Method of making 3-D printed pharmaceutical products

Abstract

The invention relates to a method for producing a 3-D printed pharmaceutical product.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application 63 / 332,397 filed on April 19, 2022, which is incorporated herein in its entirety. Technical Field

[0003] The present invention relates to methods for producing 3D printed pharmaceutical products and the resulting products. Background Art

[0004] Three-dimensional (3D) printing is emerging as an attractive technology for the design and development of personalized dosage forms with improved palatability. Three-dimensional (3D) printing is an evolving technology that has attracted considerable attention in various medical fields, especially in drug delivery, such as the fabrication of solid dosage forms (Sciutaris et al., 2018), membranes (Hafezi et al., 2019), and microneedles (Pere et al., 2018). Over the past decade, a large number of published studies have developed 3D additive applications for the design and printing of novel drug delivery systems (Goyanes et al., 2015b; Scutaris et al., 2016; Trenfield et al., 2018; Zhu et al., 2020). These studies have demonstrated that drug release can be customized to each specific patient need by adjusting tablet design and selecting compatible pharmaceutical-grade polymers for 3D printing. Widely used 3D printing technologies include fused deposition modeling (FDM), selective laser sintering (SLS), stereolithography, and inkjet printing. Most 3D printing technologies are compatible with pharmaceutical-grade polymers, which makes 3D printing an attractive and alternative method for manufacturing solid dosage forms, especially personalized medicines.

[0005] The advantage of FDM technology over other 3D printing technologies is that it is compatible with most pharmaceutical grade polymers such as hydroxypropylmethylcellulose (Kadry et al., 2018), hydroxypropylmethylcellulose acetate succinate (Goyanes et al., 2017), ethylcellulose (Yang et al., 2018), and hydroxypropylcellulose (Chai et al., 2017). FDM has been shown to be a versatile 3D printing technology in the manufacture of personalized medicines. Using this technology, tablets printed with unique designs resulted in improved drug release properties (Goyanes et al., 2015a; Jamróz et al., 2018). Polypills (Pereira et al., 2019) and bilayer solid dosage forms (Gniazadeh 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. used SLS technology to study the printability of several pharmaceutical grade polymers such as Eudragit, polyethylene oxide and ethyl cellulose (Fina et al., 2018, 2017). Wang et al. studied the applicability of SLS technology in the manufacture of PEGDA / acetaminophen tablets (Wang et al., 2016).

[0006] Martinez et al. showed that SLS can be used to prepare drug-loaded tablets with improved release by changing the tablet geometry (Martinez et al., 2018). Inkjet printing has also shown its potential in the manufacture of solid dosage forms, although the choice of compatible polymers is limited. Kyobula et al. conducted a study (Kyobula et al., 2017). SUMMARY OF THE INVENTION

[0008] The present application relates to printing based on micro-extrusion for manufacturing pharmaceuticals. On the one hand, the present application relates to 3D printed tablets, for example, pediatric ibuprofen (IBU) chewable tablets. The present application also relates to tablets based on micro-extrusion three-dimensional printing, in which a series of leading polymers are evaluated, such as polymers that can provide taste masking and increase the dissolution rate of water-insoluble drugs. The printed formulation contains a drug / polymer powder mixture or particles. In addition, sweeteners and flavoring agents can be included in the printed formulation to improve taste and palatability. Due to the compatibility of drug-polymers and the plasticization of many active pharmaceutical ingredients (APIs), micro-extrusion can be beneficial for processing taste-masked tablets, especially pediatric dosage forms. The printed tablets can produce high print quality, with high print reproducibility and smooth surface texture (surface finish) on the tablet surface. A method based on micro-extrusion for processing a powder mixture containing an active pharmaceutical ingredient for rapid printing and development of personalized dosage forms is provided. The method enables the manufacture of tablets with different designs and active drug doses. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Attached photos

[0010] Figure 1 : Schematic diagram of a micro-extrusion printhead for tablet printing

[0011] Figure 2 :TGA graphs of bulk EPO, Soluplus, VA64 and ibuprofen

[0012] Figure 3 : Optical images of 3D printed tablets based on 40% and 60% filling density. (a) Top view and (b) side view of EPO / IBU tablet. (c) Top view and (d) side view of Soluplus / IBU tablet. (e) Top view and (f) side view of VA64 / IBU tablet. (g) Pediatric design.

[0013] Figure 4 : SEM images of 3D printed tablets of (a) EPO / IBU, (b) Soluplus / IBU and (c) VA64 / IBU.

[0014] Figure 5 : XRD patterns of (a) plain EPO, Soluplus, ibuprofen, (b) physical mixture of IBU / polymer formulations and (c) 3D printed tablets.

[0015] Figure 6 :DSC differential thermograms of bulk polymer and ibuprofen

[0016] Figure 7: Raman spectra of bulk polymer, ibuprofen, and 3D printed ibuprofen / polymer tablets.

[0017] Figure 8 : (a) Explained variance of each PC for Ibu-S (left) and Ibu-VA64 samples, (b) comparison of the first PC with the spectra of IBU, SOL, and VA64, respectively, and (c) chemical profile concentrations of PC1 for Ibu-SOL and Ibu-VA64.

[0018] Fig. 9 : Dissolution rates of (a) IBU-EPO, (b) IBU-VA64, and (c) IBU-SOL 3D printed tablets with different filling densities at pH 1.2 and pH 7.4, respectively.

[0019] Fig.10 : Dissolution profile of IBU-EPO printed tablets with (a) 2.5% and 7.4% Neusilin (pH 1.2).

[0020] Fig.11 : Taste masking evaluation of ibuprofen, EPO, Soluplus, VA64, and 3D printed VA64 / IBU, SOL / IBU, and EPI / IBU tablets.

[0021] Fig.12 : Glass transition integration of (a) Soluplus / IBU, (b) VA64 / IBU and (c) EPO / IBU tablets.

