Technical Field

The invention refers to a method for manufacturing a dosage form by additive manufacturing and to a dosage form comprising at least one active pharmaceutical ingredient (API) and/or pharmaceutically acceptable excipient and/or drug product formulation manufactured by an additive manufacturing process. Further the invention concerns to a device for manufacturing a dosage form comprising a nozzle head suitable for implementing in an additive manufacturing system.

Background of the Invention

One of the most common methods of manufacturing a dosage form is by

compressing powder into a desired shape using a die and press. This method is inexpensive and suitable for many pharmaceuticals. The powder that is pressed typically includes one or more Active Pharmaceutical Ingredients (API) and substances that help hold the tablet together after completion of pressing. The term "dosage form" means a therapeutic administration unit in form of a tablet or pill for the use of oral or anal administration.

A newer technique sometimes applied to the manufacture of pharmaceutical dosage forms, which allows the creation of detailed predetermined variation of composition within a dosage form, is additive manufacturing, which is a generic term for making 3- dimensional objects by layered material construction on basis of a binary data set representing the whole shape of the object.

The document US 5,204,055 discloses a production method in which a layer of powder is created and then drops of a binder liquid are dispensed onto the layer of powder by a technique resembling ink-jet printing. At the locations wetted by binder liquid, powder particles are joined to each other and to other solid regions. Then, another layer of powder is deposited and the process is repeated for successive layers until the desired three-dimensional object is created. Unbound powder supports printed regions until the article is sufficiently dry and then the unbound powder is removed.

In making a dosage form by additive manufacturing, an API is included in the printed article, most commonly by being contained in a binder liquid which is dispensed onto the pharmaceutical excipient powder. Additive manufacturing allows for controlled placement of substances within the dosage form, and this has been used to achieve time-dependent release of one or more API, release of API only in an environment of a specified pH, etc. Additive manufactured dosage forms requiring complex release profiles and/or multiple API, as has been described in the document US 6,280,771 .

However, several drawbacks have become apparent with oral dosage forms made by additive manufacturing. One limitation has been that the surface of an additive manufactured part has typically been unacceptably rough as compared to

traditionally manufactured pressed tablets. Another limitation concerns the achievable density of the dosage form having a voidage of 40 % typically. The ratio of voidage can be reduced by multiple deposition of binder liquid at an already binder coated layer region but the amount of voidage can't be reduced of less than 25% by this measure. This circumstance also leads to the limitation that the amount of API in the dosage form is limited significantly.

To overcome the above limitations US 7931914 proposes to manufacture a dosage form on basis of additive manufacturing providing a predetermined spatially nonuniform internal composition comprising powder particles bound together by a binding substance in layers and following compressing the three-dimensionally- printed region having predetermined spatially nonuniform internal composition to reach a dosage form with a void fraction of less than 5% and a surface finish having a peak-to-valley dimension of less than or approximately equal to 3 microns.

Document WO 2016/020454 A1 discloses a conventional powder bed deposition technique for the additive manufacture of a three dimensional object comprising a cosmetic composition. The known method uses a printing head which dispenses a liquid powder binding activator, which may be a mixture of a plurality of different binding activators, stored in several containers onto a powder layer.

Document WO 2012/15251 1 A1 discloses a multicolored fused deposition modelling print which bases on the concept that a thermoplastic polymer cord is colored in the nozzle before being ejected through the nozzle for building an object. For this dyes are added to the liquefied thermoplastic polymer within a printing head before being ejected through the nozzle.

Finally document DE 20 2015 004 336 U1 discloses a device for extrusion of a material flow through an outlet. The device is conceptualized to perform a FDM method in which two different thermoplastic filaments are supplied to a 3D-printing head in which the filaments are molten and the liquefied thermoplastics are mixed before ejecting through the nozzle of the printing head. Summary of the Invention

It is a general object of the present invention to provide a method for manufacturing a dosage form which allows the production of tablets, pills or suppositories comprising any number of API and any distribution of API and/or pharmaceutically acceptable excipient and/or drug product formulation in a preferably non uniform internal composition of a dosage form. Further the amount of all material used in the additive manufacturing process shall be reduced significantly without an impact on the manufacturing and effectiveness of the dosage forms. The efficiency in terms of manufacturing and production rate shall also be optimized.

It is a further object of the invention to provide a dosage form which is produced by an additive manufacturing process comprising a consistency in terms of density and surface finish which is comparable to dosage forms being produced conventionally.

Further it is an object of the invention to provide a tool for the preparation of the aforementioned dosage form in way of additive manufacturing so that the dosage form as being a direct result of the additive manufacturing process comprises the before mentioned consistency without the need of a pressurized post-treatment.

