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

Abstract

This disclosure generally relates to the use of polyvinyl alcohol (PVA) in additive manufacturing techniques and processes. More specifically, this disclosure relates to the use of PVA in a selective laser sintering (SLS) process for additively manufacturing objects, particularly pharmaceutical dosage forms.

Description

Technical Field

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

Background Art

[0002] Background The use of hydrophilic polymers such as polyvinyl alcohol as excipients in pharmaceutical compositions has been widely described. WO 2018 / 083285 A1 discloses powdered PVA with improved properties as a polymer matrix in pharmaceutical compositions containing an active ingredient, particularly in compressed tablets forming amorphous solid dispersions containing poorly soluble active pharmaceutical ingredients (APIs).

[0003] Polyvinyl alcohol is used in amorphous solid dispersions, which is a well-known strategy for improving the bioavailability of poorly water-soluble drug substances. Although the amorphous form exhibits higher solubility, it is quite unstable and tends to recrystallize and precipitate immediately after dissolution or during pH changes when changing from an acidic gastric environment to a more neutral intestinal environment. The recrystallized fraction of the API cannot be absorbed. Since drug absorption mainly occurs in the intestine, pharmaceutical formulations that do not maintain a high concentration of the API in intestinal fluid generally result in only a slight improvement in bioavailability. Unwanted recrystallization rather reduces the bioavailability of the API. Low bioavailability is a significant problem faced in the development of pharmaceutical compositions, particularly those containing APIs with low water solubility.

[0004] In J Pharm Sci. 2008; 97 (12): 5198-211, polyvinyl alcohol was successfully evaluated for its ability to inhibit the crystallization of model compounds such as caffeine. The PVA grade used in these data is described as polyvinyl alcohol (PVA) with an average molecular weight of 47,000. Another study by Overhoff et al., Effect of Stabilizer on the Maximum Degree and Extent of Supersaturation and Oral Absorption of Tacrolimus Made By Ultra-Rapid Freezing, Pharmaceutical Research. 2008;25(1):167-75, describes the use of PVA to increase the supersaturation of a tacrolimus model compound. The solid dispersions were prepared by ultra-rapid freeze-drying. The PVA grade used is described as poly(vinyl) alcohol (PVA, Mw 13,000 - 23,000, 87 - 89% hydrolyzed). PVA can be successfully used as a stabilizer. The use of polyvinyl alcohol for hot-melt extrusion has been previously described by de Jaeghere et al., Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications, Int J Pharm. 2015;492(1-2):1-9. A partially hydrolyzed PVA grade was used to evaluate its use as a carrier for an oral immediate release dosage form. An effect on the release rate was observed, but no direct relationship between the degree of hydrolysis and the supersaturation potential was confirmed.In Brough et al., Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 1), AAPS PharmSciTech Vol. 17, No.1, p. 176 (01.02.2016), specific PVA grades including PVA4-75, PVA4-88, PVA4-98, and PVA4-38 were investigated by a non-sink gastric transplant dissolution method.

[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 sequentially deposited 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 polymer powder bed is scanned with a rasterized laser to sinter and 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 properties of the bulk material (polymer). 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. In theory, all thermoplastic polymers that can be converted into powder 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 may be selected based on the processing window of the polymer's thermal profile and its energy absorption. Laser parameters may also 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, PA6, polylactic acid (PLA), polyether ether ketone (PEEK), polyethylene (PE), polypropylene (PP), etc. are used. The most common polymer powder employed is polyamide PA12. The general 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] There is currently relatively little experience regarding the use of polyvinyl alcohol as a pharmaceutical excipient in selective laser sintering. In Basit et al. International Journal of Pharmaceutics 529 (2017) 285 - 293, Kollicoat IR, a copolymer of 75% polyvinyl alcohol and 25% polyethylene, was used in the SLS process together with paracetamol as the active pharmaceutical ingredient. Yang et al. International Journal of Pharmaceutics 593 (2021) 120127 disclosed PVA as one of several excipients for SLS printing. So far, the compatibility of various PVA grades (viscosity and degree of hydrolysis) is unknown.

[0009] There is still a need for polyvinyl alcohol as a pharmaceutical excipient with improved properties for the selective laser sintering method. Summary of the Invention

[0010] Summary of the Invention Surprisingly, it has been found that polyvinyl alcohol can be used in a process for selectively laser sintering a sintered powder to form a pharmaceutical dosage form. Furthermore, it has been found that polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20°C of 3 mPas to 8 mPas is particularly suitable for selective laser sintering.

