Apparatus and method for 3D printing

Abstract

A printhead for 3D printing of solid-dosage-forms, said printhead having an integrated powder dispenser or an integrated peristaltic pump, wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient. Related 3D printers, solid-dosage-form printing apparatuses and associated methods are also disclosed.

Description

[0001] APPARATUS AND METHOD FOR 3D PRINTING

[0002] FIELD

[0003] The invention relates to three-dimensional (3D) printing and, in particular, to methods and apparatus for 3D printing of solid-dosage-forms as well as deposition of solid and semi-solid materials for filling capsules or moulds, including pharmaceutical products for human and / or animal consumption.

[0004] BACKGROUND

[0005] 3D printing technology has been exploited in multiple industries in recent years, both as a means to prototype new parts and as a method of manufacture of finished commercial items. It has been utilized in medical applications in areas such as manufacture of bespoke implants and experimentally to create new organs by 3D printing of cell-based structures.

[0006] Since the popularisation of personalised medicine, 3D printing has emerged as an alternative to mass manufacturing of medicines, to fit the needs of specific individuals. Further discussion of recent advances in 3D printers specifically for the pharmaceutical industry is provided in International (PCT) Patent Application Number PCT / GB2021 / 050286, published as WO2021 / 160999.

[0007] US 2020 / 0146994 utilises fused filament fabrication 3D printing in combination with a separate solid and / or liquid dispenser to produce solid dosage forms, such as pharmaceutical capsules. Such forms have a shell, which is 3D printed from the fused filament fabrication printhead, and a core that is dispensed from the separated independent dispenser.

[0008] US 2023 / 0131161 A1 relates to a system for 3D printing of pharmaceuticals. This system comprises a 3D printing machine with a mechanical system movable in one or more directions, at least one print head with a nozzle, the print head being movable by the mechanical system, a base system carrying a print base for receiving a prepared mixture applied by the print head, and at least one carrier for holding at least one cartridge, where the cartridge contains a printable substance. A used cartridge can be removed and replaced with a new cartridge. The disclosure is focused on 3D printing directly into packaging, which is shaped blister packaging held in recesses of the print base. US 2017 / 0360714 relates to a method for delivery of personalized medication or nutrition for an individual. The method includes receiving parameters for the personalized medication at a 3D printer, wherein the parameters comprise one or more ingredients, mixing at least one of the ingredients at the 3D printer and microdispensing the one or more of the ingredients into dose form at the 3D printer.

[0009] WO 2020 / 104775 relates primarily to two-dimensional powder printing or dispensing using the principles of digital drop-on-demand inkjet to dispense microgram quantities of powder for 2D patterning, imaging and dispensing into 2D arrays of cavities. This requires the combination of a fluidized powder reservoir of controlled energy and a piezo-actuated dispensing element which imparts additional energy at the dispense orifice.

[0010] KR 20150078774 relates to a 3D printing apparatus including a printhead dispensing powdered material via a micronozzle and a printhead dispensing edible adhesive material via a micronozzle, combining the dispensation of these materials to produce a layered pill.

[0011] WO 2018 / 028972 relates to a method of 3D printing by combining material flows including an active pharmaceutical ingredient and a binder. The API may be stored in a reservoir with a supply line. The materials are mixed as they are expelled from the nozzle or in a separate mixing zone prior to expulsion, and the mixture is deposited onto a working plane as a self-curing material.

[0012] WO 2023 / 200954 discloses a process system and method for the making of articles, using an omnidirectional magnetic movement system with a transport surface and fabrication modules having a formation surface that ca be transported omnidirectionally over the transport surface under the control of a movement controller. An article forming system provides process unit operations for forming articles onto the formation surface as the fabrication modules are moved asynchronously between a plurality of processing positions on the transport surface, and features a depositing device for placing a construction material onto the formation surface and one or more processing devices to form the construction material into the article.

[0013] ES 2960056 relates to a 3D printing device and method with microwave thermal postprocessing. The invention relates to a method of 3D printing of products such as foods, pharmaceutical and cosmetic compositions with microwave thermal post- processing and to a device that employs said method. The invention allows for localized and controlled heat treatment of a 3D product as it is printed. The method comprises the steps of deposition of material, in one or more layers, and then of applying a predetermined amount of near-field microwave energy to one or more parts of the deposited material. These steps can be repeated to build a 3D product. The 3D printing device comprises a near-field microwave applicator capable of depositing a predetermined amount of microwave energy in a localized manner.

[0014] US 2004 / 0004303 relates to apparatus, systems and methods for use in three- dimensional printing. The focus is on more precise and controlled delivery of heat to achieve interlayer drying, isolation of the working region from the outside for reasons of cleanliness and in connection with the vapours of organic solvents, better control of the temperature of the working region, better accuracy in the flowrates of binder fluid dispensed, matching of delivered flowrates for multiple dispensers, verification of delivered flowrates or drops, provision for easier changeover of the machine from one powder to another, and cleanability.

[0015] CN 204019803 is directed to a feeding device for a 3D printer, the device comprises: a container, a peristaltic pump, and a nozzle of the 3D printer, wherein a feeding nozzle of the peristaltic pump is connected to a container for placing printing materials of the 3D printer, and the printing materials in the container enter the feeding nozzle; the peristaltic pump is used to transfer the printing materials entering from the feeding nozzle to the discharging nozzle; the discharging nozzle of the peristaltic pump is connected to a nozzle of the 3D printer that sprays printing materials, and provides printing materials to the nozzle.

