METHOD FOR MANUFACTURING A SOLID ADMINISTRATION FORM AND SOLID ADMINISTRATION

Abstract

For manufacturing a solid administration form comprising at least one active pharmaceutical ingredient, a flowable but setting composite material comprising the at least one active pharmaceutical ingredient is added together and set to generate the solid administration form. The flowable composite material is liquefied and delivered to a discharge unit. Small portions of liquefied composite material are intermittently discharged through an outlet into a setting unit. The flowable composite material comprises a polymer and at least one active pharmaceutical ingredient dispersed or dissolved within the polymer. The small portions are droplets and the solid administration form is generated by adding droplets that stick together before or during the setting of the liquefied composite material. An average diameter of the droplets can be less than 350 μm. There can be a void space between at least some small portions, resulting in a porous structure of the solid administration form.

Claims

1. A method for manufacturing a solid administration form (2) comprising at least one active pharmaceutical ingredient, wherein a flowable but setting composite material (16, 20, 25, 26, 27) comprising the at least one active pharmaceutical ingredient is added together and set to generate the solid administration form (2), characterized in that the flowable composite material (16, 20, 25, 26, 27) is liquefied and delivered to at least one discharge unit (3), and that small portions (12) of the liquefied composite material (16, 20, 25, 26, 27) are intermittently discharged through an outlet of the discharge unit (3) into a setting unit (13) where the setting of the small portions (12) occurs, thereby gradually generating the solid administration form (2).

2. The method of claim 1, characterized in that the flowable composite material (16, 20, 25, 26, 27) comprises a polymer or combination of different polymers and at least one amorphous active pharmaceutical ingredient that is dispersed or dissolved within the polymer.

3. The method of claim 1, characterized in that the flowable but setting composite material (16, 20, 25, 26, 27) includes non-soluble porous or non-porous carrier particles for altering or enhancing the properties of the solid administration form (2).

4. The method of claim 1, characterized in that the flowable composite material (16, 20, 25, 26, 27) is fabricated during delivery to the discharge unit (3).

5. The method of claim 1, characterized in that the flowable composite material (16, 20, 25, 26, 27) is made of or comprises granules prepared by known methods like e.g. hot melt extrusion, wet granulating, dry compaction or twin screw granulation or/and a particle kind of material.

6. The method of claim 1, characterized in that the small portions (12) of the liquefied composite material (16, 20, 25, 26, 27) are droplets and that the solid administration form (2) is generated by adding droplets that bond or stick together before or during the setting of the liquefied composite material (16, 20, 25, 26, 27).

7. The method of claim 6, characterized in that an average diameter of the droplets is less than 350 μm, and in that the average diameter of the droplets is larger than 20 μm.

8. The method of claim 1, characterized in that there is a void space (14, 24) between at least some small portions (12) that are placed adjacent to each other, resulting in a porous structure of the solid administration form (2).

9. The method of claim 1, characterized in that before or after discharging a predetermined first amount of a composite material (16) a predetermined second amount of a second material (18) is discharged, whereby the material of the second material (18) differs from the composite material (16).

10. The method of claim 1, characterized in that composite material (16, 20, 25, 26, 27) is discharged from more than one discharge units (3), which have different sizes.

11. The method of claim 1, characterized in that the small portions (12) of the composite material (16, 20, 25, 26, 27) are discharged into an arrangement of the small portions (12) such that the solid administration form (2) comprises at least two regions with different characteristics of the active pharmaceutical ingredient and optionally different porosity.

12. Solid administration form (2) comprising at least one active pharmaceutical ingredient, whereby the solid administration form (2) is manufactured by liquefying at least one flowable composite material (16, 20, 25, 26, 27) and delivering the liquefied composite material(s) (16, 20, 25, 26, 27) to at least one discharge unit (3), whereby small portions (12) of the liquefied composite material are intermittently discharged through the outlet(s) of the discharge unit(s) (3) into a setting unit where the setting of small portions (12) occurs, thereby gradually generating the solid administration form (2) by performing the method of claim 1.

13. The method of claim 7, wherein the average diameter of the droplets is less than 200 μm.

14. The method of claim 7, wherein the average diameter of the droplets is larger than 50 μm.

15. The method of claim 13, wherein the average diameter of the droplets is larger than 50 μm.

Description

LIST OF FIGURES

[0071] FIG. 1: Schematic view of a manufacturing device for additive manufacturing of a solid administration form.

[0072] FIG. 2: Schematic perspective view of a solid administration form composed of a large number of small portions of composite material.

[0073] FIG. 3: Schematic perspective view of another embodiment of a solid administration form composed of larger small portions that the embodiment shown in FIG. 2.

[0074] FIG. 4: Schematic perspective view of another embodiment of a solid administration form comprising void spaces within the solid administration form.

[0075] FIG. 5: Schematic perspective view of another embodiment of a solid administration form.