[0011] Surprisingly, it has been shown that there is an optimal range for the degree of hydrolysis and viscosity that results in pharmaceutical dosage forms with beneficial properties such as faster API release and / or improved API amorphization compared to commonly used PVA grades. PVA grades within this optimal range ensure and stabilize the release and supersaturation of the API for various 3D printing parameters. Furthermore, it has been shown that amorphous forms of API can be stabilized for extended periods, for example, for more than 6 months, in pharmaceutical dosage forms. In a preferred embodiment, the long-term stabilization is measured at 40°C / dry conditions, 25°C / 60% RH, 30°C / 65% RH, 30°C / 75% RH, 40°C / 75% RH, or 40°C / 75% RH for 3 or 6 months, and 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% or more of the API still exists in its amorphous form.

[0012] In a preferred embodiment of the present 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 to 4 mPas.

[0013] In another aspect, the present invention is a method for producing a pharmaceutical dosage form by selective laser sintering of a sinterable powder, the method comprising the steps of: (a) providing a sinterable powder comprising at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20°C of 3 mPas to 8 mPas, and (b) operating a selective laser sintering apparatus to produce a pharmaceutical dosage form by selectively fusing a layer of the sinterable powder The method is provided as described above.

[0014] A further aspect of the invention relates to a sintering powder for selective laser sintering, comprising at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of the 4% solution at 20 °C of 3 mPas to 8 mPas. The sintering powder can further comprise additional excipients and / or light absorbing materials.

[0015] A further aspect of the invention relates to a pharmaceutical dosage form obtainable by the process as mentioned above, in particular a pharmaceutical dosage form produced by selective laser sintering of a sintering powder, wherein the sintering powder comprises at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of the 4% solution at 20 °C of 3 mPas to 8 mPas. BRIEF DESCRIPTION OF THE DRAWINGS

[0016]

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Mode for Carrying Out the Invention

[0017] Detailed Description of the Invention An aspect of the present invention is the use of polyvinyl alcohol in a process for selective laser sintering of sinterable powder to form a pharmaceutical dosage form, wherein the sinterable powder comprises at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

[0018] According to the present invention, selective laser sintering is a process of sintering and / or melting a powder bed filled with a powder mixture containing a polymer by scanning a laser beam according to the cross-section of a digital model. The polymer version of the digital model is produced layer by layer by laser scanning a continuous layer of the powder mixture.

[0019] This process requires a selective laser sintering printer equipped with a laser light source and a galvanometer system for scanning the laser on the surface of the powder bed, or alternatively, an XY motion system for moving the actual laser light source to scan the powder bed. The printer also needs to provide a powder coating system for dispersing the powder in layers, as well as a heating function for heating the surface of the build chamber and the powder bed.

[0020] According to the present invention, the powder mixture to be used is prepared by mixing PVA, API, and, if necessary, further pharmaceutically acceptable excipients. First, PVA is sieved through a 300-micron sieve, and the sieved material is mixed with the excipient and API and mixed in a turbulent flow mixer for 30 minutes. Next, the obtained mixture is sieved through a 300-micron sieve, and the sieved material is set in the printer.

[0021] After filling the mixture, the printer is preheated to a set temperature below the Tg of PVA, 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 properties. Other parameters affecting the process are the laser energy input and the layer height of each coating 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.

[0022] When the printing process is completed, the printed tablets are slowly cooled in the printer, then taken out, and the surrounding unsintered powder is removed.

[0023] Polyvinyl alcohol (PVA) has an ideal formula of [CH2CH(OH)] nIt is a synthetic water-soluble polymer. PVA has excellent film-forming properties, adhesiveness, and emulsifying properties. PVA is prepared from polyvinyl acetate, and the functional acetate groups are partially or completely hydrolyzed to become alcohol functional groups. If it is not completely hydrolyzed, PVA becomes a random copolymer consisting of vinyl alcohol repeating units -[CH2CH(OH)]- and vinyl acetate repeating units -[CH2CH(OOCCH3)]-. The polarity of PVA is closely related to its molecular structure. The molecular properties of PVA are determined by the degree of hydrolysis and molecular weight. As the degree of hydrolysis of the acetate groups increases, the solubility of the polymer in aqueous media, as well as the crystallinity and melting temperature of the polymer, also increase. However, at a high degree of hydrolysis exceeding 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but in some cases, it is almost insoluble in almost all organic solvents excluding ethanol.

