Spot printing method and device for the additive production of active ingredient-containing dosage forms

Description

[0001] The present invention relates to a method and a device for producing solid, at least semi-solid dosage forms of pharmaceutical active ingredients, nutraceutical active ingredients and / or food supplement active ingredients, in which the dosage form is created in an additive manner by applying a building substance in the form of spots.

[0002] WO 2016 / 038356 A1 discloses an additive 3D printing process for producing pharmaceutical dosage forms using filament fusion fabrication (FFF). WO 2017 / 140239, WO 2017 / 158172, WO 2018 / 151725 and NORMAN JAMES ET AL:, ADVANCED DRUG DELIVERY REVIEWS, Vol. 108, March 18, 2016 (2016-03-18), pages 39-50 also deal with pharmaceutical dosage forms produced using various 3D printing techniques.

[0003] The object of the present invention is to provide a method and a device for producing active substance-containing objects, in particular active substance-containing dosage forms, which have a particularly light and material-saving structure.

[0004] The above object is achieved by the embodiments of the present invention as disclosed in the claims and the present description.

[0005] In particular, the present invention provides a process for producing an at least semi-solid dosage form comprising the following steps: (i) Providing a printer capable of at least 3D printing the solid dosage form, which printer has a build platform on which the dosage form is printed, a print head designed to apply an arrangement of spots of a build substance for the dosage form to the build platform, wherein the build substance is flowable in the printed state, preferably by heating, and becomes at least semi-solid upon solidification, preferably cooling, (ii) Applying an arrangement of spots of the build substance to the build platform, wherein the spots may overlap or touch or not touch; (iii) At least semi-solidifying, preferably solidifying, the spots of the build substance applied in step (ii); (iv) Applying a further arrangement of spots to the previous arrangement of spots such that the spots of the further arrangement at least partially overlap with the spots of the previous arrangement;and (v) repeating steps (ii) to (iv) until the dosage form is formed; wherein the building substance contains at least one pharmaceutical active ingredient and / or at least one nutraceutical active ingredient and / or at least one dietary supplement active ingredient;

[0006] A "spot" within the meaning of the invention is a substantially round, essentially three-dimensional structure that results from the impact of a volume unit during the application of the build substance, which is dispensed from a print head of the printing device in liquid, but at least flowable, form, usually in the form of a drop, (approximate) rotational ellipsoid or (approximate) sphere and is deposited on the build platform (in step (ii) according to the invention) or, at least partially, on previously deposited spots (in step (iii) or steps (iii)).

[0007] According to the invention, the building substance contains at least one active ingredient, which can be selected from pharmaceutical, nutraceutical, and dietary supplement active ingredients. These active ingredients are collectively referred to below as "active component(s)" or "active ingredient(s)."

[0008] The active components can essentially be selected from all available pharmaceutical, nutraceutical, and dietary supplement active ingredients that can be administered by means of semi-solid or solid dosage forms, which in turn can also be combined with one another, as long as this is compatible with the desired application. Preferred dosage forms of the invention are produced using building blocks that contain at least one pharmaceutical active ingredient. Preferred embodiments are synergistically acting combinations of two or more pharmaceutical active ingredients, which can be present in a single building block. In another embodiment, different active ingredients can be present in different

[0009] Building substances are present which form the applied spots. Thus, according to the invention, an active ingredient can be present in a building substance from which a first group of spots is formed, and one (or more) other active ingredients can be contained in another group of spots (i.e. there are at least two building substances which contain the respective active ingredient(s). Preferably, the different active ingredients are contained in different building substances. It is possible that the respective building substances, with the exception of the active ingredient(s), can otherwise be the same or different, e.g. in order to provide tailored properties for the respective active ingredient, such as pH, solubility, consistency, ionic environment, particle size, color, etc. In certain embodiments of the invention, combinations of two or more pharmaceutical active ingredients are provided, in which, for example,a pharmaceutical active ingredient intended for a specific indication is contained in a building substance and a further pharmaceutical active ingredient is present in the same or a different building substance, such as a side effect potentially caused by the first active ingredient is at least reduced, or at best suppressed, which represents a particularly preferred embodiment of the invention.

