Pharmaceutical composition and method for improving the solubility of poorly soluble active pharmaceutical ingredients

Abstract

The present disclosure generally relates to the use of poloxamers in additive manufacturing techniques and processes. More specifically, the present disclosure relates to the use of poloxamers in a selective laser sintering (SLS) process for the additive manufacturing of objects, particularly pharmaceutical dosage forms.

Description

Technical Field

[0001] Technical Field The present disclosure generally relates to the use of poloxamers in additive manufacturing techniques. More specifically, the present disclosure relates to the use of poloxamers in selective laser sintering (SLS) methods for the additive manufacturing of objects, particularly pharmaceutical dosage forms.

Background Art

[0002] Background Poloxamers are non-ionic poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO) copolymers. They have many functions in pharmaceutical formulations as surfactants, emulsifiers, solubilizers, or dispersants. All poloxamers have a similar chemical structure, however, with different molecular weights and compositions of the hydrophilic PEO block (a) and the hydrophobic PPO block (b) (BoDratti AM, AlexanDriDis P. Formulation of POloxamers for Drug Delivery. Journal of functional biomaterials. 2018;9(1):11). Poloxamers can be used to improve the oral bioavailability of poorly soluble compounds by heating the solid dispersion.

[0003] The preparation of amorphous solid dispersions with poloxamer is usually quite complex. One strategy is to dissolve the polymer and the drug substance and perform a lyophilization step to create the final ASD (Song CK, Yoon I-S, Kim D-D. POloxamer-baseD soliD Dispersions for oral Delivery of Docetaxel: Differential effects of F68 anD P85 on oral Docetaxel bioavailability. International Journal of Pharmaceutics. 2016;507(1):102-8.). Also, many triple systems have been described in the literature where a small amount of poloxamer is added to the polymer carrier to improve the oral bioavailability of poorly soluble compounds (Vasconcelos T, Prezotti F, Araujo F, Lopes C, Loureiro A, Marques S, et al. Third-generation solid dispersion combining Soluplus and Poloxamer 407 enhances the oral bioavailability of resveratrol. International Journal of Pharmaceutics. 2021;595:120245.).

[0004] Selective laser sintering (SLS) is one of the most popular additive manufacturing processes for creating three-dimensional (3D) objects layer by layer. In this process, layers of powder material are successively laid and applied on top of each other, and each powder layer is sintered or fused with a laser according to the computer-aided drawing (CAD) shape of the part.

[0005] Selective Laser Sintering (SLS) is one of the most popular additive manufacturing processes for creating three-dimensional (3D) objects layer by layer. In this process, layers of powder material are successively applied on top of each other, and each powder layer is sintered or fused with a laser according to the computer-aided design (CAD) shape of the part.

[0006] SLS is a powder bed-based additive manufacturing technology for producing complex three-dimensional parts. In SLS, a rasterized laser is used to scan a polymer powder bed and sinter it to form a solid shape layer by layer. When the laser beam scans the powder, the powder melts due to the temperature rise, and the final part approaches maximum density layer by layer, resulting in the characteristics of the bulk material (polymer) being obtained. By controlling the energy input, the density of the sintered material can be controlled, and various parts can be realized from highly porous to almost maximum density parts. Theoretically, all thermoplastic polymers that can be converted into powder form can be processed by this method. However, in reality, the behavior of each material during melting, fusing, and consolidation is different and often unpredictable, requiring unique SLS processing parameters. For example, the bed temperature and laser energy input can be selected based on the processing window of the polymer's thermal profile and its energy absorption. Also, the laser parameters can be selected based on the particle size and shape of the powder.

[0007] There are various types of polymer particles commonly used in the SLS process. Semi-crystalline resins such as polyamides including PA12, PA11, and PA6, polylactic acid (PLA), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), etc. are used. The most commonly used polymer powder is polyamide PA12. The common name for polyamide is nylon. For example, polyamide PA12 is also known as nylon 12, and polyamide PA6 is also known as nylon 6. The structure of layer upon layer is formed by sintering polymer particles with a laser above the melting point of the polymer according to the CAD shape file of the part.

[0008] At present, there is relatively little experience regarding the use of poloxamers as pharmaceutical excipients in selective laser sintering. So far, the suitability of various poloxamer grades is unknown.

