredients (whether overall or individually), because the advantages of the present invention can derive from the relative ratio of the components rather than their absolute amount or concentration. However, in some embodiments, such compositions are essentially composed of prescribed ingredients and diluents (e.g., water) or are composed of prescribed ingredients and diluents (e.g., water).

[0199] The term "mol%" is well understood by those skilled in the art, and the mol% of a particular component refers to the amount of that component (expressed in moles) divided by the total amount of all components (including that particular component) converted into a percentage (i.e., multiplied by 100). The concept of mol% is directly related to mole fraction.

[0200] The term "substantially free of" when used with respect to a given component in a composition (e.g., "liquid pharmaceutical composition substantially free of compound X") means a composition in which said component is substantially absent. When a composition is "substantially free of" a given component, the composition suitably contains no more than 0.001 wt% of said component, suitably no more than 0.0001 wt% of said component, suitably no more than 0.00001 wt% of said component, suitably no more than 0.000001 wt% of said component, and most suitably no more than 0.0001 parts per billion (by weight).

[0201] The term "entirely free" when used with respect to a given component in a composition (e.g., "liquid pharmaceutical composition that is completely free of compound X") means a composition that contains none of the component.

[0202] Appropriately, unless otherwise stated, when referring to parameters (e.g., pH, pKa, etc.) or states of materials (e.g., liquids, gases, etc.) that are dependent on pressure and / or temperature, such references shall, unless further clarification is required, refer to the parameters at standard ambient temperature and pressure (SATP). SATP is a temperature of 298.15 K (25 °C, 77 °F) and an absolute pressure of 100 kPa (14.504 psi, 0.987 atm).

[0203] In this document, the terms “particle size” or “pore size” refer to the length of the longest dimension of a given particle or pore, respectively. Particle size and pore size can be measured using methods well known in the art, including laser particle size analyzers and / or electron microscopes (e.g., transmission electron microscope, TEM or scanning electron microscope, SEM).

[0204] General points and advantages of the present invention

[0205] This invention utilizes 3D printing technology, particularly fused filament manufacturing (FFF) 3D printing, to produce solid dosage forms, most specifically relating to solid dosage forms of pharmaceuticals; however, those skilled in the art will readily understand that the principles of this invention can be readily applied to nutritional products and food supplements. The manufacturing process uses novel printing filaments (typically spools of filaments) containing the relevant active ingredients and / or other components (e.g., excipients) to actually print the relevant solid dosage forms. Such printing filaments, being in a substantially solid form, are highly stable in terms of storage and transport and can be used for printing without degrading the materials contained therein. This makes it ideal for printing solid pharmaceutical dosage forms whose production is strictly regulated to ensure that patients receive consistent pharmaceutical products that meet the regulatory standards required for market approval.

[0206] The inventors have discovered that their active ingredient-containing filaments not only provide a viable source of the active ingredient during the printing process, but also an ideal source, provided that such filaments remain "safe" for the active ingredient (i.e., stable during storage and use, for example, when exposed to high printing temperatures). This allows for careful formulation using the principles outlined in this disclosure to customize dosage forms in terms of their composition, shape, and active ingredient release profiles, while also enabling the production of consistent, consumer-ready products. This makes the invention useful both in final production and in research and development, where the associated printing apparatus can be used for prototyping. The versatility of the invention makes it ideal for both purposes.

[0207] A process for 3D printing solid dosage forms has been established, offering consumers greater choice (in terms of dosage within the solid dosage form, its aesthetics, and drug release profiles). Pharmacists can more easily customize and dispense products with limited labor (due to the use of minimal prefabricated input elements) without requiring complex and expensive equipment. Production can be tracked / recorded (at a central point if necessary) to ensure quality control and respond to batch failures and machine maintenance issues. High-dose products can be produced, high resolution is achieved, and machine failures will be minimized due to minimal print nozzle clogging. Furthermore, the fact that all materials in the process, except during printing, are solid (e.g., both the filament and the dosage form) ensures ease of handling.

[0208] This invention is expected to make a significant contribution to the field of pharmaceutical production, distribution and consumption, and will have a positive health impact on all those concerned.

[0209] Solid dosage form printing device

[0210] The present invention provides a suitable solid dosage form printing apparatus as defined herein. The printing apparatus suitably allows the printing of solid dosage forms (e.g., tablets or implants) via fused wire fabrication (FFF). Therefore, the apparatus suitably employs pre-formed filaments (at least one of which suitably contains an active ingredient) selectively extruded and deposited during a layer-by-layer printing process.

[0211] This device is suitable for printing solid dosage forms, wherein the solid dosage forms appropriately contain active ingredients.

[0212] The device appropriately includes a fused filament fabrication 3D printer (FFF 3D printer). Such printers are often referred to as fabrication deposition modeling. TM (manufacturing deposition molding) TM (FDM) 3D printer.

[0213] The apparatus suitably includes a build platform (or build plate) on which a solid dosage form is printable (i.e., on which a solid dosage form can be built). The build platform suitably provides a (substantially flat) surface that supports the solid dosage form throughout the printing process. In a particular embodiment, the build platform includes a surface, tape layer (i.e., a tape at the surface) that causes the solid dosage form to adhere to the build platform during printing (i.e., causes a first layer of the solid dosage form to be printed to adhere to the build plate, suitably after the first layer has hardened upon cooling), or surface coating, but suitably the solid dosage form is (easily) removable from the build platform after its production.

[0214] Appropriately, the device includes a computer interface (whether for wired or wireless connection to a computer operable to control the FFF 3D printer or printing device).

[0215] Appropriately, the apparatus includes a computer for controlling the FFF 3D printer and optionally also controlling the build platform.

[0216] Suitably, the apparatus includes at least one extrusion nozzle through which filament (or a portion thereof) can be extruded. Suitably, the extrusion nozzle, or each extrusion nozzle, can be a heated extrusion nozzle, suitably having variable temperature control (e.g., to allow the extrusion nozzle to be selectively heated at a desired temperature). Therefore, the apparatus can include an extrusion nozzle heating element suitably used to heat the extrusion nozzle to melt (or otherwise liquefy) the associated filament or a portion thereof. Suitably, the apparatus can include a plurality of the above-described extrusion nozzles, each of which can be assigned to one or more types of filament.

[0217] Suitably, the apparatus includes a conveyor for conveying printing filaments containing the active ingredient and any optional one or more other printing filaments to and / or through the at least one extrusion nozzle. Suitably, the conveyor clamps the associated filaments and supplies them toward and / or through the associated extrusion nozzle. Suitably, the conveyor is controlled to deliver the associated filaments at a rate and / or interval suitable for providing the desired solid dosage form. The conveyor or a portion thereof (e.g., a “feeder”) (preferably a portion en route to the extrusion nozzle) may be heated, suitably via a heating element associated therewith, optionally from and / or individually controllable from any heating element associated with the extrusion nozzle. Where the apparatus includes more than one nozzle, the apparatus suitably includes more than one feeder, one feeder associated with each extrusion nozzle.

[0218] The apparatus suitably includes printing filaments containing an active ingredient, which suitably consists of, substantially consists of, or comprises a filament composition containing an active ingredient, wherein the filament composition contains the active ingredient and optionally (and most suitably) an active ingredient carrier. Optionally, the printing filaments containing the active ingredient may contain excipients, diluents, and / or excipient carriers. In a particular embodiment, the printing filaments containing the active ingredient are provided as an active filament spool as defined herein. Therefore, the apparatus suitably includes an active filament spool as defined herein.

[0219] Suitablely, the printing filament containing active ingredients is essentially composed of (and most preferably composed of) a filament composition containing active ingredients, but in some embodiments, the filament may be further processed (e.g., coated) to enhance its stability (e.g., during storage) without compromising printability.

[0220] The apparatus may suitably include one or more additional printing filaments, each of which suitably independently comprises, substantially comprises, or contains an additional filament composition. Suitably, when present, the one or more additional printing filaments, each of which or at least one of which contains an active ingredient carrier (e.g., one or more pharmaceutically or nutritionally acceptable polymer carriers), regardless of whether it or they contain an active ingredient. Optionally or additionally, when present, the one or more additional printing filaments, each of which or at least one of which contains an excipient carrier (e.g., one or more pharmaceutically or nutritionally acceptable polymer carriers), regardless of whether it or they contain an excipient. Optionally or additionally, when present, the one or more additional printing filaments, each of which or at least one of which contains an excipient (e.g., one or more pharmaceutically acceptable excipients), regardless of whether it or they contain an active ingredient. Optionally or additionally, when present, the one or more additional printing filaments, each or at least one thereof, contain a diluent (e.g., one or more pharmaceutically or nutritionally acceptable diluents), whether or not it or they contain excipients or active ingredients. In certain embodiments, the one or more additional printing filaments, each or some thereof, are provided as additional filament spools as defined herein. Thus, the apparatus may suitably include one or more additional filament spools as defined herein.

[0221] Suitablely, the one or more additional printing filaments, or each of them, are substantially composed of (and most appropriately composed of) the additional filament composition, but in some embodiments, the filaments may be further processed (e.g., coated) to enhance their stability (e.g., during storage) without compromising printability.

[0222] Suitablely, the active ingredient may be selected from pharmaceuticals, nutritional products, or food supplements. In some embodiments, the solid dosage form may contain more than one active ingredient (suitably of the same category, whether it is a pharmaceutical, nutritional product, or food supplement), but most suitably, only a single active ingredient is present in the solid dosage form. When the solid dosage form contains multiple active ingredients, the active ingredient-containing printing filament used in its production may contain multiple active ingredients (suitably of the same category, whether it is a pharmaceutical, nutritional product, or food supplement), but most suitably, only a single active ingredient is present in the active ingredient-containing printing filament. Alternatively or additionally, when the solid dosage form contains multiple active ingredients, in addition to any active ingredients present in the active ingredient-containing printing filament, the one or more additional printing filaments may also contain one or more active ingredients (suitably of the same category, whether it is a pharmaceutical, nutritional product, or food supplement).

[0223] Suitablely, the active ingredient carrier is a substance or mixture of substances that acts as a delivery vehicle for the active ingredient in a solid dosage form and / or serves as a suitable solid matrix for retaining the active ingredient within the associated filament prior to printing therewith. Suitablely, the active ingredient is dispersible or even soluble in the active ingredient carrier.

[0224] Appropriately, any excipient may be selected from those known in the art, particularly those suitable for oral dosage forms, especially solid dosage forms for oral administration.

[0225] Suitablely, the excipient carrier is a substance or mixture thereof that acts as a carrier for any excipient present in the solid formulation and / or serves as a suitable solid matrix for retaining the excipient within the associated filament prior to printing therewith. Suitablely, the excipient is dispersible or even soluble in the associated excipient carrier.

[0226] Suitablely, a diluent is a substance or mixture of substances that acts as an inert diluent for any active ingredient and / or excipient present in the solid dosage form. Such diluents can be particularly useful when customizing the loading level of the active ingredient, which can be prudently varied according to the invention. The diluent is suitably a solid diluent and suitably a pharmaceutically and / or nutritionally acceptable diluent. The diluent may be selected from any substance defined herein with respect to a carrier (whether for the active ingredient or any excipient), or may be one of many carriers well known in the art.

[0227] An FFF 3D printer (and optional build platform) is suitably a computer-operable computer, suitably based on specialized solid dosage form printing software and optionally also based on one or more databases, to print solid dosage forms on the build platform, the printing being suitably via a process involving the printing and / or extrusion of filaments containing active ingredients and optionally also involving the printing and / or extrusion of one or more additional filaments.

[0228] Those skilled in the art will readily understand that any one or more of the build platform, the active ingredient-containing filament, additional filaments, and / or a computer, and / or any part thereof, can be suitably integrated within or form part of an FFF 3D printer. In embodiments, the printing apparatus is essentially an FFF 3D printer or a printing device.

[0229] In aspects of the invention, the apparatus includes a printing filament containing an active ingredient and any one or more of the features defined herein with respect to the apparatus. However, for the apparatus to function, in addition to the filament, a computer and an FFF 3D printer should suitably be present, and most suitably, additional filaments should be present to allow for greater flexibility and customizability regarding the final solid dosage form being produced. Furthermore, the apparatus may include multiple printing filaments containing active ingredients, each suitably containing a different active ingredient, so that different solid dosage forms, each with different functions, can be produced. Thus, the FFF 3D printer can be configured to print various different solid dosage forms containing different active ingredients.

[0230] Printing solid dosage forms and / Or the method of using the device

[0231] The present invention also provides a method for printing a solid dosage form as suitably defined herein. Suitably, this method is a method using the above-described apparatus.

[0232] Suitable of the method, the method includes providing a solid dosage form printing apparatus, an FFF 3D printer, or a printing apparatus as defined herein.

[0233] The method suitably includes operating an FFF 3D printer or printing device to print a solid dosage form, suitably printed on a build platform. Suitably, such printing is performed via a computer-implemented process (i.e., wherein printing is controlled and suitably initiated by a computer connected to or connectable to the printing device or connected to or connectable within the printing device, whether it is wired or wireless).

[0234] Appropriately, printing of solid dosage forms involves printing (and / or extruding) a filament containing an active ingredient (or printing / extruding a filament composition containing an active ingredient derived from the filament containing the active ingredient).

[0235] Appropriately, printing may involve printing (and / or extruding) one or more additional printing filaments (or printing / extruding one or more additional filament compositions derived from one or more additional printing filaments).

[0236] Appropriately, the method may involve performing one or more additional processing steps (with or without an FFF 3D printer; for example, coating or otherwise modifying the surface, shape, or properties of a solid form).

[0237] Computer-based printing methods

[0238] The present invention provides a method for operating a solid dosage form printing apparatus (or, suitably, the like as defined herein), a computer-implemented method for operating a solid dosage form printing apparatus, and a solid dosage form printing apparatus, suitably, as defined herein.

[0239] The method suitably includes providing a solid dosage form printing apparatus as appropriately defined herein, and operating said apparatus to print solid dosage forms. Suitably, the apparatus includes a computer or is otherwise connected to a computer. Suitably, operating the apparatus includes operating a computer that is suitably (whether wired or wireless) connected to or internally connected to the associated printing apparatus (so as to allow the computer to control and coordinate other parts of the apparatus, suitably including an FFF 3D printer), resulting in the printing of solid dosage forms.

[0240] Appropriately, the features described regarding the printing method (where applicable) can also be applied to the apparatus or its parts (e.g., the filament).

[0241] computer

[0242] Suitablely, the printing device includes a computer or is otherwise connected to a computer. Suitablely, the printing device (or 3D printer) is connected to the computer via an interface (suitably a digital interface), which can be wired (e.g., via a port-to-port connection with a suitable data lead, such as a USB cable) or wireless. The computer can be located at the location of the associated printing device or 3D printer (i.e., the local computer). However, the invention is also applicable to situations where the associated computer (or multiple computers) is located remotely from the associated printing device or 3D printer, but both the printing device (or 3D printer) and the remote computer include or are otherwise connected to a corresponding communicator that allows the remote computer and the printing device (or 3D printer) to communicate with each other. In this way, the remote computer can be induced to operate the printing device. In a particular embodiment, the printing device (or 3D printer) can be connected to a network, enabling multiple remote computers (and / or local computers) to communicate with it to induce operation of the printing device (or 3D printer).

[0243] A computer associated with or otherwise connected to a printing device appropriately controls the printing of relevant filaments based on the solid dosage form design and / or solid dosage form parameters (e.g., relative amounts and juxtapositions of ingredients) as described in a given solid dosage form data file (e.g., in a CAD or .STL file), which is appropriately interpreted by the relevant software on which the computer operates.

[0244] In a particular implementation, the printing device includes or is connected to a local computer, and both the printing device and the local computer are located on-site at the pharmacy, most appropriately in a printing area or space constructed for a specific purpose (which may appropriately have regulatory approval).

[0245] Suitable, the method and / or apparatus involve a computer operating based on solid dosage form printing software (and optionally one or more internal and / or external databases).

[0246] Suitablely, the computer running the solid dosage form printing software is configured to obtain information about one or more parameters (optionally including physical design parameters, such as shape) related to the solid dosage form to be printed (e.g., whether it is information manually entered by the user or information automatically obtained from another data source). Suitablely, the computer running the solid dosage form printing software is configured to request manual user input via a user interface (e.g., keyboard / screen) regarding one or more parameters related to the solid dosage form to be printed. For example, a user (who could be a pharmacist acting on instructions from a patient and / or physician) may be asked to enter information about the patient's name, a patient reference number (e.g., a healthcare number), and / or another reference name or number. The computer can then communicate (via an associated communicator) with one or more databases (whether local or remote, wired or wireless, such as via a network like the Internet) to automatically retrieve further information and / or options corresponding to said name or reference (e.g., individual patient data, medication history, repeat prescriptions, data or portions of data related to the solid dosage form to be printed, including solid dosage form data files containing design and / or other relevant parameters). Subsequently, the user may be asked to manually enter or select further information (e.g., drug, drug dosage, release profile, etc.) and / or options to allow the computer to obtain all relevant information related to the printing of the desired solid dosage form. Optionally or additionally, the user may be asked to manually enter or retrieve information about one or more specific parameters related to the solid dosage form (e.g., drug name / reference, drug dosage, drug release requirements, color, size, shape, solubility, packaging label information, etc.). Appropriately, any user input may be recorded and / or stored for future reference or for repeat prescriptions, etc.

[0247] There are various ways in which a computer can be configured to obtain relevant information to allow solid dosage forms to be printed, but it is possible that various preset information can be used (e.g., certain approved formulation / filament combinations for generating a given solid dosage form). Therefore, the computer can be appropriately associated with or connected to a solid dosage form database (appropriately, a central database accessible via a network such as the Internet), which provides all the necessary preset information (e.g., data files associated with the solid dosage form and details of variable parameters (such as drug dosage levels / limits)).

[0248] Appropriately, the solid dosage form design for printing (and optionally the parameters associated therewith) can be recorded in a solid dosage form data file that can be read by a computer running solid dosage form printing software.

[0249] Appropriately, the computer running the solid dosage form printing software is configured to calculate the mass and / or volume of the solid dosage form to be printed based on the acquired information. Appropriately, after the computer has acquired all the necessary information (whether manually entered by the user, automatically imported, or a combination of both), it is configured to perform calculations to allow the printing instructions to be completed before computer-controlled printing. At this stage, further input may be required or requested (e.g., via a user interface), such as optional size and / or shape modifications. Calculations typically involve the mass and / or volume of a given solid dosage form required to provide a given dose of active ingredient per dosage form. Although the concentration of a given active ingredient can be increased relative to other components (e.g., excipients), the formulation is typically optimized and the relative proportions are fixed / preset, while the total mass / volume can vary while maintaining the same relative proportions of the components.

[0250] Appropriately, the computer running the solid dosage form printing software is configured to appropriately control the printing and relative proportions of the components within the solid dosage form based on the information obtained and the calculations performed. Appropriately, "controlling printing" includes initiating printing, terminating printing, and any or all printing operations in between.

[0251] Appropriately, operational data is collected during printing (optionally by one or more local and / or remote computers and / or databases) and appropriately stored (most appropriately on a central computer capable of analyzing such data, for example, for quality control monitoring, fault monitoring, batch monitoring, dosage form monitoring for a given patient, etc.). Appropriately, the printing apparatus includes or is otherwise associated with one or more operational sensors (e.g., nozzle temperature sensors, filament feed rate sensors or conveyor sensors, overall temperature sensors, build platform sensors, which may, for example, monitor surface temperature and / or post-printing cooling rates, etc.), which feed back operational parameters / information to a computer, database, or data storage facility relating to the operation of the printing apparatus and its associated components during printing of each dosage form. Most preferably, such operational data is collected, stored, and / or otherwise transmitted to a central computer or database to enable independent auditing of any given printing apparatus. This may be important for maintaining quality control and keeping appropriate records to sustain regulatory approval for any given 3D printing system.

[0252] Appropriately, the computer running the solid dosage form printing software is configured to control the execution of one or more additional processing steps.

[0253] FFF 3D printer

[0254] In the context of this invention, an FFF 3D printer can be an association of parts that enables the deposition of 3D shaped objects (i.e., at a depth of at least 100 μm, at least 1 mm, or at least 2 mm at their deepest or thickest point) from one or more filaments. Conventional FFF 3D printers are well known in the art and are generally suitable for this invention; however, they can be carefully modified based on the principles outlined herein to optimize the printing of solid formulations. For technical reference, the following research articles describe the feasible operation of FFF 3D printers—SHMasood, “Application of fused deposition modelling in controlled drug delivery devices”, Assembly Automation, 27 / 3 (2007), pp. 215-221 and Khaled et al., “Desktop 3D printing of controlled release pharmaceutical bilayer tablets”, International Journal of Pharmaceutics, 461 (2014), pp. 105-111—describe the use of an FFF 3D printer to print filaments, but without the active ingredient being contained within the filament being printed (the drug compound is injected later).

[0255] The FFF 3D printers suitable for use in this invention typically include heated / heatable extruder nozzles that melt and deposit (suitably onto the build platform) molten filaments in a layer-by-layer manner. Suitably, the deposited molten filaments harden rapidly after deposition. Maintaining a relatively low surface temperature on the build platform can facilitate such cooling / hardening to improve the final structure of the solid form being printed. The FFF 3D printer also suitably includes one or more nozzle heaters (suitably associated with each nozzle, but optionally serving multiple nozzles) and suitably one or more conveyors as described above (suitably associated with each filament and / or nozzle). Suitably, the FFF 3D printer includes one or more filament spool areas (or filament spool attachment points) for receiving associated filament spools.

[0256] nozzle

[0257] Suitably, the printing apparatus or 3D printer includes one or more extrusion nozzles through which filament (or a portion thereof) can be extruded. Suitably, the extrusion nozzle or each extrusion nozzle may be a heated extrusion nozzle, suitably one that can be selectively heated via variable temperature control to obtain a desired temperature (suitably appropriate to the properties of the filament in question). Thus, the printing apparatus or 3D printer may include one or more extrusion nozzle heating elements associated with the extrusion nozzle or each extrusion nozzle, suitably for heating the extrusion nozzle to melt (or otherwise liquefy) the associated filament or a portion thereof. Suitably, the apparatus may include a plurality of the aforementioned extrusion nozzles, each of which may be assigned to one or more types of filament.

[0258] The nozzle temperature is appropriately set and controlled by a computer based on the properties of the filament in question (which the computer knows after obtaining all relevant information). In particular, it is important to balance factors such as filament extrudability (generally related to the glass transition temperature), desired resolution, and degradation performance (especially concerning active ingredients or excipients that produce potentially toxic thermal degradation products). For example, a filament with a relatively low glass transition temperature can be extruded from its corresponding nozzle at a lower temperature than a filament with a relatively high glass transition temperature. These parameters are appropriately part of the information obtained by the computer (which can refer to information in a specific database regarding a particular filament and the required nozzle temperature settings and feed rate accommodated). It is conceivable that in the case of using multiple filaments to print solid dosage forms (e.g., in a core-shell arrangement), different nozzles (for each filament) can have different operating temperatures depending on the respective properties of the relevant filaments.

[0259] Suitably, the operating temperature of the extrusion nozzle through which the active ingredient-containing printing filament passes is high enough to achieve filament extrusion, but low enough to avoid (pharmaceutically) unacceptable degradation of the active ingredient and / or any excipients at the relevant filament feed rate (those skilled in the art will understand that the active ingredient typically tolerates higher temperatures if the heat exposure time is short, as is generally the case in the printing process of this invention). Suitably, the operating temperature of the extrusion nozzle through which the active ingredient-containing printing filament passes is between 90°C and 220°C, more suitably between 120°C and 190°C, and suitably between 165°C and 190°C. However, the operating temperature of the extrusion nozzle can be as low as 65°C, particularly in systems using low-melting-point polymers (e.g., PEG) or polymers with low glass transition temperatures. Most suitably, the extrusion nozzle temperature is set to at least 65°C, more suitably at least 70°C. In a particular embodiment, the nozzle temperature is 70°C-220°C, suitably 100°C-160°C, suitably 130°C-150°C, and suitably 135°C-145°C.

[0260] Suitablely, the operating temperature of the extrusion nozzle through which the additional printing filament passes is high enough to achieve filament extrusion but low enough to avoid (pharmaceutically) unacceptable degradation of the excipient at the relevant filament feed rate. Suitablely, the operating temperature of the extrusion nozzle through which the printing filament containing the active ingredient passes is between 80°C and 300°C, more suitablely between 100°C and 220°C, and appropriately between 120°C and 190°C.

[0261] Most suitably, the operating temperature of the extrusion nozzle through which the given filament passes is set or controlled (during printing) at or within the temperature range where at least one of the components / ingredients in the given filament (“melted component”) melts to allow the filament to be extruded through the nozzle (i.e., suitably onto the build platform), and at or within the temperature range, at least one of the components / ingredients in the given filament (“non-melted component”) (suitably constituting at least 0.1 wt% of the filament, suitably at least 1 wt% of the filament, suitably at least 5 wt% of the filament, suitably at least 10 wt% of the filament, suitably at most 30 wt% of the filament, suitably at most 20 wt% of the filament, suitably at most 15 wt% of the filament) remains or otherwise transforms into solid and / or particulate form. The melted component may suitably include diluents, carriers, and / or excipients, and may suitably melt into a composite material—a combination of carrier / diluent and plasticizer may, for example, constitute the “melted component”. The non-melting component may suitably include excipients and / or active ingredients, which suitably have a melting point above the nozzle operating temperature and suitably above the melting point of the corresponding non-melting component, the composite material melting point, or the glass transition temperature (or the composite material melting point). The non-melting component suitably remains co-extruded from the relevant nozzle along with any melting component. However, the presence of the non-melting component, particularly when in particulate form at the operating temperature of the relevant nozzle, surprisingly reduces nozzle clogging and may also, alternatively, improve the overall resolution of the solid formulation.