[0016] US 2023 / 0091230 relates to a system for performing quality analysis for multidimensional printing. The system includes a multidimensional printer, wherein the multidimensional printer comprises a printing head, a printing surface, an axis system and a scale, wherein the scale is arranged to measure weight applied on the printing surface; and a control unit operatively coupled to the multidimensional printer. The control unit is configured to control the printing head to extrude a printing material, to produce a printed object on the printing surface, obtain, from the scale, a weight of the printed object, and store the weight of the printed object in a memory associated with the control unit, compare the weight with a reference weight of the printed object, and control the printing head to stop extrusion of the printing material when the weight is equal to or exceeds the reference weight. \N0 2020 / 145898 relates to personalized pills comprising multiple medicinal and / or supplemental components that may be 3D printed using a plurality of 3D printing nodes. Each printing node may print one of the components of the personalized pill onto a printing plate. The printing plate, along with the partially printed pills, may be moved to other printing nodes to print other portions of the personalized pills. The individual printing node may include a near infra-red (NIR) spectrophotometer for generating a spectra of the printed pill portion in order to ensure the portion of the pill was printed correctly. The printing node may further comprise a positioning sensor for determining a location of the printing plate.

[0017] CN 213956547 discloses a full-automatic capsule filling device with detection, comprising a base, a vertical plate fixedly connected to the top of the base, a conveyor belt movably connected to the top of the vertical plate through a rotating shaft, a frame fixedly connected to the left side of the top of the base, two frames, a filling box fixedly connected to the tops of opposite sides of the two frames, a detection box fixedly connected to the right side of the top of the base, and a support rod fixedly connected to the left side of the bottom of the inner cavity of the detection box. The advantage asserted is that of detection function through the coordinated use of a base, a vertical plate, a conveyor belt, a frame, a filling box, a detection box, a support rod, a guide plate, a high-precision medicine powder weigher, a first electric push rod, a weighing plate, a second electric push rod, a first collecting box and a second collecting box, thereby solving the problem that the existing full-automatic capsule filling device does not have the detection function, which leads to uneven capsule quality and affects the effect of medication.

[0018] In the pharmaceutical industry, capsule dosage forms have been one of the pillars of drug delivery for many years, as they are easy to administer and offer protection to the active pharmaceutical ingredients (APIs) from external factors. The capsule filling process has evolved over the years from manual to automated, allowing for a filling process in which the amount of API and excipients is highly accurate, with less human intervention. However, in hospitals and pharmacies, capsule manufacturing is performed manually or using simple filling instruments, in a process known as compounding. As the process remains largely manually performed it is subject to human error, time-consuming, and difficult to create personalised products for individual patients safely and with appropriate quality control. Ensuring that each capsule contains the correct dosage is essential for patient safety and drug efficacy. In the same way, the filling of moulds with pharmaceutical formulations has also been a topic of interest in the 3D printing pharmaceutical industry. Mould filling allows to create solid-dosage-forms of any shape by filling pharmaceutical grade moulds with liquid formulations that eventually solidify. This process allows the desired amount of API to be obtained with very high precision.

[0019] The current invention provides an innovative printhead specifically designed for 3D printing of pharmaceutical and medical device products, in addition to a 3D printer incorporating the printhead, an apparatus for printing incorporating the 3D printer, and related processes that combine the capabilities of 3D printing with the precision required for the capsule and mould filling, allowing the 3D printer / printing apparatus to distribute pellets, powder or semi-solid formulations into capsules, moulds, or hollow 3D-printed objects. It also allows the combination of two or more 3D printing technologies, allowing, for example, creation of chewable forms with pellets embedded.

[0020] It is an object of the invention to provide hardware and methods that automate and improve the filling of capsules or alternative dosage forms within a 3D printing process, for example filling dosage forms that have been 3D printed, either with solid filling (e.g. powders) or fluid filling (e.g. liquids and gels).

[0021] SUMMARY OF THE INVENTION

[0022] In a first aspect, the invention provides a printhead for 3D printing of solid-dosage- forms, said printhead having an integrated powder dispenser or an integrated peristaltic pump, wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0023] Preferably, the printhead of the invention is an interchangeable printhead. In a preferred embodiment, equally applicable to interchangeable printheads, the printhead comprises a multi-tip array.

[0024] In a second aspect, the invention provides a 3D printer suitable for printing solid- dosage-forms, said 3D printer comprising at least one printhead according to the first aspect of the invention, wherein said solid-dosage-form comprises at least one activeingredient and at least one excipient. In a preferred embodiment, the 3D printer of the invention comprises an interchangeable printhead with integrated powder dispenser, and further comprises an interchangeable printhead with integrated peristaltic pump.

[0025] In the 3D printer of the invention, preferably the integrated peristaltic pump is a thermostatic peristaltic pump and said 3D printer further comprises tubing for pumping up to 160°C.

[0026] Optionally, in the 3D printer of the invention, the printhead with integrated peristaltic pump further comprises dispensing tips. Preferably, said dispensing tips are for simultaneous printing of multiple solid-dosage-forms.

[0027] The 3D printer of the invention may further comprise a temperature-controlled container. Preferably, said integrated peristaltic pump is for pumping semi-solid material from said temperature-controlled container to one or more of said dispensing tips.

[0028] In a third aspect of the invention is provided a solid-dosage-form printing apparatus comprising i) a 3D printer according to the invention; ii) a build platform, said build platform comprising one or more integrated capsule holders and / or comprising one or more pharmaceutical grade moulds; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient and preferably wherein said build platform is integrated with the 3D printer.