[0010] Examples of pharmaceutical active ingredients that can be combined according to the invention are agonists / antagonists to reduce the addictive potential of painkillers (e.g. tilidine and naloxone), combination preparations for the treatment of e.g. high blood pressure (preferably combinations of ACE inhibitors and / or calcium channel blockers and / or beta-blockers), allergies (e.g. antihistamines and calcium), diarrhea (e.g. minerals and loperamide), stroke / heart attack prophylaxis (blood thinners and / or antihypertensives), Parkinson's disease (levodopa and benserazide), hypercholesterolemia (e.g. statins and / or fish oils), deficiency symptoms (e.g. vitamins with minerals in combination) and analgesics (e.g. an analgesic and caffeine), etc.

[0011] In preferred embodiments of the invention, spots with the same active ingredient or the same combination of active ingredients or the same concentration of active ingredients are located in a common section of the dosage form, so that the spots of the same group are at least partially adjacent to one another on at least one side. Preferably, therefore, the spots with the same active ingredient or the same combination of active ingredients or the same concentration of active ingredients each form at least one common section (e.g., at least one common layer or at least one contiguous part of at least one layer), wherein these can be aligned horizontally or vertically, relative to the longest dimension of the dosage form. In other embodiments, spots each with the same active ingredient, the same combination of active ingredients or the same concentration of active ingredients can also be combined in several sections (e.g., two or more layers and / or sub-layers).Such sections can also have different drug release properties such as different pH conditions, solubility, gastric juice resistance, other solubility behavior (e.g. in the spots of certain sections or of a certain section contain a burst release substance, wherein a method for forming a burst release embodiment is preferably designed such that the spots of the burst release sections are applied such that the burst release sections envelop the spot sections without burst release agent in the ancillary substance, i.e. at least one, preferably several layers of spots with burst release substance(s) in the ancillary substance(s) in each dimension of the dosage form surround the sections of the dosage form without burst release function).

[0012] The printer preferably has at least one print head that is connected to a reservoir containing the build-up substance, so that the at least one print head is capable of withdrawing a quantity of the build-up substance for applying the build-up substance in steps (ii) to (v). The reservoir can be designed in different ways depending on the type and consistency of the build-up substance. In the case of liquid build-up substances, the reservoir can be a liquid container that is connected to the print head via a line for the build-up substance, through which it is transported, usually pumped, to the print head. In another embodiment, the build-up substance can be present in the reservoir in solid or semi-solid form, for example as a powder or granulate, with a transport mechanism feeding the solid or semi-solid build-up substance to the print head.In this embodiment, the print head typically has a heating or melting device which converts the build substance into an at least flowable, in preferred embodiments liquid, form, which is then output by the print head, through a usually present output device, onto the build platform as a volume unit forming a spot on the build platform, i.e. is printed.

[0013] In another embodiment, the build-up substance can also be in the form of a solid or at least semi-solid filament, wherein the filament is present, for example, in a feed channel or feed tube that forms the reservoir. These reservoir shapes can be designed in different ways, although linear designs are usually provided for completely solid filament build-up substances. Preferred filament build-up substances are usually elongated, cylindrical structures that are typically more or less elastic and can therefore also be accommodated in curved, such as spiral-shaped, reservoir spools and fed to the print head, for example, by a pushing or pushing mechanism. If the elasticity is not sufficient to feed the filament spirally into reservoir spools, the filament can also be fed in short, straight filament rods from a reservoir magazine.

[0014] In the case of liquid build-up substances, the print head can comprise piezoelectrically operated devices for dispensing the unit volume, so that the build-up substance is dispensed as in an inkjet printer. Such an embodiment can also be designed as a 2D printing process, as explained in more detail below. In a 2D printing process, a liquid (examples are mentioned below) is usually applied using known techniques such as piezoelectric dispensing devices, for example, to at least a portion of the surface of a dosage form created by the above 3D printing steps, for example in an additional step (vi), wherein the liquid is usually dried or fixed in some other way to the at least one portion of the surface (e.g. chemically and / or by exposure to light, which is usually effected by a laser device).Of course, it is also possible to apply one or more 2D-printed layers within a dosage form and to continue with the 3D printing steps after applying a 2D layer (although a final 2D printing layer can of course follow).

