Preparation process of 3D printed medicines

Abstract

The present invention relates to a method for producing 3D printed pharmaceutical products.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 332,397, filed April 19, 2022, which is incorporated herein in its entirety. [Technical field]

[0002] The present invention relates to a method for producing 3D printed pharmaceutical products and the resulting products. [Background technology]

[0003] Three-dimensional (3D) printing is becoming an attractive technology for the design and development of personalized dosage forms with improved palatability. As an evolving technology, three-dimensional (3D) printing has attracted significant attention in various medical fields, especially in drug delivery, such as solid dosage forms (Scoutaris et al., 2018), films (Hafezi et al., 2019), and microneedles (Pere et al., 2018). Over the past decade, numerous research papers have been published utilizing 3D deposition to design and print novel drug delivery systems (Goyanes et al., 2015b; Scoutaris et al., 2016; Trenfield et al., 2018; Zhu et al., 2020). These studies have shown that by adjusting the tablet design and the selection of pharmaceutical-grade polymers suitable for 3D printing, drug release can be tailored to the needs of individual patients. Widely used 3D printing techniques include fused deposition modeling (FDM), selective laser sintering (SLS), stereolithography, inkjet printing, etc. Most of the 3D printing techniques are compatible with pharmaceutical grade polymers, making 3D printing an attractive and alternative approach for the production of solid dosage forms, especially in personalized medicine.

[0004] The advantage of FDM technology compared to other 3D printing techniques is its compatibility with most pharmaceutical grade polymers, such as hydroxypropyl methylcellulose (Kadry et al., 2018), hydroxypropyl methylcellulose acetate succinate (Goyanes et al., 2017), ethylcellulose (Yang et al., 2018), and hydroxypropyl cellulose (Chai et al., 2017). FDM has proven to be a versatile 3D printing technique in the construction of personalized medicine. Using this technique, uniquely designed tablets with modified drug release profiles have been printed (Goyanes et al., 2015a; Jamroz et al., 2018). Polypills (Pereira et al., 2019) and bilayer solid dosage forms (Ghanizadeh Tabriz et al., 2020; Gioumouxouzis et al., 2018) have also been printed using FDM to improve patient compliance (Castellano et al., 2014). SLS has also been applied in the manufacture of solid dosage forms. Fina et al. investigated the printability of several pharmaceutical grade polymers such as Eudragit, oxidized polyethylene and ethylcellulose using SLS technology (Fina et al., 2018, 2017). Wang et al. investigated the suitability of SLS technology in the production of PEGDA / paracetamol tablets (Wang et al., 2016).

[0005] Martinez et al. showed that SLS can be used to produce drug-loaded tablets with modified release by modifying the tablet shape (Martinez et al., 2018). Inkjet printing has also shown potential in the production of solid dosage forms, albeit with a limited selection of compatible polymers. A study by Kyobula et al. (Kyobula et al., 2017). Summary of the Invention

[0006] This application relates to microextrusion-based printing for pharmaceutical manufacturing. In an embodiment, this application relates to 3D printed tablets, such as pediatric ibuprofen (IBU) chewable tablets. This application further relates to microextrusion-based 3D printing of tablets by evaluating various potential polymer candidates, such as polymers that can mask taste and increase the dissolution rate of water-insoluble drugs. Printing formulations include drug / polymer powder blends or granules. Additionally, sweeteners and flavors can be included in the printing formulations to improve taste and swallowing experience. Due to the miscibility of drugs with polymers and the plasticizing effect of many active pharmaceutical ingredients (APIs), microextrusion is beneficial for processing taste-masked tablets, especially for pediatric dosage forms. Printed tablets can provide high quality prints with high print repeatability and smooth surface finish across the tablet surface. A microextrusion-based method is provided for processing powder blends containing active pharmaceutical ingredients for high speed printing and development of personalized dosage forms. This process allows the production of tablets with different designs and active drug dosages. [Brief description of the drawings]