[0262] Suitably, each extrusion nozzle includes an inlet opening (to which filament is supplied) and an outlet opening (from which molten filament is deposited). The outlet opening is suitably smaller than the inlet opening. The size of the inlet opening is suitably set to receive the corresponding filament passing through it. Suitably, the inlet opening has a diameter of 1.0 mm to 2.5 mm, more suitably 1.5 mm to 2.0 mm, and most preferably about 1.75 mm. The size of the outlet opening is suitably set with respect to the properties of the corresponding filament to allow the molten filament to be deposited therefrom (e.g., onto a build platform). Suitably, the outlet opening has a diameter of 50 μm to 400 μm, more suitably 100 μm to 300 μm, more suitably 150 μm to 250 μm, and most suitably about 200 μm. In an embodiment, the nozzle has an outlet opening with a diameter between 200 μm and 500 μm.

[0263] Suitablely, the nozzle, or each nozzle, may be movable (suitably in an automated manner or in a manner controlled by a computer or by a printer under instructions from a computer) to extrude filaments at different positions on the build platform (or on the portion of the solid dosage form printed thereon). The nozzle may be movable in any or all of the X, Y, and Z directions, but in some embodiments (e.g., where the build platform is movable in the Z direction, i.e., moving up and down relative to the nozzle), it is restricted to moving only in the X and Y directions.

[0264] Suitably, the extrusion nozzle or each extrusion nozzle is operable to move at a speed between 50 mm / s and 150 mm / s, more preferably between 70 mm / s and 110 mm / s, and more preferably between 80 mm / s and 100 mm / s during extrusion (i.e., when the nozzle is “on” – this can be the nozzle extrusion speed). Suitably, the extrusion nozzle or each extrusion nozzle is operable to move at a speed between 100 mm / s and 200 mm / s, more preferably between 120 mm / s and 180 mm / s, and more preferably between 140 mm / s and 160 mm / s when not extruding (i.e., when the nozzle is “off” – this can be the nozzle traveling speed).

[0265] Those skilled in the art will understand that the nozzles, each nozzle, or any nozzle can be modified to suit the characteristics of the corresponding filaments configured to be printed onto them. The nozzle performance / design and filament properties / composition are suitably complementary to each other so that the controlled extrusion of the filaments (whether continuous or intermittent, e.g., in the case of using more than one filament in solid dosage form printing) is suitably free from any nozzle clogging or obstruction, and suitably free from any unacceptable component degradation within the filaments during the printing process.

[0266] As described below regarding the cartridge, the printer nozzle can be replaced by a cartridge nozzle. Therefore, a cartridge nozzle can be used as a printer nozzle, and thus can have any of the properties attributed to printer nozzles herein, where appropriate.

[0267] Building Platform

[0268] A printing device or 3D printer appropriately includes a build platform. This provides a platform on which solid dosage forms can be printed.

[0269] Suitablely, during printing (e.g., at the relevant printing operating temperature), the solid dosage form is adhered to the surface of the build platform onto which it is printed (or at least to the layer in contact with the build platform) sufficient to prevent the solid dosage form from moving during printing. However, suitablely, after printing (e.g., optionally at a temperature different from the printing operating temperature), the printed solid dosage form can be removed from the build platform without damage (e.g., the build platform is non-sticky enough to allow the solid dosage form to be removed, or selectively adjustable, e.g., by changing the operating temperature, to allow the solid dosage form to be removed therefrom). Thus, the surface of the build platform may include a surface coating or surface strip that imparts the desired surface properties (e.g., sticky but not too sticky (the solid dosage form is permanently adhered)).

[0270] The build platform is suitably configured or operable to maintain a surface temperature (i.e., for surfaces in contact with the solid dosage form) less than or equal to 50°C, suitably less than or equal to 40°C, suitably less than or equal to 30°C, suitably greater than or equal to 5°C, or suitably greater than or equal to 15°C during printing. In other embodiments, the build platform is operable to maintain a surface temperature less than or equal to 150°C, suitably less than or equal to 100°C, or suitably greater than or equal to 15°C. This can be achieved by selectively operating heating and / or cooling elements associated with the surface of the build platform (e.g., below). In a particular embodiment, the build platform is operable and preferably operable to maintain a surface temperature between 20°C and 90°C, suitably between 20°C and 60°C, suitably between 30°C and 50°C, and most suitably about 40°C.

[0271] The build platform can be movable (appropriately in an automated manner or controlled by a computer or by a printer under instructions from a computer) to control the position or height of the extruded filament on the build platform. The build platform can be movable in any or all of the X, Y, and Z directions, but in some implementations, the build platform is movable only in the Z direction, i.e., vertically. Movement in the Z direction allows the gap (or height) between the nozzle and the printhead to remain substantially constant throughout the printing process to maintain layer-by-layer consistency.

[0272] Software and data files

[0273] The computer operating the printing device or 3D printer runs appropriately based on solid dosage form printing software (and optionally, one or more databases). As explained herein, this software can configure the computer to acquire information and perform calculations, and then configure the computer to control printing via an interface with the printing device or 3D printer.

[0274] After the computer obtains relevant information and performs relevant calculations, the software appropriately configures the computer to control the printing of solid dosage forms, wherein the printing is appropriately based on the design (shape and size, texture, layer structure, internal structure, porosity, color, etc.) and / or parameters (relative amounts of components, such as drug dosage) related to the solid dosage form contained in one or more solid dosage form data files. Solid dosage form data files may include design files (e.g., containing data and / or images related to the physical design of the solid dosage form, including its size, shape, layer structure, core-shell structure, etc.) and / or parameter files (e.g., containing data related to the chemical composition of the solid dosage form, including drug type, excipient type, drug dosage level, excipients controlling drug release, etc.). A single solid dosage form data file may contain all data related to the physical design and chemical composition. However, the physical design and chemical composition can be modified based on information obtained after user input.

[0275] In some implementations, the design file may be a CAD file depicting the solid dosage form. However, such a file format may need to be converted to a file format compatible with the printing device or 3D printer. Conventional 3D printers typically read design files in .STL format. Therefore, the design file is appropriately a .STL design file describing the solid dosage form (or at least its physical design).

[0276] Design documents may include or be associated with a parameter file containing chemical composition details, or both may be independent. Alternatively, such a parameter file may not exist; instead, relevant parameter information may be retrieved from a database, for example, in response to user input (e.g., patient reference or drug reference).

[0277] The software can also configure the computer to collect, store, and / or transmit (e.g., to a central database) operational data fed back to the computer from the printing unit or 3D printer during printing. The software can also configure the computer to detect and / or respond to any (or preset level) deviations in the expected operational data (e.g., if the nozzle temperature exceeds a maximum preset temperature level), such as warning the user / operator or any other party of concern that a malfunction has occurred and that solids produced during the malfunctioning print should be disposed of or otherwise tested.

[0278] database

[0279] The printing device and / or the computer associated therewith may be configured (e.g., via solid dosage form printing software) to communicate with one or more solid dosage form databases and / or patient databases (appropriately via a relevant communicator, and appropriately via a network such as the Internet) to obtain information about one or more parameters relating to the solid dosage form to be printed. For example, such databases may be queried in response to user input (e.g., a patient reference number) to provide the computer with relevant information (or information to be supplemented by further user input) so that calculations and printing can be performed.

[0280] As an example, a patient database containing patient records for multiple patients (which may include, for example, patient name, patient reference number, medical data, medical history, etc.) appropriately includes information about the solid dosage form to be printed for each patient (which may simply be a cross-reference or reference number to information existing in another database, such as a solid dosage form database). When the “information” is a cross-reference to a solid dosage form database, that database can subsequently be queried for additional information about the solid dosage form. This information can be any information as defined herein, but optionally the printing device or the computer associated with it can be instructed (e.g., via a user interface) to modify the information (e.g., drug dosage level) before calculation and / or printing. Any of these databases can be accessed by interested parties, preferably securely (to maintain the confidentiality of certain data), so that relevant information (whether in the patient database, the solid dosage form database, or both) can be retrieved and / or modified as needed (e.g., if the patient requires an increased dose or a different active ingredient release profile in the printed solid dosage form). Appropriately, such databases can be accessed wirelessly via a network such as the Internet. Such database architectures are well known in the art.

[0281] Each printing device and / or its associated computer may be configured (e.g., via solid dosage form printing software) to communicate with one or more device monitoring databases (appropriately via associated communicators and appropriately via networks such as the Internet), the device monitoring databases being configured to send to and store (and optionally analyze and / or report) operational data collected during each printing operation (i.e., each time a printing device prints) (optionally via one or more local and / or remote computers and / or databases). As described herein, such operational data is appropriately acquired / delivered by sensors associated with each given printing device, appropriately with sensors associated with key components of the printing device capable of affecting the quality of the final solid dosage form. Operational data may be sent to the database in real time, after printing, or at any appropriate time (e.g., at night to avoid unnecessarily overloading the communication network during working hours). Such device monitoring databases may be organized using records from each printing device, and appropriately, a log of operational data may be maintained each time the printing device is operated. Appropriately, each set of operational data is cross-referenced for a given patient solid dosage form, such that if any operational data is deemed faulty, the relevant concerned parties can be alerted. In this way, each printing device (whether in real-time or otherwise, automatically or otherwise) can be monitored and data can be submitted periodically to meet regulatory requirements. Furthermore, a central device monitoring database can trigger a response to any perceived fault in a given printing device. Additionally, a response can be triggered that prevents the associated faulty printing device from being used until its performance can be reconfirmed.

[0282] Furthermore, any of the one or more device monitoring databases can be accessed by the interested party, preferably securely (to maintain the confidentiality of certain data), so that relevant information can be retrieved and / or analyzed as needed (e.g., if a regulatory agency wants to check whether a given printing device has been in good working order throughout a given period, or if a machine maintenance professional uses the data to diagnose a problem and restore the performance of a given printing device). Suitablely, such databases can be accessed wirelessly via a network such as the Internet. Such database architectures are well known in the art.

[0283] Control printing

[0284] It will be understood that, in the absence of a computer implementation, features related to print control (where appropriate) may be considered equally pertinent, but a computer-implemented method is preferred. A computer contained in a printing device or its FFF 3D printer, or otherwise associated with the printing device or its FFF 3D printer, may be appropriately referred to as a print control computer (or print computer). A print control computer may provide different functions (and may be different entities) from other “computers” referred to herein (such as monitoring computers and analysis computers), but a single computer may perform one or more of the functions of any combination of these computers.

[0285] The printing of solid dosage forms is suitably controlled by a computer running solid dosage form printing software, suitably based on information provided to the computer via user input (drug type, drug dosage level), databases (e.g., patient databases and / or solid dosage form databases), and / or data files (e.g., design and / or parameter files), as described herein. Suitably, the FFF 3D printer is configured to print according to computer-provided instructions by: feeding filament to and through its respective nozzle at appropriate intervals and / or at appropriate rates; heating the relevant nozzle at an appropriate temperature for an appropriate duration; and moving the nozzle and / or the build platform to enable systematic layer-by-layer printing based on the obtained relevant information and calculations performed by the computer.

[0286] The feeding of filaments to and through their respective nozzles is appropriately facilitated by conveyors (or rollers) as described elsewhere in this document. Such conveyors are appropriately positioned along the filament flow path of the given filament, suitably between the filament source (e.g., filament spool or drum) and the extrusion nozzles to which the given filament is assigned to flow and through.

[0287] Appropriately, the extrusion nozzles are computer-controlled based on “acquired information” (e.g., design and / or other parameters) regarding the solid dosage form. The nozzles are appropriately controlled to extrude a given filament onto the build platform (or a portion of the solid dosage form built on the build platform) as a pattern predefined by the “acquired information.” Thus, the nozzles, or each nozzle, can be controlled to switch “on” and “off” according to a predefined schedule to provide the desired pattern during the construction of the solid dosage form. A nozzle can be switched to “on” by opening the output opening, by adjusting the nozzle’s operating temperature (e.g., increasing it to melt the associated filament), by operating the conveyor to supply filament to the nozzle, or any or all of the above combinations. Conversely, a nozzle can be switched to “off” by closing the output opening, by adjusting the nozzle’s operating temperature (e.g., decreasing it to a temperature that does not melt the associated filament), by operating the conveyor to restrict or stop the supply of filament through the nozzle, or any or all of the above combinations. As described elsewhere herein, the nozzle temperature is appropriately set and controlled by a computer according to the properties of the filament in question. Suitably, the operating temperature of the extrusion nozzle through which the active ingredient-containing printing filament passes is between 90°C and 220°C, more suitably between 120°C and 190°C, suitably between 165°C and 190°C, and suitably between 140°C and 170°C. Suitably, the operating temperature of the extrusion nozzle through which the active ingredient-containing printing filament passes is between 80°C and 300°C, more suitably between 100°C and 220°C, and suitably between 120°C and 190°C. However, the operating temperature of the extrusion nozzle can be as low as 65°C, particularly in systems using low-melting-point polymers (e.g., PEG) or polymers with low glass transition temperatures. Most suitably, the extrusion nozzle temperature is set to at least 70°C. In certain embodiments, the nozzle temperature is 110°C–160°C, suitably 110°C–130°C, suitably 130°C–150°C, and suitably 135°C–145°C. Appropriately, the operating temperature of the extrusion nozzle assigned to the given filament is higher than any corresponding hotmelt extrusion temperature used in the formation of the given filament (i.e., via extrusion), appropriately between 30°C and 90°C, more appropriately between 50°C and 70°C.

[0288] Appropriately, the build platform is computer-controlled based on “obtained information” (e.g., design and / or other parameters) regarding the solid dosage form, as appropriately 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. Appropriately, during printing, the operating temperature of the build platform or its surface is maintained substantially constant, appropriately kept at a constant temperature + / - 5°C. Such temperature control can facilitate the cooling and / or hardening of the melted filament after deposition, thereby ensuring the structural integrity of the solid dosage form as it is printed. Such temperature control can facilitate the adhesion of the solid dosage form to the surface of the build platform during printing. Such temperature control can facilitate the release (i.e., unsticking) of the solid dosage form after printing (e.g., the surface of the build platform may be heated or cooled, as appropriate, to reduce adhesion of the solid dosage form to it). During printing, the build platform is appropriately configured or operable to maintain a surface temperature (i.e., for surfaces in contact with the solid dosage form) less than or equal to 50°C, appropriately less than or equal to 40°C, appropriately less than or equal to 30°C, appropriately greater than or equal to 5°C, or appropriately greater than or equal to 15°C.

[0289] Solid dosage forms are appropriately printed layer by layer using a printing device or an FFF 3D printer. Each layer is appropriately a plane (substantially) parallel to the surface of the build platform. Any given layer can have homogeneous or non-homogeneous properties. Similarly, the solid dosage form itself can have homogeneous or non-homogeneous properties, whether based on intralayer, interlayer, or both (i.e., different layers can have different properties). The homogeneity of any given layer (or layer-to-layer) appropriately involves one or more of the following: the layer composition (e.g., the distribution of components throughout the layer—core-shell solid dosage forms may inevitably result in some properties, including regions of core material and regions of shell material), density (e.g., % fill power), porosity (the distribution of pores throughout the layer), and patterning (e.g., in cases where multiple filaments may produce a particular pattern).

[0290] Appropriately, the filament is printed / extruded onto the build platform (or onto the portion of the solid dosage form formed thereon) at a predefined “layer height” (i.e., the distance in the “Z” direction between the top and bottom of a given layer, relative to the length or width of the layer in the X or Y direction). The layer height can be determined / controlled, for example, by the size / diameter of the output opening of the corresponding nozzle (which may be variable in some embodiments, but is appropriately a fixed size), the nozzle extrusion speed (i.e., the slower the nozzle travels during extrusion, the more filament is deposited at a given location for a given filament feed rate), and the filament feed rate. Appropriately, the layer height is set or controlled between 10 μm and 1,000 μm, appropriately between 50 μm and 500 μm, more appropriately between 100 μm and 300 μm, and most appropriately between 150 μm and 250 μm.

[0291] Suitablely, different designs of solid dosage forms (as specified by the “Information Obtained,” including relevant data files containing a given design) will require different intra-layer and / or inter-layer patterns. For example, a design using a monofilament to produce a controlled-release solid dosage form may be printed / extruded to create a density gradient across a single layer or between single layers. Alternatively, for example, a design using two or more filaments (e.g., a printing filament containing the active ingredient and one or more other printing filaments) to produce a core-shell solid dosage form may be printed / extruded such that each layer is printed as a certain pattern of the extruded filament, such that the combination of layers together provides the core-shell design. Suitablely, in such a core-shell design, the core comprises one or substantially consists of one of the filaments (or corresponding filament compositions), most preferably a printing filament containing the active ingredient, and the shell (or one of the shells—since multiple shells are entirely feasible) comprises or substantially consists of different filaments (or corresponding filament compositions), most preferably another printing filament. In certain embodiments, a core-shell based solid dosage form comprises a core (suitably containing the active ingredient), a first shell (suitably controlling or delaying the release of the active ingredient, such as an enteric coating), and optionally a second shell. Suitably, the first shell (and suitably any other shell) is substantially or completely free of the active ingredient. In certain embodiments, a core-shell based solid dosage form comprises a core containing the active ingredient, and a first shell comprising or substantially composed of an enteric polymer and / or a sustained-release polymer (suitably controlling, prolonging, or delaying the release of the active ingredient, such as an enteric coating), wherein the first shell is free of the active ingredient. Suitably, the first shell (and suitably any other shell) is substantially or completely free of the active ingredient.

[0292] Depending on the shape and size of the solid dosage form to be printed, sacrificial supports or rafts may be used during printing (which can be removed after the solid dosage form is prepared, for example, by dissolving them after printing). Such sacrificial supports or rafts are appropriately printed from the corresponding filaments themselves. However, in a preferred embodiment, such supports or rafts are not required.

[0293] Typically, the total mass of a solid dosage form is controlled by controlling the volume of the printed solid dosage form. Therefore, producing a solid dosage form containing the desired dose (i.e., weight concentration) of active ingredient appropriately involves adjusting the volume accordingly (i.e., producing a larger solid dosage form if a higher dose is needed, and vice versa). Appropriately, calculations performed by a computer, based on the obtained information, include calculating the final volume of the solid dosage form. Printing is then appropriately controlled based on this.

[0294] When more than one filament is used to produce a given dosage form, the filament appropriately includes a carrier (e.g., a molten component) having a glass transition temperature (T0) below that suitable for monofilament printing. g This may help avoid nozzle clogging, as dual-filament printing inevitably requires each nozzle to be "off" for a period of time, during which time clogging can occur if the filament hardens.

[0295] Additional processing steps

[0296] It will be understood that, in the absence of a computer implementation, features related to additional processing steps can (where appropriate) be considered equally relevant. In fact, any, some, or all of these additional processing steps can be implemented without a computer, and even without an FFF 3D printer.

[0297] As an example, the solid dosage form produced via the method of the present invention can be subsequently processed in a variety of ways to provide a further processed solid dosage form. For example, the solid dosage form can be enteric coated using standard enteric coating processes known in the art. Similarly, other release control properties can be imparted to the solid dosage form through further processing, such as providing a solid dosage form having one or more shells.

[0298] However, most appropriately, all steps (including any additional processing steps) are performed by the printing device and, appropriately, controlled by the same computer.

[0299] Packaging of solid dosage forms

[0300] The solid dosage forms of the present invention can be packaged using any of a variety of methods well known in the art. For example, in the case where the pharmaceutical solid dosage form according to the invention is produced via a printing device located in a pharmacy (e.g., to provide customized medicine to patients on demand), pharmacists can package the solid dosage form in a variety of ways, including with tablet vials, or even monitored delivery systems, which can then be dispensed to hospitals, nursing homes, etc., for final distribution to patients.

[0301] In some implementations, the packaging can be formed by the same or different printing devices. In some examples, the packaging and the solid dosage form can be produced simultaneously, whereby the printing operation uses one or more filaments associated with the solid dosage form and one or more filaments associated with the packaging, and the packaging can be constructed around the solid dosage form during printing.

[0302] Database, data acquisition and monitoring operations / production

[0303] This invention provides a system for collecting data related to the production of solid dosage forms (whether relating to a single printing device / 3D printer or multiple thereof), suitably as defined herein. Examples of such systems are provided in... Figure 45 As shown in the image.

[0304] Appropriately, the system includes one or more printing devices (or FFF 3D printers), most preferably multiple such devices, as appropriately defined herein.

[0305] While each individual printing device may include different (and / or specific) print control computers or otherwise associate with them, ultimately each individual printing device is suitably associated with or otherwise communicates with one or more (preferably one) monitoring computers, each configured to collect production data relating to the operation of one or more of the printing devices. Suitably, each monitoring computer is the same as each print control computer (i.e., the print control computer that controls the printing of the printing device), and most suitably, each monitoring computer is a computer located locally on the respective printing device (or 3D printer). However, in some embodiments, each monitoring computer is different from the print control computer, and the printing device (or 3D printer) transmits production data to the associated monitoring computer via its respective print control computer (using a suitable communicator associated with it) and / or directly (again, using a suitable communicator).

[0306] Appropriately, production data relating to the operation of a given printing device (or 3D printer) includes data generated by one or more sensors associated with (or included in) the given printing device or FFF 3D printer. Such sensors are suitably configured to detect operating parameters (e.g., nozzle temperature, filament flow rate, nozzle and / or build platform movement speed, etc.) during the solid dosage form printing process, and are suitably configured to map each set of operating parameters / production data to a specific solid dosage form or its batch, and to feed back or send the operating parameters to an associated monitoring computer. Therefore, production data may include other data, including some “acquired information” described herein with respect to a specific solid dosage form and / or the patients discussed, and also includes date, time, and other information.

[0307] Appropriately, the system may include one or more analysis computers (optionally identical to one or more monitoring computers) configured or operable to analyze production data. In a particular embodiment, the monitoring and analysis computers are the same computer and may be located locally on a given printing device. The analysis computer may optionally trigger a response (e.g., data transfer and / or action) based on the analysis of the data (e.g., an alarm in the event of an operational malfunction).

[0308] The system suitably includes a central production database, which is suitably configured to record (or collect and / or store) production data collected by a monitoring computer. Therefore, the corresponding monitoring computer suitably includes or is otherwise associated with a communicator for communicating (or sending / receiving, preferably via a network computer system) with the central production database to enable the central production database to record (or collect and / or store) the collected production data. This allows for central monitoring of the production of some or all solid dosage forms. Optionally, one or more analysis computers (which may be the same as or different from the monitoring computers as described above) may be configured or operable to analyze data transmitted to the central production database and optionally trigger responses (e.g., data transmission and / or actions) based on the analysis of the data (e.g., alarms in the event of an operational malfunction). Suitably, detected malfunctions concerning a given printing device will be reported (preferably immediately) to the personnel responsible for the operation and / or maintenance of the given printing device. In some embodiments, the detected malfunction may trigger a response that prevents further printing of solid dosage forms by the given printing device.

[0309] The system suitably includes a networked computer system (which may suitably include one or more Internets, one or more local area networks, one or more local or remote servers and / or one or more associated gateways and / or routers), suitably communicating (or otherwise associated with) one or more printing devices, one or more monitoring computers, one or more optional analysis computers (e.g., if different from the monitoring computer), and an optional central production database.

[0310] The central production database can be any suitable database known in the art.

[0311] At least a portion of the production data is obtained from sensors associated with the corresponding printing device (or 3D printer), and the production data itself may include one or more of the following:

[0312] • The time and date of data collection;

[0313] • Printing device identification information (e.g., license number, location, etc.)

[0314] • Lot number of the solid dosage form;

[0315] • At least some “acquired information” related to solid dosage forms, as defined herein (e.g., design / parameters related to dosage form, patient or other relevant information);

[0316] • Printing apparatus (or 3D printer) operating parameters, such as those selected from one or more of the following: extruder nozzle operating temperature (whether measured at the relevant nozzle inlet, nozzle outlet, or by measuring the input current required for the nozzle heating element to maintain a specific temperature), filament feed rate / flow (whether measured at the conveyor, nozzle inlet opening and / or nozzle outlet opening, or elsewhere), nozzle and / or build platform movement / translation speed, appearance of the solid form during printing (appropriately, measured via optical techniques, such as photographs), power fluctuations, overall internal (within the printing apparatus) and external (ambient) temperatures, and any other parameters that may affect the quality and / or consistency of the solid form being printed.

