GB2608846A

GB2608846A - Method and apparatus for additive manufacturing

Info

Publication number: GB2608846A
Application number: GB2110128.2A
Authority: GB
Inventors: Frodsham Michael; Henry Rubinstein Michael; Fripp Thomas; Smith Benjamin
Original assignee: Quay Pharmaceuticals Ltd
Current assignee: Quay Pharmaceuticals Ltd
Priority date: 2021-07-14
Filing date: 2021-07-14
Publication date: 2023-01-18
Also published as: GB202110128D0

Abstract

A method is disclosed for the additive manufacture of a product (49). The method comprises: providing a bed of particulate material (51); forming a first channel in the bed of particulate material (52); depositing a first bead of liquid material in the first channel (53); dispensing further particulate material onto the bed of particulate material (54); forming a second channel in the bed of particulate material (55); depositing a second bead of liquid material in the second channel (56); and solidifying the first bead of liquid material and the second bead of liquid material to form a solid structure of the product (57). Also disclosed is an apparatus for the additive manufacture of a product and a product manufactured using the aforementioned method. The product is typically a pharmaceutical dosage form.

Description

METHOD AND APPARATUS FOR ADDITIVE MANUFACTURING

[0001] This invention relates to a method and apparatus for additively manufacturing a product, for example a pharmaceutical dosage form.

BACKGROUND

[0002] Tablets, for example pharmaceutical tablets, may be manufactured by first compressing a powder or granular material into tablets on a tabletting machine that applies pressure to the powder or granular material to produce core tablets. Thereafter, the core tablets are introduced into one or more ventilated coating pans. A coating material is usually dissolved or suspended in a solvent and then sprayed onto the surface of the core tablets, which are tumbled in the coating pan whilst hot air is passed through the coating pan. The solvent evaporates leaving a coating around the core tablets, which builds up over time until a suitable coating thickness is achieved.

[0003] Additive manufacturing of pharmaceutical dosage forms, such as tablets, is an emerging field. For example, it is known to use additive manufacturing techniques such as inkjet printing, hot-melt extrusion, direct powder extrusion, fused deposition modelling, selective laser sintering, and semi-solid extrusion to additively manufacture a pharmaceutical dosage form by applying a pharmaceutical material in layers to form a pharmaceutical dosage form

BRIEF SUMMARY OF THE DISCLOSURE

[0004] In accordance with the present disclosure there is provided a method of additively manufacturing a product. The method comprises: providing a bed of particulate material; forming a first channel in the bed of particulate material; depositing a first bead of liquid material in the first channel; dispensing further particulate material onto the bed of particulate material; forming a second channel in the bed of particulate material; depositing a second bead of liquid material in the second channel; and solidifying the first bead of liquid material and the second bead of liquid material to form a solid structure of the product.

[0005] In examples, the liquid material is deposited by a material deposition head. The method may further comprise moving the material deposition head and/or the bed of particulate material such that the material deposition head deposits the liquid material in the first channel and subsequently in the second channel.

[0006] In examples, the material deposition head and/or the bed of particulate material may be moved to generate a non-linear relative movement between the material deposition head and the bed of particulate material.

[0007] In some examples, a channelling member is mounted to the material deposition head. In this example, the method may further comprise moving the material deposition head and/or the bed such that the channelling member forms the first channel and subsequently the second channel.

[0008] In examples, the method may comprise simultaneously forming the first channel and depositing the first bead of liquid material in the first channel.

[0009] The method may comprise depositing the liquid material through a needle [0010] In examples, the method may comprise depositing the liquid material through an outlet in a distal end of the needle.

[0011] Alternatively or additionally, the outlet in the distal end of the needle may extend into a sidewall of the needle, or an outlet may be provided only in the sidewall of the needle, proximal to the distal end. The method may comprise depositing the liquid material through an outlet in a sidewall of the needle. In these examples, the method may further comprise moving the needle and/or the bed of particulate material to define a non-linear path of movement between the needle and the bed of particulate material, and rotating the needle such that the outlet of the needle is tangentially aligned with the non-linear path in a rearwards direction relative to the direction of movement of the material deposition head relative to the bed of particulate material.

[0012] The method may further comprise positioning an end of the needle below a surface of the bed of particulate material, for example about 1 mm below the surface of the bed of particulate material. The method may include moving the needle and/or the bed of particulate material such that the needle forms the channel and simultaneously deposits the liquid material. That is, the needle may comprise a channelling member configured to form a channel in the particulate material. Specifically, the needle body (e.g., tubular body) may provide the channelling member. The needle may form the channel and simultaneously deposit liquid material in the channel.

[0013] The method may further comprise providing a channelling member in a fixed position relative to the needle, and moving the channelling member and/or the bed of particulate material such that the channel is formed by the channelling member. The channelling member may be, for example, a plough extending from the material deposition head. The channelling member may be spaced from the needle, for example by up to about 5 mm, or up to about 2, or up to about 1mm.

[0014] The method may comprise depositing the liquid material such that a portion of the particulate material is encapsulated within the solid structure. The method may comprise depositing the liquid material to define a solid structure that surrounds and retains a portion of the particulate material within the solid structure. For example, the solid structure may comprise a container, shell, or casing within which the particulate material is retained.

[0015] The method may further comprise depositing the liquid material to form a plurality of nested solid structures, and encapsulating a portion of the particulate material in a layer between two nested solid structures. The method may comprise depositing the liquid material to define a plurality of solid structures that each surround and retain a portion of the particulate material. For example, each of the plurality of solid structures may comprise a container, shell, or casing within which particulate material is retained. The solid structures may have corresponding shapes, or may have different shapes that fit within each other in a nested manner.

[0016] According to a further aspect of the present invention, there is provided a method of additively manufacturing a product. The method comprises: providing a bed of particulate material; depositing a first bead of a liquid material and a second bead of liquid bead of liquid material into or onto the bed of particulate material; solidifying the liquid material to form a solid structure; and encapsulating a portion of the power material within the solid structure.

[0017] The method may comprise forming a first channel in the bed of particulate material and depositing the first bead of the liquid material in the first channel, and subsequently forming a second channel in the bed of particulate material and depositing the second bead of liquid material in the second channel.

[0018] Optionally, forming the second channel in the bed of particulate material comprises exposing at least a part of the first bead of liquid material and depositing the second bead of liquid material in direct contact with the first bead of liquid material.

[0019] In examples, the method may comprise depositing the second bead of liquid material onto the first bead of liquid material with an overlap of between about 5% and about 50% of the thickness of the first bead of liquid material. In such a manner the first bead and the second bead are fused or merged to ensure that the first and second bead are unified and form a solid structure.

[0020] In examples, the method may comprise depositing the liquid material through a 30 needle.

[0021] In examples, the method may comprise depositing the liquid material through an outlet in a distal end of the needle.

[0022] Alternatively or additionally, the outlet in the distal end of the needle may extend into a sidewall of the needle, or an outlet may be provided only in the sidewall of the needle, proximal to the distal end. The method may comprise depositing the liquid material through an outlet in a sidewall of the needle. In this example, the method may further comprise moving the needle and/or the bed of particulate material to define a non-linear path of movement between the needle and the bed of particulate material, and rotating the needle such that the outlet of the needle is tangentially aligned with the non-linear path in a rearwards direction relative to the direction of movement of the material deposition head relative to the bed of particulate material.

[0023] In examples, the method may further comprise: providing a first needle and a second needle spaced from the first needle; simultaneously depositing the liquid material from each of the first needle and the second needle into or onto the bed of power material to form first and second beads of liquid material; rotating the first needle and the second needle and/or rotating the bed of particulate material such that the liquid material is deposited along a first path and a second path spaced from the first path; solidifying the liquid material to form first and second solid structures, encapsulating particulate material therebetween.

[0024] The method may comprise depositing the first and second beads of liquid material to form a plurality of nested solid structures. The method may include encapsulating a portion of the particulate material in a layer between two nested solid structures.

[0025] In examples, the method may further comprise incorporating a portion of the particulate material into the deposited first and/or second bead of liquid material before the liquid material is solidified such that the particulate material forms a part of the solid structure.

[0026] The method may further comprise at least partially curing the deposited liquid material. For example, the method may comprise irradiating the liquid material with electromagnetic radiation to increase a solidity of the liquid material. The electromagnetic radiation may comprise a laser, infrared radiation, or ultraviolet radiation.

[0027] The method may comprise partially curing the liquid material as it is dispensed from the material deposition head. For example, the method may comprise partially curing the liquid material at a position in which the liquid material is dispensed from the material deposition head, for example at an outlet of a needle. Additionally or alternatively, the method may comprise partially curing the liquid material at a position separate from the outlet of the material deposition head, where the liquid material is on or in the particulate material. For example, the method may comprise partially curing the liquid material at a position within about 20mm of the outlet of the material deposition head, for example within about 10mm of the outlet of the material deposition head.

[0028] In examples, the liquid material is deposited by a syringe and a needle. The syringe may be operable to drive a flow of liquid material through the needle to form a bead of liquid material.

[0029] The syringe may be a pneumatically operated syringe. The method may comprise supplying compressed air to the pneumatically actuated syringe. The compressed air may be provided at a pressure above about 500 kPa, preferably above about 600 kPa, preferably above about 1400 kPa, preferably up to about 2800 kPa.

[0030] Alternatively, the syringe may actuated by an electric actuator, and the electric actuator may be operable to apply a pressure above about 500 kPa, preferably above about 600 kPa, preferably above about 1400 kPa, preferably up to about 2800 kPa.

[0031] In examples, the liquid material comprises a polymer. The liquid material may comprise a polymer solution or a polymer suspension. The polymer solution may comprise a polymer material and a solvent. In order to create such a polymer solution, at least one polymer material of the polymer solution may be a solute for the solvent. The polymer solution may additionally comprise a polymer powder mixed into the polymer solution (but without necessarily dissolving). The polymer solution may therefore comprise a suspension or dispersion of polymer powder.

[0032] In examples, the polymer solution or polymer suspension comprises a pharmaceutically acceptable polymer. In specific examples, the polymer solution or polymer suspension comprises an enteric polymer. For example, the polymer solution or polymer suspension may comprise a cationic synthetic polymer, for example a polymer based on methacrylate, such as a poly(methacrylic acid-co-methyl) methacrylate. In examples, the polymer solution or polymer suspension may comprise a Eudragit® polymer as marketed by Evonik Industries AG.

[0033] In other examples, the pharmaceutically acceptable polymer may comprise a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a poly(vinyl acetate phthalate) (PVAP), a hydroxypropyl methylcellulose phthalate (HPMCP), an acrylate, a polymethacrylate, a hydroxypropyl methylcellulose, a methyl cellulose, or an ethyl cellulose.

[0034] In other examples, the liquid material may comprise a non-polymer pharmaceutically acceptable material, such as an ester of aleurtic acid (e.g., a shellac), or a sugar, or a sweetener.

[0035] The polymer solution, polymer suspension, or non-polymer pharmaceutically acceptable material may be that used conventionally to form a modified-release coating on a pharmaceutical dosage form, for example an immediate or delayed release coating material.