[0029] In a fourth aspect, the invention provides a method of manufacturing solid-dosage- forms comprising use of at least one of: i) a printhead according to the invention; ii) a 3D printer according to the invention; iii) an apparatus according to the invention; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0030] In a fifth aspect, the invention provides a method of manufacturing a solid-dosage-form comprising: i) providing a 3D printer according to the invention; ii) pumping semi-solid material from the temperature-controlled container to one or more of the dispensing tips; and optionally performing one or more further processing steps; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0031] The method according to the fifth aspect may further comprise pumping up to 160 °C.

[0032] The method according to the methods of the fourth and fifth aspects of the invention may optionally further comprise depositing materials into capsules, moulds or hollow forms; and / or using a multi-tip array to print multiple solid-dosage-forms simultaneously.

[0033] In a sixth aspect the invention provides an apparatus for 3D printing of solid-dosage- forms and / or medical devices comprising: a conveyor belt and a balance; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0034] The apparatus of the sixth aspect of the invention may further comprise at least one of: i) a printhead according to the invention; ii) a 3D printer according to the invention; iii) an apparatus according to the third aspect of the invention.

[0035] In a seventh aspect the invention provides a method of manufacturing a solid-dosage- form or medical device, said method comprising use of an apparatus according to the sixth aspect of the invention; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0036] In an eighth aspect of the invention is provided the use of an apparatus according to the sixth aspect of the invention for high-throughput production and quality control in production of pharmaceutical solid-dosage forms; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0037] All features described in connection with any aspect of the invention can be used with any other aspect of the invention.

[0038] BRIEF DESCRIPTION OF FIGURES The invention will be further described with reference to a preferred embodiment, as shown in the drawings in which:

[0039] Figure 1 shows schematic views of the pellet dispenser mechanisms.

[0040] Figure 2 shows front views of the pellet dispenser mechanisms within the printhead.

[0041] Figure 3 shows the pellet dispenser printhead within the 3D printer.

[0042] Figure 4 shows the pellet dispenser printhead in the 3D printer used for capsule filling. Figure 5 shows the schematic of the of peristaltic pump mechanisms.

[0043] Figure 6 shows the schematic view of a peristaltic pump printhead in a 3D printer with a flat build plate.

[0044] Figure 7 shows the schematic view of a peristaltic pump printhead in a 3D printer with a mould on the build plate.

[0045] Figure 8 shows A) schematic view of a peristaltic pump printhead and the pellet or powder dispenser printhead in a multi-printhead pharmaceutical 3D printer with capsule filler on the build plate, and B) detail of the printheads.

[0046] DETAILED DESCRIPTION

[0047] General definitions

[0048] Throughout this application terms should be interpreted according to their standard meaning in the art unless specified otherwise. The following terms should be construed according to their standard meanings, as set out below.

[0049] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0050] The term “approximately” or “about” in connection with a number is intended to mean “in the region of”, i.e. within normal tolerance of the stated value. In other words, a value that the skilled worker in the relevant field would round up or round down to reach the “approximate” value. For example a value in the range of 95 to 104 would be “approximately 100”, or 0.96 to 1.04 would be “approximately 1”.

[0051] The term “at least” when used in connection with a number has its standard meaning, i.e. means that number is the minimum value for the specified parameter / component. For example “at least one polymer” means there is one or more polymer and discloses the options of one polymer or more than one polymer being present.

[0052] The term “comprising” is used in the sense of “including” rather than to mean “consisting of”.

[0053] The term "excipient" means a pharmacologically inactive component such as a diluent, disintegrant, carrier, etc of a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.

[0054] The term “greater than” when used in connection with a number has its standard meaning, i.e. means that the specified parameter has a value higher than the specified number.

[0055] The term “not greater than” or “no more than” when used in connection with a number has its standard meaning, i.e. means that the specified parameter has a maximum value equal to the specified number.

[0056] The term “in the range from X to Y” has its standard meaning, i.e. the value of the parameter is a minimum of X and a maximum of Y.

[0057] The term “less than” when used in connection with a number has its standard meaning, i.e. means that the specified parameter has a value lower than the specified number. The term “multiple” has its standard meaning, i.e. at least 2, more preferably at least 3.

[0058] The term “no less than” or “not less than” when used in connection with a number has its standard meaning, i.e. means that the specified parameter has a minimum value equal to the specified number.

[0059] The term “optionally” has its standard meaning, i.e. means that the specified feature is not essential and may or may not be present. Optional components or process steps disclose the claimed product or process including and not including the optional feature. In this specification, unless expressly otherwise indicated, the word “or” is used in the sense of an operator that returns a true value when either or both of the stated conditions is met, as opposed to the operator “exclusive or” which requires that only one of the conditions is met.

[0060] The term “performed using” as for example in “3D printing is performed using” has its standard meaning, i.e. when the claimed process is carried out, the specified feature applies.

[0061] The term “pharmaceutical grade” has its standard meaning of being suitable for use in pharmaceutical products. For example, the product may be in excess of 80% purity, preferably 90% purity, more preferably 95% purity, even more preferably 99% purity. Optionally “pharmaceutical grade products” may be products that are more than 99% pure and without binders, fillers, excipients, dyes, or unknown substances.

[0062] The term “solid” throughout this application is used to refer to the state of matter, i.e. to distinguish from liquids and gels.

[0063] The term “weight %” or “percent by weight” has its standard meaning throughout this application, i.e. percentage by weight based on the total weight of the relevant mixture. In other words the total weight of the mixture is 100%.

