Process for manufacture of solid pharmaceutical administration forms

Abstract

The present invention relates to a process for preparing a solid pharmaceutical administration form comprising an amorphous solid dispersion using a 3D printing process. The process is a printing process which allows the production of solid administration forms of a solid drug comprising an amorphous solid dispersion in a simple and flexible manner and makes it possible to obtain rapidly disintegrating dosage forms with high drug loading.

Description

[0001] The present invention relates to a method for preparing solid pharmaceutical dosage forms using a powder-based 3D printing method. This method allows for the production of solid pharmaceutical dosage forms in a simple and flexible manner and in accordance with the high quality standards required for pharmaceutical production, wherein the active ingredient is present as an amorphous solid dispersion in a polymer matrix.

[0002] Many recently developed active pharmaceutical ingredients (APIs) suffer from poor water solubility, which results in incomplete dissolution throughout the gastrointestinal (GI) tract, leading to low and variable bioavailability. A large number of new candidate drugs fail during the development process due to poor bioavailability, and the number is still increasing. Therefore, there is an urgent need for progress in innovative methods to overcome this important formulation challenge, making the development of new drug delivery systems highly desirable.

[0003] In this amorphous form, the compound will exhibit a higher dissolution rate compared to the crystalline state of the compound, especially when solubility is limited by high lattice energy. This in turn increases oral bioavailability, as shown by Mellaerts et al. (Eur J Pharm Biopharm 69:223 - 230, 2008). 3D printing technologies offer new possibilities for drug development. Compared to standard manufacturing techniques such as tablet manufacturing, they are able to produce personalized dosage forms and facilitate clinical trials through easy dose adjustment.

[0004] The term 3D printing refers to a method of creating 3D objects in a layer-by-layer manner. However, it is difficult to manufacture solid pharmaceutical dosage forms in which the active ingredient is present in an amorphous form using known 3D printing methods and may be accompanied by other problems as discussed below.

[0005] Fused deposition modeling (FDM) or fused filament fabrication (FFF) is a method of 3D printing using a continuous filament of a thermoplastic material. For the manufacture of pharmaceutical dosage forms, filaments containing the API are produced by hot melt extrusion (HME) and then fed into a heated printer nozzle, and the softened material is deposited layer by layer to create the pharmaceutical dosage form. FDM printed dosage forms consist of a solidified dense melt, which dissolves mainly by erosion. Although porous systems are possible, the degree of porosity is limited due to the poor resolution of the printer. In addition, recrystallization of the active ingredient may occur during the heating process of the printing step. High drug loading poses a challenge to FDM because it may weaken the mechanical properties of the filament, thus adversely affecting its printability. In addition, the second heating step required to soften the filament for printing can trigger degradation of the API.

[0006] Direct powder extrusion (DPE) is a 3D printing method in which a powder blend is melted and printed into tablets in one step, thus avoiding double heating and the filament production process. However, DPE is prone to demixing of the powder components in the powder blend during printing, resulting in impaired content uniformity of the resulting dosage form. In addition, as in the case of FDM, the printed dosage form also faces the problem of poor disintegration due to its dense structure. Moreover, the manufacture of amorphous solids may be more difficult because of the short transition time at the hot end (the heated area above the nozzle in the print head), and thus the installed screw may not provide sufficient mechanical energy to amorphize the API. The extrusion method is very sensitive to changes in mass flow, and thus, changing the printing speed in DPE may lead to considerable changes in the properties of the melt or the solidified product.

[0007] Another 3D printing technique is selective laser sintering (SLS), in which 3D printed objects are manufactured by creating powder layers and fusing the powder particles present in the powder layer with a laser. This technique can be used to produce porous dosage forms. The laser has the potential to amorphize the API in situ, but complete amorphization of the API is difficult. The technical conditions of the laser printer limit the large-scale production of tablets. In addition, due to the highly focused collimation of the laser, SLS may result in very high temperatures at certain points of the printed material, which may have an adverse effect on the stability of the API and / or other printing materials.

[0008] Powder binder jetting or "drop-on-powder" printers are an easily scalable 3D printing technique that uses a liquid to fuse powder particles. It is used to produce high-dose and fast-disintegrating dosage forms. It is currently used for APIs with good solubility, where the API is embedded in a powder bed. The manufacture of amorphous solid dispersions of poorly soluble APIs can be achieved when the API is incorporated into the ink by rapid solvent evaporation similar to spray drying. This method can produce amorphous samples, but with low drug loading. The formulation development of high-dose and poorly soluble APIs into fast-disintegrating dosage forms is a challenge.

[0009] As described above, the existing 3D printing methods available for the preparation of solid pharmaceutical dosage forms have several drawbacks that hinder their wide applicability. Therefore, there is a strong need for a 3D printing method that allows the production of solid dosage forms without being troubled by such drawbacks. Such a 3D printing method will produce solid dosage forms in which the active ingredient is present in an amorphous form, will allow the manufacture of such dosage forms that also have active ingredients with low solubility in a biologically relevant medium, and will also allow the manufacture of such dosage forms with a high active ingredient content, even if the active ingredient exhibits low solubility in a biologically relevant medium. The present invention provides a method that meets such requirements.

[0010] The method of the present invention is a method for manufacturing a solid pharmaceutical dosage form containing an active ingredient, which comprises the steps of: (a) preparing a powder of particles of an amorphous solid dispersion of the active ingredient in a polymer matrix; (b) spreading the powder prepared in step (a) on a manufacturing area; (c) jetting a printing medium onto the powder, wherein such a medium is suitable for providing adhesion of the powder; (d) spreading a layer of the powder prepared in step (a) on the surface of the powder obtained after performing steps (b) and (c) and then performing steps (b) and (c); (e) repeating step (d) as needed to construct the solid pharmaceutical dosage form; (f) separating the solid pharmaceutical dosage form from the powder bed.