[0036] In examples, the solvent may comprise a pharmaceutically acceptable solvent, for example an isopropyl alcohol.

[0037] In examples, the liquid material, for example a polymer solution or polymer suspension, may comprise a viscosity of between about 500 cP and about 3000 cP.

[0038] In examples, the particulate material may be a powder material. In some examples, the particulate material may comprise silica, chalk, or a ground polymer material.

[0039] In examples, the particulate material may comprise a pharmaceutical ingredient.

The pharmaceutical ingredient may comprise an active pharmaceutical ingredient. The particulate material may comprise a pharmaceutical ingredient and a pharmaceutically acceptable diluent, such as a starch, an anhydrous lactose, a lactose monohydrate, or a sugar or alcohol or cellulosic material, for example microcrystalline cellulose.

[0040] In various examples the pharmaceutical material may comprise a microbiological pharmaceutical product. For example, the pharmaceutical matter may be a live biotherapeutic product, for example bacteria and/or bacteriophage, microbiota, and/or phages. Alternatively, or additionally, the pharmaceutical material may comprise nonviable or dead bacteria or bacteriophage, or extracts or portions thereof. The bacteria and/or bacteriophage may be modified or natural. Any of these microbiological pharmaceutical products may be provided in lyophilised form. Consequently, the pharmaceutical material may be lyophilised live bacteria, microbiota, or phages.

[0041] In examples, the particulate material may have a grain size of between about 30 microns and about 60 microns. The particulate material may have a grain size distribution of between about 50% and about 90%.

[0042] In examples, the product is a pharmaceutical dosage form, for example a tablet, a capsule, or a suppository. The solid structure may define a coating, casing, or container for the pharmaceutical material in the particulate material.

[0043] According to another aspect of the present invention, there is provided apparatus for performing the methods described above.

[0044] In particular, there is provided apparatus for additively manufacturing a product.

The apparatus comprises a bed configured to hold a particulate material, and a material deposition head arranged to deposit a liquid material onto or into the particulate material such that a solid structure of the product is formed when the liquid material solidifies.

[0045] In examples, the apparatus may further comprise a channelling member arranged move relative to the bed to form a channel in the particulate material. The material deposition head may be arranged to deposit the liquid material in the channel.

[0046] In examples, the material deposition head and/or the bed is movable and the channelling member is mounted to the material deposition head such that as the material deposition head moves relative to the bed the channel is formed and the liquid material is deposited in the channel.

[0047] In examples, the material deposition head and/or the bed is movable in a plane parallel to the bed, and the material deposition head may comprise a needle extending from the material deposition head towards the particulate material. The needle may comprise an outlet positionable in the channel for depositing the liquid material into the channel.

[0048] The outlet may be positioned in a distal end of the needle.

[0049] Alternatively or additionally, the outlet in the distal end of the needle may extend into a sidewall of the needle, or an outlet may be provided only in the sidewall of the needle, proximal to the distal end. The outlet may be at least partly positioned on a sidewall of the needle and it may be directed in a rearwards direction relative to the direction of movement of the material deposition head relative to the bed. In this example, the material deposition head and/or the bed may be movable to define a non-linear path of movement between the needle and the bed, and the material deposition head and/or the bed may be further configured to rotate such that the outlet of the needle is tangentially aligned with the non-linear path in a rearwards direction relative to the direction of movement of the material deposition head relative to the bed.

[0050] In examples, the needle may comprise the channelling member, and the needle may be configured to be positioned such that an end of the needle is below a surface of the particulate material during use, for example about 1 mm below the surface of the particulate material. Specifically, a tubular body of the needle may provide the channelling member. The needle may be configured to form the channel as the needle moves relative to the bed. In such an example, the needle can simultaneously form the channel and deposit the liquid material in the channel.

[0051] In other examples, the material deposition head may comprise a channelling member arranged adjacent to the needle in the direction of movement of the material deposition head relative to the bed. In this example the channelling member is separate to the needle, and may be for example a plough that extends from the material deposition head in a fixed position relative to the needle. The channelling member may be spaced from the needle, for example by a distance of up to about 5 mm, or by up to about 2, or by up to about lmm.

[0052] In examples, the apparatus may be configured to deposit the liquid material such that when the liquid material solidifies to form a solid structure a portion of the power material is encapsulated within the solid structure. For example, the solid structure formed by the deposited liquid material may be a container, shell, or casing within which a portion of the particulate material is retained.

[0053] In examples, the apparatus may be configured to deposit the liquid material to form a plurality of nested solid structures arranged such that a portion of the particulate material is encapsulated in a layer between two nested solid structures.

[0054] The liquid material may be deposited to define a plurality of solid structures that each surround and retain a portion of the particulate material. For example, each of the plurality of solid structures may comprise a container, shell, or casing within which particulate material is retained. The solid structures may have corresponding shapes, or may have different shapes that fit within each other.

[0055] In examples, the material deposition head may comprise a first needle and a second needle spaced from the first needle. The material deposition head and/or the bed may be rotatable while liquid material is simultaneously deposited from each of the first and second needles such that the liquid material is deposited in a first bead along a first path by the first needle and in a second bead along a second path by the second needle, the first path being spaced from the second path. The first and second beads may form solid structures, and a portion of the particulate material may be encapsulated between the solid structures.

[0056] In examples, the material deposition head and/or bed is movable to change a distance between the particulate material and the material deposition head.

[0057] Accordingly, movement of the material deposition head and/or bed can provide for depositing a second bead of liquid material on top of a first bead of liquid material to build a three dimensional structure.

[0058] In examples, the apparatus may further comprise a particulate material dispensing system configured to deposit a layer of particulate material onto the bed.

[0059] In examples, the particulate material dispensing system may comprise a hopper for supplying particulate material. The particulate material dispensing system may additionally comprise a roller configured to spread the dispensed particulate material over the bed in a layer. The roller may additionally be configured to compact the particulate material. The particulate material dispensing system may additionally or alternatively comprise a spreader arm, and/or a doctor blade, and/or a vibrator.

[0060] The apparatus may further comprise a curing unit arranged to at least partially solidify the liquid material by curing. The curing unit may be arranged to at least partially solidify the liquid material as the liquid material is deposited onto or into the particulate material.

[0061] The curing unit may be arranged to partially cure the liquid material at a position in which the liquid material is dispensed from the material deposition head, for example at an outlet of a needle. Additionally or alternatively, the curing unit may be arranged to partially cure the liquid material at a position separate from the outlet of the material deposition head, where the liquid material is on or in the particulate material. For example, the curing unit may be arranged to partial cure the liquid material at a position within about 20mm of the outlet of the material deposition head, for example within about 10mm of the outlet of the material deposition head.

[0062] In examples, the curing unit comprises a heat source. In other examples, the curing unit comprises a source of electromagnetic radiation arranged to impart electromagnetic radiation on the liquid material. In examples, the curing unit comprises an infrared lamp, an ultraviolet lamp, and/or one or more lasers. In one example, a plurality of lasers are arranged to focus at a position where the liquid material is deposited onto or into the particulate material, or at a position close to where the liquid material is deposited onto or into the particulate material, for example within about 20mm of the outlet of the material deposition head, for example within about 10mm of the outlet of the material deposition head.

[0063] In some examples, the curing unit is disposed on the material deposition head. In other examples, the curing unit is disposed on another part of the apparatus, for example on an enclosure.

[0064] The material deposition head may comprise a needle for depositing the liquid material. The material deposition head may additionally comprise a syringe arranged to control outflow of the liquid material from the needle.

[0065] The syringe may be a pneumatically operated syringe. The apparatus may include a source of compressed air, for example a tank or pump, for supplying compressed air to the pneumatically actuated syringe. The compressed air may be provided at a pressure above about 500 kPa, preferably above about 600 kPa, preferably above about 1400 kPa, preferably up to about 2800 kPa.

[0066] Alternatively, the syringe may be actuated by an electric actuator, and the electric actuator may be operable to apply a pressure above about 500 kPa, preferably above about 600 kPa, preferably above about 1400 kPa, preferably up to about 2800 kPa.

[0067] In examples, the needle comprises a gauge of between 22-gauge and 36-gauge, for example 25-gauge.

[0068] In examples, the liquid material comprises a polymer solution or a polymer suspension. The polymer solution may comprise a polymer material and a solvent. The polymer solution may additionally comprise a polymer powder mixed into the polymer solution (but without necessarily dissolving). The polymer solution may therefore comprise a polymer suspension or polymer dispersion.

[0069] In examples, the polymer solution or polymer suspension comprises a pharmaceutically acceptable polymer. In specific examples, the polymer solution or polymer suspension comprises an enteric polymer. For example, the polymer solution or polymer suspension may comprise a cationic synthetic polymer, for example a polymer based on methacrylate, such as a poly(methacrylic acid-co-methyl) methacrylate. In examples, the polymer solution or polymer suspension may comprise a Eudragit® polymer as marketed by Evonik Industries AG.

[0070] In other examples, the pharmaceutically acceptable polymer may comprise a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a poly(vinyl acetate phthalate) (PVAP), a hydroxypropyl methylcellulose phthalate (HPMCP), an acrylate, a polymethacrylate, a hydroxypropyl methylcellulose, a methyl cellulose, or an ethyl cellulose.

[0071] In other examples, the liquid material may comprise a non-polymer pharmaceutically acceptable material, such as an ester of aleurtic acid (e.g., a shellac), or a sugar, or a sweetener.

[0072] The polymer solution, polymer suspension, or non-polymer pharmaceutically acceptable material may be that used conventionally to form a modified-release coating on a pharmaceutical dosage form, for example an immediate or delayed release coating material.

[0073] In examples, the solvent may comprise a pharmaceutically acceptable solvent, for example an isopropyl alcohol.

[0074] In examples, the liquid material, for example a polymer solution or polymer suspension, may comprise a viscosity of between about 500 cP and about 3000 cP. In examples where the liquid material is deposited by a syringe and needle, the needle size and operating pressure of the syringe may be set according to the viscosity of the liquid material and the desired delivery rate of liquid material, which will depend on the speed of relative movement between the needle and the particulate material.

[0075] In examples, the particulate material may be a powder material. In some examples, the particulate material may comprise silica, chalk, or a ground polymer material.

[0076] In examples, the particulate material may comprise a pharmaceutical ingredient.

The pharmaceutical ingredient may comprise an active pharmaceutical ingredient. The particulate material may comprise a pharmaceutical ingredient and a pharmaceutically acceptable diluent, such as a starch, an anhydrous lactose, a lactose monohydrate, a cellulose derivative, or a sugar or alcohol.

[0077] In various examples the pharmaceutical material may comprise a microbiological pharmaceutical product. For example, the pharmaceutical matter may be a live biotherapeutic product, for example bacteria and/or bacteriophage, microbiota, and/or phages. Alternatively, or additionally, the pharmaceutical material may comprise nonviable or dead bacteria or bacteriophage, or extracts or portions thereof. The bacteria and/or bacteriophage may be modified or natural. Any of these microbiological pharmaceutical products may be provided in lyophilised form. Consequently, the pharmaceutical material may be lyophilised live bacteria, microbiota, or phages.