[0007] [Figure 1] Figure 1: Schematic of the microextrusion printhead for tablet printing. [Diagram 2] Figure 2: TGA graphs of bulk EP, Soluplus, VA64 and ibuprofen. [Diagram 3] Figure 3: Optical images of 3D printed tablets based on 40% and 60% infill density. (a) Top and (b) side view of EPO / IBU tablet. (c) Top and (d) side view of Soluplus / IBU tablet. Top and (f) side view of VA64 / IBU tablet, pediatric design. [Figure 4] Figure 4: SEM images of 3D printed tablets of (a) EPO / IBU, (b) Soluplus / IBU, and (c) VA64 / IBU. [Diagram 5]Figure 5: XRD profiles of (a) plain EPO, Soluplus ibuprofen, (b) physical mixture of IBU / polymer formulation, and (c) 3D printed tablets. [Figure 6] Figure 6: DSC thermograms of bulk polymer and ibuprofen. [Figure 7] Figure 7: Raman spectra of bulk polymer, ibuprofen, and 3D printed ibuprofen / polymer tablets. [Figure 8] Figure 8: (a) Explained variance of each PC for Ibu-S (left) and Ibu-VA64 samples, (b) comparison of the spectra and first PC for IBU, SOL, and VA64, respectively, and (c) concentration of the chemical map of PC1 for Ibu-SOL and Ibu-VA64. [Figure 9] Figure 9: Dissolution rates of 3D printed tablets of (a) IBU-EPO, (b) IBU-VA64, and (c) IBU-SOL with different infill densities at pH 1.2 and pH 7.4, respectively. [Figure 10] Figure 10: (a) Dissolution profiles of IBU-EPO printed tablets with 2.5% and 7.4% Neusilin (pH 1.2). [Figure 11] Figure 11: Taste evaluation of ibuprofen, EPO, Soluplus, VA64 and 3D printed VA64 / IBU, SOL / IBU, EPI / IBU tablets. [Figure 12] Figure 12: Glass transition integrations of (a) Soluplus / IBU, (b) VA64 / IBU, and (c) EPO / IBU tablets. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The methods described herein can be used to prepare a wide variety of tablets, preferably 3D printed tablets containing an API selected from one or more of the following: astemizole, azelastine, azatadine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, phenidamine, pheniramine, phenyltoloxamine, promethazine. , pyrilamine, terfenadine, tripelennamine, triprolidine, acetyldihydrocodeine, benproperine, benzonate, benzylmorphine, bibenzonium bromide, butamirate, butorphanol, carbetapentane, chlophedianol, clobutinol, chlofedanol, cloperastine, codeine, dextromethorphan, dextromethorphan hydrobromide, diacetylmorphine, dibunate, dihydrocodeine, dimemorphan, dimethoxanate, diphenhydramine, dropropizine, droxypropine, ethylmorphine Ne, fedrylate, glaucine, hydrocodone, hydromorphone, isoaminyl, laudanum, levodropropizine, levomethadone, levopropoxyphene, meprothiol, methadone, morpholone, nepinalone, nicocodine, nicodicodine, normetadone, noscapine, oxeladin, oxolamine, pentoxyverine, pholcodine, pipazetate, piperidione, prenoxdiazine, tipepidine, zipeprol, acetylcysteine, althea root, ambroxol, antimony pentasulfide, bromhexine, carbocysteine, cineole , combination drugs, combination drugs, creosote, denbrexin hydrochloride, domiodol, dornase alfa, eprazinone, erdosteine, guaiacolsulfonic acid, guaifenesin, hedera helicis folium, ipecacuana, letosteine, levo-verbenone, mannitol, mesna, neltenexin, potassium iodide, senega, sobrerol, stepronin, tiopronin, tyloxapol, pseudoephedrine, cetirizine, loratadine, fexofenadine, diphenhydramine, levocetirizine, desloratadine, phenol, ethanol,Thymol, eucalyptol, ethanol, methyl salicylate, chlorhexidine gluconate, cetylpyridinium chloride, hexetidine, triclosan, hydrogen peroxide, domiphen bromide, bismuth subsalicylate, loperamide hydrochloride, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, dexlansoprazole, diphenoxylate, dicyclomine, loperamide, rifaximin, alosetron, cholestyramine, linaclotide, lubiprostone, polycarbof propyl, psyllium, alclometasone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, flucloron, fludrocortisone, fludroxycortide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, Fluperone, Fluticasone, Fluticasone Propionate, Fluprednidene, Formocortal, Halcinonide, Halometasone, Hydrocortisone Aceponate, Hydrocortisone Buteprate, Hydrocortisone Butyrate, Loteprednol, Medrysone, Meprednisone, Methylprednisolone, Methylprednisolone Aceponate, Mometasone Furoate, Paramethasone, Prednicarb, Prednisone, Prednisolone, Prednylidene, Rimexolone, Tixocortol, Triamcinolone, Urobetasol, 5-Fluorouracil, 5-Fluorodeoxyglucose Oxyuridine, capecitabine, calcium supplements, calcimimetics, cinacalcet, nicotine, nicotine polacrilex, bupropion, varenicline, disulfiram, calcium carbide, acamprosate, naltrexone, buprenorphine, methadone, levacetylmethadol, lofexidine, betahistine, cinaridin, flunarizine, acetylleucine, gangliosides, ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid, amifampridine, doxylamine, diphenhydramine hydrochloride,Melatonin, l-theanine, monofluorophosphate, lactoferrin, lysozyme, lactoperoxidase, glucose oxidase, mutanase, benzocaine, lidocaine, clove oil, sodium bicarbonate, citric acid, tartaric acid, aspirin, ibuprofen, aceclofenac, acemetacin, aloxiprine, azapropazone, benorylate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, facelamin, fenbufen, fenoprofen , flurbiprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, paracetamol, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylic acid, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, tolmetin, valdecoxib, acetylsalicylic acid, aloxiprine , aminophenazone, anilides, benolylate salts, benzomorphan derivatives, bezitramide, bucetin, buprenorphine, butorphanol, calcium carbasalate, choline salicylate, codeine, dextromoramide, dextropropoxyphene, dezocine, diamorphine, diflunisal, dihydrocodeine, dihydrocodone, dihydromorphine, diphenylpropylamine derivatives, dipyrocetyl, ethenzamide, fentanyl, floctafenine, flupirtine, glafenine, guacetisal, hydrocodone, hydrocodone bitartrate, hydrocodone lomorphone, hydromorphone hydrochloride, imidazole salicylate, ketobemidone, metamizole sodium, methadone, morphine derivatives, morphine, morphine sulfate pentahydrate, morphine-6-glucuronode, morpholine salicylate, nalbuphine, natural opium alkaloids, nefopam, nicomorphine, nifenazone, nonsteroidal anti-inflammatory drugs (NSAIDs), norhydrocodone, noroxycodone, opioids, opium, oripavine derivatives, oxycodeine, oxycodone, oxycodone hydrochloride, oxymorphone, papaveretam, pentazocine,Pethidine, phenacetin, phenazocine, phenazone, phenylpiperidine derivatives, piritramide, potassium salicylate, propacetamol, propyphenazone, pyrazolone, rimazolium, salicylamide, salicylic acid derivatives, salsalate, sodium salicylate, tapentadol, tilidine, tramadol, viminol, ziconotide, vitamin B12, cyanocobalamin, riboflavin, guarana, L-carnitine, vitamin A (retinol), B1 (thiamine), B2 (riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin) , C (ascorbic acid), D (cholecalciferol), E (tocopherol), F (linoleic acid), G, H (biotin), K, and choline, folic acid, inositol, niacin, pantothenic acid, para-aminobenzoic acid, terpenoids (such as carotenoid terpenoids and non-carotenoid terpenoids), resveratrol, phytosterols, anthraquinones, capsaicin, chlorophyll, betaine, oxalic acid, acetyl-L-carnitine, allantoin, androstenediol, androstenedione, betaine (trimethylglycine), pyruvate, and oleic acid. Calcium phosphate (pyruvic acid), carnitine, carnosine, carotene, carotenoids, choline, chlorogenic acid, cholic acid, chondroitin sulfate, cholestane, chrysin, coenzyme Q10, conjugated linoleic acid, corosolic acid, creatine, dehydroepiandrosterone, dichlorophene, diindolinone, dimethylglycine, dimercaptosuccinic acid, ebselen, ellagic acid, enzymes, fisetin, formononetin, glucaric acid (glucarate), glucosamine (HCl or sulfate), glucosamine (N-acetylglucosamine), glutathione, Ingredients include: hesperidin, hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-carbinol, inositol, isothiocyanates, linoleic acid-gamma, lipoic acid (alpha), melatonin, methylsulfonylmethane, naringin, pancreatin, paraaminobenzoic acid, parabens (methyl or propyl), phenols, phosphatidylcholine, phosphatidylserine, phytosterols, progesterone, pregnenolone, omega-3 fatty acids, quercetin, resveratrol, D-ribose, rutin, S-adenosylmethionine,Salicylic acid, sulforaphane, tartaric acid, taxifolin, tetrahydropalmatine, theophylline, theobromine, tigogenin, troxerutin, or mixtures or combinations thereof.