[0076] FIG. 6: Section view of the solid administration form shown in FIG. 5 along the line VI-VI in FIG. 5.

[0077] FIG. 7: Schematic perspective view of another embodiment of a solid administration form.

[0078] FIG. 8: Section view of the solid administration form shown in FIG. 7 along the line VIII-VIII in FIG. 7.

[0079] FIG. 9: Schematic perspective view of another embodiment of a solid administration form.

[0080] FIG. 10: Section view of the solid administration form shown in FIG. 9 along the line X-X in FIG. 9.

[0081] FIG. 11: Schematic perspective view of another embodiment of a solid administration form.

[0082] FIG. 12: Top view of the solid administration form shown in FIG. 11

[0083] FIG. 13: Section view of yet another embodiment of a solid administration form with a density of adjacent small portions increasing from the middle to the outer surface of the solid administration form

[0084] FIG. 14: Section view of yet another embodiment of a solid administration form with a density of adjacent small portions decreasing from the middle to the outer surface of the solid administration form.

[0085] FIG. 15: top view of yet another embodiment of a solid administration form with a ring-shaped outer structure and with a cross-shaped structure inside the ring-shaped outer structure.

[0086] FIG. 16: top view of yet another embodiment of a solid administration form similar to the embodiment shown in FIG. 15 but comprising three different composite materials.

[0087] FIG. 17: side view of yet another embodiment of a solid administration form composed of five strip-shaped structures each comprising a different composite material.

[0088] FIG. 18: top view of the solid administration form shown in FIG. 17

[0089] FIG. 19: Schematic perspective view of another embodiment of a ball-shaped hollow solid administration form with a mesh-like casing.

[0090] FIG. 20: Schematic perspective view of another embodiment of a tablet-shaped or capsule-shaped solid administration form

[0091] FIG. 21: Schematic perspective view of another embodiment of a torus-shaped solid administration form.

[0092] FIG. 22: Example 7: 3D printed tablet comprising pure PVA as suitable thermal binder with 100% filling rate.

[0093] FIG. 23: Example 8: 3D printed tablet comprising a binary dispersion of PVA as suitable thermal binder and 10% Caffeine as active pharmaceutical ingredient with 100% filling rate.

[0094] FIG. 24: Example 9; 3D printed tablet comprising a binary dispersion of PVA and 10% Caffeine with 50% filling rate.

[0095] FIG. 25: Example 10; 3D printed tablets comprising a binary dispersion of PVA and 10% Dipyridamole with 100% filling rate.

[0096] FIG. 26: Example 11; 3D printed tablets comprising a binary dispersion PVA and 10% Dipyridamole with 50% filling rate.

[0097] FIG. 27: Example 12; 3D printed tablets comprising a binary dispersion of PVA and 10% Dipyridamole with 30% filling rate.

[0098] FIG. 28: Example 13: 3D printed tablets with outer shell (100% filling rate) of pure PVA and an inner core comprising a binary dispersion of PVA as suitable thermal binder and dipyridamole (yellow/orange color) as active pharmaceutical ingredient. Printing was stopped after 2 mm height for better visibility of principle.

[0099] FIG. 29: Example 13; 3D printed tablets with outer shell (50% filling rate) of pure PVA and an inner core comprising a binary dispersion of PVA as suitable thermal binder and dipyridamole (yellow/orange color) as active pharmaceutical ingredient

[0100] FIG. 30: Release of Dipyridamole: Results achieved by dissolution measurement of 3D printed dipyridamole containing tablets (Ex. 10, 11 and 12) in phosphate buffer pH 6.8

[0101] FIG. 31: Release of Caffeine: Results achieved by dissolution measurement of 3D printed caffeine containing tablets (Ex. 8 and Ex. 9) in 0.1 n HCl.

EXAMPLES

[0102] The present description enables the person skilled in the art to apply the invention comprehensively. Even without further comments, it is assumed that a person skilled in the art will be able to utilize the above description in the broadest scope.

[0103] Practitioners will be able, with routine laboratory work, using the teachings herein, to prepare active ingredients comprising formulations as defined above in the new process.

Example 1

Preparation of a Suitable Thermal Binder in Form of Granules, to be Used in the 3D Printing Process, by Hot Melt Extrusion (HME)

[0104] Pre-treatment of the material:

[0105] For the preparation of a suitable thermal binder in form of granules for the 3D Printing process by HME 2.0 kg polyvinyl-alcohol=PVA (Parteck MXP, Cat No 141360 from Merck KGaA Germany) with optimized particle size distribution for HME is dried at 85° C. in a vacuum oven.

[0106] Extrusion is started by adjusting the dosing rate of the dosing unit and the screw speed of the extruder in small increments until the target parameters of 0.35 kg/h and 350 rpm reached. This takes about 5 minutes from starting the process until the first exit of extrudate from the nozzle. The extrudate emerges as very homogeneous, transparent strand from the nozzle (2 mm in diameter), having a yellow-orange color.

