Manufacturing pharmaceutical formulations with 3D melt dosing

Abstract

The present invention relates to the use of polymers for the manufacture of pharmaceutical formulations by 3D melt dosing, and to a process for the manufacture of pharmaceutical formulations by 3D melt dosing using polymers, as well as to pharmaceutical formulations obtainable by such a process.

Description

[Technical Field]

[0001] The present invention relates to the use of polymers for the manufacture of 3D melt-dosed pharmaceutical formulations, and to a process for the manufacture of 3D melt-dosed pharmaceutical formulations using polymers, as well as to pharmaceutical formulations obtainable by such a process. [Background technology]

[0002] Creating personalized medicines for each patient can be very complex. Standard tableting processes require developing a new formulation and adjusting a pre-mix for each strength variation. This process can be very complex and time-consuming. Traditional pharmaceutical manufacturing is based on mass production of selected dosage strengths. This can pose challenges, especially when targeting chronic diseases or considering different patient subgroups such as children or the elderly. Therefore, there is a strong need to explore alternative manufacturing techniques that offer greater flexibility in producing the final dosage form. Considering oral drug delivery in the framework of personalized medicine, it is observed that the increasing knowledge of personalized medicine is simultaneously increasing the need for individualized administration. There is an urgent need for drug dosage forms, especially for oral administration, that allow for personalized treatment. Oral administration remains the most important and most frequently used route of administration. Therefore, there is a strong need for suitable oral dosage forms with the option of individualized administration. Several different technologies are being evaluated to provide the individualized administration concept.

[0003] One common approach is tablet splitting and breaking into smaller subunits. While this can be an effective solution for providing rapid dose adjustment, it carries the risk of mis-dosing due to mass variability. Therefore, there is a strong need to achieve reliable individual dosing in oral forms. Additive manufacturing is another important technology for creating dosage forms with various dosage strengths. As an additive manufacturing technology, 3D melt dosing offers the advantage of enabling the individual dosing of multiple components, such as drug components and polymer carriers. Individual melts can be deposited directly into predefined molds. The deposition device can move freely in all directions, allowing for precise dosing of materials within the form. Dosing can also be performed within predefined blisters, which can be sealed immediately after the filling process to directly create the final primary packaging. Currently, this technology is primarily applied in decoration lines, where the deposition device equipped with CAD (computer-aided design) can move in all dimensions, allowing for highly accurate material deposition. This system also allows for the creation of multiple layers during a single manufacturing process.

[0004] Modifying the release rate of pharmaceutical formulations manufactured by 3D melt dosing can be a challenge because the system is unable to create a defined structure. When the melt solidifies in the mold, the material typically forms a dense structure with low porosity. This rigid structure does not allow for the modification of release rates that would be required to enable personalized medicine. Another problem during the manufacturing process is the appearance of a phenomenon called "edging", which results in the formation of a concave surface on the top of the mold. As a result, the surface finish is adversely affected by uneven shapes, which can be problematic for the final dose in terms of mechanical stability and appearance. Summary of the Invention

[0005] It has been found that polymers with melting points between 20°C and 200°C are particularly suitable for the production of pharmaceutical formulations by 3D melt dosing. In another aspect, the present invention provides a process for the manufacture of pharmaceutical formulations by 3D melt dosing, comprising the steps of melting a polymer having a melting point between 20°C and 200°C, adding at least one active pharmaceutical ingredient to the molten polymer, and extruding the mixture through a first nozzle into a mold, the outer shape of which is predefined by the shape of the form and adjustable to various sizes or shapes.

[0006] In some embodiments, the above-described polymers are used in conjunction with a plasticizer. Surprisingly, the addition of a plasticizer allows for modification of the release rate and / or improves the surface finish of the pharmaceutical formulation. In a further embodiment of the invention, the polymer is a low melting point polymer having a melting point between 20° C. and 100° C. In a particular embodiment, the polymer is PEG6000 or poloxamer 188. In a further embodiment of the invention, the polymer further comprises a plasticizer. In some embodiments of the present invention, a multi-dosing system is used.For example, in a system with two nozzles, the amount of drug-containing polymer can be easily changed by filling the remaining part with drug-free polymer from the other nozzle.In this way, it is possible to make tablets of the same shape and weight, even for high-dose variations.