[0009] The methods described herein may employ ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate phthalate, polyurethane, silicone polycarbonate, polychloroprene, polyisobutylene, polycyanoacrylate, poly(vinyl acetate), polystyrene, polypropylene, poly(vinyl chloride), polyethylene, poly(methyl methacrylate), poly(hydroxyethyl methacrylate), copolymers of acrylic acid and butyl acrylate, copolymers of 2-ethylhexyl acrylate and butyl acrylate, copolymers of vinyl acetate and methyl acrylate, ethylene vinyl acetate and polyethylene terephthalate, ethylene vinyl acetate and polyethylene, polyethylene and polyethylene terephthalate, or mixtures or combinations thereof.

[0010] The methods described herein may employ polyacrylic acid, polyethylene oxide polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, polyisopropylacrylamide, polycyclopropylmethacrylamide, starch, sodium starch glycolate, (lactide-co-glycolide) polymer, aliginic acid, carrageenan chitosan, hyaluronic acid, pectinic acid, or mixtures or combinations thereof.

[0011] The methods described herein include PVP / VA 64, PVP K12, PVP K15, PVP K30, PVP K60, PVP K90, PVP K120, Prasodon S630, Prasodon C12, Prasodon C15, Prasodon C17, Prasodon C30, HPMC-AS M, HPMCAS-L, HPMCAS-LMP, HPMCAS-HMP, HPMCAS-MMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, HPMCAS-HF, HPMCAS-MF, HPMCAS-LF, Eudragit L100-55, Eudragit S100, Eudragit RLPO, Eudragit RSPO, Eudragit L100, Eudragit EPO, HPMC E15, HPMC E3, HPMC K100, HPMC 4M. Polymers such as HPMC 100 LV, HPMC 15 LV, HPMCP-HP55, PVA (polyvinyl alcohol), and Soluplus can be used.

[0012] Preferably, polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone VA64 (PVP-VA64), hydroxypropylcellulose L (HPC-L), hydroxypropylmethylcellulose E3 (HPMC E3), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), and polymethacrylate (Eudragit EPO) are useful for tablet formation.

[0013] A description of the above useful polymers can be found in Martin's physical pharmacy and pharmaceutical sciences: physical chemical and biopharmaceutical principles in the pharmaceutical sciences-6th Edition / Editor, Patrick J. Sinko (ISBN 978-0-7817-9766-5).

[0014] Sweeteners such as sucrose, sucralose, mannitol, xylitol, sorbitol, aspartame, accelerant-K, cyclamate, saccharin, or combinations thereof may be used in the methods described herein.

[0015] Flavors such as orange, strawberry, raspberry, lemon, vanilla, coffee, lime, caramel, toffee, chocolate, cherry, apple, grape, watermelon, and the like may be used in the methods described herein.

[0016] The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. All combinations of the preferred aspects and / or embodiments of the present invention described herein are encompassed by the present invention. Any and all embodiments of the present invention may be combined with any or all other embodiments to describe additional, more preferred embodiments. It is also to be understood that each individual element of a preferred embodiment is an independent preferred embodiment in itself. Furthermore, all elements of an embodiment are meant to be combined with all other elements from any embodiment to describe additional embodiments. EXAMPLES

[0017] material: Soluplus (SOL) and PVP VA-64 (VA64) were kindly provided by BASF (BASF-Germany). Eudragit EPO (EPO) was kindly provided by Evonik (Evonik-Germany). Ibuprofen (IBU) was purchased from Sigma Aldrich (Sigma Aldrich, UK). Strawberry flavour was purchased from Symrise Ltd. (Marlow, UK) and sucralose was purchased from Merck Life Science UK Limited (Dorset, UK).

[0018] Preparation of formulations: PVP-VA64, EPO or Soluplus were blended with ibuprofen in a ratio of 60 / 40 (w / w) using a Turbula shaker mixer (Glen Mills T2F Shaker / Mixer, USA) at 100 rpm for 10 minutes. Each blend was prepared into tablets using microextrusion technology.

[0019] Thermogravimetric analysis (TGA) The thermal stability of bulk polymer and ibuprofen was investigated using TGA technique (TGA Q5000 Thermal instruments, USA). 2-2.5 mg of polymer and drug samples were carefully weighed and placed in standard aluminum pans. The samples were heated from 25 °C to 500 °C at a rate of 10 °C / min. The extracted raw data was analyzed using TA Universal Analysis software (Universal Analysis 2000, version 4.5A, TA instruments, USA).

[0020] Differential Scanning Calorimetry (DSC) A differential scanning calorimeter (Mettler-Toledo 823e, Switzerland) was used to investigate the thermal behavior of the bulk material and the 3D-printed tablets and to examine the physical state of ibuprofen within the 3D-printed tablets. Portions of the bulk material and the 3D-printed tablets were weighed to approximately 2–2.5 mg, placed in 40 μL aluminum pans, and quickly crimped. The bulk polymer and 3D-printed samples were heated from 25 °C to 160 °C at a rate of 10 °C / min. Ibuprofen was heated from 25 °C to 120 °C at a rate of 10 °C / min. The extracted DSC thermograms of the bulk material and the 3D-printed tablets were analyzed with STARe Excellence Thermal Analysis Software (Mettler Toledo, Switzerland).

[0021] Designing and 3D Printing an Ibuprofen Tablet Tablet designs were constructed to investigate the microextrusion (printability) of various polymer / IBU formulations, as shown in Table 1. Tablets were designed in SolidWorks software (Dassault Systems, USA) and converted to (stereolithography) stl files. The tablets, both with the same diameter of 12 mm, had different heights (3 mm or 2.4 mm), and were sliced ​​with an infill density of 40% and 60%, respectively. The infill density was designed to result in a total weight of 250 mg containing 100 mg of ibuprofen. A Bio-X (Celink, Sweden) bioprinter with a pneumatic thermoplastic print head was used to 3D print the tablets. Approximately 3 grams of each blend was placed in a heatable metal reservoir and the tablets were printed with a 0.4 mm nozzle, 0.4 mm layer height, and a print speed of 5 mm / s.

[0022] The printing temperatures for IBU / VA64, IBU / EPO, and IBU / Soluplus were set at 120°C, 90°C, and 105°C, respectively. The pressures used for each formulation were set at 120 kPa, 110 kPa, and 90 kPa, and the build plate temperature was maintained at 15°C.

[0023] [Table 1]

[0024] A schematic of the tablet microextrusion process shows pressurized air pushing a metal plunger towards the physical blend in a reservoir, as shown in Figure 1. By adjusting the horizontal and vertical translation of the printhead, tablet designs with different densities were successfully produced.

[0025] Scanning Electron Microscope (SEM) The quality / layer height of the tablets printed by microextrusion was examined using a scanning electron microscope (Hitachi SU8030, Japan). The tablets were fixed to an aluminum stub with conductive carbon adhesive tape (Agar Scientific, Stansted, UK). The tablets were then observed under SEM and images were taken at 30x magnification with an electron beam accelerating voltage of 1KV.