[0317] To provide feedback or transmit the aforementioned operating parameters, the printing apparatus (or 3D printer) may include one or more sensors associated with (and configured to detect the associated operating parameters): one or more extruder nozzles or their corresponding heating elements (i.e., monitoring nozzle temperature); one or more filament sources (e.g., spools or barrels), one or more corresponding conveyors, or the input or output of one or more nozzles (i.e., monitoring filament feed rate / flow); one or more nozzle or build platform translation elements (i.e., monitoring nozzle / build platform movement); the build platform (e.g., a camera monitoring the appearance of the solid form during printing); circuitry (for monitoring any power fluctuations or electrical parameters), etc. Thus, the sensors may be thermal detectors, motion detectors, electrical detectors, and / or optical detectors, etc. Each sensor is suitably configured to transmit sensing data (or production data) to a monitoring computer (wirelessly or wired). Suitably, all sensors are configured to transmit their respective sensing data in a substantially simultaneous manner, enabling real-time monitoring (and / or analysis) of the associated printing apparatus (or 3D printer).

[0318] Production data can be analyzed (e.g., via a computer using appropriate monitoring / analysis software, which can be integrated with solid form printing software) or compared against expected preset values ​​(e.g., expected nozzle temperature or temperature fluctuations for a given filament / solid form; expected physical appearance of the solid form at a specific point in the printing cycle; expected filament feed rate, etc.), which can be predetermined based on the design and parameters of the solid form in question (thus the preset values ​​can be provided as part of the “Information Obtained” described herein). When actual production data (or its operating parameters) conform to the expected preset values ​​within defined permissible limits, a favorable response can be issued to the analysis of the production data against the expected preset values ​​(indicating that the printing apparatus and / or 3D printer are within permissible quality control limits). This can trigger a response indicating satisfactory operation or not trigger a response (e.g., if no response indicates satisfactory operation). However, when actual production data (or its operating parameters) deviate from the preset values ​​expected by a defined degree, an adverse response can be issued to the analysis of the production data against the expected preset values ​​(indicating a faulty printing unit and / or 3D printer, whether temporary, intermittent, or permanent). This can trigger a response indicating unsatisfactory operation (e.g., to warn relevant parties), optionally along with information allowing for correction of the fault, optionally along with information identifying solid formaldehyde produced during the fault (or a defined time before or after the fault), and may even trigger a shutdown of the printing unit to ensure that no more solid formaldehyde is produced until satisfactory quality control is restored. Therefore, it is desirable to monitor the operation of the printing unit (or 3D printer) in real time to allow for appropriate responses from monitoring and / or analysis computers in real time.

[0319] It is conceivable that production data collected in connection with a given printing device (or 3D printer) can be used to obtain or maintain regulatory approval for printed solid dosage forms.

[0320] solid dosage form

[0321] This invention provides solid dosage forms as defined herein. The solid dosage forms of this invention are generally distinguishable by chemical and / or microscopic analysis, which suitably reveals that the solid dosage form has been produced in a layer-by-layer manner by extruded filaments.

[0322] The solid dosage forms of the present invention are suitably intended for oral administration. Examples of solid dosage forms are tablets, capsules, granules, powders, beads, and microcapsules. Most suitably, the solid dosage forms are tablets or implants, and most suitably, pharmaceutical tablets or medical implants (e.g., implants that allow sustained and / or controlled release of the active ingredient).

[0323] The solid dosage forms of the present invention are advantageously customizable in the following aspects: the type / nature of the active ingredient dosage, the dosage of the active ingredient within the solid dosage form (whether it is the absolute dose per solid dosage form or the concentration of the active substance within the dosage form), the mass / volume of the solid dosage form (which can generally be adapted to change the absolute dose of the active ingredient without changing the concentration of the active ingredient within the dosage form), the release profile of the active ingredient (which can be modified by careful use and / or distribution of suitable excipients, such as core-shell arrangements for delayed or sustained release), or the shape and appearance (including novel shapes, colors, and patterns, such as those that can help encourage medication adherence in particular patients).

[0324] Many of the preferred features of solid dosage forms are described elsewhere herein. For example, the features described with respect to the methods of producing solid dosage forms may suitably reflect the features of the solid dosage forms themselves (e.g., layer height). Inevitably, solid dosage forms contain components provided by the filaments used in their formation and may be considered to contain related filament compositions. Since the printing conditions suitably do not (substantially) alter or degrade the composition of the corresponding filaments, the subsequent descriptions of the filaments also apply to solid dosage forms.

[0325] Solid dosage forms can be immediately released, sustained-release, or / or delayed-release solid dosage forms (where "release" refers to the release of the active ingredient). Typically, immediately released formulations are substantially homogeneous solid dosage forms. However, sustained-release and / or delayed-release formulations are suitably non-homogeneous solid dosage forms, typically comprising a core matrix (which suitably contains the active ingredient) and at least one shell matrix surrounding the core (which suitably delays and / or controls the release of the active ingredient from the core). The shell matrix can be substantially enteric-coated, although this can be produced using the printing method of the present invention. Alternatively, solid dosage forms produced according to the present invention can be further processed outside the printing apparatus to produce a shell or coating thereon (e.g., an enteric coating surrounding a substantially homogeneous core).

[0326] Suitably, the solid dosage forms of the present invention comprise 0.5 wt% or more of the active ingredient, suitably 1 wt% or more of the active ingredient, suitably 5 wt% or more of the active ingredient, suitably 9 wt% or more of the active ingredient, suitably 19 wt% or more of the active ingredient, and suitably 39 wt% or more of the active ingredient. Suitably, the solid dosage forms of the present invention comprise less than or equal to 60 wt% or more of the active ingredient, suitably less than or equal to 50 wt% or more of the active ingredient, and suitably less than or equal to 30 wt% or more of the active ingredient. Suitably, after the active ingredient, the weight balance of the solid dosage form consists substantially of a carrier, a diluent, and / or excipients (all of which may be considered to constitute "excipients").

[0327] Suitably, the solid dosage forms of the present invention comprise 10 wt% or more of excipients and / or active ingredient carriers (suitably excluding any plasticizers), 20 wt% or more, 30 wt% or more, 50 wt% or more, or 79 wt% or more. Suitably, the solid dosage forms of the present invention comprise 99 wt% or more of excipients and / or active ingredient carriers (suitably excluding any plasticizers), 90 wt% or more, 80 wt% or more, or 60 wt% or more. In a particular embodiment, the solid dosage form comprises 40 wt% to 60 wt% of excipients and / or active ingredient carriers (suitably excluding any plasticizers), preferably 45 wt% to 55 wt%.

[0328] Suitably, the solid dosage form of the present invention comprises greater than or equal to 0.1 wt% of a plasticizer, suitably greater than or equal to 1 wt%, suitably greater than or equal to 4 wt%, or suitably greater than 9 wt%. Suitably, the solid dosage form of the present invention comprises less than or equal to 50 wt% of a plasticizer, suitably less than or equal to 30 wt%, suitably less than or equal to 15 wt%, or suitably less than or equal to 11 wt%.

[0329] Suitably, the solid dosage form of the present invention comprises one or more fillers, wherein the fillers are suitably components different from any carrier component / polymer. The one or more fillers are suitably selected from organic or inorganic compounds, suitably having a melting point of at least 150°C, suitably at least 200°C, suitably at least 500°C, or suitably at least 1000°C. The one or more fillers are suitably fillers approved for pharmaceutical and / or nutritional uses, or at least GRAS approved. Suitably, the one or more fillers constitute or form part of a non-melting or infusible component of the solid dosage form (suitably referring to the fusibility of the component under prevailing 3D printing conditions). Suitably, the solid dosage form (and / or filament) comprises at least 10 wt% filler, suitably at least 25 wt%, more suitably at least 40 wt%. Suitably, the solid dosage form (and / or filament) comprises no more than 70 wt% filler, suitably no more than 60 wt%. The presence of fillers can significantly improve the structure of the corresponding filament and / or printing formulation, and can also benefit the printing itself, especially when the filler does not melt (or undergo any glass transition) within the heated extrusion nozzle.

[0330] Printing filaments and compositions containing active ingredients

[0331] The solid dosage form of the present invention is produced using printing filaments containing active ingredients. Therefore, the solid dosage form suitably comprises or is substantially composed of a filament composition containing active ingredients. Alternatively, in the case where the solid dosage form is formed from many different filaments, the resulting dosage form is suitably a composite material of all the filaments in corresponding ratios. In a particular embodiment, the core of the solid dosage form is substantially composed of a filament composition containing active ingredients.

[0332] In aspects of the invention, filaments or filament compositions comprising a fusible component and an infusible component (and suitably a corresponding solid formulation or a corresponding portion / layer of a solid formulation) are provided. Suitably, the "fusible" component is a component that melts (or undergoes a glass transition and thus softens) at a specified operating temperature of any corresponding 3D printer extrusion nozzle configured to process the filament, while the "infusible" component is suitably a component that does not melt (or undergo a glass transition) at the same temperature. Suitably, the "fusible" component can be a mixture of components that together melt or undergo a glass transition as a mixture—e.g., a carrier polymer and a plasticizer. However, the "infusible" component is more likely to be a single component with different melting points or glass transition temperatures. Suitably, the fusible component has a melting point (or T... g At or below 220°C, suitably at or below 150°C, suitably at or below 100°C, suitably at or below 80°C, suitably at or below 60°C. Suitably, the fusible component has a melting point (or T...) g —that is, at least one T g ) greater than or equal to 20°C, suitably greater than or equal to 30°C, suitably between 30°C and 65°C, suitably between 30°C and 35°C. Suitably, the infusible component has a melting point (or T... g At or above 150°C, appropriately at or above 200°C, appropriately at or above 500°C, appropriately at or above 1000°C.

[0333] As explained above, references to "fusible" and "infusible" components respectively cover "softenable" and "non-softenable" components, where the component "softens" instead of "melts" at a specific temperature. Therefore, in this context, references to melting point may additionally or optionally refer to the glass transition temperature. Such a glass transition is particularly applicable to thermoplastic components. Thus, a "fusible" component can be a thermoplastic component, suitably with a glass transition temperature (the temperature at which the thermoplastic component softens rather than melts) lower than the temperature at which the component is exposed (e.g., during printing).

[0334] Each of the various filament compositions described herein is suitably either a fusible component or an infusible component (not both). For example, the carrier polymer (such as the active ingredient carrier) is typically a fusible component and is suitably selected to undergo a melting or glass transition during printing. In contrast, fillers (such as tricalcium phosphate, talc, etc.) are suitably infusible components and are suitably selected to remain solid during printing. Despite the contrasting melting / glass transition properties of the various components, the filament itself suitably possesses a characteristic glass transition temperature. Suitably, 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 fusible and infusible components can provide viable filaments for 3D printing. Suitablely, the ratio of fusible component to infusible component is between 1:10 and 10:1, more suitablely between 3:7 and 7:3, and suitablely between 4:6 and 6:4, wherein suitablely, the fusible component collectively includes all relevant fusible components (e.g., carrier polymer, plasticizer, etc.), and the infusible component includes all relevant infusible components (e.g., filler, lubricant, active ingredient, etc.). Suitablely, the active ingredient itself is an infusible component.

[0335] Appropriately, the active ingredient is (substantially) evenly distributed within the active ingredient-containing printing filament (appropriately within the active ingredient carrier). Distributing the active ingredient within the relevant filament prior to printing typically allows for higher active material loading and reduces overall processing.

[0336] However, in some embodiments, the active ingredient may be (substantially) non-uniformly distributed within the active ingredient-containing printing filament (appropriately within the active ingredient carrier). In some cases, such embodiments may include the active ingredient through a gradient of filament thickness.

[0337] The filament containing the active ingredient is suitably stiff enough to allow it to be feasiblely fed (at a consistent rate) into and through the corresponding extrusion nozzle within the printing unit or 3D printer. The filament containing the active ingredient is also suitably stiff enough to prevent it from being stretched during printing. However, the filament is suitably not so stiff that the nozzle operating temperature required for filament extrusion would reduce the content of the ingredient (e.g., resulting in a compositional change greater than or equal to 1 wt%).

[0338] The active ingredient-containing printing filament is suitably flexible and / or soft enough to be extruded (at a consistent rate) from the corresponding extrusion nozzle within the printing device or 3D printer. The active ingredient-containing printing filament is suitably flexible and / or soft enough to allow the filament to be feasiblely wound / wound around a filament spool.

[0339] The active ingredient-containing printing filament is appropriately neither too brittle (and prone to breakage during printing / winding) nor too flexible (impeding its feasible transport through the printing apparatus or 3D printer). The composition of the filament (e.g., active ingredient loading, concentration and type of excipient) and dimensions (e.g., thickness) can be carefully modified using the principles taught in this disclosure to obtain an optimal filament structure.

[0340] The thickness (i.e., diameter or maximum thickness) of the printing filaments containing active ingredients is suitably between 0.1 mm and 5 mm, suitably between 0.5 mm and 4 mm, more suitably between 1 mm and 3 mm, and most suitably between 1.5 mm and 2 mm. In a particular embodiment, the printing filaments containing active ingredients have a thickness of approximately 1.75 mm. However, the filament thickness can be adjusted to suit the extrusion nozzles (in particular, the size / diameter of their respective openings) through which they will be extruded.

[0341] Appropriately, the printing filament containing the active ingredient can be wound (or wrapped) around a spool, appropriately having a hub diameter of about 20 cm, appropriately having a hub diameter of about 10 cm, appropriately having a hub diameter of about 5 cm, appropriately having a hub diameter of about 2.5 cm, appropriately having a hub diameter of about 1 cm, and appropriately being free from breakage and / or stretching.

[0342] Suitably, the printing filament containing the active ingredient comprises at least one component that melts at a corresponding nozzle operating temperature (which may be a temperature as defined herein, suitably to allow the filament to be extruded through the nozzle) (“molten component”), and at least one component that remains in or otherwise transforms into a solid and / or particulate form at the corresponding nozzle operating temperature (suitably such that the solid and / or particulate form is present within the nozzle during filament extrusion through the nozzle) (“non-molten component”). The molten component suitably includes at least an active ingredient carrier. However, the molten component may suitably include a diluent, carrier, and / or excipient, and may suitably melt into a composite material—a combination of carrier / diluent and plasticizer may, for example, constitute the “molten component”. The non-molten component suitably includes at least the active ingredient itself (preferably this does not melt during printing, such that its polymorphism is sufficiently preserved). However, the non-melting component may suitably include excipients and / or active ingredients, which suitably have a melting point above the nozzle operating temperature and suitably above the melting point of the corresponding non-melting component, the composite material melting point, or the glass transition temperature (or composite material melting point). The non-melting component is suitably still co-extruded from the relevant nozzle along with any melting component. However, the presence of the non-melting component, particularly when in particulate form at the operating temperature of the relevant nozzle, surprisingly reduces nozzle clogging and may also, alternatively, improve the overall resolution of the solid formulation. Furthermore, the non-melting component also helps reduce bubble formation during printing and the degradation of excipients and active ingredients. Particularly useful non-melting components include lubricants, such as those discussed (such as talk).

[0343] This invention is applicable to any FFF printing filament, as aspects of the invention provide an FFF printing filament comprising a material that melts at a given nozzle operating temperature and a material that remains in or otherwise transforms into a solid and / or granular form at the given nozzle operating temperature (appropriately such that the solid and / or granules are present within the nozzle during filament extrusion through the nozzle).

[0344] Printing filaments containing active ingredients have a glass transition temperature (T0). g Suitablely, the glass transition temperature (T0) is between 20°C and 200°C, between 45°C and 165°C, or between -10°C and 165°C. In the absence of any infusible components, the glass transition temperature of the filament typically needs to be higher. Suitablely, printing filaments containing active ingredients have a glass transition temperature (T0) of [specific value missing]. gSuitablely, the glass transition temperature is between 30°C and 65°C (especially in the presence of an infusible component, whether it is a filler, a pharmaceutical and / or both or others). In an embodiment, the printing filament containing the active ingredient has a glass transition temperature between 30°C and 35°C. The printing filament containing the active ingredient suitably has a glass transition temperature lower than the melting point of the active ingredient, suitably at least 20°C lower, more suitably at least 50°C lower, and more suitably at least 80°C lower.

[0345] Appropriately, printing filaments containing active ingredients are carefully tailored with suitable ratios and types of active ingredients and carriers / excipients to produce the desired T. g And / or wires with high melting point, so as to minimize the corresponding nozzle operating temperature required for extrusion.

[0346] Suitablely, the active ingredient-containing printing filament of the present invention comprises greater than or equal to 0.001 wt% of active ingredient, suitablely greater than or equal to 0.01 wt% of active ingredient, suitablely greater than or equal to 0.005 wt% of active ingredient, suitablely greater than or equal to 0.1 wt% of active ingredient, suitablely greater than or equal to 0.5 wt% of active ingredient, suitablely greater than or equal to 1 wt% of active ingredient, suitablely greater than or equal to 5 wt% of active ingredient, suitablely greater than or equal to 9 wt% of active ingredient, suitablely greater than or equal to 19 wt% of active ingredient, and suitablely greater than or equal to 39 wt% of active ingredient. Suitablely, the remaining weight of the active ingredient-containing printing filament after the active ingredient consists essentially of a carrier, diluent, and / or excipient (all of which can be considered to constitute "excipients").

[0347] Suitablely, the active ingredient-containing printing filament of the present invention comprises greater than or equal to 10 wt% of excipients and / or active ingredient carriers (suitably excluding any plasticizers), suitablely greater than or equal to 20 wt%, suitablely greater than or equal to 30 wt%, suitablely greater than 50 wt%, suitablely greater than or equal to 70 wt%, and suitablely greater than or equal to 79 wt%. Suitablely, the active ingredient-containing printing filament of the present invention comprises less than or equal to 99 wt% of excipients and / or active ingredient carriers (suitably excluding any plasticizers), suitablely less than or equal to 95 wt%, suitablely less than or equal to 80 wt%, and suitablely less than or equal to 60 wt%.

[0348] Suitablely, the active ingredient-containing printing filament of the present invention contains greater than or equal to 0.1 wt% of a plasticizer, suitablely greater than or equal to 1 wt%, suitablely greater than or equal to 3 wt%, suitablely greater than or equal to 4 wt%, and suitablely greater than 9 wt%. Suitablely, the active ingredient-containing printing filament of the present invention contains less than or equal to 50 wt% of a plasticizer, suitablely less than or equal to 40 wt%, suitablely less than or equal to 30 wt%, suitablely less than or equal to 15 wt%, and suitablely less than or equal to 11 wt%.

[0349] Appropriately, the combined concentration of the active ingredient carrier and the plasticizer is between 30 wt% and 80 wt%, appropriately between 40 wt% and 60 wt%, and most appropriately between 45 wt% and 55 wt%.

[0350] As described regarding solid dosage forms, the composition of which substantially reflects the composition of the filament in which only a single filament is used, the filament suitably containing one or more fillers, suitably a single filler. When multiple filaments are used during printing (e.g., core-shell tablets), the core of any resulting printed dosage form suitably has a composition that substantially reflects the composition of the filament containing the active ingredient. However, such fillers can also be present in any non-active-ingredient-containing filament. Suitably, the one or more fillers are present in the solid dosage form, core, or active-ingredient-containing filament (and any associated non-active-ingredient-containing filament) at a concentration of at least 10 wt%, suitably at least 25 wt%, more suitably at least 40 wt%. Suitably, the solid dosage form, core, or active-ingredient-containing filament (and any associated non-active-ingredient-containing filament) contains no more than 70 wt% filler, suitably no more than 60 wt%.

[0351] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0352] 0.01wt%-50wt% of active ingredients;

[0353] 20wt%-99.99wt% of excipients and / or active ingredient carriers;

[0354] Optional 1wt%-30wt% of plasticizer.

[0355] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0356] 0.01wt%-50wt% of active ingredients;

[0357] 20wt%-99.99wt% of active ingredient carrier;

[0358] 10wt%-70wt% filler;

[0359] Optional 1wt%-30wt% of plasticizer.

[0360] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0361] 5wt%-30wt% of active ingredients;

[0362] 55wt%-95wt% of excipients and / or active ingredient carriers;

[0363] Optional 1wt%-15wt% of plasticizer.

[0364] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0365] 5wt%-30wt% of active ingredients;

[0366] 55wt%-90wt% of excipients and / or active ingredient carriers;

[0367] 5wt%-15wt% plasticizer.

[0368] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0369] 15wt%-60wt% of active ingredients;

[0370] 25 wt% to 85 wt% of excipients and / or active ingredient carriers (in this case, most appropriately acrylate-based polymers as defined herein);

[0371] Optionally (and preferably) 1 wt% to 15 wt% of plasticizer.

[0372] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0373] 40wt%-60wt% of active ingredients;

[0374] 35 wt% to 55 wt% of excipients and / or active ingredient carriers (in this case, most appropriately acrylate-based polymers as defined herein);

[0375] 1wt%-15wt% plasticizer.

[0376] In a particular embodiment, the printing filament containing the active ingredient comprises:

[0377] 0.1wt%-40wt% of active ingredients;

[0378] 35wt%-65wt% of active ingredient carrier;

[0379] 35wt%-65wt% filler;

[0380] Optional 1wt%-20wt% of plasticizer.

[0381] Active ingredients

[0382] This invention is suitably applicable to any active ingredient. This disclosure allows those skilled in the art to readily develop active ingredient-containing printing filaments for FFF 3D printing by carefully selecting suitable active ingredient carriers and / or excipients, which may accompany the active ingredient within the filament.

[0383] The active ingredient is most preferably a pharmaceutical substance (which may be any suitable pharmaceutical compound or its pharmaceutically acceptable salt, solvate, prodrug, or polymorph). Therefore, any carrier, diluent, and / or excipient used in the printing filament containing the active ingredient, or in any other printing filament that can be used to prepare the corresponding solid dosage form, is preferably a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0384] The active ingredient is suitably in the same form as the active ingredient in the approved pharmaceutical product. The active ingredient is suitably in the same form as the active ingredient before it was incorporated into the filament (and has substantially the same purity).

[0385] In a particular embodiment, the active ingredient is extremely soluble, soluble, or soluble according to the standard USP (United States Pharmacopeia) definition of solubility. In another embodiment, the active ingredient is sparingly soluble, slightly soluble, or very slightly soluble according to the standard USP definition of solubility.

[0386] In a particular implementation, the active ingredient is extremely soluble according to the standard USP definition of solubility.

[0387] In a particular implementation, the active ingredient is readily soluble according to the standard USP definition of solubility.

[0388] In a particular implementation, the active ingredient is soluble according to the standard USP definition of solubility.

[0389] In some implementations, the active ingredient is poorly soluble according to the standard USP definition.

[0390] In some implementations, the active ingredient is slightly soluble, according to the standard USP definition.

[0391] In some implementations, the active ingredient is extremely slightly soluble, according to the standard USP definition.

[0392] In some implementations, the active ingredient is virtually insoluble, according to the standard USP definition.

[0393] The active ingredient appropriately has a higher melting point than the overall active ingredient-containing printing filament or glass transition temperature (softening temperature).

[0394] The active ingredient appropriately has a melting point that is higher than the melting point or glass transition temperature (softening temperature) of the active ingredient carrier or active ingredient excipient composition within the filament.

[0395] The active ingredient suitably has a melting point higher than the operating temperature of the extrusion nozzle used in printing the associated filament during solidification. This is preferred to avoid a change in the form (e.g., polymorphism) of the active ingredient during solidification. It is also preferred to reduce the risk of nozzle clogging. This is also preferred for providing high-resolution printing of the solid form. Finally, the active ingredient that meets this condition is likely to be stable (e.g., for degradation) at a given nozzle operating temperature, at least for the period of time the filament is exposed to such a temperature during 3D printing.

[0396] The active ingredient appropriately has a melting point higher than the operating temperature of the extrusion nozzle used in the initial formation of the filament containing the active ingredient.

[0397] Appropriately, the active ingredient has a melting point greater than or equal to 150°C, more appropriately greater than or equal to 190°C, and more appropriately greater than or equal to 250°C.

[0398] In a particular embodiment, the active ingredient is selected from theophylline, dipyridamole, prednisolone, or diclofenac potassium. In a preferred embodiment, the active ingredient is theophylline or dipyridamole.

[0399] The same parameters are appropriately applied when the solid dosage form is a nutritional product or a food supplement solid dosage form.

[0400] Active ingredient carrier

[0401] Printing filaments containing active ingredients suitably include active ingredient carriers, and may suitably include one or more active ingredient carriers. Suitably, one active ingredient carrier is more dominant than all other cases in filaments containing more than one active ingredient carrier.

[0402] Any suitable carrier can be used. In the case of pharmaceuticals, carriers are typically used in the compounding of solid dosage forms such as tablets and capsules. Solid oral dosage forms can be designed to release the active portion of the formulation at a location in the gastrointestinal tract, where bioavailability is maximized and pre-systemic degradation is minimized. At least one additional agent may be included to facilitate the absorption of the active ingredient of this disclosure and / or any additional therapeutic agent. In such solid dosage forms, the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as lactose, sodium citrate, or dicalcium phosphate and / or one or more of the following: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, 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 glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, for example, using excipients such as lactose or high molecular weight polyethylene glycol.

[0403] The melting point (or glass transition temperature) of the active ingredient carrier is suitably lower than that of the active ingredient, suitably at least 20°C lower, more suitably at least 40°C lower, and more suitably at least 50°C lower. The melting point of the active ingredient carrier is suitably between 140°C and 250°C, more suitably between 150°C and 200°C, and most suitably between 155°C and 175°C.

