Extrusion-printable pharmaceutical formulation, printing cartridge containing such a formulation, and process for preparing a medicinal product using it

Abstract

The invention relates to a pharmaceutical formulation adapted for manufacturing unit doses of a solid or semi-solid drug by 3D printing, to a printing cartridge containing such a pharmaceutical formulation, to the use of this pharmaceutical formulation for manufacturing unit doses of a solid or semi-solid drug by 3D printing, to a printing cartridge containing such a pharmaceutical formulation, and to a method for preparing a drug in the form of unit doses by 3D printing using such a formulation. Figure to be published with the abstract: 1

Description

Title of the invention: Extrusion-printable pharmaceutical formulation, printing cartridge containing such a formulation, and method for preparing a medicinal product using it

[0001] The present invention is in the field of manufacturing medicines by three-dimensional (3D) printing.

[0002] More specifically, the present invention relates to a pharmaceutical formulation adapted for manufacturing unit doses of a solid or semi-solid drug by 3D printing, to a printing cartridge containing such a pharmaceutical formulation, to the use of this pharmaceutical formulation for manufacturing unit doses of a solid or semi-solid drug by 3D printing, to a printing cartridge containing such a pharmaceutical formulation, and to a method for preparing a drug in the form of unit doses by 3D printing implementing such a formulation.

[0003] 3D printing, or additive manufacturing, encompasses manufacturing processes that create three-dimensional parts by adding material in successive layers using a 3D printer, a digital file, and certain materials. This family of processes began to develop in the early 1980s with the primary objective of facilitating rapid prototyping.

[0004] In the healthcare sector, and particularly in the manufacturing of pharmaceuticals, the pharmaceutical forms used to treat patients often require personalized dosage of active ingredients. 3D printing technology offers the possibility of producing drugs with a precise dose of active ingredient, based on its initial concentration in the printing ink, but also influenced by the physical dimensions of the part to be printed. This approach thus makes it possible to achieve personalized dosage of the active ingredient, offering the flexibility to modify the size of the printed part. In particular, dosages in young children and the elderly can be very different from those in adults due to physiological differences (body weight, height, age) and in the pharmacokinetics of the drugs (metabolism, drug clearance, for example).Furthermore, some medications with complex dosing, such as those with a narrow therapeutic index, require precise dosing to ensure treatment efficacy and patient safety. Adjustments made by healthcare professionals to adjust the dosage from unsuitable forms pose risks to the patient.

[0005] To reduce and / or avoid these risks, 3D printing could be used to prepare a drug with the exact dosage for the patient. Furthermore, with an aging population and the increase in chronic diseases, polypharmacy is becoming common and is a factor that can influence medication adherence. The personalized combination of several active ingredients and / or dosages in a single formulation could also improve acceptability and ease of administration.

[0006] There are different categories of 3D printing technologies, and not all are compatible with the formulation of active ingredients for therapeutic purposes, either because they use materials that are not biocompatible, particularly those incompatible with oral administration, or because they are used under temperature conditions that are incompatible with the integrity of the active ingredients. This is the case, for example, with FDM (Fused Deposition Modeling) or FFF (Fused Filament Fabrication) printing technologies, which use plastic filaments such as polylactic acid (PLA) or acrylonitrile butadiene styrene (ABS). While PLA is biocompatible because it is derived from bio-based raw materials such as corn starch or sugar cane, this is not the case for ABS.Furthermore, these polymers have melting temperatures in the range of 100°C to 200°C, which are not necessarily compatible with the formulation of active ingredients, particularly heat-sensitive active ingredients.

[0007] A formulation suitable for 3D printing of medicinal products has already been proposed, notably in utility model application ES1296080U. This formulation comprises a gelling agent selected from gelatin, pullulan, carrageenan, and agar; a thickening agent selected from mannitol, cellulose, and silica; and 40 to 70% by weight of at least one solvent such as water, in particular purified water, or glycerol. This formulation is thermoreversible and requires a heating step at a temperature between 37 and 55°C before it can be used for 3D printing of medicinal products by extrusion. After printing, the mixture solidifies upon cooling, for example, to a temperature of 25°C. Although this technique allows the formulation of active ingredients resistant to a temperature of up to 55°C, it is not compatible with the implementation of thermosensitive active ingredients.Furthermore, it involves the use of a heating device to bring the formulation to be printed to the desired temperature, which complicates implementation or requires a 3D printer with a heating module.

