The Use of natural Products in 3D Printing of Pharmaceutical Dosage Forms

Background: Three-dimensional printing (3DP) has been investigated widely for applications in pharmaceutical sciences. Different 3DP techniques have been employed such as fused deposition modelling (FDM 3DP), powder bed 3DP, stereolithography 3DP (SLA 3DP), selective laser sintering (SLS 3DP), pates-extrusion 3DP and inkjet 3DP. Aim: This article aims to explore the use of natural products as active ingredient or excipient. Methods: Literature search was conduced for latest applications of 3DP for pharmaceutical dosage forms, and typical employed materials were identified. Results: Polymeric materials form the main bulk of 3DP excipients such as polyvinyl alcohol or ploy lactic acid. Chemical stabilisers may be added to these polymers to increase their stability at high temperatures during hot melt extrusion for making filaments or printing. In addition, photoinitiators have been added such as diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide in SLA 3DP, or candurin gold sheen in SLS 3DP. Presence of lead has been detected in FDM £DP, which originated from the nozzle. Currently, natural products have been employed only in paste extrusion 3DP of pharmaceutical dosage forms. We have identified a protentional natural thermoplastic polymer that may be used in 3DP FDM. Conclusion: Natural products may be employed in 3DP of pharmaceutical dosage forms to improve the safety profile of printed objects

The Effect of Ethanol Evaporation on the Properties of Inkjet Produced Liposomes

Background: Inkjet method has been used to produce nano-sized liposomes with a uniform size distribution. However, following the production of liposomes by inkjet method, the solvent residue in the product could have a significant effect on the properties of the final liposomes. Objective: This research paper aimed to find a suitable method to remove ethanol content and to study its effect on the properties of the final liposomal suspension. Method: Egg phosphatidylcholine and lidocaine were dissolved in ethanol; and inkjet method at 80 kHz was applied to produce uniform droplets, which were deposited in an aqueous solution to form liposomes. Dry nitrogen gas flow, air-drying, and rotary evaporator were tested to remove the ethanol content. Liposome properties such as size, polydispersity index (PDI), and charge were screened before and after ethanol evaporation. Results: Only rotary evaporator (at constant speed and room temperature for 2 hours) removed all of the ethanol content, with a final drug entrapment efficiency (EE) of 29.44 ± 6.77%. This was higher than a conventional method. Furthermore, removing ethanol led to liposome size reduction from approximately 200 nm to less than 100 nm in most samples. Additionally, this increased the liposomal net charge, which contributed to maintain the uniform and narrow size distribution of liposomes. Conclusion: Nano-sized liposomes were produced with a narrow PDI and higher EE compared to a conventional method by using an inkjet method. Moreover, rotary evaporator for 2 hours reduced effectively the ethanol content, while maintaining the narrow size distribution

Next steps in 3D Printing of Fast Dissolving oral Films for Commercial Production.

3D printing technique has been utilised to develop novel and complex drug delivery systems that are almost impossible to produce by employing conventional formulation techniques. For example, this technique may be employed to produce tablets or fast dissolving oral films (FDFs) with multilayers of active ingredients, which are personalised to patient's needs. In this article, we compared the production of FDFs by 3D printing to conventional methods such as solvent casting. Then, we evaluated the need for novel methods of producing fast dissolving oral films; and why 3D printing may be able to meet the short falls of FDF production. The challenges of producing 3D printed FDFs are identified at commercial scale by referring to the identification of suitable materials, hardware, quality control tests and Process Analytical Technology. In this paper we discuss that the FDF market will grow to more than $1.3 billion per annum in next few years and 3D printing of FDFs may share part of this market. Although, companies are continuing to invest in technologies which provide alternatives to standard drug delivery systems, the market for thin film products is already well established. Market entry for a new technology such as 3D printing of FDFs will, therefore, be hard, unless, this technology proves to be a game changer. A few approaches are suggested in this paper

The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease.

Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments

Development of High-Throughput Glass Inkjet Devices for Pharmaceutical Applications

The application of the inkjet method to pharmaceutical products is promising. To make this realistic, not only does the throughput of this method need to be increased, but also the components should be inert to pharmaceutical preparations. We present designs of glass‐based inkjet devices that are capable of producing droplets at high rates. To achieve this, inkjet devices from glass capillary tubes were manufactured with orifice diameters of 5, 10 and 20 μm and were actuated with diaphragm piezoelectric disks. Also, a pressure capsule was formed by creating a manifold at a distance from the orifice tip. Placing the piezoelectric disk at 0.5 mm distance from the tip allowed the formation of a jet at 3.2 MHz in certain designs, but for a short period of time because of overheating. The length of the pressure capsule, its inlet diameter, and the nozzle tip geometry were crucial to lower the required power. Actuating an inkjet device with 10 μm orifice diameter comfortably at 900 kHz and drying the droplets from 1% salbutamol sulphate solution allowed the formation of particles with diameters of 1.76 ± 0.15 μm and the geometric standard deviation of 1.08. In conclusion, optimising internal design of glass inkjet devices allowed the production of high‐throughput droplet ejectors. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3733–3742, 201

The Application of 3D Printing in the Formulation of Multilayered Fast Dissolving Oral Films.