[0024] Typical PVA nomenclature indicates the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA3-83 is a PVA grade with a viscosity of 3 mPas and 83% hydrolysis, that is, it has 83% vinyl alcohol repeating units and 17% vinyl acetate repeating units. Those skilled in the art recognize that an 83% hydrolysis grade and a viscosity of 3 mPas include a calculated hydrolysis grade of 82.50% - 83.49% and a calculated viscosity of 2.50 mPas - 3.49 mPas% according to the general rounding method. The viscosity according to the present invention is measured as described in the Monograph “Polyvinyl Alcohol” with the method Viscosity-Rotational Method (912).

[0025] The degree of hydrolysis according to the present invention is measured by determining the saponification value of polyvinyl alcohol as described in USP 39 under Monograph “Polyvinyl Alcohol” under “Degree of Hydrolysis”.

[0026] Sample: 1 g of polyvinyl alcohol that has been dried in advance to a constant weight at 110 °C Analysis: Transfer the sample to a wide-mouth 250 ml conical flask attached to a reflux condenser using a suitable glass joint. Add 35 ml of dilute methanol (3 to 5), mix gently, and ensure complete wetting of the solid. Add 3 drops of phenolphthalein TS, and neutralize by adding 0.2 N hydrochloric acid or 0.2 N sodium hydroxide as necessary. Add 25.0 ml of 0.2 N sodium hydroxide VS, and reflux gently on a hot plate for 1 hour. Wash the condenser with 10 ml of water, collect the washing liquid in the flask, cool, and titrate with 0.2 N hydrochloric acid VS. At the same time, perform a blank determination in the same manner using the same amount of 0.2 N sodium hydroxide VS.

[0027] Calculation of saponification value: Calculate the saponification value. Result = [(V B - V S ) × N × M r / W V B = Volume of 0.2 N hydrochloric acid consumed in the blank titration VS (ml) V S = Volume of 0.2 N hydrochloric acid VS consumed in the titration of the sample solution (ml) N = Actual normality of hydrochloric acid VS M r = Molecular weight of potassium hydroxide, 56.11 W = Weight of polyvinyl alcohol used (g)

[0028] Calculation of degree of hydrolysis: Calculate the degree of hydrolysis expressed as the degree of hydrolysis of polyvinyl acetate. Result = 100 - [7.84 × S / (100 - 0.075 × S)) S = Saponification value of polyvinyl alcohol

[0029] The use of the PVA grades according to the invention is interesting for the formulation of solid oral pharmaceutical dosage forms with immediate, prompt or prolonged API release. Preferred PVAs have a degree of hydrolysis of 70% to 90% and a viscosity of the 4% solution at 20 °C of 3 mPas to 5 mPas, more preferably a viscosity of the 4% solution at 20 °C of 3 mPas to 4 mPas, and most preferably a viscosity of the 4% solution at 20 °C of 4 mPas.

[0030] In a further aspect of the invention, the polyvinyl alcohol has a degree of hydrolysis of 70% to 90%, preferably 80% to 90%, and a viscosity as mentioned above. In a further aspect of the invention, the polyvinyl alcohol has a degree of hydrolysis of 80% to 90% and a viscosity of the 4% solution at 20 °C of 3 mPas, or a degree of hydrolysis of 80% to 90% and a viscosity of the 4% solution at 20 °C of 4 mPas.

[0031] In a further aspect 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. In a further aspect of the invention, the polyvinyl alcohol is PVA3-82, PVA4-88, or PVA5-74, more preferably PVA3-82, or PVA4-88, most preferably PVA3-82.

[0032] The aspects as mentioned above for the API and / or the PVA grades are equally applicable to the use of polyvinyl alcohol in a process for selective laser sintering of sintered powders, a process for the production of 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 as mentioned above.

[0033] A further aspect of the invention is a sintering powder for selective laser sintering comprising at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

[0034] For the avoidance of doubt, the process according to the invention encompasses selective laser sintering with any of the PVAs, PVA specifications, or PVA grades as defined below.

[0035] In a further aspect of the invention, the sintering 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.