[0011] The process can be run on a 3D printer, which consists of a pair of horizontal X-Y axes suspended above a vertical piston, thus providing control in three directions of movement and equipped with a jet head known from inkjet printing technology. Suitable jet heads can operate, for example, according to the continuous inkjet principle (the fluid is pressurized and discharged as a continuous stream of droplets) or the drop-on-demand principle (the fluid is discharged from the jet nozzle one drop at a time).

[0012] To manufacture a solid pharmaceutical dosage form, powder is spread on a mounting plate to create a powder bed, and the medium is precisely distributed above a predetermined area of the powder bed by moving the jet head above the powder bed or moving the powder bed under a fixed jet head. After the mounting plate is lowered by a fixed distance, a powder layer is spread, and the process is repeated. Instead of lowering the mounting plate, the spreading means can be raised by a fixed distance.

[0013] The above method in which a medium suitable for providing adhesion of the powder is jet printed onto the powder bed is called the Droplet Deposition on Powder (DoP) technique. It belongs to powder-based 3D printing technology and can be described as in-situ wet granulation, where small ink or binder droplets are jetted onto a thin powder layer, causing fusion of the powder particles. The iterative process of powder spreading and ink application is carried out until the 3D object is printed.

[0014] As used herein, the term "solid pharmaceutical dosage form" means any solid pharmaceutical preparation that provides a dosage unit of an active pharmaceutical ingredient and can be administered to a patient by any mode of application such as oral, rectal, vaginal, implant. The solid pharmaceutical dosage form can have any shape suitable for the application needs, such as round, oval, rod-like, torpedo-shaped, etc. Examples of solid pharmaceutical dosage forms are tablets, pills, capsule-type tablets, suppositories, implants. Preferably, the solid pharmaceutical dosage form is a tablet.

[0015] As used herein, the term "active ingredient" means any ingredient that provides a pharmacological or biological effect when applied to a biological system. The active ingredient can be a drug, a virus, or a biological substance of living origin. Examples of active ingredients that can be used in the methods of the present invention are hydrocortisone, prednisone, budesonide, methotrexate, mesalazine, sulfasalazine, amphotericin B, fenofibrate, carbamazepine, ibuprofen, glibenclamide, dipyridamole, itraconazole, celecoxib, haloperidol, indomethacin, posaconazole, ketoconazole.

[0016] As used herein, the term "solid dispersion" refers to a drug substance dispersed or distributed in a dispersion medium. In the present invention, the dispersion medium is a polymer, which forms a polymer matrix. Based on the possible combinations of the physical states of the drug substance and the polymer, the drug substance can be crystalline or amorphous, and the polymer matrix can also be crystalline and amorphous, resulting in four possible combinations: crystalline drug substance - crystalline polymer (solid suspension); amorphous drug substance - amorphous polymer; crystalline drug - amorphous polymer; and amorphous drug - crystalline polymer.

[0017] As used herein, the term "amorphous solid dispersion" (ASD) refers to a dispersion in which at least the active ingredient is present in a substantially amorphous form. Preferably, both the active ingredient and the polymer are present in a substantially amorphous form. With respect to the active ingredient, the term "substantially amorphous form" means that at least 80 wt%, usually at least 85 wt%, preferably at least 90 wt%, more preferably at least 95 wt%, still more preferably at least 96 wt%, still more preferably at least 97 wt%, more preferably at least 98 wt%, more preferably at least 99 wt%, more preferably at least 99.9 wt%, more preferably all of the active ingredient is present in an amorphous form.

[0018] As used herein, the term "amorphous" refers to the non-crystalline form of a solid. Amorphous solids typically have a short-range molecular arrangement similar to that of a crystal, i.e., without the long-range order of molecular packing found in crystalline solids. The solid form of the solid in the solid dispersion can be determined by polarized light microscopy, X-ray powder diffraction, differential scanning calorimetry, or other techniques known to those skilled in the art. The amorphous form of the active ingredient in the solid dispersion can typically be identified by a unique broad X-ray powder diffraction pattern, while crystalline solids produce specific isolated peaks. The amorphous form can exist in two states: a rubbery state and a glassy state, and one state transforms into the other at the glass transition temperature (Tg).

[0019] As used herein, the term "polymeric matrix" describes a three-dimensional solid formed from one or more polymers. In the powders used in the present invention, the polymeric matrix serves to encapsulate the active ingredient. Further compounds such as, for example, one or more further active ingredients or other excipients can be incorporated (such as dissolved or dispersed) in such a polymeric matrix.

[0020] The preparation of the powder in step (a) involves preparing an amorphous solid dispersion of the active ingredient in the polymeric matrix and, if desired, reducing its size to a particle size suitable for use in the method, which can be carried out by using suitable methods known in the art such as, for example, grinding. If the powder contains further materials, the amorphous solid dispersion particles are mixed with such materials to produce the powder for further steps. If no further materials are required, the solid dispersion particles represent the powder prepared in step (a), which is used in the further steps.

[0021] Powders suitable for carrying out the further steps of the method generally have a d50 particle diameter of from about 1 μm to about 200 μm, preferably from about 10 μm to about 100 μm, more preferably from about 30 μm to about 70 μm. The d50 value mentioned herein refers to the particle diameter that divides the distribution into half above and half below that diameter, in micrometers. The d50 is the median of the volume distribution and is commonly also referred to as Dv50 (or Dv0.5). The d50 value mentioned herein is the value that can be measured by laser diffraction using a Malvern Mastersizer 2000.

[0022] As used herein, the term "spreading" refers to the method of applying a planar layer of powder onto a planar substrate. The spreading of the powder can be achieved by using means suitable for creating a planar layer of the powder. Examples of such means are a spatula or a roller, which can be moved parallel to the planar substrate (such as the mounting area or an existing powder layer) to distribute the powder from a reservoir onto the planar substrate. By using a roller, a certain level of compaction can be obtained, which may be beneficial for the manufacture of solid pharmaceutical dosage forms.