[0022] The method described herein can be used to prepare a 3-D printed tablet containing a plurality of tablets, preferably, one or more APIs selected from the group consisting of astemizole, nitrogen Azelastine, azatadine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine ne), fexofenadine, hydroxyzine, levocetirizine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine, tripelennamine, triprolidine, acetyl dihydrocodeine), benproperine, benzonatate, benzylmorphine, bibenzonium bromide, butamirate, butorphanol, carbetapentane, chlophedianol, clobutinol, clofedanol, cloperastine, codeine, dextromethorphan, dextromethorphan hydrochloridehydrobromide), diacetylmorphine, dibunate, dihydrocodeine, dimemorfan, dimethoxanate, diphenhydramine, dropropizine, droxypropine, ethylmorphine, fedrilate, glaucine, hydrocodone, hydromorphone, isoaminile, laudanum, levodropropizine, levomethadone, levopropoxyphene, meprotixol, methadone, morclofone, nepinalone, nicocodine, nicodicodine, normethadone, noscapine, oxeladin, oxolamine, pentoxyverine, pholcodine, pipazetate, piperidone, prenoxdiazine, tipepidine, zipeprol, acetylcysteine, althearoot, ambroxol, antimony pentasulfide pentasulfide, bromhexine, carbocisteine, cineole, combinations, creosote, dembrexine hydrochloride, domiodol, dornase alfa, eprazinone, erdosteine, guaiacolsulfonate, guaifenesin, hederae helixhelicis folium, ipecacuanha, letosteine, levo verbenone, mannitol, mesna, neltenexine, potassium iodide, senega, sobrerol, stepronin, tiopronin, tyloxapol, pseudoephedrine, cetirizine, loratadine, fexofenadine, diphenhydramine, levocetirizine, desloratadine, phenol, ethanol, thymol, eucalyptol, ethanol, methyl salicylate salicylate, chlorhexidine gluconate, cetylpyridinium chloride, hexetidine, triclosan, hydrogen peroxide, domiphenbromide, bismuth subsalicylatesubsalicylate, loperamide hydrochloride, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, dexlansoprazole, diphenoxylate, dicyclomine, loperamide, rifaximin, alosetron, cholestyramine, linaclotide, lubiprostone, polycarbophil, psyllium, alclometasone, amcinoni de), beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortivazol, deflazacort, deoxycorticosterone, desonide ide), desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone, fluticasone propionate, fluprednidene, formocortal, halcinonide, halometasone, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate furoate, paramethasone, prednicarbate, prednisone, prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone, ulobetasol, 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, calcium supplements, calcimimetics, cinacalcet, nicotine, nicotine resin complexpolacrilex, bupropion, varenicline, disulfiram, calcium carbimide, acamprosate, naltrexone, buprenorphine, methadone, levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides, ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid, amifampridine, doxylamine, diphenhydramine hydrochloride 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, aloxiprin, azapropazone, benolate, bromfenac, carprofen, celecoxib, choline magnesium salicylatesalicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, paracetamol, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, tolmetin, valdecoxib, acetylsalicylic acid, aloxiprin, aminophenazone, anilides, benolide, benzomorphan derivatives derivatives), bezitramide, bucetin, buprenorphine, butorphanol, carbasalate calcium, choline salicylatesalicylate, codeine, dextromoramide, dextropropoxyphene, dezocine, diamorphine, diflunisal, dihydrocodeine, dihydrocodone, dihydromorphine, diphenylpropylamine derivatives, dipyrocetyl, ethenzamide, fentanyl, floctafenine, flupirtine, glafenine, guacetisal, hydrocodone, hydrocodone bitartrate, hydromorphone, hydromorphone hydrochloride, imidazole salicylate salicylate, ketobemidone, metamizole sodium, methadone, morphinan derivatives, morphine, morphine sulphate pentahydrate, morphine-6-glucuronode, morpholine salicylate, nalbuphine, natural opium alkaloids, nefopam, nicomorphine, nifenazone, non-steroidal anti-inflammatory drugsdrugs (NSAIDs), norhydrocodone, noroxycodone, opioids, opium, oripavine derivatives, oxycodeine, oxycodone, oxycodone hydrochloride, oxymorphone, papaveretum, pentazocine, pethidine, phenacetin, phenazocine, phenazone, phenylpiperidine derivatives, piritramide, potassium salicylate salicylate, propacetamol, propyphenazone, pyrazolones, rimazolium, salicylamide, salicylic acid derivatives, salsalate, sodium salicylate, tapentadol, tilidine, tramadol, viminol, ziconotide, vitamin B12 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 (cholecalciferol), vitamin E (tocopherol), vitamin F (linoleic acid), vitamin G, vitamin H (biotin), and vitamin K, choline, folic acid, inositol, niacin, pantothenic acidacid, 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, androstendione, betaine (trimethylglycine), calcium pyruvate (pyruvic acid), carnitine, carnosine, carotene, carotenoid, choline, chlorogenic acid, cholic acid acid, chondroitin sulfate, chondroitin sulfate, cholestan, chrysin, coenzyme Q10, conjugated linoleic acid, corosolic acid, creatine, dehydroepiandrosterone, dichlorophen, diindolymethane, dimethylglycine, dimercapto succinic acid, ebselen, ellagic acid, enzymes, fisetin, formononetin, glucaric acid (glucarate), glucosamine (HCl or sulfate)sulfate), glucosamine (N-acetyl), glutathione, hesperidine, hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-carbinol, inositol, isothiocyanates, linolenic acid-gamma, lipoic acid (alpha), melatonin, methylsulfonylmethane, naringin, pancreatin, para-aminobenzoic acid, paraben (methyl or propyl) ester propyl), phenolics, phosphatidylcholine, phosphatidylserine, phytosterols, progesterone, pregnenolone, omega-3 fatty acids, quercetin, resveratrol, D-ribose, rutin, S-adenosylmethionine, salicylic acid, sulforaphane, tartaric acid, taxifolin, tetrahydropalmatine, theophyline, theobromine, tigogenin, troxerutin, or a mixture or combination thereof.

[0023] Polymers such as ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate, polyurethanes, silicones polycarbonate, polychloroprene, polyisobutylene, polycyanoacrylates, poly(vinyl acetate), polystyrene, polypropylene, poly(vinyl chloride), polyethylene, poly(methyl methacrylate), poly(hydroxyethyl methacrylate), acrylic acid and butyl acrylate copolymers, 2-ethylhexyl acrylate and butyl acrylate copolymers, vinyl acetate and methyl acrylate copolymers, ethylene vinyl acetate and polyethylene terephthalate, ethylene vinyl acetate and polyethylene, polyethylene and polyethylene terephthalate, or mixtures or combinations thereof can be used in the methods described herein.

[0024] Polymers such as polyacrylic acid, polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylamide, polyisopropylacrylamide and polycyclopropylmethacrylamide, starch, sodium starch glycolate, (lactic acid-co-glycolide) polymers, alginic acid, carrageenan, chitosan, hyaluronic acid and pectinic acid, or mixtures or combinations thereof can be used in the methods described herein.

[0025] Polymers such as PVP / VA 64, PVP K12, PVP K15, PVP K30, PVP K60, PVP K90, PVP K120, Plastodene S630, Plastodene C12, Plastodene C15, Plastodene C17, Plastodene C30, HPMC-ASM, 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, HPMCK100, HPMC 4M, HPMC 100LV, HPMC 15LV, HPMCP-HP55, PVA (polyvinyl alcohol), and Soluplus can be used in the methods described herein.

[0026] Preferably, polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone VA64 (PVP-VA64), hydroxypropyl cellulose L (HPC-L), hydroxypropyl methylcellulose E3 (HPMC E3), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) and polymethacrylate (Eudragit EPO) are used for tablet formation.

[0027] A description of the useful polymers listed above is found in Martin's physical pharmacy and pharmaceutical sciences: physical chemical and biopharmaceutical principles in the pharmaceutical sciences - 6th edition / Patrick J. Sinko ed. (ISBN 978-0-7817-9766-5).

[0028] Sweeteners such as sucrose, sucralose, mannitol, xylitol, sorbitol, aspartame, atramitine-K, cyclamate, saccharin, or combinations thereof can be used in the methods described herein.

[0029] Flavors such as orange, strawberry, raspberry, lemon, vanilla, coffee, lime, caramel, toffee, chocolate, cherry, apple, grape, or watermelon can be used in the methods described herein.

[0030] The present invention can be implemented in other specific forms without departing from its spirit or essential attributes. The present invention includes all combinations of preferred aspects of the present invention and / or embodiments mentioned herein. It should be understood that any and all embodiments of the present invention can be combined with any other one or more embodiments to describe other more preferred embodiments. It should also be understood that each individual element of the preferred embodiment is its own independent preferred embodiment. In addition, any element of the embodiment is intended to be combined with any and all other elements from any embodiment to describe other embodiments. Example

[0031] Material:

[0032] Soluplus (SOL) and PVP VA-64 (VA64) were kindly donated by BASF (BASF-Germany). Eudragit EPO (EPO) was kindly donated by Evonik (Evonik-Germany). Ibuprofen (IBU) was purchased from Sigma Aldrich (SigmaAldrich, UK). Strawberry flavor was purchased from Symrise Ltd. (Marlow, UK), and sucralose was purchased from Merck LifeScience UK Limited (Dorset, UK).

[0033] Preparation of formulations:

[0034] PVP-VA64, EPO or Soluplus were mixed 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 ten minutes. Tablets were prepared from each mixture using microextrusion technology.

[0035] Thermogravimetric analysis (TGA)

[0036] The TGA technique (TGA Q5000 Thermal Instruments, USA) was used to study the thermal stability of bulk polymer and ibuprofen. 2-2.5 mg polymer and drug samples were carefully weighed and placed in a standard aluminum pan. The samples were heated from 25°C to 500°C at 10°C / min. The extracted raw data were analyzed by TA Universal analysis software (Universal Analysis 2000, Version 4.5A, TA Instruments, USA).

[0037] Differential Scanning Calorimetry (DSC)

[0038] A differential scanning calorimeter (Mettler-Toledo 823e, Switzerland) was used to study the thermal behavior of bulk materials and 3D printed tablets and to study the physical state of ibuprofen within 3D printed tablets. About 2-2.5 mg of bulk raw materials and a small portion of 3D printed tablets were weighed, placed in a 40 μL aluminum pan and quickly curled. Bulk polymers 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 bulk raw materials and 3D printed tablets were analyzed by STARe Excellence thermal analysis software (Mettler Toledo, Switzerland).