[0026] X-ray powder diffraction (XRPD) The physical state of the plain polymer, ibuprofen, and 3D printed tablets (VA64 / IBU, EPO / BU, and Soluplus / IBU) was investigated by XRPD. XRPD data were collected using a D8 Advance X-ray diffractometer (Bruker AXS, Germany) equipped with a LynxEye silicon strip position sensitive detector and parallel beam optics. The diffractometer was operated in transmission geometry with Cu Kα radiation at 40 kV and 40 mA. The instrument was computer controlled using XRD Commander software (version 2.6.1, Bruker AXS, Germany) and the data were analyzed using EVA software (version 5.2.0.3, Bruker AXS, Germany). Samples were measured between 2.5 μm thick Mylar foils. Data were analyzed using a step size of 0.04 μm. O , 0.2 second count time per step, 5 to 60 O A range of 2θ was collected.

[0027] In vitro dissolution and HPLC analysis In vitro dissolution studies were performed to investigate the release of API in acidic and neutral media from 3D printed ibuprofen tablets. Drug release studies were performed using a Varian 705 DS (USA) dissolution bath equipped with a paddle apparatus. The experiments were performed at 37 ± 1 °C with 800 mL of phosphate buffered saline (PBS, pH 7.4) in each vessel, and the paddle rotation speed was set at 100 rpm. PBS was prepared using 1.44 g of disodium hydrogen phosphate, 0.24 g of potassium dihydrogen phosphate, and 8 g of sodium chloride (Barbero et al., 2016). At 15, 30, 60, 90, and 120 min intervals, 2 mL of sample medium was taken each time and the same amount of fresh PBS medium was also added to keep the volume of dissolution medium constant. The taken samples were filtered using a 0.45 mm disc filter and poured into high performance liquid chromatography vials for ibuprofen concentration analysis. The study was carried out using an Agilent 1200 series HPLC system equipped with a gradient elution system, an autosampler, a HICHROM S5ODS2-4889 (5 × 150 × 4 mm) column, and a UV detector set at a wavelength of 214 nm. Samples were eluted with a mobile phase consisting of acetonitrile:water:orthophosphoric acid (49.5:49.3:0.2 v / v) and delivered at a flow rate of 1.5 mL / min.

[0028] With these specifications, the column back pressure was approximately 115 bar with a retention time of 3 minutes. A calibration curve was also prepared by dissolving IBU in HPLC grade methanol at concentrations of 10, 20, 30, 40, and 50 μg / mL. All experiments were performed in triplicate using the same methodology described above.

[0029] Taste masking and sensory evaluation The in vivo taste masking study was first conducted on 10 healthy volunteers with informed consent (approved by the ethical committee of the University of Greenwich). This study also complied with the World Medical Association Code of Ethics (Declaration of Helsinki). Volunteers were selected from age groups (either gender) ranging from 18 to 30 years old. Volunteers were trained to orally test the bulk material and the 3D-printed tablet in their mouths for 2 minutes and promptly expectorate them. The material and tablet were not swallowed, and the mouth was immediately rinsed after the experiment. The bitterness of the bulk material and the 3D-printed tablet was recorded on an intensity scale of 1 to 5, with 1, 2, 3, 4, and 5 representing no bitterness, threshold, slight, moderate, and strong bitterness.

[0030] The sensory evaluation training included a detailed explanation of the approach, the proper use of the scale, and ensuring that the prepared samples had sweetness levels perceived as "sugar-free", "sweet", "very sweet" and "very sweet" compared to a reference sample (equivalent sample of sucrose). Similarly, strawberry aroma was rated with the attributes "sweet", "strawberry", "sour", "fruity" and "aftertaste" compared to natural stripped strawberry juice without the stem. The panel survey was conducted in accordance with the World Medical Association Code of Ethics (Declaration of Helsinki).

[0031] Raman spectra and mapping The ibuprofen-based samples and their excipients (or additives, excipients) were analyzed using a Horiba LabRam I microscope equipped with a frequency-doubled Nd:YAG laser (λ=532 nm) with a 50x long working objective. The spectra of IBU / EPO tablets and EPO polymer were recorded with 8 accumulations at 25% laser power and 1 s accumulation time. Meanwhile, the remaining spectra were recorded with 4 accumulations at 25% laser power and 2 s accumulation time. Finally, the spectra were acquired at 20 μm intervals and mapped over an area of ​​120x180 μm. The Raman mapping was performed for Ibuprofen-EPO and Ibu-SOL samples, covering an area of ​​160x120 μm2 by recording 20x20 spectra in the x and y axes. Meanwhile, for IBU-VA64, it was performed covering 33x25.

[0032] Spectra were first baseline corrected by the Asymmetric Least Squares (AsLS) method with parameters lambda = 105, p = 10-3 ((Eilers and Boelens, 2005; R Core Team, 2019; Wehrens et al., 2015)). Spectra were normalized using standard normal variates to correct for defocusing and scattering effects due to tablet surface anomalies. Subsequently, the matrix was decomposed into its most prevalent factors using principal component analysis. The analysis was carried out using the R programming language (R 4.03) (R Core Team 2019) and the ptw package to apply AsLS (Wehrens, Bloemberg, and Eilers 2015).

[0033] result Thermal Analysis of Bulk Materials To identify the appropriate microextrusion temperature, TGA analysis was performed to evaluate the thermal stability of IBU and bulk polymer (Figure 2). IBU was thermally stable even when heated up to 140 °C, above which the drug decomposed with a rapid weight loss.

[0034] Soluplus (SOL) showed a gradual weight loss of 4% up to 90°C due to moisture removal. It remained stable up to 260°C, above which the polymer decomposed. PVP VA64 (VA64) showed a slightly higher initial weight loss (5.5%) due to its higher moisture content, with no significant decomposition observed up to 260°C. Eudragit EPO (EPO) was stable with no weight loss up to 220°C, after which rapid weight loss was observed due to polymer decomposition.

[0035] DSC thermal analysis was also performed to evaluate the thermal properties of IBU and bulk polymers (Figure 5a). IBU, a crystalline solid, exhibited a sharp melting endotherm at 77.99 °C. The bulk polymers SOL, VA64, and EPO exhibited glass transition temperatures (Tg) of 66.33 °C, 107.10 °C, and 46.99 °C, respectively. The change in heat capacity at the glass transition temperature confirmed that the polymers were amorphous.

[0036] The operating temperature of microextrusion should be kept below the decomposition temperature of each component. Furthermore, to facilitate mixing of the drug with the polymer, the drug / polymer blend may be processed near the glass transition temperature of the polymer. Thus, the 3D printing initiation temperatures for IBU / SOL, IBU / VA64, and IBU / EPO powders were 62.0°C, 105.0°C, and 46°C, respectively.