[0023] As used herein, "a" or "an" shall mean one or more. As used herein, when used in conjunction with the word "comprising", the words "a" or "an" mean one or more than one. As used herein, "another" means at least a second or more. Further, unless the context otherwise requires, singular terms include plural referents and plural terms include singular referents.

[0024] As used herein, "about" refers to a numerical value, including, for example, integers, fractions, and percentages, whether or not explicitly stated. The term "about" generally refers to a range of numerical values (e.g., + / - 1 - 3% of the stated value) that a person of ordinary skill in the art would consider equivalent to the stated value (e.g., having the same function or result). In some cases, the term "about" may include a numerical value rounded to the nearest significant digit.

[0025] As used herein, "jet printing" refers to a method of distributing a medium onto a powder bed by jetting droplets of the medium at high speed towards the powder bed. The jetting of the droplets to a predetermined target position can be carried out with the highest precision. By managing the size and / or amount of the droplets and the specific target position, the exact position on the substrate and the penetration depth into the substrate can be precisely controlled. Jet printing is known from inkjet printing technology, but different from this technology, the medium printed in the method of the present invention is not an ink for printing an image, but a medium containing materials that can be used for printing solid pharmaceutical dosage forms.

[0026] The amorphous solid dispersion of the active ingredient present in the powder prepared in step (a) of the method according to the invention in the polymer matrix can be prepared using any method known in the art that is feasible for preparing an amorphous solid dispersion of an active ingredient in a polymer matrix. According to suitable embodiments, hot melt extrusion, co-precipitation, or spray drying is used to prepare the amorphous solid dispersion. Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, wherein an amorphous solid dispersion of the active ingredient present in the powder prepared in step (a) in the polymer matrix is prepared using hot melt extrusion, co-precipitation, or spray drying. It is particularly preferred to prepare the powder by hot melt extrusion.

[0027] As used herein, the term "hot melt extrusion" refers to a method of mixing two or more components using high-shear mixing at a controlled temperature. When used to prepare the powder according to step (a) of the method, hot melt extrusion includes mixing the active ingredient and at least one polymer together until a soft mass is produced. The mixing of the active ingredient and the polymer can occur before, during, or after the formation of the soft mass. For example, the ingredients required to produce the soft mass can be mixed first and then extruded, or they can be mixed and melt-extruded simultaneously. Finally, the melt is homogenized in order to disperse or encapsulate the active ingredient into the polymer.

[0028] The hot melt extrusion process can be carried out by using conventional extruders known in the art. Suitable extruders include, but are not limited to, single screw extruders, intermeshing screw extruders or multi-screw extruders, preferably twin screw extruders, which can be co-rotating or counter-rotating, and optionally equipped with kneading mixing and / or conveying elements. The operating temperature for preparing the hot melt extrudate typically depends on the API and polymer properties as well as the extruder type and screw configuration. The extrudate obtained by hot melt extrusion can be further processed, for example by grinding, to provide a powder having dimensions and shape that can be used in the method.

[0029] As used herein, the term "co-precipitation" refers to a method in which two or more solid components are dissolved in a common solvent and precipitated by rapid mixing with a common anti-solvent. The anti-solvent is miscible with the common solvent. The rapid co-precipitation of the active ingredient and the polymer can produce a suspension of amorphous particles, which can be further washed and dried into a powder.

[0030] As used herein, the term "spray drying" in principle refers to a solvent extraction method. The components of the product to be obtained are dissolved / dispersed in a liquid, and then fed, for example by using a peristaltic pump, to the atomizer of a spray dryer. Suitable atomizers that can be used for the atomization of the liquid include nozzles or rotary disks. In the case of nozzles, atomization occurs due to the action of compressed gas or pressurized liquid, while in the case of using a rotary disk, atomization occurs due to the rapid rotation of the disk. In both cases, atomization causes the liquid to break up into small droplets and enter the drying chamber, where the solvent is extracted from the aerosol droplets and discharged, for example through an exhaust pipe to a solvent trap.

[0031] The medium for jet printing is a liquid. As used herein, the term "liquid" refers to a solvent that is fluid at ambient temperature (about 25 °C). Examples of liquids are water, organic solvents such as ethanol or mixtures of both, where the organic solvents may be soluble or insoluble in each other. Thus, the present invention also relates to a method for manufacturing a solid pharmaceutical dosage form, wherein the medium for jet printing in step (c) is a liquid.

[0032] The liquid may also contain auxiliaries, which can be dissolved, suspended or emulsified in the liquid. Auxiliaries that can be used include surfactants, for example, to improve the spreading or wetting of the particles in the powder bed. Further examples of auxiliaries include viscosity regulators, such as glycerol, to achieve jet printing by preventing excessive wetting of the nozzle plate or by controlling the flow of the liquid through the channels and nozzles of the printhead; reagents for controlling the hydrophilicity or hydrophobicity of the ink, such as co-solvents, such as ethanol, butanol, diethylene glycol, polyethylene glycol, dimethyl sulfoxide, hexane, to improve the spreading or wetting of the particles in the powder bed; humectants, such as glycerol or propylene glycol, to prevent nozzle clogging due to ink evaporation; film formers, sometimes referred to as binders or resins, to control the spreading of the ink on the substrate and prevent bleeding or smudging of the ink on the substrate; dyes or pigments; and defoamers.

[0033] The liquid jet-printed onto the powder in step (c) itself provides the binding of the powder, such that there is no need for the presence of a binder as known in binder jetting methods. However, in some cases, it may be advantageous for the powder spread on the build area to contain a binding material, which provides additional binding after activation by the medium jet-printed onto the powder. Accordingly, the present invention also relates to a method wherein the powder contains a binding material. If the powder contains a binding material, the binding material is present in the powder as a physical mixture with the other powder particles.