The object is achieved by a method given in claim 1 . Subject matter of claim 9 relates to an inventive dosage form. Claims 1 1 and 12 disclose alternative embodiments of an inventive device for manufacturing a dosage form comprising a nozzle head suitable for implementing in an additive manufacturing system. All features of the aforementioned independent claims can be modified advantageously by the features disclosed in the corresponding subclaims as well as in the following description especially referring to preferred embodiments.

The basic idea of the inventive method deviates from conventionally processing of dosage forms using the aforementioned 3D printing technic in which a powder bed is prepared in layers into which a binder liquid is deposited on basis of a defined geometrically trajectory clearly. In contrast the inventive method provides at least two mass flows, of which at least one mass flow contains at least one active pharmaceutical ingredient, abbreviated as API and/or pharmaceutically acceptable excipient and/or drug product formulation. The at least two mass flows will be merged to form a mixture which is deposited hereinafter in form of a self-curing material layer onto a working plan in layers for forming said dosage form.

For ease of further description, the abbreviation "API" is intended to mean at least one of the following substances: active pharmaceutical ingredient (API) and/or at least one pharmaceutically acceptable excipient and/or at least one drug product formulation.

The at least two mass flows are preferably selected such that self-curing of the mixture occurs instantaneously after depositing onto the working plane at ambient atmosphere conditions. At least one of the two mass flows comprises a liquid, preferably a binder liquid which is known from 3D printing as mentioned before. Not necessarily but advantageously at least one API can be mixed in the binder liquid.

The at least one other mass flow preferably contains a solid powder being mixed in a carrier gas or in a carrier liquid. Preferably the solid powder can be the at least one API, i.e. the solid powder is of pure API, or can serve as a carrier for the at least one API. Depending on the setup of the powder it can be carried in a further embodiment by gravitational force only.

The at least two mass flows which are emitted by a special designed nozzle head, which is explained in detail below, are merged together in a fluid dynamical process, i.e. the at last two mass flows, each having a nonzero flow velocity, penetrate each other and form the mixture with a homogeneous mass distribution.

In a first preferred embodiment merging the at least two mass flows takes place by directing the at least two separate mass flows on a common local, preferable largely punctual merging area located directly on or close above the working plane, i.e. less than 2 mm above the working plane. In a second preferred embodiment merging of the at least mass flows takes place by directing the at least two separate mass flows into a at least partially encapsulated merging chamber having at least one outlet through which the mixture is deposited in form of a mixture flow onto the working plane.

The before mentioned alternative embodiments for preparing the mixture to be deposited onto the working plane share a common effect that depositing of the mixture onto the working plane is performed by a dynamical impingement onto the working plane. The before mentioned fluid dynamical process of mixing the at least two mass flows in combination with the dynamical impingement of the mixture onto the working plane help to consolidate a compact and dense self-curing material layer onto the working plane which leads to a compact and dense dosage form having a reduced amount of voidage.

The term "working plane" as used above and below means the plane in which material deposition takes place. When starting the manufacturing process the working plane corresponds to an empty surface a work table which preferably is supported lowered. Alternatively of lowering the working plane the nozzle head can be positioned freely in space relative to the working plane. After having finished the first layer of deposited self-curing material layer onto the surface of the working table the working plane for depositing the second self-curing material layer corresponds to the upper side of the first deposited self-curing material layer. The additive

manufacturing process is repeated by layers such that only self-cured material is deposited in the working plane preferably. This is a reason why the inventive method is a highly economical process since almost all material used in mass flows is deposited as self-curing material layer. Remaining unused material can be avoided preferably completely or at least reduced significantly.

Beside of the before mentioned advantage concerning the material saving aspect the inventive method can be performed with a significant higher process velocity respectively with an increased deposition rate compared to conventional powder bed based 3D printing processes, because the inventive method deposits just only one mixture material onto an otherwise clean working plane which doesn't need to be pre-treated like a powder-bed preparation.

A further advantageous aspect of the inventive method is the free choice of the use of different kind of materials and also APIs, from which the at least two mass flows can be composed. In contrast known 3D printing technics are bound to one kind of powder material which is used as powder bed.

In this connection a further preferably embodiment of performing the inventive method provides at least three different mass flows each having a different kind of material and/or API. In case of providing at least three mass flows a selection is made possible of at least two mass flows for merging a mixture of a first kind and depositing said mixture of the first kind in form of a self-curing material layer of a first kind onto the working plane. By selecting at least once during or after depositing the mixture of the first kind at least two mass flows for merging a mixture of a second kind and depositing said mixture of the second kind in form of a self-curing material layer of a second kind onto the working plane, where the mixture of the first kind and the mixture of the second kind deviate each other in concentration of API or composition of API, multi-API containing dosage forms are possible to produce in one continuously running additive manufacturing process.