[0404] Suitablely, the specific heat of the active ingredient carrier is between 0.1 cal / g °C and 1 cal / g °C, and most suitablely between 0.3 cal / g °C and 0.5 cal / g °C.

[0405] The density of the active ingredient carrier is appropriately between 1.1 g / mL and 1.6 g / mL, and most appropriately between 1.2 g / mL and 1.4 g / mL.

[0406] The active ingredient carrier appropriately has a glass transition temperature lower than the melting point of the active ingredient, appropriately at least 20°C lower, more appropriately at least 40°C lower, and more appropriately at least 50°C lower.

[0407] The active ingredient carrier (especially in cases where immediate release of a solid dosage form is desired) is suitably selected from carriers (suitably cationic polymers, neutral polymers, or copolymers) having the following viscosities: not exceeding 50 mPa·s, suitably not exceeding 30 mPa·s, suitably not exceeding 10 mPa·s, but suitably having a viscosity of at least 1 mPa·s—most suitably between 2 mPa·s and 8 mPa·s. The active ingredient carrier (especially in cases where immediate release of a solid dosage form is desired) is suitably selected from carriers having the following molecular weights: at least 20,000 g / mol, more suitably at least 35,000 g / mol, more suitably at least 45,000 g / mol, but suitably less than 1,000,000 g / mol, more suitably less than 100,000 g / mol—most suitably between 35,000 g / mol and 65,000 g / mol. The active ingredient carrier (especially in cases where immediate release of a solid dosage form is desired) is suitably selected from carriers having the following glass transition temperature (T0). g The carrier temperature is: at most 100°C, preferably at most 80°C, preferably at most 50°C, but preferably at least -10°C, more preferably at least 35°C – most preferably between 30°C and 60°C. g In some embodiments, the active ingredient carrier may not have such a glass transition temperature, but the observed softening can still occur. The active ingredient carrier (especially where immediate release of a solid dosage form is desired) is suitably a copolymer of (optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate, and / or ethacrylate (suitably containing amine-containing monomer units), suitably having a viscosity between 2 mPa·s and 8 mPa·s, suitably having a molecular weight between 35,000 g / mol and 65,000 g / mol, and / or suitably having a glass transition temperature between 30°C and 60°C. g In a particular embodiment, the relevant copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate), with a suitable molar ratio of monomers of 1:2:1 (molar value + / - 5% for each ratio). The active ingredient carrier is suitably Eudragit E.

[0408] The active ingredient carrier (especially in cases where a sustained-release solid dosage form is desired) is suitably selected from carriers having the following viscosities: not exceeding 30 mPa·s, suitably not exceeding 20 mPa·s, suitably not exceeding 16 mPa·s, but suitably having a viscosity of at least 1 mPa·s—most suitably between 1 mPa·s and 15 mPa·s. The active ingredient carrier (especially in cases where a sustained-release solid dosage form is desired) is suitably selected from carriers having the following molecular weights: at least 10,000 g / mol, more suitably at least 250,000 g / mol, more suitably at least 30,000 g / mol, but suitably less than 100,000 g / mol, more suitably less than 40,000 g / mol—most suitably between 29,000 g / mol and 35,000 g / mol. The active ingredient carrier (especially in cases where a sustained-release solid dosage form is desired) is suitably selected from carriers having the following glass transition temperature (T0). g The carrier temperature is: at most 100°C, appropriately at most 80°C, appropriately at most 70°C, but appropriately at least 40°C, more appropriately at least 50°C—most appropriately between 55°C and 70°C. g In some embodiments, the active ingredient carrier may not have such a glass transition temperature, but the observed softening can still occur. The active ingredient carrier (especially where a sustained-release solid dosage form is desired) is suitably (optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate, and / or ethylacrylate copolymer (suitably containing amine-containing monomer units), suitably having a viscosity between 1 mPa·s and 15 mPa·s, suitably having a molecular weight between 29,000 g / mol and 35,000 g / mol, and / or suitably having a glass transition temperature between 55°C and 70°C. g In a particular embodiment, the relevant copolymer is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), with a suitable molar ratio of monomers of 1:2:0.2 (molar values ​​+ / - 5% for each ratio). The active ingredient carrier is suitably Eudragit RL.

[0409] The active ingredient carrier (particularly in cases where a delayed-release solid dosage form is desired) is suitably selected from carriers having the following viscosities: at least 20 mPa·s, suitably at least 40 mPa·s, suitably at least 50 mPa·s, but suitably having a viscosity not exceeding 300 mPa·s, suitably not exceeding 210 mPa·s—most suitably between 40 mPa·s and 210 mPa·s. The active ingredient carrier (particularly in cases where a delayed-release solid dosage form is desired) is suitably selected from carriers having the following molecular weights: at least 10,000 g / mol, more suitably at least 15,000 g / mol, but suitably less than 400,000 g / mol—in certain embodiments, the molecular weight is between 10,000 g / mol and 25,000 g / mol, while in other embodiments, the molecular weight is between 100,000 g / mol and 350,000 g / mol. The active ingredient carrier (particularly in cases where a delayed-release solid dosage form is desired) is suitably selected from carriers having the following glass transition temperatures (T0). g The carrier temperature should be at least 80°C, preferably at least 90°C, preferably at least 100°C, but preferably at most 200°C, more preferably at most 160°C – most preferably between 90°C and 160°C. g In some embodiments, the active ingredient carrier may not have such a glass transition temperature, but the observed softening can still occur. The active ingredient carrier (especially in cases where a delayed-release solid dosage form is desired) is suitably selected from:

[0410] • (Optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate, and / or ethylacrylate polymers or copolymers (suitably free of any amine-containing monomer units), suitably having a viscosity between 90 mPa·s and 210 mPa·s, suitably having a molecular weight between 100,000 g / mol and 350,000 g / mol, and / or suitably having a glass transition temperature between 90 °C and 140 °C; wherein the corresponding polymer or copolymer is suitably selected from: poly(methacrylate-co-ethyl acrylate), suitably with a monomer molar ratio of 1:1 (molar value + / - 5% for each ratio); poly(methacrylate-co-methyl methacrylate), suitably with a monomer molar ratio of 1:1 (molar value + / - 5% for each ratio); poly(methacrylate-co-methyl methacrylate), suitably with a monomer molar ratio of 1:2 (molar value + / - 5% for each ratio); or

[0411] • Cellulose or cellulose derivatives, suitably hydroxypropyl methylcellulose (HPMC) derivatives, most suitably hydroxypropyl methylcellulose acetate (HPMC) succinate (HPMCAS), suitably having a molecular weight between 10,000 g / mol and 25,000 g / mol and / or suitably having a glass transition temperature between 100 °C and 145 °C (or suitably between 100 °C and 165 °C); wherein the associated HPMC is suitably selected from Aqoat LG, Aqoat MG and / or Aqoat HG. However, suitable HPMC derivatives may also include hydroxypropyl methylcellulose phthalate (HPMCP), such as its HP-50, HP-55 and HP-55S grades.

[0412] In principle, any suitable carrier may be used, including any one or more of the following: (optionally alkyl-, suitably methyl- or ethyl-)acrylates, methacrylates and / or ethylacrylate copolymers (suitably containing amine-containing monomer units); (optionally alkyl-, suitably methyl- or ethyl-)acrylates, methacrylates and / or ethylacrylate polymers or copolymers (suitably not containing any amine-containing monomer units); cellulose or cellulose derivatives; polyvinyl alcohol (PVA); poly(lactic-co-glycolic acid) (PLGA); and / or any suitable pharmaceutically acceptable carrier.

[0413] (Optionally alkyl-, suitably methyl- or ethyl-)acrylate, methacrylate and / or ethyl acrylate polymers or copolymers are particularly advantageous in supporting high loadings of active ingredients.

[0414] The active ingredient carrier is suitably selected from Eudragit E, Eudragit NE, HPC SSL, Eudragit RS, Eudragit RL, HPC SL, HPC M, HPC H, Eudragit L100-55, Eudragit L100, Eudragit S100, Aqoat LG, Aqoat MG, Aqoat HG and / or polyvinyl alcohol (PVA), or any combination thereof.

[0415] In some embodiments, particularly when the active ingredient has limited solubility in the target solubilization medium (e.g., in vivo), an active ingredient carrier, such as a polyvinylpyrrolidone polymer or a polyvinylpyrrolidone-derived polymer, can be used. Such polymers can facilitate the dissolution of active ingredients that would otherwise exhibit limited solubility. In certain embodiments, PVP K29-32 (povidone) can be used. When present, PVP or a PVP-based carrier is suitably present at concentrations between 20 wt% and 80 wt% (e.g., in filaments, solid dosage forms, or cores), suitably between 40 wt% and 60 wt%, suitably 45 wt%–55 wt%. PVP and PVP-based carrier polymers can be used with one or more fillers and optionally with other components such as plasticizers. Mixtures of different PVPs or PVP-based carriers (e.g., PVPs of different molecular weights) can also be used or optionally used.

[0416] In some embodiments, polyalkylene glycols and polyalkylene glycol-derived polymers can be used as carrier polymers, such as carriers for active ingredients. In specific embodiments, the polyalkylene glycol or polyalkylene glycol-derived carrier polymer is polyethylene glycol (PEG) or a polyethylene glycol-derived carrier polymer. Suitably, whether utilizing PEG or a PEG-based carrier polymer, at least a portion of the PEG or PEG-based carrier polymer has a molecular weight of at least 100,000 g / mol, but suitably at most 1,000,000 g / mol. However, mixtures of different polyalkylene glycols and polyalkylene glycol-derived polymers (e.g., PEG or PEG-based carrier polymers) can be incorporated into filaments and / or corresponding dosage forms. For example, high molecular weight PEG can be used with relatively low molecular weight PEG to achieve an optimal performance balance. Higher molecular weight PEG and PEG-based polymers (e.g., M... w ≥80,000) can be used as carrier molecules, while lower molecular weight PEG and PEG-based polymers (e.g., M) w (200-20000) can be used as a plasticizer and / or solubility enhancer. Increasing the proportion of low molecular weight PEG may decrease the T of the resulting filament. g In addition, increasing lower M w The proportion of PEG also helps to accelerate drug release. Appropriately, any PEG or PEG-based carrier polymer can be used with one or more fillers, but such polymers can be used with or without non-molten components.

[0417] filler

[0418] As described above, suitably, the filaments (and their corresponding formulations or layers thereof) of the present invention contain one or more fillers, suitably in the amounts stated. Suitably, the fillers are contained together with a carrier polymer (such as those described herein) and optionally also with other excipients (such as plasticizers, binders, and the like). By following the teachings of this specification, it is possible to achieve an ideal balance between the components. Generally, the inclusion of one or more fillers in the filament or filament composition enhances the resulting filament and thus facilitates their generation and handling during 3D printing. However, too much filler can lead to a degree of brittleness, which can be mitigated by the careful use of other components (e.g., plasticizers that can be used to soften the filament), by reducing the proportion of filler, and / or by altering the properties of the filler (e.g., its melting point).

[0419] Many fillers are known in the pharmaceutical and nutritional products field, and any of these can be utilized where appropriate or desired for a particular pharmaceutical or nutritional formulation. Suitably, at least one (preferably all) of the fillers has a melting point exceeding the relevant operating temperature of the component in contact with the filament (e.g., printing nozzle, extrusion nozzle, and / or heated conveyor or feeder). Suitably, the filler is substantially inert and / or suitably has minimal or no interaction with other components (e.g., pharmaceuticals or polymers) in the filament or dosage form. The inclusion of fillers is particularly suitable in systems where the pharmaceutical has a relatively low melting point or imparts a plasticizing effect. The inclusion of fillers in systems containing pharmaceuticals only in relatively low concentrations (e.g., within the filament) can also be suitable. In certain embodiments, the filler may include lactose and / or tricalcium phosphate. Talc is another ideal filler for use in the filaments and dosage forms of the present invention, particularly in combination with PVP or PEG polymers.

[0420] Optional plasticizers

[0421] Printing filaments containing active ingredients may appropriately include plasticizers. Such plasticizers can improve filament quality (e.g., in terms of smoothness, flexibility, and flowability during extrusion). Plasticizers can be used to lower the glass transition (or softening) temperature of the filament (or carrier), and thus allow for the use of lower extrusion nozzle operating temperatures during filament printing and / or formation.

[0422] Typically, if the filament has a glass transition temperature that is too high (T... gIf the filament has a glass transition temperature that is too low, it may be too brittle for FFF 3D printers to handle (i.e., unable to wind onto a spool without damaging the filament), and / or may require very high extrusion nozzle operating temperatures, potentially leading to degradation of the filament's components. When the filament has a glass transition temperature that is too low, it may be too soft and / or flexible for FFF 3D printers to handle, too easily distorted for consistent printing, and result in poor shape control and inconsistent solids products. Plasticizers can be used as additives to optimize filament performance by achieving the optimal glass transition or softening temperature and a proper performance balance.

[0423] The fiber can contain any suitable plasticizer. Many pharmaceutically acceptable plasticizers are known in the art for use in forming solid dosage forms of pharmaceuticals.

[0424] In a particular embodiment, the plasticizer may be selected from one or more of triethyl citrate (TEC), glycerin, castor oil, oleic acid, glycerin, triacetin, and polyalkylene glycols (such as polyethylene glycol or polypropylene glycol, such as PEG400).

[0425] Depending on the specific active ingredient and its carrier, some plasticizers may be more suitable than others. Specific combinations that provide superior performance include:

[0426] • TEC and / or triacetin (0.5wt%-10wt% of which are present in the filament as a whole) plasticizers are combined with cellulose-based carriers (such as HPC, HPMC and HPMCAS);

[0427] • Glycerin plasticizer combined with a PVA-based carrier;

[0428] • TEC plasticizer (appropriately comprising 0.5 wt% to 30 wt% in the filament as a whole) is combined with (optionally alkyl-, appropriately methyl- or ethyl-)acrylate, methacrylate and / or ethyl acrylate polymers or copolymers.

[0429] More than one plasticizer may be used (optionally as defined herein).

[0430] The printing filament (and / or optionally solid form or its core) containing active ingredients may suitably contain between 0.1 wt% and 50 wt% of plasticizer, more suitably between 2.5 wt% and 40 wt%, more suitably between 5 wt% and 20 wt%, and most suitably between 8 wt% and 12 wt%, especially where the glass transition temperature of the filament without plasticizer is greater than or equal to 180°C.

[0431] In alternative embodiments, instead of incorporating the plasticizer into the filament, the plasticizer can be coated onto the surface of the relevant filament, suitably to provide the required elongation and feasible nozzle operating temperature. In a particular embodiment, during the printing process, the filament (with or without plasticizer) can be fed to the corresponding extrusion nozzle via a plasticizer dispenser that coats the surface (or a portion thereof) of the filament with plasticizer. Thus, in a particular embodiment, the printing filament containing the active ingredient may suitably contain or be in contact with plasticizer before it is extruded from the corresponding extrusion nozzle.

[0432] Other ingredients

[0433] In addition to the above, printing filaments containing active ingredients may also contain one or more other components. These other components may suitably include one or more excipients, excipient carriers, and / or diluents, all of which may be included in the active filament.

[0434] In particular, the one or more other components in the printing filament containing the active ingredient may be selected from one or more fillers / diluents, anti-adhesion agents, adhesives, disintegrants, lubricants, flow aids, fragrances, preservatives, sweeteners, and coatings.

[0435] Suitable anti-adhesives may include magnesium stearate. Suitable diluents / fillers may include plant cellulose, dicalcium phosphate, vegetable oils and fats, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate, and / or microcrystalline cellulose. Suitable binders may include sugars; polysaccharides / derived forms such as starch, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and their derivatives; sugar alcohols such as xylitol, sorbitol, or maltitol; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc. Suitable disintegrants may include crosslinked polyvinylpyrrolidone (crosspovidone), crosslinked sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, modified sodium starch, and / or hydroxyacetic acid starch. Suitable lubricants may include silica; fats such as vegetable stearin; magnesium stearate or stearic acid; and / or talc. Suitable flow aids may include pyrolytic silica, talc, magnesium carbonate, and / or colloidal silica. Suitable coatings may include tablet coatings to protect the tablet components from deterioration by moisture in the air and to make large or unpleasant-tasting tablets easier to swallow (e.g., cellulose ether hydroxypropyl methylcellulose (HPMC) film coatings; synthetic polymers, shellac, corn protein zein or other polysaccharides, gelatin; enteric coatings, such as those including fatty acids, waxes, shellac, plastics, plant fibers). The general categories of excipients are well understood by those skilled in the art.

[0436] In certain embodiments, the printing filament containing the active ingredient includes talc. Talc can be used as a non-melting particle to improve the performance of the extrusion nozzle. The filament or final solid formulation (or its core) may contain 0.5 wt% to 20 wt% talc, but preferably up to 15 wt%, because too much lubricant may result in poor adhesion of the solid formulation to the build platform during printing.

[0437] Excipients can be selected to suit the properties of the final solid dosage form, the properties of the filament, or both, or a careful compromise between the two. For example, with regard to solid dosage forms, excipients can be selected to facilitate administration to the target patient population via the intended route; improve dosing adherence; ensure consistency and control of drug bioavailability; achieve bioavailability; improve the stability of the active ingredient, including preventing degradation; and ensure a robust and reproducible solid product. With regard to filaments (e.g., for FFF 3D printing), excipients can be selected to optimize the physical morphology and / or stability of the filament; the stability of the active ingredient, including preventing degradation; ensure a robust and reproducible solid product; the flexibility and rigidity of the filament (an optimal balance between the flexibility and rigidity of the filament is desirable to ensure that the filament can be successfully fed into the extrusion nozzle but then easily extruded from the nozzle); and to enable the production of an optimal solid dosage form (e.g., according to each of the points above).

[0438] Silk coating

[0439] The filament of the present invention may suitably include a protective filament coating, suitably applied to the outermost surface of the filament. Such a filament coating can be used whether single-head or multi-head (e.g., dual-head) printing is used, but such a coating may be most suitable for multi-head printing situations where the filament is at risk of prolonged exposure to heat (and the resulting filament degradation) while temporarily resting (when not being printed) within its respective nozzle.

[0440] The protective filament coating is suitably derived from a corresponding protective filament coating composition. Suitably, the protective filament coating contains pharmaceutically and / or nutritionally acceptable ingredients. Suitably, the protective filament coating uses a liquid or oil, suitably having a high boiling point (e.g., at least 150°C, suitably at least 170°C, suitably at least 220°C). The coating suitably reduces filament degradation upon exposure to heat. The protective filament coating (or composition) suitably contains liquid and / or oil. Suitably, the protective filament coating is inert to the printing filament containing active ingredients and its components. Suitably, the protective filament coating does not mix with or dissolve the printing filament containing active ingredients and / or any of its components. Suitably, the protective coating does not prevent the associated filament from melting or undergoing a glass transition at the operating temperature of the extrusion nozzle.

[0441] The inventors have discovered that the use of olive oil BP, oleic acid, arachidonic acid, and glycerin facilitates coordination between the dual nozzles and avoids degradation of the drug-polymer filaments. Coating the filaments with such components is believed to provide a protective layer on the filament surface. These components also have relatively high melting points and do not degrade at the processing temperatures of the 3D nozzles.

[0442] Active silk spool

[0443] In a preferred embodiment of the printing apparatus of the present invention, the active filament is suitably provided as an active filament spool containing the active filament as defined herein (suitably for fused filament manufacturing 3D printing).

[0444] Silk spools are well known in the art and suitably include hubs around which silk is wound or can be wound. The dimensions of the spool and / or hub can vary, but most suitably, the hub diameter is between 3 cm and 30 cm, more suitably between 5 cm and 25 cm, and most suitably between 10 cm and 20 cm. The length of the hub generally depends on how much silk is intended to be wound around the spool.

[0445] Appropriately, the filament spool can be attached (appropriately rotatably attached) to or within the FFF 3D printer to allow the filament to be dispensed therefrom and delivered to the extrusion nozzle during printing.

[0446] barrel

[0447] Any spool or reel as defined herein may optionally be contained within a cartridge. Therefore, the present invention provides a cartridge containing a spool as defined herein (e.g., an active spool containing printing filaments with an active ingredient as defined herein; or a separate spool containing other printing filaments as defined herein). The cartridge is suitably configured (e.g., having a suitable shape, profile, and / or attachment mechanism) for releasable engagement with a printer or for mounting within a printer (e.g., in a docking position / station within the printer). When engaged with / mounted within a printer, the cartridge is suitably configured to operatively deliver and print the contained filaments, suitably via a nozzle that may be suitably associated with (or integrated with) the printer, or the cartridge itself (which may replace the nozzle associated with the printer).

[0448] The barrel suitably includes a housing or box, and suitably contains a spool. Suitably, the barrel is configured to protect the filament wound around the spool. Suitably, the box is (substantially) sealed (or sealable – e.g., with a stopper) and / or humidity controlled (or controllable).

[0449] The spool suitably includes a conveying mechanism operable to feed filament from the spool to the nozzle (e.g., the filament is suitably printed outside the nozzle). The conveying mechanism suitably includes a feed channel along which the filament is fed during its delivery to the nozzle. The feed channel suitably includes one or more conveying elements that frictionally engage or clamp the filament as it is conveyed. In a particular embodiment, one or more conveying elements may comprise rollers (or a set of rollers) that engage (or clamp) the filament as it is fed through them. The conveying elements are suitably coupled to complementary drive elements that, when driven, actuate the associated conveying elements.

[0450] The feed mechanism of the filament cartridge is suitably engaged with or can be engaged with a mechanical drive mechanism associated with (or integrated with) the printer. In this way, when the mechanical drive mechanism is operated (e.g., under instructions from a computer), it can in turn engageably operate the feed mechanism of the filament cartridge to feed the filament from the spool to the nozzle. Therefore, the filament cartridge is suitably configured and / or engageable with the printer to enable operable coupling between the feed mechanism of the filament cartridge and the mechanical drive mechanism of the printer. For example, suitably, each of the feed mechanism and the mechanical drive mechanism includes complementary drive elements (e.g., gears) that are mutually engageable (and engaged during use) to enable the feed mechanism to be operated by the printer via its mechanical drive mechanism.

[0451] Suitablely, the conveying mechanism is contained within the barrel to the extent that it allows (suitably unobstructed) operational engagement between the complementary drive elements of each conveying mechanism of the barrel and the mechanical drive mechanism of the printer. Therefore, the drive elements (e.g., gears) of the barrel's conveying mechanism may (partially or entirely) be outside the housing / casing to facilitate engagement with the drive elements of the printer's mechanical drive mechanism. If the housing / casing is configured (e.g., having an opening) to allow the drive elements of the printer's mechanical drive mechanism to approach and engage with the drive elements of the conveying mechanism, then the drive elements (e.g., gears) of the barrel's conveying mechanism may (partially or entirely) be located within the housing / casing. In some embodiments, the barrel and printer are configured such that when the barrel is engaged with (or mounted within) the printer, a cavity (suitably sealed) is formed therebetween, containing (partially or entirely) the two sets of corresponding drive elements (suitably engaging with each other).

[0452] Most preferably, the filament cartridge includes a cartridge nozzle through which the filament is dispensed (and / or printed). While dispensed through the cartridge nozzle, the filament can subsequently be fed to the printer nozzle, through which it is ultimately printed. This arrangement allows for handling of the filament within the printer for printer durability (e.g., the printer can cut off excess filament residing between the cartridge nozzle and the printer nozzle and self-clean its nozzle, thereby reducing printer nozzle clogging, while allowing the cartridge nozzle to make alternative sacrifices). However, in a preferred embodiment, the cartridge nozzle replaces the printer nozzle (at least during printing from the cartridge) – that is, the cartridge nozzle can be the printer nozzle. Such a cartridge can be considered a fully integrated cartridge comprising a spool (with filament wound around it), a delivery mechanism, and a nozzle (through which the filament can be printed).

[0453] The nozzle of a fully integrated barrel is suitably selectively heatable, suitably via a heat source external to the barrel (although in some embodiments, the barrel may contain its own internal heating mechanism). In a particular embodiment, the barrel and / or printer are configured (suitably in a complementary manner) to enable a heater located inside (or associated with) the printer to heat the nozzle (suitably in a selectively controllable manner to a predetermined temperature). Therefore, the nozzle suitably comprises a thermally conductive material (e.g., steel) (or is made of it) to facilitate its selective heating. In a preferred embodiment, the nozzle is configured to receive a plug that can be inserted therein to seal (and optionally treat, e.g., lubricate) the nozzle head.

[0454] Such barrels of the present invention are particularly advantageous because they reduce cross-contamination between fibers and, through self-sacrifice, reduce undesirable wear on printer components (especially vulnerable components, such as printer nozzles, which may otherwise become prone to clogging by a particular type of filament).

[0455] Methods for preparing printing filaments containing active ingredients

[0456] Appropriately, printing filaments containing active ingredients are prepared by methods as defined herein.

[0457] In some embodiments, printing filaments containing active ingredients are prepared by first producing filaments without active ingredients, but which contain an active ingredient carrier and optionally any other components as defined herein with respect to printing filaments containing active ingredients, and then incorporating the active ingredient into the filament or coating the active ingredient onto (or embedding the active ingredient therein) the filament surface or into the exposed pores of the filament. However, this often results in a non-uniform distribution of the active ingredient throughout the filament and frequently excludes high drug loading.

