Oral drug delivery systems using core–shell structure additive manufacturing technologies: a proof-of-concept study

Abstract Objectives The aim of this study was to couple fused deposition modelling 3D printing with melt extrusion technology to produce core–shell-structured controlled-release tablets with dual-mechanism drug-release performance in a simulated intestinal fluid medium. Coupling abovementioned technologies for personalized drug delivery can improve access to complex dosage formulations at a reasonable cost. Compared with traditional pharmaceutical manufacturing, this should facilitate the following: (1) the ability to manipulate drug release by adjusting structures, (2) enhanced solubility and bioavailability of poorly water-soluble drugs and (3) on-demand production of more complex structured dosages for personalized treatment. Methods Acetaminophen was the model drug and the extrusion process was evaluated by a series of physicochemical characterizations. The geometries, morphologies, and in vitro drug-release performances were compared between directly compressed and 3D-printed tablets. Key findings Initially, 3D-printed tablets released acetaminophen more rapidly than directly compressed tablets. Drug release became constant and steady after a pre-determined time. Thus, rapid effectiveness was ensured by an initially fast acetaminophen release and an extended therapeutic effect was achieved by stabilizing drug release. Conclusions The favourable drug-release profiles of 3D-printed tablets demonstrated the advantage of coupling HME with 3D printing technology to produce personalized dosage formulations.

Download Full-text

3D-Printed Isoniazid Tablets for the Treatment and Prevention of Tuberculosis—Personalized Dosing and Drug Release

AAPS PharmSciTech ◽

10.1208/s12249-018-1233-7 ◽

2019 ◽

Vol 20 (2) ◽

Cited By ~ 39

Author(s):

Heidi Öblom ◽

Jiaxiang Zhang ◽

Manjeet Pimparade ◽

Isabell Speer ◽

Maren Preis ◽

...

Keyword(s):

3D Printing ◽

Drug Release ◽

Oral Drug Delivery ◽

Dosage Forms ◽

Oral Dosage ◽

Oral Drug ◽

Fused Deposition ◽

3D Printed ◽

Hot Melt ◽

Release Profiles

Abstract The aim of the present work was to produce 3D-printed oral dosage forms with a sufficient drug dose displaying various release profiles. Hot-melt extrusion was utilized to produce drug-loaded feedstock material that was subsequently 3D-printed into 6, 8, and 10 × 2.5 mm tablets with 15% and 90% infill levels. The prepared formulations contained 30% (w/w) isoniazid in combination with one or multiple pharmaceutical polymers possessing suitable properties for oral drug delivery. Thirteen formulations were successfully hot-melt extruded of which eight had properties suitable for fused deposition modeling 3D printing. Formulations containing HPC were found to be superior regarding printability in this study. Filaments with a breaking distance below 1.5 mm were observed to be too brittle to be fed into the printer. In addition, filaments with high moisture uptake at high relative humidity generally failed to be printable. Different release profiles for the 3D-printed tablets were obtained as a result of using different polymers in the printed formulations. For 8 mm tablets printed with 90% infill, 80% isoniazid release was observed between 40 and 852 min. Drug release characteristics could further be altered by changing the infill or the size of the printed tablets allowing personalization of the tablets. This study presents novel formulations containing isoniazid for prevention of latent tuberculosis and investigates 3D printing technology for personalized production of oral solid dosage forms enabling adjustable dose and drug release properties.

Download Full-text

Biodegradable 3D Printed Polymer Microneedles for Transdermal Drug Delivery

10.26434/chemrxiv.5851950.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michael A. Luzuriaga ◽

Danielle R. Berry ◽

John C. Reagan ◽

Ronald A. Smaldone ◽

Jeremiah J. Gassensmith

Keyword(s):