[0009] For the selective laser sintering method, there is a need for polymers that are suitable as pharmaceutical excipients with improved properties. In particular, laser sintering of polymers should result in pharmaceutical dosage forms in which the API is dispersed within the polymer to form an amorphous solid dispersion. The polymers for this purpose need to show improvement in the amorphization of the API and / or beneficial API release. Furthermore, there is a need for polymers that can be effectively used in the SLS method to stabilize the API or prevent the degradation of the API. SUMMARY OF THE INVENTION

[0010] Summary of the Invention Surprisingly, it has been found that certain poloxamers can be beneficially used to form pharmaceutical dosage forms in a process for selective laser sintering of sinterable powders. Poloxamers having a melting point of 20 °C or higher are particularly suitable for selective laser sintering.

[0011] Unexpectedly, it has been shown that a low process temperature is required to successfully produce an amorphous solid dispersion with the poloxamers of the present invention. The low temperature has several advantages compared to alternative polymers, such as, by way of example, the reusability of the poloxamer after the printing cycle, the increase in printing speed, the accessibility to the method for a wide range of SLS printers, and the reduction of the energy required for printing. Certain poloxamers exhibit surprisingly fast API release.

[0012] In addition, for the melting point (Tm), molecular weight (MW), and weight percentage of ethylene oxide (EO) chains (weight EO%), as mentioned above, there is an optimal range leading to pharmaceutical dosage forms with beneficial properties.

[0013] In a further aspect of the present invention, the poloxamer has a melting point between 20°C and 60°C, and / or an average molecular weight of 3000 Da, and / or a weight percentage of ethylene oxide chains between 50% and 90%. In another aspect, the poloxamer is poloxamer P188P or 407.

[0014] In a further aspect of the present invention, the poloxamer has a melting point between 40°C and 55°C, and / or an average molecular weight between 7000 Da and 12000 Da, and / or a weight percentage of ethylene oxide chains between 75% and 85%. In another aspect, the poloxamer is poloxamer P188.

[0015] In another aspect, a process for producing a pharmaceutical dosage form by selective laser sintering of the sintered powder of the present invention, the following steps: (a) providing a sintered powder comprising at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher; and (b) operating a selective laser sintering apparatus to selectively fuse a layer of the sintered powder to produce a pharmaceutical dosage form. The process as described above is provided.

[0016] A further aspect of the present invention relates to a sintered powder for selective laser sintering comprising at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher.

[0017] A further aspect of the present invention relates to a pharmaceutical dosage form obtainable by the process mentioned above, in particular a pharmaceutical dosage form produced by selective laser sintering of a sintered powder, wherein the sintered powder comprises at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

Figure 1

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Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

[0019] DETAILED DESCRIPTION OF THE INVENTION One aspect of the present invention is the use of a poloxamer in a process for selective laser sintering of a sinterable powder for forming a pharmaceutical dosage form, where the sinterable powder comprises at least one active pharmaceutical ingredient and a poloxamer. According to the present invention, selective laser sintering is a process of sintering and / or melting by scanning a powder bed filled with a powder mixture containing a polymer according to the cross-section of a digital model using a laser beam. The polymer version of the digital model is produced layer by layer by laser scanning of successive layers of the powder mixture.

[0020] This process requires a selective laser sintering printer equipped with a laser light source, a galvanometer system for scanning the laser on the powder bed surface, or, alternatively, an XY motion system that moves the actual laser light source to scan the powder bed. The printer must also provide a powder coating system for dispersing the powder in layers, as well as a build chamber and a heating function for heating the surface of the powder bed.

[0021] According to the present invention, the powder mixture used is prepared by mixing poloxamer powder, excipients, and API (excipients: pigments, colloidal silica). First, the poloxamer powder is sieved through a 300-micron sieve, and the sieved material is mixed with the excipients and API and mixed for 30 minutes in a turbulent flow mixer. Next, the obtained mixture is sieved through a 300-micron sieve, and the sieved material is filled into the printer.

[0022] After filling the mixture, the printer is preheated to a set temperature below the Tg of the poloxamer, and the printing process is started. In the printing process, parameters such as the temperature of the chamber and the printing bed are set to appropriate values obtained from experimental studies in order to provide printed tablets with desirable properties regarding mechanical and morphological characteristics. Other parameters that affect the process are the laser energy input and the layer height of each applied layer. The laser energy input can be controlled in various ways depending on the type of printer used, usually by adjusting the laser scan speed and the hatching space (the distance between the scanned laser lines) or by adjusting the energy output by the laser.