[0458] In a preferred embodiment, the active ingredient-containing printing filament is prepared by mixing all relevant filament components together (optionally, except for a plasticizer, which may be applied in-situ to the surface of the post-produced filament during printing), and forming the active ingredient-containing printing filament directly from the mixture, suitably via extrusion (such as hot melt extrusion).

[0459] The method appropriately involves loading all relevant components of a printing filament containing the active ingredient into a hot melt extruder, preferably in powder / solid form, to form a hot melt mixture. The hot melt mixture is then appropriately heated for a suitable time (e.g., 1-10 minutes) at a “mixing temperature” (T1) (optionally mixed simultaneously or otherwise stirred) before extrusion. The mixing temperature (T1) is typically between 70°C and 150°C (more preferably 110°C-130°C or 115°C to 135°C), but will depend on the active ingredient carrier and other components in the hot melt mixture. The heated melt mixture is then extruded (appropriately via an extrusion nozzle) at a “processing temperature” (T2) suitable for achieving a torque between 0.1 Nm / screw and 2.0 Nm / screw, more appropriately between 0.3 Nm / screw and 1.0 Nm / screw, and more appropriately between 0.5 Nm / screw and 0.7 Nm / screw (appropriately using a counter-current extruder, appropriately setting a speed of approximately 50 rpm to 200 rpm). The processing temperature (T2) is appropriately lower than the mixing temperature (T1), appropriately between 10°C and 50°C, appropriately between 10°C and 25°C, more appropriately between 20°C and 30°C, and therefore the processing temperature is appropriately between 40°C and 130°C (more appropriately 90°C to 110°C), and appropriately between 105°C and 125°C. Appropriately, the processing temperature (T2) is between 30°C and 90°C lower than the printing temperature (T3), more appropriately between 50°C and 70°C lower, which is ultimately used to produce solid dosage forms from the corresponding filaments.

[0460] The hot melt mixture is appropriately extruded via a hot melt extrusion nozzle. The hot melt extrusion nozzle appropriately has a nozzle size (or output diameter) between 0.4 mm and 3.0 mm, most appropriately between 0.9 mm and 2.1 mm. Since the filament may sometimes expand or contract upon cooling, a nozzle size between 0.9 mm and 1.4 mm is most preferred (appropriately to allow for post-extrusion expansion). Most appropriately, the nozzle size is selected to provide cooled filaments with a diameter within the preferred range (see above). The hot melt extrusion nozzle appropriately operates with a torque between 0.1 Nm / screw and 2.0 Nm / screw, more appropriately between 0.3 Nm / screw and 1.0 Nm / screw, more appropriately between 0.5 Nm / screw and 0.7 Nm / screw, appropriately about 0.6 Nm / screw. The extruded filament is then appropriately received on a non-sticky surface (e.g., Teflon). The extruded filament is then cooled.

[0461] The mixing temperature is appropriately high enough to allow the filament to be extruded, but low enough to avoid unacceptable degradation of the active ingredient and / or any excipients (pharmaceutically) at the relevant filament feed rate (those skilled in the art will understand that the active ingredient will generally tolerate higher temperatures if the heat exposure time is short, as is typically the case in the printing process of this invention).

[0462] Other printing filaments and compositions

[0463] The associated printing apparatus may include one or more additional printing filaments in combination with the active ingredient-containing printing filament. Since the principles applicable to the active ingredient-containing printing filament generally apply equally to the additional printing filaments, suitably, any additional printing filament may be defined in exactly the same manner as the active ingredient-containing printing filament. Any additional printing filament suitably contains substantially or completely no active ingredient, but in some embodiments, one of the additional printing filaments may optionally contain another active ingredient. Therefore, any additional printing filament suitably comprises or substantially consists of: one or more carriers as defined herein with respect to the active ingredient-containing printing filament (including any carriers defined herein as active ingredient carriers), diluents, and / or excipients (including plasticizers).

[0464] Most appropriately, additional printing filaments are used in combination with filaments containing active ingredients to adjust or enhance the properties of the final formulation. Appropriately, the additional printing filaments provide additional (and optionally different) carriers, diluents, and / or excipients for those already present in the printing filaments containing active ingredients.

[0465] Any other printing filament may contain any, some, or all of the components (or even parameters, such as glass transition temperature, filament thickness, etc.) described herein with respect to printing filaments containing active ingredients, even if the appropriate active ingredient is not present. A technician will be able to readily adjust the specific proportions of the components accordingly (the figures given for printing filaments containing active ingredients can be adjusted proportionally, or the weight ratio of the components can be readily deduced).

[0466] Similar to the active ingredient-containing printing filament, any additional printing filament can be supplied as part of a filament spool having any or all of the characteristics stated regarding active ingredient filament spools. Furthermore, any additional printing elements can be formed using the same methods as those used to form the active ingredient-containing printing filament.

[0467] Any methods and / or apparatus defined herein with respect to printing filaments containing active ingredients can be equally applied to other printing filaments, including nozzle operating temperature and the like. Those skilled in the art can readily and prudently modify filament manufacturing and / or printing conditions to suit the properties of a given additional printing filament.

[0468] Appropriately, when additional printing filaments are involved in the formation of a solid dosage form, the solid dosage form may still be defined herein as a solid dosage form as a whole (e.g., regarding the prescribed proportions of the components), or the core of the solid dosage form (e.g., in the production of a core-shell arrangement) may instead be defined in accordance with any or all of the definitions set forth herein regarding a solid dosage form as a whole.

[0469] Using multiple filaments for printing is very similar to using different colors in a 3D printer. Therefore, a printing apparatus can be operated to print a solid formulation incorporating both a filament composition containing active ingredients and one or more other filament compositions. The pattern and / or distribution of each filament composition is appropriately determined by a predetermined design to be printed.

[0470] In a particular embodiment, additional printing filaments are used in combination with printing filaments containing active ingredients to produce a core-shell formulation that suitably has a core formed (mainly) by printing / extrusion of printing filaments containing active ingredients, and a shell formed (mainly) by printing / extrusion of additional printing filaments.

[0471] Suitablely, when the solid dosage form is a core-shell dosage form, the shell is suitably formed from additional printing filaments containing (optionally combined with plasticizers) one or more HPMC-AS polymers.

[0472] Therefore, additional printing filaments can be used for printing to alter the release properties of the active ingredient in the final solid dosage form. Example

[0473] Example 1 - Printing of a design using commercially available soluble PVA filament experimental tablets

[0474] 1.1 Materials and Equipment

[0475] Prednisolone was purchased from Severn Biotech Ltd, UK. Polyvinyl alcohol (PVA) filament (melting point: 160℃-170℃, specific heat: 0.4 Cal / g℃, density: 1.25 g / cm³) 3 -1.35g / cm 3 The following were purchased from Reprapcentral (UK). Glycerin, acetonitrile, and methanol were supplied by British Drug Houses (BDH) (London, UK). Castor oil was purchased from Sigma-Aldrich (St. Louis, USA). Oleic acid was obtained from VWR (Radnor, USA). The 5mm Scotch blue painter's tape was supplied by 3M (Bracknell, UK).

[0476] Using MakerBot The 2X Experimental 3D printer (MakerBot Industries, LLC, New York, USA) is used to print blank PVA tablets (i.e., tablets without any active ingredients).

[0477] Blank tablets (PVA only) were printed using the default settings for the software used for PLA filament, as follows: Printer type: Replicator 2X; Filament type: PLA; Resolution: Standard; Nozzle temperature: 230°C; Build plate temperature: 20°C; Extruder speed: 90 mm / s during extrusion and 150 mm / s during travel; Fill: 100%; Layer height: 200 μm; Number of shells: 2. No supports or rafts were used during printing. No further modifications were implemented.

[0478] 1.2 Research Overview

[0479] First, the feasibility of using 3D printing methods to print tablets for oral administration was explored through model studies. This involved the production and research of various homogeneous and core-shell model tablets. Subsequently, attempts were made to "load" different drug molecules into model polyvinyl alcohol (PVA) filaments.

[0480] 1.3 Experiment 1A - Using the default red acrylonitrile butadiene styrene (ABS) filament provided by Makerbot to uniformly... Experimental printing of tablet design

[0481] Blank tablets (ABS only) were printed using the default settings for the software used for ABS filament, as follows: Printer type: Replicator 2X; Filament type: PLA; Resolution: Standard; Nozzle temperature: 230°C; Build plate temperature: 20°C; Extruder speed: 90 mm / s during extrusion and 150 mm / s during travel; Fill: 100%; Layer height: 200 μm; Number of shells: 2. No supports or rafts were used during printing. No further modifications were implemented.

[0482] Figure 1 (a) and Figure 1 (b) shows top and bottom projections of ABS-based model tablets produced using ABS filaments.

[0483] 1.4 Experiment 1B Experimental printing of core-shell tablet design as a reference for enteric-coated tablets or core-shell storage systems The model of the core-shell reservoir system uses red and white ABS filaments provided by Makerbot.

[0484] Blank core-shell model tablets (white and red ABS only, with a red core and a white shell) were printed using the default settings for the software used for ABS filament, as follows: Printer type: Replicator 2X; Filament type: ABS; Resolution: Standard; Nozzle temperature: 250°C; Build plate temperature: 100°C; Extruder speed: 90 mm / s when extruding and 150 mm / s when traveling; Fill: 100%; Layer height: 200 μm; Number of shells: 2. No supports or rafts were used during printing. No further modifications were implemented.

[0485] Figure 2 (a) and Figure 2 (b) shows top and bottom projections of ABS-based core-shell model tablets produced using white and red ABS filaments. Note that the ABS filaments lack flexibility when forming the film layer.

[0486] 1.5 Experiment 1C - Experimental printing of homogeneous core-shell disc tablets using PVA filaments

[0487] Blank tablets (PVA only) were printed using the default settings for the software used for PLA filament, as follows: Printer type: Replicator 2X; Filament type: PLA; Resolution: Standard; Nozzle temperature: 230°C; Build plate temperature: 20°C; Extruder speed: 90 mm / s during extrusion and 150 mm / s during travel; Fill: 100%; Layer height: 200 μm; Number of shells: 2. No supports or rafts were used during printing. No further modifications were implemented.

[0488] Figure 3 Top projections of several PVA-based disc-shaped homogeneous model tablets produced using PVA filaments are shown.

[0489] Figure 4 A top projection of a PVA-based disc-shaped core-shell model tablet produced using PVA filaments and its open cross-section is shown.

[0490] 1.5 Experiment 1D – Loading various drugs onto PVA filaments using various solvents and printing tablets together with them.

[0491] Before attempting to manufacture various custom-designed drug-loaded filaments for testing, the inventors explored the possibility of using default filaments, such as commercially available PVA filaments, to evaluate drug release properties. Commercial PVA filaments were chosen because PVA is widely used in the pharmaceutical industry and is considered a promising model for tablets or sustained-release implants.

[0492] The ability to form drug-loaded filaments was evaluated using different drug-loaded solvents (i.e., solvents in which the relevant drug is dissolved and in which drug-free PVA filaments are impregnated). Acetone, ethanol, and water caused the filaments to break completely. However, methanol maintained the integrity of the filaments. Therefore, methanol is considered the preferred solvent for drug-loaded PVA filaments.

[0493] Different drug compounds were used to evaluate their ability to be incorporated into PVA filaments after prolonged incubation. Prednisolone, dipyridamole, or diclofenac potassium were selected as model drug candidates. In each case, after immersing / incubating the PVA filaments in a methanol solution of the corresponding drug, the drug content was found to be approximately 2% by weight of the dry filaments.

[0494] Figure 5 (a) Figure 5 (b) and Figure 5 (c) Projection diagrams of PVA filaments treated with methanol, PVA filaments loaded with prednisolone, and PVA filaments loaded with dipyridamole are shown respectively.

[0495] Prednisolone was chosen as the drug model due to the need for low doses (up to 60 mg per day) and a wide dose range. Methods for optimizing drug loading are summarized in Example 2.

[0496] Then, model tablets were printed using PVA-based printing methods outlined in this paper with PVA filaments loaded with prednisolone.

[0497] Figure 6 A top projection of a PVA model tablet loaded with prednisolone is shown. Note that a better tablet finishing is achieved by printing at 250°C instead of 220°C.

[0498] 1.6 Conclusions from Example 1

[0499] These experiments help optimize the design and direction of 3D printing of tablets.

[0500] It has been recognized that in order to successfully print PVA-based tablets, especially PVA-based tablets with a core-shell structure, several modifications are ideally required, including increasing the nozzle temperature and, where possible, plasticizing with plasticizers such as glycerol.

[0501] It is noted that incubation in a saturated methanol solution resulted in 2% drug incorporation in the PVA filaments.

[0502] In the subsequent experimental model used to evaluate the drug release properties, prednisolone was chosen.

[0503] Example 2 - Control of drug dosage in 3D-printed tablets and physical and in vitro characterization of the product

[0504] 2.1 Research Overview

[0505] In this embodiment, the inventors examined the ability of a 3D printer to control the drug loading (i.e., dosage) of a tablet by controlling the volume of the printed solid dosage form. Furthermore, the inventors evaluated the drug loading level within the formed tablet and the accuracy of drug administration.

[0506] Typically, the same materials and equipment as those described in Example 1 are used, but with the modifications described below.

[0507] 2.2 Modifications to Experiment 2A-3D Printer

[0508] The following modifications were made before printing PVA tablets loaded with prednisolone:

[0509] a) The default Kapton tape layer provided poor adhesion to the build platform design. Therefore, this tape was replaced with blue Scottish Painter tape applied to the surface of the build platform to improve adhesion to the surface layer.

[0510] b) The drug-loaded PVA filament is relatively less flexible than the corresponding blank PVA filament from which the drug-loaded filament is formed. Therefore, the 3D printer was modified to introduce a plasticizing station upstream (i.e., before) the filament supplied to the extrusion nozzle. Castor oil, oleic acid, and glycerin were all tested as plasticizers. Figure 7 As shown in Figures (a) and (b), a plasticizing station is constructed, which serves as a special cover through which the filaments can pass. Figure 7 (a) and Figure 7(b) illustrates a special cap (or plasticizing station) that dispenses plasticizer from a fabric pre-soaked in plasticizer onto the filament as it passes through the print nozzles inside the 3D printer. Inside the cap is fabric (or other suitable absorbent material) already pre-soaked in plasticizer (in this case, glycerin), against which the filament must pass through the cap. As the filament passes through the cap, it comes into contact with the pre-soaked fabric and becomes impregnated and / or coated with the plasticizer dispensed from the fabric. This can be used to lubricate the filament before it is drawn into the printer. The quality of the tablets is visually compared, and glycerin is selected as the plasticizer.

[0511] c) Increase the temperature of the extrusion nozzle (i.e., the printing nozzle) from 230°C to 250°C to maintain a constant flow of the prednisolone-loaded PVA filament.

[0512] Print PVA tablets loaded with prednisolone using the previously outlined protocol, except that the extrusion nozzle temperature is increased to 250°C.

[0513] 2.3 Experiment 2B - Preparation of PVA filaments loaded with prednisolone

[0514] PVA filaments were loaded with prednisolone by incubating them in methanol at 30°C for 24 hours with a saturated solution of the drug. The filaments were then dried in an oven at 40°C and weighed every hour until the weight stabilized. Other solvents, such as ethanol and acetone, have a degradative effect on the original filaments or poor loading efficiency, and are considered unsuitable for the loading process.

[0515] Three representative samples (100 mg each) of PVA loaded with prednisolone were sonicated in 100 ml of methanol and water (using the same procedure described in the next section regarding the evaluation of prednisolone content in drug-loaded PVA filaments and printed tablets), and then evaluated using the same HPLC method detailed in the next section (i.e., Section 2.4). The percentage of drug loading in the filaments was calculated as shown in Table 1 below:

[0516] Table 1 - Drug loading results (in triplicate)

[0517]

[0518] 2.4 Experiment 2C - Determination of drug loading in tablets

[0519] To assess the prednisolone content in drug-loaded filaments and printed tablets, the following procedure is used. This procedure can be easily modified to assess the filaments, as described in the preceding section.

[0520] Each tablet was weighed and transferred to a 500 mL volumetric flask. Each tablet was then sonicated with 150 mL of distilled water for 1 hour, followed by the addition of 500 mL of methanol, and the entire mixture was then sonicated at 50 °C for another 4 hours. After cooling to room temperature, the sample was filtered through a 0.22 μm Millex-GP syringe filter (Merck Millipore, USA) for HPLC analysis.

[0521] Prednisolone concentrations were established by HPLC analysis using an Agilent HPLC 1260 series (Agilent Technologies, Inc., Germany) equipped with a Kinetex C18 column (100 × 2.1 mm, using C18 with a particle size of 2.6 μm (Phenomenex, Torrance, USA)). A mobile phase consisting of acetonitrile and water was used at a flow rate of 0.5 mL / min, with gradient concentrations (Table 2). The injection volume was 40 μl, and the UV detector was set to an absorption wavelength of 250 nm. The column temperature was 45 °C, and the stop time for each sample was 14 min.

[0522] Table 2. Gradient overview of HPLC methods for the detection of prednisolone

[0523]

[0524] 2.5 Experiment 2D Tablet Design and Printing Process

[0525] use 3ds Design 2012 software version 14.0 (Autodesk, Inc., USA) designs blank and drug-loaded PVA tablets as elliptical shapes and saves them in STL format. Figure 8 ).

[0526] Figure 8 (a) Figure 8 (b) and Figure 8 (c) Schematic top projection, side view and plan view of the tablet design are shown respectively.

[0527] The design was imported into the 3D printer's software, MakerWare version 2.4.0.17 (Makerbot Industries, LLC., USA). A series of tablets with different volumes were printed by modifying the dimensions of the design: length x width x height (L, H, W) without changing the proportions between these dimensions.

[0528] Promising results enabled the printing of tablets with the following target drug doses: 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, and 10 mg. Volumes and dimensions were calculated and are shown in Table 3. The measured tablet mass was similar to the theoretical mass of the product.

[0529] Table 3: Mass, Theoretical Dose, and Measured Dose of PVA Tablets Loaded with Prednisolone

[0530]

[0531] Figure 9 Top projection images of several tablets are shown, with the top row showing PVA tablets loaded with prednisolone at the corresponding prednisolone doses of 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, and 10 mg; and the bottom row showing blank PVA-only tablets of the same size as the tablets corresponding to the 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, and 10 mg doses in the top row. Due to modifications made to the printing process, the amount of prednisolone-loaded tablets is similar to that of the blanks.

[0532] Figure 10 A graph illustrating the linear correlation between theoretical volume and the mass of a printed default (drug-free) PVA tablet is shown.

[0533] Figure 11 A graph illustrating the linear correlation between theoretical volume and the mass of printed PVA tablets loaded with prednisolone is shown.

[0534] To correlate the design volume with the mass of the printed tablets, a series of tablets with increased weight were printed. Figure 9 (Bottom row). A good correlation was established, and the "measurement coefficient" was calculated as R. 2 =0.9996, such as Figure 10 As shown. This demonstrates that this volumetric modeling has the ability to control print quality. When a similar tablet series (such as...) Figure 9 When printing with tablets loaded with prednisolone (as shown in the top row), the same correlation is maintained (R). 2 =0.9983), such as Figure 11 As shown. Therefore, it is possible to use this equation to design drugs with appropriate tablet weights (to achieve the target dose).

[0535] Compare the theoretical dose and the measured dose of prednisolone (as shown in Table 4).

[0536] Table 4: Mass, Theoretical Dose, and Measured Dose of PVA Tablets Loaded with Prednisolone

[0537]

[0538] Figure 12A graph illustrating the relationship between the target dose and the dose achieved in a prednisolone-loaded tablet is shown.

[0539] The dose accuracy tested here ranged between 88.70 ± 0.79 for 10 mg tablets and 107.71 ± 9.96 for 3 mg tablets. The relationship between the target dose and the achieved dose is as follows: Figure 12 As shown in the image.

[0540] The value of the determination coefficient (R) 2 =0.9905), such as Figure 12 As shown, it is possible to prepare tablets with a desired dose of prednisolone.

[0541] 2.6 Experiment 2 Surface Morphology Analysis of E-filament, Printer Extrudate and Tablet

[0542] The surface morphology of the initial PVA filament, the 3D printer extrudate, and the printed tablets was evaluated using a Quantac-200 SEM microscope at 20 kV. Samples were placed on metal stubs and vacuum-plated with gold for 2 minutes using a JFC-1200 fine coating machine (Jeol, Tokyo, Japan).

[0543] Figure 13 SEM images of a) surface view and b) cross-sectional view of default PVA filament (PVA only) are shown; and SEM images of c) surface view and d) cross-sectional view of PVA filament loaded with prednisolone are shown.

[0544] Figure 14 SEM images of PVA after extrusion from the nozzle of a fused deposition modeling 3D printer are shown at a) 1000 μm magnification and b) 50 μm magnification.

[0545] Figure 15 SEM images of the sides of PVA tablets loaded with prednisolone are shown at different magnifications: a) at 2000 μm; b) at 200 μm; c) at 20 μm.

[0546] Figure 16 SEM images of the top surface of a PVA tablet loaded with prednisolone are shown at different magnifications: a) at 1000 μm; and b) at 100 μm.

[0547] Figure 17 SEM images of cross-sections of PVA tablets loaded with prednisolone are shown: a) overall view; b) magnified view of the peripheral structural domain; and c) magnified view of the central structural domain.

[0548] Initial SEM images of the prednisolone-loaded PVA filament (1.75 mm) showed a smooth surface. However, after extrusion through the nozzle of a 3D printer at 250°C, the surface of the extruded filament (200 μm) appeared generally rough, with irregular pores and voids between layers, likely due to rapid moisture and other solvent evaporation following rapid exposure to high temperatures.

[0549] SEM images of the PVA surface loaded with prednisolone show an irregular and rough surface with partially melted filaments. One side of the tablet shows a coating of filaments approximately 200 μm in height. This indicates minimal compression after printing. When evaluating the internal portion of the 50% printed layer, the orientation of the melted filaments differs between the peripheral and central structural domains.

[0550] 2.7 Experiment 2F - Evaluation of the crystallinity of prednisolone in drug-loaded tablets

[0551] The crystallinity of prednisolone in drug-loaded tablets was evaluated using a powder X-ray diffractometer with a Lynxeye D2 Phaser (Bruker, Germany). Samples were scanned over 30 minutes using a scintillation counter with scan type coupled to 2θ / θ from 2θ = 5° to 50°.

[0552] Figure 18 The spectra obtained from powder X-ray diffraction are shown for default prednisolone (top spectrum), PVA filament (middle spectrum), and PVA filament and tablet loaded with prednisolone (bottom spectrum).

[0553] Prednisolone exhibits peaks at 2θ = 8, 14, and 18.6. The absence of such peaks indicates that most prednisolone exists in an amorphous form.

[0554] 2.7 Experiment 2G - Thermal analysis by differential scanning calorimetry (DSC)

[0555] A Mettler Toledo DSC823e DSC (Mettler, Switzerland) was used for thermal analysis. In each case, approximately 5 mg of sample was accurately weighed and placed in a 40 μL standard aluminum dish for DSC analysis. Analysis was performed under a nitrogen atmosphere (50 mL / min). To eliminate the influence of moisture, the sample was heated to 100 °C for 5 min and then cooled to -20 °C at 10 °C / min. Thermal scans were then performed from -20 °C to 300 °C at 10 °C / min. All samples were tested in triplicate. This method is suitably specific for the determination of glass transition temperature.

[0556] Figure 19The DSC temperature records for prednisolone (top spectrum), default PVA filament (middle spectrum), and PVA tablet loaded with prednisolone (bottom spectrum) are shown.

[0557] 2.8 Experiment 2H - Drug release study using flow-through dissolution

[0558] The flow-through cell (Sotax, Switzerland) dissolution apparatus used in this study is an open-loop system through which fresh solvent (maintained at 37 ± 0.5 °C) is continuously passed from the reservoir through the cell. This is connected to a piston pump and a fraction collector (Sotax, Switzerland). During the study, a 12 mm diameter cell containing 5 mm glass beads was used. Filtration was performed using a 25 mm glass microfiber filter disc (FG / B) (Whatman, US) placed on the cell. Prednisolone-loaded tablets were analyzed using a dissolution medium of pH 1.2 (0.1 M HCl) for 2 hours, followed by analysis for an additional 22 hours using phosphate-buffered saline (pH 6.8). A flow rate of 8 ml / min was used, and samples were collected in a Sotax fraction collector at time intervals of 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 15, 18, 21, and 24 hours. The samples were further filtered through a 0.22 μm Millex-GP syringe filter (MerckMillipore, USA) for HPLC analysis (Section 2.5). The strength of each tablet was evaluated in triplicate.

[0559] Figure 20 This is a graph showing the time versus prednisolone concentration for 3D-printed PVA tablets during a flow dissolution test with pH variation.

[0560] Figure 21 This is a diagram illustrating the in vitro release pattern of prednisolone from 3D-printed PVA tablets using a pH-varying flow dissolution system.