Drug Delivery ◽

3D Printing ◽

Transdermal Drug Delivery ◽

Fused Deposition Modeling ◽

Fused Deposition ◽

Modeling Software ◽

Deposition Modeling ◽

3D Printed ◽

Microfabrication Technique ◽

Mechanical Strengths

Biodegradable polymer microneedle (MN) arrays are an emerging class of transdermal drug delivery devices that promise a painless and sanitary alternative to syringes; however, prototyping bespoke needle architectures is expensive and requires production of new master templates. Here, we present a new microfabrication technique for MNs using fused deposition modeling (FDM) 3D printing using polylactic acid, an FDA approved, renewable, biodegradable, thermoplastic material. We show how this natural degradability can be exploited to overcome a key challenge of FDM 3D printing, in particular the low resolution of these printers. We improved the feature size of the printed parts significantly by developing a post fabrication chemical etching protocol, which allowed us to access tip sizes as small as 1 μm. With 3D modeling software, various MN shapes were designed and printed rapidly with custom needle density, length, and shape. Scanning electron microscopy confirmed that our method resulted in needle tip sizes in the range of 1 – 55 µm, which could successfully penetrate and break off into porcine skin. We have also shown that these MNs have comparable mechanical strengths to currently fabricated MNs and we further demonstrated how the swellability of PLA can be exploited to load small molecule drugs and how its degradability in skin can release those small molecules over time.

Download Full-text

Novel On-Demand 3-Dimensional (3-D) Printed Tablets Using Fill Density as an Effective Release-Controlling Tool

Polymers ◽

10.3390/polym12091872 ◽

2020 ◽

Vol 12 (9) ◽

pp. 1872 ◽

Cited By ~ 4

Author(s):

Rishi Thakkar ◽

Amit Raviraj Pillai ◽

Jiaxiang Zhang ◽

Yu Zhang ◽

Vineet Kulkarni ◽

...

Keyword(s):

Drug Release ◽

Hydroxypropyl Methylcellulose ◽

Amorphous State ◽

Dosage Forms ◽

Water Soluble ◽

Patient Specific ◽

3 Dimensional ◽

Fused Deposition ◽

3D Printed ◽

The Impact

This research demonstrates the use of fill density as an effective tool for controlling the drug release without changing the formulation composition. The merger of hot-melt extrusion (HME) with fused deposition modeling (FDM)-based 3-dimensional (3-D) printing processes over the last decade has directed pharmaceutical research towards the possibility of printing personalized medication. One key aspect of printing patient-specific dosage forms is controlling the release dynamics based on the patient’s needs. The purpose of this research was to understand the impact of fill density and interrelate it with the release of a poorly water-soluble, weakly acidic, active pharmaceutical ingredient (API) from a hydroxypropyl methylcellulose acetate succinate (HPMC-AS) matrix, both mathematically and experimentally. Amorphous solid dispersions (ASDs) of ibuprofen with three grades of AquaSolveTM HPMC-AS (HG, MG, and LG) were developed using an HME process and evaluated using solid-state characterization techniques. Differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), and polarized light microscopy (PLM) confirmed the amorphous state of the drug in both polymeric filaments and 3D printed tablets. The suitability of the manufactured filaments for FDM processes was investigated using texture analysis (TA) which showed robust mechanical properties of the developed filament compositions. Using FDM, tablets with different fill densities (20–80%) and identical dimensions were printed for each polymer. In vitro pH shift dissolution studies revealed that the fill density has a significant impact (F(11, 24) = 15,271.147, p < 0.0001) and a strong negative correlation (r > −0.99; p < 0.0001) with the release performance, where 20% infill demonstrated the fastest and most complete release, whereas 80% infill depicted a more controlled release. The results obtained from this research can be used to develop a robust formulation strategy to control the drug release from 3D printed dosage forms as a function of fill density.

Download Full-text

O22 3D printed polyethylene oxide oral doses with innovative ‘radiator-like’ design: impact of molecular weight on mechanical and rheological properties and drug release

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.22 ◽

2019 ◽

Vol 104 (6) ◽

pp. e10.1-e10 ◽

Cited By ~ 2

Author(s):

M Peak ◽

K Baj ◽

A Isreb ◽

M Wojsz ◽

I Mohammad ◽

...