[0078] In examples, the particulate material may have a grain size of between about 30 microns and about 60 microns. The particulate material may have a grain size distribution 20 of between about 50% and about 90%.

[0079] In examples, the product is a pharmaceutical dosage form, for example a tablet, a capsule, or a suppository. The solid structure may define a coating, casing, or container for the pharmaceutical material in the particulate material.

[0080] In examples, the apparatus is configured to deposit material in layered beads to form the product. For example, a first bead of liquid material can be deposited onto or into the particulate material and at least partially solidified. Subsequently, a second bead of liquid material can be deposited on top of the first bead, preferably in direct contact with the first bead, and at least partially solidified. A third bead, and so on, can be deposited to form a three-dimensional solid structure from the deposited liquid material.

[0081] In examples, the apparatus is configured to deposit the second bead of liquid material onto the first bead of liquid material with an overlap of between about 5% and about 50% of the thickness of the first bead of liquid material. For example, a needle may be positioned with a distal end outlet overlapping approximately 5% -50% of the thickness of the first bead of liquid material while depositing the second bead. In such a manner the first bead and the second bead are fused or merged to ensure that the first and second bead are unified and form a solid structure.

[0082] According to a further aspect of the present invention there is provided a product manufactured using the method and/or the apparatus described above.

[0083] In examples, the product may be a non-pharmaceutical product. In such examples, the liquid material may comprise a polymer solution or a polymer suspension, and the particulate material may comprise a silica, chalk, or ground polymer material.

[0084] According to a further aspect of the present invention there is provided a pharmaceutical dosage form comprising an additively manufactured solid structure encapsulating a particulate material comprising a pharmaceutical ingredient.

[0085] In examples, the pharmaceutical dosage form comprises a primary solid structure within which one or more secondary solid structures are disposed. In particular, the pharmaceutical dosage form may comprise a primary solid structure within which is encapsulated a portion of particulate material and one or more secondary solid structures within which is encapsulated a portion of particulate material. A plurality of secondary slid structures may be arranged distributed through the particulate material disposed within the primary solid structure. Two or more secondary solid structures may be joined together.

[0086] In some examples the pharmaceutical dosage form may comprise a first solid structure portion encapsulating a first portion of particulate material, and a second solid structure portion, joined to the first solid structure portion, and encapsulating a second portion of particulate material. The first and second portions of particulate material may be different.

[0087] In examples, the pharmaceutical dosage form comprises a plurality of nested solid structures with a layer of particulate material disposed between each nested solid structure.

[0088] In examples, a first of the plurality of nested solid structures comprises a first material, and a second of the plurality of nested solid structures comprises a second material, different to the first material.

[0089] The disclosed processes of additively manufacturing a pharmaceutical dosage form enables various formats of pharmaceutical dosage form to be readily manufactured. In particular, pharmaceutical dosage forms with various solid structures and sub-structures may be provided with different materials and/or encapsulating different particulate materials, allowing for a high level of customisation.

[0090] In examples, the or each solid structure of the pharmaceutical dosage form, for example the or each primary, secondary, or nested solid structure of the pharmaceutical dosage form, comprises a pharmaceutically acceptable polymer, for example an enteric polymer. Specifically, the pharmaceutically acceptable polymer may comprise an enteric polymer. The pharmaceutically acceptable polymer may comprise a material that is conventionally used to form a modified-release coating on a pharmaceutical dosage form, for example an immediate or delayed release coating material. In examples, the pharmaceutically acceptable polymer may comprise a cationic synthetic polymer, for example a polymer based on methacrylate, such as a poly(methacrylic acid-co-methyl) methacrylate. In examples, the pharmaceutically acceptable polymer may comprise a Eudragit® polymer as marketed by Evonik Industries AG.

[0091] In other examples, the pharmaceutically acceptable polymer may comprise a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a poly(vinyl acetate phthalate) (PVAP), a hydroxypropyl methylcellulose phthalate (HPMCP), an acrylate, a polymethacrylate, a hydroxypropyl methylcellulose, a methyl cellulose, or an ethyl cellulose.

[0092] In other examples, the liquid material may comprise a non-polymer pharmaceutically acceptable material, such as an ester of aleurtic acid (e.g., a shellac), or a sugar, or a sweetener.

[0093] In various examples the pharmaceutical material may comprise a microbiological pharmaceutical product. For example, the pharmaceutical matter may be a live biotherapeutic product, for example bacteria and/or bacteriophage, microbiota, and/or phages. Alternatively, or additionally, the pharmaceutical material may comprise nonviable or dead bacteria or bacteriophage, or extracts or portions thereof. The bacteria and/or bacteriophage may be modified or natural. Any of these microbiological pharmaceutical products may be provided in lyophilised form. Consequently, the pharmaceutical material may be lyophilised live bacteria, microbiota, or phages.

[0094] In examples, the particulate material may comprise a pharmaceutical ingredient and a pharmaceutically acceptable diluent, such as a starch, an anhydrous lactose, a lactose monohydrate, a cellulose derivative, or a sugar or alcohol.

[0095] In various examples, the particulate material, including the pharmaceutical ingredient, may have a have a grain size of between about 30 microns and about 60 microns. The particulate material may have a grain size distribution of between about 50% and about 90%.

[0096] In examples, the pharmaceutical dosage form is a tablet, a capsule, or a suppository. The solid structure may define a coating, casing, or container for the pharmaceutical material in the particulate material.

BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: FIG. 1 is a schematic diagram of apparatus for additively manufacturing a product, in particular a pharmaceutical dosage form; FIG. 2 shows a perspective view of the apparatus of FIG. 1; FIG. 3 shows a perspective view of the material deposition head of the apparatus of FIG. 1; FIG. 4 shows a perspective view of the bed, powder dispensing system, and roller of the apparatus of FIG. 1; FIG. 5 shows a perspective view of the stamper of the apparatus of FIG. 1; FIG. 6 shows an alternative material deposition head of the apparatus of FIG. 1, having a plurality of syringes and needles; FIG. 7 illustrates an alternative material deposition head of the apparatus of FIG. 1, having a plurality of needles adapted to be rotated by the material deposition head; FIGS. 8A and 8B show examples of the needle of the material deposition head of FIG. 1 during use; FIGS. 9A and 9B show examples of the needle of the material deposition head of FIG. 1 during use, together with a separate channelling member; FIG. 10 illustrates deposition of the polymer solution in overlapping beads within the powder material; FIGS. 11A and 11B illustrate an additively manufactured pharmaceutical dosage form having a capsule shell encapsulating a powder material; FIGS. 12A and 12B illustrate an additively manufactured pharmaceutical dosage form having a plurality of capsule shells encapsulating a powder material; FIG. 13 is a flow diagram illustrating a method of additively manufacturing a product, in particular a pharmaceutical dosage form; and, FIG. 14 is a flow diagram illustrating an alternative method of additively manufacturing a product, in particular a pharmaceutical dosage form.

DETAILED DESCRIPTION

[0098] As detailed below, the invention provides methods and apparatus for additively manufacturing a product, in particular a pharmaceutical dosage form.

[0099] As schematically illustrated in FIG. 1 and also shown in FIGS. 2 to 5, apparatus 1 for additively manufacturing a product includes a bed 2 and a material deposition head 3.

The bed 2, shown in FIGS. 1, 2 and 4, is configured to hold a particulate material, in this example a powder material 4. The material deposition head 3 is configured to move relative to the bed 2 to deposit a liquid material, in this example a polymer solution 5, onto, or into, the powder material 4 to form a product.

[00100] As shown in FIGS. 1 and 4, the bed 2 is formed by a generally planar surface on which the powder material 4 is deposited. The bed 2 may be in the form of a container, having at least one side wall, optionally three or four side walls that retain the powder material 4 on the bed 2. A powder dispensing system 6, shown in FIGS. 1, 2 and 4, is provided to dispense powder material from a source 7. In the illustrated examples a hopper 7 is provided to dispense powder material 4 onto the bed 2. The hopper 7 has a gate 8 at an outlet of the hopper 7 to open and close the hopper 7 for dispensing powder material 4 onto the bed 2. An actuator 36 is provided to operate the gate 8.

[00101] A powder spreader 9, shown in FIGS. 1, 2 and 4, is provided to spread newly deposited powder material 4 across the bed 2 so that the powder material 4 is substantially level on the bed 2, defining a surface 10 of the powder material 4.

[00102] As illustrated, the powder spreader 9 may comprises a roller 11 arranged to be moved across the bed 2 to level the dispensed powder material 4. An actuator 12 and guide rail 13 are provided for movement of the roller 11 across the bed 2. The roller 11 may rotate to spread the powder material 4. An actuator 37 is provided to rotate the roller 11. The roller 11 may act to compress the powder material 4 onto the bed 2. For example a weight of the roller 11 may act on the powder material 4, or an actuator may press down on the roller 11 as it moves across the bed 2. In another example, the roller 11 may make a first sweep across the bed 2 to spread powder material 4, and a subsequent sweep across the bed 2 to compress the powder material 4. During the second sweep the roller 11 may be moved closer to the bed 2 (or the bed 2 moved closer to the roller 11), for example by about 0.5mm.

[00103] In other examples, the powder spreader 9 may comprise an arm, optionally with a doctor blade, configured to be moved across the bed 2 to level and compress the powder material 4.

[00104] A collector 35 is provided to collect powder material 4 that is swept off of the bed 2 during levelling and compression, as described above.

[00105] In other examples, as illustrated in FIG. 5, the apparatus 1 may include a stamp 14 configured to press down on the powder material 4 after it has been levelled to compress the powder material 4 onto the bed 2. The stamp 14 may be provided in addition to a roller (11, see FIGS. 1, 2 and 4), arm, doctor blade, or other powder spreader. As illustrated in FIG. 5, the stamp 14 may be provided on the material deposition head 3 and may be operable by one or more actuators 15 to move the stamp 14 against the powder material 4 to compress the powder material 4. The stamp 14 may include an opening 16 for a needle of the material deposition head 4, as described below.

[00106] In some examples, the bed 2 may additionally or alternatively comprise a vibrator arranged to vibrate the bed 2 and thereby compact the powder material 4 on the bed 2.

[00107] In the illustrated example, as shown in FIGS. 2 and 3, the material deposition head 3 is moveable relative to the bed 2 along linear guides 17, 18. The material deposition head 3 is directly mounted to linear guide 18, and linear guide 18 is mounted to linear guide 17. The material deposition head 3 is movable by actuators 19, 20, in this example motors, arranged to move the material deposition head 3 along each of the linear guides 17, 18. The linear guides 17, 18 form a gantry on which the material deposition head 3 is suspended and can be moved in any combination of the two directions defined by the linear guides 17, 18, so that the material deposition head 3 is movable in plane that is substantially parallel to the bed 2.

[00108] The actuators 19, 20 are provided to move the material deposition head 3 by rotating leadscrews or complementary nut of a leadscrew. The actuators 19, 20 are preferably stepper motors, or servo motors and may include an encoder or similar to accurately control the position of the material deposition head 3.

[00109] In other examples, the material deposition head 3 may be moveable along the one or more linear guides 17, 18 by an arrangement of belts (e.g., toothed belts), chains, or other actuators.

