Embedded 3D Printing of Novel Bespoke Soft Dosage Form Concept for Pediatrics

Embedded three-dimensional printing (e-3DP) is an emerging method for additive manufacturing where semi-solid materials are extruded within a solidifying liquid matrix. Here, we present the first example of employing e-3DP in the pharmaceutical field and demonstrate the fabrication of bespoke chewable dosage forms with dual drug loading for potential use in pediatrics. LegoTM-like chewable bricks made of edible soft material (gelatin-based matrix) were produced by directly extruding novel printing patterns of model drug ink (embedded phase) into a liquid gelatin-based matrix (embedding phase) at an elevated temperature (70 °C) to then solidify at room temperature. Dose titration of the two model drugs (paracetamol and ibuprofen) was possible by using specially designed printing patterns of the embedded phase to produce varying doses. A linearity [R2 = 0.9804 (paracetamol) and 0.9976 (ibuprofen)] was achieved between percentage of completion of printing patterns and achieved doses using a multi-step method. The impact of embedded phase rheological behavior, the printing speed and the needle size of the embedded phase were examined. Owning to their appearance, modular nature, ease of personalizing dose and geometry, and tailoring and potential inclusion of various materials, this new dosage form concept holds a substantial promise for novel dosage forms in pediatrics.

[1]  L. Hartling,et al.  Combined and alternating paracetamol and ibuprofen therapy for febrile children. , 2013, The Cochrane database of systematic reviews.

[2]  J. Rivera-Leyva,et al.  Comparative Studies on the Dissolution Profiles of Oral Ibuprofen Suspension and Commercial Tablets using Biopharmaceutical Classification System Criteria , 2012, Indian journal of pharmaceutical sciences.

[3]  Chaomin Wan,et al.  Alternating Acetaminophen and Ibuprofen versus Monotherapies in Improvements of Distress and Reducing Refractory Fever in Febrile Children: A Randomized Controlled Trial , 2017, Pediatric Drugs.

[4]  Abdullah Isreb,et al.  ‘Temporary Plasticiser’: A novel solution to fabricate 3D printed patient‐centred cardiovascular ‘Polypill’ architectures , 2019, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[5]  Simon Gaisford,et al.  3D printed medicines: A new branch of digital healthcare , 2018, International journal of pharmaceutics.

[6]  Maren Preis,et al.  3D-Printed Drugs for Children—Are We Ready Yet? , 2017, AAPS PharmSciTech.

[7]  H. Kokki Nonsteroidal Anti-Inflammatory Drugs for Postoperative Pain , 2003, Paediatric drugs.

[8]  C. Giaquinto,et al.  Paediatric drug development: the impact of evolving regulations. , 2014, Advanced drug delivery reviews.

[9]  I. Paul,et al.  Efficacy of standard doses of Ibuprofen alone, alternating, and combined with acetaminophen for the treatment of febrile children. , 2010, Clinical therapeutics.

[10]  K. Imai Alendronate sodium hydrate (oral jelly) for the treatment of osteoporosis: review of a novel, easy to swallow formulation , 2013, Clinical interventions in aging.

[11]  M. Sierakowski,et al.  Specific modifications of galactomannans , 2000 .

[12]  Pamela Robles Martinez,et al.  Fabrication of drug-loaded hydrogels with stereolithographic 3D printing. , 2017, International journal of pharmaceutics.

[13]  Matthew Roberts,et al.  Content uniformity of quartered hydrocortisone tablets in comparison with mini-tablets for paediatric dosing , 2018, BMJ Paediatrics Open.

[14]  C. Tuleu,et al.  Patient-Centered Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations , 2014, Drugs.

[15]  H. Batchelor,et al.  COMPARISON OF HYDROCORTISONE 10 MG TABLETS: TABLET HARDNESS OPTIMISED FOR ADULT USE HAS NEGATIVE CONSEQUENCES FOR PAEDIATRIC USE , 2016, Archives of Disease in Childhood.

[16]  T. Hanawa,et al.  New oral dosage form for elderly patients: preparation and characterization of silk fibroin gel. , 1995, Chemical & pharmaceutical bulletin.