[0036] Depending on the wavelength of the light emitted by the laser, a light absorbing material (pigment) that absorbs the light of the emitted wavelength may be required. These light absorbing materials can include transition metals that absorb at about 450 nm or a broader range of carbon that covers the visible and near infrared ranges. Light absorption is the process of absorbing light and converting it into energy. When light is absorbed, heat is generated. Thus, selective absorption of light by a particular substance occurs because the frequency of the light wave matches the frequency at which the electrons in the atoms of that substance vibrate.

[0037] The light absorbing materials are all materials suitable for the SLS process as described above and are materials known to those skilled in the art. Preferably, a light absorbing material that has been demonstrated to function with laser irradiation at 455 nm is used, for example, Candurin NXT, Ruby Red, Candurin Gold, Sheen, Aluminum Lake, activated carbon (which also acts at 808 nm), or iron oxide (Fe2O3). More preferably, Ruby Red is used.

[0038] When a carbon dioxide laser emits at about 10 microns, the C-H bond absorbs energy at this wavelength, and since this type of bond is found in most polymers, usually no additional light-absorbing material needs to be added.

[0039] For the sake of avoiding misunderstanding, it should be noted that for the beneficial properties according to the present invention, no further pharmaceutically acceptable excipients as defined above are necessary. However, these excipients can also be used for other purposes, such as, for example, to optimize the manufacturing process of the pharmaceutical composition or oral dosage form according to the present invention.

[0040] Furthermore, the pharmaceutical composition according to the present invention may contain additional pharmaceutically acceptable hydrophilic or lipophilic polymers. In a preferred embodiment, the sintered powder further contains a light-absorbing material.

[0041] 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, and absorption delaying agents, etc., which do not produce allergic reactions or similar troublesome reactions when administered to humans. The use of such materials in pharmaceutical compositions is well known in the art.

[0042] 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.

[0043] In a preferred embodiment, the PVA has a D50 of 200 μm or less. Preferably, the particle size (D50) of the PVA is between 20 μm and 200 μm, between 20 μm and 150 μm, or between 20 μm and 100 μm.

[0044] In a further preferred embodiment, the particle size of the PVA has a D90 of 250 μm or less. Preferably, the particle size (D90) of the PVA is between 100 μm and 250 μm, more preferably between 140 μm and 220 μm.

[0045] A further aspect of the invention is a method 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 polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas, and (b) operating a selective laser sintering apparatus to produce a pharmaceutical dosage form by selectively fusing a layer of the sintered powder. The method comprises the above.

[0046] For the avoidance of doubt, the process according to the invention comprises selective laser sintering with any of the PVAs, PVA specifications or PVA grades defined below.

[0047] 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 sintered powder as described above.

[0048] In a further aspect, a pharmaceutical dosage form is produced by selective laser sintering of a sintered powder, wherein the sintered powder comprises at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

[0049] For the avoidance of doubt, the pharmaceutical dosage forms according to the invention include pharmaceutical dosage forms having any of the PVAs, PVA specifications or PVA grades defined below.

[0050] The API is a biologically active agent. The API may be a small molecule in the form of a weak base, a weak acid, or a neutral molecule, and may also be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. The sintered powder and pharmaceutical dosage form may contain multiple APIs. In one aspect, the API is a poorly soluble or lipophilic API.

[0051] As used herein, the terms "poorly soluble API", "poorly water-soluble API", and "lipophilic API" refer to an API having a solubility such that the maximum therapeutic dose of a particular API administered to an individual cannot be dissolved in 250 ml of an aqueous medium in the pH range of 1 to 8, in accordance with the definition of low solubility according to the Biopharmaceutics Classification System (BCS) classes 2 and 4. Poorly soluble APIs with weak basic or weak acidic properties 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.

[0052] 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) that is not completely ionized in water. At least one active pharmaceutical ingredient (API) according to the present invention may be dispersed in polyvinyl alcohol to form an amorphous solid dispersion.

[0053] A further aspect of the present invention is the use of polyvinyl alcohol in a process for selective laser sintering of a sintered powder for producing a pharmaceutical dosage form, wherein an amorphous solid dispersion of at least one active pharmaceutical ingredient is formed in polyvinyl alcohol, and the polyvinyl alcohol has a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20°C of 3 mPas to 8 mPas.

[0054] 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, formulations containing amorphous solid dispersions can achieve higher solubility in aqueous media than crystalline APIs.