[00110] As illustrated in FIGS. 1 and 3, the material deposition head 3 comprises a needle 21 and a syringe 22 adapted to deposit the polymer solution 5. The polymer solution 5 is provided in the syringe 22, for example in batches or by a feed tube 23 as illustrated in FIG. 2. The syringe 22 is operable to control flow of the polymer solution 5 through the needle 21 for depositing the polymer solution 5 onto or into the powder bed 2.

[00111] As illustrated in FIG. 3, the syringe 22 is pneumatically operated, and includes a reservoir 24 holding the polymer solution and having a high pressure pneumatic connector connected to a source of pneumatic pressure, for example a tank or pump. Pneumatic pressure provided to the reservoir 24 drives the polymer solution through the feed tube 23 and into the syringe 22, in particular into a valve 26 of the syringe. The valve 26 is openable to permit flow of the polymer solution to the needle 21. The valve 26 is normally (e.g., sprung) to a closed position, and pneumatically opened by a low pressure pneumatic connection through connector 27. The low pressure pneumatic connection 27 is closed or opened by operation of shut off valve 28. Accordingly, operating the shut off valve 28 controls supply of the polymer solution to the needle 21.

[00112] In other examples, the syringe 22 may comprise an electric actuator, for example an electric motor and leadscrew, arranged to apply pressure to the polymer solution 5 in the syringe 22 or in the reservoir 24 for outputting the polymer solution 5 via the needle 21. The electric motor is controlled to control deposition of the polymer solution 5.

[00113] The needle 21 has a luer lock 62 for removal from the syringe 22, for example for replacement or maintenance.

[00114] During operation, the material deposition head 3 is moved relative to the powder material 4 on the bed 2 while polymer solution 5 is output through the needle 21 to deposit the polymer solution 5 onto or into the powder material 4, as described further hereinafter.

After the polymer solution 5 is deposited it cures, sets, or hardens to form the product.

[00115] As set in more detail hereinafter, the polymer solution 5 may be a liquid solution comprising a polymer material. For example, the polymer solution 5 may comprise a polymer solute in a solvent, for example an alcohol. The polymer solution 5 may additionally comprise powdered polymer. The amount of solvent may be selected to provide a viscosity appropriate for additive manufacturing, in particular flow through the needle.

[00116] Once deposited, the polymer solution 5 cures, sets, hardens or polymerises to form a solid. Any solvent is evaporated away, leaving the polymer that forms a solid structure. As explained further below, beads of the polymer solution are deposited on top of each other to build up the polymer material and form the product in an additive manufacturing process.

[00117] In some examples, in particular if the product being additively manufactured is a pharmaceutical dosage form, the polymer may comprise an enteric polymer.

[00118] As detailed further hereinafter, depending on the viscosity of the polymer solution 5 being deposited, and the desired form of the product, the needle 21 may have a gauge of between 22-gauge (0.406mm internal diameter), and 36 gauge (0.05mm internal diameter), for example 25-gauge needle (0.254mm internal diameter).

[00119] The operating pressure of the syringe 22 (i.e., the pressure applied to drive the polymer solution 5 through the needle 21) can be determined according to the viscosity of the polymer solution 5, the gauge of the needle 21, and the desired material deposition rate. In examples, for depositing a polymer solution 5 having a viscosity of between about 500 cP and about 3000 cP, the operating pressure of the syringe may be above about 500 kPa, preferably above about 600 kPa, preferably above about 1400 kPa, preferably up to about 2800 kPa.

[00120] The material deposition head 3 may additionally comprise a switching valve arranged to fluidly connect the needle 21 to either: the syringe 22, for depositing the polymer solution 5; or a source of compressed fluid, such as compressed air and/or a cleaning fluid. The switching valve is operated after a period of material deposition when the needle 21 is not directed towards the powder material 4 (e.g., it has been moved to one side of the bed 2, or rotated to a different orientation), and the compressed fluid is used to flush and clean the needle 21 to prevent blockages.

[00121] In the example of FIG. 3 a curing unit 29 is provided to increase the rate at which the deposited polymer solution 5 cures, sets, hardens, or polymerises. Depending on the particular characteristics of the polymer solution 5 being deposited, the curing unit 29 may impart electromagnetic radiation, for example infrared or ultraviolet radiation, onto the deposited polymer solution 5 to increase the rate at which the deposited polymer solution 5 cures, sets, hardens, or polymerises.

[00122] In the example illustrated in FIG. 3, and referring also to FIG. 1, the curing unit 29 comprises infrared and/or UV lamps 30a, 30b are arranged to heat the deposited polymer solution 5 at the position at which it is deposited onto the powder material 4 in bed 2.

[00123] In the illustrated example, a bracket 31 is provided to mount the lamps 30a, 30b to the material deposition head 3.

[00124] In an alternative example, one or more lasers are directed to the deposited polymer solution 5 and configured to locally heat the deposited polymer solution 5. The lasers can each be directed at, or near, the location where the polymer solution 5 is deposited so that the deposited polymer solution 5 is irradiated as it is deposited, or soon after being deposited, onto or into the powder material 4. Advantageously, the laser radiation can be focussed on a small area corresponding to the deposited polymer solution 5 so that the surroundings, for example nearby powder material 4, is not heated or only insignificantly heated. This may be particularly advantageous in examples where the powder material 4 comprises a heat-sensitive material, for example an active pharmaceutical ingredient such as a microbe.

[00125] In some examples, the lasers can be focussed at, or near, an outlet of the needle 21 to partially cure the polymer solutions 5 as it leaves the needle 21.

[00126] In examples, the curing unit 29, in particular any lamps or lasers, are mounted to another part of the apparatus 1, for example the gantry to an enclosure.

[00127] In examples where the polymer solution 5 comprises a solvent, application of heat by the curing unit 29 increases the rate of evaporation of the solvent and so speeds up the curing of the polymer solution 5.

[00128] In other examples, for example when the polymer solution 5 comprises a photopolymer such as an epoxy, an acrylate, or a urethane, then curing of the polymer solution I can be accelerated by an ultraviolet lamp irradiating the deposited polymer solution 5.

[00129] The curing unit 29 may be operable to at least partially cure, set, harden or polymerise the deposited polymer solution 5 before further powder material is dispensed onto the bed 2 by the powder dispensing system 6, as described above. In examples, the curing unit 29 is operable to only partially cure, set, harden or polymerise the deposited polymer solution 5 before further powder material is dispensed onto the bed 2 by the powder dispensing system 6, as described above. Partial curing, setting, hardening or polymerisation provides for a second bead of polymer solution to be deposited onto the first bead to fuse to create a polymer structure.

[00130] As illustrated in FIGS. 1, 2 and 4, the bed 2 is mounted on a movable support 32 that is operable to change a distance between the bed 2 and the material deposition head 3. In particular, as illustrated, the bed 2 is mounted on a leadscrew 33 such that operation of the leadscrew 33 moves the bed up or down. An actuator 34, for example a motor, is provided to operate the leadscrew 33.

[00131] During operation, as described further hereinafter, the material deposition head 3 is operated to deposit a first bead of polymer solution 5 onto or into the powder material 4 when the bed 2 and the material deposition head 4 are spaced at a first distance. Subsequently, the bed 2 is moved away from the material deposition head 4 by an incremental distance, the powder dispensing system 6 dispenses additional powder material 4 onto the bed 2, the powder spreader 9 levels and optionally compresses the additional powder material 4, and the material deposition head 3 is operated to deposit a second bead of polymer solution 5 onto or into the powder material 4. The second bead may be deposited on top of the first bead, or overlapped with the first bead, as described further hereinafter. This process is repeated to build up beads of polymer to form a polymer structure of the product.

[00132] In alternative examples, the material deposition head 3 and/or the gantry (i.e., linear guides 17, 18) may be mounted so as to be movable towards and away from the bed 2. In this example, the material deposition head 3 is moved away from the bed 2 after the first bead of polymer solution 5 has been deposited onto or into the powder material 4, and the bed 2 remains in a fixed position.

[00133] In further examples, the material deposition head 3 maintains a fixed position, and the bed 2 is moveable in a plane parallel to the bed 2, and in a direction towards and away from the material deposition head 3, to generate relative movement between the bed 2 and the material deposition head 3 for depositing the polymer solution 5 to form the product. It will therefore be appreciated that relative movement between the material deposition head 3 and the bed 2 can be provided in different ways.

[00134] The apparatus 1 illustrated in FIG. 1 may be provided within an enclosure to provide a controlled environment to prevent contamination of the powder material 4 and/or the deposited polymer solution 5, and to prevent the powder material 4 circulating in the environment of the apparatus 1. An enclosure is particularly advantageous in examples where the powder material 4 contains a pharmaceutical ingredient, for example an active pharmaceutical ingredient. The enclosure may comprise an atmospheric control system operable to maintain a desired temperature and/or humidity, and/or to provide an inert atmosphere, for example a low-oxygen and/or nitrogen-rich atmosphere, within the enclosure. For example, the enclosure maintains an atmosphere appropriate for sustaining cultures of anaerobic bacteria. The enclosure may also be opaque so as to exclude external light and/or ultra violet light.

[00135] The enclosure, and in particular the controlled environment of the enclosure, may be particularly beneficial for manufacturing particular pharmaceutical dosage forms where the pharmaceutical ingredient is susceptible to degradation. For example, manufacture of a pharmaceutical dosage form that contains an anaerobic microorganism (for example, an anaerobic bacteria) can be performed in a low-oxygen atmosphere within the enclosure. Similarly, if the pharmaceutical ingredient is susceptible to light, for example a live biotherapeutic product (such as a live bacteria), then the enclosure can provide a dark environment for the additive manufacturing process. In particular, elimination of ultra violet light will aid in the survival of live biotherapeutic products. In some examples, the temperature of the atmosphere within the enclosure may also be controlled to prevent degradation of heat-sensitive pharmaceutical ingredients, for example live microorganisms (such as bacteria).

[00136] FIGS. 6 and 7 illustrate alternative material deposition heads 3 for use with the apparatus 1 of FIG. 1. In these examples, a polymer solution 5 can be deposited onto or into the powder material 4 from a plurality of deposition points.

[00137] In the example of FIG. 6, the material deposition head 3 comprises two syringes 22a, 22b and two needles 21a, 21b arranged to independently deposit a polymer solution onto or into the powder material 4. It will be appreciated that more than two syringes 22 and needles 21 can be provided on the material deposition head 3, for example three, four, or more syringes 22 and needles 21.

[00138] In one example, each of the syringes 22a, 22b contains a different polymer solution, allowing a product to be additively manufactured with different polymers. For example, a first portion of the product may be manufactured with a first polymer, and a second portion of the product may be manufactured with a second polymer. The syringes 22a, 22b may be operated at different times and the appropriate needle aligned with the product by moving the material deposition head 3 and/or bed 2 accordingly.

[00139] In another example, each of the syringes 22a, 22b may contain the same or different polymer solution and are operated simultaneously to simultaneously additively manufacture a plurality of products.

[00140] In the example of FIG. 7, the material deposition head 3 comprises two needles 21a, 21b, and corresponding syringes 22a, 22b arranged to supply the two needles 21a, 21b. The two needles may be provided with the same or different polymer solutions. In an alternative example, a single syringe 22 may be provided to supply both needles 21a, 21b with a polymer solution.