[0008] There is therefore a need for formulations usable for the preparation of drugs in solid or semi-solid form by additive manufacturing at room temperature according to a process not requiring any heating step.

[0009] The invention described below makes it possible to meet this need.

[0010] The Inventors have indeed developed a pharmaceutical formulation comprising at least one suitably selected gelling agent, at least one suitably selected thickening agent, and a solvent in a sufficiently small proportion, said formulation being usable for the preparation of a medicinal product by additive manufacturing at room temperature.

[0011] The invention therefore has as its primary object a printable pharmaceutical formulation comprising at least one gelling agent, at least one thickening agent, at least one solvent and at least one active ingredient, characterized in that:

[0012] - said at least one gelling agent is present in an amount of 3 to 24% in weight approximately relative to the total weight of said formulation and is selected from alginates, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (or crospovidone), polyvinyl alcohol and polyethylene glycol (PVA-PEG) copolymers, cross-linked sodium carboxymethylcellulose (or croscarmellose sodium), hydroxypropylmethylcellulose, poly N-vinylpyrrolidone and polyvinyl acetate (PVP-PVAc) copolymers, sodium starch glycolate and mixtures thereof,

[0013] - said at least one thickening agent is present in an amount of 3 to 65% in weight approximately relative to the total weight of said formulation and is selected from mannitol, lactose and mixtures thereof, and

[0014] - said solvent is present in an amount of approximately 20 to 35% by weight relative to to the total weight of said formulation.

[0015] The printable pharmaceutical formulation according to the present invention is particularly well suited to the preparation of drugs for oral administration. Indeed, this formulation has the characteristic of being in the form of a semi-solid paste and possesses both good extrudability at room temperature, an essential parameter for 3D printing, and good mechanical strength, which prevents the oral dosage form from collapsing after printing. This formulation therefore requires no heating step for its implementation during extrusion printing.

[0016] The printable pharmaceutical formulation according to the present invention thus allows the production of solid or semi-solid pharmaceutical forms with a personalized dosage of active ingredients, adapted to each patient by modulating the manufacturing and / or design parameters of the part. This 3D printing technology offers the possibility of producing drugs with a precise dose of active ingredient, based on its initial concentration in the ink, but This approach is also influenced by the physical dimensions of the part to be printed. It allows for personalized dosing of the active ingredient, offering the flexibility to modify the size of the printed part (for a higher dose with increased size) and the percentage of fillers (for a higher dose with a constant volume). Furthermore, the use of software associated with 3D printers allows for the selection of various drug product shapes, notably promoting more appealing designs adapted to the specific needs of patients, such as children, compared to traditional solid forms that can be rigid and difficult to swallow.

[0017] Another advantage of the printable pharmaceutical formulation according to the invention is that it contains a small amount of solvent, which minimizes the risks of contamination and bacterial growth, thus allowing the use of small amounts of preservative. Thanks to the judicious choice of ingredients constituting the pharmaceutical formulation according to the invention, in particular the choice of gelling agent(s), this small amount of solvent remains compatible with 3D printing by extrusion at room temperature, i.e., using a process that does not require any heating step.

[0018] The extrudability profile is a measure of the force required to extrude a paste through an orifice. This profile is obtained using a texture analyzer, by measuring the compression of the product in a cartridge using a measuring cell. By examining the force-time graph during extrusion, it is possible to determine the force required to maintain a constant extrusion rate of the paste.

[0019] According to the invention, a pharmaceutical formulation is said to be too pasty to allow its printing when it exhibits an extrusion force greater than approximately 55 N.

[0020] According to the invention, a pharmaceutical formulation is said to be semi-solid and printable when it exhibits an extrusion force ranging from approximately 15 N to 55 N.