[0561] Prednisolone was chosen as a model drug due to its high thermal stability, neutral properties, and wide dosage range. All prednisolone tablets studied exhibited similar release profiles. Figure 20 and Figure 21Interestingly, the first two hours showed a faster rate of drug release compared to the intestinal phase (pH 6.8). Most of the drug release (>80%) occurred after 12 hours for 2 mg and 3 mg tablets, and after 18 hours for tablets with doses of 4 mg, 5 mg, 7.5 mg, and 10 mg. For tablets with 2 mg and 3 mg loadings, approximately 100% of prednisolone release was reached within 16 hours. However, after a 24-hour test, nearly 85% of the initial amount of prednisolone was released for 4 mg, 5 mg, 7.5 mg, and 10 mg tablets, and 100% for 2 mg and 3 mg. This may be related to the smaller surface area / mass of the larger tablets, which increases tablet diffusion and delays erosion.

[0562] 2.9 Conclusions from Example 2

[0563] The quality of printed tablets can be controlled by controlling the volume of the design.

[0564] By controlling the weight of the printed design, the final dosage can be controlled.

[0565] The accuracy of dose control is between 88.7% and 107%.

[0566] Based on DSC and XRPD analysis, prednisolone may exist in an amorphous form within the tablet.

[0567] The sustained-release pattern of tablets suggests that drug release occurs through a combination of erosion and diffusion mechanisms.

[0568] Therefore, controlling drug release by controlling the designed volume has been reliably validated.

[0569] Example 3 - Development of Pharmaceutical-Grade Filaments for 3D Printing

[0570] Numerous experiments were conducted in the development and optimization of pharmaceutical-grade filaments. The following experiments elucidate some key considerations in the preparation of pharmaceutical-grade filaments and the solid dosage forms printed from them. Clarifying these fundamental considerations helps technicians utilize a wealth of knowledge to develop a wide range of pharmaceutical formulations with various drugs, excipients, and release profiles. For example, subsequent experiments enabled the preparation of solid dosage forms with immediate-release, sustained-release, and delayed-release properties.

[0571] 3.1 Preparation of Experiment 3A-filament

[0572] Printed filaments containing active ingredients (those that do indeed contain active ingredients, typically pharmaceuticals in these examples) and other printed filaments (which do not necessarily contain active ingredients) are prepared via a hot melt extrusion process. This process typically involves first mixing the relevant components (e.g., pharmaceuticals, carriers, and optional plasticizers) in a hot melt extruder at a suitable temperature (T1 – mixing temperature) adapted to the mixture in question (i.e., allowing fluid mixing) to obtain a substantially homogeneous mixture, and then extruding the mixture through a heated filament-forming nozzle (with the desired size / diameter, N1) at a suitable temperature (T2 – processing temperature) adapted to the mixture and reaching the required torque. The filaments are extruded from the filament-forming nozzle using a counter-current extruder, which rotates at a suitable speed to produce filaments with the desired properties. The filaments are typically dispensed into Teflon. TM The coating is applied to the surface and stored in a plastic bag before being used for 3D printing.

[0573] Typically, approximately 7g (total formulation mass) of the formulation is accurately weighed—for example, to achieve an 80:20 polymer-to-drug ratio, 5.6g of polymer and 1.4g of drug are weighed. The resulting weighed formulation is then manually loaded into a HAAKE MiniCTW hot melt extruder, where the formulation is allowed to mix at an appropriate mixing temperature (T1—typically 110°C–130°C) to adapt the mixture and allow substantial homogenization prior to extrusion for at least 5 minutes. The counter-current extruder is set to 100 rpm. After proper mixing, the mixture is extruded from a heated filament-forming nozzle at an extrusion temperature (T2—typically 90°C–110°C), suitable for achieving a torque of approximately 0.6 Nm / screw (extrusion temperature T2 is typically 20°C–30°C lower than preparation temperature T1, i.e., T1–T2 = between 20°C and 30°C). Extrusion is performed using torque control at 0.6 Nm / screw and with different nozzle sizes (0.5 mm–2.0 mm). The extrudate is received on a Teflon-coated conveyor belt and stored in plastic bags until it is used as filament for 3D printing.

[0574] In the presence of a drug, the resulting filaments typically exhibit a substantially uniform distribution of the drug within the carrier / polymer matrix. The drug loading within the filaments is typically 10 wt% or more, and usually 60 wt% or less.

[0575] The target diameter of the filament (i.e. its thickness) is approximately 1.75 mm, as this diameter is most compatible with the 3D printers currently in use.

[0576] After the polymer is thermally extruded into filaments, they are used as filaments (inks) for 3D printing of tablets.

[0577] Specific embodiments and results relating to both the filament and the printing formulation are provided below. However, the following components are used in the formation of the filament described above:

[0578] Active ingredients:

[0579] The drugs used in the drug-infused silks were either drug A: dipyridamole (mp 163℃; water solubility 9.22e-01g / L; 25mg-75mg tablets); or drug B: theophylline (mp 273℃; water solubility 7360mg / L at 25℃; 100mg-300mg immediate-release or sustained-release tablets). These drugs were within a good spectrum for these studies.

[0580] Active ingredient carrier:

[0581] Testing different carriers to evaluate the feasibility of various drug release modalities:

[0582] Immediate Release: Eudragit E, Eudragit NE, HPC SSL

[0583] Sustained-release: Eudragit RS, Eudragit RL, HPC SL, HPC M, and HPC H

[0584] Delayed release (i.e., enteric-coated formulations): Eudragit L100-55, Eudragit L100, Eudragit S100 and Aqoat LG, MG, HG (also known as AS-LG, AS-MG and AS-HG).

[0585] All carriers are commercially available. Eudragit carriers are acrylate polymers with different properties. HPC carriers are hydroxypropyl cellulose (HPC) polymers with different properties. Aqoat carriers are hydroxypropyl methylcellulose acetate-succinate (HPMCAS) polymers with different properties.

[0586] Plasticizer:

[0587] In some cases, plasticizers are used to optimize the melting and glass transition temperatures of the wire. In subsequent experiments, plasticizers used included glycerol, TEC, triacetin, and PEG400.

[0588] If necessary, use plasticizers to optimize the physical morphology of the filament. A glass transition temperature T that is too high... g The silk will be too brittle and will break during handling. On the other hand, if the silk's T... g If it's too low, the filament will be too flexible for loading through the nozzle of the 3D printer. Furthermore, using a filament with a low T... gThe filament may molten and extrude from the nozzle of a 3D printer. This can result in a poor shape of the final product. A skilled technician can well assess, based on the guidance provided in this application, whether, how much, and what type of plasticizer can be used to improve the quality and properties of the filament. Generally, the filament will appropriately have a sufficiently high TT. g To avoid the aforementioned drawbacks, and to allow for filament formation and printing at temperatures low enough to minimize any degradation of the ingredients (especially the active ingredients). This can be assessed using simple stability studies.

[0589] Other excipients:

[0590] Talc is sometimes used to improve the flow properties and shape of printed tablets. This is believed to be due to the lubricating effect provided by talc, which reduces friction between the filament and the printing nozzle. It also provides non-melting particles at the relevant processing temperature, which can be very advantageous.

[0591] Fillers (such as lactose) can be used in immediate-release formulations due to their high water solubility. They can increase tablet size and also provide non-melting particles in the filament at processing temperatures.

[0592] 3.2 Experiment 3B - Printing 3D tablets with filament

[0593] Based on the previous section, use 3ds Design 2012 software version 14.0 (Autodesk, Inc., USA) designs blank and drug-loaded tablets as elliptical shapes and saves them in STL format. Figure 8 The design was imported into the 3D printer's software, MakerWare version 2.4.0.17 (Makerbot Industries, LLC., USA). A series of tablets with different volumes were printed by modifying the dimensions of the design: length x width x height (L, H, W) without changing the proportions between these dimensions. The 3D printer was modified to print filaments as described in the previous section (2.2). Other variations in 3D printing or its operation are illustrated in the examples below. For example, the printing temperature (T3) is varied according to the composition of the filament in question, as are the mixing temperature (T1) and processing temperature (T2) during the relevant filament formation. Typically, the printing temperature (T3) is 50°C–70°C higher than the processing temperature (T2). The printing / extrusion nozzle typically has a diameter / size (N2) of approximately 200 μm.

[0594] 3.3 Experiment 3C - Based on various embodiments in Sections 3.1 and 3.2

[0595] Table 5 (below) provides details of several experiments on filament formation (and in some cases, filament printing). Weight percentage values ​​associated with a particular component are based on the total weight of the associated filaments in wt%. Any proportion (e.g., if multiple carriers are given) is appropriately a weight ratio.

[0596] The main difference between this section and the previous two sections in the drug loading examples is that the drug (or active ingredient) is present from the outset (i.e., during filament formation), rather than being injected into the filament after it has already formed. This allows for much higher drug loading.

[0597]

[0598]

[0599] 3.4 Conclusions from Example 3

[0600] Printing appears to be more successful in terms of the final solid form when the filament contains a reasonable amount of high-melting-point particles (i.e., above the print nozzle temperature T3). These particles can simply be pharmaceutical particles or filler particles (such as lactose or talc). Interestingly, the presence of such particles during printing seems to produce a much better final solid form in terms of shape and integrity than the default filament from the 3D printer manufacturer. The absence of these particles typically leads to nozzle clogging, bubble formation during printing, or degradation of the polymer matrix.

[0601] Glass transition temperature appears to be important for successful filaments because the optimal glass transition temperature produces the best processing / printing temperature, which minimizes problems regarding the filaments formed and the final formulation.

[0602] Generally, the 3D printing temperature (T3) appears to be 50°C-70°C higher than the ideal filament preparation temperature (T2). 3D printers may require higher temperatures for printing than thermomelt extruders need during filament formation because the filament spends less time in contact with the nozzles in the 3D printer.

[0603] The most suitable plasticizer for Eudragit polymers appears to be TEC (triethyl citrate) (0.5%-30%), and triacetin appears to be optimal for cellulose-based polymers (0.5%-10%).

[0604] In the case of dual printing (2-color or core-shell structure), lower T g The polymer is most suitable because the filaments may remain in the nozzle for a long time at high temperatures (i.e., there is downtime when one filament is printed while the others are not).

[0605] Adding a high percentage of talc (>15%) may make the printed work more prone to detaching from the substrate during printing. Therefore, this may be the optimal amount.

[0606] Example 4 - Model Study of Theophylline (Model Drug) and Eudragit RL (Model Carrier Polymer)

[0607] Various modeling studies were conducted to explore the variables and parameters in the production of solid dosage forms from pharmaceutical-grade filaments. The following experiments elucidate further considerations in the preparation of pharmaceutical-grade filaments and the solid dosage forms printed from them. Clarifying these considerations helps technicians utilize a wealth of knowledge to develop a wide range of pharmaceutical formulations with various drugs, excipients, and release profiles. For example, subsequent experiments enabled the preparation of solid dosage forms with immediate-release, sustained-release, and delayed-release properties.

[0608] 4.1 Preparation of Experiment 4A-filament

[0609] Theophylline was purchased from Arcos (UK). RL100 (glass transition temperature (T) g ): 63℃+ / -5℃ and RS100 formulation (glass transition temperature (T) g (65℃) was generously donated by Evonik Industries (Darmstadt, Germany). Hydroxypropyl cellulose SSL grade was donated by Nisson. Triethyl citrate (TEC) and triacetin were provided by Sigma-Aldrich (UK). Scottish Blue Painter's tape 50mm was provided by 3M (Bracknell, UK).

[0610] Using MakerBot A 2X Experimental 3D printer (MakerBot Industries, LLC, New York, USA) was used to print theophylline tablets. To obtain new formulations, a hot melt extrusion method was implemented using a Thermo Scientific HAAKE MiniCTW (Thermo Fisher Scientific, Karlsruhe, Germany).

[0611] The composition and proportions of the drug, polymer, and plasticizer mixture are shown in Table 6 below. Carefully weigh approximately 6 g of the total mixture and gradually add it to a counter-current twin-screw extruder. Allow the molten material to mix for at least 5 minutes to ensure uniform distribution of the drug and polymer within the matrix. Then, extrude the molten material through a cylindrical die nozzle of appropriate diameter. Manually feed the sample into the extruder inlet using a funnel, setting the feed temperature and speed to 80 rpm as shown in Table 6. Set the mixing temperature to 120°C and the speed to 50 rpm. Extrude the filament at 120°C using a control torque of 0.6 Nm.

[0612] Store the filaments in a sealed plastic bag at room temperature before extrusion.

[0613] 4.2 Experiment 4B - Tablet Design and Printing

[0614] Blank and drug-loaded Eudragit RL are used 3ds Design 2012 software version 14.0 (Autodesk, Inc., USA) was used to design a typical capsule-like shape and saved in STL format. The design was imported into the 3D printer's software, MakerWare version 2.4.0.17 (Makerbot Industries, LLC., USA). A series of tablets with increasing volume were printed by modifying the dimensions of the design: length x width x height (L, H, W) without changing the proportions between these dimensions.

[0615] Table 6 - Processing parameters for filament production and subsequent 3D printing using HME

[0616]

[0617]

[0618] Using MakerBot A 2X Experimental 3D printer (MakerBot Industries, New York, USA) was used to print tablets based on the Eudragit HPC SSL. The tablets were printed using the default settings of the software used to produce the filament, as follows: Printer type: Replicator 2X; Filament type: PLA; Resolution: Standard; Nozzle temperature: 230°C; Build plate temperature: 20°C; Extruder speed: 90 mm / s during extrusion and 150 mm / s during travel; Infill: 100%; Layer height: 200 μm. No supports or rafts were used in the printed model.

[0619] In order to be able to print PVA tablets loaded with prednisolone, the following modifications were made:

[0620] i) The Kapton tape layer (default) provides poor adhesion to the build board. Apply Blue Scottish Painter tape to the surface of the print board to improve adhesion to the surface layer.

[0621] ii) As specified in Table 6, changing the extruder temperature during printing is crucial for maintaining a constant flow of theophylline-loaded filaments.

[0622] 4.3 Experiment 4C - Protocol for Analysis of Filaments and 3D Printed Tablets

[0623] 4.3.1 Determination of drug content

[0624] To assess the theophylline content in the printed tablets, each tablet was weighed and transferred to a 1000 mL volumetric flask. The tablets were sonicated with 0.1 M HCl to a final volume of 1000 mL for 4 hours, left overnight, and then sonicated for another 4 hours the following day. After cooling to room temperature, the theophylline drug content in the resulting solution was determined spectrophotometrically (Jenway, Japan). The absorbance was measured at 272 nm. For higher concentrations, 10 mL of the resulting solution was diluted with 0.1 M HCl to a final volume of 20 mL.

[0625] 4.3.2 Scanning Electron Microscopy

[0626] The produced filaments, the filaments extruded from the nozzle of the 3D printer, and the surface morphology of the printed tablets were evaluated using a Quantac-200 SEM microscope at 20 kV. Prior to imaging, the samples were placed on metal posts and vacuum-plated with gold for 2 minutes using a JFC-1200 fine coating machine (Jeol, Tokyo, Japan).

[0627] 4.3.3 X-ray powder diffraction

[0628] The crystallinity of theophylline in drug-loaded tablets was evaluated using a powder X-ray diffractometer with a Lynxeye D2 Phaser (Bruker, Germany). Samples were scanned from 2θ(2Theta)(2θ) = 5° to 50° using 0.01° steps and 1-second time counts. The divergence slit was 1 mm, and the scatter slit was 0.6 mm. An X-ray wavelength of 0.154 nm was used with a Cu source. The voltage used was 30 kV. Filament emission was 10 mA, and the scan type coupled with a 2θ / θ scintillation counter was used for over 60 minutes. Samples from the extruded filament and printed tablets were immersed in liquid nitrogen to aid the grinding process.

[0629] 4.3.4 Differential Scanning Calorimetry

[0630] Thermal analysis was performed using a differential scanning calorimeter (DSC) Q2000 (TA Instruments, Elstree, Hertfordshire, UK). Approximately 5 mg of sample was accurately weighed and placed in a 40 μL standard aluminum disk for DSC analysis. Analysis was conducted under a nitrogen atmosphere (50 mL / min). To eliminate the influence of moisture and obtain clearer T values... g The sample was cooled to -10°C and then heated to 100°C. The temperature was held isothermally for 5 minutes, then cooled to -20°C and left to stand for 2 minutes. Heating and cooling of the sample were performed at a rate of 10°C / min. This was followed by thermal scanning from -20°C to 300°C at the same rate. All measurements were performed in triplicate. Data were analyzed using TA2000 analysis software.

[0631] All samples were subjected to a heating / cooling / heating cycle to ensure accurate readings and drying of the polymer matrix. Samples were cooled to -20°C and held isothermally for 2 minutes, then heated to 100°C according to the heating sequence. Samples were held isothermally at 100°C for 5 minutes. This was followed by a cooling step back to -20°C. The temperature was held isothermally for 2 minutes. Finally, a heating step to 300°C was performed to determine the endothermic peak of theophylline (if present). All heating and cooling sequences were performed at a rate of 10°C / min.

[0632] 4.3.5 Thermogravimetric Analysis (TGA)

[0633] Thermogravimetric analysis (TGA) Q5000 (TA Instruments, Elstree, Hertfordshire, UK) is used to measure the thermal decomposition profiles of extruded filaments and printed tablets, in addition to raw materials.

[0634] Approximately 5-7 mg of sample was added to a peeled aluminum dish in the TGA apparatus. The sample was heated between 25°C and 600°C at a heating rate of 10°C / min. Data were analyzed using TA 2000 analysis software.

[0635] 4.3.6 In vitro drug release studies via pH change USP II dissolution test

[0636] In vitro drug release studies for all gastro-resistant coating formulations used in this study were conducted in a dissolution USP II apparatus (AT 7Smart, SOTAX, Switzerland). Each experiment was performed in triplicate in dissolution medium at 37°C ± 0.5°C at a paddle speed of 50 rpm. Tablets were tested in 750 mL of simulated gastric fluid (0.1 M HCl, pH 1.2) for 2 h, followed by exposure to phosphate buffer at pH 6.8 for 16 h. In all experiments, the amount of theophylline released was determined at 5-min intervals using a UV / VIS spectrophotometer (PG Instruments Limited, UK) at a wavelength of 272 nm and a path length of 1 mm. Data were analyzed using IDISis software (Automated Lab, 2012).

[0637] 4.4 Experiment 4D - Analysis Results and Discussion

[0638] 4.4.1 Phase 1: Control of theophylline dosage from Eudragit RL-based 3D-printed tablets

[0639] Using Eudragit RL tablets with increased volume, tablets with increased weight can be printed, and a linear relationship between volume and tablet weight can be established, as shown in Table 7. Figure 46 As shown in the image.

[0640] Figure 46 This is a graph showing the linear relationship between the theoretical printed volume and the re-obtained mass.

[0641] Table 7 shows the target and actual tablet weight, volume, and size.

[0642]

[0643] The equation was chosen to be used to print different tablets of theophylline with therapeutic doses: 60 mg, 124 mg, 200 mg, 250 mg, and 300 mg, as shown in Table 8.

[0644] The printed tablets exhibit a good morphology, having the following characteristics: Figure 47 The aesthetic quality shown is comparable to that of commercially available tablets.

[0645] When analyzing the drug content of the tablets, a linear relationship was found with the target dose (Table 8 and...). Figure 48 ).

[0646] When studying release profiles, slower release was observed for larger tablets due to the increased surface area. Figure 49 ).

[0647] Figure 47 An array of 3D-printed theophylline tablets with increased size and strength is shown.

[0648] Figure 48 This is a graph showing the linear relationship between the achieved dose and the expected dose of theophylline tablets.

[0649] Figure 49 This is a graph showing the in vitro release curves of theophylline from 3D tablets of different strengths.

[0650] Table 8 shows the target and actual theophylline doses in 3D-printed Eudragit RL-based tablets.

[0651]

[0652] 4.4.2 Phase 2: The Impact of Printing Resolution (Printing Speed)

[0653] Theophylline tablets were 3D printed at three different speeds: low resolution, standard resolution, and high resolution.

[0654] Table 9 provides details on their weight and printing time. Clearly, larger tablets require longer printing times. Low resolution and standard resolution appear to have similar printing times, while high resolution requires almost twice as long. The quality of the printed tablets and the variations reflected in SD appear to be similar across all three formulations. Figures 51-53 Provides SEM images of the printed tablets. When higher resolution is applied, the number of layers per height increases significantly.

[0655] Resolution settings appear to have little effect on the pattern of drug release from the tablet. Figure 50 ).

[0656] Figure 50 This is a graph illustrating the effect of 3D printing resolution on drug release patterns.

[0657] Figure 51 The image shows a low-resolution SEM image of a 3D-printed tablet of theophylline Eudragit RL.

[0658] Figure 52 SEM images of a theophylline Eudragit RL 3D-printed tablet are shown at standard resolution.

[0659] Figure 53 SEM images of a theophylline Eudragit RL 3D-printed tablet are shown at high resolution.

[0660] Table 9 shows the quality and 3D printing time of Eudragit RL-based tablets using low-resolution, standard-resolution, or high-resolution methods.

[0661]

[0662] 4.4.3 Phase 3: Modulating drug release using polymers based on other methacrylates and cellulose

[0663] To test the applicability of this method to modulate drug release from 3D-printed tablets, different polymers or mixtures of polymers were used instead of Eudragit RL. Details of the formulations and preparation methods are available in Table 6. Two immediately-release polymers, HPC SSL and Eudragit E, were applied. For sustained-release formulations, Eudragit RS was used. To test the possibility of controlling drug release, mixtures of Eudragit RL with Eudragit RS or Eudragit E were also investigated.

[0664] a. Immediately release the system

[0665] Achieving immediate release of theophylline in 3D-printed tablets using Eudragit E ( Figure 54 However, a slower drug release pattern was observed with SSL HPC tablets. In both embodiments, it was evident that drug release was slowed after 3D printing (compared to non-printed filaments). This could be due to the loss of surface area after printing. It is also possible that further heat treatment of the drug polymer filaments during printing increased drug-polymer interactions within the polymer matrix and reduced the chance of water uptake after the introduction of the dissolution medium.

[0666] Figure 54 This is a graph showing the drug release curves of Eudragit E filament (hollow rhombus), Eudragit E 3D printed tablet (solid rhombus), HPC SSL filament (hollow circle), and HPC SSL 3D printed tablet (solid circle).

[0667] b. Sustained-release system

[0668] Figure 55The diagrams shown are derived from the drug release profiles of: a) Eudragit RL:E filaments (hollow square), Eudragit RL:RS 1:1 (hollow rhombus), Eudragit RL (hollow triangle), and Eudragit RS (hollow circle); and b) 3D-printed tablets of the drug formulated with Eudragit RL:E (solid square), Eudragit RL:RS 1:1 (solid rhombus), Eudragit RL (solid triangle), and Eudragit RS (solid circle).

[0669] 4.4.4 Stage 4: The Impact of Fill Percentage

[0670] The effect of fill percentage on drug release pattern was investigated using SSL HPC tablets. Increasing the fill percentage allowed for the printing of tablets with the same size but increased weight (100% to 141.4% when the fill percentage increased from 10% to 100%).

[0671] The reduced fill percentage allows for the design of hollow tablets, which is impossible using conventional compression techniques. It also allows for the design of low-density systems that can float in the stomach and exhibit gastric-retentive properties. Figure 56 Drug release appears to be slightly increased for low-filling tablets due to the increased contact surface with the dissolution medium.

[0672] Figure 56 This is a graph showing the effect of infill settings on the quality of 3D-printed tablets.

[0673] Figure 57 This is a graph showing the effect of filling settings on theophylline release from 3D-printed HPC SSL tablets.

[0674] 4.4.5 Stage 5: Thermal and X-ray Analysis of 3D-printed Tablets

[0675] Eudragit RL tablets containing theophylline

[0676] TGA Analysis:

[0677] Thermogravimetric analysis was used to analyze the printed tablets in order to compare the thermal decomposition patterns of the printed tablets with those of the extruded filaments and raw materials.

[0678] Note that the pure polymer loses approximately 3% of its weight at 110°C, which is considered to be the polymer's moisture content. Figure 58 ).

[0679] The degradation pattern of the physical mixture revealed two degradation steps. The first degradation step, which began at approximately 200°C, represents the degradation of approximately 60% of the theophylline in the sample. On the other hand, the second degradation step, which began at approximately 340°C, represents the degradation of Eudragit RL. It can be noted that the degradation of theophylline in the physical mixture is steeper than that in the flakes or tablets, which may be related to the distribution and interaction of theophylline particles with the polymer matrix.

[0680] Figure 58 This is a graph showing the thermal degradation curves of theophylline, Eudragit RL, a physical mixture of theophylline and Eudragit RL, extruded filaments of theophylline and Eudragit RL, and tablets of theophylline and Eudragit RL.

[0681] DSC analysis:

[0682] The printed tablets reveal Eudragit's T g The temperature has been changed from approximately 70°C for pure polymers to approximately 46°C for extruded filaments and printed tablets. The Ta for polymers in printed tablets and extruded filaments... g The differences between them are minimal and negligible. Figure 59 ).

[0683] Figure 59 The glass transition temperature for Eudragit in the first heating step in the form of pure polymer, physical mixture with theophylline, extruded filament, and printed tablets.

[0684] The first heating step revealed that Eudragit's glass transition temperature did not vary significantly between the pure polymer CA 50°C and the extruded filament or printed tablet, but at T... g The scope has been significantly expanded.

[0685] On the other hand, the third heating sequence revealed the presence of an endothermic peak of theophylline at approximately 259°C in the printed tablet sample and 254°C for the extruded filament.