[0007] This process allows for the production of pharmaceutical formulations with the same shape but different final drug contents, allowing for easy variation in dosage form production throughout the manufacturing process. In addition to monolayer tablets, tablets with different layer structures can be produced using one-shot or multi-shot techniques. Using CAD-based deposition technology, multiple defined regions can be melt-deposited within a single mold, enabling the creation of complex multi-drug systems. Furthermore, the process can also be used to create the final product in a corresponding primary package by direct dosing of the melt into a blister and sealing it. [Brief explanation of the drawings]

[0008] DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description of the Invention One aspect of the present invention is a process for producing a pharmaceutical formulation by 3D melt dosing, comprising the steps of: (i) melting a polymer having a melting point between 20°C and 200°C; (ii) adding at least one active pharmaceutical ingredient to the molten polymer; and (iii) extruding the mixture through a first nozzle into a mold.

[0010] According to the present invention, the term "3D melt dosing" refers to the process of producing a melt of polymer and drug components, which is then dispensed with high precision into a predefined mold. This process can be performed in a single dose format, or by combining different melts using a multi-dose dispenser. In this case, a multi-layered material can be produced. The first step in a suitable manufacturing process is the transfer of the melt from the beaker to the equipment container. The tray containing the molded forms or blisters is placed on the transfer conveyor at a predetermined position. The conveyor transports the tray until it reaches the fill sensor, where it stops exactly under the nozzle. Meanwhile, the nozzle moves to its initial position. During this process, the pump fills the specified volume. The nozzle lowers to the target position (near the bottom of the form / blister) and the piston rotates to begin discharging the melt. The nozzle remains in this position for a wait delay time to allow complete discharging. The nozzle then moves vertically upwards and the piston continues discharging the melt. After discharging is complete, the piston rotates to the suction position and the nozzle rises to its initial position. After the filling dwell time has ended, the conveyor transfers the tray to the next mold. The piston's suction cycle also occurs simultaneously. The optimum distance between each molded part can be adjusted using the distance centering button.

[0011] This procedure is repeated until the desired number of moldings is filled, after which the tray moves to a stop sensor and the manufacturing process is complete. In a preferred embodiment, a second polymer, with or without the polymer, is simultaneously or sequentially ejected into the mold through the same nozzle. This configuration allows the production of pharmaceutical formulations in a single dose (also known as a one-shot system), resulting in a shell / core structured pharmaceutical formulation containing a drug component. A simple version of the one-shot food process is described, for example, in WO 94 / 02027. This is known from confectionery engineering, where a chocolate shell is injected into a cavity through a nozzle, and then a praline filling is filled into the forming chocolate shell using another nozzle, thereby creating a closed praline. According to the present invention, this one-shot system provides a polymer feed line in a nozzle arranged around the feed lines for polymer and API in the same nozzle, i.e., the outlets of both feed lines are located on the same or above the cavity, and only the addition of shell material and drug substance needs to be controlled separately.

[0012] In further preferred embodiments, more than two polymers (with or without an API) can be used. In a further preferred embodiment, a second polymer is simultaneously or sequentially extruded into the mold through a second nozzle. This configuration is an alternative system (multi-shot system) of a 3D melt dosing device that uses multiple nozzles for dosing the polymer melt with or without an API. In an expanded application, the melt is not prepared outside the 3D melt dosing device and then placed in the device container, but is instead placed in the 3D melt dosing device in the form of a cartridge. The cartridge contains a polymer with or without an API. Depending on the desired composition of the pharmaceutical formulation, different cartridges can be combined to produce the pharmaceutical formulation. The cartridges are equipped with heating devices, which are preferably individually controllable. The 3D melt dosing device with a cartridge system is particularly suitable for polymers with high melting points, for example, above 80°C or 100°C.

[0013] In a more extended application, deposition equipment with CAD control allows the deposition head to be freely moved in any direction, offering great flexibility in the detailed composition of the final tablet. Different melt systems can be distributed within one tablet.