[0064] Features which are described herein with reference only to a single aspect or embodiment of the invention apply equally to all other aspects and embodiments of the invention. Hence features from one aspect or embodiment may be combined with features from another aspect or embodiment. For example, the disclosed activeingredients and excipients may be combined in any way with each other and with the disclosed features of the apparatus and methods disclosed.

[0065] The pharmaceutical industry is shifting to a more personalised future that requires new, safe, and effective techniques for the manufacture of medicines tailored to the patient’s needs. Mould and capsule filling are safe, efficient, and fast methods that can meet the requirements of the industry. However, they must be adapted to be used in a clinical setting at the point of care.

[0066] Pharmaceutical 3D printers enable the integration of these two technologies in a GMP setting that can be automated to obtain personalised doses in a safe and efficient manner. This invention provides alternative solutions to the same problem: how to provide high-throughput technologies for pharmaceutical 3D printers, including the filling of moulds / capsules / 3D-printed hollow forms with pellets and powder or with semisolid pharmaceutical formulations.

[0067] This invention provides a printhead interchangeable into a pharmaceutical 3D printer, having a technical configuration and features that provide for the 3D printer to perform the operation of dosing powder or pellets, or that allows filling moulds, capsules, or 3D- printed forms with semi-solid pharmaceutical formulations at a high throughput.

[0068] The flexibility of 3D printers allows the use of multiple printheads simultaneously. Therefore, the described technologies can be used in combination with other 3D printing technologies used in the pharmaceutical area, such as Fused Deposition Modeling (FDM), Direct Powder Extrusion (DPE), or Semi-Solid Extrusion (SSE). This innovative functionality brings together the capsule filling, mould filling and the 3D pharmaceutical printing, all in a single device, offering a flexible solution for pharmaceutical manufacturing.

[0069] Solid-dosage-forms

[0070] In one aspect the invention provides a solid-dosage-form printing apparatus, which is an apparatus for printing solid-dosage-forms. Solid-dosage-forms as provided by the methods and apparatus of the invention are administrable to humans and comprise at least one active-ingredient and at least one excipient. Solid-dosage-forms as provided herein are for consumption by humans and / or animals.

[0071] Solid-dosage-forms as provided herein include tablets, pills, films, capsules, moulds, shells and 3D printed hollow-forms that have been filled with pellets, powder, liquid, fluid, paste, gel or semi-solid filling comprising at least one active-ingredient and at least one excipient.

[0072] Examples of solid-dosage-forms include tablets, printlets, caplets, capsules, granules, polypills, polyprintlets, mini-tablets, orally-disintegrating tablets, films, suppositories, pessaries, drug-loaded implantable devices, gastroretentive devices and the like.

[0073] In a preferred embodiment, applicable to all aspects, the solid-dosage-forms are selected from the group consisting of tablets, printlets, caplets, capsules, granules, polypills, polyprintlets, mini-tablets, orally-disintegrating tablets, films, suppositories, pessaries, drug-loaded implantable devices, and gastroretentive devices. More preferably selected from the group consisting of tablets, printlets, caplets, capsules, granules, polypills, polyprintlets, mini-tablets, orally-disintegrating tablets, films, suppositories, and pessaries.

[0074] Component Materials

[0075] For all aspects and embodiments of the invention the component materials used may be pharmaceutical-grade, in order to provide end products which are suitable for the administration of active-ingredients.

[0076] The active-ingredients and excipient materials suitable for use in the aspects and embodiments of the invention are described hereinafter individually. The skilled worker will readily understand that each component can be combined with the other components described and such combinations are applicable to all aspects and embodiments of the invention.

[0077] In a preferred embodiment the printheads may be made of pharmaceutical grade stainless steel (304 or 316L), Teflon, silicon or anodized aluminium in the component parts which in use are in contact with the printing mixture (pharma-ink) / powder or pellets prior to printing.

[0078] Active-ingredients or “Active Pharmaceutical Ingredients” (API)

[0079] Active-ingredients suitable for use with the apparatus and methods of the invention are not particularly limited, insofar as these are administrable to humans and / or animals by any administration route. Active-ingredients are selected from the group consisting of pharmaceuticals, nutraceuticals and food supplements.

[0080] In all aspects and embodiments it is preferred that the active-ingredients are pharmaceuticals (also referred to as drugs). Pharmacologically acceptable derivatives and / or salts of the drugs may also be used or contained in the solid-dosage-forms provided by the apparatus and methods of the invention.

[0081] Dosage of the active-ingredient will vary depending on the condition to be treated and the subject. The skilled person can readily select the appropriate dosage to be used, or if preparing according to a prescription, this will have been set out be appropriately trained and qualified medical staff.

[0082] Excipients In the context of this invention the term “excipient” has its standard meaning in the art, i.e. a substance formulated alongside the active-ingredient of a solid-dosage-form, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active-ingredients, or to confer a therapeutic enhancement on the active-ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients are pharmacologically inactive components such as a diluent, disintegrant, carrier, etc of a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use.

[0083] In addition to transporting the active-ingredient to the site in the body where it is intended to exert its action, excipients play an important part in the manufacturing process. They may also be important for keeping the active-ingredient from being released too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset.

[0084] Other excipients help the active-ingredient to disintegrate into particles small enough to reach the blood stream more quickly and still others protect the product's stability so it will be at maximum effectiveness at time of use. In addition, some excipients are used to aid the identification of a drug product.

[0085] Last, but not least, some excipients are used simply to make the product taste and look better. This improves patient compliance, especially in children. Although technically "inactive" from a therapeutic sense, pharmaceutical excipients are critical and essential components of a modern dosage product. In many products, excipients make up the bulk of the total dosage form.