Fast dissolving oral films (FDFs) provide an alternative approach to increase consumer acceptance by advantage of rapid dissolution and administration without water. Usually FDFs require taste-masking agents. However, inclusion of these excipients could make developing the formulation a challenging task. Hence, this work employed fused-deposition modelling three-dimensional (FDM 3D) printing to produce single-layered (SLFDFs), or multilayered (MLFDFs) films, with taste-masking layers being separated from drug layer. Filaments were prepared containing polyethylene oxide (PEO) with ibuprofen or paracetamol as model drugs at 60°C. Also filaments were produced containing polyvinyl alcohol (PVA) and paracetamol at 130°C. Furthermore, a filament was prepared containing PEO and strawberry powder for taste-masking layer. FDFs were printed at temperatures of 165°C (PEO) or 190ºC (PVA) with plain or mesh designs. HPLC and mass-spectroscopy analysis indicated active ingredient stability during film preparation process. SLFDFs had thicknesses as small as 197±21μm, and MLFDFs had thicknesses starting from 298±15μm. Depending on the formulation and design, mesh SLFDFs presented disintegration time as short as 42±7s, and this was 48±5s for mesh MLFDFs. SLFDFs showed drug content uniformity in the range of 106.0%-112.4%. In conclusion, this study provides proof-of-concept for the manufacturing of FDFs by using 3D printing

The Use of Micro-Ribbons and Micro-Fibres in the Formulation of 3D Printed Fast Dissolving Oral Films

Three-dimensional printing (3DP) allows production of novel fast dissolving oral films (FDFs). However, mechanical properties of the films may not be desirable when certain excipients are used. This work investigated whether adding chitosan micro-ribbons or cellulose microfibres will achieve desired FDFs by fused deposition modelling 3DP. Filaments containing polyvinyl alcohol (PVA) and paracetamol as model drug were manufactured at 170 °C. At 130 °C, filaments containing polyvinylpyrrolidone (PVP) and paracetamol were also created. FDFs were printed with plain or mesh patterns at temperatures of 200 °C (PVA) or 180 °C (PVP). Both chitosan micro-ribbons and cellulose micro-fibres improved filament mechanical properties at 1% w/w concentration in terms of flexibility and stiffness. The filaments were not suitable for printing at higher concentrations of chitosan micro-ribbons and cellulose micro-fibres. Furthermore, mesh FDFs containing only 1% chitosan micro-ribbons disintegrated in distilled water within 40.33 ± 4.64 s, while mesh FDFs containing only 7% croscarmellose disintegrated in 55.33 ± 2.86 s, and croscarmellose containing films showed signs of excipient scorching for PVA polymer. Cellulose micro-fibres delayed disintegration of PVA mesh films to 108.66 ± 3.68 s at 1% w/w. In conclusion, only chitosan micro-ribbons created a network of hydrophilic channels within the films, which allowed faster disintegration time at considerably lower concentrations

The Inclusion of a Matrix Metalloproteinase-9 Responsive Sequence in Self-assembled Peptide-based Brain-Targeting Nanoparticles Improves the Efficiency of Nanoparticles Crossing the Blood-Brain Barrier at Elevated MMP-9 Levels

This study investigated whether the inclusion of a matrix metalloproteinase-9 (MMP-9) responsive sequence in self-assembled peptide-based brain-targeting nanoparticles (NPs) would enhance the blood-brain barrier (BBB) penetration when MMP-9 levels are elevated both in the brain and blood circulation. Brain-targeting peptides were conjugated at the N-terminus to MMP-9-responsive peptides, and these were conjugated at the N-terminus to lipid moiety (cholesteryl chloroformate or palmitic acid). Two constructs did not have MMP-9-responsive peptides. NPs were characterised for size, charge, critical micelle concentration, toxicity, blood compatibility, neural cell uptake, release profiles, and in vitro BBB permeability simulating normal or elevated MMP-9 levels. The inclusion of MMP-9-sensitive sequences did not improve the release of a model drug in the presence of active MMP-9 from NPs compared to distilled water. 19F NMR studies suggested the burial of MMP-9-sensitive sequences inside the NPs making them inaccessible to MMP-9. Only cholesterol-GGGCKAPETALC (responsive to MMP-9) NPs showed <5% haemolysis, <1 pg/mL release of IL-1β at 500 μg/mL from THP1 cells, with 70.75 ± 5.78% of NPs crossing the BBB at 24 h in presence of active MMP-9. In conclusion, brain-targeting NPs showed higher transport across the BBB model when MMP-9 levels were elevated and the brain-targeting ligand was responsive to MMP-9

Potential of a cyclone prototype spacer to improve in vitro dry powder delivery

Copyright The Author(s) 2013. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPurpose: Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrierbased DPIs was investigated. Methods: Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30-60 Lmin-1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography. Results: Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89 ± 6.51 % at 30 Lmin-1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08 ± 0.05 μm vs. 3.00 ± 0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates. Conclusion: This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.Peer reviewe