[0021] The extrusion force of the pharmaceutical form according to the invention can be measured using a texture analyzer and a flat probe (reference PL50) with a compression speed of 0.15 mm / s (see table 1 below).

[0022] According to the invention, semi-solid extrusion (or SSE, from the English expression "Semi Solid Extrusion") means an extrusion carried out using a semi-solid material, in particular a pharmaceutical formulation according to the invention, i.e. having the form of a gel or a paste.

[0023] According to a preferred embodiment of the invention, said at least one gelling agent is present in an amount of approximately 3 to 10% by weight relative to the total weight of said formulation.

[0024] Among the gelling agents usable according to the present invention, polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymers and sodium starch glycolate are particularly preferred. Thus, according to a particular and preferred embodiment of the invention, the pharmaceutical formulation comprises approximately 3 to 10% by weight of a mixture comprising a polyvinyl alcohol-polyethylene glycol copolymer and sodium starch glycolate, as gelling agents, relative to the total weight of said formulation.

[0025] According to a preferred embodiment of the invention, said at least one thickening agent is present in an amount of approximately 45 to 65% by weight relative to the total weight of said formulation.

[0026] According to a particular and preferred embodiment of the invention, the pharmaceutical formulation comprises approximately 50 to 65% by weight of mannitol as a thickening agent, relative to the total weight of said formulation.

[0027] According to another particular and preferred embodiment of the invention, the pharmaceutical formulation comprises approximately 45 to 55% by weight of lactose as a thickening agent, relative to the total weight of said formulation.

[0028] The solvent(s) usable in the pharmaceutical formulation according to the present invention are preferably chosen from water, purified water, ethanol, and mixtures thereof. Purified water is the preferred solvent. Purified water is potable water that has undergone a purification process to meet quality standards and be usable in pharmacies and laboratories. Furthermore, it conforms to international water standards, such as ISO 3696. This water is free of chlorine and other chemicals. The purification systems may be filtration, reverse osmosis, or any other system known to those skilled in the art.

[0029] According to one embodiment, the pharmaceutical formulation according to the invention comprises approximately 25 to 30% by weight of water or purified water relative to the total weight of said formulation.

[0030] According to one embodiment, the formulation further comprises at least one preservative. In this case, said at least one preservative is present in an amount of approximately 0.1 to 1% by weight relative to the total weight of said formulation, and preferably in an amount of approximately 0.1 to 0.5% by weight.

[0031] The preservative(s) may, in particular, be chosen from the group including antibacterials such as potassium sorbate, sorbic acid, and sodium benzoate. The preservatives may also be chosen from the group of antioxidants such as propyl gallate, ascorbic acid, citric acid, and mixtures thereof.

[0032] The pharmaceutical formulation according to the invention can carry any type of active ingredient, whether or not it is soluble in the solvent used. Thus, the nature of the active ingredient(s) present in the pharmaceutical formulation is not limited. The pharmaceutical formulation according to the invention is nevertheless particularly well-suited to the formulation of temperature-sensitive active ingredients, since said formulation can be shaped by 3D printing, and in particular by semi-solid extrusion, at room temperature.

[0033] By way of examples of active principles which may be formulated in the pharmaceutical formulation according to the present invention, we may mention in particular by way of example analgesics and antipyretics, hormones, antiarrhythmics, diuretics, antihypertensives and antianginals, anticholinergic agents, sedative hypnotics, antidepressants, agents against impotence, antimuscarinics, opiate antagonists, etc.

[0034] Among the hormones, we can mention in particular melatonin (or N-acetyl-5-methoxytryptamine), hydrocortisone, and prasterone (or dehydroepiandrosterone: DHEA).

[0035] Among diuretics, spironolactone can be mentioned in particular.

[0036] Among the antiarrhythmics, amiodarone can be mentioned in particular.

[0037] Among the sedative hypnotics, nitrazepam can be mentioned.

[0038] Among the antihypertensive and antianginal drugs, nadolol, captopril, metoprolol or nitrendipine can be mentioned in particular.