[0039] Design and 3D printing of ibuprofen tablets

[0040] Tablet design is constructed to study the micro extrusion (printability) of various polymer / IBU formulations as shown in Table 1. Tablets are designed by SolidWorks software (Dassault Systems, USA) and converted into (stereolithography) stl files. Two tablets have the same 12mm diameter, but different heights (i.e. 3mm or 2.4mm), and are sliced ​​with a filling density of 40% and 60%, respectively. The design mode of filling density is that the total weight is 250 mg, including 100 mg of ibuprofen. Bio-X (Celink, Sweden) bioprinter 3D printing tablets are used with a pneumatic thermoplastic print head. About 3 grams of each mixture is placed in a heatable metal reservoir, and tablets are printed using a 0.4mm nozzle, a 0.4mm layer height and a 5mm / s printing speed.

[0041] 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 the formulations were set at 120 kPa, 110 kPa, and 90 kPa, respectively, while the build plate temperature was maintained at 15° C.

[0042] Table 1: 3D printed IBU tablet formulation for pediatric dosage form

[0043]

[0044] VA64: Vinyl pyrrolidone-vinyl acetate, EPO: Amino Methacrylate Copolymer, XLT: Xylitol, NEU: Neusilin, SCR: Sucralose

[0045] like Figure 1 Schematic diagram of the microextrusion process of tablets shows that pressurized air pushes a metal plunger toward the physical mixture in a reservoir. Tablet designs with different densities were successfully manufactured by coordinating the horizontal movement of the print head with the vertical movement of the print head.

[0046] Scanning electron microscopy (SEM)

[0047] The quality / layer height of printed tablets by microextrusion was investigated using a scanning electron microscope (Hitachi SU8030, Japan). The tablets were held fixed on an aluminum stub with conductive carbon tape (Agar Scientific, Stansted, UK). The tablets were then examined by SEM and images were captured with an electron beam acceleration voltage of 1 KV and a magnification of 30X.

[0048] X-ray powder diffraction (XRPD)

[0049] The physical state of common polymers, ibuprofen and 3D printed tablets (VA64 / IBU, EPO / BU and Soluplus / IBU) was studied by XRPD. XRPD data were collected using a D8Advance 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 using 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 data were analyzed using EVA software (version 5.2.0.3, Bruker AXS, Germany). The samples were placed between 2.5 μm thick Mylar foils for measurement. Data were collected between 5–60° 2θ with a step size of 0.04° and a counting time of 0.2 seconds / step.

[0050] In vitro dissolution and HPLC analysis

[0051] In vitro dissolution studies were performed to study the API release of 3D printed ibuprofen tablets in acidic and neutral media. Drug release studies were performed using a Varian 705DS (USA) dissolution bath connected to a paddle device. Experiments were performed using 800 mL of phosphate buffered saline (PBS, pH 7.4) in each container at 37 ± 1 ° C, and the paddle rotation was set to 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). 2 mL of sample medium was collected at time intervals of 15, 30, 60, 90, and 120 minutes, and the same amount of fresh PBS medium was added to maintain a constant volume of the dissolution medium. The collected samples were filtered using a 0.45 mm disc filter and poured into a high performance liquid chromatography vial for ibuprofen concentration analysis. The study was completed using an Agilent 1200 series HPLC system equipped with a gradient elution system, an autosampler, a HICHROM S5ODS2-4889 (5×150 66 66150×4 mm) column and a UV detector set at a wavelength of 214 nm. The sample was eluted using a mobile phase consisting of acetonitrile: water: orthophosphoric acid (49.5: 49.3: 0.2 v / v) and pumped at a flow rate of 1.5 mL / min.

[0052] This specification showed a column back pressure of approximately 115 bar and a retention time of 3 min. A calibration curve was also prepared using IBU in HPLC grade methanol at concentrations of 10, 20, 30, 40 and 50 μg / mL. All experiments were studied in triplicate using the same method described above.

[0053] Taste masking and sensory evaluation

[0054] An in vivo taste masking study was conducted in 10 healthy human volunteers, from whom informed consent was first obtained (approved by the Ethics Committee of the University of Greenwich). The study also followed the Code of Ethics of the World Medical Association (Declaration of Helsinki). The age category of the volunteers (either sex) was selected from 18-30. The volunteers were trained and tested to orally ingest the bulk substances and 3D printed tablets in the mouth for 2 minutes and immediately spit them out. No substances and tablets were swallowed, and the mouth was rinsed immediately after the experiment. The bitterness of the bulk substances and 3D printed tablets was recorded on a scale intensity from 1 to 5, where 1, 2, 3, 4 and 5 represent no bitterness, threshold bitterness, slight bitterness, moderate bitterness and strong bitterness.

[0055] The sensory training included a complete description of the method, the correct use of the scale, and confirmation that the prepared samples were considered to have sweetness levels of "not sweet", "sweet", "very sweet", and "extremely sweet" compared to a reference sample (sucrose sample of equal amount). Similarly, strawberry flavor (aroma) was evaluated in terms of "sweet", "strawberry", "sour", "fruity", and "aftertaste" attributes compared to natural peeled strawberry juice. This panelist study was conducted in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).

[0056] Raman spectroscopy and mapping

[0057] Ibuprofen-based samples and their excipients were analyzed using a Horiba LabRamI microscope equipped with a frequency-doubled Nd:YAG laser (λ=532 nm) and a 50x long working distance objective. Spectra of IBU / EPO tablets and EPO polymers were recorded using 25% laser power, 1 s accumulation time, and 8 accumulations; at the same time, 25% laser power, 2 s accumulation time, and 4 accumulations were used for the remaining spectra. Finally, a map was generated over a 120×180 μm area, with spectra collected every 20 μm. Raman imaging was performed, which covers 160×120 μm 2 For the area of ​​20 × 20 spectra were recorded in the x and y directions for ibuprofen-EPO and ibuprofen-SOL samples, and 33 × 25 for IBU-VA64.

[0058] The spectra were initially baseline corrected using the asymmetric least squares (AsLS) method with a parameter λ equal to 10 5 , p is equal to 10 -3 ((Eilers and Boelens, 2005; R Core Team, 2019; Wehrens et al., 2015)). To correct for focusing loss and scattering effects caused by tablet surface anomalies, the spectra were normalized using a standard normal variate. The matrix was subsequently decomposed into the most prevalent factors using principal component analysis. The analysis was completed using the R programming language (R 4.03) (R Core Team 2019) and the ptw package to apply AsLS (Wehrens, Bloemberg, and Eiler 2015).

[0059] result

[0060] Thermal Analysis of Bulk Raw Materials

[0061] In order to determine the appropriate microextrusion temperature, TGA analysis was performed to evaluate the thermal stability of IBU and bulk polymer ( Figure 2 ). IBU is thermally stable when heated up to 140°C, above which the drug degrades and loses weight rapidly.

[0062] Soluplus (SOL) gradually loses 4% weight up to 90°C due to water removal and remains stable until 260°C, above which the polymer degrades. PVP VA64 (VA64) shows a slightly higher initial weight loss (5.5%) due to higher water content and no significant degradation until 260°C. Eudragit EPO (EPO) remains stable with no weight loss until 220°C, after which it loses rapidly due to polymer degradation.

[0063] DSC thermal analysis was also used to characterize the thermal properties of IBU and bulk polymers ( Figure 5 a). IBU is a crystalline solid showing a sharp melting endotherm at 77.99°C, while bulk polymers SOL, VA64 and EPO show glass transition temperatures (Tg) at 66.33°C, 107.10°C and 46.99°C, respectively. The change in heat capacity at the glass transition temperature confirms the amorphous nature of the polymer.

[0064] The operating temperature of microextrusion should be kept below the degradation temperature of each component. In addition, the drug / polymer mixture can be processed near the glass transition temperature of the polymer to facilitate the mixing of the drug and polymer. Therefore, the 3D starting printing temperatures of IBU / SOL, IBU / VA64, and IBU / EPO powders were performed at 62.0°C, 105.0°C, and 46°C, respectively.

[0065] Tablet design and 3D printing

[0066] The mixtures were printed into tablets with the same 10 mm diameter and two packing densities (40% and 60%) to evaluate printability and the effects of polymer type and packing density on drug release. The IBU / polymer ratio for all mixtures was 40 / 60 (w / w). Each tablet contained 100 mg of IBU and had a total weight of 250 mg. Previous studies have demonstrated that VA64, SOL, and EPO are not suitable for 3D printing using fused deposition modeling (FDM) technology. The ductility of the polymers makes it challenging to form filaments of the diameter and length required for subsequent 3D printing (Alhijjaj et al., 2016; Fuenmayor et al., 2018; Sadia et al., 2016). High levels of plasticizers (e.g., 20%–30%) must be added to the polymers to improve their printability, which limits the maximum drug loading in the final tablet.