[0014] In a further embodiment, different stacking equipment is used to prepare multi-layer tablets. To enable the process of individualized administration, it was necessary to identify suitable polymers. Polymers with melting points between 20°C and 200°C were found to be suitable candidates for this technology. According to the present invention, preferred polymers are those with melting points between 20°C and 200°C. Many amorphous polymers do not crystallize under normal conditions and are considered amorphous. Amorphous polymers do not have a precise melting point, but their amorphous regions undergo an important phase transition, the so-called glass transition temperature. This temperature is associated with the motion of the polymer's conjugated backbone. This is associated with the softening of the polymer, an effect that can be detected as a step change in the baseline of differential scanning calorimetry.

[0015] Crystalline or semi-crystalline polymers also exhibit more distinct melting points. The melting point is determined as the temperature at which a polymer transitions from a crystalline state to a viscous, flowing state. The endotherm upon melting can be detected by thermal characterization, for example, differential scanning calorimetry. In a preferred embodiment, the polymer of the present invention is a low melting point polymer, having a melting point between 20°C and 100°C, more preferably between 20°C and 80°C. According to the present invention, suitable polymers are poloxamers, polyethylene glycols, or polyvinyl alcohols with a melting point between 20°C and 200°C, preferably poloxamers and polyethylene glycols with a melting point between 20°C and 200°C. In a preferred embodiment of the invention, the polymer used is a crystalline or semi-crystalline polymer.

[0016] Crystalline polymer: The polymer is arranged in a crystalline structure and exhibits a distinct melting point in a thermogram. A semi-crystalline polymer still contains many amorphous regions beneath the crystalline structure, in which case both a Tg and a Tm may be detected in the thermogram. Poloxamers are amphiphilic polymers with two hydrophilic blocks and a central hydrophobic block. They are polyethylene glycol (PEG) / polypropylene glycol (PPG) triblock copolymers, with one PPG block flanked by PEG blocks. The polyethylene glycol (PEG) portion is often called polyethylene oxide (PEO). The polypropylene glycol (PPG) portion is often called polypropylene oxide (PPO).

[0017] Poloxamer grades are designated by the letter P (poloxamer) plus a three-digit number, which is officially used in the United States Pharmacopoeia (USP) and the European Pharmacopoeia (EP). It represents the polymer composition as follows: the first two digits x 100 indicate the molecular weight of the PO block, and the last digit x 10 indicates the EO content (%). For example, poloxamer P188 contains an average of 80% EO, with the remaining 20% ​​PO having a molecular weight of approximately 1800 g / mol. Poloxamer P407 has an average polyoxypropylene moiety molecular weight of 4000 g / mol and a polyoxyethylene content of 70%. The general formula of poloxamers is represented by the following formula (I): [ka] The number of units x (PEO), y (PPO chain), and z (PEO) varies greatly depending on the type of poloxamer. For example, in poloxamer P188, the PPO chain consists of an average of 25–30 units, each PEO block consists of an average of 75–85 EO units, and the molecular weight ranges from 7680–9510 Da.

[0018] On the other hand, in poloxamer P407, the PPO chain consists of an average of 56 units, each PEO block consists of an average of approximately 101 EO units, and the molecular weight ranges from 9840 to 14600 Da. For example, poloxamer 407 (a=101, b=56) has a molecular weight in the range of 9840 to 14600 Da. Table 1 shows the types of poloxamers listed in the European Pharmacopoeia (Ph.Eur.) and the United States Pharmacopoeia (USP).

[0019] [Table 1] Table 2 shows the melting point, molecular weight, and weight percentage of ethylene oxide chains (Weight EO%) of the most common poloxamers, as published in the paper "Poloxamer Hydrogels for Biomedical Applications" by Russo and Villa (Pharmaceutics. 2019;11:671). [Table 2] JPEG2026501184000004.jpg42117Poloxamers, with different ratios of ethylene oxide (EO) and propylene oxide (PO) units, are commercially available in various forms, such as liquids, pastes, and waxy solids, as, for example, Synperonic® (Croda International PLC), Pluronic® (BASF SE), Lutrol® (formerly Kolliphor® and Kollisolv® by BASF SE), or Poloxamer 188 EMPROVE® EXPERT. Alternatively, poloxamers can be prepared from raw materials according to methods known in the art (see, eg, US Pat. Nos. 3,579,465 and 3,740,421).