[0686] These peaks are expected to be from theophylline crystals, as the melting point of pure theophylline is 272°C. However, the impurity effect of the polymer causes this slight change in the endothermic melting process.

[0687] Figure 60 DSC scans of a physical mixture of theophylline, theophylline, and Eudragit, extruded filaments of theophylline and Eudragit RL, and printed tablets are shown.

[0688] Powder X-ray diffraction:

[0689] The diffraction pattern of theophylline-containing tablets reveals diffraction peaks at 7 Å, 12 Å, 14 Å, and 24 Å. E. et al., Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy. Journal of Pharmaceutical Sciences, 2001, 90(3): 389-396), the diffraction peaks matched the theophylline diffraction pattern. The same diffraction pattern appeared for filaments from hot melt extrusion and extruded from physical mixtures, and... Figure 61 It can be noted that the decreased peak intensity indicates that more theophylline is dissolved in the Eudragit RL polymer matrix.

[0690] Figure 61 The following X-ray diffraction patterns are shown: pure theophylline, pure Eudragit RL, a physical mixture of the two, extruded filaments, and printed tablets.

[0691] HPC SSL and theophylline printed tablets

[0692] TGA Analysis:

[0693] The thermal degradation profile of HPC SSL tablets containing theophylline revealed two additional degradation steps besides a weight loss of approximately 3% at around 110°C, presumably due to the evaporation of moisture from the polymer. The first thermal decomposition begins around 210°C and is associated with the thermal degradation of theophylline. This step results in a loss of approximately 60% of the total weight, consistent with the formulation concentration of the drug in the extruded filament or tablet. The second step begins around 330°C and is associated with the thermal degradation of the polymer. This degradation is associated with the thermal degradation of HPC SSL, as it is shown in... Figure 62 This can be noticed in the text.

[0694] Figure 62 The following thermal degradation curves are shown: pure theophylline, pure HPC SSL, physical mixtures, extruded filaments, and printed tablets.

[0695] DSC analysis:

[0696] The thermal profiles of SSL tablets revealed the Tg of the polymer. g From a slight variation of 63°C for pure HPC SSL to 46°C and 56°C for extruded filaments and printed tablets, respectively ( Figure 63 ).

[0697] Figure 63DSC scans showing the glass transition temperatures of a physical mixture of pure HPC SSL, theophylline, and HPC SSL, extruded filaments, and printed tablets are presented.

[0698] The final heating tests revealed an endothermic peak at around 262°C, which corresponds to the endothermic melting of theophylline. The variation in the endothermic melting of theophylline is likely due to the impurity effect of HPC on theophylline. It can be noted that there is a minimal difference in the endothermic melting of the extruded filament and the printed tablet. However, the difference is negligible. Figure 64 ).

[0699] Figure 64 The DSC scans show the endothermic melting of pure theophylline, HPC SSL, physical mixtures, extruded filaments, and printed tablets.

[0700] Powder X-ray diffraction from printed tablets and extruded filaments revealed four significant peaks for theophylline at 7 Å, 12 Å, 14 Å, and 24 Å. E. et al., Novel identification of pseudopolymorphic changes of theophylline during wet granulation using nearinfrared spectroscopy. Journal of Pharmaceutical Sciences, 2001.90(3): pp. 389-396) ( Figure 65 Therefore, both X-ray diffraction data and DSC analysis can confirm that all or part of theophylline still exists as crystalline particles.

[0701] Figure 65 The following X-ray diffraction patterns are shown: pure theophylline, HPC SSL, physical mixture, extruded filament, and printed tablet.

[0702] 4.5 Conclusion

[0703] The 3D printing process has proven to be universal, regardless of the specific methacrylic polymers used, such as Eudragit RL, Eudragit RS, and Eudragit E. HPC SSL polymers can also be used to print tablets. The use of our internal drug filaments maintains a linear relationship between mass and print volume and allows for effective dose control (R0). 2=0.9995) and dosage accuracy (91%-95%). High resolution doubles printing time but has little impact on release pattern and weight accuracy. Manipulating the fill percentage allows for dosage manipulation (40+%) and the formation of hollow tablets. Thermal analysis indicates that the potential amount of theophylline in 3D-printed tablets remains in crystalline form, where the percentage of crystallinity may be lower compared to non-printed filaments.

[0704] Example 5 - Disposable filament spool with integrated or associated nozzles

[0705] This embodiment employs an alternative 3D printer that, instead of having its own integral nozzle (which may be prone to clogging in some cases), is configured to receive and operate disposable filament spools with their own nozzles. In this embodiment, the nozzle and spool are integral; however, in other embodiments, the nozzle may be releasably secured (or releasably fixable) to the filament spool to allow the nozzle to be replaced (e.g., if it becomes clogged) without having to replace the entire spool.

[0706] This type of filament spool with nozzles can be used in situations where printer nozzle clogging would otherwise be an expensive and / or laborious problem to replace, fix, or clean (e.g., an integrated 3D printer nozzle can be expensive and difficult to replace and / or clean). Instead, cheaper disposable nozzles that are part of the spool can be preferred over other options.

[0707] The 3D printer itself may be specifically designed for releasably receiving and manipulating a nozzle-equipped barrel, or it may be a conventional 3D printer that has been carefully modified to releasably receive and manipulate such a barrel. Such modified 3D printers may require modifications such that the nozzle of the barrel is positioned substantially in the same location as the nozzle of the now-replaced printer. In light of this disclosure, those skilled in the art can readily modify conventional 3D printers to achieve this using standard workshop practices.

[0708] Figure 66 A filament spool with nozzles is shown that can be releasably fixed inside a 3D printer.

[0709] A filament spool with nozzles contains a drug filament 1a wound around a rotatable spool 11 within its body (which may be made of standard plastic material and / or suitable metal or alloy material). In this embodiment, the spool also has a humidity-controlled, sealed housing 10 through which the drug filament 1a can be conveyed from its spool. The housing 10 itself surrounds a conveying mechanism 12 (which in this embodiment includes built-in gears within the spool to allow the filament to be driven to the nozzle without exposing the filament to the external environment), which can be externally engaged and operated (e.g., via suitable mechanical contact and gear transmission), for example via a mechanical drive / gear mechanism 22 associated with the printer itself, to drive the drug filament 1a through the housing, toward and through the nozzle 30 without exposing the filament to the external environment or contacting internal components of the printer itself. The nozzle 30 itself is made of a thermally conductive material, such as steel. In this way, a heating mechanism 24 within the 3D printer can heat the nozzle (including the filament contained therein) so that the drug filament 1a can be easily extruded through and from the nozzle 30. When the nozzle 30 is not in use, it can be protected by a plug 32, which can be inserted into the end of the nozzle 30 to seal and lubricate the nozzle head.

[0710] The filament-to-nozzle delivery mechanism 12 is suitably configured and / or arranged to allow the mechanical drive / gear mechanism 22 to engage and (effectively and consistently) operate the delivery mechanism 12. In this particular embodiment, the gears 22 of the 3D printer surround and engage the gears of the delivery mechanism 12.

[0711] The nozzle 30 of the barrel is appropriately configured and / or set to allow the heating mechanism 24 within the 3D printer to heat the nozzle 30 to a pre-specified temperature (effectively and consistently).

[0712] In use, the relevant filament cartridge is installed inside the 3D printer (appropriately in a pre-specified docking position / station, the cartridge is configured relative to the printer components so that all relevant components can properly engage with each other), and the 3D printer is operated to heat the nozzle 30 via its own heating mechanism 24. Once the nozzle is at the correct temperature (appropriately verifiable using suitable sensors / detection features as described above), the 3D printer can operate according to a pre-programmed or manually operated printing cycle. During operation, the printer's mechanical drive / gear mechanism 22 is operated to engageably drive the conveying mechanism 12 within the filament cartridge, which in turn conveys the filament 1a from its spool to the nozzle 30. When the nozzle is at the appropriate temperature, the filament is transformed into a printable form (e.g., by softening and / or melting) before “printing.” The filament is conveyed and “printed” through the nozzle 30 until the 3D printing is complete. After printing, the cartridge can be left in place for a future printing cycle (appropriately, plug 32 is inserted into nozzle 30 to seal and lubricate the nozzle head) or removed and optionally stored or discarded. A new cartridge (optionally containing filament containing a new pharmaceutical substance or a new pharmaceutical formulation) can be inserted, and another printing cycle can be performed using that new cartridge / filament. The 3D printer may optionally have capacity for multiple cartridges (e.g., docking stations) to allow for the selection of individual cartridges for use.

[0713] This type of disposable nozzle arrangement reduces clogging during the printing process, as well as cross-contamination (within the nozzle), which would otherwise occur when using a single 3D printer nozzle to extrude different drug filaments (which may contain different drug substances).

[0714] Additionally, during the shelf life of the barrel, it can be modified to maintain the quality of the filaments it contains. Ideally, a sealed humidity control chamber 10 properly ensures the stability of the filaments and prevents moisture absorption, which would otherwise affect the quality of the printed tablets.

[0715] The barrel also allows for consistent filament flow, ensuring highly accurate dosing of the 3D tablets being produced.

[0716] These types of cartridges can also be easily installed inside 3D printers, especially 3D printers that have been specially modified to receive such cartridges.

[0717] This type of barrel configuration also allows for control over the increase in the number of printed tablets, for example, by appropriately adjusting the length of the filaments contained therein.

[0718] Independent hopper arrangements (especially those with integrated delivery mechanisms) can help prevent or at least mitigate cross-contamination problems that might otherwise be unavoidable when a non-disposable part of a 3D printer comes into contact with two or more different filaments (e.g., containing different pharmaceutical substances). Furthermore, such hoppers can alleviate certain mechanical stresses on the 3D printer (or some of its components) that would otherwise inevitably lead to wear and tear on printer parts, potentially resulting in inconsistent operation and batch variation in printed tablets. For example, gears can be susceptible to wear when the entire delivery mechanism is incorporated into the 3D printer itself (including all drives), which can lead to inconsistent filament clamping, potentially resulting in inconsistent filament flow during printing. This reduces dosing accuracy. The aforementioned hoppers address this problem by making some vulnerable parts disposable and thus replaceable for each new filament run.

[0719] Example 6 - Model Study of Immediate-Release Formulation

[0720] For immediate-release tablets containing limited concentrations of a potent drug (typical doses of 0.01 mg–40 mg), a solid diluent must be included to achieve a minimum mass easily handled by the patient (traditionally a minimum of 150 mg in most commercially available tablets). Our previous results have shown that immediate-release tablet printing is more consistent when one or more non-melting components are used in combination with Eudragit E100 and a plasticizer.

[0721] The following analytical tests and techniques were used during the research process of these models:

[0722] Determination of drug loading in 3D tablets

[0723] To ensure the drug content in the 3D-printed tablets, accurately weighed tablets were sonicated in 950 ml of 0.1 M HCl for 2 hours in a 1000 ml volumetric flask. The flasks were then stored at room temperature. The cooled volume was increased by adding 0.1 M HCl to 1000 ml. The drug content in each tablet was then determined spectrophotometrically (Jenway, Japan) using specific absorbance λmax of 230, 232, 272, 278, and 204 for aspirin, 5-ASA, theophylline, hydrochlorothiazide, and captopril, respectively. The solution was further diluted with 0.1 M HCl if appropriate.

[0724] Differential scanning calorimetry (DSC)

[0725] Thermal analysis was performed using a differential scanning calorimeter (DSC) Q2000 (TA Instruments, Elstree, Hertfordshire, UK). Samples were precisely weighed to approximately 5 mg and placed in a 40 μL LTA standard aluminum dish for DSC analysis. The analysis was performed under nitrogen atmosphere. To obtain more accurate T values... g The samples were cooled to -50°C. Heating and cooling of the samples were performed at a rate of 10°C / min. Thermal scanning was conducted on all samples except theophylline, from -50°C to 280°C. The data were then analyzed using TA 2000 analysis software. All measurements were performed in triplicate.

[0726] Thermogravimetric analysis (TGA)

[0727] The TGA of the raw material and extruded filament was measured using a METTLER TGA / sDTA851e thermogravimetric analyzer. Approximately 10 mg of sample was added to an aluminum pan and heated from 25 °C to 500 °C at a heating rate of 10 °C / min. The data obtained after the experiment were analyzed using Microsoft Excel.

[0728] Scanning electron microscopy

[0729] After gold coating was performed by placing the tablet on a metal post under vacuum for two minutes in a JFC-1200 fine coating machine (Jeol, Tokyo, Japan), the surface morphology of the printed tablet was evaluated. The coated tablet was then imaged at 20 kV using a Quanta-200 SMS microscope.

[0730] In vitro drug release study dissolution test:

[0731] By using A manual dissolution apparatus was used to study tablets that released drugs immediately. The experiment was conducted at a paddle speed of 50 rpm for 1 hour. The temperature was maintained constant at 37 ± 5 °C. Samples were manually removed after every 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes. Drug release was studied by spectrophotometric measurements (Jenway, Japan) of absorbance λmax for aspirin, 5-ASA, theophylline, hydrochlorothiazide, and captopril, which were 230, 232, 272, 278, and 204, respectively. Samples were diluted as needed. Triples of each drug were tested.

[0732] Disintegration test

[0733] Perform a disintegration test to determine if the tablets disintegrate within a specified time period. The test is conducted according to the British Pharmacopoeia. The tablet disintegration test is performed in a basket rack assembly with six inner cylinders. Take 750 ml of 0.1 M HCl into each cylinder. The time and temperature are set at 37°C and 15 minutes, respectively. Accurately weigh the tablets before testing. For each tablet, note the exact time it takes for them to disintegrate. Perform the drug disintegration test on six tablets at a time.

[0734] Hardness test

[0735] The hardness of six tablets, each containing a drug and a blank, was tested using a Newton (N) Erwika hardness tester.

[0736] Fragility

[0737] The fragility of 20 tablets was tested. The tablets were accurately weighed before and after the test, and the percentage of weight loss was calculated.

[0738] 6.1 - Develop standard formulations containing fillers

[0739] 6.1A - Preparations containing spray-dried lactose

[0740] In this formulation, a widely used diluent (spray-dried lactose) is included in the silk in different proportions, as shown in Table 10:

[0741] Table 10 - Silk Formulations with Spray-Dried Lactose Filler (wt% Composition)

[0742]

[0743] According to the notes in Table 10 and the referenced figures, the dark and coarse filaments were produced by HME, and the color intensity increased after 3D printing. This is likely a result of the interaction between the plasticizer, polymer, and sugar. The increased browning suggests that lactose may have degraded (e.g., caramelized) at elevated temperatures.

[0744] 6.1B - Formulations containing directly compressible lactose (including binders)

[0745] Also uses directly compressible lactose (Ludipress) TM The formula contains lactose with larger particles due to the introduction of a binder (96.5% lactose monohydrate and 3.5% povidone). This type of lactose (with binder) is incorporated in different proportions, as described in Table 11 below:

[0746] Table 11 - Silk Formulations with Compressible Lactose Filler (wt% Composition)

[0747]

[0748] According to the notes in Table 11 and the referenced figures, the presence of larger lactose particles resulted in lighter-colored filaments, but the filament printing color was not significantly improved.

[0749] 6.1C - Preparations containing tricalcium phosphate

[0750] Tricalcium phosphate is widely used as a water-insoluble diluent in tablets. Given previous research surrounding this invention, the high melting point (1391°C) of tricalcium phosphate is considered a good candidate as a filler, capable of producing more filaments than corresponding lactose-based filaments (considering lactose has an mp of approximately 202°C). Tricalcium phosphate will not melt under typical 3D printing conditions. Various ratios of molten component to non-molten component were tested, as shown in Table 12 below. However, in most embodiments, the ratio between TEC and Eudragit E remains constant.

[0751] Table 12 - Silk preparations containing tricalcium phosphate (wt% composition)

[0752]

[0753] The incorporation of tricalcium phosphate allows for the preparation of easily printable and consistent filaments. Filaments with tricalcium phosphate concentrations ranging from 35% to 55% appear to be compatible with the 3D printing process. However, increasing the tricalcium phosphate concentration to 60% and above results in thicker and more brittle filaments that are less practical for 3D printing, especially when supplied in rolls.

[0754] like Figure 70 As shown, thermal analysis of these filaments indicates that all filaments in Table 12 exhibit a T0 value in the range of 31°C–33°C. g .

[0755] 6.1.1 Study on tablet dissolution rate

[0756] Dissolution patterns of the above-mentioned drug-free tablets were observed using a USP II dissolution apparatus equipped with 750 ml HCl and a rotation speed of 50 rpm (based on formulations 6.1A, 6.1B, and 6.1C). Dissolution time was recorded when complete drug dissolution was observed to the naked eye. Increasing the percentage of tricalcium phosphate resulted in a decrease in dissolution time, but the dissolution time still exceeded the time required by regulations for "immediate-release tablets" (according to the British and United States Pharmacopoes, more than 85% drug dissolution must occur within 30 min). Tables 13 and 14 show the dissolution and disintegration rates of model 3D-printed solid form formulations containing various concentrations of tricalcium phosphate (CAP). %CAP was varied relative to other Eudragit EPO / TEC components, where the Eudragit EPO / TEC ratio remained constant.

[0757] Table 13 - Dissolution rates of various formulations

[0758]

[0759] 6.1.2 Study on tablet disintegration rate

[0760] Table 14 - Disintegration rates of various formulations

[0761]

[0762]

[0763] Increasing the percentage of tricalcium phosphate leads to faster tablet disintegration. However, with increasing tricalcium phosphate, both the tablet and the flocs become more brittle.

[0764] 6.1.3 - Study on plasticizer concentration

[0765] The effect of plasticizer (TEC was used in this study) concentration was examined at plasticizer concentrations between 2.5 wt% and 5 wt%, while the concentration of the non-melting (filler) component was kept at the same 50 wt%.

[0766] Table 15 - Observation of the effect of plasticizer concentration

[0767]

[0768] Figure 72 DSC temperature records of filaments with different concentrations of TEC are shown.

[0769] The Eudragit E:TEC ratio of 46.75:3.25 appears to be the most suitable filament for 3D printing. Thermal analysis indicates that the optimal T for filaments used in 3D printing... g The temperature is 34℃.

[0770] 6.2 - Development of filler-containing formulations with lubricants

[0771] To study filament flow in 3D printer nozzles, talc was used as an additional component or as a substitute for tricalcium phosphate.

[0772] Table 16 - Observation of the effect of plasticizer concentration

[0773]

[0774] When using talc without tribasic phosphoric acid or using talc with tribasic phosphoric acid, feasible filaments and printed tablets can be achieved. However, adding talc results in darker filaments and tablets.

[0775] Figure 74 TGA diagrams of different filler combinations used with Eudragit E are shown.

[0776] Figure 75 DSC temperature records for different filler combinations used with Eudragit E are shown. Thermal analysis indicates that both lactose and MCC tend to begin degrading after 140°C, while talc and tricalcium phosphate remain stable above 240°C.

[0777] 6.3 - Development of filler-containing formulations with disintegrants

[0778] The use of FDM and HME processes for tablet production typically requires the incorporation of thermoplastic polymers, such as Eudragit E. Although this polymer has high solubility in gastric media, the overall dissolution rate of 3D-printed tablets tends to be slower than that of conventional tablets.

[0779] Clearly, tablet size will determine the dissolution rate, at least to some extent. The inclusion of disintegrants (fillers that swell upon introduction into an aqueous medium) is a common technique in conventional tablet formulations to accelerate dissolution rates. In this work, various disintegrants were tested, including AcDiSol, sodium carboxymethyl starch (Primojel), and Primolose.

[0780] Table 17 - Observations on the effect of additional disintegrants

[0781]

[0782]

[0783] Figure 77 The diagram shows drug release profiles for tablets containing different amounts of crospovidone (according to Table 17 above). These model studies used hydrochlorothiazide as the test drug.

[0784] Table 18 - Disintegration times for various tablet formulations with and without disintegrants

[0785] serial number Ratio / Ingredients Disintegration Time 1 Cap:EPO:TEC (50:46.75:3.25) Comparison 10:10min 2 Cap:EPO:TEC(50:47.5:2.5) 7:45min 3 Cap:Pjel:EPO:TEC(47.5:2.5:46.75:3.25) 9.40min 4 Cap:Ac.disol:EPO:TEC(47.5:2.5:46.75:3.25) 15:18min 5 Cap:Ac.disol:EPO:TEC(30:10:46.75:3.25) 16:10min

[0786] Table 19 - Disintegration times of different filaments with and without disintegrants

[0787] serial number Cap:epo:tec(50:46.75:3.25) silk Cap:epo:tec(65:46.75:3.25) 1 6:22min 5:34min 2 6:59min 5.53min

[0788] 6.4 - Development of drug-loaded silk

[0789] In the following drug-loaded filaments, tricalcium phosphate was selected along with Eudragit E and TEC as a non-melting filler. In these specific studies, the amount of drug incorporated into the formulation directly replaced the amount of tricalcium phosphate to produce compositions corresponding to those in Table 20 below:

[0790] Table 20 - Typical Drug-Containing Silk Preparations

[0791]

[0792]

[0793] The addition of a drug is expected to cause changes in the glass transition temperature of the mixture / filament. However, the present invention can compensate for this by modifying the concentration of a plasticizer (e.g., TEC) to optimize the glass transition temperature of the drug-loaded filament. g .

[0794] 6.4.1 - Via hot melt extrusion (HME) Production of drug-loaded silk

[0795] for The operating temperature in EPO and HME is maintained between 95°C and 115°C (most commonly 105°C). However, for printing, the optimal working temperature is between 135°C and 145°C (except for lactose formulations exceeding 165°C).

[0796] To optimize the feasibility of the printing formulation, blank filaments (without drugs) were first prepared using Thermo Scientific HAAKE MiniCTW (Karlsruhe, Germany).

[0797] Precisely weigh specific proportions of polymer, plasticizer, and filler. Feed them into a counter-current twin-screw extruder at 90 rpm for hot melt extrusion to melt, mix, and then extrude. The melting and mixing temperatures are kept constant, and the temperature used for extrusion is 10°C lower than the feed temperature. This allows the components to mix during feeding to ensure a uniform distribution of the drug and other components. Reduce the temperature to begin extrusion through a die nozzle with a cylindrical shape and a diameter of 1.25 mm (depending on the formulation) under torque control of 0.8 Nm.

[0798] The extruded filament is then placed in a sealed plastic bag for use in a 3D printer. After the working ratio is optimized, the drug is incorporated into the filament using the same HAAKE hot melt extruder.

[0799] 6.5 - Printing of tablets loaded with drugs

[0800] 6.5.1 - Tablet Design

[0801] Blank and drug-loaded tablets were designed in a typical capsule shape using the techniques described in Section 3.2 above. A series of tablets containing increased volume hydrochlorothiazide were printed by modifying the designed dimensions: length x width x height (L, W, H) without changing the ratios between these dimensions (W = 0.3636L, H = 0.396L). In the drug-loaded examples, all tablets were 12 mm in length.

[0802] 6.6 - Incorporating model drugs into standard formulations

[0803] To verify the applicability of this model to different drug candidates, five different drug molecules were incorporated into the test formulation at a concentration of 12.5% ​​w / w. These drugs were considered non-melting components and were therefore included in the formulation by directly replacing a portion of the tricalcium phosphate, resulting in formulations according to Table 21 below:

[0804] Table 21 - General composition of the drug-loaded formulation to be tested

[0805]

[0806] for The operating temperature in EPO and HME is maintained between 95°C and 115°C (most commonly 105°C). However, for printing, the optimal working temperature is between 135°C and 145°C (except for lactose formulations exceeding 165°C).

[0807] The standard ratio of drugs incorporated into the filament is 12.5:37.5 (drug:cap). Different drugs, such as aspirin, 5ASA, captopril, theophylline, and hydrochlorothiazide, are tested using the filaments used for printing. After tablets are printed with each drug, they then undergo different pharmacopoeia tests to ensure they meet all the standards for the drug. Figure 78 The relevant in vitro drug release curves for each drug formulation in Table 21 are shown.

[0808] Table 22 shows further data for each relevant pharmaceutical formulation, including mean (Av) and standard deviation (SD).

[0809] Table 22 - Disintegration time, fragmentation strength, weight homogeneity, and friability of tablets for each type of drug being tested.

[0810]

[0811] Table 23 details the drug content (in percentage of drug content) by way of mean and standard deviation. The results here indicate that the dose expected from the tablet weight is close to the amount of drug detected under UV absorbance. This strongly suggests that no significant drug loss occurred during the HME and FDM printing processes.

[0812] Table 23 - Drug Content of Each Related Pharmaceutical Formulation

[0813]

[0814] The standard formulation developed based on the above model was effective for all five drug compounds tested in this manner, despite variations in the physiological properties of each drug. Dissolution rate, disintegration rate, and fragility met standard pharmacopoeia standards, while drug content was within the expected dose range of 0.78%–4% based on weight, which is a reasonable margin of error.

[0815] Example 7- Further modeling studies on alternative active ingredient carriers (PVP and PEG)

[0816] 7.1- Model Study Using PVP K29-32 (Polyvinyl Chloroprene) in FDM 3D Printing

[0817] PVP (K 29-32, MW 40000-58000, also known as cyclopovidone) is widely used in the pharmaceutical industry as a disintegrant, dissolving agent, and solubility enhancer for poorly soluble drugs. These polymers have also been shown to prevent or inhibit the precipitation of poorly soluble drugs in relevant dissolution media. The following modeling studies evaluate the feasibility of incorporating such polymers and analogues as carriers of active ingredients into the 3D printing method of this invention.