[0015] In a further preferred embodiment, the printer has more than one print head, with 2 to 10 print heads being particularly preferred. Embodiments of the invention with multiple print heads can serve different functions: In one embodiment, it is provided that printing takes place on a unit of the dosage form, e.g. in order to print different building substances with the different properties as set out above. In an embodiment with multiple printers, 3D and 2D print heads can also be used, whereby it is also possible, as explained below, for print heads that can be used according to the invention to be designed for both 3D printing and 2D printing. The invention also provides for the use of more than one print head in order to print multiple dosage forms simultaneously.It is of course also possible according to the invention to print several different dosage forms simultaneously, i.e. print head sets are formed, so to speak, or at least referred to as sets, which simultaneously print with different building substances on several dosage forms, wherein the simultaneously printed dosage forms can again be the same or different in their structure. The number of print heads can therefore also be well in excess of 10 print heads in order to be able to increase the number of printed dosage forms accordingly. In the embodiment of the method with more than one print head, it is further preferred that each of the print heads is connected to a reservoir with the building substance, so that the respective print head is capable of withdrawing a quantity of the building substance for applying the building substance in steps (ii) to (v).The above reservoir designs can be the same or different for the print heads, independently of one another.

[0016] According to the invention, the spots are preferably created by applying a volume unit of the build-up substance, with each volume unit preferably having a volume of 20 pl to 30 µl. If necessary, several volume units can, of course, also be applied consecutively.

[0017] According to a further preferred embodiment, the print head or, in the case of multiple print heads, at least one of the print heads is designed for both 2D printing and 3D printing. In another embodiment of the invention, the device comprises at least one or more 3D print heads and, if required, a 2D print head. 3D print heads are designed for applying semi-solid and molten build-up substances, while 2D print heads are designed for applying build-up substances that are already liquid without heating in the print head, such as inks or active ingredient solutions, active ingredient emulsions, and active ingredient suspensions.

[0018] In a preferred embodiment, the spots are applied such that the spots used in step (ii) and the further steps (ii) (according to step (v) of the method according to the invention) overlap with the spots used in the previous step (step (ii) or each step (ii) of the further build-up steps according to step (v)). This embodiment thus results in a dosage form that can form a particularly stable arrangement in the sense of a brick arrangement of the applied spots if the spots of one layer have a complete overlap with the previous layer.On the other hand, by applying a layer of spots which partially overlap with the previous layer, a particularly light arrangement with spaces is provided, whereby the solubility or degradation rate of the dosage form in the surrounding environment, in particular in the digestive tract of the subject ingesting the dosage form, for example a human patient, can be controlled by creating a larger surface area of the dosage form exposed to the surrounding environment.

[0019] As described above, in preferred embodiments of the invention, the build substance is present as a filament and the print head is designed, in the case of 3D printing, to melt a quantity of the filament, preferably by the print head comprising a heating device as described above, in order to apply the arrangement of spots of the build substance on the build platform in step (iii) as well as the further arrangement(s) of spots on the previous arrangement of spots in step (iv).

[0020] The solidification (at least into a semi-solid state of the printed build-up substance) as well as the bonding between the individual applied spots in step (iii) can take place in different ways. In one embodiment, for example, when using a fusible material, the bonding between such spots can take place through solidification after application to the carrier structure, whereby this can be carried out through various mechanisms such as simple cooling and / or chemically using known substances. In another embodiment, a suitable binder can be added to the build-up substance, e.g. a dispersion or a solution, which causes the spot to harden after it has been applied. The hardening by the binder can take place, for example, through heat, which can be supplied by a suitable heat source in the printing device, such as a light source, preferably a laser device.Curing by the binder can also occur chemically using appropriate starter molecules and / or light of a suitable wavelength, the latter preferably being emitted using a laser device. In a further embodiment, the build-up substance can contain one or more starting compounds, typically monomers, of one or more polymers. After the spot(s) have been applied, a polymerization is initiated by suitable means such as, for example, light, heat, or other polymerization initiators, which cures the applied spot and bonds or bonds it to neighboring spots.

[0021] Suitable carrier materials that flow at the printing temperature and in which the active ingredient(s) are present are, for example, carriers that are generally suitable for hot melt extrusion (HME), such as low-melting waxes and polymers. The HME mixture or, in general, the building substance mixture can contain, in addition to the low-melting carrier, other processing agents and excipients such as binders, plasticizers, antioxidants, fragrances, sweeteners, or the like. Suitable HME carriers and plasticizers are known to the person skilled in the art and are disclosed, for example, in Crowley et al. (2007) Drug Development and Industrial Pharmacy, 33, 909-926 (Carrier: pages 917 to 919, in particular Table 1; Plasticizers: pages 917 and 920, in particular Table 2), wherein in the present description in express words reference is made to the passages mentioned.