[0023] When the printing process is completed, the printed tablets are slowly cooled in the printer and then taken out, and the surrounding unsintered powder is removed.

[0024] Poloxamer is an amphiphilic polymer and has two hydrophilic blocks and one central hydrophobic block. Poloxamer is a triblock copolymer of polyethylene glycol (PEG) / polypropylene glycol (PPG), with PEG blocks located on both sides of one PPG block. The polyethylene glycol (PEG) moiety is often also referred to as the polyethylene oxide (PEO) moiety. The polypropylene glycol (PPG) moiety is often also referred to as the polypropylene oxide (PPO) moiety.

[0025] Poloxamer grades are named generally with the letter P (for Poloxamer) as officially used in USP and EP, followed by three digits. This describes the polymer composition as follows: multiplying the first two digits by 100 gives the molecular weight of the PO block, and multiplying the last digit by 10 gives the percentage (%) of EO.

[0026] Poloxamer P188 is composed on average of 80% EO, with the remaining 20% PO making up 1800 g / mol. Poloxamer P407 is a poloxamer with an average polyoxypropylene molecular weight of 4000 g / mol and a polyoxyethylene content of 70%.

[0027] Poloxamer has the general formula (I).

Chemical formula

[0028] For different poloxamers, depending on the type of poloxamer, the numerical values of x (PEO), y (PPO chain), and z (PEO) vary over a wide range. In the case of poloxamer P188, the PPO chain contains an average of 25 - 30 units, each PEO is composed of an average of 75 - 85 EO units, and has a molecular weight ranging from 7680 - 9510 Da. In the case of poloxamer P407, the PPO chain contains an average of 56 units, each PEO is composed of an average of 101 EO units, and has a molecular weight ranging from 9840 - 14600 Da.

[0029] Poloxamer 407 (a = 101, b = 56) having a molecular weight ranging from 9840 to 14600 Da.

[0030] Table 1 shows the types of poloxamers for which monographs are written in the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP). Table 1

Table 1

[0031] Table 2 shows the melting points, molecular weights, and weight percentages of ethylene oxide chains (weight EO%) of the most common poloxamers, as published in Russo, Villa. Poloxamer Hydrogels for Biomedical Applications. Pharmaceutics. 2019;11:671. Table 2

Table 2-1

Table 2-2

[0032] Some poloxamers are commercially available in various forms, such as Synperonic® (CroDa International PLC), Pluronic® (BASF SE), Lutrol® (renamed to Kolliphor® and Kollisolv® by BASF SE), or Poloxamer 188 EMPROVE® EXPERT, with various ratios of EO units to PO units, and in liquid, paste, and wax-like solid forms.

[0033] Alternatively, the poloxamer can also be made from raw materials according to methods known in the art (see, for example, U.S. Pat. Nos. 3,579,465 and 3,740,421).

[0034] Further information on poloxamers can be found in Hagers Handbuch der Pharmazeutischen Praxis, volume 9 “Stoffe P-Z”, 1994, pages 282-284, or Russo, Villa. Poloxamer Hydrogels for Biomedical Applications. Pharmaceutics. 2019;11:671.

[0035] The use of specific poloxamer grades according to the present invention is of interest for the formulation of solid oral pharmaceutical dosage forms with immediate, instant, or long-term API release. Immediate or instant release is preferred.

[0036] The poloxamer according to the present invention has a melting point of 20°C or higher.

[0037] In a further aspect, the poloxamer according to the present invention has 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 a further aspect, the poloxamer according to the present invention has an average molecular weight of 3000 Da or more, between 4000 and 15000 Da, or between 7000 and 13000 Da. In a further aspect, the poloxamer according to the present invention has a weight percentage of ethylene oxide chains between 50% and 90%, or between 70% and 85%. In another aspect, the poloxamer is poloxamer P188P or 407.

[0038] In a further aspect, 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%.

[0039] In a further aspect, the poloxamer according to the 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 75% and 90%.

[0040] In a further aspect, the poloxamer according to the 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%.