[0107] Extruder conditions used:

[0108] Pressure at the nozzle 14-15 bar.

[0109] Melting temperature 192° C. and a torque of 41-42%,

[0110] Heating zones HZ 1=80° C./HZ 2−HZ 7=200° C.

[0111] Nozzle temperature=200° C.

[0112] The extrudate strand is discarded for about 10 minutes until it emerges homogeneously from the die. Thereafter, the strand is started to be conveyed to the pelletizer by means of a conveyor belt, which gives the extrudate a short cooling phase at room temperature and then it is cut into 1.5 mm pellets in length. The material is finally dried under vacuum conditions at 85° C. before it is used in 3D printing device to a LOD<0.1%.

Example 2

Preparation of a Binary Dispersion Comprising Dipyridamole as Active Pharmaceutical Ingredient (API) and PVA as Thermal Binder in Form of Granules for Use in the 3D Printing Process, by Hot Melt Extrusion (HME)

[0113] Preparation of the mixture:

[0114] The binary mixture of PVA polymer (dried at 85° C. in a vacuum oven) and 10% API is prepared by mixing of 1.8 kg of PVA 4-88 (Parteck MXP, Cat No 141360 from Merck KGaA Germany) and 0.2 kg Dipyridamole Ph. Eur (LGM Pharma) as model API with yellow colour in a 10 L drum using a Röhnradmischer for 15 minutes.

[0115] Extrusion is started by adjusting the dosing rate of the dosing unit and the screw speed of the extruder in small increments until the target parameters of 0.35 kg/h and 350 rpm reached. This takes about 5 minutes from starting the process until the first exit of extrudate from the nozzle. The extrudate emerges as very homogeneous, transparent strand from the nozzle (2 mm in diameter), having a yellow-orange colour.

[0116] Extruder conditions:

[0117] Pressure at the nozzle 14-15 bar.

[0118] Melting temperature 192° C. and a torque of 41-42%,

[0119] Heating zones HZ 1=80° C./HZ 2−HZ 7=200° C.

[0120] Nozzle temperature=200° C.

[0121] The extrudate strand is discarded for about 10 minutes until it emerges homogeneously from the die. Thereafter, the strand is started to be conveyed to the pelletizer by means of a conveyor belt, which gives the extrudate a short cooling phase at room temperature and then it is cut into 1.5 mm pellets in length. The material is finally dried under vacuum conditions at 85° C. before use in 3D printing device to a LOD<0.1%.

Example 3

Preparation of a Suitable Thermal Binder for Use in the 3D Printing Process, by “Dry Compaction”

[0122] For the preparation of a suitable thermal binder in form of dry compacted granules for the 3D Printing process 2.6 kg polyvinyl-alcohol (PVA; Parteck MXP, Cat No 141360 from Merck KGaA Germany) are compacted by a physical dry compaction process.

[0123] For the dry compaction process a Powtec-Kompaktor RCC 100x20 (Powtec Maschinen und Engineering GmbH, Remscheid, Deutschland) is used, equipped with a sieve of 2.24 mm mesh size. The product introduction of PVA powder is carried out with 30 rpm. For compaction, lumbers provided with lines and a lumber speed of 3 rpm a hydraulic pressure of 125 bars with a lumber slit of 2.1 mm as well as a sieving mill speed of 50 rpm is used.

[0124] Dry compacted PVA 4-88 granules (>710 μm) are prepared with a yield of 2.28 kg under conditions as described before. The material is finally dried under vacuum conditions at 85° C. before use in 3D printing device to a LOD<0.1%.

Example 4

Preparation of a Binary Dispersion of an API and PVA as Suitable Thermal Binder in Form of Granules, to be Used in the 3D Printing Process, by “Dry Compaction”

[0125] Preparation of the mixture:

[0126] The binary mixture of PVA polymer and 10% API is prepared by mixing 1.8 kg of PVA 4-88 (Parteck MXP, Art No 141360 from Merck KGaA Germany) with 0.2 kg Caffeine (from Shandong Xinhua Pharmaceuticals China) as model API in a 12 L drum using a Röhnradmischer Elte 650, (Engelsmann AG, Ludwigshafen, Deutschland) for 5 minutes (36 rpm). After the first mixing time the mixture of PVA polymer and caffeine are homogenized by using a 710 μm sieve followed by another 5 minutes of mixing.

[0127] For dry compaction 1.9 kg of the resulting mixture is dry compacted using a Powtec-Kompaktor RCC 100x20 (Powtec Maschinen und Engineering GmbH, Remscheid, Deutschland), equipped with a sieve of 2.24 mm mesh size. Product introduction of PVA powder is carried out with 30 rpm. For compaction, lumbers provided with lines and a lumber speed of 3 rpm a hydraulic pressure of 125 bars with a lumber slit of 1.5 mm as well as a sieving mill speed of 50 rpm is used.