Using more than one API each contained in a separate mass flow offers the possibility of the production of personalized individual dosage forms providing multilayer structure with at least in regions of different kind of APIs or different concentrations of the same API or different APIs.

In some cases it may be suitable to use support material for the construction of dosage forms having a complex geometry for example overhanging surface portions. Such portions must be supported during the additive manufacturing process. This it is an extra mass flow is provided containing support material which is to be deposited onto the working plane in regions above which self-curing material layer will be deposited in a following layer.

Only the sake of completeness it should be noted that there is no limitation concerning the number of mass flows which are provided for building a dosage form basically.

The inventive method can be applied for ennoblement of existing, prefabricated dosage forms for example in form of semi-products like pre-pressed tablets, to which a special arrangement of API and/or an outer shell in form of a coating is to be added.

The inventive method can be performed in a temperature range preferably between 5°C and 50°C, particularly preferably at room temperature, so that all non- temperature resistant APIs can be processed. Process temperatures which are beyond 50°C can be reached for example in a uniaxial pressing process which however is not necessary in connection with the inventive method for reaching a dosage form with a sufficiently high density.

As a consequence of the before described inventive method a new dosage form will be possible which comprises at least one API being merged in a matrix made of solidified material where the at least one API is distributed homogenously at least in a region of the matrix by way of an additive manufacturing process. The at least one API is at least part of at least one mass flow being merged with at least one other mass flow forming an API containing matrix material which is deposited and solidified as a material layer onto a working plane for forming the solidified API containing matrix material in layers such, that the at least one region of API containing matrix material provides a voidage of less than 20%, preferably less than 10%, particularly preferably less than 5%.

The dosage form is the direct result of the additive manufacturing process without a required pressurized post-treatment. The before described method and as well the above mentioned dosage form can be realized by using a new device for manufacturing a dosage form comprising a nozzle head which is suitable for implementing in an additive manufacturing system, like an arrangement for performing 3D-printing in which at least one nozzle head is deflectable mounted along at least two orthogonally oriented axis being parallel to the working plane. Said working plane can be adapted in a vertical axis so that a vertical distance between the nozzle head and the working plane remains constant. Of course deviating relative mobilities between the at least one nozzle head and the working plane for depositing a solidify-able, at least one API containing material onto a working plane in layers are conceivable.

The inventive nozzle head encloses at least two separate flow channels, each of the channels comprises an in- and outlet of which one of the inlets is directly or indirectly coupled to a source for providing a first mass flow and at least the other inlet is directly or indirectly coupled with a source for providing a second mass flow. At least one of the mass flows contains the at least one API. The outlets of the at least two separate flow channels enclosed by the nozzle head are arranged such that the mass flows emitting out of the outlets penetrate each other in a mixing zone positioned outside of the nozzle head.

The nozzle head has to be positioned relative to the working plane such that the mixing zone is located directly on or close above the working plane. In the mixing zone the at least two mass flows merge each other and form a homogenous mixture in form of a self-curing material layer onto the working plane.

In an alternative embodiment of the inventive device the mixing zone in which the at least two mass flows penetrate each other for the purpose of forming a mixture is located inside the nozzle such that the outlets of the at least two separate flow channels being enclosed by the nozzle head enter a mixing chamber encapsulated by the nozzle head having an outlet through which a mass flow of the solidify-able, at least one API containing material emits. Both nozzle heads according to the invention comprise sources for providing the mass flows. Each source comprises a reservoir for storing the mass and a driving unit for generating a mass flow having a non-zero flow velocity when entering one of the inlets of the flow channels. In at least one of the reservoirs at least one API is provided.

At least one API containing source is designed such that the API containing mass flow is an aerosol or a suspension.

Preferably the API containing source contains a powder into which the API is mixed or the powder itself is the API. A driving unit in form of a blower arrangement generates an air- or gas flow to which the API containing powder or API powder is mixed for obtaining the mass flow in form of an aerosol. It is also possible to generate the mass flow by using gravity only which accelerates the powder as a free-flowing bulk material from a higher position to the lower-lying working plane.

Alternatively in case of a source comprising a reservoir storing a liquid, a liquid solution or liquid suspension the driving unit is in form of a pump being fluidly coupled to the reservoir for generating a mass flow in form of a suspension or a liquid solution. Each source is fluidly coupled by a supply line with the inlets of the flow channels enclosed by the nozzle head, which will be described in more detail in connection with the following illustrations.