[0022] The present additive 3D printing process or the present combined additive 3D and 2D printing process is preferably carried out with computer support. Thus, typically in a step preceding step (i), a calculated two- or three-dimensional image of the object to be printed is created, for example using a common CAD program. The computer-generated reproduction of the object to be printed can also be created by scanning an existing object, e.g. a pharmaceutical dosage form or a medical device. In the present process, the computer-generated model image is then divided into the desired spots, whereby the resolution of the real object increases the smaller the volume units of the building substance applied to create the spots. Each individual spot can be assigned, for example, an active ingredient, a carrier substance orCarrier compositions and / or other auxiliaries such as coloring substances, pH-dependent soluble substances, temperature-dependent melting substances, and other materials that may be required, as well as their quantity (concentration in the unit volume deposited to apply the spot), are assigned and finally printed. Regarding suitable components for common printing devices, reference is made, for example, to US 2017 / 03,68755 A1 and US 6,070,107 B2.

[0023] Active ingredient-containing objects that can be printed using the process include, in particular, semi-solid or solid pharmaceutical dosage forms, such as tablets, capsules, implants, patches, suppositories, pellets, printed granules, or oral or topical thin films. Tablets that can be produced using the process according to the invention are diverse and include, for example, oblong tablets, lozenges, implant tablets, multiple-application tablets, dispersible tablets, sustained-release tablets, vaginal tablets, ophthalmic tablets, coated tablets, matrix tablets, chewable tablets, film-coated tablets, modified-release tablets, coated tablets, and margin-resistant tablets.

[0024] Other particularly suitable objects are medical devices such as active ingredient-containing topical dosage forms, contact lenses, and plasters, which preferably release the active ingredient(s), preferably for local application. In one embodiment, the method according to the invention is carried out under sterile conditions. This embodiment also provides active ingredient-containing implants. Other active ingredient-containing objects provided under sterile conditions according to the invention are injectable.

[0025] As already disclosed at the outset, the invention relates, from a further aspect, to a device for producing a solid dosage form, in particular for carrying out the method according to the invention, with (a) a build platform on which the dosage form is printed; (b) at least one print head designed to apply an arrangement of spots of a build substance for the dosage form on the build platform, wherein the build substance is flowable in the printed state and becomes at least semi-solid, preferably solid, after printing, wherein the building substance contains at least one pharmaceutical active ingredient and / or at least one nutraceutical active ingredient and / or at least one food supplement active ingredient.

[0026] Preferred embodiments of the device have already been set out in the context of the disclosure of the method according to the invention.

Claims

1. A method of preparing a solid dosage form comprising the steps of: (i) providing a printer capable of at least 3D printing the solid dosage form, the printer comprising a building platform on which the dosage form is printed; a print head designed for applying an arrangement of dots of a building substance for the dosage form on the building platform, wherein the building substance is flowable, preferably through heating, when it is printed, and becomes at least semi-solid by solidification, preferably by cooling, (ii) applying an array of dots of the building substance on the building platform, wherein the dots may overlap or contact or not contact each other; (iii) at least semi-solidifying, preferably solidifying, preferably by cooling, the dots applied in step (ii) such that the building substance becomes at least semi-solid; (iv) applying a further array of dots to the previous array of dots in such a manner that the dots of the further array overlap with the dots of the previous array; and (v) repeating steps (ii) to (iv) until the dosage form is formed, wherein the building substance comprises at least one pharmaceutically active agent and / or at least one nutraceutical active agent and / or at least one dietary supplement active agent.

2. The method of claim 1, wherein the printer comprises at least one print head connected to a reservoir containing the building substance, such that the at least one print head is capable of withdrawing an amount of the building substance for applying the building substance in steps (ii) to (v).

3. The method of claim 2, wherein the printer comprises more than one, preferably 2 to 10 or more, print head(s).

4. The method of claim 3 wherein each of the print heads is in communication with a reservoir with the building substance such that the respective print head is capable of withdrawing an amount of the building substance for applying the building substance in steps (ii) to (v).

5. The method of claim 1 wherein the building substance is in the form of a filament and the print head is designed to melt an amount of the filament for applying the array of dots of the building substance on the building platform in step (ii) and the further array of dots on the previous array of dots in step (iv).

6. The method according to any one of claims 1 to 5 wherein the dots are generated by applying a volume increment of the building substance and the volume increments have a volume of 20 pl to 30 µl.

7. The method according to any one of the preceding claims wherein the dots applied in step (ii) or each further step (ii) according to step (v) partially overlap.

8. The method according to any one of claims 1 to 6, wherein the dots applied in step (ii) or each further step (ii) according to step (v) completely overlap.