[17]  M. M. Alves,et al.  Phase equilibria and mechanical properties of gel-like water-gelatin-locust bean gum systems. , 2000, International journal of biological macromolecules.

[18]  Maren Preis,et al.  3D-Printed Isoniazid Tablets for the Treatment and Prevention of Tuberculosis—Personalized Dosing and Drug Release , 2019, AAPS PharmSciTech.

[19]  C. Tuleu,et al.  Age-appropriate and acceptable paediatric dosage forms: Insights into end-user perceptions, preferences and practices from the Children's Acceptability of Oral Formulations (CALF) Study. , 2016, International journal of pharmaceutics.

[20]  Amine Bermak,et al.  Recent Developments in Printing Flexible and Wearable Sensing Electronics for Healthcare Applications , 2019, Sensors.

[21]  Antonios G Mikos,et al.  Gelatin as a delivery vehicle for the controlled release of bioactive molecules. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Soo‐Yeun Lee,et al.  Consumer Acceptance of Bars and Gummies with Unencapsulated and Encapsulated Resveratrol. , 2016, Journal of food science.

[23]  P. Timmins,et al.  On demand manufacturing of patient‐specific liquid capsules via co‐ordinated 3D printing and liquid dispensing , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[24]  Dennis Douroumis,et al.  3D Printed “Starmix” Drug Loaded Dosage Forms for Paediatric Applications , 2018, Pharmaceutical Research.

[25]  M. Zilberman,et al.  Drug delivery from gelatin-based systems , 2015, Expert opinion on drug delivery.

[26]  Matthew Peak,et al.  3D printed oral theophylline doses with innovative 'radiator-like' design: Impact of polyethylene oxide (PEO) molecular weight. , 2019, International journal of pharmaceutics.

[27]  Waqar Ahmed,et al.  Emergence of 3D Printed Dosage Forms: Opportunities and Challenges , 2016, Pharmaceutical Research.

[28]  Howard A Stone,et al.  Viscoplastic Matrix Materials for Embedded 3D Printing. , 2018, ACS applied materials & interfaces.

[29]  Daniel M. Vogt,et al.  Soft Somatosensitive Actuators via Embedded 3D Printing , 2018, Advanced materials.

[30]  A. Schilder,et al.  Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children. , 2016, The Cochrane database of systematic reviews.

[31]  K. S. Parvathy,et al.  A simple non-aqueous method for carboxymethylation of galactomannans , 2005 .

[32]  Peter Timmins,et al.  From ‘fixed dose combinations’ to ‘a dynamic dose combiner’: 3D printed bi‐layer antihypertensive tablets , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[33]  Sharmila Baliga,et al.  Salivary pH: A diagnostic biomarker , 2013, Journal of Indian Society of Periodontology.

[34]  C. Wagner,et al.  Bioequivalence Studies of Vitamin D Gummies and Tablets in Healthy Adults: Results of a Cross-Over Study , 2019, Nutrients.

[35]  I. Endo,et al.  A Comparative Study of Intravenous Injection Form and Oral Jelly Form of Alendronate Sodium Hydrate for Bone Mineral Disorder after Gastrectomy , 2017, Digestion.

[36]  Jennifer R. Brown,et al.  Rheology of dispersions of xanthan gum, locust bean gum and mixed biopolymer gel with silicon dioxide nanoparticles. , 2015, Materials science & engineering. C, Materials for biological applications.

[37]  Daniel M. Vogt,et al.  Embedded 3D Printing of Strain Sensors within Highly Stretchable Elastomers , 2014, Advanced materials.

[38]  W. J. Irwin,et al.  The Effect of Selected Water-Soluble Excipients on the Dissolution of Paracetamol and Ibuprofen , 2005, Drug development and industrial pharmacy.

[39]  L. Hartling,et al.  Combined and alternating paracetamol and ibuprofen therapy for febrile children. , 2013, Evidence-based child health : a Cochrane review journal.

[40]  L. Hartling,et al.  Cochrane in context: Combined and alternating paracetamol and ibuprofen therapy for febrile children. , 2014, Evidence-based child health : a Cochrane review journal.

[41]  Rohith R Malya Does combination treatment with ibuprofen and acetaminophen improve fever control? , 2013, Annals of emergency medicine.