Brief Description of the Figures

The invention shall subsequently be explained in more detail based on exemplary embodiments in conjunction with the drawings. The drawing

Fig. 1 a, b, c schematic representation for illustrating the method for manufacturing a dosage form,

Fig. 2 preferred embodiment of a dosage form, schematic view of a first embodiment of a nozzle head and a schematic view of a second embodiment of the nozzle head according to the invention.

Detailed Description of exemplary Embodiment

Figures 1 a and b show views of sequential steps of the method for manufacturing a dosage form by additive manufacturing technique. Figure 1 a shows a working plane 1 which corresponds to the surface 2 of a work table being vertically and/or horizontally deflectable or movable as indicated by double arrow. Two separate mass flows 3, 4 are directed onto the working plane 1 . At least one of the two mass flows 3, 4 contains at least one API and/or at least one pharmaceutically acceptable excipient and/or at least one drug product formulation. Both mass flows 3, 4 joins each other in a mixing zone 5 which is positioned on or close above the working plane 1 . In the mixing zone 5 both mass flows 3, 4 forms a mixture 6 which is deposited onto the working plane 1 in form of a self-curing material layer 7.

The at least two mass flows 3, 4 each providing a nonzero flow velocity V3, v ₄ impact onto the working plane 1 and merges each other in a flow dynamical process by which a high degree of mixture density is reached forming a very compact self-curing material layer preferably with a voidage of less than 20%, preferably less than 10%, especially preferably less than 5%.

The at least two mass flows 3, 4 move simultaneously parallel relative to the working plane 1 on basis of a predetermined trajectory based on a binary dataset

representing the three dimensional shape of the dosage form, for example in shape of a tablet or pill for oral or anal administration. Figure 1 b shows a process situation in which a first self-curing material layer 7.1 is deposited onto the surface 2 of the working table already. The second self- curing material layer 7.2 on top of the first is carried out in the same way, i.e. both mass flows 3, 4 are directed onto the working plane 1 which corresponds to the upper surface of the first self-cured material layer 7.1 deposited onto the surface 2 of the working table directly. Preferably but not necessarily the second self-cured material layer 7.2 is made of a same material composition as the first layer. By using three or more mass flows, not illustrated, all being directed onto the working plane 1 a selection between the mass flows can be made so that a tablet or pill can be processed with an individual arrangement of material layers containing individual composed APIs.

Figure 1 c illustrates an alternative method for mixing the at least two mass flows 3, 4 before depositing the mixture 6 onto the working plane 1 . In case of Figure 1 c two mass flows 3, 4 are directed into a mixing zone 5 which is an encapsulated mixing chamber 8. After entering both mass flows 3, 4 through inlets 9, 10 into the mixing chamber 6 a homogenous mixture 6 is generated. The mixture 6 emits through an outlet 1 1 of the mixing chamber 8 and is directed in form of a material flow onto the working plane 1 forming a self-curing material layer 7.

Figure 2 shows a perspective view of a dosage form 12 in shape of annular tablet having a central recess 13. The ring shaped tablet 12 is build up in layers 14 which preferably contain different amount and/or kind of API.

In a preferred embodiment the ring shaped tablet 12 provides at least one layer 14 in which a non-uniform distribution of concentration c of at least one API and/or at least one pharmaceutically acceptable excipient and/or at least one drug product formulation is contained. The disclosed diagram 2.1 in Figure 2 indicates a maximum concentration 15 in the middle region along the ring.

Alterations of the concentration profile c are also shown in figures 2.2 and 2.3 in a non exhaustive way. Diagram 2.2 shows a linear rising profile and Diagram 2.3 provides lowest concentration at the mid region of the ring shaped tablet 12. In this first preferred embodiments according to diagram 2.1 and diagram 2.2 the concentration profile could be adjusted to provide an extended release of the active ingredient over time, wherein a sloped plasma concentration level increase occurs. In the third preferred embodiment according to diagram 2.3 the concentration profile could be adjusted to provide a burst release of the active ingredient to provide an immediate onset of the intended therapeutic effect.

The dosage form 12 is a direct product of an additive manufacturing process, having a voidage of less than 20% at least in a region of the volume of the dosage form 12. The dosage form 12 and can be manufactured in terms of shape, size, composition and concentration of API individually depending on a therapeutically need of each individual person.

Figure 3 illustrates a schematically sketch of a preferred embodiment of an inventive nozzle head NH. The nozzle head NH comprises at least two separated flow channels 16, 17 each providing an inlet 9 and 10 and an outlet 18, 19.