[0818] 7.1.1 - Screening various PVP-based silk formulations

[0819] Table 24 provides details of formulation screening for specific formulation models incorporating theophylline as a model poorly soluble drug. This formulation screening clarifies more about the factors and parameters involved in the 3D printing of filaments containing PVP polymers.

[0820] Table 24 - Formulation screening and observation of PVP-based systems

[0821]

[0822]

[0823]

[0824] The highlighted formulation (PVP:TEC:Theo 50%:15%:35%) appears to be most feasible for producing filaments compatible with the 3D printing process. The next goal is to incorporate different modeling drugs at a concentration of 10%. These drugs are aspirin, diclofenac, prednisolone, and theophylline.

[0825] Table 25 - Further Screening of PVP-Based Filaments Containing Drugs

[0826]

[0827]

[0828]

[0829]

[0830] 7.1.2 - Preparation of PVP-based filaments for manufacturing immediate-release formulations

[0831] Preparation of filaments: hot melt extrusion

[0832] The sample (10g: 50% PVP40, 15% TEC, 25% talc, 10% theophylline) was prepared by weighing the components in the desired proportions and mixing them using a mortar and pestle. The feed temperature was set to 100°C. Once the temperature was reached, the screw speed was set to 80 rpm, and the mixture was manually fed into the running extruder. The sample was mixed for 5 minutes and extruded at 95°C. The torque was set to 0.4 Nm.

[0833] Table 26 - Formulation and NME Parameters

[0834]

[0835] 7.1.3 - Tablet Design

[0836] For this study, a design for an oblong-shaped tablet was created. For example... Figure 79 As shown, the tablet structure is set to have dimensions of 10.00mm × 3.96mm × 3.64mm (X, Y, Z). The STL model was imported into the MakerBot desktop software. .stl (StereoLithography) is a popular 3D printing file format and contains information about the printed object.

[0837] 7.1.4 - Printing Parameters

[0838] Tablets made by MakerBot Printing was performed using a 2X Experimental 3D printer (MakerBot Industries, LLC, New York, USA). The process was controlled by the MakerBot desktop software. The settings used during the printing process are listed in Table 27 below.

[0839] The tablet model is imported into the software by adding an .stl file. It appears in the center of the construction plate. The required dimensions (10.00mm × 3.96mm × 3.64mm (X, Y, Z)) are set according to the selected scale function.

[0840] After the extruder reaches a temperature of 110°C, the filament is loaded into the extruder. After loading the filament, the following settings are selected in the MakerBot desktop software: Resolution: Standard, Fill: 100%, Layer Height: 0.2mm, Extruder Temperature: 110°C, Plate Temperature: 40°C. The tablets are then printed and packaged into airtight plastic bags.

[0841] Table 27 - Settings used during 3D printing

[0842]

[0843] To achieve the highest quality printed tablets, minimal modifications were made. Blue Scottish Blue Painter tape was added to the build board to aid adhesion. It prevents objects from shifting during the printing process and secures them firmly to the build board. Furthermore, the blue tape requires no changes between processes and the tablets are easy to peel off.

[0844] Taking theophylline as an example, the extruder temperature is set to 110°C. During filament production, this is 15°C higher than the extrusion temperature. This is high enough to ensure smooth filament extrusion through the nozzle, and low enough to prevent theophylline decomposition.

[0845] The build plate temperature was set to 40°C. This temperature did not provide enough heat to melt the tablets, as was observed at higher build plate temperatures. 40°C provided sufficient adhesion to the build plate.

[0846] 7.1.5 - Storage of Silk and Printed Tablets

[0847] Because polyvinylpyrrolidone is hygroscopic, the filaments and tablets are stored in airtight plastic bags in a cool, dry place.

[0848] 7.1.6 - Characteristics of Tablets

[0849] Evaluate the physical parameters of the printed tablets. Mass uniformity, content uniformity, hardness, friability, dissolution rate, and disintegration time are assessed according to the European Pharmacopoeia (Ph.Eur.).

[0850] Tablet shape and size

[0851] The dimensions of the 3D-printed tablets were determined using an electronic digital micrometer (Marathon Management Company, Fisher Scientific). Ten tablets were randomly selected, measured individually, and then compared to the design. The tablet geometry was determined in... Figure 80 Described in the text.

[0852] Quality uniformity

[0853] The weights were determined using a Kern analytical balance. Twenty tablets were randomly selected and weighed individually.

[0854] Content uniformity

[0855] Ten printed tablets were randomly selected and weighed individually. To assess the theophylline content in the printed tablets, each tablet was sonicated in a 500 ml volumetric flask containing 0.1 M HCl in an ultrasonic water bath (VWR ultrasonic cleaner) for 2 hours. After sonication, the samples were cooled to room temperature. The absorbance was measured at 272 nm using a spectrophotometer (Jenway) with 0.1 M HCl as a reference.

[0856] Drug dissolution

[0857] Dissolution tests were performed using an Erweka DT 600 dissolution tester (paddle unit) in 900 ml of 0.1 M HCl at 50 rpm and 37 ± 0.5 °C. Manual sampling was performed. Six tablets were placed in each container. Using a 5 ml Luer-Lok syringe, 4 ml of dissolution sample was taken at predetermined time intervals (5, 10, 15, 20, 25, 30, 40, 50, 60, and 70 min). The sample was filtered through a Millex-HA 0.45 μm filter. The 4 ml of 0.1 M HCl was replaced after each sampling. The absorbance of the sample was measured at 272 nm using a spectrophotometer (Jenway) with 0.1 M HCl as a reference.

[0858] Disintegration

[0859] The disintegration test was performed using an Erweka ZT x20 disintegration tester. Six tablets were placed in each of the six tubes in the basket and added to the dish. The test was performed in 750 ml of 0.1 M hydrochloric acid at 37 °C ± 0.5 °C. At the end of 15 minutes, the basket was removed from the medium.

[0860] Fragility

[0861] The fragility of the tablets was determined using an Erweka fragility tester. For this test, a sample of twenty tablets was weighed and placed in a rotating drum. The drum was rotated 100 times at 25 rpm. The tablets were then removed from the drum, dusted, and reweighed. The test was run once. Ideally, the weight loss should not exceed 1%.

[0862] hardness

[0863] The hardness of each tablet was determined using an Erweka tablet hardness tester. Each tablet was placed between the jaws of the device, and measurements were performed on 10 tablets. The average of the ten readings was taken to determine the final hardness.

[0864] 7.1.7 - Testing

[0865] Figure 81 Images of all successfully printed PVP-based tablets with uniform designs are shown. This illustrates the feasibility and consistency of filament 3D printing in tablet production.

[0866] Figure 82 The drug release profile for a PVP-based tablet loaded with theophylline is shown. This release profile indicates that the PVP carrier contributes to a faster and more complete release (reference). Figures 49-50 ).

[0867] Table 28 shows the statistical ensemble weight of the 3D-printed theophylline-loaded PVP-based tablets and demonstrates a very high degree of weight uniformity.

[0868] Table 28 - Individual weights of representative statistical populations (total 20 tablets), PVP-based tablets loaded with theophylline. It exhibits high weight uniformity

[0869]

[0870]

[0871] The statistical overall disintegration rate of 3D-printed theophylline-loaded PVP-based tablets (a total of 6) was measured, all of which disintegrated within approximately 13 minutes.

[0872] Table 29 shows the total weight of 20 3D-printed theophylline-loaded PVP-based tablets before and after the fragility test. The results indicate that the tablets have statistically similar weights and are therefore not easily brittle.

[0873] Table 29 - Weights of 20 tablets before and after fragility test of PVP-based tablets loaded with theophylline.

[0874] 25rev / min Tablet weight 0 2198.4mg 100 2204.9mg

[0875] Table 30 - Hardness Measurement of PVP-Based Tablets Loaded with Theophylline

[0876] Hardness test (11 tablets)

[0877] Tablet number Force (N) 1 333 2 349 3 377 4 420 5 409 6 362 7 349 8 415 9 372 10 388 11 397 average value 379 STDEV 29

[0878] Table 30 shows the hardness test results for the statistical population (all 11 tablets) of 3D-printed theophylline-loaded PVP-based tablets. These results indicate that the hardness of all tablets is generally consistent.

[0879] Figure 83 The drug release profile for a PVP-based tablet loaded with aspirin is shown.

[0880] Table 31 shows the total statistical weight of 3D-printed PVP-based tablets loaded with aspirin, and demonstrates a very high degree of weight uniformity.

[0881] Table 31 - Individual weights of representative statistical populations (total 20 tablets), PVP-based aspirin loading. The tablets exhibit high weight uniformity.

[0882] Tablet number Tablet weight 1 103.39 2 106.09 3 106.47 4 106.63 5 106.85 6 109.56 7 110.51 8 110.79 9 111.28 10 112.47 11 112.55 12 113.15 13 114.33 14 114.36 15 114.39 16 114.82 17 116.4 18 118.53 19 118.86 20 119.63 average value 112.053 STDEV 4.58 %STDEV 4.09

[0883] The statistical overall disintegration rate of 3D-printed, PVP-based tablets loaded with aspirin (6 tablets in total) was measured, all of which disintegrated within approximately 8 minutes.

[0884] Table 32 shows the total weight of 20 3D-printed PVP-based tablets loaded with aspirin before and after the fragility test. The results indicate that the tablets have statistically similar weights and are therefore not easily brittle.

[0885] Table 32 - Weights of 20 aspirin tablets before and after the fragility test.

[0886] 25rev / min Tablet weight 0 2218.63mg 100 2220.36mg

[0887] Table 33 - Hardness Measurement of PVP-Based Tablets Loaded with Aspirin

[0888] Tablet number Force (N) 1 411 2 397 3 426 4 445 5 423 6 397 7 415 8 372 9 388 10 397 average value 407.1 STDEV 21.15

[0889] Table 33 shows the hardness test results for the statistical population (all 10 tablets) of 3D-printed, PVP-based tablets loaded with aspirin. These results indicate that the hardness of all tablets is substantially consistent.

[0890] Figure 84 The drug release profiles for PVP-based tablets loaded with diclofenac are shown.

[0891] Table 34 shows the total statistical weight of 3D-printed PVP-based tablets loaded with diclofenac, and demonstrates a very high degree of weight uniformity.

[0892] Table 34 - Individual weights of representative statistical populations (total 20 tablets), PVP-based tablets loaded with diclofenac. The tablets exhibit high weight uniformity.

[0893]

[0894]

[0895] The statistical overall disintegration rate of 3D-printed PVP-based tablets loaded with diclofenac (6 tablets in total) was measured, all of which disintegrated within approximately 22 minutes.

[0896] Table 32 shows the total weight of 20 3D-printed PVP-based tablets loaded with aspirin before and after the fragility test. The results indicate that the tablets have statistically similar weights and are therefore not easily brittle.

[0897] Table 35 - Weights of 20 aspirin tablets before and after the fragility test of tablets loaded with diclofenac.

[0898] 25rev / min Tablet weight 0 2508.83mg 100 2512.02mg

[0899] Table 36 - Hardness Measurement of PVP-Based Tablets Loaded with Diclofenac

[0900] Tablet number Force (N) 1 406 2 383 3 414 4 428 5 445 average value 415 STDEV 23

[0901] Table 36 shows the hardness test results for the statistical population (all 5 tablets) of 3D-printed PVP-based tablets loaded with diclofenac. These results indicate that the hardness of all tablets is substantially consistent.

[0902] Immediate-release tablets can be prepared using a combination of PVP-TEC as the molten component and talc as the non-molten component. It is important to vary the concentration of TEC to achieve the appropriate flexibility for the filament used in the 3D printing process. Tricalcium phosphate is less suitable for 3D printing due to the stickiness of the filament, which tends to adhere to itself or the printer gears. Theophylline and aspirin tablets can be 3D printed and meet most pharmacopoeia standards. The tablets exhibit high breakage strength and negligible friability.

[0903] 7.2 - Model Study of Various PEG Polymer Drug Carriers in FDM 3D Printing

[0904] Polyethylene glycol (PEG) is one of the most commonly used polymers in pharmaceutical and medical applications. Many oral, parenteral, skin, ophthalmic, and rectal formulations contain PEG as an ingredient. In many formulations, PEG is used as a coating agent; ointment matrix; plasticizer; solvent; suppository matrix; tablet and capsule diluent; and tablet and capsule lubricant. It is generally considered safe and is classified as GRAS by the FDA. Incorporating such an important polymer into the 3D printing process is crucial. The aim of this work is to explore the feasibility of printing tablets based on a combination of PEG as a molten component and talc as a non-molten component. PEGs with different molecular weights will be included in this screening.

[0905] Table 37 illustrates the details of the formulation screening performed to better understand the factors and parameters involved in 3D printing filaments containing PEG polymers. Various molecular weights of PEG are used, including Mws of 0.4k, 10k, 20k, 100k, 200k, 300k, and 400k, and sometimes mixtures thereof (e.g., 200k with 0.4k). The ratio of PEG to non-melting components (e.g., talc) also varies, and in some embodiments, PEG is blended with other carrier polymers, such as Eurdigit and PVP-based polymers. In some embodiments, a model drug compound (containing theophylline) is used.

[0906] Table 37 - Formulation screening and observation of various PEG-based systems

[0907]

[0908]

[0909]

[0910]

[0911]

[0912] Figure 85 The theophylline release profiles of the successfully printed filament compositions shown in Table 37, containing PEG 200,000:talc:Theo in a ratio of 70%:20%:10%, are illustrated.

[0913] Figure 86 and Figure 87 This is a photographic image of a successfully printed PEG 200,000-based tablet.

[0914] In the context of these model studies, low molecular weight PEG grades (e.g., <100,000) appear to produce brittle and easily broken filaments when combined with talc.

[0915] Increasing the molecular weight of PEG results in the formation of increasingly stronger filaments. PEG 200,000-300,000 appears to produce the most suitable filaments for the 3DFDM printing process.

[0916] The idea is that a higher M w PEG contributes to the structural integrity of the filament (and corresponding 3D-printed tablets), while low M w PEG may be more useful as a plasticizer (e.g., as a substitute for other plasticizers). Therefore, a mixture of PEGs with different molecular weights may be suitable.

[0917] Example 8 - Study on glass transition temperature in 3D printing

[0918] The inventors investigated the glass transition temperature (Tg) of various HME-produced filaments considered compatible with FDM 3D printing. g The glass transition temperature of the filament itself is considered potentially important when developing filament formulations, especially those specific to a particular drug, where maintaining a low nozzle temperature may be preferred to minimize any degradation.

[0919] The glass transition temperature was calculated based on a simplified version of the Gordon-Taylor equation, and we performed the calculation based on the following assumptions:

[0920] 1. The effect of drug addition on the T of the polymer matrix g It has negligible impact

[0921] 2. The addition of non-melting components (such as talc and tricalcium phosphate) to the T of the polymer matrix g It has a negligible impact.

[0922] 3. The different components in the matrix have the same density.

[0923] Table 38 shows details of the glass transition temperature studies, including the relevant formulations.

[0924] Table 38 - Details of the study and calculation of glass transition temperature

[0925]

[0926] *The measured values ​​may be significantly lower due to interference from added drug molecules on the required TEC concentration for successful printing.

[0927] For the molten component, there appears to be a preferred T value in the range of 30°C to 95°C. g The range. More specifically, this range is likely to be between 31°C and 60°C. We expect any molten components within this range to be compatible with 3D printing, provided they are thermally stable.

[0928] Example 9 - Study on the design and manufacture of enteric-coated tablets

[0929] Enteric-coated tablets are typically designed to protect the stomach from the effects of medications, or to protect acid- or enzyme-labile drugs from gastric effects. The fabrication of such solid dosage forms presents a significant challenge because dosage needs to be precisely controlled. Breaking the enteric coating inevitably compromises the integrity of the coating and impairs its gastric resistance function. Therefore, 3D printing of enteric-coated tablets should allow for patient-specific dosage adjustments without compromising the integrity of the dosage form.

[0930] In these model studies, enteric-coated tablets were 3D printed using a dual-nozzle FDM 3D printer. One nozzle head was loaded with an enteric polymer (e.g., Eudragit L55-100), and the other nozzle was loaded with the drug (a PVP filament loaded with theophylline as a model drug).

[0931] Five different designs were implemented, all sharing the same core (theophylline), while having different shell thicknesses of 0.3mm, 0.6mm, 0.9mm, 1.2mm and 1.5mm. Figure 88 , Figure 89 and Figure 90 The design of the array, shown using 3D Max software, is illustrated to represent the core (red) and shell (white).

[0932] A major challenge when printing these shell-and-chip agents is coordinating the two nozzles during the printing process. While one nozzle is printing, the other will remain at elevated temperatures, which can lead to material degradation while the filament remains in contact with the temporarily unused nozzle. Many attempted solutions involve retracting the filament from the "wait nozzle head." However, significant degradation can still occur under these conditions.

[0933] In these experiments, the inventors discovered that the use of olive oil BP, oleic acid, arachidonic acid, and glycerin facilitates coordination between the two nozzles and avoids degradation of the drug-polymer filament. Coating the filament with such components is believed to provide a protective layer on the filament surface. These components also have relatively high melting points and do not degrade at the processing temperatures of the 3D nozzles.

[0934] The idea is that, regardless of whether single-head or multi-head (e.g., dual-head) printing is used, this type of protective filament coating can be applied to any or all filaments.

[0935] Example 9.1 - Manufacturing of the filaments for the shell and core

[0936] shell

[0937] Eudragit L100-55, TEC, and talc were mixed using a mortar and pestle at a ratio of 50% : 16.66% : 33.33%, respectively. The feed temperature into the HME was 135°C, and the filaments were extruded at 125°C for a mixing time of 5 minutes (HME nozzle 1 mm).

[0938] core

[0939] PVP, TEC, talc, and theophylline were used in a mortar and pestle, and in proportions respectively.

[0940] The mixture was prepared in a ratio of 50%:9.5%:30.5%:10%. The feed temperature in the HME was 100°C, and the filament was extruded at 90°C after a 5-minute mixing time (HME nozzle 1.25mm).

[0941] Example 9.2 - 3D Printing of Core-Shell Tablets

[0942] Tablets made by MakerBot Printing was performed using a 2X Experimental 3D printer (MakerBot Industries, LLC, New York, USA). The process was controlled by MakerBot desktop software. The settings used during the printing process...

[0943] Table 27 - Settings used during 3D printing

[0944] Listed in Table 39 below.

[0945] The tablet model was imported into the software by adding two different .stl files for the shell and core. The left nozzle was assigned to print the core and the right nozzle to print the shell. It appears in the center of the build plate. The desired core size (10.00mm × 3.96mm × 3.64mm (X, Y, Z)) was selected according to the scaling function.

[0946] After the extruder reaches a temperature of 110°C, the filament is loaded into the extruder. After loading the filament, select the following settings in the MakerBot desktop software: Resolution: Standard, Fill: 100%, Layer Height: 0.2 mm, Extruder Temperature: 110°C, Plate Temperature: 40°C. Print the tablets and pack them into airtight plastic bags. Table 40 shows the dimensions and X, Y, Z coordinates for the core-shell tablets.

[0947] Table 39 - Setup used during 3D printing of core-shell tablets

[0948]

[0949]

[0950] Table 40 - Dimensions and X, Y, Z coordinates for core-shell structures

[0951] X(mm) Y(mm) Z(mm) Core (0mm shell) 17.19 6.81 6.25 0.3mm shell 17.79 7.40 6.85 0.6mm shell 18.38 8.00 7.45 0.9mm shell 18.99 8.61 8.05 1.2mm shell 19.59 9.20 8.65 1.5mm shell 20.19 9.81 9.25

[0952] 9.3-pH Change Dissolution Test

[0953] In vitro drug release studies of all anti-gastric coating formulations used in this study were conducted in a dissolution USP II apparatus (AT 7Smart, SOTAX, Switzerland). Each experiment was performed in triplicate in dissolution medium at 37°C ± 0.5°C and a paddle speed of 50 rpm. Tablets were tested in 750 mL of simulated gastric fluid (0.1 M HCl, pH 1.2) for 2 hours, followed by exposure to phosphate at pH 6.8 for 4 hours.

[0954] In all experiments, the amount of theophylline released was determined at 5-minute intervals using a UV / VIS spectrophotometer (PG Instruments Limited, UK) at a wavelength of 272 nm and a path length of 1 mm. Data were analyzed using IDISis software (AutomatedLab, 2012).

[0955] Figure 91 Photographs show 3D-printed PVA-based cores (left) and shell-core structures loaded with theophylline, the shell-core structures having increased shell thicknesses of Eudragit L100-55 shells of 0.3 mm, 0.6 mm, 0.9 mm, 1.2 mm and 1.5 mm.

[0956] Figure 92 The image shows a sliced ​​core-shell tablet (left) and a 100% finished tablet (middle and right).

[0957] Figure 93 Drug release profiles for in vitro dissolution based on core-only structures and shell-core structures are shown, with the shell-core structure having an increased thickness of the enteric shell.

[0958] In vitro dissolution tests indicated that the core-shell structure appeared to exhibit a pH-dependent release profile. Drug release initiation rates were 30, 60, and 180 for shell thicknesses of 0.6 mm, 0.9 mm, and 1.2 mm, respectively. Despite spaces between the molten polymer filaments (as previously observed with SEM), the coating layer inhibited drug release from the core. This may be related to the swelling behavior of the Eudragit polymer in aqueous media, which could seal the spaces between the filaments within the shell structure. Coating thicknesses of 0.3 mm and 1.5 mm were either too thin or too thick for enteric-coated formulations. Fine-tuning and further optimization of the shell thickness and core size would allow for the creation of enteric-coated sustained-release (e / cm / r) systems.

[0959] Example 10 - Zero-order sustained-release formulation with shell structure

[0960] 10.1 Preparation of a shell structure for zero-order sustained release

[0961] The filaments for the solid "shell" were prepared by mixing Eudragit RL, Tec, and talc together in a 45%:5%:50% ratio using a mortar and pestle. The feed temperature into the HME was 130°C, and the filaments were extruded at 120°C for a mixing time of 5 min (HME nozzle was 1.25 mm).

[0962] Active ingredient-containing fibers were prepared by mixing PVP, Tec, talc, and theophylline together in a mortar and pestle ratio of 50%:9.5%:30.5%:10%. The fibers were fed into an HME at a temperature of 100°C and extruded at 90°C after a 5-minute mixing time (HME nozzle was 1.25 mm).

[0963] Table 41 shows the key parameters used for producing and printing the corresponding filaments.

[0964] Table 41 - Parameters used for preparing and printing core and shell filaments

[0965]

[0966] Figure 94 The image shows a PVP-based core (far left) theophylline tablet and a series of core-shell structures with increased shell diameter (from right to left).

[0967] Figure 95 The corresponding drug release profiles for dosage forms, with and without oil (in this case, olive oil BP), applied to the surface of the filament before printing are shown.

[0968] The results showed that the application of oil slowed the release of the drug from the core. This was expected, as the oil may make the core more hydrophobic and prolong the release time.

[0969] Figure 96 It shows Figure 94 The drug release curves for each drug described herein illustrate that zero-order kinetics can be achieved using the 3D printing filaments of this invention.

[0970] The results showed that the shell-core structures (thicknesses of 0.3 mm, 0.6 mm, and 0.9 mm) were slightly elongated, but no sustained-release mode was observed. This is likely due to the poor physical resistance of the decapsulated shell during dissolution testing, thus a...

Claims

1. A cartridge comprising a printing filament containing an active ingredient, the printing filament being used for fused filament fabrication of 3D-printed orally administered, immediately-release, sustained-release, or delayed-release solid dosage forms, comprising an active ingredient and an active ingredient carrier; The filaments have a thickness of 0.1-5 mm; The active ingredient is selected from pharmaceuticals or nutritional products; The active ingredient carrier is or contains one or more pharmaceutically or nutritionally acceptable polymer carriers; The barrel includes a housing or shell that contains the printing filament containing the active ingredient, and the barrel is configured to be releasably engaged within the fused filament fabrication 3D printer. The barrel includes a conveying mechanism operable to convey the active ingredient-containing printing filament through and out of the barrel; The conveying mechanism is operably engaged with a mechanical drive mechanism associated with the printer, within which the barrel is configured for releasable engagement; The barrel includes an integrated nozzle, and the active ingredient-containing printing filament is configured to be deliverable through the integrated nozzle. The integrated nozzle is heatable; and The cartridge is configured to allow a heater located inside or associated with the printer to heat the integrated nozzle.

2. The barrel according to claim 1, wherein the housing or casing of the barrel is a sealed or sealable housing or casing.

3. The barrel according to claim 2, wherein the sealed or sealable housing or casing is sealed or sealable by a movable plug.

4. The barrel according to claim 1, wherein the barrel comprises a spool around which the active ingredient-containing printing filament is wound.

5. The barrel according to claim 1, wherein the printing filament containing active ingredients comprises a variety of active ingredients, wherein all of the active ingredients are selected from pharmaceuticals or nutritional preparations.

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