[0128] Resulting dry compacted mixture with a yield of 1.66 kg of PVA 4-88/caffeine granules (>710 μm) prepared using conditions as described before. The material is finally dried under vacuum conditions at 85° C. before use in 3D printing device to a LOD<0.1%.

Example 5

Preparation of a Suitable Thermal Binder for Use in the 3D Printing Process, by Twin Screw Wet Granulation (TSG)

[0129] Granulation:

[0130] 1.6 kg of PVA 4-88 (Parteck MXP, Cat. No 141360, Merck KGaA Germany) are weighed into a stainless-steel bowl and sieved through a 1 mm sieve into a 5 L stainless-steel barrel and mixed for 10 min in a drum hoop mixer.

[0131] For the granulation a Pharma 11 hot melt extruder modified with a TSG conversion kit (ThermoFisher Scientific) is used. The powder mixture is added with a gravimetric feeder (Brabender Congrav OP1T), and DI water is added with a peristaltic pump (Cole-Parmer Masterflex L/S). Each screw consists of 4 Long Helix Feed Screws 3/2 UD, 4 Feed Screws 1 L/D, 7 mixing elements 60° offset, 26 Feed Screws 1 L/D, 1 Distributive Feed Screw (front to end).

[0132] Before granulation, the barrel temperature is set to 30° C. Then the barrel is flooded with water at slow screw speed (10 rpm) and a water addition of ˜200 mL/h. To prepare the granules the water addition is reduced to 30.1 mL/h, which corresponds to the L/S ratio of 0.086. The screw speed is increased to 50 rpm and powder addition is started with an amount of 0.1 kg/h. Then the screw speed and the powder feed-rate are increased stepwise (50-, then 100 rpm steps) until the desired screw speed of 500 rpm is reached and the powder feed-rate is increased up to a feed rate of 0.35 kg/h (0.05 kg/h steps).

[0133] The first material processed in this manner is discarded. When the torque has reached a constant level (after approx. 5 min) the resulting granules are collected in a stainless-steel bowl. To get the desired amount of 1 kg granules, the granulation is run for almost 3 hours. Resulting granules are tray dried in a vacuum oven for 24 h at 50° C./0.1 bar to a LOD<0.1%.

[0134] Before use in the 3D printing process material the product is additionally sieved through a 5 mm sieve in order to avoid a blocking of the dosing of granules into the 3D printer by contained coarse particles.

Example 6

Preparation of a Binary Dispersion of an API and PVA by Twin Screw Wet Granulation as Suitable Thermal Binder for Use in the 3D Printing Process

[0135] a) Preparing the mixture:

[0136] 1.6 kg of PVA 4-88 (Parteck MXP, Cat. No 141360, Merck KGaA Germany) and 0.4 kg of Dipyridamole Ph. Eur (LGM Pharma) are weighed into a stainless-steel bowl. Then both components are sieved through a 1 mm sieve into a 5 L stainless-steel barrel and mixed for 10 min in a drum hoop mixer.

[0137] b) Granulation:

[0138] For the granulation process a Pharma 11 hot melt extruder is used modified with a TSG conversion kit (ThermoFisher Scientific). The powder mixture is added with a gravimetric feeder (Brabender Congrav OP1T) DI water is added with a peristaltic pump (Cole-Parmer Masterflex L/S). Each screw consisted of 4 Long Helix Feed Screws 3/2 L/D, 4 Feed Screws 1 L/D, 7 mixing elements 60° offset, 26 Feed Screws 1 L/D, 1 Distributive Feed Screw (front to end).

[0139] Before granulation, the barrel temperature is set to 30° C. Then the barrel is flooded with water at slow screw speed (10 rpm) and a water addition of ˜200 mL/h. To prepare the granules the water addition is reduced to 30.1 mL/h, which corresponds to the L/S ratio of 0.086. Then the screw speed is increased to 50 rpm and the powder addition is started with 0.1 kg/h. the screw speed and the powder feed-rate are increased stepwise until the desired screw speed of 500 rpm (50-, then 100 rpm steps) and a powder feed-rate of 0.35 kg/h (0.05 kg/h steps) are reached.

[0140] The first material processed in this manner is discarded. When the torque has reached a constant leave (after approx. 5 min) the resulting granules are collected in a stainless-steel bowl. To get the desired amount of 1 kg granules, the granulation is run for almost 3 hours. The resulting granules are tray dried in a vacuum oven for 24 h at 50° C./0.1 bar to a LOD<0.1%.

[0141] Before use in the 3D printing process the material is additionally sieved through a 5 mm sieve in order to avoid a blocking of the dosing of granules into the 3D printer by contained coarse particles.