[0034] In some cases, if the binding material is a polymer, the binding material present in the powder can be the same material as the polymer used as the matrix material of the amorphous solid dispersion.

[0035] When the medium is jet-printed onto the powder, the binding of the powder is provided by partial dissolution and fusion of the polymer matrix and activation of the binding material (if present in the powder). Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, wherein the medium is a fluid liquid that partially dissolves the polymer matrix and / or the binding material present therein.

[0036] Partial dissolution of the polymer matrix means that a part of the polymer matrix of the particles dissolves and softens to some extent, thereby inducing the sticking and / or partial fusion of the particles in close contact with each other and constructing a porous structure of the adhering and / or fused particles.

[0037] Advantageously, the medium to be jet-printed onto the powder for causing the sticking and adhesion of the particles contains at least one volatile solvent. A volatile solvent is a liquid that readily evaporates into a gas at room temperature (about 25 degrees Celsius) and atmospheric pressure (about 76 mmHg), such as organic solvents such as methanol and ethanol. When in contact with the powder containing the polymer matrix and causing partial dissolution and / or fusion of the polymer matrix of the powder particles adjacent to each other, the volatile solvent disappears by evaporation, thereby causing re-solidification of the polymer matrix present in the powder and sticking of the powder.

[0038] The physicochemical properties of the medium required to cause sticking and / or partial fusion of the matrix polymer present in the powder, such as its ability to dissolve the polymer of the polymer matrix and / or its volatility, can be easily adjusted to suit the specific requirements of the specific polymer and the needs of carrying out the printing process by using different volatile solvents and / or mixing volatile solvents alone or together with non-volatile solvents. Accordingly, the present invention also relates to a method in which the medium comprises one or more volatile solvents alone or a mixture of one or more volatile solvents and one or more non-volatile solvents or consists of one or more volatile solvents alone or a mixture of one or more volatile solvents and one or more non-volatile solvents. A non-volatile solvent is a liquid that is not readily vaporized into a gas at room temperature (about 25 degrees Celsius) and atmospheric pressure (about 76 mmHg) and has a vapor pressure equal to or less than that of water under such conditions.

[0039] Suitable volatile solvents that can be used as the medium in the method of the present invention are methanol, ethanol, propanol, 2-propanol, and acetone; suitable non-volatile solvents are water, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, in which the volatile solvent is selected from methanol, ethanol, propanol, 2-propanol, and acetone, and the non-volatile solvent is selected from water, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. Methanol and ethanol are particularly preferred.

[0040] In some cases, the medium jetted onto the powder may also contain a binder material. Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, in which the medium is liquid and contains a binder material. If the medium contains a binder material, then such binder material is present in dissolved or dispersed form. Preferably, it is present in dissolved form.

[0041] As used herein, the term "binder material" refers to a material that provides adhesion or sticking of the particles. When applied to a powder bed, the particles in contact with the binder material adhere to each other, thereby producing a solid composed of particles attached to each other. In the present invention, the binder material provides cohesion and strength to the solid preparation.

[0042] Binder materials that can be employed in the present invention are, for example, lactose, sorbitol, mannitol, xylitol, maltitol, glucose, fructose, sucrose, sucrose fatty acid esters (such as sucrose stearate, sucrose palmitate), sorbitan esters (such as ), glycerol fatty acid esters (such as glyceryl monostearate), fatty acids, fatty alcohols (solid at room temperature), esters of fatty acids and fatty alcohols, and polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starches such as corn starch or pregelatinized starch, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose acetate succinate or microcrystalline cellulose, copolymers of acrylic acid or methacrylic acid and acrylate or methacrylate, preferably copolymers of methacrylic acid and methacrylate or acrylate, such as, for example, poly(methacrylic acid-co-methyl methacrylate) (1:1) (such as L 100), poly(methacrylic acid-co-methyl methacrylate) (1:2) (such as S100) or poly(methacrylic acid-co-ethyl acrylate) (1:1) (such as L 100-55), copolymers of ethyl acrylate, methyl methacrylate and a low content of methacrylate with a quaternary ammonium group, such as, for example, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylaminoethyl methacrylate chloride) 1:2:0.2 (such as RL) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylaminoethyl methacrylate chloride) 1:2:0.1 (such as RS), copolymers of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, such as, for example, poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (2:1:1) (such as E PO), preferably hydroxypropylmethylcellulose acetate succinate or polyvinyl alcohol, more preferably hydroxypropylmethylcellulose acetate succinate. Accordingly, the present invention also relates to a method for manufacturing a solid pharmaceutical dosage form, wherein the binder material comprises or consists of: lactose, sorbitol, mannitol, xylitol, maltitol, glucose, fructose, sucrose, sucrose fatty acid esters (such as sucrose stearate, sucrose palmitate), sorbitan esters (such as ) glycerol fatty acid esters (such as glycerol monostearate), fatty acids, fatty alcohols (solid at room temperature), esters and polymers of fatty acids and fatty alcohols such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starches such as corn starch or pregelatinized starch, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate or microcrystalline cellulose, copolymers of acrylic acid or methacrylic acid and acrylate or methacrylate, preferably copolymers of methacrylic acid and methacrylate or acrylate, such as for example poly(methacrylic acid-co-methyl methacrylate)(1:1)(e.g. L 100), poly(methacrylic acid-co-methyl methacrylate)(1:2)(e.g. S100) or poly(methacrylic acid-co-ethyl acrylate)(1:1)(e.g. L 100-55), copolymers of ethyl acrylate, methyl methacrylate and a low content of methacrylate with a quaternary ammonium group, such as for example poly(ethyl acrylate-co-methyl methacrylate-co-trimethylaminoethyl methacrylate chloride) 1:2:0.2 (e.g. RL) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylaminoethyl methacrylate chloride) 1:2:0.1 (e.g. RS), copolymers of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, such as for example poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate)(2:1:1)(e.g. E PO), preferably hydroxypropyl methylcellulose acetate succinate or polyvinyl alcohol, more preferably hydroxypropyl methylcellulose acetate succinate.