[0037] Tablet Design and 3D Printing The blends were printed into tablets with the same 10 mm diameter and two infill densities (40% and 60%) to evaluate the printability and the effect of polymer type and filler density on drug release. The IBU / polymer ratio for all blends was 40 / 60 (w / w). Each tablet had a total weight of 250 mg and consisted of 100 mg IBU. Previous studies have shown that VA64, SOL, and EPO are not suitable for 3D printing using the Fusion Deposition Modelling (FDM) technique. The ductility of the polymers made it difficult to form filaments of the required diameter and length for subsequent 3D printing (Alhijjaj et al., 2016; Fuenmayor et al., 2018; Sadia et al., 2016). To improve printability, high levels of plasticizers (e.g., 20%–30%) must be added to the polymer, limiting the maximum loading of drug in the final tablet.

[0038] The main advantage of microextrusion technology is that it allows direct printing of drug / polymer blends without the need for a prior filament production step. With this method, drug / polymer blends in various ratios are melted or softened in a cartridge. The softened drug / polymer blend is then extruded through a nozzle by applying air pressure (200-700 kPa). The resulting thermoplastic filament can be directly printed into tablets. Compared to FDM and SLS, microextrusion technology can reduce the overall processing time of 3D printing and the waste of printing material. The latter is particularly beneficial in the production of personalized medicines containing expensive APIs (active pharmaceutical ingredients).

[0039] Tablets with both infill densities were produced with good reproducibility by the microextrusion 3D printing technique, as shown in Figure 3. SEM images of the printed tablets showed that the deposited layer thickness was consistent, indicating excellent print quality of the tablets (Figure 4).

[0040] The speed of 3D printing depends on the nozzle size, the print temperature, and the air pressure applied to the blend. In this study, a 0.4 mm nozzle was used at the specified print temperature and the air pressure was maintained at 90–120 kPa to achieve a print speed of approximately 5 mm / s. The print time for all three drug / polymer tablets was approximately 3 min. The build bed temperature was set to 10–40 °C to allow easy removal of the tablets.

[0041] Tablet Characteristics All three polymers used in this study are miscible with IBU at a drug level of 40% based on solubility parameters (δ) (Islam et al., 2015; Maniruzzaman et al., 2015). X-ray powder diffraction analysis was used to assess the physical state of IBU within the 3D printed tablets. As shown in Figure 6a, the XRPD patterns of the pure polymers (EPO, VA64, and SOL) showed broad halos indicating that all three polymers were in an amorphous state on their own. The IBU solids showed crystallinity with a δ of 5.8. O , 12.2 O , 16.1 O , 17.4 O , 18.5 O , 20.0 O , 22.2 O The characteristic diffraction peaks of IBU were observed at / 2θ. The characteristic XRD patterns of IBU were also observed in the physical blends of IBU (IBU / EPO, IBU / SOL, IBU / VA64), confirming that the drug remained as a crystalline solid before 3D printing. The characteristic diffraction peaks of IBU were not observed in the XRPD patterns of the 3D printed tablets, suggesting that IBU became amorphous after microextrusion (Figure 7c). The XRPD patterns of the 3D printed tablets were also collected after 1 week. It was confirmed that IBU remained in an amorphous state in the tablets stored at ambient conditions (25 °C, 40% RH).

[0042] Thermal analysis was also performed to investigate the physical state of IBU before and after 3D printing and possible drug-polymer interactions in the printed tablets. Bulk IBU exhibited a melting endotherm at 77.99 °C. Meanwhile, the glass transition (Tg) temperatures of SOL, VA64, and EPO were 63.86 °C, 107.10 °C, and 46.99 °C, respectively. No melting endotherm was observed for IBU upon heating the printed tablets. As shown in Figure 12, the thermograms of IBU / SOL, IBU / VA64, and IBU / EPO exhibited a single glass transition at 37.69 °C, 77.99 °C, and 15.35 °C, respectively. Both observations suggested that the crystalline IBU was completely dissolved in the polymer upon subsequent 3D printing with a drug loading of 40%. Amorphous IBU, with a glass transition temperature of -45.15 °C (Dudognon et al., 2008), acted as a plasticizer in the printed tablets, lowering the Tg (Gryczke et al., 2011; Islam et al., 2015; Maniruzzaman et al., 2012). Interestingly, the measured glass transition temperatures were higher than those predicted based on the Fox equation. The Fox equation is widely used to estimate the glass transition temperature of physical mixtures without interactions between the components. This discrepancy suggests that there are strong intramolecular interactions between IBU and the studied polymer.

[0043] Raman spectra and mapping The interaction of IBU with polymers was further investigated using Raman spectroscopy. The vibrational bands in the Raman spectrum of IBU are well reported in the recent literature (Breitenbach et al., 1999; Vueba et al., 2008). As shown in Figure 7, crystalline IBU is characterized by hydroxyl methyl and aromatic peaks. More specifically, at 637 cm -1 The peak at 746 cm represents the out-of-plane stretching of the C-O-H bond. -1 , 850cm -1 , 1609cm -1 , 3047cm -1The other peaks at 1181 cm correspond to out-of-plane deformation of the C-H bond, out-of-plane bending of the C-H bond, stretching of the C-C bond, and stretching of the C-H bond, respectively. -1 , 1452cm -1 , and 2965 cm -1 The peaks in are associated with the stretching of non-aromatic C-C bonds, the asymmetric deformation of CH3, and the asymmetric stretching of CH3 bonds, respectively. The same bands were observed in the Raman spectrum of the 3D-printed IBU / polymer tablets (Figure 7), but they were broadened compared to the IBU alone case.

[0044] As shown in Figure 7, when 3D printed with the polymer, the C=C vibration peak of the aryl group of IBU is at 1608 cm -1 From 1616cm -1 This suggests the possible presence of hydrogen bonds between IBU and the polymer (Hedoux et al., 2011). In addition, the spectrum of IBU alone shows a shift to 1652 cm -1 The C=O stretching vibration, which was previously observed, was 1734 cm in the spectrum of the printed tablet. -1 This suggests a strong drug-polymer interaction, similar to that observed in cyclodextrin molecular complexes (Bras et al., 2008). -1 and 663 cm -1 The out-of-plane bending of the CO-H of bulk IBU in the 3D-printed tablet is 605 cm -1 It was also observed that the solubility of the crystalline solids shifted to or disappeared completely (Vueba et al., 2008). This shift suggested a static and disordered molecular environment resulting from the formation of a glassy solution.