[0142] c) 3 D printing process using a suitable thermal binder as composite material with and without addition of API:

[0143] The process of printing is performed whereby the flowable composite material is liquefied and delivered to a discharge unit, whereby small portions of the liquefied composite material are intermittently discharged through an outlet of the discharge unit into a setting unit where the setting of small portions occurs, thereby gradually generating the solid administration form. This manufacturing method of additive manufacturing does not require the tedious prefabrication of a filament that is fed to the 3D printing device.

[0144] The suitable thermal binder as pure polymer or mixtures of polymer and API additives prepared in examples 1-6 are used for the printing of solid administration forms in an additive manufacturing process (3D Printing) with a “Freeformer” from ARBURG GmbH+Co KG, Lossburg, Germany.

Example 7

3D Printing of Tablets of Pure PVA as Suitable Thermal Binder with 100% Filling Rate

[0145] The suitable thermal binder in granulated form, prepared in Example 1, with a material density of 1.27 g/cm.sup.3 was pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.32%.

[0146] When the preconditioned, granulated material which is prepared in Examples 1, is used, neither bridging nor feeding problems are observed throughout the experimental series

Evaluation of Printing Parameter and Printing of Solid Administration Form

[0147] a) Determination of processing parameters & discharge properties:

[0148] Granulated material, which is prepared in Examples 1, forms well separable droplets, and homogeneously drops out from the nozzle. At a nozzle temperature of 220° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% was achieved with 70% discharge.

[0149] b) Conditions used for the printing process:

[0150] Temperature discharge unit: 200° C.

[0151] Temperature zone 2: 190° C.

[0152] Temperature zone 1: 180° C.

[0153] Temperature printing room: 80° C.

[0154] Dynamic pressure: 40 bar

[0155] Metering stroke: 6 mm

[0156] Decompression speed: 2 mm/s

[0157] Decompression space: 5 mm

[0158] Discharge: 70%

[0159] In order to find the suitable aspect ratio, test printing with different slicer volume (ratio of width and layer thickness) is adjusted. Best properties can be achieved with an aspect ratio of 1.36 using a material as prepared in Example 1.

[0160] If conditions are used as described before and if the binder of Example 1 is used an optimized 3D printing process can be performed to generate the solid administration form as projected and depicted in FIG. 2. Resulting solid administration form with 100% filling rate of polyvinyl alcohol was analyzed by optical method (FIG. 22).

Example 8

3D Printing of Tablets of Binary Dispersion PVA as Suitable Thermal Binder and 10% Caffeine as Active Pharmaceutical Ingredient with 100% Filling Rate

[0161] The suitable thermal binary binder (PVA+10% caffeine) in granulated form, prepared in Example 4, are pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.07%.

[0162] Using the preconditioned granulated material prepared in Examples 4 neither bridging nor feeding problems are observed throughout the experimental series [0163] Evaluation of printing parameter and printing of solid administration form:

Determination of Processing Parameters & Discharge Properties

[0164] Granulated material prepared in Examples 4 formed well separable droplets, homogeneously dropping out from the nozzle. At a nozzle temperature of 200° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% was achieved with 65% discharge.

[0165] Conditions used for the printing process:

[0166] Temperature discharge unit: 190° C.

[0167] Temperature zone 2: 180° C.

[0168] Temperature zone 1: 170° C.

[0169] Temperature printing room: 80° C.

[0170] Dynamic pressure: 80 bar

[0171] Metering stroke: 5 mm

[0172] Decompression speed: 2 mm/s

[0173] Decompression space: 5 mm

[0174] Discharge: 65%

[0175] In order to find the suitable aspect ratio, test printings with different slicer volume (ratio of width and layer thickness) are adjusted. Best properties can be achieved with an aspect ratio of 1.34 using material prepared in Example 4.

[0176] By using conditions describe before, optimize 3D printing process is performed with suitable binder of Example 4 (polyvinyl alcohol+10% caffeine) to generate the solid administration form as projected and depicted in FIG. 2. Resulting solid administration form with 100% filling rate of the binder mixture of polyvinyl alcohol+10% caffeine as API is analyzed by optical method (FIG. 23).

Example 9

3D Printing of Tablets of Binary Dispersion PVA as Suitable Thermal Binder and 10% Caffeine as Active Pharmaceutical Ingredient with 50% Filling Rate

[0177] The suitable thermal binary binder (PVA+10% caffeine) in granulated form, prepared in Example 4, is pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.07%.

[0178] Using the preconditioned granulated material prepared in Example 4 neither bridging nor feeding problems are observed throughout the experimental series

[0179] Evaluation of printing parameter and printing of solid administration form: [0180] Determination of processing parameters and discharge properties

[0181] Granulated material prepared in Examples 4 form well separable droplets, homogeneously dropping out from the nozzle. At a nozzle temperature of 200° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% is achieved with 65% discharge. [0182] Conditions used for the printing process:

[0183] Temperature discharge unit: 190° C.

[0184] Temperature zone 2: 180° C.

[0185] Temperature zone 1: 170° C.

[0186] Temperature printing room: 80° C.