[0043] Polymers that can be used as matrix polymers to prepare powders for amorphous solid dispersions containing active ingredients in a polymer matrix are vinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), ( L100-55) and poly(methacrylic acid-co-methyl methacrylate)( L and S), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), Hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT) or hydroxypropyl methylcellulose acetate trimellitate (HPMCAT). Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, wherein the polymeric matrix comprises or consists of: vinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), ( L100-55) and poly(methacrylic acid-co-methyl methacrylate)( L and S), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), Hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT) or hydroxypropyl methylcellulose acetate trimellitate (HPMCAT).

[0044] In some cases, depending on the type and amount of the medium jet-printed onto the powder, especially the volatility of the liquid, and the physico-chemical properties of the powder after jet-printing the medium according to step (c), it may be necessary to wait for a period of time for the liquid to evaporate before proceeding with the next step. In such cases, it may be necessary to accelerate the evaporation of the liquid, which will allow the process to proceed faster. In such cases, a drying step may be introduced after performing step (c) and / or step (d). Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, wherein a drying step is performed after performing step (c) and / or step (d).

[0045] According to a suitable embodiment, the drying step is performed by using heating, reducing the air pressure or convection. Since each of such measures itself favors evaporation, each of such measures can be combined with one or more other measures to achieve an additive effect and accelerate the drying step. Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, wherein the drying step comprises heating, low (air) pressure and / or convection. A suitable low air pressure is a pressure below atmospheric pressure, for example, a pressure in the range of 100 to 80,000 Pa, preferably in the range of 5,000 to 50,000 Pa. Convection can be applied, for example, by a blower. An example of an embodiment of the drying step is one in which heating is combined with convection by blowing heated air towards the powder bed using a blower.

[0046] Heating can be applied by infrared radiation, hot air flow, and / or a heated surface. Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, in which heating is applied by infrared radiation, hot air flow, and / or a heated surface. The gas of the hot air flow can be a gas of any element or chemical compound, such as nitrogen or carbon dioxide, for example, or a mixture of elemental and chemical compound gases, such as air. The heated surface can be provided, for example, by heating a mounting plate or a part or all of the housing of a 3D printer used to run the process.

[0047] In principle, solid pharmaceutical dosage forms for any mode of administration, such as oral, rectal, vaginal, implantable, can be manufactured by the method described herein. However, the method is particularly suitable for manufacturing solid pharmaceutical dosage forms for oral use. Accordingly, an advantageous embodiment of the invention described herein relates to a method of manufacturing a solid pharmaceutical dosage form, in which the pharmaceutical dosage form is for oral use.

[0048] Since the active ingredient is present in an amorphous solid state, its dissolution in a biologically relevant medium is increased. Accordingly, the method of the present invention is particularly suitable for manufacturing immediate-release formulations. Correspondingly, a preferred embodiment of the present invention relates to a method of manufacturing a solid pharmaceutical dosage form, in which the pharmaceutical dosage form provides immediate release of the active ingredient.

[0049] As used herein, the term "immediate release" means that a majority of the active pharmaceutical ingredient is rapidly released from the pharmaceutical dosage form. Preferably, at least 80% of the active substance is released within 30 minutes, more preferably within 15 minutes, after administration. Release (dissolution) of the active ingredient from the pharmaceutical dosage form is measured in pH 6.8 buffer or 0.1 N HCl using a conventional dissolution test that complies with the standard dissolution test described in the applicable pharmacopoeia (e.g., USP Chapter 711).

[0050] In some cases, after separating it from the powder bed in step (f) of the method, the solid pharmaceutical dosage form may still contain some residual liquid that has not evaporated, and this residual liquid needs to be removed before further processing to, for example, avoid physical damage. In such cases, a subsequent drying step may be required to remove the remaining liquid from the solid pharmaceutical dosage form. Accordingly, the present invention also relates to a method of manufacturing a solid pharmaceutical dosage form, in which a drying step is performed after step (f). Such a drying step includes heating, low (air) pressure, and / or convection.

[0051] Hereinafter, the present invention will be described with reference to its exemplary embodiments, which should not be considered as limiting the present invention. Examples

[0052] Printing device

[0053] The following examples are manufactured using a device comprising a powder bed which can be moved in the x and y directions of the machine and serves as the build area for the object described. A print head assembly is located above the powder bed. The assembly comprises a modified HP C6602 inkjet cartridge. The cartridge is connected to an electronic circuit which can activate the nozzles to eject fluid droplets synchronized with the movement of the powder bed. The cartridge is modified such that the ink contained in a normal cartridge can be replaced. In addition, a connector is introduced to connect the cartridge to a pressure regulator. A negative pressure of 20 mm H 2 O is applied to the ink reservoir of the cartridge. For the inkjet printing of media containing a binder, the original nozzle pitch of the cartridge is used. Powder reservoirs are mounted above the build plate containing the powder at different positions. The material can be deposited onto the build area of the powder bed in a controlled manner.

[0054] The printing process is controlled via software commands executed in sequence. First, a thin powder layer is prepared in the powder bed. Subsequently, the powder bed is moved under the print assembly and liquid material is inkjet printed onto the surface of the powder bed. After all the print commands for a particular layer and an optional dwell time have been executed, the next layer of particulate material (height: 0.1 mm) is deposited onto the surface of the powder bed that has been prepared and liquid material is inkjet printed onto this new powder layer. The process is repeated until all the layers of the object have been printed.

[0055] The print pattern and the movements required to manufacture a particular object are defined by software that employs a digital three-dimensional model and a setup file.