[0045] To investigate the spatial resolution of IBU in the printed tablets, Raman spectra were recorded continuously. PCA was applied to decompose the spectra into scores and loadings that approximately represent the initial spectra. The main advantage of PCA is that it is not necessary to use the spectra of the bulk compounds, which may change during the printing process due to molecular interactions. The number of principal components required to decompose a hyperspectral matrix is ​​usually determined by the analysis of eigenvalues, which represent the total variance captured by a given principal component. In simple systems, where only two compounds are well mixed, as in this case, two to three PCs are sufficient for resolution. In more complex systems, more PCs are used and it is not uncommon for compounds to be identified in much later components (Scoutaris et al., 2014). Figure 8a shows the cumulative variance corresponding to each PC. In the 3D printed sample of IBU-SOL, the PC (left) accounts for 99.4% of the total variance, whereas in Ibu-VA64, the PC (right) accounts for 96.7% of the total variance. In the former sample, the very high variance accounted for by PC is due to a very broad peak in the SOL spectrum that is indistinguishable from that of IBU.

[0046] Figure 8b presents a spectral overview of the PC and individual components of the tablet. It is clear that in the IBU-VA64 sample, the PC contains peaks corresponding to both API and polymer components. However, in the IBU-SOL sample, they could not be differentiated due to the presence of broad peaks. As shown in Figure 8c, the plot of the concentration map of the first PC of Ibu-SOL and Ibu-VA64 indicates that the compounds are uniformly distributed within the tablet. This is evidence of the strong intermolecular interactions between the drug and the polymer, and the molecular dispersion of IBU within the polymer matrix.

[0047] Dissolution Test Drug release can be modified by dispersing the drug in the polymer matrix at the molecular level after 3D printing of the drug / polymer blend (Douroumis et al., 2007; Islam et al., 2015; Maniruzzaman et al., 2015). The dissolution of IBU from 3D printed tablets was evaluated in both acidic (pH 1.2) and alkaline (pH 7.4) media to determine the effect of polymer type and infill density (40% and 60%) on drug release from the tablets. Eudragit EPO is a basic methacrylate copolymer that is typically practically insoluble above pH 5 (in saliva) but highly soluble in acidic media (in gastric juice), making it widely used in immediate release pharmaceuticals that require masking. As expected, IBU / EPO tablets showed slow dissolution at pH 7.4, even though IBU was dispersed in the polymer matrix at the molecular level (Fine-Shamir and Dahan, 2019; Gryczke et al., 2011). Tablets with an infill density of 40% showed ~15% drug release in 2 hours. On the other hand, tablets with an infill density of 60% showed ~10% drug release in the same period (Figure 9a). Slightly higher drug release from tablets with lower fill density was due to the larger surface area of ​​the tablets. IBU / EPO tablets dissolved rapidly at pH 1.2, with ~89% drug released within 15 minutes, resulting in a high degree of supersaturation. As EPO is a poor crystallization inhibitor, the IBU concentration in the dissolution medium dropped significantly after the initial drug release due to crystallization of IBU. PVP VA 64 is a neutral vinylpyrrolidone-vinyl acetate copolymer with good water solubility over a wide pH range. IBU is an acidic compound (pKa 4.6) and has low solubility at low pH. The release of IBU from 3D printed IBU / VA64 tablets was low at pH 1.2, with ~13% drug release observed in 2 h (Figure 9b). Sustained release of IBU from VA64 matrices with high drug loading at low pH 2 has also been observed previously (Tres et al., 2016).The authors concluded that VA64 preferentially dissolved from the outside of the printed tablets (compacts), forming a hydrophobic shell rich in amorphous IBU. This hydrophobic shell acts as an enteric coating in situ, inhibiting dissolution. At pH 7.4, IBU solubility was significantly higher, and IBU was released at a rate similar to that of the polymer. The compatibility of IBU with the polymer led to supersaturation of IBU. Furthermore, PVP VA64 inhibited the crystallization of IBU in solution, maintaining the supersaturation level throughout the dissolution study. IBU / VA64 tablets with a 40% fill density showed a slightly higher dissolution rate than tablets with a 60% fill density. This comparison reaffirms that a larger tablet surface area leads to a higher drug release rate.

[0048] Soluplus is a polymeric solubilizer that has been found in several cases to enhance drug release by enhancing drug-polymer interactions. However, as shown in Figure 9c, all IBU / SOL tablets showed slow dissolution at both pH 1.2 and pH 7.4. Pudlas et al. obtained similar observations for IBU / SOL extrusions and investigated the root cause using spectroscopic analysis. The slow release of IBU was attributed to the strong hydrogen bonds between IBU and VA64, which significantly reduced the hydrophilicity of the polymer by consuming a large amount of hydrophilic groups in the polymer chain. Meanwhile, drug release at pH 1.2 was the slowest due to the low solubility of IBU under acidic conditions. The effect of infill density on drug release was again observed; i.e., IBU / Sol tablets with a fill density of 40% showed slightly faster dissolution than those with a fill density of 60%. Overall, tablets with lower infill density showed higher dissolution rates due to their larger surface area. The effect of the polymer on the dissolution of the IBU / polymer tablet depends on the properties of the compound, the polymer, and their interaction.

[0049] Additionally, dissolution studies were performed on F4-F6 using sweeteners (e.g., xylitol or combinations) and inorganic excipients (magnesium aluminum metasilicate) in combination with IBU / EPO. The results (Figure 10) showed a rapid IBU dissolution rate within the first 5-10 minutes. The dissolution rate was influenced by the shape of the printed tablets (e.g., ring > banana > heart) due to differences in surface area.

[0050] Taste masking evaluation Pediatric medicines are subject to stricter regulations introduced by the European Medicines Agency (EMEA, 2007). Strickley et al. (2008) identified challenges in pediatric product development related to dose flexibility and taste masking. IBUs are known to have a bitter or salty taste, which necessitates taste masking in the final product that constitutes a pediatric IBU formulation. As shown in Figure 11, the taste of IBUs and 3D printed IBU / polymer tablets were evaluated by healthy panelists. The average score of IBUs was 4, confirming the bitter taste of the drug, while the bitterness scores of bulk polymers were below 2, within the acceptable range. All 3D printed IBU / polymer tablets had a bitterness score of 1 and were pleasant tasting. As previously reported, effective taste masking of bitter APIs is directly related to hydrogen bonding interactions between the drug and the polymer carrier (Gryczke et al., 2011; Maniruzzaman 2012). The effective taste masking of IBUs in chewable tablets demonstrated that microextrusion can be effectively used for 3D printing of personalized tablets for pediatric use.

[0051] This study demonstrated a simple microextrusion 3D printing technique that allows for reproducible printability suitable for 3D printing of tablets. Such a 3D printing technique can omit pre- and post-processing required by other 3D printing techniques. Furthermore, material waste can be minimized compared to other 3D printing techniques. As with other 3D printing techniques, microextrusion 3D printing can also be used to manufacture medicines with specific release profiles tailored to individual patients by selecting the polymer matrix and modifying the infill density of the tablet.