Keyword(s):

Molecular Weight ◽

3D Printing ◽

Drug Release ◽

Rheological Properties ◽

Oral Dosage ◽

Parallel Plates ◽

Fused Deposition ◽

Plate Spacing ◽

3D Printed ◽

The Impact

BackgroundDespite regulatory advances, lack of age-appropriate formulations (AAFs) remains a challenge in paediatric practice. 3D-printing of oral dosage forms (ODFs) offers potential for AAFs for children. Optimising drug release from 3D-printed ODFs is an important technological step. Despite the abundant use of polyethylene oxides (PEOs) and their extensive use as an excipient, there have been no previous reports of applying this thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. We assessed the impact of polymer molecular weight (MW) on the mechanical properties of the resultant filaments and their rheological properties. In the FDM 3D printing process, we also tested the effect of an innovative radiator-like design of the ODF on the acceleration of drug release patterns.MethodsBlends of PEO (MW: 100K, 200K, 300K, 600K or 900K) with PEG 6K (plasticiser) and a model drug (theophylline) were prepared by hot-melt extrusion. The resultant filaments were used as a feed for a FDM 3D printer to fabricate innovative designs of ODFs in a radiator-like geometry with inter-connected paralleled plates and inter-plate spacing of either 0.5mm, 1mm, 1.5mm or 2mm.ResultsVarying blends of PEO and PEG allowed formation of mechanically resistant filaments (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with 100K, 200K, 300K, 600K or 900K, respectively). Filaments of PEO at a MW of 200K-600K were compatible with FDM 3D printing. Further increase in PEO MW resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing. A minimum spacing (1 mm) between parallel plates of the radiator-like design was essential to boost drug release from the structure.ConclusionThese findings are essential in the development of next-generation personalised drug delivery doses using specialised polymer/polymer blends purposely optimised for FDM 3D printing.Disclosure(s)Nothing to disclose

Download Full-text

Biodegradable 3D Printed Polymer Microneedles for Transdermal Drug Delivery

10.26434/chemrxiv.5851950 ◽

2018 ◽

Author(s):

Michael A. Luzuriaga ◽

Danielle R. Berry ◽

John C. Reagan ◽

Ronald A. Smaldone ◽

Jeremiah J. Gassensmith

Keyword(s):

Drug Delivery ◽

3D Printing ◽

Transdermal Drug Delivery ◽

Fused Deposition Modeling ◽

Fused Deposition ◽

Modeling Software ◽

Deposition Modeling ◽

3D Printed ◽

Microfabrication Technique ◽

Mechanical Strengths

Download Full-text

The Accuracy and the Printing Resolution Comparison of Different 3D Printing Technologies

Transactions on Aerospace Research ◽

10.2478/tar-2018-0023 ◽

2018 ◽

Vol 2018 (3) ◽

pp. 69-86 ◽

Cited By ~ 1

Author(s):

Ewelina Kluska ◽

Piotr Gruda ◽

Natalia Majca-Nowak

Keyword(s):

3D Printing ◽

Fused Deposition Modeling ◽

Selective Laser Sintering ◽

Water Soluble ◽

Optical Methods ◽

Fused Deposition ◽

Material Texture ◽

Deposition Modeling ◽

3D Printed ◽

Reference Specimens

Abstract The article presents a research conducted with the project: ‘Additive technology used in conduction with optical methods for rapid prototyping of 3D printed models’ [13]. In this article selected three different 3D printing technologies: Fused Deposition Modeling (FDM), Selective Laser Sintering (SLS) and Material Jetting (MJ). Each of them was tested paying special attention to accuracy and resolution of printed elements. Accuracy tests were conducted on the reference specimens which also showed material texture. These specimens were scanned to verified dimensional deviations of printing methods. Printing resolution was verified on a heat exchanger model which was characterized by complicated structure. The highest accuracy and printing resolution was noticed in the MJ technology, PolyJet method on the Objet Eden 260 VS printing machine and the SUP 707 water soluble support material.