[0067] The main advantage of microextrusion technology is that drug / polymer mixtures can be printed directly without having to make filaments as a pre-step. Using this method, drug / polymer mixtures in various ratios are melted or softened in a cartridge. The softened drug / polymer mixture is then extruded through a nozzle by applying pneumatic pressure (200–700 kPa). The resulting thermoplastic filament can be directly printed into tablets. Compared with FDM and SLS, microextrusion technology reduces the total processing time and waste of printed materials for 3D printing. The latter is particularly valuable in the preparation of personalized medicines composed of expensive APIs.

[0068] like Figure 3 As shown, tablets with two packing densities were successfully manufactured using microextrusion 3D printing technology with good reproducibility. SEM images of the printed tablets showed consistent deposited layer heights, which demonstrated excellent tablet printing quality ( Figure 4 ).

[0069] The speed of 3D printing depends on the size of the nozzle, the printing temperature, and the pneumatic pressure applied to the mixture. In this study, the pneumatic pressure was maintained at 90–120 kPa with a 0.4 mm nozzle at the specified printing temperature to provide a printing speed of about 5 mm / s. The printing time for all three drug / polymer tablets was about 3 minutes. The temperature of the build bed was set at 10-40°C to allow the tablets to be easily removed.

[0070] Tablet Characterization

[0071] All three polymers used in this study were miscible with IBU at drug levels of 40% (based on their solubility parameters (δ), Islam et al., 2015; Maniruzzaman et al., 2015). X-ray powder diffraction analysis was used to evaluate the physical state of IBU in 3D printed tablets. Figure 6 As shown in a, the XRPD patterns of the pure polymers (EPO, VA64 and SOL) are characterized by broad halos, indicating that all three individual polymers are in an amorphous state. The IBU solid exhibits its crystalline properties, with characteristic diffraction peaks at 5.8°, 12.2°, 16.1°, 17.4°, 18.5°, 20.0° and 22.2° / 2θ. The characteristic XRPD pattern of IBU was also observed in the physical mixtures (IBU / EPO, IBU / SOL, IBU / VA64), which confirms that the drug remained a crystalline solid before 3D printing. The characteristic diffraction peaks of IBU were not observed in the XRPD pattern of the 3D printed tablets, indicating that IBU became an amorphous state after microextrusion ( Figure 7c). XRPD patterns of the 3D printed tablets were also collected after one week. It was confirmed that IBU remained amorphous in the tablets stored under ambient conditions (25°C, 40% RH).

[0072] 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, while the glass transition (Tg) temperatures of SOL, VA 64, and EPO were 63.86 °C, 107.10 °C, and 46.99 °C, respectively. When the printed tablets were heated, no melting endotherm of IBU was observed. Fig.12 As shown, the thermograms of IBU / SOL, IBU / VA 64, and IBU / EPO exhibited a single glass transition at 37.69°C, 77.99°C, and 15.35°C, respectively. These two observations indicate that 40% of the drug loading of crystalline IBU was completely dissolved in the polymer after 3D printing. Amorphous IBU with a glass transition temperature of -45.15°C (Dudognon et al., 2008) acts as a plasticizer in the printed tablets and leads to a lower Tg [(Gryczke et al., 2011; Islam et al., 2015; Maniruzzaman et al., 2012). Interestingly, the measured glass transition temperature is higher than the value predicted based on the Fox equation. The Fox equation has been widely used to estimate the glass transition temperature of physical mixtures without interactions between the components. This difference indicates a strong intramolecular interaction between IBU and the studied polymers.

[0073] Raman spectroscopy and mapping

[0074] The interaction between IBU and polymer was further investigated using Raman spectroscopy. The vibrational bands in the Raman spectrum of IBU have been well documented in recent literature (Breitenbach et al., 1999; Vueba et al., 2008). Figure 7 As shown, crystalline IBU is characterized by hydroxymethyl and aromatic peaks, more specifically, 637 cm -1 The peak at 746 cm represents the out-of-plane stretching of the CO-H bond. -1 、850cm -1 、1609cm -1 and 3047cm -1 The other peaks at 1181 cm-1 correspond to the out-of-plane deformation of the CH bond, the out-of-plane bending of the CH bond, the stretching of the CC bond, and the stretching of the CH bond. -1 、1452cm -1 and 2965cm -1The peaks of are related to the stretching of non-aromatic CC bonds, asymmetric deformation of CH3, and asymmetric stretching of CH3 bonds. The same bands were observed in the Raman spectra of 3D printed IBU / polymer tablets ( Figure 7 ), but with a widened graph compared to a separate IBU.

[0075] like Figure 7 As shown, after 3D printing with the polymer, the peak of the C=C vibration of the aromatic group in IBU changes from 1608 cm -1 Move to 1616cm -1 , indicating the potential H-bonding between IBU and the polymer (Hédoux et al., 2011). In addition, the C=O stretching of IBU was detected from the 1652 cm -1 Move to 1734cm in the spectrum of the printed tablet -1 , which correlates with strong drug–polymer interactions and suggests strong drug-polymer interactions similar to those observed in cyclodextrin molecular complexes (Brás et al., 2008). It was also observed that in 3D printed tablets, the bulk IBU at 637 cm -1 and 663cm -1 The CO–H out-of-plane bending at 605 cm -1 or disappear completely (Vueba et al., 2008). This shift indicates a static disordered molecular environment caused by the formation of a glass solution.

[0076] To investigate the spatial resolution of IBU in printed tablets, Raman spectra were recorded continuously. PCA was applied to decompose the spectra into loadings and scores that approximately represent the initial spectra. The main advantage of PCA is that it does not require the use of spectra of bulk compounds, which may undergo changes during the printing process due to molecular interactions. The number of principal components required to decompose the hyperspectral matrix is ​​usually determined by the analysis of the eigenvalues, which represent the total variance captured by the specified principal components. In simple systems, such as in this case, where only two compounds are present and well mixed, two to three PCs are sufficient to decompose the system. In more complex systems, it is not uncommon to use more PCs, where compounds can be identified in very late components (Scouaris et al., 2014). Figure 8 a shows the cumulative variance corresponding to each PC. In the IBU–SOL 3D-printed sample, the PCs (left) represent 99.4% of the total variance, while in Ibu–VA64, the PCs (right) account for 96.7% of the total variance. For the former sample, the very high variance covered by the PCs is due to the very broad peaks of the SOL spectrum, which cannot be distinguished from the peaks of IBU.

[0077] Figure 8 b Summarizes the spectra of the PC and individual components of the tablet. For the IBU–VA64 sample, it is clear that the PC contains peaks corresponding to both the API and the polymer. However, this is not the case for the IBU–SOL sample, which has broad peaks that cannot be distinguished. Figure 8 (c) The concentration plots of the first PCs of Ibu-SOL and Ibu-VA64 demonstrate that the compounds are uniformly distributed within the tablet. This is evidence of strong drug-polymer intermolecular interactions and the dispersion of IBU molecules within the polymer matrix.

[0078] Dissolution studies

[0079] Drug release can be improved by dispersing the drug at the molecular level into a polymer matrix and then 3D printing the drug / polymer mixture (Douroumis et al., 2007; Islam et al., 2015; Maniruzzaman et al., 2015). The dissolution of IBU from 3D printed tablets was evaluated in acidic (pH 1.2) and alkaline media (pH 7.4) and the effect of polymer type as well as packing density (40 and 60%) on drug release from tablets was revealed. Eudragit EPO is a basic methacrylate copolymer that is commonly used for immediate-release drug products that require taste masking because it is almost insoluble at pH greater than 5 (in saliva) but very soluble in acidic media (in the stomach). As expected, the IBU / EPO tablets showed slow dissolution at pH 7.4 despite the molecular dispersion of IBU in the polymer matrix (Fine-Shamir and Dahan, 2019; Gryczke et al., 2011). Tablets with a fill density of 40% showed ~15% drug release within 2 hours, while tablets with a fill density of 60% showed ~10% drug release within the same time period ( Fig. 9 a). The slightly higher drug release from tablets with lower packing density is due to the larger surface area of ​​the tablets. IBU / EPO tablets dissolved rapidly at pH 1.2 with ~89% of the drug released within 15 minutes and a high supersaturation. Since EPO is not a good crystallization inhibitor, the concentration of IBU 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 that has good solubility in water over a large pH range. IBU is an acidic compound (pKa 4.6) that has low solubility at low pH. It was found that at pH 1.2, the release of IBU from 3D printed IBU / VA 64 tablets was low with ~13% drug release in 2 hours ( Fig. 9b). It has also been previously observed that IBU is slowly released from a high drug load VA 64 matrix at low pH ≤ 2 (Tres et al., 2016). The authors concluded that VA 64 preferentially dissolved from the outside of the printed tablet (dense), producing a shell rich in amorphous IBU and hydrophobic. The hydrophobic shell acted as an in situ enteric coating and inhibited dissolution. At pH 7.4, the solubility of IBU was significantly higher and IBU was released at a rate similar to that of the polymer. The consistency of IBU and polymer produced supersaturation of IBU. In addition, PVP VA 64 inhibited the crystallization of IBU in solution, thereby maintaining the supersaturation level throughout the dissolution test. IBU / VA 64 tablets with 40% fill density showed slightly higher dissolution rates than tablets with 60% fill density. This comparison again confirms that a larger tablet surface leads to higher drug release.