[0187] Dynamic pressure: 80 bar

[0188] Metering stroke: 5 mm

[0189] Decompression speed: 2 mm/s

[0190] Decompression space: 5 mm

[0191] Discharge: 65%

[0192] In order to find the suitable aspect ratio, test printings with different slicer volume (ratio of width and layer thickness) are adjusted. Best properties can be achieved with an aspect ratio of 1.34 using material prepared in Example 4.

[0193] By using conditions as described before, an optimized 3D printing process is performed with a suitable binder of Example 4 (polyvinyl alcohol+10% caffeine) to generate the solid administration form as projected and depicted in FIG. 3. Resulting solid administration form with 50% filling rate of binder mixture polyvinyl alcohol+10% caffeine as API is analyzed by an optical method (FIG. 24).

Example 10

3D Printing of Tablets of Binary Dispersion PVA as Suitable Thermal Binder and 10% Dipyridamole with 100% Filling Rate

[0194] The suitable thermal binary binder (PVA+10% Dipyridamole) in granulated form, prepared in Example 2, is pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.28%.

[0195] Using the preconditioned granulated material prepared in Example 2 neither bridging nor feeding problems are observed throughout the experimental series

[0196] Evaluation of printing parameter and printing of solid administration form: [0197] Determination of processing parameters and discharge properties

[0198] Granulated material prepared in Example 2 forms well separable droplets, homogeneously dropping out from the nozzle. At a nozzle temperature of 200° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% is achieved with 65% discharge. [0199] Conditions used for the printing process:

[0200] Temperature discharge unit: 190° C.

[0201] Temperature zone 2: 170° C.

[0202] Temperature zone 1: 160° C.

[0203] Temperature printing room: 80° C.

[0204] Dynamic pressure: 80 bar

[0205] Metering stroke: 6 mm

[0206] Decompression speed: 2 mm/s

[0207] Decompression space: 5 mm

[0208] Discharge: 65%

[0209] In order to find the suitable aspect ratio, test printings with different slicer volume (ratio of width and layer thickness) are adjusted. Best properties can be achieved with an aspect ratio of 1.31 using material prepared in Example 2.

[0210] By using conditions described before, optimized 3D printing process is performed with suitable binder of Example 2 (polyvinyl alcohol+10% Dipyridamole) to generate the solid administration form as projected and depicted in FIG. 2. Resulting solid administration form with 100% filling rate of binder mixture polyvinyl alcohol+10% Dipyridamole as API is analyzed by an optical method (FIG. 25).

Example 11

3D Printing of Tablets of Binary Dispersion PVA as Suitable Thermal Binder and 10% Dipyridamole with 50% Filling Rate

[0211] The suitable thermal binary binder (PVA+10% Dipyridamole) in granulated form, prepared in Example 2, is pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.28%.

[0212] Using the preconditioned granulated material prepared in Example 2 neither bridging nor feeding problems are observed throughout the experimental series

[0213] Evaluation of printing parameter and printing of solid administration form: [0214] Determination of processing parameters & discharge properties

[0215] Granulated material prepared in Example 2 forms well separable droplets, homogeneously dropping out from the nozzle. At a nozzle temperature of 200° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% is achieved with 65% discharge. [0216] Conditions used for the printing process:

[0217] Temperature discharge unit: 190° C.

[0218] Temperature zone 2: 170° C.

[0219] Temperature zone 1: 160° C.

[0220] Temperature printing room: 80° C.

[0221] Dynamic pressure: 80 bar

[0222] Metering stroke: 6 mm

[0223] Decompression speed: 2 mm/s

[0224] Decompression space: 5 mm

[0225] Discharge: 65%

[0226] In order to find the suitable aspect ratio, a test printing with different slicer volume (ratio of width and layer thickness) is adjusted. Best properties can be achieved with an aspect ratio of 1.31 using material prepared in Example 2.

[0227] By using conditions as described before, optimized 3D printing process is performed with suitable binder of Example 2 (polyvinyl alcohol+10% Dipyridamole) to generate the solid administration form as projected and depicted in FIG. 3. Resulting solid administration form with 50% filling rate of binder mixture polyvinyl alcohol+10% Dipyridamole as API is analyzed by optical method (FIG. 26).

Example 12

3D Printing of Tablets of Binary Dispersion PVA as Suitable Thermal Binder and 10% Dipyridamole with 30% Filling Rate

[0228] The suitable thermal binary binder (PVA+10% Dipyridamole) in granulated form, prepared in Example 2, is pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.28%.

[0229] Using the preconditioned granulated material prepared in Example 2 neither bridging nor feeding problems are observed throughout the experimental series

[0230] Evaluation of printing parameter and printing of solid administration form: [0231] Determination of processing parameters & discharge properties

[0232] Granulated material prepared in Example 2 forms well separable droplets, homogeneously dropping out from the nozzle. At a nozzle temperature of 200° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% is achieved with 65% discharge. [0233] Conditions used for the printing process:

[0234] Temperature discharge unit: 190° C.