[00141] The two needles 21a, 21b are spaced apart and the material deposition head 3 has an axis of rotation 38 about which the two needles 21a, 21b can be rotated. During operation, polymer solution is deposited onto or into the powder material 4 from both of the needles 21a, 21b simultaneously while the material deposition head 3 rotates about the axis of rotation 38. Accordingly, if no other relative movement between the material deposition head 3 and bed 2 is provided, the polymer solution is deposited in two concentric circles.

[00142] In other examples, the material deposition head 3 of FIG. 1 may comprise a printhead in place of the syringe(s) and needle(s) described above. The printhead may be arranged to deposit the polymer solution onto or into the powder bed 4. The printhead may comprise one or more nozzles through which the polymer solution 5 is deposited, for example extruded, onto or into the powder material 4. The printhead may be configured to receive more than one type of polymer solution and to mix or switch between the different polymer solutions.

[00143] In some examples, a plurality of material deposition heads 3, for example those shown in FIGS. 3, 6 or 7 may be provided on the apparatus of FIG. 1, each being independently movable relative to the bed 2 to simultaneously additively manufacture a plurality of products.

[00144] In some examples the needle 21 may be positioned above the powder material 4, for example by a distance of 0.5mm to 10mm, to deposit the polymer solution 5 onto a surface 10 of the powder material 4 as illustrated in FIG. 1.

[00145] In other examples, as described below, the needle 21 may be positioned below the surface 10 of the powder material 4 to deposit the polymer solution 5 into the powder material 4.

[00146] FIGS. 8A to 9B illustrate examples of a process of additively manufacturing a product using the apparatus of FIGS. 1 and 2 and the material deposition head of FIGS. 3, 6 or 7. In each of these examples, the needle 21 is placed below the surface 10 of the powder material 4 on the bed 2 and deposits the polymer solution 5 into the powder material 4.

[00147] Preferably, as illustrated, the material deposition head 3 and/or bed 2 are operable to position a distal end 39 of the needle 21 about 1mm below the surface 10 of the powder material 4, although larger distances up to 5mm or smaller distances of between 0.5mm and 1mm are also possible.

[00148] In the examples of FIG. 8A and 9A the needle 21 comprises an outlet 40 at the distal end 39 of the needle 21. The polymer solution 5 is deposited into the powder material 4 via the outlet 40. In the example of FIGS. 8B and 9B, the needle 21 comprises an outlet 40 in a sidewall 41 of the needle 21, proximal to the distal end 39, and the polymer solution 5 is output through the outlet 40 into the powder material 4.

[00149] In the examples of FIGS. 8B and 9B the outlet 40 extends from the distal end 39 of the needle 21 into the sidewall 41 of the needle 21. In other examples, the outlet 40 may be formed only in the sidewall 41 of the needle 21, and the distal end 39 of the needle 21 may be closed.

[00150] As illustrated in FIG. 8A and 8B, as the needle 21 and the powder material 4 move relative to each other (through movement of the material deposition head 3 and/or the bed 2 as described above), the needle 21 forms a channel 42 in the powder material 4 and deposits the polymer solution 5 into the channel 42. In other words, the needle 21 acts as a channelling member 43. The channel 42 will have a width of approximately the width of the needle 21.

[00151] In these examples the needle 21 beneficially has a short length, for example between 1mm and 10mm, to prevent flexing of the needle 21 as it forms the channel 42 in the powder material 4.

[00152] In the example of FIG. 8B the material deposition head 3 is adapted to rotate the needle 21 as the needle 21 and the powder material 4 move relative to each other to ensure that the outlet 40 remains aligned with the channel 42. That is, the material deposition head 3 is adapted to rotate the needle 21 such that the outlet 40 is orientated in a direction tangential to the path of relative movement between the needle 21 and the powder material 4. It will be appreciated that the bed 2 may be rotated as well as, or instead of, the material deposition head 3 to provide relative rotation between the needle 21 and the powder material 4 so that the outlet 40 remains aligned with the channel 42.

[00153] In these examples, the polymer solution 5 is deposited into the channel 42 formed in the powder material 4 by the needle 21, as described above. Advantageously, the channel 42 helps to maintain a shape of the polymer solution 5 as it is deposited and before it is sufficiently cured to hold its shape independently, so that the deposition of the polymer solution 5 is controlled.

[00154] As explained previously, after a first bead of polymer solution 5 has been deposited in the channel 42, further powder material 4 is dispensed onto the powder material 4 on the bed 2, which will cover the channel 42 and the deposited polymer solution 5. During a subsequent pass the needle 21 will form a further channel in the powder material 4 while depositing a second bead of polymer solution 5 into the newly formed channel.

[00155] In the examples of FIGS. 9A and 9B the material deposition head 3 further comprises a channelling member 43, in particular a plough 44, arranged adjacent to the needle 21 and configured to form the channel 42 in the powder material 4 as the material deposition head 3 and the bed 2 move relative to each other.

[00156] The plough 44 may comprise a tapered or otherwise shaped surface 45 adapted to form the channel 42 in the powder material 4 by moving powder material 4 to one side and/or upwards and sideways. The plough 44 may be arranged proximal to the needle 21, for example between about 1mm and about 5mm ahead of the needle 21 in a direction of movement of the needle 21 relative to the powder material 4.

[00157] In the examples of FIGS. 9A and 9B the material deposition head 3 is adapted to rotate the needle 21 and the plough 44 as the material deposition head 3 and the bed 2 move relative to each other to ensure that the plough 44 remains in front of the needle 21 and aligned in a direction tangential to the path of relative movement between the needle 21 and the powder material 4, such that the needle 21 remains positioned in the channel 42.

[00158] The plough 44, as illustrated in FIGS. 9A and 9B, may help to prevent blockages of the needle 21 as a result of accumulation of the powder material 4 around the outlet 40.

The plough 44 may form a channel 42 of sufficient width and depth that the needle 21 does not contact the powder material 4.

[00159] In these examples, the polymer solution 5 is deposited into the channel 42 formed in the powder material 4 by the plough 44, as described above. Advantageously, the channel 42 helps to maintain a shape of the polymer solution 5 as it is deposited and before it is sufficiently cured to hold its shape independently, so that the deposition of the polymer solution 5 is controlled.

[00160] As explained previously, after a first bead of polymer solution 5 has been deposited in the channel 42, further powder material 4 is dispensed onto the powder material 4 on the bed 2, which will cover the channel 42 and the deposited polymer solution 5. During a subsequent pass the plough 44 will form a further channel in the powder material 4 while the needle 21 deposits a second bead of polymer solution 5 into the newly formed channel.

[00161] FIG. 10 illustrates deposition of a second bead 5b of polymer solution after a first bead 5a of polymer solution has already been into a first channel 42a in the powder material 4. The first channel 42a and first bead 5a have been deposited as described with reference to FIGS. 8A to 9B, and subsequently further powder material 4 has been dispensed onto the bed 2, as described previously, to cover the first channel 42a and first bead 5a.

[00162] As illustrated in FIG. 10, a second bead 5b has been deposited into a second channel 42b formed in the powder material 4, by the same process as described with reference to FIGS. 8A to 9B. As shown, the second bead 5b is deposited on top of the first bead 5a. The second bead 5b is deposited to overlap the first bead 5b, for example by between about 5% and about 50% of the thickness of the first bead 5a. The overlap ensures that the deposited polymer solution of the first and second beads 5a, 5b fuses to produce a coherent product.

[00163] The overlap may be formed by controlling the spacing between the material deposition head 3 and the bed 2 such that the distal end 39 of the needle 21 contacts the first bead 5a as the second bead 5b is deposited.

[00164] The second channel 42b retains the shape and position of the second bead 5b, and the overlap ensures bonding of the second bead 5b to the first bead 5a.

[00165] The overlap(s) can help to ensure that the powder material 4 dispensed on top of the first bead 5a is moved and is not trapped between the first and second beads 5a, 5b and thereby incorporated into the product where it may reduce the integrity of the polymer structure.

[00166] As also illustrated in FIG. 10, the beads 5a and/or 5b of polymer solution may additionally or alternatively be deposited with a transverse overlap with a further bead 5c and/or 5d in the powder material 2. The overlap between transversely adjacent beads (e.g., 5a and 5c, and/or 5b and 5d) may be between about 5% and about 50% of the width of the initial bead 5c, 5d.

[00167] FIG. 10 illustrates an overlap being provided by a needle 21 that has an outlet 40 at the distal end 39 and that defines the channelling member 43, as described with reference to FIG. 8A. However, it will be appreciated that the same overlap may be provided by a needle 21 having an outlet 40 in the sidewall 41, as described with reference to FIG. 8B. Alternatively, the overlap may be provided using the material deposition heads of FIGS. 9A and 9B, in which the channelling member 43, particularly the plough 44, forms the second channel 42b.

[00168] The above description provides an apparatus 1 for additively manufacturing a product where a polymer solution 5 is deposited onto or into powder material 4 on a bed 2 to form a polymer structure of the product. After a bead of polymer solution 5 is deposited, further powder material 4 is dispensed onto the bed 2 and will fill in the gaps between, and optionally over, the deposited polymer solution 5.

[00169] Accordingly, in examples a product can be additively manufactured by depositing the polymer solution 5 onto or into the powder material 4 to encapsulate the powder material 4 within the product. In particular, the polymer solution 5 can be deposited onto or into the powder material 4 to form a container, casing, or shell, within which a part of the powder material 4 will be encapsulated.

[00170] In some examples, the powder material 4 comprises a pharmaceutical ingredient, for example an active pharmaceutical ingredient, and the product within which the pharmaceutical ingredient is encapsulated is a pharmaceutical dosage form, for example a tablet, capsule, or suppository. The liquid material may comprise an enteric polymer, forming an enteric shell of the pharmaceutical dosage form.

[00171] FIGS. 11A and 11B illustrate an example product, in particular a pharmaceutical dosage form 46, manufactured by the above-described apparatus 1 and methods. FIG. 11A shows the exterior of the pharmaceutical dosage form 46, and FIG. 11B shows a cross-section through plane 48 as indicated in FIG. 11A.

[00172] The pharmaceutical dosage 46 form comprises a shell 47 formed by the deposited polymer solution, which is preferably an enteric polymer solution that cures to form an enteric polymer shell. The shell 47 may have an equal thickness throughout, or may vary in thickness. As explained previously, the shell 47 may be made from one or more different materials in one or more different portions of the shell 47. The additive manufacturing process also provides for creating the pharmaceutical dosage form 46, in particular the shell 47, in any shape or size.

[00173] Within the shell 47 a dosage of powder material 4 is encapsulated. The dosage of powder material 4 may include a pharmaceutical ingredient.

[00174] FIGS. 12A and 12B illustrate another example product, in particular a pharmaceutical dosage form 46, manufactured by the above-described apparatus and methods. FIG. 12A shows the exterior of the pharmaceutical dosage form 46, and FIG. 11B shows a cross-section through plane 48 as indicated in FIG. 12A.