[0041] In a further aspect, the poloxamer according to the 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 a further aspect, the poloxamer according to the invention has an average molecular weight between 4000 and 12000 Da, or between 7000 and 12000 Da. In a further aspect, the poloxamer according to the invention has a weight percentage of ethylene oxide chains between 75% and 85%, or between 80% and 85%. In another aspect, the poloxamer is poloxamer P188.

[0042] In a further aspect, the poloxamer according to the invention has a melting point between 50 °C and 55 °C, an average molecular weight between 7000 and 12000 Da, and a weight percentage of ethylene oxide chains between 80% and 85%.

[0043] In a further aspect, the poloxamer according to the invention has a melting point between 40 °C and 55 °C, an average molecular weight between 7000 and 12000 Da, and a weight percentage of ethylene oxide chains between 75% and 85%.

[0044] In a further aspect, the poloxamer according to the invention has a melting point between 50 °C and 55 °C, an average molecular weight between 7000 and 12000 Da, and a weight percentage of ethylene oxide chains between 80% and 85%.

[0045] In a further aspect, the poloxamer according to the invention has a melting point of about 52 °C and / or an average molecular weight between 7680 and 9510 Da and / or a weight percentage of ethylene oxide chains between 80% and 85%. In a further aspect of the invention, the poloxamer is poloxamer P188.

[0046] In a further aspect, the poloxamer according to the invention has a melting point of about 56 °C, and / or an average molecular weight between 9840 and 14600 Da, and / or a weight percentage of ethylene oxide chains between 70% and 75%. In a further aspect of the invention, the poloxamer is poloxamer P407.

[0047] The poloxamer, the poloxamer specifications, and the poloxamer grades of the aspects mentioned above are equally applicable to the use of the poloxamer in the process for selective laser sintering of sintered powders, the process for producing pharmaceutical dosage forms by selective laser sintering of sintered powders, the sintered powders for selective laser sintering, and the pharmaceutical dosage forms produced by selective laser sintering of sintered powders.

[0048] A further aspect of the invention is a sintered powder for selective laser sintering comprising at least one active pharmaceutical ingredient according to the invention and at least one poloxamer.

[0049] To avoid doubt, the sintered powders according to the invention include sintered powders with any of the poloxamers, poloxamer specifications, or poloxamer grades defined above.

[0050] In a further aspect of the invention, the sintered powder, and the pharmaceutical dosage form may further comprise a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include flow control agents such as silicon dioxide, fillers, plasticizers, surfactants, light-absorbing materials such as Ruby Red or Candurin pigments, and other suitable components well known to those skilled in the art.

[0051] Depending on the wavelength of the light emitted by the laser, an optical absorption material (pigment) that absorbs the light of the emitted wavelength may be required. These optical absorption materials can contain transition metals that absorb at about 450 nm, or a wider range of carbon that covers the visible and near-infrared ranges. Light absorption is a process by which light is absorbed and converted into energy. When light is absorbed, heat is generated. Therefore, the selective absorption of light by a specific substance occurs because the frequency of the light wave coincides with the frequency at which the electrons in the atoms of that substance vibrate.

[0052] All optical absorption materials are materials suitable for the SLS method as described above and are known to those skilled in the art. Preferably, an optical absorption material that has been demonstrated to function with a 445 nm laser irradiation is used (examples: Candurin NXT, Ruby Red, Candurin Gold Sheen, Aluminum Lake, activated carbon (which also functions at 808 nm), iron oxide (Fe2O3)). More preferably, Ruby Red is used.

[0053] A carbon dioxide laser that emits at about 10 microns usually does not require the addition of an optical absorption material because C-H bonds absorb energy well at this wavelength and this type of bond can be found in most polymers.

[0054] To avoid doubt, a flow control agent, plasticizer, surfactant, or other suitable components are not necessary for the beneficial properties according to the present invention, such as the stabilization of the amorphous form of the API. However, those components can also be used for other purposes (such as optimizing the manufacturing process of a pharmaceutical composition or an oral dosage form according to the present invention).

[0055] Furthermore, the pharmaceutical composition according to the present invention can contain additional pharmaceutically acceptable hydrophilic or lipophilic polymers.

[0056] In a preferred embodiment, the sintered powder further comprises a light-absorbing material.