[0080] Soluplus is a well-known polymer solubilizer that has been found to enhance drug release in several cases due to enhanced drug-polymer interactions. Fig. 9 c, all IBU / SOL tablets exhibited slow dissolution at pH 1.2 and 7.4. Pudlas et al. made similar observations on IBU / SOL extrudates and investigated the underlying causes using spectroscopic analysis. The slow release of IBU is attributed to the strong hydrogen bonds between IBU and VA64, which consume a large number of hydrophilic groups in the polymer chain, thus significantly reducing the hydrophilicity of the polymer. In contrast, drug release was slowest at pH 1.2 due to the low solubility of IBU under acidic conditions. The effect of packing density on drug release was observed again, i.e., IBU / Sol tablets with a packing density of 40% dissolved faster than tablets with a packing density of 60%. In summary, tablets with lower packing density provide higher dissolution rates due to larger surface areas. The effect of polymers on the dissolution of IBU / polymer tablets depends on the properties of the compound, polymer, and their interactions.

[0081] In addition, dissolution studies were performed on F4-F6, where sweeteners (e.g., xylitol or a combination thereof) and inorganic excipients (magnesium aluminometacilicates) were added in combination with IBU / EPO. Results ( Fig.10 ) shows rapid dissolution of IBU within the first 5-10 minutes. The dissolution rate was affected by the shape of the printed tablets due to different surface areas (e.g., ring > banana > heart).

[0082] Taste masking evaluation

[0083] Medicinal products for pediatric use 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 dosage flexibility and taste masking. IBUs are known to have a bitter or salty taste, so taste masking is required in finished products composed of IBUs for pediatric use. Fig.11 As shown, the taste of IBU and 3D printed IBU / polymer tablets was evaluated in healthy panelists. The average IBU score was 4, which confirmed the bitter taste of the drug, while the bulk polymer had an acceptable taste with a bitterness score of 2 or less. All 3D printed IBU / polymer tablets had a pleasant taste with a bitterness score of 1. 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 IBU in chewable tablets suggests that microextrusion can be successfully used for 3D printing of personalized tablets for pediatric use.

[0084] This study demonstrated a simple microextrusion 3D printing technique that can be used to 3D print tablets with suitable and reproducible printability. This 3D printing technique can bypass the pre- and post-processing processes required by other 3D printing techniques. In addition, this method minimizes material waste compared to other 3D printing techniques. Similar to other 3D printing techniques, microextrusion 3D printing can also be used to manufacture pharmaceutical products with specific release properties that are customized for individual patient needs by selecting the polymer matrix and changing the packing density of the tablet.

[0085] Ibuprofen (IBU) was found to form a glass solution due to drug-polymer interactions induced during the printing process, which was confirmed by differential calorimetry (DSC), while hydrogen bonding interactions were determined 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 a panelist and revealed excellent bitter taste masking of IBU. Overall, microextrusion demonstrated promising processing capabilities of powder blends for rapid printing and personalized dosage form development.

[0086] Sensory analysis of the 3D printed tablets involved their evaluation in terms of sweetness intensity and strawberry / orange aroma. Several studies have shown possible interactions between sweeteners and flavors, which ultimately change the sweetener potency. A key consideration in these studies is to determine the optimal ratio of sweeteners / flavors, including their total concentration in the dosage form. Here, the optimized ratios of sucralose / strawberry and aspartame / orange were 0.9:1.1wt / wt% and 1.0 / 1.5wt / wt%, while several other ratios were tested.

[0087] Tables 2-3 show that bulk sucralose and aspartame exhibited very sweet to extremely sweet intensity and very strong aftertaste, respectively. For the 3D printed tablets, the subjects' ratings for intensity were reduced, and for both flavors, most subjects reported "very sweet" and a few reported "medium sweet". For the perceived aftertaste, the subjects' ratings for the sweet aftertaste were reduced compared to bulk sucralose and aspartame.

[0088] Similarly, for the strawberry and orange flavor evaluation of bulk powder, the subjects scored strong strawberry / orange and fruity intensity. Interestingly, the evaluation of 3D tablets showed strong sweet, strawberry (or orange), fruity intensity, and most subjects scored strong aftertaste. This result is related to the synergistic interaction between sweeteners and flavoring agents, where the total intensity of the mixture is greater than the total intensity of a single excipient. In addition, despite the presence of other excipients in the formulation, the local flavor (strawberry / orange) and fruity sensation of 3D tablets are not affected and remain strong. In a word, the optimized sweetener / flavoring agent ratio provides excellent taste perception and has superiority.

[0089] Table 2: Evaluation of sweetness and strawberry aroma of bulk and 3D printed fruit chewable tablets.

[0090]

[0091]

[0092] Table 3: Evaluation of sweetness and orange flavor of bulk material and 3D printed fruit chewable tablets.

[0093]

[0094] References

[0095] Alhijjaj,M.,Belton,P.,Qi,S.,2016.An investigation into the use ofpolymer blends to improve the printability of and regulate drug release frompharmaceutical solid dispersions prepared via fused deposition modeling(FDM)3D printing.Eur.J.Pharm.Biopharm.108,111–125.

[0096] https: / / doi.org / https: / / doi.org / 10.1016 / j.ejpb.2016.08.016

[0097] Barbero,N.,Barolo,C.,Viscardi,G.,2016.Bovine Serum AlbuminBioconjugation with FITC.World J.Chem.Educ.4,80–85.https: / / doi.org / 10.12691 / wjce-4-4-3

[0098] Brás,A.R.,Noronha,J.P.,Antunes,A.M.M.,Cardoso,M.M., A.,Affouard,F.,Dionísio,M.,Correia,N.T.,2008.Molecular Motions in AmorphousIbuprofen As Studied by Broadband Dielectric Spectroscopy.J.Phys.Chem.B 112,11087–11099.

[0099] https: / / doi.org / 10.1021 / jp8040428

[0100] Breitenbach,J.,Schrof,W.,Neumann,J.,1999.Confocal Raman-Spectroscopy:Analytical Approach to Solid Dispersions and Mapping of Drugs.Pharm.Res.16,1109–1113.

[0101] http s: / / doi.org / 10.1023 / A:1018956304595

[0102] Castellano,J.M.,Sanz,G., JL,Bansilal,S.,Fernández-Ortiz,A.,Alvarez,L.,Guzmán,L.,Linares,JC,García,F.,D'Aniello,F.,Arnáiz,JA,Varea,S.,Martínez,F.,Lorenz proceedings,A.,Imaz,I.,Sánchez-Gómez,LM,Roncaglioni,MC,Baviera,M.,Smith,SC,Taubert,K.,Pocock,S.,Brotons,C.,Farkouh,ME,Fuster,V.,2014.A Polypill Strategy to Improve Adherence:Results From the FOCUSProject.J.Am.Coll.Cardiol.64,2071–2082.