[00175] The pharmaceutical dosage 46 form of FIGS. 12A and 12B comprises a plurality of nested shells 47, in this example four nested shells 47a-47d, formed by deposited polymer solution. Each shell 47a-47d is formed of beads of the despotised polymer solution, and the despotised polymer solution is cured as previously described so that the shells 47a-47d are solid. Between adjacent nested shells 47a-47d a portion of powder material 4a-4c, is encapsulated, and a portion of powder material 4d is also encapsulated within the central shell 47d.

[00176] Each nested shell 47a-47d may be made from one or more different materials in one or more different portions. In some examples, at least some of the nested shells 47a- 47d comprise an enteric polymer, and the enteric polymers may differ so that the nested shells 47a-47d dissolve at different rates, or in response to different solvents (e.g., in different parts of the digestive system).

[00177] The portions of powder material 4a-4d may differ by forming a first shell 47d in a first powder material 4d, and then transferring that shell 47d and encapsulated powder material 4d to a second bed 2 of powder material 4 to form a subsequent shell 47c.

[00178] Accordingly, the pharmaceutical dosage form 46 of FIGS. 12A and 12B can be configured to provide a specific release profile for specific pharmaceutical ingredients. The nested shells 47-47d of FIGS. 12A and 12B may be formed using the apparatus of FIGS. 1 to 6 and 8A to 10 by depositing a plurality of separate beads onto or into the powder material 4 at each pass (i.e., before further powder material 4 is dispensed onto the bed 2).

Alternatively, the material deposition head of FIG. 7 may be used to simultaneously deposit the polymer solution 5 in concentric circles that define the nested shells 47a-47d.

[00179] In some examples, a pharmaceutical dosage form may be manufactured that includes a primary (outer) shell and a plurality of separate secondary shells within the primary shell. The second shells may be nested, as described above, or separate. Each secondary shell may contain a portion of a powder material and/or one or more further shells.

[00180] In another example, the pharmaceutical dosage form may comprise two shells attached along sides by a separating wall, defining two distinct spaces. Each shell may contain a powder material and/or one or more secondary shells, for example nested shells.

[00181] Accordingly, use of the apparatus described above provides for various formats of pharmaceutical dosage form to be additively manufactured.

[00182] In the examples described above, a polymer solution 5 is deposited onto or into a powder material 4, for example onto a surface 10 of the powder material 4 or into a channel 42 formed in the powder material 4.

[00183] In some examples, the formulation of the polymer solution 5, the formulation of the powder material 4, and/or the mechanism for depositing the polymer solution 5 onto or into the powder material 4 is determined such that the polymer solution 5 and the powder material 4 remain separate and do not mix. In this way, no (or very little) powder material 4 is incorporated into the polymer solution 5 and the subsequent polymer structure.

[00184] This can be achieved, for example, by using a higher viscosity polymer solution 5 that doesn't flow as readily into the spaces between the granules of powder material 4. Additionally or alternatively, a needle 21 can be selected to provide a bead thickness matching the thickness of the desired polymer structure so that only a single pass is required for each bead 5a, 5b, avoiding any unintended mixing of the powder material 4 into the deposited polymer solution 5. Additionally or alternatively, the overlap between adjacent beads 5a, 5b, as described with reference to FIG. 10, can be minimised, for example to 5% of the bead thickness, to reduce mixing of the powder material 4 into the polymer solution 5. Additionally or alternatively, the needle 21 illustrated in FIGS. 8B and 9B, with an outlet 40 on the sidewall 41 of the needle 21, may be used so that the polymer solution 5 is not being deposited directly towards the powder material 4, so is less inclined to mix with the powder material 4. A separate channelling member 43, for example the plough 44 illustrated in FIGS. 8B and 9B, may also reduce mixing of the powder material 4 and the polymer solution 5. Additionally or alternatively, the curing unit 29 may be operated to cure the polymer solution 5 to a higher degree, and/or more quickly after deposition, to discourage mixing of the powder material 4 and the polymer solution 5. For example, the curing unit 29 may be operated to cure the polymer solution 5 to at least 50% of its fully cured state within about 0.5 seconds of deposition.

[00185] In some examples, it may be advantageous for the curing unit 29 to cure the polymer solution 5 at a specified position relative to the material deposition head 3, or at a specified time after the polymer material 5 has been deposited onto or into the powder material 4. In one example, the material deposition head 3 may be configured to deposit a bead or layer of polymer solution onto or into the powder material 4, and subsequently the curing unit 29 may be operated to at least partially cure the polymer solution 5. Curing the polymer solution 5 as a separate process to depositing the polymer solution 5 may provide process efficiency advantages.

[00186] In other examples, the formulation of the polymer solution 5, the formulation of the powder material 4, and/or the mechanism for depositing the polymer solution 5 onto or into the powder material 4 is determined such that a portion of the powder material 4 is incorporated into the polymer solution 5 as the polymer solution 5 cures, such that the portion of powder material 4 forms a part of the polymer structure of the product.

[00187] This can be achieved, for example, by selecting a low viscosity polymer solution 5 that would flow into the spaces between granules of the powder material 4 and thereby incorporate a portion of the powder material 4. Alternatively or additionally, a powder material 4 may be selected according to its characteristics (e.g., granule size, variation, etc...) that encourages the polymer solution 5 to flow into the spaces between granules of the powder material 4 and thereby incorporate a portion of the powder material 4. Additionally or alternatively, the material deposition head 3 may operated such that the needle 21 mixes powder material 4 into each bead of deposited polymer solution 5. For example, the needle 21 may mix powder material 4 into a first bead 5a of polymer solution as it deposits a second bead 5b of polymer solution. This may be achieved by increasing an overlap between the first and second beads 5a, 5b, as described with reference to FIG. 10. Additionally or alternatively, after a first bead 5a of polymer solution is deposited, the additional powder material 4 can be dispensed before the first bead 5a of polymer solution has cured or set, such that the additional powder material 4 is mixed with the first bead 5a of polymer solution as it is dispensed or spread/compacted, as previously described.

[00188] In some examples the powder material 4 and polymer solution 5 can be mixed entirely, so that the product or pharmaceutical dosage form comprises a block of the solidified liquid material 5 interspersed with particles of the powder material 4, which are effectively encapsulated within the solidified liquid material 5. Such a pharmaceutical dosage form may provide sustained release of the powder material 4 from the solidified liquid material.

[00189] FIGS. 13 and 14 illustrate methods 49, 50 of additively manufacturing a product using the apparatus described above.

[00190] FIG. 13 illustrates a method 49 of additively manufacturing a product, for example a pharmaceutical dosage form 46 as shown in FIGS. 11A to 12B. The method 49 comprises providing a bed of powder material 51. In particular, as described above, the bed of powder material may be provided as a layer of powder material 4 substantially evenly spread over the bed 2 of the apparatus 1.

[00191] The method further includes forming a first channel in the bed of powder material 52. As described above, particularly with reference to FIGS. 8A to 9B, a channelling member 43, for example a needle 21 or a plough 44 of the material deposition head 3, forms a channel 42 in the powder material 4 as the material deposition head 3 moves relative to the powder material 4.

[00192] The method 49 further includes depositing a first bead of polymer solution in the first channel 53. As described above, the polymer solution 5 may be deposited by a needle 21 having an outlet 40. Alternatively, the polymer solution 5 may be dispensed by a printhead.

[00193] The method 49 further includes dispensing further powder material onto the bed of powder material 54. As described above, a powder dispensing system 6 may be provided to dispense further powder material 4 onto the bed 2 after a first bead 5a of polymer solution is deposited. A spreader 9 and/or compactor and/or vibrator may be used to level and optionally compact the dispensed powder material 4 to provide a substantially level surface 10.

[00194] In some examples, either before or after the further powder material 4 is dispensed onto the bed 2 a distance between the material deposition head 3 and the bed 2 is increased, for example by incrementing the bed 2 away from the material deposition head 3. The magnitude of the increment may be, for example, between about 0.1mm and 1.5mm and should be substantially the same as the thickness of the further powder material 4 that is applied.

[00195] The method 49 further comprises forming a second channel in the bed of powder material 55, and depositing a second bead of polymer solution in the second channel 56. As described above, the second channel 42b can be formed in the same manner as the first channel 42a, and the second bead of polymer solution 5 cam be deposited in the same manner as the first bead of polymer solution. Optionally, as described previously, a second bead 5b of polymer solution can be deposited into a second channel 42b to overlap a first bead 5a of polymer solution deposited into a first channel 42a. The first and second beads 5a, 5b may be fused so that polymer solution is accumulated to form a polymer structure that defines the product.

[00196] The method 49 also comprises solidifying the first bead of liquid material and the second bead of liquid material to form a solid structure of the product 57.

[00197] Accordingly, the method 49 provides for additively manufacturing a product by depositing beads of a polymer solution into channels formed in the bed of powder material. As described previously, the channels in the bed of powder material help to control the position of the deposited polymer solution.

[00198] The method 49 may include operation of the apparatus 1 described above with reference to FIGS. 1 to 10.

[00199] In particular, the method 49 may include encapsulating a portion of the powder material 4 within the product being manufactured. This is particularly beneficial for pharmaceutical dosage forms such as capsules, tablets, and suppositories.

[00200] In examples, the polymer solution 5 may be deposited to form a plurality of nested shells 47a-47d, such as illustrated in FIGS. 12A and 12B. In examples, the product is a pharmaceutical dosage form 46, for example a capsule, tablet, or suppository, and the deposited polymer solution 5 forms a shell within which a portion of the powder material 4 is encapsulated. Where a plurality of nested shells 47a-47d are additively manufactured, a portion of the powder material 4 can be encapsulated between adjacent nested shells 47a-47d.

[00201] As described above with reference to the apparatus 1, the polymer solution 5 is deposited by a material deposition head 3. The material deposition head 3 and/or the bed 2 holding the powder material 4 is moved to create relative movement between the material deposition head 3 and the powder material 4.

[00202] In some examples, a channelling member 43 is mounted to the material deposition head 3. The channelling member 43 may be a needle 21 through which the polymer solution 5 is deposited, or it may be a separate channelling member 43, for example a plough 44. Moving the material deposition head 3 and/or the bed 2 holding the powder material 4 will cause the channelling member 43 to form first and second channels 42a, 42b in the powder material 4.

[00203] In some examples, the channel 42 is formed and the polymer solution 5 is simultaneously deposited in the channel.

[00204] In examples where the polymer solution 5 is deposited through an outlet 40 at least partly formed in a sidewall 41 of a needle 21, then the method 49 may include rotating the needle 21 (for example by rotating the material deposition head 3) such that the outlet 40 of the needle 21 is tangentially aligned with the path of relative movement of the material deposition head 3 and the bed 2. The outlet 40 is directed tangentially rearwards relative to the direction of travel of the needle 21, so that the outlet 40 is aligned with the channel 42.

[00205] As described above, the needle 21 may be positioned below a surface 10 of the powder material 4 on the bed 2. For example, a distal end 39 of the needle 21 may be positioned about 1mm below the surface 10 of the powder material 4. Accordingly, the needle 21 can form the channel 42 and act as the channelling member 43.