[0020] Further information on poloxamers can be found in Hagers Handbuch der Pharmazeutischen Praxis, Vol. 9 "Stoffe PZ" (1994, pp. 282-284) and Russo and Villa, "Poloxamer Hydrogels for Biomedical Applications" (Pharmaceutics, 2019; 11:671). The use of the particular poloxamer grades according to the present invention is of interest in formulating solid oral pharmaceutical dosage forms with immediate, fast or sustained release of API, with immediate or fast release being preferred.

[0021] The poloxamers of the present invention have a melting point of 20°C or higher. In further embodiments, the poloxamers of the present invention have a melting point between 20°C and 60°C, between 30°C and 60°C, between 40°C and 60°C, or between 50°C and 60°C. In further embodiments, the poloxamers of the present invention have an average molecular weight of 3,000 Da or more, between 4,000 and 15,000 Da, or between 7,000 and 13,000 Da. In further embodiments, the poloxamers of the present invention have a weight percentage of ethylene oxide chains between 50% and 90% or between 70% and 85%. In another embodiment, the poloxamer is poloxamer P188 or P407.

[0022] In a further embodiment, the poloxamer according to the present invention has a melting point between 20°C and 60°C, an average molecular weight of 3000 Da or more, and a weight percentage of ethylene oxide chains between 50% and 90%. In a further embodiment, the poloxamer according to the present invention has a melting point between 30°C and 60°C, an average molecular weight between 4000 and 15000 Da, and a weight percentage of ethylene oxide chains between 70% and 85%. In a further embodiment, the poloxamer according to the present invention has a melting point between 50°C and 60°C, an average molecular weight between 7000 and 13000 Da, and a weight percentage of ethylene oxide chains between 70% and 85%. In further embodiments, the poloxamer of the present invention has a melting point between 20°C and 55°C, between 30°C and 55°C, between 40°C and 55°C, or between 50°C and 55°C. In further embodiments, the poloxamer of the present invention has an average molecular weight between 4000 and 12000 Da, or between 7000 and 12000 Da. In further embodiments, the poloxamer of the present invention has a weight percentage of ethylene oxide chains between 75% and 85%, or between 80% and 85%. In another embodiment, the poloxamer is poloxamer P188.

[0023] Polyethylene glycol (PEG) is a petroleum-derived polyether compound, also known as polyethylene oxide (PEO) or polyoxyethylene (POE). The structure of PEG is generally represented by H-(O-CH2-CH2)n-OH. The abbreviation "PEG MW" generally indicates molecular weight (MW). PEG is widely used as a drug carrier in the pharmaceutical industry. It is a water-soluble polymer that is non-flammable, non-toxic, and biodegradable, making it harmless to the environment. The polyethylene glycol (PEG) according to the present invention has an average molecular weight in the range of 1,000 to 35,000 daltons, and is preferably PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 10,000, PEG 20,000, PEG 35,000, and particularly PEG 6000. Polyethylene glycol is defined and identified according to the monograph "Macrogol" in the European Pharmacopoeia 11.0.

[0024] Polyvinyl alcohol (PVA) is a synthetic, water-soluble polymer with the idealized formula [CH2CH(OH)] n PVA has excellent film-forming, adhesive, and emulsifying properties. It is prepared from polyvinyl acetate, in which the functional acetate groups have been partially or completely hydrolyzed to alcohol groups. Without complete hydrolysis, PVA is a random copolymer consisting of vinyl alcohol units (-[CH2CH(OH)]-) and vinyl acetate units (-[CH2CH(OOCCH3)]-). The polarity of PVA is closely related to its molecular structure. The degree of hydrolysis and molecular weight determine its molecular properties. As the degree of hydrolysis of the acetate groups increases, the polymer's solubility in aqueous media, crystallinity, and melting point increase. However, at a high degree of hydrolysis (>88%), the solubility of PVA decreases again. PVA is generally soluble in water but is nearly insoluble in most organic solvents, with the exception of ethanol.