[0235] Temperature zone 2: 170° C.

[0236] Temperature zone 1: 160° C.

[0237] Temperature printing room: 80° C.

[0238] Dynamic pressure: 80 bar

[0239] Metering stroke: 6 mm

[0240] Decompression speed: 2 mm/s

[0241] Decompression space: 5 mm

[0242] Discharge: 65%

[0243] In order to find the suitable aspect ratio, a test printing with different slicer volume (ratio of width and layer thickness) is adjusted. Best properties can be achieved with an aspect ratio of 1.31 using material prepared in Example 2.

[0244] By using conditions described before, an optimized 3D printing process is performed with suitable binder of Example 2 (polyvinyl alcohol+10% Dipyridamole) to generate the solid administration form as projected and depicted in FIG. 4. Resulting solid administration form with 30% filling rate of binder mixture polyvinyl alcohol+10% Dipyridamole as API is analyzed by an optical method (FIG. 27).

Example 13

3D Printing of Tablets with Outer Shell (100% Filling Rate) of Pure PVA and an Inner Core of a Binary Dispersion PVA as Suitable Thermal Binder and Dipyridamole (Yellow/Orange Color) as Active Pharmaceutical Ingredient

[0245] To prepare a solid administration form as depicted in FIGS. 5 and 6 an instrumental printer setup with two nozzles is used. Printing properties of both suitable thermal binders have to be evaluated before alternate printing using both nozzles.

[0246] Tablet dimensions planed with a total diameter of 10 mm and height of 4 mm containing a core of API mixture with a diameter of 5 mm and a height of 2 mm:

[0247] As properties of the first nozzle, the printing of pure PVA as suitable thermal binder prepared in example 1, same results used as evaluated for example 7:

[0248] As suitable thermal binary binder (PVA+20% Dipyridamole) printed by using the second nozzle material, prepared in Example 6, is pre-dried before feeding into the printing device. The residual moisture (goal<0.5%) is measured with an Aquatrac gauge at a temperature of 120° C. with 0.44%.

[0249] Using the preconditioned granulated material, prepared in Examples 1 and 6, neither bridging nor feeding problems are observed throughout the experimental series [0250] Evaluation of printing parameter (second nozzle) and printing of solid administration form: [0251] Determination of processing parameters and discharge properties

[0252] Granulated material prepared in Example 6 forms well separable droplets, homogeneously dropping out from the nozzle. At a nozzle temperature of 200° C. the material shows translucent droplets. The required drop height of 200 μm+10-20% is achieved with 60% discharge. [0253] Conditions used for the printing process:

[0254] Temperature discharge unit: 190° C.

[0255] Temperature zone 2: 180° C.

[0256] Temperature zone 1: 170° C.

[0257] Temperature printing room: 80° C.

[0258] Dynamic pressure: 80 bar

[0259] Metering stroke: 5 mm

[0260] Decompression speed: 2 mm/s

[0261] Decompression space: 5 mm

[0262] Discharge: 60%

[0263] In order to find the suitable aspect ratio, test printings with different slicer volume (ratio of width and layer thickness) are adjusted. Best properties can be achieved with an aspect ratio of 1.32 using material prepared in Example 6.

[0264] By using conditions as described before, an optimized 3D printing process is performed with suitable binder of Example 1 (pure polyvinyl alcohol) for the outer part of the solid administration form. The core containing a mixture of PVA and 20% Dipyridamole (Example 6) is printed by the second nozzle. Using the set-up a solid administration form as projected and depicted in FIGS. 5 and 6 is printed.

[0265] FIG. 5 illustrates a schematic perspective view of one embodiment of a solid administration form. FIG. 6 illustrates a section view of the solid administration form shown in FIG. 5 along the line VI-VI in FIG. 5.

[0266] Resulting solid administration form with 100% filling rate containing in the outer part pure PVA and an inner core of a binary dispersion PVA as suitable thermal binder and 20% Dipyridamole (yellow color) as active pharmaceutical ingredient is analyzed by an optical method (FIG. 28).

Example 14

3D Printing of Tablets with Outer Shell (50% Filling Rate) of Pure PVA and an Inner Core of a Binary Dispersion PVA as Suitable Thermal Binder and Dipyridamole (Yellow/Orange Color) as Active Pharmaceutical Ingredient

[0267] To prepare the solid administration form an instrumental printer setup with two nozzles is used. The printing properties of both suitable thermal binders have to be evaluated before alternate printing using both nozzles.

[0268] Tablets with tablet dimensions having a total diameter of 10 mm and height of 4 mm containing a core of an API mixture with a diameter of 5 mm and a height of 2 mm are prepared.

[0269] Same parameters are set for the first nozzle as found in the evaluation of example 7 for printing of pure PVA, as prepared in example 1 as suitable thermal binder.