The inlet 10 of the centrally arranged flow channel 17 is fluid tightly connected with a source S1 providing a reservoir 20.1 in which a liquid binder is stored. Further source S1 provides a pump unit 21 .1 for generating a mass flow of liquid binder directed via a supply line 22.1 into the flow channel 17 of the nozzle head NH.

Further at least a second source S2 is provided having a reservoir 20.2 in which powder material is stored comprising at least one API. The stored API powder material is set in motion by a driving unit 21 .2 which is a blower arrangement preferably which mixes the powder with an air- or gas- flow, preferably inert-gas, for generating the mass flow in form of an aerosol which is directed via supply line 22.2 through the inlet 9 into the flow channel 16. Of course, it is also possible to supply the liquid binder over the flow channel 16 and to supply the API containing aerosol over the central flow channel 17. The flow channel 16 is conically shaped and arranged coaxially around the centrally arranged flow channel 17 such that the mass flow emitting through the outlet 19 is focused into a mixing zone 5 into which the mass flow of liquid binder supplied by the centrally arranged flow channel 17 emitted through the outlet 18 is directed as well.

Within the mixing zone 5 the liquid binder and the API/powder material are mixed homogeneously and form a mixture 6 having the nature of a self-curing material which leads to a self-cured material layer 7 onto the working plane 1 which in case of figure 3 corresponds to a surface 2 of a working table being arranged vertically lowered.

Moving the nozzle head NH laterally relative to the working plane 1 on basis of a defined trajectory material deposition onto the working plane 1 can be performed individually so that tablet or pills of arbitrary shape can be produced in layers.

A further embodiment, not shown, provides at least one further separate flow channel in addition to flow channel 16, which can be arranged coaxially around the already existing flow channels 16 and 17 or decentrally next to the flow channel 16 at least in form of a straight hollow channel, which is enclosed inside the nozzle head as well.

Such additional flow channel is connected by a supply line 22.3 (see dotted line) with a separate source S3 having a reservoir 20.3 in which a different kind of API is stored which is set in motion by a driving unit 21 .3 in form of a separated mass flow. On basis of the same idea the nozzle head NH can be adapted such that a multitude of different sources S1 , S2, S3, ... can be connected to separate flow channels inside the nozzle head NH for the purpose of optimizing the choice of and possible combination of different APIs.

Basically the chemical and physical nature of stored material inside the reservoir of each source can be chosen freely. In case of powder material into which at least one API is added preferably the mass flow provides the nature of an aerosol which is directed into the mixing zone 5 onto the working plane 1 . This can cause contamination of the environment around the nozzle head by parts of roving aerosol not being mixed with the liquid binder. To prevent contamination and to restrict all mass flows emitting the nozzle head NH onto the mixing zone 5 a further, so called shielding gas flow 24 is provided to guide the powder material and to shield from the outside exposer. To generate the shielding gas flow 24, which is preferably an inert gas flow the nozzle head provides at its radial outer contour a conically shaped flow channel 23 which inlet is connected to a shielding gas reservoir 25.

Figure 4 shows a sketch of a further embodiment of an inventive nozzle head NH comprising at least the sources S1 , S2 as described before. Optionally further sources S3 etc. can be provided. All sources are connected each by a supply line with a central mixing chamber 8, in which the mass flows from all sources enter and merge to form a homogenous mixing material which is emitted through an outlet 1 1 of the nozzle head NH to be deposited as onto the working plane 1 . The consistency of the emitted mixed material 6 is pasty so that the before described shielding flow 24 is not necessary.

Concerning the embodiment shown in figure 3 in which the at least two flow channels are arranged coaxially it is also possible to arranged flow channels around the central flow channel 17 decentrally, i. e. a multitude of single flow channels can be arranged in an arbitrary arrangement so that the amount of different flow channel outlets can be multiplied in order to at numbers of different API.

List of References Numerous

1 Working plane

Surface of the working table , 4 Mass flow

5 Mixing zone

6 Mixture

7 Self-cured material layer

7.1 , 7.2 Self-cured material layers

8 Mixing chamber

9, 10 Inlet

1 1 Outlet

1 Dosage form, tablet, pill

13 Central recess

14 Tablet layers

15 Maximum

16 Flow channel

17 Central flow channel

18, 19 Outlet

20.1 , 20.2, 20.3 Reservoir

21 .1 , 21 .2, 21 .3 Driving unit, pump unit, flower unit

22.1 , 22.2, 22.3 Supply line

23 Shield air flow channel

24 Shielding flow

25 Shielding gas reservoir

S1 , S2, S3 S3 source

API Active Pharmaceutical Ingredient c Concentration

NH Nozzle head