[0039] Among the agents against impotence, we can mention sildenafil.

[0040] Among analgesics and antipyretics, paracetamol and aspirin (acetylsalicylic acid) can be mentioned in particular.

[0041] Among the antimuscarinics, one can in particular mention bethanechol chloride.

[0042] Among the opiate antagonists, naltrexone can be mentioned.

[0043] Amitriptyline can be mentioned among the antidepressants.

[0044] Finally, among the anticholinergic agents, hyoscine can be mentioned in particular.

[0045] The quantity of active ingredient within the pharmaceutical formulation conforming to the present invention will of course have to be adapted according to the very nature of the active ingredient, the shape and size of the solid or semi-solid drug to be printed, and the dosage.

[0046] The active ingredient(s) are generally present in an amount of approximately 3 to 65% by weight relative to the total weight of said formulation.

[0047] The pharmaceutical formulation according to the invention may also include one or more pH adjusting agents and / or one or more flavoring agents and / or one or more colorings.

[0048] Examples of pH adjusting agents include citric acid, sodium citrate, malic acid, and mixtures thereof.

[0049] When used, the pH adjusting agent(s) are generally present in an amount of approximately 0.1 to 0.8% by weight relative to the total weight of said formulation, and preferably approximately 0.1 to 0.4% by weight.

[0050] Among the flavouring agents, examples include marshmallow flavour, molasses flavour, vanilla flavour, peanut butter flavour, fruit flavour and mixtures thereof.

[0051] When used, the flavoring agent(s) are generally present in an amount of approximately 1 to 5.0% by weight relative to the total weight of said formulation, and preferably approximately 1 to 3% by weight.

[0052] The colorant(s) are preferably chosen from food colorings. They may be chosen from any harmless colorant. By way of non-limiting example, the food coloring(s) are chosen from curcumin, riboflavin, lactoflavin, lactoflavin phosphate, indigotine, chlorophylls A and B, chlorophyll-copper complexes and chlorophyllins, carotenoids, xanthophylls, betanin, anthocyanins, calcium carbonate and iron oxide.

[0053] When used, the colorant(s) are generally present in an amount of approximately 0.1 to 1% by weight relative to the total weight of said formulation, and preferably approximately 0.1 to 0.3% by weight.

[0054] The pharmaceutical formulation according to the present invention can be prepared using conventional techniques known to those skilled in the art, in particular by adding the various separately weighed ingredients (gelling agent, diluent, active ingredients, etc.) in dry form (powders) to the solvent, and mixing them. The mixing of the dry and wet products can, for example, be carried out in a mixer by double asymmetric centrifugation, with a mixing speed of between approximately 100 and 2500 rpm for approximately 30 seconds to 5 minutes.

[0055] The pharmaceutical formulation according to the invention can be packaged in a printing cartridge such as a syringe having an outlet orifice for said pharmaceutical formulation and a piston for applying pressure to the pharmaceutical formulation to obtain its extrusion through said outlet orifice.

[0056] Thus, a second object of the invention is a printing cartridge comprising the pharmaceutical formulation as defined according to the first object of the invention.

[0057] According to a preferred embodiment, said printing cartridge is in the form of a syringe, in particular a syringe having an outlet orifice compatible with a 3D printer.

[0058] A third object of the present invention is the use of a pharmaceutical form as defined according to the first object of the invention, or of a printing cartridge as defined according to the second object of the invention, for the manufacture of unit doses of a solid or semi-solid drug by three-dimensional printing, in particular by semi-solid extrusion.

[0059] A fourth object of the present invention is a method for preparing a medicinal product in the form of one or more unit doses, said method being characterized in that it comprises the following steps: A) filling a printer cartridge with a pharmaceutical formulation as defined according to the first object of the invention, B) the insertion of said printing cartridge into a 3D printer, C) the printing of said pharmaceutical formulation in the form of at least one 3D object, D) the drying of said at least one 3D object to obtain said medicine, and in that each of said steps A) to C) is carried out without a heating step.