[0025] Typical PVA designations indicate the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA 3-83 is a PVA grade with a viscosity of 3 mPas and a degree of hydrolysis of 83%, i.e., 83% vinyl alcohol units and 17% vinyl acetate units. Skilled artisans understand that a degree of hydrolysis of 83% and a viscosity of 3 mPas mathematically encompasses degrees of hydrolysis ranging from 82.50% to 83.49% and viscosities ranging from 2.50 mPas to 3.49 mPas, according to common rounding practices. Viscosity in this invention is measured by the viscosity rotation method (912) described in USP 39 "Polyvinyl Alcohol" monograph. The degree of hydrolysis in the present invention is determined by measuring the saponification number of the polyvinyl alcohol, for example, by the method described in USP 39 "Polyvinyl Alcohol" monograph, "Degree of Hydrolysis."

[0026] [sample] 1 g of polyvinyl alcohol dried to a constant weight at 110°C [analysis] Transfer the sample to a wide-bore 250 mL Erlenmeyer flask connected to a reflux condenser with an appropriate glass fitting. Add 35 mL of dilute methanol (3:5) and gently stir to thoroughly wet the solid. Add 3 drops of phenolphthalein indicator TS and, as needed, add 0.2 N hydrochloric acid or 0.2 N sodium hydroxide for neutralization. Add 25.0 mL of 0.2 N sodium hydroxide VS and gently reflux on a hot plate for 1 hour. Rinse the condenser with 10 mL of water and collect the rinse solution in the flask. After cooling, titrate with 0.2 N hydrochloric acid VS. A blank test is also performed using the same volume of 0.2 N sodium hydroxide VS.

[0027] [Saponification value calculation] The saponification number is calculated according to the following formula: Result=[(VB-VS)×N×Mr] / W VB = Volume (mL) of 0.2N hydrochloric acid VS consumed in the blank titration VS = Volume (mL) of 0.2N hydrochloric acid VS consumed in titration of the sample solution N = measured equivalent concentration of hydrochloric acid VS Mr = molecular weight of potassium hydroxide (56.11) W = weight of polyvinyl alcohol taken (g)

[0028] [Calculation of degree of hydrolysis] The degree of hydrolysis (%) of polyvinyl acetate is calculated using the following formula: Result=100-[7.84×S / (100-0.075×S)] S = saponification value of polyvinyl alcohol The use of PVA grades according to the present invention is of interest for the formulation of solid oral pharmaceutical dosage forms with immediate, fast or sustained release of API.

[0029] Preferred PVA has a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20°C in the range of 3 to 5 mPas, more preferably 3 to 4 mPas, most preferably 4 mPas. In a further embodiment of the invention, the polyvinyl alcohol has a degree of hydrolysis of between 70% and 90%, preferably between 80% and 90%, and has the above-mentioned viscosity.

[0030] In a further embodiment of the invention, the polyvinyl alcohol has a degree of hydrolysis of 80% to 90% and a viscosity of a 4% solution at 20°C of 3 mPas, or a degree of hydrolysis of 80% to 90% and a viscosity of a 4% solution at 20°C of 4 mPas. In a further embodiment of the invention, the polyvinyl alcohol is PVA3-80, PVA3-82, PVA4-88, or PVA5-74, preferably PVA3-80, PVA3-82, or PVA4-88, more preferably PVA4-88. Additionally, surfactants may be added to the melt. Surfactants in the context of the present invention are compounds that adsorb to a surface or interface to reduce surface or interfacial tension. These agents typically act by reducing the interfacial tension between different surfaces. There are several common classes of surfactants used in pharmaceutical formulations. Examples of anionic surfactants are carboxylates (alkyl carboxylate-fatty acid salts), sulfates (sodium lauryl sulfate, alkyl ether sulfates), sulfonates (dioctyl sodium sulfosuccinate, alkyl benzene sulfonates), and phosphate esters (alkyl aryl ether phosphates, alkyl ether phosphates).