[0052] Due to the drug-polymer interactions induced during the printing process, ibuprofen (IBU) formed a glassy solution confirmed by differential scanning calorimetry (DSC), while hydrogen bonding interactions were confirmed by confocal Raman mapping. IBU was also found to be uniformly distributed within the polymer matrix at the molecular level. The palatability of the tablets was evaluated by panelists, revealing that the bitter taste of IBU was effectively taste-masked. Overall microextrusion demonstrated promising processing capabilities of the powder blends towards high speed printing and development of personalized dosage forms.

[0053] Sensory analysis of the 3D printed tablets showed an evolution in terms of sweetness intensity and strawberry / orange aroma. Several studies have shown that interactions between sweeteners and flavors can ultimately alter the potency of the sweetener. An important consideration in such studies is to identify the optimal ratios including the total concentration of sweetener / flavor in the dosage form. Here, the optimal ratios of sucrose / strawberry and aspartame / orange were found to be 0.9:1.1 wt / wt% and 1.0 / 1.5 wt / wt%. Meanwhile, several other ratios were also tested.

[0054] Tables 2-3 show that bulk sucralose and aspartame exhibited very high to extremely high sweetness intensity, respectively, and a very strong aftertaste. For the 3D printed tablets, subjects rated the sweetness intensity as reduced, and for both flavors, some subjects reported it as "moderately sweet," while most subjects reported it as "very sweet." For aftertaste, subjects rated the sweetness aftertaste as reduced compared to bulk sucralose and aspartame.

[0055] Similarly, in the strawberry and orange aroma evaluation of the bulk powder, subjects rated the strawberry / orange and fruity flavors as strong. Interestingly, the evaluation of the 3D tablet revealed strong sweetness, strawberry (or orange) and fruity intensity, with most subjects rating the aftertaste as strong. This result is related to the synergistic interaction of the sweetener with the flavor, where the total intensity of the mixture is greater than the intensity of the individual excipients. Furthermore, the flavor (strawberry / orange) and fruity sensations of the 3D tablet remained unaffected and strong despite the presence of other excipients in the formulation. Overall, the optimized sweetener / flavor ratio provided an excellent taste perception.

[0056] [Table 2]

[0057] [Table 3]

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Claims

1. A method for preparing 3D printed tablets, comprising the following steps: The steps include providing a microextrusion printhead having a heatable reservoir, a plunger, a printing nozzle, and optionally a heater; The steps include: filling the reservoir with a blend of one or more active pharmaceutical ingredients (APIs) and a polymer suitable for tablet preparation; The steps include: heating the blend of polymer and API to a temperature suitable for extrusion through the nozzle; The steps include applying pressure to the plunger to extrude the heated blend of polymer and API, and Methods that include...

2. The method according to claim 1, wherein the API-polymer powder blend or granules are partially melted or softened within a thermoplastic printhead.

3. The method according to claim 1, wherein an API-polymer powder blend or granules are printed at a temperature 30 to 60°C higher than the glass transition point or melting point of the polymer.

4. The method according to claim 1, wherein the polymer support further comprises a nonionic or ionic / pH-dependent polymer, a super-disintegrant, a sweetener, a flavoring, or a combination thereof.

5. The method according to claim 1, wherein the blend of polymer and API is heated to a temperature of about 50°C to about 200°C.

6. The method according to claim 1, wherein the API comprises 10 to 70%, most preferably 30 to 60%, of the API-polymer powder blend or granules.

7. The method according to claim 1, wherein the API-polymer powder blend or granules have a melt viscosity of 10 to 1500 Pa.s at the nozzle outlet.

8. The method according to claim 1, wherein the API-polymer powder blend or granules preferably have a suitable flowability index of 4 to 10 and a moldability index of 5 to 20.

9. The method according to claim 1, wherein the API-polymer powder blend or granules have a particle size (D50) of 50 to 1000 μm, most preferably 100 to 300 μm.

10. The method according to claim 1, wherein the API and polymer form a glass suspension (type IV or V) or glass solution when the solid dosage form is printed.