[0056] The shape of the printed object can be defined via a digital three-dimensional model.

[0057] Each nozzle of the print head ejects up to 500 droplets per second.

[0058] Droplet volume

[0059] The droplet volume of the print head is measured by printing a defined number of droplets into the wells of an acrylic 96-well plate. The deposited material is diluted and the concentration of the incorporated dye is determined via UV / VIS spectrometry. The droplet volume is calculated using the following formula:

[0060]

[0061] Preparation of powder bed

[0062] The powder used in the printing process is prepared by hot melt extrusion. Ketoconazole, copovidone, and fumed silica are blended in a drum mixer at ratios of 20:79:1 and 40:59:1. Ketoconazole is used as a poorly soluble model compound. Extrusion is carried out on a co-rotating twin-screw extruder equipped with an 11 mm screw. The extrusion is carried out at a temperature above the melting temperature of ketoconazole. The powder blend is fed by gravity at a rate of 0.2 kg / h. The screw speed is set at 300 rpm. The extrudate strands are pulled out using a conveyor belt. The collected extrudate strands are ground using a supercentrifugal mill equipped with a sieve (sieve hole size 200 μm). The grinding is carried out at 10,000 rpm.

[0063] Glossary

[0064] Copovidone: A copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4 (European Pharmacopoeia 11.0 monograph "Copovidone")

[0065] Fumed silica: Colloidal silica according to the European Pharmacopoeia 11.0 monograph "Anhydrous Colloidal Silica"

[0066] Methylene blue: IUPAC name 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride

[0067] Non-sedimentation dissolution

[0068] 1.2 ml of FaSSIF is prepared according to the instructions from FaSSIF powder (Biorelevant.com Ltd, London, UK) (L. Klumpp, Dissolution behavior of various drugs in different FaSSIF versions, European Journal of Pharmaceutical Sciences, 2020) and heated to 37 °C in an Eppendorf cap. After introducing the ground and weighed sample into the medium, the Eppendorf cap is vortexed. Before sampling, the medium is centrifuged and then 50 μl of the supernatant is taken. After sampling, the solid fraction is resuspended by vortexing. The sample is diluted with an organic solvent to prevent precipitation of ketoconazole, and the concentration of ketoconazole in the sample is determined via UPLC.

[0069] The drug loading of the object is determined by diluting the medium with an organic solvent after the dissolution experiment to fully dissolve ketoconazole and measuring the concentration of ketoconazole via UPLC. The mass of API in the printed object is calculated from all the sampled and final values.

[0070] Sedimentation dissolution

[0071] The formulation prototype was analyzed in a paddle-equipped dissolution apparatus according to USP Apparatus Type 2. The dissolution medium (0.1 N hydrochloric acid) was heated to 37 °C. The paddle speed was set at 100 rpm. Samples were withdrawn at different time points, mixed with an equal volume of organic solvent, and the concentration was analyzed via UPLC.

[0072] Tensile strength

[0073] The crushing strength of the tablets was determined according to European Pharmacopoeia 11.0, 2.9.8. “Crushing strength of tablets”. The tensile strength was calculated according to the equation for flat-face compact by Pitt, K.G. and M.G. Heasley (2013). "Determination of the tensile strength of elongated tablets." Powder Technology 238:169-175.

[0074] Storage conditions

[0075] The formulation prototype was stored in a desiccator at 40 °C for four weeks.

[0076] Differential scanning calorimetry (DSC)

[0077] The sample was weighed into an aluminum pan and sealed airtight. The pan was pierced before analysis. The sample was heated from 0 °C to 180 °C (physical mixture) or from 0 °C to 200 °C (formulation prototype), and then cooled to 0 °C at a rate of 10 K / min.

[0078] Powder X-ray diffraction (pXRD)

[0079] Powder X-ray diffraction was performed in Bragg-Brentano geometry. The X-rays were generated by a copper anode at 30 kV and 10 mA. Kβ radiation was reduced by using a nickel foil. Sample preparation was carried out on a zero-background holder in the range of 6° - 35°. The step size was 0.02 mm. In the case of the formulation prototype, the measurement time per step was set at 6 seconds, and in the case of the physical mixture, it was set at 1 second.

[0080] Hereinafter, the present invention will be further described with reference to its exemplary embodiments, which should not be construed as limiting the present invention.

[0081] Example A

[0082] The medium is made by mixing ethanol and purified water in a volume ratio of 7:3. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 20% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 30 droplets per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed and the printing process is repeated for a total of 24 layers.

[0083] The process produces an object (shape: cylinder with a diameter of 10 mm and a height of 2.4 mm), with a mass of 150.6 mg ± 6.2 mg (mean ± sd, n = 75), a drug loading of 19.85% ± 0.09% (mean ± sd, n = 3), and a tensile strength of 0.9 MPa ± 0.3 MPa (mean ± sd, n = 10).

[0084] Example B

[0085] The medium is made by mixing ethanol and purified water in a volume ratio of 7:3. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 30 droplets per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed and the printing process is repeated for a total of 24 layers.

[0086] The process produces an object (shape: cylinder with a diameter of 10 mm and a height of 2.4 mm), with a mass of 157.6 mg ± 69.7 mg (mean ± sd, n = 24), and a tensile strength of 1.1 MPa ± 0.2 MPa (mean ± sd, n = 3).

[0087] Example C

[0088] The medium is pure methanol. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 20% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 30 droplets per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed and the printing process is repeated for a total of 24 layers.

[0089] The process produces an object (shape: cylinder with a diameter of 10 mm and a height of 2.4 mm), with a mass of 148.5 mg ± 3.7 mg (mean ± sd, n = 27), a drug loading of 16.1% ± 0.8% (mean ± sd, n = 3), and a tensile strength of 0.6 MPa ± 0.2 MPa (mean ± sd, n = 3).