[0057] As used herein, the phrase "pharmaceutically acceptable" generally refers to all excipients, polymers, compounds, solvents, dispersion media, flow control agents, carriers, coatings, active agents, isotonic agents, absorption delaying agents, etc. that do not produce an allergic reaction or similar adverse reaction when administered to humans. The use of such materials in pharmaceutical compositions is well known in the art.

[0058] In a preferred embodiment, the sintered powder has a D50 of 200 μm or less. Preferably, the particle size (D50) of the sintered powder is between 20 μm and 200 μm, between 20 μm and 150 μm, or between 20 μm and 100 μm.

[0059] In a preferred embodiment, the poloxamer has a D50 of 200 μm or less. Preferably, the particle size (D50) of the poloxamer is between 20 μm and 200 μm, between 20 μm and 150 μm, or between 20 μm and 100 μm.

[0060] A further aspect of the present invention is a process for producing a pharmaceutical dosage form by selective laser sintering of a sintered powder, the following steps: (a) providing a sintered powder comprising at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20 °C or higher, and (b) operating a selective laser sintering apparatus to selectively fuse a layer of the sintered powder to produce a pharmaceutical dosage form comprising said process.

[0061] To avoid ambiguity, the process according to the present invention includes selective laser sintering with any of the poloxamers, poloxamer specifications, or poloxamer grades defined above.

[0062] A further aspect of the invention is a pharmaceutical dosage form obtainable by a process for producing a pharmaceutical dosage form by selective laser sintering of a sinterable powder, as described above.

[0063] In a further aspect, the pharmaceutical dosage form is produced by selective laser sintering of a sinterable powder, where the sinterable powder comprises at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher.

[0064] To avoid doubt, pharmaceutical dosage forms according to the invention include pharmaceutical dosage forms having any of the poloxamers, poloxamer specifications, or poloxamer grades defined above.

[0065] The API is a biologically active agent. The API may be a small molecule in the form of a weak base, weak acid, or neutral molecule, as well as in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. The sinterable powder, and the pharmaceutical dosage form, may comprise a plurality of APIs. In one aspect, the API is a poorly soluble or lipophilic API.

[0066] As used herein, the terms "poorly soluble API", "poorly water-soluble API", and "lipophilic API" refer to APIs having a solubility such that the maximum therapeutic dose of a particular API administered to an individual is not soluble in 250 ml of an aqueous medium in the pH range of 1 - 8, according to the definition of low solubility by the Biopharmaceutics Classification System (BCS) classes 2 and 4. Poorly soluble APIs with weakly basic, or weakly acidic, characteristics have a pH-dependent solubility profile and can have solubility in a wide range of aqueous environments in the gastrointestinal tract. APIs corresponding to BCS class 2 or 4 respectively are well known to those skilled in the art.

[0067] In one aspect, the API is a weakly basic API. As used herein, the term "weakly basic API" refers to a basic active pharmaceutical ingredient (API), where the basic API is not completely ionized in water.

[0068] According to the present invention, at least one active pharmaceutical ingredient (API) can be dispersed in a poloxamer to form an amorphous solid dispersion.

[0069] A further aspect of the present invention is the use of a poloxamer in a process for selective laser sintering of a sinterable powder for forming a pharmaceutical dosage form, as described above, wherein an amorphous solid dispersion of at least one active pharmaceutical ingredient in the poloxamer is formed.

[0070] As used herein, the term "amorphous solid dispersion" is a dispersion of at least one amorphous API in a polymer matrix. Preferably, the amorphous API is distributed in a molecularly dispersed state within the polymer matrix. In this case, the solid dispersion is a solid solution. When dissolved, a formulation containing an amorphous solid dispersion can achieve higher solubility in an aqueous medium than a crystalline API.

[0071] The API included in the pharmaceutical dosage form of the present invention has an amount sufficient to be therapeutically effective. For a particular API, a therapeutically effective amount is generally known or readily accessible to those skilled in the art. Typically, the API can be present in the pharmaceutical dosage form at a weight ratio of the API to the poloxamer of 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.

[0072] It has been found that poloxamers can be beneficially used in a process for selective laser sintering of a sinterable powder for forming a pharmaceutical dosage form.

[0073] The selective laser sintering process requires surprisingly low process temperatures. Example 1 shows, surprisingly, that an advanced SLS printing technology with the above-mentioned poloxamer was able to successfully produce amorphous solid dispersions at a printing bed temperature of about 50 °C and a chamber temperature at room temperature. It was not expected that pharmaceutical dosage forms with amorphous APIs stabilized within a polymer matrix could be manufactured using SLS technology at that range of temperatures.