[0055] The APIs included in the pharmaceutical dosage forms of the present invention are present in a sufficient amount to be therapeutically effective. For specific APIs, therapeutically effective amounts are generally known or readily available to those skilled in the art. Typically, the API may be present in the pharmaceutical dosage form at a weight ratio of API to polyvinyl alcohol from 0.1:99.1 to 60:40, preferably from 1:99 to 50:50, more preferably from 5:95 to 40:60, and most preferably from 10:90 to 30:70.

[0056] When PVA having a degree of hydrolysis and viscosity within the ranges as mentioned above is used in the process for selective laser sintering of sinterable powders to form a pharmaceutical dosage form containing an active pharmaceutical ingredient, it has been found to exhibit surprisingly excellent performance compared to PVA outside the ranges as mentioned above.

[0057] Selective laser sintering of sinterable powders containing an active pharmaceutical ingredient and PVA of the viscosity and degree of hydrolysis confirmed above · results in faster and higher API release, and · improved amorphization of the API, has unexpectedly been found to lead to obtaining a pharmaceutical dosage form showing

[0058] Improved amorphization of pharmaceutical dosage forms produced by SLS printing with PVA having a degree of hydrolysis and viscosity within the ranges as mentioned above is seen when powder X-ray diffraction (PXRD) data and / or differential scanning calorimetry (DSC) data are compared with those of pharmaceutical dosage forms produced by SLS printing with PVA having a degree of hydrolysis and viscosity outside the ranges as mentioned above under the same process conditions. Preferred PVA is polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of 4% solution at 20 °C of 3 mPas to 8 mPas, more preferably polyvinyl alcohol having a degree of hydrolysis of 80% to 90% and a viscosity of 4% solution at 20 °C of 3 mPas to 4 mPas. Preferred PVA grades are PVA3-80, PVA3-82, PVA4-88, or PVA5-74. The best amorphization results have been demonstrated by PVA4-88 and PVA3-82, preferably PVA4-88.

[0059] Furthermore, PVA having a viscosity and hydrolysis grade as mentioned above guarantees and stabilizes the release and supersaturation of APIs, especially poorly soluble APIs, in an aqueous medium, thereby preventing crystallization and phase separation. Generally, the low water solubility of APIs is associated with low bioavailability after administration of pharmaceutical formulations. Therefore, the compositions according to the present invention also contribute to the improvement of the bioavailability of poorly soluble APIs, especially weakly basic APIs.

[0060] It has been shown that pharmaceutical dosage forms produced by SLS printing with PVA having a degree of hydrolysis and viscosity within the ranges as mentioned above have significantly faster and more pronounced API release. Dissolution experiments have proven that the PVA grades of the present invention, such as PVA3-82, PVA5-74, and PVA4-88, are particularly suitable as polymers for that purpose. PVA3-82 has the highest API release compared to other PVA grades (Figure 23) and provides improved solubility compared to crystalline indomethacin. This is particularly surprising because the results could not be predicted from the PXRD and / or DSC data.

[0061] Furthermore, PVA having the viscosity and hydrolysis grades as mentioned above has improved surface quality due to a smooth surface finish as seen by the scanning electron microscope (SEM) method. They differ in surface area measurable by BET (gas adsorption), tablet hardness and porosity measurable by μCT measurement.

[0062] PVA having the viscosity and hydrolysis grades as described above further shows improved API stability. As used herein, "bioavailability" is a term that means how available the API becomes to the target tissue after being administered into the patient's body.

[0063] After dissolving the pharmaceutical dosage form of the present invention, improved supersaturation is observed and the API is better retained in the solution. Furthermore, it may be better to incorporate the API into the PVA matrix during the sintering process.

[0064] When entering the gastrointestinal tract, the pharmaceutical dosage form swells and disintegrates in the aqueous environment of the gastrointestinal fluid, 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 the more neutral intestinal fluid where the free base form of the API has a significantly lower equilibrium concentration. PVA according to the present invention maintains an improved API concentration in model solutions simulating acidic and neutral gastrointestinal solutions compared to commonly used PVA. Therefore, the pharmaceutical dosage form according to the present invention has the potential to provide improved bioavailability of poorly soluble APIs. In the presence of the PVA grade according to the present invention, the API in a form with improved solubility provides a concentration of API in gastric juice or simulated gastric juice that is greater than the concentration of API provided in the presence of commonly used PVA grades.