[0031] Examples of cationic surfactants are quaternary ammonium salts (cetrimonium bromide, cetylpyridinium chloride, dimethyldioctadecylammonium chloride), amine-based (triethylamine hydrochloride, octenidine hydrochloride dihydrate), and pyridinium-based surfactants (benzethonium chloride). Examples of nonionic surfactants are polyol esters (fatty acid esters of sorbitan), polyoxyethylene esters (polysorbates), poloxamers (poloxamer 188), amphoteric phospholipids (phosphatidylcholine or lecithin), carboxylic acids / quaternary ammonium salts (cocamidopropyl betaine or amidosulfobetaine-16), phosphates / quaternary ammonium salts (hexadecylphosphatidylcholine), betaines (alkylamidopropyl betaines).

[0032] In further embodiments, examples of suitable surfactants include polyoxyethylene sorbitan fatty acid esters (polyoxyethylene 15-hydroxystearate (macrogol 15-hydroxystearate, Solutol HS15®), polyoxyethylene castor oil derivatives), polyoxyethylene stearates, sorbitan fatty acid esters (Span®), polyoxyethylene alkyl ethers (Brij®), and polyoxyethylene nonylphenol ethers (Nonoxynol®). It has surprisingly been found that the addition of plasticizers makes it possible to modify the release rate and / or improve the surface finish of the pharmaceutical formulation.

[0033] One of the unique challenges of the 3D melt-dosing method is the appearance of "edging," which leads to the formation of a concave surface on the top surface of the mold. The resulting surface finish is adversely affected by uneven shapes, which can lead to problems with the final dose due to mechanical stability and optical appearance. The present invention demonstrates that edging can be minimized by adding a plasticizer to the polymer. This effect is shown in Figures 11 and 12, where triacetin and triethyl citrate are used as exemplary plasticizers. The pharmaceutical formulations in these figures are inverted to enhance the visibility of the effect. Pharmaceutical formulations containing triacetin or triethyl citrate have a less concave, preferably flat, surface. In yet another aspect, the drug release rate from pharmaceutical formulations manufactured by 3D melt dosing is generally known to be slow due to the relatively dense melt. The addition of these same plasticizers has been found to accelerate the dissolution rate. Pharmaceutical formulations containing triacetin and triethyl citrate, especially when combined with polyethylene glycol polymers, exhibit faster drug release (Figure 10).

[0034] In addition, the use of polymers with relatively high melting points typically requires a reduction in the melting point, which can be achieved by blending with excipients with more suitable thermoplastic properties. Excipients with relatively low melting points can produce a plasticizing effect when they are compatible with and well blended with polymer carriers with higher Tg. These plasticizers can be small molecules or other polymers.

[0035] Examples of plasticizers include glycerin, acetyl tributyl citrate, polyethylene glycol, acetyl triethyl citrate, polyethylene glycol monomethyl ether, castor oil, propylene glycol, diacetylated monoglyceride, sorbitol, sorbitan, dibutyl sebacate solution, diethyl phthalate, triacetin, tributyl citrate, triethyl citrate, or polyols.

[0036] The API is a biologically active agent. The API is a small molecule having a weak base, a weak acid, or a neutral molecular form, and may be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates. The polymer and pharmaceutical formulation may contain multiple APIs. In some embodiments, the API is a poorly soluble or lipophilic API. As used herein, the terms "poorly soluble API," "poorly water-soluble API," and "lipid-soluble API" refer to APIs that have a solubility such that the highest therapeutic dose of the particular API cannot be dissolved in 250 ml of aqueous media in the pH range of 1 to 8, which conforms to the definition of low solubility according to Biopharmaceutics Classification System (BCS) Classes 2 and 4. Poorly soluble APIs with weakly basic or weakly acidic properties have pH-dependent solubility profiles and may exhibit a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs that fall into BCS Classes 2 or 4 are well known to those skilled in the art.

[0037] In some embodiments, the API is a weakly basic API. As used herein, the term "weakly basic API" refers to a basic active pharmaceutical ingredient (API) that does not completely ionize in water. At least one active pharmaceutical ingredient (API) according to the present invention may be dispersed in a polymer that forms an amorphous solid dispersion. As used herein, the term "amorphous solid dispersion" refers to an API in an amorphous state dispersed in a polymer matrix. Preferably, the amorphous API is uniformly dispersed at the molecular level within the polymer matrix. In this case, the solid dispersion becomes a solid solution. Upon dissolution, a formulation containing an amorphous solid dispersion can achieve a higher solubility in aqueous media than a crystalline API.