[0270] As properties of the second nozzle, for printing of pure PVA+20% Dipyridamole as suitable binary thermal binder as prepared in example 6, same parameters are set as found in the evaluation of example 13.

[0271] By using conditions described before, an optimized 3D printing process is performed with 50% filling rate of the suitable binder of Example 1 (pure polyvinyl alcohol) for the outer part of the solid administration form. The core containing of a mixture of PVA and 20% Dipyridamole (Example 6) is printed with 100% filling rate by the second nozzle.

[0272] The resulting solid administration form with 50% filling rate containing in the outer part pure PVA and having an inner core with 100% filling rate of a binary dispersion of PVA as suitable thermal binder and 20% by weight of Dipyridamole (yellow color) as active pharmaceutical ingredient is analyzed by an optical method (FIG. 29).

Analytical Evaluation (Dissolution) of Tablets Prepared by 3D Printing Process

[0273] Release of dipyridamole as active ingredient is determined using the Sotax Freisetzungsapparatur Sotax AT 7smart (Sotax AG, Lörrach, Germany)

[0274] The release determinations are carried out using Phosphate buffer pH 6.8 (900 ml) as the dissolution medium while stirring (paddle speed: 50 rpm) and measuring the absorbance with online UV-spectroscopy at 298 nm using 10 mm Cuvette.

[0275] Each sample is collected in a test tube with the automatic sampler.

Release of Active Ingredient (Sotax)

[0276] Device: Release apparatus: Sotax AT 7smart (Sotax AG, Lörrach, Germany), Photometer Agilent 8453 (Agilent Technologies, Waldbronn, Germany)

[0277] Number of vessels: 6

[0278] Method: Paddle

[0279] Medium: Phosphate buffer pH 6.8

[0280] Amount of medium: 900 mL

[0281] Temperature of medium: 37° C.

[0282] Rotation: 50 rpm

[0283] Duration: 2 h

[0284] Time of sampling: 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120 min

[0285] Final spin: no

[0286] Cuvette layer thickness: 10 mm

[0287] Wavelength: 289 nm

[0288] FIG. 30 illustrates results achieved by dissolution measurement of 3D printed dipyridamole containing tablets in 900 ml of phosphate buffer pH 6.8. The release study comparing different filling rate of the 3D printed tablets (Example 10=100% Tablet Filling rate/Example 11=50% Tablet Filling rate/Example 12=30% Tablet Filling rate) shows substantial differences in the release of the active ingredient (dipyridamole). To dissolute and release the full API amount of an 100% filled tablet 150 minutes measured, while a 50% filled 3D printed tablet already releases 100% of its API amount after approximately 60 minutes in the dissolution equipment. As expected, a 30% filled 3D printed tablet dissolved much faster and 100% release of its API amount could be achieved after app 30 minutes of test time.

Standardized Release of 3D-Printed Tablets (Dipyridamole) in PP, pH 6.8

Release 3D-Printed Tablets (Caffeine) in 0.1 M HCl

FIG. 31

Analytical Evaluation (Dissolution) of Tablets Prepared by 3D Printing Process.

[0289] Release of caffeine as active ingredient is determined using the Sotax Freisetzungsapparatur Sotax AT 7smart (Sotax AG, Lörrach, Germany)

[0290] Phosphate buffer pH 6.8 (900 ml) was used as the dissolution medium with 50 rpm, paddle speed and the release determinations are carried out with online UV, 298 nm 10 mm Cuvette

[0291] Each sample is collected in a test tube with the automatic sampler.

Release of Active Ingredient (Sotax)

[0292] Device: Release apparatus: Sotax AT 7smart (Sotax AG, Lörrach, Germany), Photometer Agilent 8453 (Agilent Technologies, Waldbronn, Germany)

[0293] Number of vessels: 6

[0294] Method: Paddle

[0295] Medium: 0.1 M HCl

[0296] Amount of medium: 900 mL

[0297] Temperature of medium: 37° C.

[0298] Rotation: 100 rpm

[0299] Duration: 6 h

[0300] Time of sampling: 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240, 300, 360 min

[0301] Final spin: no

[0302] Cuvette layer thickness: 10 mm

[0303] Wavelength: 272 nm

[0304] FIG. 31 illustrates results achieved by dissolution measurement of 3D printed caffeine containing tablets in 900 ml of 0.1 n HCl. The release study compares different filling rates of the 3D printed tablets (Example 8=100% Tablet Filling rate/Example 9=50% Tablet Filling rate) and shows substantial differences in the release of the active ingredient (caffeine). To dissolute and release the full API amount of a filled tablet (100%) needs 360 minutes for entire release of the comprising API, while a 3D printed tablet, 50% filled, already releases 100% of the comprising API amount after app 30 minutes in the dissolution equipment. The time measured is not much faster than dissolving pure crystalline caffeine particles tested in comparison by 100% after app 5 minutes.