[0086] Suitable excipients include diluents or fillers, binders, disintegrants, colouring agents, preservatives, plasticizers, and lubricants.

[0087] Without being bound by theory, it is believed to be the excipient or combination of excipients which have the greatest impact upon release of the active-ingredient, for example in the digestive system, by means of its dissolution properties e.g. under the conditions found in the stomach and intestine.

[0088] Selection of the excipient(s) is therefore influenced by the active-ingredient used and the release-behaviour desired in the end-product solid-dosage-formulations. The skilled person is able to select the appropriate excipients using their skill in the art. Further discussion of drugs and excipients in the 3D printing of pharmaceuticals is provided in International (PCT) Patent Application Number PCT / GB2017 / 053558 published as WO2018 / 096363.

[0089] Pellet and powder dispenser printhead

[0090] Where the term “powder dispenser” is used, this is synonymous and interchangeable with the term “pellet and powder dispenser” or “pellet / powder dispenser”.

[0091] The principle underpinning pellets and powder dispensing technology is the filling of capsules, moulds, shells or other 3D-printed hollow objects with powder or pellets. A pharmaceutical mixture is used which comprises at least an active-ingredient and an excipient.

[0092] The preparation of suitable pharmaceutical mixtures for use in the apparatus according to the invention is within the knowledge and ability of the skilled person. The printing mixture can include pre-prepared small particles, pellets, or powder with or without drug loaded.

[0093] The pellet / powder dispenser that is integrated into the printhead of the invention comprises a hopper, a dose-regulator and a dispensing funnel.

[0094] The dose regulator comprises a moving element that displaces a fixed quantity of microgranules corresponding to a fixed amount of active ingredient. Preferably the dose regulator comprises a shuttle and a sliding chassis (see Figure 1A) or comprises an endless screw (see Figure 1B).

[0095] In one embodiment the dispensing funnel is of fixed diameter. In another, equally preferred embodiment, the dispensing funnel is of adjustable diameter. In the adjustable diameter embodiment, variation of the funnel diameter may be used to control or modify the amount of material dispensed and / or the speed of material dispensed.

[0096] In an exemplary process, the material (powder or pellets) is loaded into the hopper of the printhead. After that, electrical signals are sent to the dose regulator mechanism (the shuttle and sliding chassis shown in Figure 1A or endless screw mechanism shown in Figure 1 B). The hopper provides the material to the dose regulator - the moving element that displaces a fixed quantity of microgranules corresponding to a fixed amount of active ingredient - and the fixed quantity of material is deposited in the right place of the build plate of the 3D printing apparatus. The electrical signals control the movement of the shuttle and sliding chassis (Figure 2A) or the rotation of the endless screw (Figure 2B), allowing these to deposit the exact amount of material into the desired capsules, moulds, shells or other hollow forms as illustrated in Figure 3 and Figure 4. The capsules, moulds and hollow forms typically are made by other 3D printing technologies like fused deposition modelling (FDM), direct powder extrusion (DPE) or semisolid extrusion (SSE).

[0097] Peristaltic pump printhead

[0098] The purpose of the printhead with integrated peristaltic pump is to produce a controlled flow of liquids, fluids, gels, paste or semi-solid material from the material container to the dispensing tip(s) of the printhead. This surpasses the limitations of dispensing material from a single syringe with a fixed volume and enables a high throughput printing process. The peristaltic pump provides for the use of pharmaceutical formulations in the form of a liquid, fluid, gel, paste or semi-solid formulation without exposing these formulations to contamination from exposed pump components.

[0099] The printhead comprises at least one dispensing tip and preferably comprises multiple dispensing tips. The term “dispensing tip” is synonymous with “nozzle” or “needle” and refers to the point of exit of the printhead, where the formulation is provided, to fill the capsules, moulds, shells or other 3D printed hollow forms. Where there are multiple dispensing tips these are generally referred to as a multi-tip array.

[0100] In an exemplary process, the formulation is placed in a thermostatic container that is connected to the pump (Figure 5). For convenience of access and physical form, the container is typically located close to the printhead and may be connected or attached to the printhead. The container is preferably connected to the pump by tubing.

[0101] Suitable tubing may be made from, for example, elastomeric polymer materials such as nitrile, silicone, Hypalon, Viton, Tygon, Pharmed, PTFE, Teflon, fluoro-rubber, PVC, EPDM rubber, EPDM+Polypropylene, polyurethane and natural rubber.

[0102] The peristaltic pump and tubing are preferably thermostatic up to 160°C. This provides for maintenance of the physicochemical and rheological properties of the formulation while being pumped to the dispensing tip(s). The peristaltic pump is capable of pumping thermo-reversible formulations that are liquid when heated and solidify when cooled down. Typically the formulations have a viscosity that is in the range of 0.1- 250,000 mPa.s, for example 0.5-15,000 mPa.s, as measured at 20°C according to ASTMD7042. Additionally, the peristaltic pump printhead can also work at room temperature to pump paste-like pharmaceutical formulations that solidify after a drying post-process.

[0103] The dispensing tip of the printhead, see Figure 5A, could also be exchanged for a multi-tip array (see Figure 5B), comprising two or more dispensing tips, for example four dispensing tips. It is preferred in all embodiments comprising the printhead with integrated peristaltic pump that a multi-tip array is used. The multi-tip array provides for simultaneous printing of the number of solid-dosage forms corresponding to the number of dispensing tips in the array. For example, two or more, such as four or five solid-dosage-forms. This improves the performance of the process. In an embodiment there can be hundreds of dispensing tips in the array, for example at least 100, at least 200, at least 300, at least 400, or at least 500 dispensing tips in the array. In preferred embodiments the muti-tip array comprises 7-20 dispensing tips. In addition, a mechanism composed by a conveyor belt and a balance could be implemented allowing a high throughput production while ensuring the quality control of the process.