[0103] https: / / doi.org / https: / / doi.org / 10.1016 / j.jacc.2014.08.021

[0104] Chai, X., Chai, H., Wang, X., Yang, J., Li, J., Zhao, Y., Cai, W., Tao, T., Xiang, Domperidone.Sci.Rep.7,2829.https: / / doi.org / 10.1038 / s41598-017-03097-x

[0105] Douroumis,D.,Bouropoulos,N.,Fahr,A.,2007.Physicochemicalcharacterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method.J.Pharm.Pharmacol.59,645–653.https: / / doi.org / https: / / doi.org / 10.1211 / jpp.59.5.0004

[0106] Dudognon,E.,Danède,F.,Descamps,M.,Correia,N.T.,2008.Evidence for aNew Crystalline Phase ofRacemic Ibuprofen.Pharm.Res.25,2853–2858. https: / / doi.org / 10.1007 / s11095-008-9655-7

[0107] Eilers,P.H.C.,Boelens,H.F.M.,2005.Baseline Correction with AsymmetricLeast Squares Smoothing.LifeSci.

[0108] Elbadawi,M.,Gustaffson,T.,Gaisford,S.,Basit,A.W.,2020.3D printingtablets:Predicting printability anddrug dissolution from rheologicaldata.Int.J.Pharm.590,119868.

[0109] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2020.119868

[0110] Fina,F.,Goyanes,A.,Gaisford,S.,Basit,A.W.,2017.Selective lasersintering(SLS)3D printing ofmedicines.Int.J.Pharm.529,285–293.

[0111] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2017.06.082

[0112] Fina,F.,Goyanes,A.,Madla,C.M.,Awad,A.,Trenfield,S.J.,Kuek,J.M.,Patel,P.,Gaisford,S.,Basit,A.W.,2018.3D printing of drug-loaded gyroid latticesusing selective laser sintering.Int.J.Pharm.547,44–52.https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2018.05.044

[0113] Fine-Shamir,N.,Dahan,A.,2019.Methacrylate-Copolymer Eudragit EPO as aSolubility-EnablingExcipient for Anionic Drugs:Investigation of DrugSolubility,Intestinal Permeability,and Their Interplay.Mol.Pharm.16,2884–2891.https: / / doi.org / 10.1021 / acs.molpharmaceut.9b00057

[0114] Fuenmayor,E.,Forde,M.,Healy,A.V,Devine,D.M.,Lyons,J.G.,McConville,C.,Major,I.,2018.Material Considerations for Fused-Filament Fabrication of SolidDosage Forms.Pharmaceutics

[0115] https: / / doi.org / 10.3390 / pharmaceutics10020044

[0116] Ghanizadeh Tabriz,A.,Nandi,U.,Hurt,A.P.,Hui,H.-W.,Karki,S.,Gong,Y.,Kumar,S.,

[0117] Douroumis,D.,2020.3D Printed Bilayer Tablet with Dual Controlled DrugRelease for

[0118] Tuberculosis Treatment.Int.J.Pharm.120147.

[0119] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2020.120147

[0120] Gioumouxouzis,C.I.,Baklavaridis,A.,Katsamenis,O.L.,Markopoulou,C.K.,Bouropoulos,N.,Tzetzis,D.,Fatouros,D.G.,2018.A 3D printed bilayer oral soliddosage form combining metformin for prolonged andglimepiride for immediatedrug delivery.Eur.J.Pharm.Sci.120,40–52.https: / / doi.org / https: / / doi.org / 10.1016 / j.ejps.2018.04.020

[0121] Goyanes,A.,Buanz,A.B.M.,Hatton,G.B.,Gaisford,S.,Basit,A.W.,2015a.3Dprinting of modified-releaseaminosalicylate(4-ASA and 5-ASA)tablets.Eur.J.Pharm.Biopharm.89,157–162. https: / / doi.org / https: / / doi.org / 10.1016 / j.ejpb.2014.12.003

[0122] Goyanes,A.,Fina,F.,Martorana,A.,Sedough,D.,Gaisford,S.,Basit,A.W.,2017.Development ofmodified release 3D printed tablets(printlets)withpharmaceutical excipients using additive manufacturing.Int.J.Pharm.527,21–30.

[0123] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2017.05.021

[0124] Goyanes,A.,Wang,J.,Buanz,A.,Martínez-Pacheco,R.,Telford,R.,Gaisford,S.,Basit,A.W.,2015b.3DPrinting of Medicines:Engineering Novel Oral Deviceswith Unique Design and Drug Release Characteristics.Mol.Pharm.12,4077–4084.

[0125] https: / / doi.org / 10.1021 / acs.molpharmaceut.5b00510

[0126] Gryczke,A.,Schminke,S.,Maniruzzaman,M.,Beck,J.,Douroumis,D.,2011.Development and evaluationof orally disintegrating tablets(ODTs)containing Ibuprofen granules prepared by hot melt extrusion.ColloidsSurf.B.Biointerfaces 86,275–284.

[0127] https: / / doi.org / 10.1016 / j.colsurfb.2011.04.007

[0128] Hafezi,F.,Scoutaris,N.,Douroumis,D.,Boateng,J.,2019.3D printedchitosan dressing crosslinked withgenipin for potential healing of chronicwounds.Int.J.Pharm.560,406–415.

[0129] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2019.02.020

[0130] Hédoux,A.,Guinet,Y.,Derollez,P.,Dudognon,E.,Correia,N.T.,2011.Ramanspectroscopy of

[0131] racemic ibuprofen:Evidence of molecular disorder in phaseII.Int.J.Pharm.421,45–52.

[0132] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2011.09.015

[0133] Islam,M.T.,Scoutaris,N.,Maniruzzaman,M.,Moradiya,H.G.,Halsey,S.A.,Bradley,M.S.A.,Chowdhry,B.Z.,Snowden,M.J.,Douroumis,D.,2015.Implementation oftransmission NIR as a PAT tool for monitoringdrug transformation during HMEprocessing.Eur.J.Pharm.Biopharm.Off.J.Arbeitsgemeinschaft furPharm.Verfahrenstechnik e.V 96,106–116.

[0134] https: / / doi.org / 10.1016 / j.ejpb.2015.06.021

[0135] Jamróz,W.,Kurek,M.,Czech,A.,Szafraniec,J.,Gawlak,K.,Jachowicz,R.,2018.3D printing of tabletscontaining amorphous aripiprazole by filaments co-extrusion.Eur.J.Pharm.Biopharm.131,44–47.https: / / doi.org / https: / / doi.org / 10.1016 / j.ejpb.2018.07.017

[0136] Januskaite,P.,Xu,X.,Ranmal,S.R.,Gaisford,S.,Basit,A.W.,Tuleu,C.,Goyanes,A.,2020.I Spy with MyLittle Eye:A Paediatric Visual PreferencesSurvey of 3D Printed Tablets.Pharmaceutics 12.https: / / doi.org / 10.3390 / pharmaceutics12111100

[0137] Kadry,H.,Al-Hilal,T.A.,Keshavarz,A.,Alam,F.,Xu,C.,Joy,A.,Ahsan,F.,2018.Multipurposablefilaments of HPMC for 3D printing of medications withtailored drug release and timed-absorption.Int.J.Pharm.544,285–296.https: / / doi.org / 10.1016 / J.IJPHARM.2018.04.010

[0138] Kyobula,M.,Adedeji,A.,Alexander,M.R.,Saleh,E.,Wildman,R.,Ashcroft,I.,Gellert,P.R.,Roberts,C.J.,2017.3D inkjet printing of tablets exploitingbespoke complex geometries for controlled and tuneabledrugrelease.J.Control.Release 261,207–215.

[0139] https: / / doi.org / https: / / doi.org / 10.1016 / j.jconrel.2017.06.025

[0140] Maniruzzaman,M.,Boateng,J.S.,Bonnefille,M.,Aranyos,A.,Mitchell,J.C.,Douroumis,D.,2012.Tastemasking of paracetamol by hot-melt extrusion:An invitro and in vivo evaluation.Eur.J.Pharm.Biopharm.80,433–442.https: / / doi.org / https: / / doi.org / 10.1016 / j.ejpb.2011.10.019

[0141] Maniruzzaman,M.,Pang,J.,Morgan,D.J.,Douroumis,D.,2015.MolecularModeling as a Predictive Toolfor the Development of SolidDispersions.Mol.Pharm.12,1040–1049.