[0074] Low temperatures have numerous advantages compared to alternative SLS processes with different polymers. 1. Due to the low temperature, after the printing cycle, the sintered powder remaining on the printing bed can be reused several times without degradation of the print quality. This is a phenomenon not seen with any other polymer. 2. The low printing temperature enables printing of parts without a heated printing chamber, allowing the use of simpler and lower-cost printers. 3. The low printing temperature enables the use of fast printing speeds and, thereby, reduced printing times. Additionally, with higher printing speeds, the thermal stress on the API is reduced. 4. The low printing temperature of the polymer reduces the amount of energy required for the printing process. Thus, the SLS printing process with the above-mentioned poloxamer has better environmental sustainability.

[0075] This process was carried out at a temperature far below the melting point of the model drug substance, but the crystalline drug was successfully converted into the amorphous form to produce an amorphous solid dispersion.

[0076] Certain poloxamers exhibit surprisingly fast drug release compared to other poloxamers. In particular, poloxamers having a melting point between 40°C and 55°C, preferably between 50°C and 55°C, and / or an average molecular weight between 7000 Da and 12000 Da, preferably between 7000 Da and 9000 Da, and / or a weight percentage of ethylene oxide chains between 75% and 85%, preferably between 75% and 80%, show faster dissolution of the API in pharmaceutical dosage forms compared to poloxamers outside of those specifications. In another aspect, poloxamer P188 shows relatively fast API dissolution. The rapid dissolution of the drug is, surprisingly, the result of a combination of the process (SLS technology) for manufacturing the pharmaceutical dosage form and the selection of the poloxamer. This was confirmed by using different 3D printing technologies with the same poloxamer grade, but did not result in improved API dissolution.

[0077] Certain poloxamers exhibit surprisingly improved amorphization of the API compared to other poloxamers. In particular, poloxamers having a melting point between 40°C and 55°C, preferably between 50°C and 55°C, and / or an average molecular weight between 7000 Da and 12000 Da, preferably between 7000 Da and 9000 Da, and / or a weight percentage of ethylene oxide chains between 75% and 85%, preferably between 75% and 80%, show faster dissolution of the API in pharmaceutical dosage forms compared to poloxamers outside of those specifications. In another aspect, poloxamer P188 shows improved amorphization of the API compared to other poloxamers.

[0078] Furthermore, poloxamers having the melting point, molecular weight, and / or weight percentage of ethylene oxide chains identified above guarantee and stabilize the release and supersaturation of the API, particularly poorly soluble APIs, in aqueous media, thereby preventing crystallization and phase separation. Generally, the low water solubility of APIs is associated with low bioavailability after administration of pharmaceutical formulations, and thus the compositions according to the present invention also contribute to the improvement of the bioavailability of poorly soluble APIs, particularly weakly basic APIs.

[0079] As used herein, "bioavailability" is a term that means to what extent an API becomes available to a target tissue after being administered into a patient's body.

[0080] After dissolving the pharmaceutical dosage form of the present invention, an improved supersaturation is observed and the API is better maintained in solution. Moreover, the API can be successfully incorporated into the poloxamer matrix during the sintering process.

[0081] Upon entering the gastrointestinal tract, the pharmaceutical dosage form swells and disintegrates in the aqueous environment of gastrointestinal fluids, thereby releasing the API. The salt form of a weakly basic API may exhibit an improved initial water concentration in acidic gastric juice, while the weakly basic API rapidly changes to the free base form in more neutral intestinal fluid where the free base form of the API has a significantly lower equilibrium concentration. The poloxamer according to the present invention maintains an enhanced concentration of the API in model solutions simulating acidic and neutral gastrointestinal solutions as compared to poloxamers deviating from the recited specifications. Thus, the pharmaceutical dosage form according to the present invention has the potential to provide improved bioavailability of poorly soluble APIs. The form in which the solubility of the API is improved in the presence of the poloxamer according to the present invention provides a higher concentration of the API in gastric juice, or simulated gastric juice, than the concentration of the API provided in the presence of poloxamers outside the recited specifications.