Download Full-text

Formulation and Evaluation of 3D Printed Pregabalin Tablets Targeted For Neuropathic Pain By Qbd Approach For Personalized Medicine

International Journal of Pharma and Bio Sciences ◽

10.22376/ijpbs/lpr.2021.11.6.p1-13 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1-13

Author(s):

Bhusnure omprakash Gadgeppa ◽

Mule Shrikrishna Tukaram ◽

Gholvesachin Baburo ◽

Giram padamja Sidram ◽

Gaurav Agarwal Prof.(Dr) ◽

...

Keyword(s):

Neuropathic Pain ◽

3D Printing ◽

Drug Release ◽

Thermo Gravimetric Analysis ◽

Processing Condition ◽

Gravimetric Analysis ◽

Printing Technology ◽

3D Printing Technology ◽

Fused Deposition ◽

3D Printed

The 3D printing technology has been newly employed in the design and formulation of different dosage forms with the aim formulation and evaluation of 3D printed Pregabalin tablets for the treatment of neuropathic pain by QbD approach. Drug (Pregabalin) together with other excipients, were mixed and extruded into filaments by hot melt extrusion. Then with the help of fused deposition modeling these obtained filaments were printed into tablets. Due to the use of different polymers in the printed formulation different release profiles for the 3D printed tablets were obtained. Drug release characteristics change the infill or the size of the printed tablets, allowing the personalization of the tablets. Filaments and tablets were characterized by means of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X- RAY powder diffraction (XRPD), and thermo gravimetric analysis (TGA). The results showed that after printing, the processing condition did not have a significant impact on the stability of the drug and the crystalline nature of the drug remained. FDM 3D printing makes it possible not only to formulate 3D printing Pregabalin tablets for the treatment of neuropathic pain but also to modify the potential of additive manufacturing in the development of personalized dose medicines. This study presents novel formulations containing Pregabalin for prevention of neuropathic pain and investigates 3D printing technology for personalized production of oral solid dosage from enabling adjustable dose as well as drug release properties.

Download Full-text

Preformulation Studies and Bioavailability Enhancement of Curcumin with a ‘Two in One’ PEG-β-Cyclodextrin Polymer

Pharmaceutics ◽

10.3390/pharmaceutics13101710 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1710

Author(s):

Ádám Haimhoffer ◽

Eleftheria Dossi ◽

Monika Béresová ◽

Ildikó Bácskay ◽

Judit Váradi ◽

...

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Oral Drug Delivery ◽

Porous Matrix ◽

Water Soluble ◽

Oral Drug ◽

Phase Solubility ◽

Bioavailability Enhancement ◽

Preformulation Studies ◽

Biopharmaceutical Properties

Drug delivery systems are used to improve the biopharmaceutical properties of curcumin. Our aim was to investigate the effect of a water-soluble ‘two in one’ polymer containing covalently bonded PEG and βCD moieties (βCPCD) on the solubility and bioavailability of curcumin and compare it to a polymeric β-cyclodextrin (βCDP) cross-linked with epichlorohydrin. Phase-solubility and dynamic light scattering (DLS) experiments showed that the solubility of curcumin increased significantly in 10 m/m % βCPCD and βCDP solutions, but βCPCD–curcumin particles had higher hydrodynamic volume. The formation of the βCPCD–curcumin complex in solution and sedimented phase was confirmed by NMR spectroscopy. Biocompatibility and permeability experiments were performed on Caco-2 cells. Polymers did not show cytotoxicity up to 10 m/m % and βCPCD significantly increased the permeability of curcumin. DLS measurements revealed that among the interaction of polymers with mucin, βCPCD formed bigger aggregates compared to βCDP. Curcumin complexes were lyophilized into capsules and structurally characterized by micro-CT spectroscopy. Drug release was tested in a pH 1.2 medium. Lyophilized complexes had a solid porous matrix and both βCPCD and βCDP showed rapid drug release. βCPCD provides an opportunity to create a swellable, mucoadhesive matrix system for oral drug delivery.