[0142] https: / / doi.org / 10.1021 / mp500510m

[0143] Martinez,P.R.,Goyanes,A.,Basit,A.W.,Gaisford,S.,2018.Influence ofGeometry on the Drug ReleaseProfiles of Stereolithographic(SLA)3D-PrintedTablets.AAPS PharmSciTech 19,3355–3361.https: / / doi.org / 10.1208 / s12249-018-1075-3

[0144] Nasereddin,J.M.,Wellner,N.,Alhijjaj,M.,Belton,P.,Qi,S.,2018.Development of a Simple MechanicalScreening Method for Predicting theFeedability of a Pharmaceutical FDM 3D Printing Filament.Pharm.Res.35,151. https: / / doi.org / 10.1007 / s11095-018-2432-3

[0145] H.,Zhang,J.,Pimparade,M.,Speer,I.,Preis,M.,Repka,M.,Sandler,N.,2019.3D-PrintedIsoniazid Tablets for the Treatment and Prevention ofTuberculosis—Personalized Dosing and Drug Release.AAPS PharmSciTech 20,52.https: / / doi.org / 10.1208 / s12249-018-1233-7

[0146] Pere,C.P.P.,Economidou,S.N.,Lall,G.,Ziraud,C.,Boateng,J.S.,Alexander,B.D.,Lamprou,D.A.,Douroumis,D.,2018.3D printed microneedles for insulin skindelivery.Int.J.Pharm.544,425–432.https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2018.03.031

[0147] Pereira,B.C.,Isreb,A.,Forbes,R.T.,Dores,F.,Habashy,R.,Petit,J.-B.,Alhnan,M.A.,Oga,E.F.,2019.‘Temporary Plasticiser’:A novel solution tofabricate 3D printed patient-centred cardiovascular‘Polypill’architectures.Eur.J.Pharm.Biopharm.135,94–103.

[0148] https: / / doi.org / https: / / doi.org / 10.1016 / j.ejpb.2018.12.009

[0149] R Core Team,2019.R:A language and environment for statisticalcomputing.R Found.Stat.Comput.

[0150] Rycerz,K.,Stepien,K.A.,Czapiewska,M.,Arafat,B.T.,Habashy,R.,Isreb,A.,Peak,M.,Alhnan,M.A.,2019.Embedded 3D Printing of Novel Bespoke Soft DosageForm Concept for Pediatrics.Pharmaceutics 11,630.https: / / doi.org / 10.3390 / pharmaceutics11120630

[0151] Sadia,M., A.,Arafat,B.,Isreb,A.,Ahmed,W.,Kelarakis,A.,Alhnan,M.A.,2016.Adaptation ofpharmaceutical excipients to FDM 3D printing for thefabrication of patienttailored immediate release tablets.Int.J.Pharm.513,659–668.

[0152] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2016.09.050

[0153] Scoutaris,N.,Ross,S.,Douroumis,D.,2016.Current Trends on Medical andPharmaceutical Applications ofInkjet Printing Technology.Pharm.Res.33,1799–1816.

[0154] https: / / doi.org / 10.1007 / s11095-016-1931-3

[0155] Scoutaris,N.,Ross,S.A.,Douroumis,D.,2018.3D Printed“Starmix”DrugLoaded Dosage Forms forPaediatric Applications.Pharm.Res.35,34.https: / / doi.org / 10.1007 / s11095-017-2284-2

[0156] Strickley,R.G.,Iwata,Q.,Wu,S.,Dahl,T.C.,2008.Pediatric drugs--areview of commercially available oralformulations.J.Pharm.Sci.97,1731–1774.https: / / doi.org / 10.1002 / jps.21101

[0157] Tagami,T.,Ito,E.,Kida,R.,Hirose,K.,Noda,T.,Ozeki,T.,2021.3D printingof gummy drug formulationscomposed of gelatin and an HPMC-based hydrogel forpediatric use.Int.J.Pharm.594,120118. https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2020.120118

[0158] Trenfield,S.J.,Awad,A.,Goyanes,A.,Gaisford,S.,Basit,A.W.,2018.3DPrinting Pharmaceuticals:DrugDevelopment to Frontline Care.TrendsPharmacol.Sci.39,440–451.

[0159] https: / / doi.org / https: / / doi.org / 10.1016 / j.tips.2018.02.006

[0160] Tres,F.,Treacher,K.,Booth,J.,Hughes,L.P.,Wren,S.A.C.,Aylott,J.W.,Burley,J.C.,2016.Indomethacin-Kollidon VA64 Extrudates:A Mechanistic Study ofpH-Dependent Controlled Release.Mol.Pharm.13,1166–1175.https: / / doi.org / 10.1021 / acs.molpharmaceut.5b00979

[0161] Vueba,M.L.,Pina,M.E.,Batista de Carvalho,L.A.E.,2008.ConformationalStability of Ibuprofen:Assessed by DFT Calculations and Optical VibrationalSpectroscopy.J.Pharm.Sci.97,845–859.https: / / doi.org / https: / / doi.org / 10.1002 / jps.21007

[0162] Wang,H.,Dumpa,N.,Bandari,S.,Durig,T.,Repka,M.A.,2020.Fabrication ofTaste-MaskedDonut-Shaped Tablets Via Fused Filament Fabrication 3D PrintingPaired with Hot-Melt Extrusion Techniques.AAPS PharmSciTech 21,243.https: / / doi.org / 10.1208 / s12249-020-01783-0

[0163] Wang,J.,Goyanes,A.,Gaisford,S.,Basit,A.W.,2016.Stereolithographic(SLA)3D printing of oralmodified-release dosage forms.Int.J.Pharm.503,207–212.

[0164] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2016.03.016

[0165] Wehrens,R.,Bloemberg,T.G.,Eilers,P.H.C.,2015.Fast parametric timewarping of peak lists.Bioinformatics.https: / / doi.org / 10.1093 / bioinformatics / btv299

[0166] Xu,P.,Li,J.,Meda,A.,Osei-Yeboah,F.,Peterson,M.L.,Repka,M.,Zhan,X.,2020.Development of aquantitative method to evaluate the printability offilaments for fused deposition modeling 3D printing.Int.J.Pharm.588,119760.

[0167] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2020.119760

[0168] Yang,Y.,Wang,H.,Li,H.,Ou,Z.,Yang,G.,2018.3D printed tablets withinternal scaffold structure usingethyl cellulose to achieve sustainedibuprofen release.Eur.J.Pharm.Sci.115,11–18.

[0169] https: / / doi.org / https: / / doi.org / 10.1016 / j.ejps.2018.01.005

[0170] Zhang,J.,Feng,X.,Patil,H.,Tiwari,R.V,Repka,M.A.,2017.Coupling 3Dprinting with hot-meltextrusion to produce controlled-releasetablets.Int.J.Pharm.519,186–197.

[0171] https: / / doi.org / https: / / doi.org / 10.1016 / j.ijpharm.2016.12.049

[0172] Zhu,X.,Li,H.,Huang,L.,Zhang,M.,Fan,W.,Cui,L.,2020.3D printingpromotes the development ofdrugs.Biomed.Pharmacother.131,110644.

[0173] https: / / doi.org / https: / / doi.org / 10.1016 / j.biopha.2020.110644。

Claims

1. A method for preparing a 3-D printed tablet, the method comprising the following steps: Providing a microextrusion print head having a heatable reservoir, a plunger, a print nozzle, and optionally a heater; loading a mixture of one or more active drug substances (API) and a polymer suitable for tablet preparation into the reservoir; Applying heat so that the mixture of polymer and API reaches a temperature suitable for extrusion through a nozzle; Applying pressure on the plunger results in extrusion of the heated polymer and API mixture.

2. The method of claim 1, wherein the API-polymer powder mixture or granules are partially melted or softened in the thermoplastic print head.

3. The method of claim 1, wherein the API-polymer powder mixture or granules are printed at a temperature 30-60°C above the glass transition temperature or melting point of the polymer.

4. The method of claim 1, wherein the polymer carrier further comprises a nonionic or ionic / pH dependent polymer, a super disintegrant, a sweetener, a flavorant, or a combination thereof.

5. The method of claim 1, wherein the polymer carrier ranges from 20-90%, more preferably from 40-60%.

6. The method of claim 1, wherein the superdisintegrant comprises 2-10%.

7. The method of claim 1, wherein the sweetener or combination comprises 0.5-20%.

8. The method of claim 1, wherein the flavoring agent comprises 1-5%.

9. The method of claim 1, wherein the ratio of flavor to sweetener ranges from 0.5 to 20%.

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

11. The method of claim 1, wherein the API is a BCS class I drug.

12. The method of claim 1, wherein the API is a BCS class 2 drug.

13. The method of claim 1, wherein the API is a BCS class 3 drug.

14. The method of claim 1, wherein the API is a BCS class 4 drug.

15. The method of claim 1, wherein the API comprises 10-70%, most preferably 30-60% of the API-polymer powder mixture or granules.