[0065] Examples Example 1: SLS printing with PVA4 - 88 Preparation of powder formulations Powder formulations filled with indomethacin were prepared according to Table 1. 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 flowability of the powder during the layer - by - layer coating process, respectively. As the polyvinyl alcohol, PVA4 - 88Parteck® MXP (Merck KGaA) was used. The formulations were prepared in batches (about 1500 mL) in sufficient amounts to partially fill the build volume (100x100x100 mm) of a Sintratec Kit SLS 3D printer (Sintratec, Brugg, Switzerland).

[0066] Table 1. Composition of the prepared powder formulations

Table 1

[0067] 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 with Sintratec software using the process parameters shown in Table 2. The energy density was calculated according to the following formula.

Number

[0068] P - Laser power (2.3 W), HS - Hatching space (0.05 mm), V - Scan speed (mm / s), α - Absorption rate of powder (Absorption rate at 455 nm needs to be measured / calculated for each powder type).

[0069] Table 2. Process parameters used for each formulation

Table 2

[0070] Figure 1 shows a schematic diagram and 3D model of the tablet (4x9.5 mm).

[0071] The 3D printing process was further carried out as follows. The prepared powder formulation (Table 1) was placed and packed into the powder reservoir platform (100x100x100 mm) of the SLS 3D printer. Then, after spreading a thin layer of the formulation on the build platform, the powder bed was slowly heated to the temperature specified in Table 2. The sintering process was performed layer by layer using a 2.3 W diode (λ = 455 nm) according to the model described in the STL file. Using a layer height of 125 μm, a total of 36 tablets were printed batch by batch according to the build platform. Specific values of the laser scan speed were selected when printing different batches, and each speed was used at three different printing bed temperatures. The completed batches were sieved from the build platform and recovered 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.

[0072] Characterization of Powder Formulations and 3D Printed Dosage Forms Powder X-ray diffraction (PXRD) diffractograms of neat and heat-treated powder formulations, as well as printed dosage forms, were recorded using Cu-Kα 1,2Collected on a Bruker D8 Advance TwinTwin diffractometer (Bremen, Germany) using radiation with λ = 0.5418 Å. The instrument was operated at 40 mA and 40 kV, with a step size of 0.02° and a data collection time of 1 hour. Differential scanning calorimetry (DSC) thermograms were obtained using a Mettler Toledo DSC 3+ (Schwerzenbach, Switzerland), with a heating / 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). Friability tests were 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 rotations. The tablets were carefully weighed before and after the measurement, and the total weight loss of the tablets (i.e., friability) was calculated.

[0073] Figure 2 shows the process parameters and properties of the 3D printed dosage forms. For the batch printed at 75 °C and 300 mm / s, a small amount of crystalline API remains, while at 200 mm / s, the result is a completely amorphous API. In the figure, PVA4-88 is called Parteck MXP.

[0074] Figure 3 shows the DSC thermogram of the batch printed at 75 °C using PVA4-88. Figure 4 shows the diffraction patterns of the batch printed at 75 °C using PVA4-88 and indomethacin (the numbers in parentheses reflect the batch numbers). For batches printed at 100 °C and 300 mm / s and 400 mm / s, a small amount of crystalline API remains, while at 200 mm / s, the result is a completely amorphous API.

[0075] Figure 5 shows the DSC thermogram of a batch printed at 100 °C using PVA4-88. Figure 6 shows the diffraction patterns of a batch printed at 100 °C using PVA4-88 and indomethacin (the numbers in parentheses reflect the batch number). For batches printed at 125 °C and 400 mm / s, a small amount of crystalline API remains, while at 200 mm / s and 300 mm / s, the result is a completely amorphous API.

[0076] Figure 7 shows the DSC thermogram of a batch printed at 125 °C using PVA4-88. Figure 8 shows the diffraction patterns of a batch printed at 125 °C using PVA4-88 and indomethacin (the numbers in parentheses reflect the batch number).

[0077] Example 2: SLS printing with PVA3-82 The preparation of the powder formulation was carried out according to Example 1. As the polyvinyl alcohol, PVA3-82 was used. Selective laser sintering 3D printing of the dosage form was carried out according to Example 1. In Example 2, a layer height of 150 μm was used.

[0078] Characterization of the powder formulation and the 3D-printed dosage form The method for characterizing the powder formulation and the 3D-printed dosage form was carried out as described in Example 1.

[0079] Figure 9 shows the process parameters and characteristics of the 3D-printed dosage form. For batches printed at 75 °C and 300 mm / s, a small amount of crystalline API remains, while at 200 mm / s, the result is a completely amorphous API. In the figure, PVA3-82 is referred to as Polymer 1.

