Understanding Direct Powder Extrusion for Fabrication of 3D Printed Personalised Medicines: A Case Study for Nifedipine Minitablets

Fuse deposition modelling (FDM) has emerged as a novel technology for manufacturing 3D printed medicines. However, it is a two-step process requiring the fabrication of filaments using a hot melt extruder with suitable properties prior to printing taking place, which can be a rate-limiting step in its application into clinical practice. Direct powder extrusion can overcome the difficulties encountered with fabrication of pharmaceutical-quality filaments for FDM, allowing the manufacturing, in a single step, of 3D printed solid dosage forms. In this study, we demonstrate the manufacturing of small-weight (<100 mg) solid dosage forms with high drug loading (25%) that can be easily undertaken by healthcare professionals to treat hypertension. 3D printed nifedipine minitablets containing 20 mg were manufactured by direct powder extrusion combining 15% polyethylene glycol 4000 Da, 40% hydroxypropyl cellulose, 19% hydroxy propyl methyl cellulose acetate succinate, and 1% magnesium stearate. The fabricated 3D printed minitablets of small overall weight did not disintegrate during dissolution and allowed for controlled drug release over 24 h, based on erosion. This release profile of the printed minitablets is more suitable for hypertensive patients than immediate-release tablets that can lead to a marked burst effect, triggering hypotension. The small size of the minitablet allows it to fit inside of a 0-size capsule and be combined with other minitablets, of other API, for the treatment of complex diseases requiring polypharmacy within a single dosage form.

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Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms

Pharmaceutics ◽

10.3390/pharmaceutics12040345 ◽

2020 ◽

Vol 12 (4) ◽

pp. 345 ◽

Cited By ~ 8

Author(s):

Jose R. Cerda ◽

Talaya Arifi ◽

Sejad Ayyoubi ◽

Peter Knief ◽

Maria Paloma Ballesteros ◽

...

Keyword(s):

Drug Loading ◽

Dosage Forms ◽

Passive Diffusion ◽

Oral Dosage ◽

Solubility Parameters ◽

Support Vector ◽

Clinical Settings ◽

Solid Dosage Forms ◽

Solid Dosage ◽

3D Printed

Although not readily accessible yet to many community and hospital pharmacists, fuse deposition modelling (FDM) is a 3D printing technique that can be used to create a 3D pharmaceutical dosage form by employing drug loaded filaments extruded via a nozzle, melted and deposited layer by layer. FDM requires printable filaments, which are commonly manufactured by hot melt extrusion, and identifying a suitable extrudable drug-excipient mixture can sometimes be challenging. We propose here the use of passive diffusion as an accessible loading method for filaments that can be printed using FDM technology to allow for the fabrication of oral personalised medicines in clinical settings. Utilising Hansen Solubility Parameters (HSP) and the concept of HSP distances (Ra) between drug, solvent, and filament, we have developed a facile pre-screening tool for the selection of the optimal combination that can provide a high drug loading (a high solvent-drug Ra, >10, and an intermediate solvent–filament Ra value, ~10). We have identified that other parameters such as surface roughness and stiffness also play a key role in enhancing passive diffusion of the drug into the filaments. A predictive model for drug loading was developed based on Support Vector Machine (SVM) regression and indicated a strong correlation between both Ra and filament stiffness and the diffusion capacity of a model BCS Class II drug, nifedipine (NFD), into the filaments. A drug loading, close to 3% w/w, was achieved. 3D printed tablets prepared using a PVA-derived filament (Hydrosupport, 3D Fuel) showed promising characteristics in terms of dissolution (with a sustained release over 24 h) and predicted chemical stability (>3 years at 25 °C/60% relative humidity), similar to commercially available NFD oral dosage forms. We believe FDM coupled with passive diffusion could be implemented easily in clinical settings for the manufacture of tailored personalised medicines, which can be stored over long periods of time (similar to industrially manufactured solid dosage forms).

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An Effective Technology for the Development of Immediate Release Solid Dosage Forms Containing Low-Dose Drug: Fused Deposition Modeling 3D Printing

Pharmaceutical Research ◽

10.1007/s11095-019-2655-y ◽

2019 ◽

Vol 36 (9) ◽

Cited By ~ 13

Author(s):

Hazal Ezgi Gültekin ◽

Serdar Tort ◽

Füsun Acartürk

Keyword(s):

3D Printing ◽

Fused Deposition Modeling ◽

Low Dose ◽

Immediate Release ◽

Dosage Forms ◽

Solid Dosage Forms ◽

Solid Dosage ◽

Fused Deposition ◽

Effective Technology ◽

Deposition Modeling

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A comparative in vitro dissolution study of generic moxifloxacin immediate-release film coated tablets and referent pharmaceutical product

Macedonian Pharmaceutical Bulletin ◽

10.33320/maced.pharm.bull.2018.64.02.003 ◽

2019 ◽

Vol 64 (02) ◽

pp. 27-34

Author(s):

Emilija Janeva ◽

Liljana Anastasova ◽

Irena Slaveska Spirevska ◽

Tatjana Rusevska ◽

Tanja Bakovska Stoimenova ◽

...