[0082] Example Example 1: SLS Printing Preparation of Powder Formulation The API-combined powder formulations were prepared according to Table 3. All powder mixtures were sieved using a 315 μm stainless steel test sieve (VWR International AB, Sweden) and mixed for 15 minutes using a Turbula shaker (Turbula T2F shaker, Glen Mills, Inc., Glen Mills, Inc., NJ, US). CanDurin Ruby ReD and colloidal silica (Aerosil) were added to the formulations to improve the laser energy absorption of the powder and the fluidity of the powder during the layer coating process, respectively. As poloxamers, P188 (Poloxamer 188 EMPROVE® EXPERT, Merck) and P407 (Merck) were used. The formulations were prepared in a sufficient amount of batch (about 1500 mL) to partially fill the build volume (100x100x100 mm) of the Sintratec KitSLS3D printer (Sintratec, Brugg, Switzerland).

[0083] Table 3. Composition of the Prepared Powder Formulations

Table 3

[0084] Selective Laser Sintering 3D Printing of Dosage Forms The tablet template was created and designed in Solidworks 2019 SP05 (Figure 1), and then the obtained standard triangle language file (STL file) was prepared to be printable in Sintratec software using the process parameters shown in Table 2. The energy density was calculated according to the following formula.

Equation

[0085] The 3D printing process was further carried out as follows. The prepared powder formulation (Table 1) was placed in the powder reservoir platform (100x100x100 mm) of the SLS 3D printer and packed. A thin layer of the formulation was then spread on the build platform, and the powder bed was slowly heated to the temperature specified in Table 4. The sintering process was carried out layer by layer with a 2.3 W diode (λ = 455 nm) according to the model described in the STL file. Using the layer height specified in Table 4, a total of 36 tablets were printed flat against the build platform for each batch. When printing different batches, a specific value of the laser scan speed was selected. The completed batch was recovered from the build platform by sieving at the end of the printing process. The tablets were further dusted using pressurized air to remove excess powder and stored in a sealed container for further analysis.

[0086] Figure 1 shows a schematic diagram and a 3D model of the tablet (4x9.5 mm).

[0087] Considering that different materials have different melting points and different particle sizes and require different temperatures to sinter correctly, the printing speed, printing bed temperature, and hatching space were adjusted to apply an appropriate amount of energy to the materials.

[0088] Table 4. Process parameters used for each formulation

Table 4

[0089] Characterization of powder formulations and 3D printed dosage forms Powder X-ray diffraction (PXRD) diffractograms of the neat and heat-treated powder formulations, as well as the printed dosage forms, were obtained using Cu-Kα 1,2(λ = 1.5418 Å) radiation was used, and the data was collected using a Bruker D8 Advance TwinTwin diffractometer (Bremen, Germany). This device was operated at 40 mA and 40 kV, with a step size of 0.02° and a data collection time of 1 hour.

[0090] Figures 9 and 10 show the diffraction patterns of indomethacin-filled tablets and ketoconazole-filled tablets. The X-ray diffraction patterns confirm the amorphization of the drug substances within the 3D printed tablet matrix.

[0091] Differential scanning calorimetry (DSC) thermograms were obtained using a Mettler Toledo DSC 3+ (Schwerzenbach, Switzerland), with a heating and cooling rate of 10 °C min-1 and nitrogen as the purge gas. Repeated heating / cooling measurements were performed at -40 to 200 °C and 200 to 10 °C in the first cycle, and at 10 to 200 °C in subsequent cycles. The dimensions (n = 10) and weights (n = 30) of the printed tablets were examined using a digital caliper and an analytical balance (Mettler Toledo XS 64 Analytical Balance, Schwerzenbach, Switzerland).

[0092] Figures 2 - 8 show the DSC thermograms of pure indomethacin (Figure 2), pure polymer / placebo tablets without API (Figure 3), indomethacin-filled P188 (Figure 4), indomethacin-filled P407 (Figure 5), ketoconazole-filled P188 and P407 (Figure 6), ketoconazole-filled P188 (Figure 7), and ketoconazole-filled P407 (Figure 8). The batch numbers (Table 3) are indicated by # numbers in the figures. The thermogram of indomethacin shows a distinct melting peak of the drug substance. In the 3D printed tablets, the melting peak of indomethacin is no longer observable, indicating that the drug substance has been completely amorphized.