[0038] The API contained in the pharmaceutical formulation of the present invention is present in an amount sufficient to be therapeutically effective. Therapeutically effective amounts for a particular API are generally known or readily obtainable by those skilled in the art. Typically, the API may be present in the pharmaceutical formulation in a weight ratio of API to polyvinyl alcohol ranging from 0.1:99.1 to 60:40, preferably 1:99 to 50:50, more preferably 5:95 to 40:60, and most preferably 10:90 to 30:70. Yet another aspect of the present invention is a pharmaceutical formulation obtainable by the process for the manufacture of a pharmaceutical formulation by 3D melt-dosing as defined above.

[0039] example: Example 1 Formulations 1-19 (Examples 1-19) were prepared using poloxamer 188 (Parteck PLX 188) or PEG 6000 as the polymer. In some formulations, APIs (caffeine or ketoconazole) and / or additives (SDS, Tween 20, PEG 200, triacetin, or triethyl citrate) were added. The exact weights and mixing times are shown in Figures 1 and 2.

[0040] The procedure for preparing the formulation is as follows: The polymer is heated to 80°C in a drying tank to melt it. 2. Weigh out the molten material and place it in a beaker on a hot plate (80°C) and stir at 750 rpm to create a vortex. Weigh out the correct amount of API (10%) and / or additives (10% or 20%) and disperse them in the melt, respectively. Add API and / or additives by stirring using a paddle stirrer (see Figures 1 and 2 for stirring times); Stir for 5 minutes.

[0041] Tablets were molded using a KCM Omega 9-18-35 machine (manufactured by Knobel). The first step in the procedure is to transfer the melt from the beaker to the machine's container. The molding tray is positioned and placed on a conveyor. The conveyor transports the tray to a fill sensor, a software-adjustable parameter that stops the tray exactly beneath the nozzle. The nozzle moves to position Z. During this process, the pump is filled to fill the specified amount of melt. The nozzle descends to position X near the bottom of the mold, and the piston rotates to begin discharging the melt. The nozzle remains in this position for a wait delay time W. The nozzle then rises vertically to position Y while the piston continues discharging the melt. After the melt is discharged, the piston rotates to the suction position, and the nozzle returns to position Z. After the fill dwell time is over, the conveyor transfers the tray to the next mold. The piston's suction cycle also occurs simultaneously. The appropriate distance between each molding can be adjusted using the distance centering button. This procedure is repeated until the desired number of moldings is filled, after which the tray moves to a stop sensor and the manufacturing process is complete. The detailed machine settings for each formulation are shown in Figures 3-6.

[0042] Example 2 The elution performance was measured using a Sotax AT7 smart (with a fraction collector) under the following conditions. Dissolution medium: 900 ml 0.1 M hydrochloric acid, 37°C ●Stirring speed: 50 rpm, paddle type Pre-filter: Glass microfiber filter GE Whatman GF / D, 25mm diameter Sampling time points: 5, 15, 30, 60, 90, 120, 180 minutes ●Collection volume: 2.5 ml (do not refill after collection) Sample preparation (for HPLC, ketoconazole): All samples were filtered through a PTFE 0.45 μm filter (VWR 13 mm syringe filter / 0.45 μm PTFE membrane) and diluted with ethanol.

[0043] HPLC conditions: • The mobile phase for ketoconazole consists of two types of eluents. Eluent A: 10 ml of diisopropylamine and 5 L of methanol Eluent B: 25 g of ammonium acetate and 5 L of MilliQ water Ratio: Eluent A 70% : Eluent B 30% (isocratic) Column: SUPELCOSIL LC-18-18, 5 μm, 300 mm x 4 mm HPLC equipment: Agilent 1260 Infinity or 1260 Infinity II with UV detector ●Parameters: Runtime 8 minutes, flow rate 2 ml / min, detection wavelength 252 nm, injection volume 10 μl, column temperature 40°C ● Retention time peak: 6.5 minutes

[0044] Example 3 Disintegration test equipment used: ERWEKA TA 420 (ERWEKA GmbH, Heusenstamm, Germany). The test method complies with Ph.EUR.EP10.7, section 2.9.7 "Disintegration of uncoated tablets." For tablets with a unit mass of 650 mg or less, sample the entire tablet equivalent to approximately 6.5 g. For tablets with a mass of more than 650 mg, sample 10 whole tablets. Carefully remove dust from the tablets before testing. Accurately weigh the tablet sample and place it in the drum. Rotate the drum 100 times, remove the tablets, remove dust again, and accurately weigh them. Implementation method: The weight of the tablet after dedusting is m0, and the weight after 100 revolutions of the drum is m1. The abrasion rate should be less than 1% (Ph.Eur.).