[0090] Example D

[0091] The medium is pure methanol. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 30 droplets per mm in the printing direction. A new layer of powder (0.1 mm) is applied to the surface of the powder bed and the printing process is repeated for a total of 24 layers.

[0092] The process produces an object (shape: cylinder with diameter = 10 mm and height = 2.4 mm), with a mass of 151.9 mg ± 6.9 mg (mean ± sd, n = 36), a drug loading of 35.7% ± 1.3% (mean ± sd, n = 3), and a tensile strength of 0.5 MPa ± 0.1 MPa (mean ± sd, n = 4).

[0093] Example E

[0094] The medium is made by mixing ethanol and pure water in a volume ratio of 7:3. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 40 droplets per mm in the printing direction.

[0095] The process produces a single-layer object.

[0096] Example F

[0097] The medium is pure methanol containing methylene blue at a concentration of 0.15 mg / mL. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 40 droplets per mm in the printing direction.

[0098] The process produces a single-layer object.

[0099] Example G

[0100] The medium is pure methanol containing methylene blue at a concentration of 0.15 mg / mL. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 50 droplets per mm in the printing direction.

[0101] The process produces a single-layer object.

[0102] Example H

[0103] The medium is made by mixing isopropyl alcohol and pure water in a volume ratio of 9:1 and adding methylene blue at a concentration of 0.16 mg / mL. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% ketoconazole. The medium is jet-printed onto the surface of the powder bed at 40 droplets per mm in the printing direction.

[0104] The process produces a single-layer object.

[0105] Example I

[0106] The medium is made by mixing isopropyl alcohol and pure water in a volume ratio of 9:1 and adding methylene blue with a concentration of 0.16 mg / mL. A powder bed made by hot melt extrusion and grinding is used, and the powder bed contains 40% (w / w) ketoconazole. The medium is jet-printed onto the surface of the powder bed at 50 droplets per mm in the printing direction.

[0107] The process produces a single-layer object.

[0108] The present invention is illustrated in the accompanying drawings.

[0109] Figure 1

[0110] Figure 1 The non-settling dissolution curves of the formulation prototypes are shown (mean ± SD, n = 3). Solid line: Example A. Dashed line: After storing Example A for four weeks. Dotted line: Crystalline ketoconazole in a physical mixture with copovidone.

[0111] The examples show that the supersaturation of ketoconazole in the dissolution medium is higher than that of the physical mixture of ketoconazole and the polymer. After storing for four weeks under accelerated storage conditions, the supersaturation curves remain similar, indicating that the samples are physically stable.

[0112] Figure 2

[0113] Figure 2 The non-settling dissolution curves of the formulation prototypes are shown (mean ± SD, n = 3). Solid line: Example B. Dotted line: Crystalline ketoconazole in a physical mixture with copovidone.

[0114] The examples show that the supersaturation of ketoconazole in the dissolution medium is higher than that of the physical mixture of ketoconazole and the polymer.

[0115] Figure 3

[0116] Figure 3 The non-settling dissolution curves of the formulation prototypes are shown (mean ± SD, n = 3). Solid line: Example C. Dashed line: After storing Example C for four weeks. Dotted line: Crystalline ketoconazole in a physical mixture with copovidone.

[0117] The examples show that the supersaturation of ketoconazole in the dissolution medium is higher than that of the physical mixture of ketoconazole and the polymer. After storing for four weeks under accelerated storage conditions, the supersaturation curves remain similar, indicating that the samples are physically stable.

[0118] Figure 4

[0119] Figure 4 The non-sedimenting dissolution curves (mean ± SD, n = 3) of the formulation prototypes are shown. Solid line: Example D. Dashed line: After storage of Example D for four weeks. Dotted line: Crystalline ketoconazole in the physical mixture with copovidone.

[0120] The examples show that the supersaturation of ketoconazole in the dissolution medium is higher than that in the physical mixture of ketoconazole and the polymer. After storage for four weeks under accelerated storage conditions, the supersaturation curves remained similar, indicating physical stability of the samples.

[0121] Figure 5

[0122] Figure 5 The sedimenting dissolution curves (mean ± SD, n = 3) of the formulation prototype from Example A are shown. Solid line: Immediately after preparation of Example A. Dashed line: After storage of Example A for twelve weeks.

[0123] Example A: The formulation released 80% of ketoconazole in less than 30 minutes, meeting the criteria for an immediate-release solid oral dosage form.

[0124] Figure 6

[0125] Figure 6 The pXRD measurements before and after storage of Examples A and C are shown, compared with the physical mixture containing the polymer and 20% ketoconazole.

[0126] The graphs show that the formulation prototypes are amorphous after preparation and after storage.

[0127] Figure 7

[0128] Figure 7 The pXRD measurements of Example B after preparation and of Example D before and after storage are shown, compared with the physical mixture containing the polymer and 40% (w / w) ketoconazole.

[0129] The graphs show that the formulation prototype of Example D is amorphous after preparation and after storage. The formulation prototype of Example B shows signs of crystallization.

[0130] Figure 8

[0131] Figure 8 The DSC thermograms of Examples E–I are shown, compared with the physical mixture of the polymer and ketoconazole. The first heating cycle is shown. No melting events were observed for the prepared formulation types, indicating that they are amorphous after preparation.

[0132] Figure 9

[0133] Figure 9 Shows a scheme of a printing device. The build plate (E) is connected to a control system. By means of an axis, the build plate can be moved to different positions so that it is aligned with other parts of the printing device. For the manufacture of a single layer, the build plate is moved to the powder supply (C), where powder is applied to the surface of the build plate or the surface of the powder bed. A blade (D) is used to spread a thin layer (J) of powder while the build plate moves linearly under the blade. An inkjet printing assembly (A) can be used to apply droplets (H) of fluid onto the surface of the powder layer in a spatially controlled manner. A halogen lamp (K) can be used to irradiate the powder bed.