11. The active pharmaceutical ingredients are astemizole, azelastine, azatadine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, phenindamine, pheniramine, phenyltroxamine, promethazine, pyriramine, terfenadine, triperenamin, triprolidine, acetyldihydrocodeine, benproperine, benzonate, and be Dylmorphine, bibenzonium bromide, butamyrart, butorphanol, carbetapentane, clofedianol, clobutinol, clofedanol, cloperastine, codeine, dextromethorphan, dextromethorphan hydrobromide, diacetylmorphine, dibunate, dihydrocodeine, dimemorphan, dimethoxanate, diphenhydramine, dropropidine, droxypropine, ethylmorphine, phedrylate, glaucine, hydrocodone, hydromorphone, isoaminyl, laudanum, levodopropidine, levometadone Levopropoxifen, meproticol, methadone, molcrophone, nepinalone, nicocozin, nicodicozin, normethadone, noscapine, oxerazine, oxolamine, pentoxyverine, forcozin, pipezetate, piperidione, prenoxdiazine, tipepidine, dipeprole, acetylcysteine, Althaea root, ambroxol, antimony pentasulfide, bromhexine, carbocysteine, cineole, combination preparations, combination preparations, creosote, dembrexin hydrochloride, domiodur, dorunase alfa, eprazinon, erdosteine, g Iacol sulfonate, guaifenesin, Hederae helisis folium, Ipecaquanha, Retostein, Levo-verbenone, Mannitol, Mesna, Nertenexin, Potassium iodide, Senega, Sobrelol, Stepronin, Thiopronin, Tyroxapol, Pseudoephedrine, Cetirizine, Loratadine, Fexofenadine, Diphenhydramine, Levocetirizine, Desloratadine, Phenol, Ethanol, Thymol, Eucalyptol, Ethanol, Methyl salicylate, Chlorhexidine gluconate, Cetylpyridinium chloride,Hexetidine, triclosan, hydrogen peroxide, domiphen bromide, bismuth subsalicylate, loperamide hydrochloride, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, dexlansoprazole, diphenoxylate, dicyclomin, loperamide, rifaximin, alosetron, cholestyramine, linaclotide, lubiprostone, polycarbophil, psyllium, alclomethasone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, cucumber Lobetasol, clobetazone, crocortol, cloprednol, cortibazole, deflazacort, deoxycorticosterone, desonide / desoxymethasone, dexamethasone, diflorazone, diflucortol, difluprednate, flurolon, fludrocortisone, fludroxicortide, flumetazone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, flucortolone, fluorometholone, fluperolon, fluticasone, fluticasone propionate, flupredniden, formocortar, halcinonide, ha Lometasone, hydrocortisone aceponate, hydrocortisone buteplate, hydrocortisone butyrate, loteprednol, medrezon, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, parametasone, prednicarbart, prednisone, prednisolone, prednylidene, rimexolone, thixocortol, triamcinolone, urobetasol, 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, calcium supplements, calcimimetics, cinacalcet, nicotine, Nicotine polarilex, bupropion, varenicline, disulfiram, calcium carbide, acamprosate, naltrexone, buprenorphine, methadone, revacetyl methadol, lofexidine, betahistine, cynarinidine, flunarinidine, acetylleucine, ganglioside, ganglioside derivatives, tililazad, riluzole, xaliproden, hydroxybutyrate, amifampridine, doxylamine, diphenhydramine hydrochloride, melatonin, 1-theanine, monofluorophosphate, lactoferrin, lysozyme, lactoperoxidase,Glucose oxidase, mutanase, benzocaine, lidocaine, clove oil, sodium bicarbonate, citric acid, tartaric acid, aspirin, ibuprofen, aceclofenac, acemetacin, alloxiprine, azapropazon, benolilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faesalamine, fenbufen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen Meloxicam, meclofenamic acid, mefenamic acid, meloxicam, metamisole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimeslide, paracetamol, oxyfenbutazone, parecoxib, phenylbutazone, piroxicam, salicylate, sulindac, sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, tolmetin, valdecoxib, acetylsalicylic acid, alloxyprine, aminophenazone, anilide, benolilate, benzomorphan derivatives, vegitramide, busetin, bupu Lenorphine, Butorphanol, Calcium Carbasalate, Choline Salicylate, Codeine, Dextromoramide, Dextropropoxifen, Dezosin, Diamorphine, Diflunisal, Dihydrocodeine, Dihydrocodone, Dihydromorphine, Diphenylpropylamine Derivatives, Dipyrocetyl, Ethenzamide, Fentanyl, Flutaphenine, Flupirtin, Graphenine, Guacetisal, Hydrocodone, Hydrocodone Tartrate, Hydromorphone, Hydromorphone Hydrochloride, Imidazole Salicylate, Ketobemidone, Metamisole Sodium , methadone, morphinan derivatives, morphine, morphine sulfate pentahydrate, morphine-6-glucuronode, morpholin salicylate, nalbuffine, natural opioid alkaloids, nefopam, nicomorphine, niphenazone, nonsteroidal anti-inflammatory drugs (NSAIDs), norhydrocodone, noroxycodone, opioids, opium, olipavin derivatives, oxycodeine, oxycodone, oxycodone hydrochloride, oxymorphone, papaveretam, pentazocine, pethidine, phenacetin, phenazosin, phenazone, phenylpiperidine derivatives, pyritramide,Potassium salicylate, propacetamol, propifenazone, pyrazolone, limazolium, salicylamide, salicylic acid derivatives, salsalate, sodium salicylate, tapentadol, tyridine, tramadol, biminol, diconotide, vitamin B12, cyanocobalamin, riboflavin, guarana, L-carnitine, vitamin A (retinol), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B complex, vitamin B6 (pyridoxine), vitamin B12 (cobalamin), vitamin C (ascorbic acid), vitamin D (cholecal) Vitamins (Cypherol), Vitamin E (Tocopherol), Vitamin F (Linoleic Acid), Vitamin G, Vitamin H (Biotin), and Vitamin K, Choline, Folic Acid, Inositol, Niacin, Pantothenic Acid, Para-aminobenzoic Acid, Terpenoids (e.g., Carotenoid Terpenoids and Non-Carotenoid Terpenoids), Resveratrol, Phytosterols, Anthraquinones, Capsaicin, Chlorophyll, Betaine, Oxalic Acid, Acetyl-L-Carnitine, Allantoin, Androstenediol, Androstenedione, Betaine (Trimethylglycine), Calcium pyruvate (pyruvic acid), carnitine, carnosine, carotene, carotenoids, choline, chlorogenic acid, cholic acid, chondroitin sulfate, chondroitin sulfate, cholestane, chrysin, coenzyme Q10, conjugated linoleic acid, corosolic acid, creatine, dehydroepiandrosterone, dichlorophene, diindrimethane, dimethylglycine, dimercaptosuccinate, ebuselene, ellagic acid, enzymes, fisetin, formononetin, glucaric acid (glucarate), glucosamine (hydrochloride or sulfate), glucosamine (N-acetyl), g Lutathione, hesperidin, hydroxy-3-methylbutyrate, 5-hydroxytryptophan, indole-3-carbinol, inositol, isothiocyanate, gamma-linolenic acid, lipoic acid (alpha), melatonin, methylsulfonylmethane, naringin, pancreatin, para-aminobenzoic acid, parabens (methyl or propyl), phenols, phosphatidylcholine, phosphatidylserine, phytosterol, progesterone, pregnenolone, omega-3 fatty acids, quercetin, resveratrol, D-ribose, rutin, S-adenosylmethionine,The method according to claim 1, comprising salicylic acid, sulforaphane, tartaric acid, taxifolin, tetrahydropalmatine, theophylline, theobromine, tygogenin, troxerutin, or one or more mixtures or combinations thereof.

12. The method according to claim 1, wherein the tablet is chewable and has a masked taste.

13. The method according to claim 1, wherein the tablet is for pediatric use, is chewable, and is a taste-masked formulation.

14. The method according to claim 1, wherein the polymer is selected from ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate, polyurethane, silicone polycarbonate, polychloroprene, polyisobutylene, polycyanoacrylate, poly(vinyl acetate), polystyrene, polypropylene, poly(vinyl chloride), polyethylene, poly(methyl methacrylate), poly(hydroxyethyl methacrylate), acrylic acid and butyl copolymer of acrylic acid, copolymer of 2-ethylhexyl acrylate and butyl acrylate, copolymer of vinyl acetate and methyl acrylate, ethylene vinyl acetate and polyethylene terephthalate, ethylene vinyl acetate and polyethylene, polyethylene and polyethylene terephthalate, or mixtures or combinations thereof.

15. The method according to claim 1, wherein the polymer is selected from poly(acrylic acid), poly(ethylene oxide), poly(ethylene glycol), poly(vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(isopropylacrylamide), and poly(cyclopropyl methacrylamide), starch, sodium starch glycolate, (lactidoglycolide) polymer, alginic acid, carrageenan chitosan, hyaluronic acid, and pectic acid, or mixtures or combinations thereof.

16. The method according to claim 1, wherein the polymer is selected from Soluplus, PVP / VA 64, and Eudragit EPO.

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