[00206] FIG. 14 illustrates a method 50 of additively manufacturing a product, for example a pharmaceutical dosage form such as a capsule, tablet, or suppository. The method 50 comprises providing a bed of powder material 58. In particular, as described above, a layer of powder material 4 may be substantially evenly spread over a bed 2 of the apparatus 1.

[00207] The method 50 further comprises depositing a first bead of a liquid material and a second bead of a liquid material into or onto the bed of powder material 59. In particular, polymer solution 5 is deposited either onto a surface 10 of the powder material 4, or into a channel 42 formed in the powder material 4 as described previously.

[00208] The method 50 further comprises solidifying the polymer solution to form a solid structure 60. The deposited polymer solution 5 may be cured, for example by a curing unit 29, to form a solid polymer structure that defines the product.

[00209] The method 50 further comprises encapsulating a portion of the power material within the solid structure 61.

[00210] In particular, an additively manufactured pharmaceutical dosage form is provided by depositing the polymer solution 5 onto or into a powder material 4 on a bed 2 to form a shell that surrounds and encapsulates a portion of the powder material 4.

[00211] The method 50 may include operation of the apparatus 1 described above with reference to FIGS. 1 to 10.

[00212] In some examples, the polymer solution 5 is deposited onto a surface 10 of the powder material 4. In other examples, the method of depositing beads of a polymer solution into or onto the bed of powder material 59 may comprise forming channels in the powder material 52, 55 and depositing the polymer solution in the channels 53, 56, as per the method of FIG. 13.

[00213] As described previously, the polymer solution 5 may be deposited through a needle 21. As per the example of FIG. 7, the apparatus 1 may have first and second needles 21a, 21b that are spaced apart, and the method 50 may comprise simultaneously depositing the polymer solution 5 from each of the first needle 21a and the second needle 21b into or onto the power material 4 while rotating the first needle 21a and the second needle 21b (and/or rotating the bed 2 holding the powder material 4) such that the polymer solution 5 is deposited along a first path and a second path spaced from the first path, encapsulating powder material 4 therebetween. In this manner, nested capsule shells 47a-47d, such as those shown in FIG. 12B, can be simultaneously formed.

[00214] In particular, the method 50 may include depositing the polymer solution to form a plurality of nested capsule shells 47a-47d, and encapsulating a portion of the powder material 4 in a layer between two nested capsule shells 47a-47d. Accordingly, a pharmaceutical dosage form 46 such as that illustrated in FIGS. 12A and 12B can be additively manufactured.

[00215] In some examples, the method 49 or the method 50 may include a purge cycle in which a purge fluid is passed through the needle 21 to clear the needle 21 of debris, such as accumulated polymer solution 5 and/or powder material 4. A switching valve may be operated to direct a purging fluid, such as compressed air or a cleaning fluid, through the needle 21. The needle 21 may be moved, for example translated or rotated, to be directed away from the powder material 4 during the purge cycle.

[00216] As described above with reference to the apparatus 1, the method 49 or method 50 may include at least partially curing the polymer solution 5 to increase an solidity of the polymer solution 5. For example, an infrared lamp or one or more lasers may be provided to heat the deposited polymer solution 5 to evaporate any solvent and increase the solidity of the polymer solution 5. In other examples, an ultraviolet lamp can be provided to cause curing of a photopolymer of the polymer solution 5. It will be appreciated that the type of curing unit 29 provided will depend on the properties of the polymer solution 5.

[00217] In some examples, the polymer solution 5 is at least partially cured between an outlet 40 of the needle 21 and the powder material 4, or immediately adjacent to the needle 21 (for example in the channel 42), to provide solidification of the polymer solution during or immediately after deposition. Accordingly, the polymer solution 5 can be at least partially solidified to help it remain in the correct position and shape, and to prevent it flowing into spaces between the granules of powder material 4. Moreover, the polymer solution 5 can be at least partially cured before further powder material 4 is dispensed onto the bed 2 to cover the deposited polymer solution 5.

[00218] In examples, a plurality of lasers are directed to focus on the polymer solution 5 at a position immediately adjacent to the needle 21 depositing the polymer solution 5. The one or more lasers may provide constant radiation, or may be flashed on and off. Each laser may have a power of between 4W and 30W, and so are relatively low power. The lasers may be focussed only on the polymer solution 5 such that they do not irradiate or heat the surrounding powder material 4. Such an example is beneficial when the powder material 4 comprises a heat-sensitive material, such as an active pharmaceutical ingredient or.

[00219] As described with reference to FIGS. 1 to 7, the polymer solution 5 may be deposited by a syringe 22 and a needle 21, or by a printhead. Multiple syringes 22 and needles 21, or multiple printheads, may be provided to either simultaneously deposit polymer solution 5 to simultaneously additively manufacture a plurality of products, or to deposit different polymer solutions to form a product comprises two different polymer materials.

[00220] As described above, the method 49 or method 50 may include depositing the polymer solution in layered beads to form the product. The beads may be layered one on top of another, or adjacent to each other, to build-up a polymer structure of the product, and adjacent beads may be deposited with an overlap of between about 5% and about 50% to facilitate bonding of each bead to the adjacent beads. The overlap can improve the integrity of the polymer structure and the product, and may also allow a portion of the powder material to be incorporated into the polymer solution if desired.

[00221] In examples, as described with reference to FIG. 10, a first bead is deposited and a second bead is deposited in contact with the first bead (for example through an overlap of between 5% and 50%) after partial (but not complete) solidification of the polymer solution of the first bead. Accordingly, the overlap provides for combining the first and second beads to form a polymer structure of the product.

[00222] In some examples, the formulation of the polymer solution, the formulation of the powder material, and/or the mechanism for depositing the polymer solution onto or into the powder material is determined such that the polymer solution and the powder material remain separate and do not mix. In this way, no (or very little) powder material is incorporated into the polymer solution and subsequent polymer structure.

[00223] This can be achieved, for example, by using a higher viscosity polymer solution that doesn't flow as readily into the spaces between the granules of powder material. Additionally or alternatively, the needle can be selected to provide a bead thickness matching the thickness of the desired polymer structure so that only a single pass is required for each bead, avoiding any unintended mixing of the powder material into the deposited polymer solution during a subsequent pass. Additionally or alternatively, the overlap between adjacent beads, as described with reference to FIG. 10, can be minimised, for example to 5% of the bead thickness, to reduce mixing of the powder material into the polymer solution. Additionally or alternatively, the needle illustrated in FIGS. 8B and 9B, with an outlet on the sidewall of the needle, may be used as the polymer solution is not being deposited directly towards the powder material, so is less inclined to mix with the powder material. A separate channelling member, for example the plough illustrated in FIGS. 8B and 9B, may also reduce mixing of the powder material and the polymer solution. Additionally or alternatively, the curing unit may be operated to cure the polymer solution to a higher degree, or more quickly after deposition, to discourage mixing of the powder material and the polymer solution. For example, the curing unit may be operated to cure the polymer solution to at least 50% of its fully cured state within about 0.5 seconds of deposition.

[00224] In other examples, the formulation of the polymer solution, the formulation of the powder material, and/or the mechanism for depositing the polymer solution onto or into the powder material is determined such that a portion of the powder material is incorporated into the polymer solution and as the polymer solution cures.

[00225] This can be achieved, for example, by selecting a low viscosity polymer solution that would flow into the spaces between powder granules and thereby incorporate a portion of the powder material. Alternatively or additionally, a powder material may be selected according to its characteristics (e.g., granule size, variation, etc...) that encourages the polymer solution to flow into the spaces between powder granules and thereby incorporate a portion of the powder material. Additionally or alternatively, the needle may be configured to mix powder material into a first bead of deposited polymer solution as it is depositing a second bead of polymer solution. This may be achieved by increasing an overlap between the first and second beads, as described with reference to FIG. 10. Additionally or alternatively, after a first bead of polymer solution is deposited, the additional powder material can be dispensed before the first bead of polymer solution has cured or set, such that the additional powder material is mixed with the first bead of polymer solution as it is dispensed or spread/compacted, as previously described.

[00226] During operation of the apparatus the speed of relative movement between the material deposition head 3 and the bed 2 holding the powder material 4 may be in the range of between about 5mm/s to about 40mm/s. The speed of relative movement should be determined based on the flow rate of the polymer solution 5 being deposited and the desired thickness of the beads 5a, 5b of polymer solution 5 being deposited. In examples, the speed of relative movement may be between about 5mm/s and about 15mm/s.

[00227] In examples, the polymer solution 5 comprises a pharmaceutically acceptable polymer, such as an enteric polymer. For example, the polymer solution 5 may comprise an anionic copolymer based on methacrylic acid and methyl methacrylate (e.g., Eudragit 12.5 as marketed by Evonik Healthcare). A pharmaceutical dosage form formed with an enteric polymer may have an enteric shell when that enteric polymer forms the outer coating on the dosage form.

[00228] In other examples, the polymer solution 5 may comprise an alternative pharmaceutically acceptable material, such as a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a poly(vinyl acetate phthalate) (PVAP), a hydroxypropyl methylcellulose phthalate (HPMCP), an acrylate, a polymethacrylate, a hydroxypropyl methylcellulose, a methyl cellulose, or an ethyl cellulose.

[00229] In other examples, an alternative, non-polymer pharmaceutically acceptable liquid material may be used, for example an ester of aleurtic acid (e.g., a shellac), or a sugar, or a sweetener.

[00230] In examples where the polymer solution 5 is deposited by a material deposition head 3 having a syringe 22 and needle 21, for example a pneumatic or electric syringe 22, the syringe 22 may be operated at a pressure above about 500 kPa, preferably above about 600 kPa, preferably above about 1400 kPa, preferably up to about 2800 kPa. The needle 21 may have a gauge of between 22-gauge and 25-gauge. The polymer solution 5 may have a viscosity of between about 500 cP and about 3000 cP. This combination of operating parameters has proven to provide stable and accurate material deposition, allowing a product to be additively manufactured on or in the powder material as described above.

[00231] In one specific example, the polymer solution 5 may have a viscosity of between about 1000cps and about 1500 cps, and the polymer solution 5 may be deposited through a 25-gauge needle. The polymer solution 5 may be deposited by a syringe 22 operating at a pressure of 120 kPa. In such an example, the speed of relative movement between the material deposition head 3 and the bed 2 may be between about 5mm/s and about 40mm/s to provide stable and accurate deposition of the polymer solution 5 onto or into the powder material 4. A preferred range for control of the polymer solution 5 as it is deposited is between about 5mm/s and about 15 mm/s. Increasing the pressure, for example to in excess of about 200 kPa, may permit the speed to be increased up to about 40 mm/s.

[00232] The viscosity of the polymer solution 5 may be controlled by adjusting the proportions of solute and solvent in the polymer solution 5. The polymer solution 5 may additionally comprise a polymer powder, for example a polymer powder that is mixed into the polymer solution 5 without dissolving. In some examples, an Eudragit® L12.5 (marketed by Evonik Industries AG) solution can be mixed with Eudragit® L100 powder (marketed by Evonik Industries AG) and a solvent such as isopropyl alcohol. A higher viscosity polymer solution 5 may be beneficial for forming the product.