16. The method of claim 1, wherein the API-polymer powder mixture or granules has a melt viscosity of 10-1500 Pa.s at the nozzle outlet.

17. The method of claim 1, wherein the API-polymer powder mixture or granules has a suitable flowability index, preferably 4-10, and a compactability index of 5-20.

18. The process of claim 1, wherein the particle size diameter (D50) of the API-polymer powder mixture or granules is in the range of 50 - 1000 μm, most preferably 100-300 μm.

19. The method of claim 1, wherein the API and the polymer form a glass suspension (Form IV or Form V) or a glass solution when the solid dosage form is printed.

20. The method of claim 1, wherein the active drug substance comprises one or more of: astemizole, nitrogen azatadine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, mepyramine, terfenadine, tripeliramine, triprolidine, acehydrocodeine, phen Properine, benzonatate, benzylmorphine, benzylmorphine bromide, butamidate, butorphanol, pentoxyverine, clobutinol, clophedanol, cloperastine, codeine, dextromethorphan, dextromethorphan hydrochloride, diamorphine, dibunate, dihydrocodeine, dimethorphan, dimesophanate, diphenhydramine, dropperazine, dropperine, ethylmorphine, fecal ester, papaverine , hydrocodone, hydromorphone, isominiol, tincture of opium, levoproprazine, levomethadone, levomethadone, meptidol, methadone, morpholinone, nepinarone, nicotinic acid, nicotinic acid, normethadone, noscapine, oxadiazine, oxolamine, pentoxyverine, pholcodine, pyraclostrobin, epazote, epadione, prenodizine, tiperidine, zipeprol, acetylcysteine, marshmallow root, ambroxol, antimony pentasulfide, bromhexine, carbocysteine, eucalyptus, combination, combination, creosote, denbrocine hydrochloride, dominol, dornase alfa, epradone, erdosteine, guaiacol sulfonate, guaifenesin, ivy spiral leaf, ipecac, letosteine, levoverdenone, mannitol, mesna, netexine, potassium iodide, polygala, sorrel Bruton, sitoronine, tiopronin, tyloxapol, pseudoephedrine, cetirizine, loratadine, fexofenadine, diphenhydramine, levocetirizine, desloratadine, phenol, ethanol, thymol, eucalyptol, ethanol, methyl salicylate, chlorhexidine gluconate, cetylpyridinium chloride, hexetidine, triclosan, hydrogen peroxide, domiphene, bismuth subsalicylate, loperamide hydrochloride, Cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, dexlansoprazole, diphenoxylate, dicyclomine, loperamide, rifaximin, alosetron, cholestyramine, linaclotide, rubiprostone, polycarbophil, psyllium, alclometasone, amcinonide, beclomethasone, betamethasone, budesonide, Ciclesonide, clobetasol, clobetasone, clocortolone, clopredniol, cortivalazole, deflazacort, deoxycorticosterone, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorol, fludrocortisone, flurandrenolide, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone, fluocinolone, fluorometholone, fluperone, fluocinolone fluticasone, fluticasone propionate, fluprednidine, formocortal, clofloxacin, halometasone, hydrocortisone acepromate, hydrocortisone butyrate, hydrocortisone butyrate, loteprednol, medrysone, methylprednisone, methylprednisolone, methylprednisolone acepromate, mometasone furoate, paramethasone, prednicarbate, prednisone, prednisolone, prednilide, rimexolone, tixocortolone, triamcinolone,Ubetasol, 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, calcium supplements, calcimimetics, cinacalcet, nicotine, nicotine resin complex, bupropion, varenicline, disulfiram, cyanamide calcium, acamprosate, naltrexone, buprenorphine, methadone, levomethadol acetate, lofexidine, betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides, ganglioside derivatives, tirazad, riluzole, xaliproden, hydroxybutyric acid, amipyridine, doxylamine, diphenhydramine hydrochloride, melatonin, 1-theanine, monofluorophosphate, lactoferrin, lysozyme, lactoperoxidase, glucose oxidase, dextranase, benzocaine, lidocaine, clove oil, sodium bicarbonate, citric acid, tartaric acid, aspirin, ibuprofen, vinegar Clofenac, acemetacin, aloprin, azapropazone, benolate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamic acid, mefenamic acid, meloxicam, antipyrine methylamine methane, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, acetaminophen, oxybutazone, parecoxib, phenylbutazone, piroxicam, disalsalate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, tolmetin, valdecoxib, acetylsalicylic acid, aloprin, aminophenazone, anilides , benoyl ester, benzomorphane derivatives, bezitamide, butibutine, buprenorphine, butorphanol, carbaspirin calcium, choline salicylate, codeine, dextromorphamide, dextropropoxyphene, dezocine, diacetylmorphine, diflunisal, dihydrocodeine, dihydrocodeinone, dihydromorphine, diphenylamine derivatives, dipyramide, ethyl salicylamide, fentanyl, flufenine, flupirtine, glafenine, guancetirsal, hydrocodone, hydrocodone bitartrate, hydromorphone, hydromorphone hydrochloride, imidazole salicylate, ketobemidone, analgin, methadone, morphine derivatives, morphine, morphine sulfate pentahydrate, morphine-6-glucuronide, salicylic morphine, nalbuphine, natural opium alkaloids, nefopam, nicomorphine, nifenazone, nonsteroidal anti-inflammatory drugs (NSAIDs), Norhydrocodone, noroxycodone, opioids, opium, northebaine derivatives, hydroxycodeine, oxycodone, oxycodone hydrochloride, oxymorphone, opium base, pentazocine, pethidine, phenacetin, phenazocine, antipyrine, phenylpiperidine derivatives, pirithromide, potassium salicylate, propacetamol, isopropyl antipyrine, pyrazolones, rimaazole, salicylamide, salicylic acid derivatives, salsalate, sodium salicylate, tapentadol, tilidine, tramadol, vimiol, ziconotide, 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 (cholecalciferol), 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, Betaine, Capsaicin, Betaine, Oxalic acid, Acetyl-L-carnitine, Allantoin, Androstenediol, Androstenedione, Betaine (trimethylamino) ... Acid, dimercaptosuccinic acid, ebselen, ellagic acid, enzymes, fisetin, formononetin, glucaric acid (glucarate / ester), glucosamine (HCl or sulfate), glucosamine (N-acetyl), glutathione, hesperidin, hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-carbinol, inositol, isothiocyanate compounds, linolenic acid-gamma, lipoic acid (alpha), melatonin, methylsulfonylmethane, citrus aurantium glucoside, pancreatic enzyme, p-aminobenzoic acid, p-hydroxybenzoic acid (methyl or propyl) ester, phenolic compounds, phosphatidylcholine, phosphatidylserine, phytosterols, progesterone, pregnenolone, omega-3 fatty acids, quercetin, resveratrol, D-ribose, rutin, S-adenosylmethionine, salicylic acid, sulforaphane, tartaric acid, taxifolin, tetrahydropamagine, theophylline, theobromine, tigloginine, troxerutin, or mixtures or combinations thereof.

21. A method according to any one of the preceding claims, wherein the tablet is chewable and taste-masked.

22. A method according to any one of the preceding claims, wherein the tablet is a pediatric, chewable, taste-masked formulation.

23. The method according to any of the preceding claims, wherein the polymer is selected from the group consisting of ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose and 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), acrylic acid and butyl acrylate copolymers, 2-ethylhexyl acrylate and butyl acrylate copolymers, vinyl acetate and methyl acrylate copolymers, ethylene-vinyl acetate and polyethylene terephthalate, ethylene-vinyl acetate and polyethylene, polyethylene and polyethylene terephthalate, or mixtures or combinations thereof.

24. The method of any one of claims 1-22, wherein the polymer is selected from the group consisting of poly(acrylic acid), poly(ethylene oxide), poly(ethylene glycol), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(isopropylacrylamide), and poly(cyclopropylmethacrylamide), starch, sodium starch glycolate, (lactic-co-glycolic acid) polymer, alginic acid, carrageenan, chitosan, hyaluronic acid, and pectinic acid, or mixtures or combinations thereof.

25. The method of any one of claims 1-22, wherein the polymer is selected from Soluplus, PVP / VA64 and Eudragit EPO.

Images