[0080] Figure 10 shows the DSC thermogram of the batch printed at 75 °C using PVA3-82. Figure 11 shows the diffraction patterns of the batch printed at 75 °C using PVA3-82 and indomethacin (the numbers in parentheses reflect the batch numbers). For the batches printed at 100 °C and 300 mm / s and 400 mm / s, a trace amount of crystalline API remains, while at 200 mm / s, the result is a completely amorphous API.

[0081] Figure 12 shows the DSC thermogram of the batch printed at 100 °C using PVA3-82. Figure 13 shows the diffraction patterns of the batch printed at 100 °C using PVA3-82 and indomethacin (the numbers in parentheses reflect the batch numbers). For the batch printed at 125 °C and 400 mm / s, a trace amount of crystalline API remains, while at 200 mm / s and 300 mm / s, the result is a completely amorphous API.

[0082] Figure 14 shows the DSC thermogram of the batch printed at 125 °C using PVA3-82. Figure 15 shows the diffraction patterns of the batch printed at 125 °C using PVA3-82 and indomethacin (the numbers in parentheses reflect the batch numbers).

[0083] Example 3: SLS printing with PVA5-74 The preparation of the powder formulation was carried out according to Example 1. As the polyvinyl alcohol, PVA5-74 was used. Selective laser sintering 3D printing of the dosage form was carried out according to Example 1. In Example 3, a layer height of 150 μm was used.

[0084] Characterization of the powder formulation and the 3D printed dosage form The method for characterizing the powder formulation and the 3D printed dosage form was carried out as described in Example 1.

[0085] Figure 16 shows the process parameters and properties of the 3D printed dosage form. A small amount of crystalline API remained in the batch printed at 75 °C and 200 mm / s. In the figure, PVA5-74 is referred to as Polymer 2.

[0086] Figure 17 shows the DSC thermogram for the batch printed at 75 °C and 200 mm / s using PVA5-74. Figure 18 shows the diffraction patterns of the batch printed at 75 °C using PVA5-74 and indomethacin.

[0087] A small amount of crystalline API remained in all batches printed at 100 °C. However, for the batches printed at 300 mm / s and 400 mm / s, the results of DSC and XRD do not match. The size of the API peak in DSC does not correspond to the number of API characteristic peaks in the XRD results.

[0088] Figure 19 shows the DSC thermogram of the batch printed at 100 °C using PVA5-74. Figure 20 shows the diffraction patterns of the batch printed at 100 °C using PVA5-74 and indomethacin (the numbers in parentheses reflect the batch numbers).

[0089] A small amount of crystalline API remains in the batch printed at 125 °C and 400 mm / s, while there is no trace of API crystallization at 200 mm / s. According to DSC, there is no trace of API crystallization for the batch printed at 300 mm / s. However, there is one small peak in the XRD results of the batch printed at 300 mm / s, which may indicate a certain degree of crystallinity.

[0090] Figure 21 shows the DSC thermogram of the batch printed at 125 °C using PVA5-74. Figure 22 shows the diffraction patterns of the batch printed at 125 °C using PVA5-74 and indomethacin (the numbers in parentheses reflect the batch numbers).

[0091] Example 4: Dissolution Test Preparation of Powder Formulations PVA3-82 and PVA5-74 were prepared in various formulations for selective laser sintering (SLS) together with PVA4-88, Kollidon VA64 (registered trademark), and Plasdone (trademark) S-630. Each polymer was prepared in a formulation of 88.5% polymer, 1% pigment, 0.5% silicon dioxide, and 10% indomethacin by weight calculation. The formulations were weighed using a 315 μm stainless steel test sieve (VWR International AB, Stockholm, Sweden) and prepared by manual mixing and sieving. The sieved formulations were remixed for 20 minutes using a Turbula shaker (Turbula T2F shaker, Glen Mills, Inc., Clifton, NJ, US). Pigment and colloidal silica 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. Next, the mixed powder was heat-treated overnight at 70 °C using a thermostat (Incucell (registered trademark), BMT Medical Technology s.r.o., Brno, Czech Republic) and remixed using a Turbula shaker.