[0060] The printing cartridge usable according to the process of the invention generally comprises a reservoir provided with an outlet orifice and a means of exerting a force on the pharmaceutical formulation present in said cartridge so as to cause its extrusion through said orifice.

[0061] When filling the print cartridge, a person skilled in the art will take care to avoid the formation of air bubbles, the presence of which could cause defects in the 3D object printed in step C).

[0062] The printing in step C) is preferably carried out by semi-solid extrusion of one or more layers of said pharmaceutical formulation onto a substrate (printing platform). The number of layers will depend on the shape and volume of the unit doses of medication that are desired. This step can be controlled by software.

[0063] The extrusion of the pharmaceutical formulation onto said support can be obtained by applying a force generally between 15 N and 55 N. The application of such a force makes it possible to obtain a constant extrusion rate.

[0064] The drying of step D) is preferably carried out by evaporation of the solvent.

[0065] Steps A) to C) of the process according to the invention are carried out without a step of heating, that is to say, at room temperature.

[0066] According to the invention, ambient temperature is understood to mean a temperature generally between 20 and 25°C.

[0067] The drying step D) can be carried out at room temperature or at a temperature above room temperature. In this case, the 3D object obtained at the end of step C) is subjected to a heating step using a device to accelerate the evaporation of the solvent such as an oven or a furnace. Brief description of the figures

[0068] Figures 1 to 4 and the following examples illustrate the invention:

[0069] [Fig-1] Fig. 1 is a graph showing the rheological results of the Composition 1 of example 1. On this graph the extrusion force (in N) is expressed as a function of time (in sec.).

[0070] [Fig.2] Fig.2 is a graph showing the rheological results of the Composition 2 of example 2. On this graph the extrusion force (in N) is expressed as a function of time (in sec.).

[0071] [Fig.3] Fig.3 is a graph showing the rheological results of the Composition 3 of example 3. On this graph the extrusion force (in N) is expressed as a function of time (in sec.).

[0072] [Fig.4] Fig.4 is a graph showing the rheological results of the Composition 4 of example 4. On this graph the extrusion force (in N) is expressed as a function of time (in sec.). EXAMPLES

[0073] The following products were used in the examples: - Mannitol, sold under the trade name Pearlitol 160C ® (Roquette) - Copolymer of polyvinyl alcohol and polyethylene glycol sold under the trade name Kollicoat IR ® (Sigma Aldrich), - Sterile water, sold under the trade name Versylene ® (Fresenius) - Lactose, sold under the trade name Pharmatose 200 M ® (DFE Pharma) - Sodium starch glycolate sold under the trade name Glycolys ® (Roquette) - HydroxyPropylMethylCellulose (HPMC), sold under the trade name Metolose SM-100 ® (Shin Etsu) - Hydrocortisone, sold by INRESA - Nadollol, sold by INRESA - Melatonin, sold by INRESA.

[0074] The ingredients were used as received from the manufacturers, without further purification.

[0075] The texture of the pharmaceutical formulations prepared in these examples was studied using a TEX'AN 200® texture analyzer (Lamy Rheology). The measurement parameters are described in Table 1 below:

[0076] [Tables 1] Compression speed 0.15 mm / s Compression distance 10 mm Detection threshold 1 N Measurement method Compression Measuring probe Flat probe (ref: PL50) Measuring bench Syringe test bench (ref: TX-SAF) Syringe used BD 10mL Syringe Luer-lock tip

[0077] A graph representing the force applied (in N) by the measuring cell on the syringe piston to extrude the formulation is plotted. If the formulation is homogeneous, a plateau is obtained at a given force, which corresponds to the force to be applied to the piston to extrude the formulation at a constant flow rate.

[0078] EXAMPLE 1: Preparation of test formulations without active ingredient

[0079] In this example, a test formulation was prepared without active ingredient in order to study its texture and extrudability properties.

[0080] The various ingredients (powders) and the solvent were weighed separately. The solvent was added to a container, followed by the various ingredients in powder form. The resulting paste-like mixture was then thoroughly homogenized using a mixer by double asymmetric centrifugation until all air bubbles were completely eliminated.