[0134] Figure 10

[0135] Figure 10 Illustrates the spreading step (a) of the method. The powder provided by the powder reservoir (3a) is spread onto the mounting plate (1) by moving a squeegee (4) in the direction indicated by the arrow to obtain a powder layer. A part of the already spread powder layer is indicated by (3). By repeating the spreading of the powder as needed on one or more already existing powder layers, a powder bed is created.

[0136] Figure 11

[0137] Figure 11 Shows the powder bed (2) step - by - step created on the mounting plate (1) according to step (a).

[0138] Figure 12

[0139] Figure 12 Shows the inkjet printing according to step (b) or (c) of the method. The print head (7) moves along the x - axis and / or y - axis, thereby jet - printing the fluid (6) (in fine droplets) onto the powder bed (2). Such inkjet printing results in powder (5) saturated with the fluid created by voxels adjacent to each other.

[0140] Figure 13

[0141] Figure 13 Shows as Figure 9 in the inkjet printing step, where an intermediate product as shown in Figure 9 is used on which a powder layer has been spread. Compared with Figure 9 , the fluid is not jet - printed on a continuous area, but on defined powder areas bounded by each other, thus creating a layer of powder voxels (8) saturated with the fluid and powder voxels (8a) without fluid.

Claims

1. A method for manufacturing a solid pharmaceutical dosage form comprising an active ingredient, said method comprising the steps (a) preparing a powder of particles of an amorphous solid dispersion of the active ingredient in a polymer matrix; (b) spreading the powder prepared in step (a) on a manufacturing area; (c) jetting a printing medium onto said powder, wherein such a medium is suitable for providing adhesion of said powder; (d) spreading a layer of the powder prepared in step (a) on the surface of the powder obtained after performing steps (b) and (c) and then performing steps (b) and step (c); (e) repeating step (d) as needed to build up said solid pharmaceutical dosage form; (f) separating said solid pharmaceutical dosage form from the powder bed.

2. The method for manufacturing a solid pharmaceutical dosage form according to claim 1, wherein hot melt extrusion, co-precipitation or spray drying is used to prepare said amorphous solid dispersion of the active ingredient in the polymer matrix present as particles in the powder prepared in step (a).

3. The method for manufacturing a solid pharmaceutical dosage form according to claim 1 or 2, wherein the medium for jet printing in step (c) is a liquid.

4. The method for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 3, wherein said powder comprises a binder material.

5. The method for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 4, wherein the medium is a liquid which partially dissolves the polymer matrix and / or the binder material present therein.

6. The method for manufacturing a solid pharmaceutical dosage form according to claim 5, wherein the medium comprises one or more volatile solvents alone or a mixture of one or more volatile solvents and one or more non-volatile solvents or consists of one or more volatile solvents alone or a mixture of one or more volatile solvents and one or more non-volatile solvents.

7. The method for manufacturing a solid pharmaceutical dosage form according to claim 6, wherein the volatile solvent is selected from methanol, ethanol, propanol, 2-propanol and acetone, and the non-volatile solvent is selected from water, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethylformamide, dimethylacetamide and dimethyl sulfoxide.

8. The method for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 7, wherein the medium is a fluid and comprises a binder material.

9. The method for manufacturing a solid pharmaceutical dosage form according to any one of claims 4 to 8, wherein the binder material comprises or consists of the following Composition: Lactose, sorbitol, mannitol, xylitol, maltitol, glucose, fructose, sucrose, sucrose fatty acid esters (such as sucrose stearate, sucrose palmitate), sorbitan esters (such as ), glycerol fatty acid esters (such as glycerol monostearate), fatty acids, fatty alcohols (solid at room temperature), esters and polymers of fatty acids and fatty alcohols such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, starches such as corn starch or pregelatinized starch, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose acetate succinate or microcrystalline cellulose, copolymers of acrylic acid or methacrylic acid and acrylates or methacrylates, preferably copolymers of methacrylic acid and methacrylates or acrylates, such as for example poly(methacrylic acid-co-methyl methacrylate)(1:1)(such as L 100), poly(methacrylic acid-co-methyl methacrylate)(1:2)(such as S100) or poly(methacrylic acid-co-ethyl acrylate)(1:1)(such as L 100-55), copolymers of ethyl acrylate, methyl methacrylate and a low content of methacrylate with a quaternary ammonium group, such as for example poly(ethyl acrylate-co-methyl methacrylate-co-trimethylaminoethyl methacrylate chloride) 1:2:0.2 (such as RL) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylaminoethyl methacrylate chloride) 1:2:0.1 (such as RS), copolymers of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, such as for example poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate)(2:1:1)(such as E PO), preferably hydroxypropylmethylcellulose acetate succinate or polyvinyl alcohol, more preferably hydroxypropylmethylcellulose acetate succinate.

10. The method for manufacturing a solid pharmaceutical dosage form according to any one of claims 1 to 9, wherein the polymer matrix comprises or consists of the following Composition: Vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), ( L100-55) and poly(methacrylic acid-co-methyl methacrylate) ( L and S), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT) or hydroxypropyl methylcellulose acetate trimellitate (HPMCAT).

11. The method for manufacturing a solid pharmaceutical dosage form according to any one of the preceding claims, wherein a drying step is performed after performing step (c) and / or step (d).

12. The method for manufacturing a solid pharmaceutical dosage form according to any one of the preceding claims, wherein the pharmaceutical dosage form is for oral use.

13. A method of manufacturing a solid pharmaceutical dosage form according to claim 12, wherein the pharmaceutical dosage form provides immediate release of the active pharmaceutical ingredient.

14. A method of manufacturing a solid pharmaceutical dosage form according to any one of the preceding claims, wherein a drying step is carried out after step (f).

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