[0092] Selective Laser Sintering 3D Printing of Dosage Forms Before printing, the tablets were created in Fusion 360 (Student Edition, Autodesk, USA) and then uploaded as STL files to Sintratec Central 1.2.7 (Sintratec AG, Brugg, Switzerland). A batch of 36 tablets was created and placed in the printing chamber. Next, for all formulations, parameters of a 50 μm peripheral offset, 50 μm hatching space, 150 μm hatching offset, and three peripheral passes were set. Sintering was performed layer by layer using a 2.3 W diode (λ = 455 nm) according to the template model described in the STL file. The tablets were printed flat onto the build platform using a layer height of 150 μm for Kollidon VA64® and 125 μm for all other polymers. Specific values of the laser scan speed were selected when printing different batches, and each speed was used at three different printing temperatures. Batches made with PVA3-82, PVA5-74, and PVA4-88 were printed at 75, 100, and 125 °C, and batches made with Kollidon VA64® and Plasdone™ S-630 were printed at 75, 100, and 112.5 °C. For the laser scan speed, three speeds of 200, 300, and 400 mm / s were selected. The completed batches were recovered from the build platform by sieving at the end of the printing process. In addition, the tablets were dusted using pressurized air to remove excess powder and stored in airtight containers for further analysis.

[0093] Dissolution test The dissolution test was performed using a Sotax AT7 Smart Dissolution Tester (Aesch, Switzerland). The in vitro drug release profiles for 3D printed tablets (n = 3) were carried out in 500 mL of simulated gastric fluid (SGF: 800 ml 1M HCl, 20 g NaCl ad 10 L, pH 1.2.) at 37 ± 0.5 °C and 50 rpm using weights to measure the weight of the tablets. The drug concentration in the dissolution medium was determined by high performance liquid chromatography (HPLC) (Agilent 1260 Infinity II, Agilent Technologies, Inc., Santa Clara, USA) on 10 μL of filtered samples (0.45 μm PTFE filter, VWR International GmbH). The HPLC assay was run using a mobile phase composition of acetonitrile and phosphate buffer in a 1:1 ratio (0.01M NaH2PO*H2O 1.38 g / L + 0.01M Na2HPO4 1.41 g / L). Samples were injected onto a Supelcosil LC-18 column (30 x 4 mm, 5 μm) at a flow rate of 1 mL min -1 , and 40 °C, and the eluent was analyzed at 254 nm. These dissolution tests were performed on batches of each polymer with the best properties in terms of weight distribution, PXRD, DSC, and friability. For PVA3-82, PVA5-74, and PVA4-88, these are printed batches at 125 °C and 200 mm / s. For Kollidon VA64® and Plasdone™ S-630, these are printed batches at 112.5 °C and 200 mm / s.

[0094] Figure 23 shows the dissolution results for the best batches of each formulation drug loading test.

Claims

1. Use of polyvinyl alcohol in a process for selective laser sintering of a sintering powder for forming a pharmaceutical dosage form, wherein the sintering powder comprises at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

2. The use according to claim 1, wherein 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 to 4 mPas.

3. The use according to claim 1 or 2, wherein the polyvinyl alcohol is PVA3-80, PVA3-82, PVA4-88, or PVA5-74.

4. The use according to any one of claims 1 to 3, wherein the sintering powder further comprises at least one light-absorbing material.

5. A process for producing a pharmaceutical dosage form by selective laser sintering of a sintering powder, comprising the following steps: (a) providing a sintering powder comprising at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas, and (b) operating a selective laser sintering apparatus to produce a pharmaceutical dosage form by selectively fusing a layer of the sintering powder.

6. The process according to claim 5, wherein 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 to 4 mPas.

7. The process according to claim 5 or 6, wherein the sintering powder further comprises at least one light-absorbing material.

8. The process according to any one of claims 5 to 7, wherein the sintering powder has a D50 of 200 μm or less.

9. A sintering powder for selective laser sintering, comprising at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

10. The sintering powder according to claim 9, wherein 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 to 4 mPas.

11. The sintering powder according to claim 9 or 10, further comprising at least one light-absorbing material.

12. ​ A pharmaceutical dosage form obtainable by the process according to any one of claims 5 to 8.

13. A pharmaceutical dosage form produced by selective laser sintering of a sinterable powder, wherein the sinterable powder comprises at least one active pharmaceutical ingredient and polyvinyl alcohol having a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution at 20 °C of 3 mPas to 8 mPas.

14. The pharmaceutical dosage form according to claim 13, wherein 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 to 4 mPas.

15. The pharmaceutical dosage form according to claim 13 or 14, wherein the sinterable powder further comprises at least one light-absorbing material.

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