[0081] The mixture was then transferred into a 55 mL Luer-Lock® printing syringe, as well as into a 10 mL Luer-Lock® syringe for texture analysis.

[0082] The printing was carried out under the following conditions using a MED-U MODULAR 3D printer sold by MB Therapeutics, according to the parameters shown in Table 2 below:

[0083] [Tables2] Nozzle 20 G, Extrusion % 0.60, Layer Height 0.45 mm, Infill 40%, Infill Type Concentric, Speed ​​50 mm / s, Number of Printed Objects 6, Height and Diameter of Each Object 3.7 mm x 3.7 mm

[0084] The composition of the test formulation without active ingredient (Composition 1) is described in Table 3 below.

[0085] [Table 3] - Composition 1: Ingredient Functionality Quantity (% by weight) Lactose Diluent 52 Kollicoat IR® Gelling agent 3.5 Glycolys® Gelling agent 11.8 Ultrapure water Solvent 32.7

[0086] The attached [Fig. 1] is a graph showing the results of the study of the texture of composition 1. On this graph the force (in N) is a function of time (in sec).

[0087] It is observed that the force required for extrusion was on average 21 N for composition 1.

[0088] EXAMPLE 2: Preparation of a hydrocortisone-based medicinal product according to the process of the invention

[0089] In this example, a paste-like formulation based on hydrocortisone was prepared.

[0090] The various ingredients (powders) and the solvent were weighed separately. The solvent was added to a container, followed by the various ingredients in powder form. The resulting paste-like mixture was then thoroughly homogenized using a mixer with double asymmetric centrifugation until all air bubbles were eliminated.

[0091] The mixture was then transferred into a 55 mL Luer-Lock® printing syringe, as well as into a 10 mL Luer-Lock® syringe for texture analysis.

[0092] The printing was carried out under the conditions described above in Table 2.

[0093] The prepared formulation is composed of the products described in Table 4, shown below:

[0094] [Table 4] - Composition 2: Ingredient Functionality Quantity (% by weight) Lactose Diluent 45.5 Glycolys® Gelling agent 13 Hydrocortisone Active ingredient 6.5 Ultrapure water Solvent 35

[0095] The attached [Fig. 2] is the graph showing the results of the texture study of the composition 2. On this graph the force (in N) is a function of time (in sec).

[0096] It is observed that the force required for extrusion was on average 51 N for composition 2.

[0097] EXAMPLE 3: Preparation of a melatonin-based medicinal product according to the process of the invention

[0098] In this example, a paste-like formulation based on melatonin was prepared.

[0099] The various ingredients (powders) and the solvent were weighed separately. The solvent was added to a container, followed by the various ingredients in powder form. The resulting paste-like mixture was then thoroughly homogenized using a mixer with double asymmetric centrifugation until all air bubbles were eliminated.

[0100] The mixture was then transferred into a 55 mL Luer-Lock® printing syringe, as well as into a 10 mL Luer-Lock® syringe for texture analysis.

[0101] The printing was carried out under the conditions described above in Table 2.

[0102] The prepared formulation is composed of the products described in Table 5, shown below:

[0103] [Table 5] - Composition 3: Ingredient Functionality Quantity (% by weight) Mannitol Diluent 57.7 HPMC Gelling agent 5 Melatonin Active ingredient 3.3 Ultrapure water Solvent 34

[0104] The attached [Fig.3] is the graph showing the results of the study of the texture of composition 4. On this graph the force (in N) is a function of time (in sec).

[0105] It is observed that the force required for extrusion was on average 46 N for composition 3.

[0106] EXAMPLE 4: Preparation of a nadolol-based medicinal product according to the process of the invention

[0107] In this example, a paste-like formulation based on nadolol was prepared.

[0108] The various ingredients (powders) and the solvent were weighed separately. The solvent was added to a container, followed by the various ingredients in powder form. The resulting paste-like mixture was then thoroughly homogenized using a mixer by double asymmetric centrifugation until all air bubbles were eliminated.