[0045] Calculation formula: Wear [%] = (1-(m1 / m0)) x 100 The physical properties of the tablets were measured automatically using an Erweka Multicheck 5.1 (ERWEKA GmbH, Heusenstamm, Germany) to measure the dimensions, hardness, and tablet weight. Twenty tablets were randomly selected for each setting and measured. Surface uniformity is improved by the addition of the plasticizers triethyl citrate and triacetin (see Figures 11 and 12), an important aspect in further optimizing the finished quality of the formulation. These plasticizers in particular were found to improve the surface finish and allow for a more uniform production.

[0046] Example 4 Equipment: MiniFlex 300 / 600 (Rigaku Corporation, Tokyo / Japan) For the measurements, the tablets were ground in a Tube Mill 100 (IKA-Werke GmbH & Co. KG) and sieved through a 250 μm sieve. The samples were measured in transmission mode at 40 kV, 15 mA, a rotation speed of 10° / min, and a measurement range of 3° to 60° (2θ). The anode material was copper, and the wavelength was 1.54060 Å. The step size was 0.02°. In the examples provided, traces of crystalline caffeine are also observed (around 12° 2θ and around 26-27° 2θ). Ketoconazole also exhibits traces of crystalline form around 7° and 17° 2θ. Equipment: DSC3+ (Mettler Toledo) The crushed tablets were weighed into 40 μl aluminum pans. The weight of each sample ranged from 5 mg to 6 mg. The temperature program was set from -25 to 230 °C for ketoconazole and from -25 to 260 °C for caffeine, with a heating rate of 30 K / min. Nitrogen gas was supplied at a flow rate of 50 ml / min.

[0047] Thermal analysis suggested that the drug substance was completely amorphized, but the observed effect was primarily due to process-related melting of the polymer at approximately 60°C. Thermal analysis indicates complete amorphization of the pharmaceutical ingredient, while the effect is attributed to process-related melting of the polymer upon heating to approximately 60°C-70°C.

Claims

1. 1. Use of a polymer for the manufacture of a pharmaceutical formulation in 3D melt dosing, wherein the polymer has a melting point between 20°C and 200°C.

2. 2. The use according to claim 1, wherein the polymer is a semi-crystalline polymer.

3. 3. The use according to claim 1 or 2, wherein the polymer comprises a plasticizer.

4. The use according to any one of claims 1 to 3, wherein the polymer has a melting point between 20°C and 80°C.

5. The use according to any one of claims 1 to 4, wherein the polymer is a poloxamer or a polyethylene glycol.

6. 1. A process for producing a 3D melt-dosing pharmaceutical formulation, comprising:

1. Melting a polymer having a melting point between 20°C and 200°C; 2. Adding at least one active pharmaceutical ingredient to the molten polymer; and 3. Discharging the mixture through a first nozzle into a mold. The process comprising:

7. 7. The process of claim 6, wherein a second polymer is simultaneously or sequentially extruded through a nozzle into the mold.

8. 8. The process of claim 6 or 7, wherein a second polymer is simultaneously or sequentially extruded through a second nozzle into the mold.

9. The process of any one of claims 6 to 8, wherein the polymer is a semi-crystalline polymer.

10. The process of any one of claims 6 to 9, wherein a plasticizer is added to the molten polymer.

11. The process of any one of claims 6 to 10, wherein the polymer has a melting point between 20°C and 80°C.

12. The process according to any one of claims 6 to 11, wherein the polymer is a poloxamer or polyethylene glycol.

13. A pharmaceutical formulation obtainable by the process according to any one of claims 6 to 12.

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