[0104] Interchangeable Print heads

[0105] The printheads of the invention may be interchangeable, which means each can be removed from the 3D printer and replaced by another printhead. The replacing printhead can be the same as or different from the printhead that is removed. Alternatively, and equally applicable to all embodiments, the printheads may be non- interchangeable, for example each may be fixed or otherwise integrated into the 3D printer such that it cannot be removed from the 3D printer. It is also possible in embodiments where more than one printhead is present in the apparatus, for there to be a mixture of interchangeable and non-interchangeable printheads. For example, with two printheads, for one printhead to be non-interchangeable and the other to be interchangeable.

[0106] It is preferred in all embodiments that the pellet / powder dispenser printhead is interchangeable. In other words, that it can be removed easily from the 3D printer and switched for an alternative printhead. It is most preferred that the pellet / powder dispenser printhead is interchangeable with the peristaltic pump printhead. It is preferred in all embodiments that the peristaltic pump printhead is interchangeable. In other words, that it can be removed easily from the 3D printer and switched for an alternative printhead. It is most preferred that the peristaltic pump printhead is interchangeable with the pellet / powder dispenser printhead.

[0107] Typically the print heads of the invention are manually interchanged, for example by manually disconnecting one print head and manually connecting another. In an embodiment the interchanging of print heads may be automated and / or computer- controlled.

[0108] 3D Printer

[0109] The 3D printers according to the invention provide solid-dosage-forms comprising active-ingredients, administrable by any route and for human and / or animal consumption, and must therefore comply with the rules and laws for preparing and providing medicinal products for human and animal use, for example, with respect to safety and quality control.

[0110] 3D printers suitable for use in the preparation of pharmaceutical solid-dosage-form are described and discussed in International (PCT) Patent Application Number PCT / GB2021 / 050286, published as WO2021 / 160999. The 3D printers disclosed therein are suitable for use with the printheads of this invention, in the interchangeable embodiment and in the non-interchangeable embodiment.

[0111] Most 3D printers that are available for use in current additive manufacturing processes are not suitable for use in preparing solid-dosage-forms as defined and discussed herein. Some of the problems with such printers include that they are made of or incorporate e.g. plastic, paints, metals or other leachable component parts which can contaminate the products. This is a major problem and prevents standard 3D printers being used in the manufacture of solid-dosage-forms. Further problems include that 3D printers known in the art are not configured for access and cleaning to the standard required when making solid-dosage-forms as defined herein. Standard printers are often open and exposed to the environment, which makes them susceptible to dust and the contamination of the printing environment making them unsuitable for printing medicines. The transference of the movement of the motor to the different parts of the printer is normally through straps that need lubrication that can cause contamination. Standard printers normally have a mobile build platform that make them unsuitable for incorporation of quality control systems like balances and spectroscopic equipment. These printers do not allow printing onto blister packing since the build platform is not adapted for that.

[0112] For example with a Fused Deposition Modelling print head, many of the standard printers have the drive at the back of the printer far from the tip of the nozzle: this makes printing with drug-loaded filaments technically very challenging.

[0113] The 3D printer according to the invention must be suitable for printing solid-dosage- forms including active-ingredients, which are administrable and fit for human and / or animal consumption. Hence the 3D printer according to the invention may be described as being free of components made of plastic or leachable materials and / or may be described as being configured to permit ease of access and cleaning to the standard required when manufacturing or providing solid-dosage-forms for human and / or animal consumption.

[0114] In a preferred embodiment the 3D printer may be made of pharmaceutical grade stainless steel (304 or 316L), Teflon, or anodized aluminium in the component parts which in use are in contact with the printing mixture prior to printing.

[0115] Equally preferably the paint used on the 3D printer may be based on polyethylene and approved for pharmaceutical used and the non-metallic parts may be made of polyamide. To avoid external contamination the printer preferably has a cover which may be made of e.g. poly(methyl methacrylate) preferably including a UV filter, to avoid degradation of light-sensitive materials. The printer may use printer spindles for movement of the movable parts, that do not need lubricant, and the build platform does not move while printing, which allows the use of quality control systems like balances and spectroscopic technologies.

[0116] In a preferred embodiment, applicable to all aspects of the invention, the 3D printer may include one or more of the following features, and in the most preferred embodiment may include all of the following features: made of pharmaceutical grade stainless steel (304 or 316L), Teflon, or anodized aluminium, in the component parts which in use are in contact with the printing mixture prior to printing; non-metallic parts made of polyamide or Teflon; any paint used may be polyethylene-based and approved for pharmaceutical use; comprises a cover including a UV filter; comprises printer spindles for movement of mobile parts, said printer spindles operable without lubricant.

[0117] The 3D printer according to the first aspect of the invention comprises at least one of the printheads of the invention. In other words, comprises a printhead having either the integrated powder / pellet dispenser, or having the integrated peristaltic pump.

[0118] In a preferred embodiment, the 3D printer comprises both printheads of the invention. It is further preferred that each of these is an interchangeable printhead.