Keyword(s):

Immediate Release ◽

Dosage Forms ◽

Pharmaceutical Product ◽

Generic Product ◽

In Vitro Dissolution ◽

Dissolution Behavior ◽

Solid Dosage Forms ◽

Solid Dosage ◽

Similarity Factor

Dissolution testing of generic immediate release solid dosage forms represents a valuable tool to obtain dissolution profiles and to establish the similarity/dissimilarity between tested dosage forms. In this study, the in vitro dissolution profiles of generic immediate-release moxifloxacin (MOX) film coated tablets and a referent pharmaceutical product were compared and evaluated. The dissolution behavior of the generic product was investigated in three different dissolution media (pH=1.2, 4.5 and 6.8). The amount of dissolved MOX was determined using validated UV spectrophotometric method. For comparison of the dissolution behavior, the similarity factor, f2, was used. The dissolution profile of the generic product showed a release of >85 % MOX in the time frame of 30 min, in all the tested dissolution media. The similarity factor, f2, calculated from the comparison of the dissolution profiles of the generic and the referent pharmaceutical product in pH=1.2 dissolution medium was 50, 58, thus the products were established as similar. Based on the results of our study, the dissolution similarity between the generic MOX immediate-release film coated tablet and the referent product could be successfully used as a part of the approach to ensure their in vivo bioequivalence. Keywords: moxifloxacin, immediate-release solid dosage forms, dissolution, in vitro similarity

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Recent Strategic Developments in the Use of Superdisintegrants for Drug Delivery

Current Pharmaceutical Design ◽

10.2174/1381612826666200122124621 ◽

2020 ◽

Vol 26 (6) ◽

pp. 701-709

Author(s):

Phuong H.L. Tran ◽

Thao T.D. Tran

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Controlled Drug Release ◽

Dosage Forms ◽

Delivery Systems ◽

Therapeutic Effects ◽

Drug Bioavailability ◽

Solid Dosage Forms ◽

Solid Dosage ◽

Innovative Materials

Improving drug bioavailability in the pharmaceutical field is a challenge that has attracted substantial interest worldwide. The controlled release of a drug can be achieved with a variety of strategies and novel materials in the field. In addition to the vast development of innovative materials for improving therapeutic effects and reducing side effects, the exploration of remarkable existing materials could encourage the discovery of diverse approaches for adapted drug delivery systems. Recently, superdisintegrants have been proposed for drug delivery systems as alternative approaches to maximize the efficiency of therapy. Although superdisintegrants are well known and used in solid dosage forms, studies on strategies for the development of drug delivery systems using superdisintegrants are lacking. Therefore, this study reviews the use of superdisintegrants in controlled drug release dosage formulations. This overview of superdisintegrants covers developed strategies, types (including synthetic and natural materials), dosage forms and techniques and will help to improve drug delivery systems.

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LUBRICANTS IN PHARMACEUTICAL SOLID DOSAGE FORMS WITH SPECIAL EMPHASIS ON MAGNESIUM STEARATE

World Journal of Pharmaceutical Research ◽

10.20959/wjpr20179-9170 ◽

2017 ◽

pp. 131-146

Author(s):

Poonam R. Kanher

Keyword(s):

Magnesium Stearate ◽

Dosage Forms ◽

Solid Dosage Forms ◽

Solid Dosage

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Controlled Release of 5-Fluorouracil from Alginate Beads Encapsulated in 3D Printed pH-Responsive Solid Dosage Forms

AAPS PharmSciTech ◽

10.1208/s12249-018-1084-2 ◽

2018 ◽

Vol 19 (8) ◽

pp. 3362-3375 ◽

Cited By ~ 22

Author(s):

Christos I. Gioumouxouzis ◽

Aikaterini-Theodora Chatzitaki ◽

Christina Karavasili ◽

Orestis L. Katsamenis ◽

Dimitrios Tzetzis ◽

...

Keyword(s):

Controlled Release ◽

Alginate Beads ◽

Dosage Forms ◽

Ph Responsive ◽

Solid Dosage Forms ◽

Solid Dosage ◽

3D Printed

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Polyvinyl Alcohol-Based 3D Printed Tablets: Novel Insight into the Influence of Polymer Particle Size on Filament Preparation and Drug Release Performance

Pharmaceuticals ◽

10.3390/ph14050418 ◽

2021 ◽

Vol 14 (5) ◽

pp. 418

Author(s):

Andrea Gabriela Crișan ◽

Alina Porfire ◽

Rita Ambrus ◽

Gábor Katona ◽

Lucia Maria Rus ◽

...

Keyword(s):

Particle Size ◽

Drug Release ◽

Polyvinyl Alcohol ◽

Fused Deposition Modeling ◽

Dosage Forms ◽

Solid Dosage Forms ◽

Manufacturing Method ◽

Solid Dosage ◽

Fused Deposition ◽

3D Printed

Three-dimensional printing (3DP) by fused deposition modeling (FDM) has gained momentum as a promising pharmaceutical manufacturing method due to encouraging forward-looking perspectives in personalized medicine preparation. The current challenges the technology has for applicability in the fabrication of solid dosage forms include the limited range of suitable pharmaceutical grade thermoplastic materials. Hence, it is important to investigate the implications of variable properties of the polymeric carrier on the preparation steps and the final output, as versatile products could be obtained by using the same material. In this study, we highlighted the influence of polyvinyl alcohol (PVA) particle size on the residence time of the mixtures in the extruder during the drug-loaded filament preparation step and the consequent impact on drug release from the 3D printed dosage form. We enhanced filament printability by exploiting the plasticizing potential of the active pharmaceutical ingredient (API) and we explored a channeled tablet model as a design strategy for dissolution facilitating purposes. Our findings disclosed a new perspective regarding material considerations for the preparation of PVA-based solid dosage forms by coupling hot melt extrusion (HME) and FDM-3DP.

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