[0109] The mixture was then transferred into a 55 mL Luer-Lock® printing syringe, as well as into a 10 mL Luer-Lock® syringe for texture analysis.

[0110] The printing was carried out under the conditions described above in Table 2.

[0111] The prepared formulation is composed of the products described in Table 6, shown below:

[0112] [Table 6] - Composition 4: Ingredient Functionality Quantity (% by weight) Mannitol Diluent 17.3 Kollicoat IR® Gelling agent 18.7 Nadollol Active ingredient 36 Ultrapure water Solvent 28

[0113] The attached [Fig.4] is the graph showing the results of the study of the texture of composition 4. On this graph the force (in N) is a function of time (in sec).

[0114] It is observed that the force required for extrusion was on average 47 N for composition 4.

Claims

Demands

1. A printable pharmaceutical formulation comprising at least one gelling agent, at least one thickening agent, at least one solvent, and at least one active ingredient, characterized in that: - said at least one gelling agent is present in an amount of 3 to 24% by weight relative to the total weight of said formulation and is selected from alginates, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymers, cross-linked sodium carboxymethylcellulose, hydroxypropylmethylcellulose, poly-N-vinylpyrrolidone-polyvinyl acetate (PVP-PVAc) copolymers, sodium starch glycolate, and mixtures thereof; - said at least one thickening agent is present in an amount of 3 to 65% by weight relative to the total weight of said formulation and is selected from mannitol, lactose, and mixtures thereof.and - said solvent is present in an amount of 20 to 35% by weight relative to the total weight of said formulation.

2. Pharmaceutical formulation according to claim 1, characterized in that said at least one gelling agent is present in an amount of 3 to 10% by weight relative to the total weight of said formulation.

3. Pharmaceutical formulation according to claim 1 or 2, characterized in that it comprises from 3 to 10% by weight of a mixture comprising a copolymer of polyvinyl alcohol and polyethylene glycol and a sodium starch glycolate, as gelling agents, relative to the total weight of said formulation.

4. Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that said at least one thickening agent is present in an amount of 45 to 65% by weight relative to the total weight of said formulation.

5. Pharmaceutical formulation according to any one of claims 1 to 4, characterized in that it comprises from 50 to 65% by weight of mannitol as a thickening agent, relative to the total weight of said formulation or from approximately 45 to 55% by weight of lactose as a thickening agent, relative to the total weight of said formulation.

6. Pharmaceutical formulation according to any one of claims 1 to 5, characterized in that the solvent(s) are selected from water, purified water, ethanol, and mixtures thereof.

7. Pharmaceutical formulation according to any one of claims 1 to 6, characterized in that it comprises from 25 to 30% by weight of water or purified water approximately relative to the total weight of said formulation.

8. Pharmaceutical formulation according to any one of claims 1 to 7, characterized in that the active ingredient(s) are selected from analgesics and antipyretics, hormones, antiarrhythmics, diuretics, antihypertensives and antianginals, anticholinergic agents, sedative hypnotics, antidepressants, agents against impotence, antimuscarinics, and opiate antagonists.

9. Printing cartridge characterized in that it comprises the pharmaceutical formulation as defined in any one of claims 1 to 8.

10. Use of a pharmaceutical dosage form as defined in any one of claims 1 to 8 or of a printing cartridge as defined in claim 9, for the manufacture of unit doses of a solid or semi-solid medicinal product by three-dimensional printing, in particular by semi-solid extrusion.

11. A method for preparing a medicinal product in the form of one or more unit doses, said method being characterized in that it comprises the following steps: A) filling a printing cartridge with a pharmaceutical formulation as defined in any one of claims 1 to 8, B) introducing said printing cartridge into a 3D printer, C) printing said pharmaceutical formulation in the form of at least one 3D object, D) drying said at least one 3D object to obtain said medicinal product, and in that each of said steps A) to C) is carried out without a heating step.

12. A preparation method according to claim 11, characterized in that step C) is carried out by semi-solid extrusion of a or several layers of said pharmaceutical formulation on a support.

Images