Download Full-text

3D Printing Technology in Customized Drug Delivery System: Current State of the Art, Prospective and the Challenges

Current Pharmaceutical Design ◽

10.2174/1381612825666190110153742 ◽

2019 ◽

Vol 24 (42) ◽

pp. 5049-5061 ◽

Cited By ~ 6

Author(s):

Farooq A. Khan ◽

Kaushik Narasimhan ◽

C.S.V. Swathi ◽

Sayyad Mustak ◽

Gulam Mustafa ◽

...

Keyword(s):

Drug Delivery ◽

3D Printing ◽

Drug Delivery System ◽

Delivery System ◽

Pharmaceutical Products ◽

Drug Formulation ◽

Formulation Development ◽

Fused Deposition ◽

Current State ◽

3D Printed

Background: 3D printing/Additive Manufacturing seems a pragmatic approach to realize the quest for a truly customized and personalized drug delivery. 3DP technology, with innovations in pharmaceutical development and an interdisciplinary approach to finding newer Drug Delivery Systems can usher a new era of treatments to various diseases. The true potential of this is yet to be realized, and the US-FDA is focusing on the regulatory science of 3D printed medical devices to help patients access this technology safely and effectively. The approval of the first 3D printed prescription medicine by FDA is a promising step in the translation of more research in this area. Methods: A web-search on PubMed, ScienceDirect, and Nature was performed with the keywords Customized 3D printing and Drug delivery, publications dealing with the aspects of drug delivery using 3D printing for personalized or customized delivery were further considered and analyzed and discussed. Results: We present the advantages offered by 3DP over conventional methods of formulation development and discuss the current state of 3DP in pharmaceutics and how it can be used to develop a truly customized drug delivery system, various 3DP technologies including Stereolithography (SLA), Selective Laser Sintering (SLS), Fused Deposition Modelling (FDM), Pressure Assisted Microsyringe (PAM) that have been used to develop pharmaceutical products have been discussed along with their limitations and also the regulatory considerations to help formulation scientists envisaging research in this area with the necessary information. Conclusion: 3D printing has the potential to fabricate a customized drug delivery system. Presence of many drug formulation and the devices are already in the regulatory approval process indicating its success.

Download Full-text

Probing the Release of Bupropion and Naltrexone Hydrochloride Salts from Biopolymeric Matrices of Diverse Chemical Structures

Polymers ◽

10.3390/polym13091456 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1456

Author(s):

Angeliki Siamidi ◽

Aikaterini Dedeloudi ◽

Marilena Vlachou

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Oral Drug Delivery ◽

Ethyl Acrylate ◽

Water Soluble ◽

Oral Drug ◽

High Molecular Weight Polymer ◽

Molecular Weight Polymer ◽

Chemical Structures ◽

Naltrexone Hydrochloride

In the last decades, the notion of including excipients in the formulations, as inert substances aiding production processes, has changed and they are recently viewed as multifunctional discrete entities. It is now well documented that excipients serve several roles, spreading from the stabilization and modified release, to providing biocompatible properties and targeting moieties. The aim of this study was to develop matrix-based oral drug delivery systems of bupropion hydrochloride (BUP·HCl) and naltrexone hydrochloride (NTX·HCl), suitable for releasing these active substances in a modified manner, providing a stable level of drug release, which is simultaneously therapeutically effective and non-toxic, thus reducing side effects, after a single dose administration, throughout the gastrointestinal tract. The new formulations, employing hydroxypropylmethycellulose (HPMC K15M) (a cellulosic polymer, which, generally hydrates to form a gelatinous layer that is critical to prevent wetting and rapid drug release from the matrices), poly(methacylic acid-co-ethyl acrylate) 1:1 (Eudragit® L100-55: effective for site specific drug delivery in intestine), poly(ethylene oxide) (PEO) (7 × 106: a high molecular weight polymer, water-soluble, in micro-granular powder form), as the rate controlling polymers, were chosen to lead to a “soothing out” release pattern of these drugs, at 0 ≤ t ≤ 120 min. Moreover, the release of the two drugs from the ulvan-based tablets, was found to follow the desired profile, throughout the entire course of the dissolution experiments.

Download Full-text