[0119] More preferably, the printhead with integrated peristaltic pump has a thermostatic peristaltic pump, and further comprises tubing for pumping up to 160°C. It is further preferred that said printhead comprises multiple dispensing tips, preferably at least four, in a multi-tip array. These multiple dispensing tips provide for simultaneous printing of multiple products. It is most preferred that the 3D printer further comprises a temperature controlled container. The material to be pumped is contained within the temperature controlled container and pumped from there through the tubing to the dispensing tip(s).

[0120] Solid-dosage-form printing Apparatus

[0121] The apparatus according to the third aspect of the invention comprises the 3D printer according to the invention and a build platform.

[0122] The build platform may be integrated into the 3D printer or may be separate from the 3D printer.

[0123] The build platform is typically static, i.e. is non-mobile, such that it remains steady during the printing process.

[0124] The build platform comprises one or more integrated capsule holders or pharmaceutical grade moulds. The solid-dosage-forms are printed into the capsules held in the capsule holders, or into the moulds.

[0125] Optional quality control features

[0126] The apparatus according to the invention optionally may further comprise features for quality control. For example, a balance and / or a camera or scanner for scanning datamatrix or QR code (or other 2D codes) that identify the raw material and packing material in order to provide a full traceability of the materials and medicines to the patient.

[0127] Additional components

[0128] The apparatus according to the invention may further comprise a computer with suitable data connections to the apparatus, which is configured to control and / or operate the apparatus.

[0129] The apparatus may further comprise an access-control system, including a fingerprint reader and a RFID (radio frequency identification) reader (that can be used if the user is wearing gloves). Such an access control system may be used to ensure that the use of the printer is restricted to authorized users.

[0130] Methods

[0131] The invention further provides a method of manufacturing solid-dosage-forms comprising use of at least one of: i) a printhead according to the invention; ii) a 3D printer according to the invention; iii) an apparatus according to the invention; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0132] In other words, the invention further provides the use of at least one of: i) a printhead according to the invention; ii) a 3D printer according to the invention; iii) an apparatus according to the invention; in the manufacture of solid-dosage-forms, wherein said solid-dosage-forms comprise at least one active-ingredient and at least one excipient.

[0133] The invention also provides a method of manufacturing a solid-dosage-form comprising: i) providing a 3D printer according to the invention; ii) pumping semi-solid material from the temperature-controlled container to one or more of the dispensing tips; and optionally performing one or more further processing steps; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient. Preferably this method may further comprise pumping up to 160 °C.

[0134] Each of these methods optionally may further comprise depositing materials into capsules, moulds or hollow forms; and / or using a multi-tip array to print multiple solid- dosage-forms simultaneously.

[0135] Apparatus

[0136] The invention further provides an apparatus for 3D printing of solid-dosage-forms and / or medical devices comprising: a conveyor belt and a weighing balance; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0137] In this embodiment, the balance is incorporated within or is otherwise coupled beneath the build-plate and is used to record the weight of the printed materials and hence provide a means to determine the amount of material dispensed. The conveyor belt functions to move the build plate and / or the balance to automatically position the build plate appropriately for printing.

[0138] By appropriate coordination of software with the instrument components it is possible to enable quality control of the printed materials. In a preferred embodiment, further analytics, such as infra-red detection, can be combined with the balance and print-head to enable determination of the concentration of the drug material printed, hence providing further quality control over the printed dosages.

[0139] The apparatus may further comprise at least one of: i) a printhead according to the invention; ii) a 3D printer according to the invention; iii) an apparatus according to the third aspect of the invention.

[0140] This apparatus of the invention is particularly useful when further comprising the apparatus according to the third aspect of the invention, with use of the printhead having integrated peristaltic pump. This apparatus is especially useful for systems producing filled capsules or filled alternative dosage forms.

[0141] The invention further provides a method of manufacturing a solid-dosage-form or medical device, said method comprising use of the above apparatus. In other words, the invention further provides the use of the above apparatus in the manufacture of a solid-dosage-form or medical device, wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

[0142] The use of the above apparatus of the invention for high-throughput production and quality control in production of pharmaceutical solid-dosage forms is a further aspect of the invention.

[0143] A high throughput system is one which handles things at a high rate. In other words where the total amount of an element transmitted successfully from source to destination within a given time duration is high. There is no fixed definition of when something becomes 'high throughput'; it is simply 'high' relative to earlier methods. In the current case, this would apply when the new method is many times faster than the existing method. For example, a conventional 3D printer that can print 1 solid-dosage- form at a time would be low throughput. The apparatus of the invention has higher throughput than this and is therefore ‘high throughput’.

[0144] Whilst the invention has been described with reference to preferred embodiments, it will be appreciated that various modifications are possible within the scope of the invention.

[0145] All prior teachings acknowledged above are hereby incorporated by reference. No acknowledgement of any prior published document herein should be taken to be an admission or representation that the teaching thereof was common general knowledge in the United Kingdom or elsewhere at the date hereof.

[0146] DETAILED DESCRIPTION OF FIGURES

[0147] Figure 1 shows schematic views of the pellet dispenser mechanisms. It presents A) a dose regulator mechanism comprising a shuttle and a sliding chassis, and B) a mechanism comprising an endless screw.

[0148] Figure 2 shows front views of the pellet dispenser mechanisms within the printhead. It presents A) a dose regulator mechanism comprising a shuttle and a sliding chassis, and B) a mechanism composed by an endless screw. Figure 3 shows the pellet dispenser printhead within the 3D printer. Figure 3A) front view, Figure 3B) lateral view.

[0149] Figure 4 shows the pellet dispenser printhead in the 3D printer used for capsule filling. Figure 4A) front view, Figure 4B) lateral view.