[0093] The friability test was carried out on approximately 6.5 g of tablets according to the European Pharmacopoeia (Ed. 10.0), using a Pharmatest PTF E friabilator (Hainberg, Germany) at 25 rpm and 100 revolutions. Before and after the measurement, the tablets were carefully weighed and the total weight loss of the tablets (i.e., friability) was calculated.

[0094] The dissolution data were obtained using a Sotax AT7 dissolution tester via HPLC from an Agilent 1260 infinity II. The mobile phase contained a mixture of 1000 ml of acetonitrile + 1000 ml of buffer USP (1.38 g / L of 0.01 M NaH2PO4·H2O + 1.41 g / L of 0.01 M Na2HPO4). Both were mixed 1:1 and sonicated for 15 minutes. Prepare an appropriate 5-point calibration of indomethacin with the mobile phase.

[0095] Dissolution was carried out with n = 3, using tablets in 500 ml of SGF_sp, at a paddle speed of 50 rpm for 3 hours, at sampling points (15, 30, 60, 90, 120, 180 minutes). 2 ml of the sample was filtered through a 0.45 μm PTFE syringe filter and directly measured by HPLC on an LC-18, 30 cm x 4 mm, 5 μm column at a flow rate of 1 ml / min, an injection volume of 10 μl, and a run time of 5 minutes at 254 nm.

[0096] To define the hardness of the tablets (expressed in Newtons, N), a hardness test was carried out on 10 cylindrical tablets (10 mm in diameter) from each batch. A Pharmatest PTB 311E tablet hardness tester (Hainberg, Germany) was used.

[0097] In the case of a cylindrical shape, the splitting tensile strength was calculated according to the following formula.

Equation

[0098] The abrasion test was carried out in accordance with EP 5.0, paragraph 2.9.7 - Friability of uncoated tablets.

[0099] For tablets with a weight of up to 0.65 g per tablet, a sample of 20 tablets is taken. For tablets with a weight exceeding 0.65 g per tablet, a sample of 10 tablets is taken. Place the tablets on a 1000 - mesh sieve and remove the loose powder with air pressure or a soft brush. Weigh the tablet sample accurately and place the tablets in the drum. Rotate the drum 100 times and take out the tablets. As described above, remove the loose powder from the tablets. If the tablets are not cracked, broken, or shattered, weigh the tablets in milligrams.

[0100] Table 5. Evaluation of the characteristics of 3D - printed dosage forms [Table 5]

Claims

1. Use of a poloxamer in a process for selective laser sintering of sintered powder for forming a pharmaceutical dosage form, wherein the sintered powder comprises at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher.

2. The use according to claim 1, wherein the melting point of at least one poloxamer is between 40°C and 60°C.

3. The use according to claim 1 or 2, wherein the average molecular weight of at least one poloxamer is 3000 Da or higher.

4. The use according to any one of claims 1 to 3, wherein at least one poloxamer has a weight percentage of ethylene oxide chains between 50% and 90%.

5. The use according to any one of claims 1 to 4, wherein at least one poloxamer is poloxamer P188 or P407.

6. The use according to any one of claims 1 to 5, wherein the sintered powder further comprises at least one light-absorbing material.

7. A process for producing a pharmaceutical dosage form by selective laser sintering of sintered powder, comprising the following steps: (a) providing a sintered powder comprising at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher, and (b) operating a selective laser sintering apparatus to produce a pharmaceutical dosage form by selectively fusing a layer of the sintered powder. The process as described above.

8. The method according to claim 7, wherein the pharmaceutical dosage form is an amorphous solid dispersion of at least one active pharmaceutical ingredient in at least one poloxamer.

9. The process according to claim 7 or 8, wherein at least one poloxamer is poloxamer P188 or P407.

10. The process according to any one of claims 7 to 9, wherein the processing temperature is below the melting point of at least one poloxamer.

11. The process according to any one of claims 7 to 10, wherein the sintered powder has a D50 of 200 μm or less.

12. The process according to any one of claims 7 to 11, wherein the sintered powder further comprises at least one light-absorbing material.

13. A sintered powder for selective laser sintering, comprising at least one active pharmaceutical ingredient and at least one poloxamer having a melting point of 20°C or higher.

14. The sintered powder according to claim 13, further comprising at least one light-absorbing material.

15. A pharmaceutical dosage form obtainable by the process according to any one of claims 7 to 12.

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