[00233] For each of the methods illustrated in FIGS. 13 and 14, the powder material may comprise a pharmaceutical ingredient, for example an active pharmaceutical ingredient.

The powder material may additionally comprise a pharmaceutical excipient or diluent such as a starch, an anhydrous lactose, a lactose monohydrate, or a sugar or alcohol.

[00234] The pharmaceutical ingredients may, in examples, comprise live biotherapeutic product, for example bacteria and/or bacteriophage. Alternatively, or additionally, the pharmaceutical material may comprise non-viable or dead bacteria or bacteriophage, or extracts or portions thereof. The bacteria and/or bacteriophage may be modified or natural. Any of these microbiological pharmaceutical products may be provided in lyophilised form. Consequently, the pharmaceutical material may be lyophilised live bacteria. In examples, the powder material has a grain size of between about 30 microns and about 60 microns and a grain size distribution of between about 50% and about 90%. Advantageously, such a powder material may, particularly when a channel is formed, help to maintain the form of the deposited bead of polymer solution and prevent bleeding of the polymer solution into the surrounding powder material. As mentioned above, selecting a powder material with narrower grain size distribution may help to prevent incorporation of the powder material into the deposited polymer solution. In addition, a relatively dry powder material may also help to prevent incorporation of the powder material into the deposited polymer solution.

[00235] Accordingly, if it is desired to incorporate a portion of the powder material into the deposited polymer solution then a powder material with a larger grain size, and/or a wider grain size distribution, and/or more humidity, may be selected.

[00236] In examples, the apparatus and methods relate to depositing a polymer solution 5 onto or into a powder material 4, particularly a powder material comprising a pharmaceutical ingredient, to additively manufacture a pharmaceutical dosage form.

[00237] In various examples, the pharmaceutical dosage form is a capsule, for example a hard or soft coated capsule, or a chewable capsule. In other examples, the pharmaceutical dosage form is a tablet, such as a coated tablet, or a chewable tablet. In other examples, the pharmaceutical dosage form is a lozenge, or a pill, or a pillule. The pharmaceutical dosage form may be for oral use, or for use as a suppository, or for use as a vaginal pharmaceutical dosage form, or for use an inhalable pharmaceutical dosage form, or for use as an intrauterine pharmaceutical dosage form.

[00238] The additive manufacturing apparatus and methods offer several advantages for manufacturing pharmaceutical dosage forms. In particular, the additive manufacturing processes described herein are simpler than existing methods for manufacturing coated pharmaceutical dosage forms, such as coated tablets, and provide improved accuracy and reduced wastage.

[00239] Additively manufacturing a pharmaceutical dosage form by the methods described above may provide improved control over thickness of the shell/coating. In particular existing coating processes, such as a tablet coating process, relies on estimating when the coating has been applied in sufficient quantity to provide the desired coating thickness. The nature of the tumbling process for coating tablet cores means that coatings are inevitably uneven, leading to variability across individual tablets and across batches of tablets, and accurate control of coating thickness is difficult. An additive manufacturing process closely controls the thickness of the shell, providing improved control over the pharmaceutical dosage form.

[00240] In addition, as described above the curing unit may be configured to focus heat on the deposited polymer solution to reduce heat that may be imparted on the surrounding powder material. This advantageously prevents or reduces heating of the powder material, which is something that is not achievable in existing tablet coating apparatus where hot air is required to be passed through the drum to facilitate bonding of the coating material to the tablets. This is particularly advantageous where the powder material is heat-sensitive, for example if the powder material comprises an active pharmaceutical ingredient.

[00241] The additive manufacturing processes described herein also provide improved variability over the size and shape of the pharmaceutical dosage form. In particular, as set above, existing tablet coating technologies require the tablet to be tumbled in a drum to be coated. Such tumbling means that the tablets must have even, rounded forms. With the additive manufacturing processes described herein the pharmaceutical dosage form can be produced in any shape and size that may be beneficial for delivery of the pharmaceutical dosage form and/or may be more difficult to counterfeit.

[00242] The additive manufacturing processes described herein also provide advantageous manufacturing solutions for smaller productions runs. For example, during development and testing of a pharmaceutical medicine and/or pharmaceutical dosage form, small batches of pharmaceutical dosage forms can be produced with limited amounts of pharmaceutical ingredients. This is in contrast to existing manufacturing processes that require large amounts of pharmaceutical ingredients because of the large capacity of the manufacturing apparatus and the inevitable wastage due to the tablet forming-and-coating process.

[00243] The additive manufacturing processes described herein may also provide advantages for personalised medicines. In particular, the additive manufacturing processes described herein may provide for small production runs with customisable pharmaceutical dosages and shell thicknesses, allowing the pharmaceutical dosage form to be personalised to a particular patient or sub-set of patients. This may overcome many disadvantages of the current 'one size fits all' approach to manufacturing pharmaceutical dosage forms.

[00244] The additive manufacturing processes described herein may also provide advantages for the location of manufacturing pharmaceutical dosage forms. For example, the additive manufacturing apparatus may be significantly smaller, and require significantly less energy, than exiting manufacturing apparatus, allowing it to be deployed remotely with relatively small amounts of pharmaceutical ingredients required. For example, the additive manufacturing apparatus may be remotely deployed in emergency zones, war zones, refugee camps, etc... to provide on-site manufacture of pharmaceutical dosage forms. The adaptability of the additive manufacturing apparatus provides for customising the pharmaceutical dosage forms to the particular needs at that location, and only requires the relevant pharmaceutical ingredients and polymer solution to operate.

[00245] The above-described apparatus and methods relate to depositing a liquid material, particularly a polymer solution, onto or into a bed of particulate material, particularly a powder material comprising a pharmaceutical ingredient, to produce a pharmaceutical dosage form. However, it will be appreciated that the apparatus and methods described herein may alternatively be used to additively manufacture a non-pharmaceutical product by depositing a liquid material onto or into a particulate material in the same way as described above.

[00246] For example, the apparatus and methods described herein may be used to manufacture food products, containers of unstable powders (e.g., fireworks), prosthetics, orthotics, and other medical devices. In such examples the liquid material may comprise a polymer solution or other liquid material capable of being solidified, and the particulate material may comprise a powder material appropriate for the product.

[00247] It will be appreciated that many of the advantages described above may also apply to the manufacture of non-pharmaceutical products.

[00248] In various examples, including examples where a pharmaceutical dosage form is additively manufactured and examples where a non-pharmaceutical product is additively manufactured, the deposited material may be a liquid material other than a polymer solution.

[00249] For example, the liquid material may comprise a foodstuff for manufacture of a food product. For example, the liquid material may comprise a sugar, a sweetener, or other solidifiable liquid material.

[00250] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00251] Features, integers, characteristics or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

CLAIMS1. A method of additively manufacturing a product, the method comprising: providing a bed of particulate material; forming a first channel in the bed of particulate material; depositing a first bead of liquid material in the first channel; dispensing further particulate material onto the bed of particulate material; forming a second channel in the bed of particulate material; depositing a second bead of liquid material in the second channel; and solidifying the first bead of liquid material and the second bead of liquid material to form a solid structure of the product.
2. The method of claim 1, wherein the liquid material is deposited by a material deposition head, and wherein the method further comprises moving the material deposition head and/or the bed of particulate material such that the material deposition head deposits the liquid material in the first channel and subsequently in the second channel.
3. The method of claim 2, wherein a channelling member is mounted to the material deposition head, and wherein the method further comprises moving the material deposition head and/or the bed such that such that the channelling member forms the first channel and subsequently the second channel.
4. The method of claim 3, comprising simultaneously forming the first channel and depositing the first bead of liquid material in the first channel.
5. The method of any preceding claim, comprising depositing the liquid material through a needle.
6. The method of claim 5, further comprising positioning an end of the needle below a surface of the bed of particulate material, for example about 1 mm below the surface of the bed of particulate material, and moving the needle and/or the bed of particulate material such that the needle forms the channel and simultaneously deposits the liquid material.
7. The method of claim 5, further comprising providing a channelling member in a fixed position relative to the needle, and moving the channelling member and/or the bed of particulate material such that the channel is formed by the channelling member.
8. The method of any preceding claim, comprising depositing the liquid material such that a portion of the particulate material is encapsulated within the solid structure.
9. The method of claim 8, comprising depositing the liquid material to form a plurality of nested solid structures, and encapsulating a portion of the particulate material in a layer between two nested solid structures.
10. A method of additively manufacturing a product, the method comprising: providing a bed of particulate material; depositing a first bead of a liquid material and a second bead of a liquid material into or onto the bed of particulate material; solidifying the liquid material to form a solid structure; and encapsulating a portion of the particulate material within the solid structure.
11. The method of claim 10, further comprising forming a first channel in the bed of particulate material and depositing the first bead of the liquid material in the first channel, and subsequently forming a second channel in the bed of particulate material and depositing the second bead of liquid material in the second channel.
12. The method of any preceding claim, wherein forming the second channel in the bed of particulate material comprises exposing at least a part of the first bead of liquid material and depositing the second bead of liquid material in direct contact with the first bead of liquid material.
13. The method of any of claims 10 to 12, comprising depositing the first and second beads of liquid material to form a plurality of nested solid structures, and encapsulating a portion of the particulate material in a layer between two nested solid structures.
14. The method of any preceding claim, wherein the liquid material comprises an enteric polymer.
15. The method of any preceding claim, wherein the particulate material comprises a pharmaceutical ingredient, in particular an active pharmaceutical ingredient such as a microbe.
16. The method of any preceding claim, further comprising incorporating a portion of the particulate material into the deposited first and/or second bead of liquid material before the liquid material is solidified such that the particulate material forms a part of the solid structure.
17. Apparatus for additively manufacturing a product, the apparatus comprising: a bed configured to hold a particulate material, and a material deposition head arranged to deposit a liquid material onto or into the particulate material such that a solid structure of the product is formed when the liquid material solidifies.
18. The apparatus of claim 17, further comprising a channelling member arranged move relative to the bed to form a channel in the particulate material, and wherein the material deposition head is arranged to deposit the liquid material in the channel.
19. The apparatus of claim 18, wherein the material deposition head and/or the bed is movable and the channelling member is mounted to the material deposition head such that as the material deposition head moves relative to the bed the channel is formed and the liquid material is deposited in the channel.
20. The apparatus of any of claims 17 to 19, wherein the material deposition head and/or bed is movable to change a distance between the particulate material and the material deposition head.
21. The apparatus of any of claims 17 to 20, further comprising a particulate material dispensing system configured to deposit a layer of particulate material onto the bed.
22. The apparatus of any of claims 17 to 21, further comprising a curing unit arranged to at least partially solidify the liquid material by curing, the curing unit being arranged to at least partially cure the liquid material as the liquid is deposited onto or into the particulate material.
23. A product manufactured using the method of any of claims 1 to 16, or the apparatus of any of claims 17 to 22.
24. A pharmaceutical dosage form comprising an additively manufactured solid structure encapsulating a particulate material comprising a pharmaceutical ingredient.
25. The pharmaceutical dosage form of claim 24, comprising a plurality of nested solid structures with a layer of particulate material disposed between each nested solid structure.