[0150] Figure 5 shows the schematic of the of peristaltic pump mechanisms. Figure 5A) one line of tubes, Figure 5B) one line of tubes with multiple dispensing tips, and Figure 5C) several line of tubes.

[0151] Figure 6 shows the schematic view of a peristaltic pump printhead in a 3D printer with a flat build plate.

[0152] Figure 7 shows the schematic view of a peristaltic pump printhead in a 3D printer with a mould on the build plate.

[0153] Figure 8 shows A) schematic view of a peristaltic pump printhead and the pellet or powder dispenser printhead in a multi-printhead pharmaceutical 3D printer with capsule filler on the build plate, and B) detail of the printheads.

[0154] List of elements shown in figures:

[0155] Shuttle (1)

[0156] Sliding Chassis (2)

[0157] Feeder (3)

[0158] Endless Screw (4)

[0159] Motor (5)

[0160] Pellet or powder dispenser (6)

[0161] 3D Printer (7)

[0162] Build platform (8)

[0163] Balance (9)

[0164] Capsule holder (10)

[0165] Peristaltic Pump (11)

[0166] Thermostatic container (12)

[0167] Tubing (13)

[0168] Dispensing tip (14)

[0169] Multi-tip array (15)

[0170] Build platform with integrated moulds (16) EXAMPLES

[0171] Example 1 : Filling of 100 capsules with the pellet-powder dispenser:

[0172] Enteric coated pellets were acquired from Sunpharma. 20 g were added to the hopper of the pellet dispenser printhead of a pharmaceutical 3D printer as discussed above. A capsule holder of 100 size 1 capsules was placed as a build plate. The start position of the filling process was the lower left corner of the capsule holder. The Z position was changing during the dispensing process to leave less than 0.3mm between the printhead and the top of the capsules (Figure 4).

[0173] Example 2: Peristaltic pump mould filling

[0174] To prepare the formulations, Paracetamol (30% of total weight) and PEG4000 (70% of total weight) were heated (75°C) in a beaker and mixed using an overhead stirrer. The mixture was immediately transferred to the heated container. The mixture was then transferred through the tubes using the heated peristaltic pump. The deposited amount and the x,y,z movement of the nozzles was controlled by the software of the pharmaceutical printer allowing the manufacture of 3D structures (Figure 6) or the deposition of specific doses of drug moulds (Figure 7) or in capsules (Figure 8).

Claims

CLAIMS1. A printhead for 3D printing of solid-dosage-forms, said printhead having an integrated powder dispenser or an integrated peristaltic pump, wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

2. The printhead according to claim 1 , wherein said printhead is an interchangeable printhead.

3. The printhead according to any preceding claim, comprising a multi-tip array.

4. A 3D printer suitable for printing solid-dosage-forms, said 3D printer comprising at least one printhead according to any preceding claim, wherein said solid- dosage-form comprises at least one active-ingredient and at least one excipient.

5. The 3D printer as defined in claim 4, said 3D printer comprising an interchangeable printhead with integrated powder dispenser, and further comprising an interchangeable printhead with integrated peristaltic pump.

6. The 3D printer as defined in claim 4 or claim 5 wherein said integrated peristaltic pump is a thermostatic peristaltic pump and said 3D printer further comprises tubing for pumping up to 160°C.

7. The 3D printer as defined in any of claims 4-6 wherein the printhead with integrated peristaltic pump further comprises dispensing tips.

8. The 3D printer as defined in claim 7 wherein said dispensing tips are for simultaneous printing of multiple solid-dosage-forms.

9. The 3D printer as defined in any of claims 7-8, further comprising a temperature-controlled container.

10. The 3D printer as defined in claim 9, wherein said integrated peristaltic pump is for pumping semi-solid material from said temperature-controlled container to one or more of said dispensing tips.

11. A solid-dosage-form printing apparatus comprising i) a 3D printer as defined in any of claims 4-10; ii) a build platform, said build platform comprising one or more integrated capsule holders and / or comprising one or more pharmaceutical grade moulds; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient and preferably wherein said build platform is integrated with the 3D printer.

12. A method of manufacturing solid-dosage-forms comprising use of at least one of: i) a printhead as defined in any of claims 1-3; ii) a 3D printer as defined in any of claims 4-10; iii) an apparatus as defined in claim 11 ; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

13. A method of manufacturing a solid-dosage-form comprising: i) providing a 3D printer as defined in any of claims 9-10; ii) pumping semi-solid material from the temperature-controlled container to one or more of the dispensing tips; and optionally performing one or more further processing steps; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

14. The method of claim 13 further comprising pumping up to 160 °C.

15. The method of any of claims 12-14 further comprising depositing materials into capsules, moulds or hollow forms.

16. The method of any of claims 12-15 further comprising use of a multi-tip array to print multiple solid-dosage-forms simultaneously.

17. An apparatus for 3D printing of solid-dosage-forms and / or medical devices comprising: a conveyor belt and a balance; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

18. The apparatus as defined in claim 17 further comprising at least one of: i) a printhead as defined in any of claims 1-3; ii) a 3D printer as defined in any of claims 4-10; iii) an apparatus as defined in claim 11.

19. A method of manufacturing a solid-dosage-form or medical device, said method comprising use of an apparatus as defined in claim 17 or claim 18; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

20. The use of an apparatus as defined in claim 17 or claim 18 for high-throughput production and quality control in production of pharmaceutical solid-dosage forms; wherein said solid-dosage-form comprises at least one active-ingredient and at least one excipient.

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