Reducing Temperature of Fused Deposition Modelling 3D Printing for Linalool Fast Dissolving Oral Films by Increasing Printer Nozzle Diameter.

Oral thrush and throat infections can occur in a wide range of patients. Treatments are available; however, resistance to drugs is a major problem for treating oral and throat infections. Three-dimensional printing (3DP) of fast dissolving oral films (FDFs) of linalool oil may provide an alternative solution. Linalool oil FDFs were printed by fused deposition modelling across 1-18 % w/w linalool content range with nozzle diameters of 0.4 or 1 mm at the temperature range of 150 °C-185 °C. The FDFs were evaluated for physicochemical and mechanical properties. Increasing the printer nozzle diameter to 1 mm allowed reducing the printing temperature from 185 °C to 150 °C; consequently, more linalool was quantified in the films with improved content uniformity. The higher linalool content in the films increased the film disintegration time and mechanical strength. FDFs containing 10% w/w linalool showed clear antifungal activity against Candida albicans. Raman spectroscopy suggested linalool separation from excipients at higher temperature printing. Viscoelastic measurements indicated that to achieve printing; the elastic modulus of molten filament needed to be higher than the loss modulus at low angular frequencies. In conclusion, increasing the printing nozzle diameter may avoid loss of the active ingredient by reducing the temperature of the 3DP process.

Special Issue for "3D Printing of Drug Formulations".

Three-dimensional printing (3DP) is rapidly innovating the manufacturing process and provides opportunities that have never been seen before [...].

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-ß 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 17ß-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.

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 Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered- Dose Inhaler in the Treatment of COVID-19 Patients.

INTRODUCTION: Serious COVID-19 respiratory problems start when the virus reaches the alveolar level, where type II cells get infected and die. Therefore, virus inhibition at the alveolar level would help preventing these respiratory complications. METHOD: A literature search was conducted to collect physicochemical properties of small molecule compounds that could be used for the COVID-19 treatment. Compounds with low melting points were selected along with those soluble in ethanol, hydrogen-bond donors, and acceptors. RESULTS: There are severe acute respiratory syndrome coronavirus inhibitors with physicochemical properties suitable for the formulation as an ultrafine pressurised metered-dose inhaler (pMDI). Mycophenolic acid, Debio 025, and cyclosporine A are prime candidates among these compounds. Cyclosporine A (hereafter cyclosporine) is a potent SARS-CoV-2 inhibitor, and it has been used for the treatment of COVID-19 patients, demonstrating an improved survival rate. Also, inhalation therapy of nebulised cyclosporine was tolerated, which was used for patients with lung transplants. Finally, cyclosporine has been formulated as a solution ultrafine pMDI. Although vaccine therapy has started in most countries, inhalation therapies with non-immunological activities could minimise the spread of the disease and be used in vaccine-hesitant individuals. CONCLUSION: Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19.

Physiological and Pathological Factors Affecting Drug Delivery to the Brain by Nanoparticles.

The prevalence of neurological/neurodegenerative diseases, such as Alzheimer's disease is known to be increasing due to an aging population and is anticipated to further grow in the decades ahead. The treatment of brain diseases is challenging partly due to the inaccessibility of therapeutic agents to the brain. An increasingly important observation is that the physiology of the brain alters during many brain diseases, and aging adds even more to the complexity of the disease. There is a notion that the permeability of the blood-brain barrier (BBB) increases with aging or disease, however, the body has a defense mechanism that still retains the separation of the brain from harmful chemicals in the blood. This makes drug delivery to the diseased brain, even more challenging and complex task. Here, the physiological changes to the diseased brain and aged brain are covered in the context of drug delivery to the brain using nanoparticles. Also, recent and novel approaches are discussed for the delivery of therapeutic agents to the diseased brain using nanoparticle based or magnetic resonance imaging guided systems. Furthermore, the complement activation, toxicity, and immunogenicity of brain targeting nanoparticles as well as novel in vitro BBB models are discussed.

SARS-CoV-2: characterisation and mitigation of risks associated with aerosol generating procedures in dental practices.

Introduction The objectives were to characterise the particle size distribution of aerosols generated by standard dental aerosol generating procedures (AGPs) and to assess the impact of aerosol-management interventions on 'fallow time'. Interventions included combinations of high-volume intraoral suction (HVS[IO]), high-volume extraoral suction (HVS[EO]) and an air cleaning system (ACS).Method A sequence of six AGPs were performed on a phantom head. Real-time aerosol measurements (particle size range 0.0062-9.6 µm) were acquired from six locations within a typical dental treatment room (35 m3).Results The majority (>99%) of AGP particles were <0.3 µm diameter and remained at elevated levels around the dental team during the AGPs. With no active aerosol-management interventions, AGP particles were estimated to remain above the baseline range for up to 30 minutes from the end of the sequence of procedures.Conclusions The results emphasise the importance of personal protection equipment, particularly respiratory protection. Use of HVS(IO), either alone or in combination with the ACS, reduced particle concentrations to baseline levels on completion of AGPs. These data indicate potential to eliminate fallow time. The study was performed using a phantom head so confirmatory studies with patients are required.

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-1ß 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.

Development of Brain Targeting Peptide Based MMP-9 Inhibiting Nanoparticles for the Treatment of Brain Diseases with Elevated MMP-9 Activity.

Latent and active levels of cerebral matrix metalloproteinase 9 (MMP-9) are elevated in neurological diseases and brain injuries, contributing to neurological damage and poor clinical outcomes. This study aimed developing peptide-based nanoparticles with ability to cross the blood-brain-barrier (BBB) and inhibit MMP-9. Three amphiphilic peptides were synthesised containing brain-targeting ligands (HAIYPRH or CKAPETALC) conjugated with MMP-9 inhibiting peptide (CTTHWGFTLC) linked by glycine (spacer) at the N-terminus, and the peptide sequences were conjugated at the N- terminus to cholesterol. 19F NMR assay was developed to measure MMP-9 inhibition. Cell toxicity was evaluated by the LDH assay, and dialysis studies were conducted with/without fetal bovine serum. An in vitro model was employed to evaluate the ability of nanoparticles crossing the BBB. The amphiphilic peptide (Cholesterol-GGGCTTHWGFTLCHAIYPRH) formed nanoparticles (average size of 202.8 nm) with ability to cross the BBB model. MMP-9 inhibiting nanoparticles were non-toxic to cells, and reduced MMP-9 activity from kobs of 4.5 × 10-6s-1 to complete inhibition. Dialysis studies showed that nanoparticles did not disassemble by extreme dilution (40 folds), but gradually hydrolysed by serum enzymes. In conclusion, the MMP-9 inhibiting nanoparticles reduced the activity of MMP-9, with acceptable serum stability, minimal cell toxicity and ability to cross the in vitro BBB model.

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 h) 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 h reduced effectively the ethanol content, while maintaining the narrow size distribution. Graphical abstract.

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 shortfalls of FDF production. The challenges of producing 3D printed FDFs are identified at commercial scale by referring to the identification of suitable materials, hardware, qualitycontrol 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 the 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.

Formulation and optimisation of novel transfersomes for sustained release of local anaesthetic.

OBJECTIVE: To investigate the effect of formulation parameters on the preparation of transfersomes as sustained-release delivery systems for lidocaine and to develop and validate a new high-performance liquid chromatography (HPLC) method for analysis. METHOD: Taguchi design of experiment (DOE) was used to optimise lidocaine-loaded transfersomes in terms of phospholipid, edge activator (EA) and phospholipid : EA ratio. Transfersomes were characterised for size, polydispersity index (PDI), charge and entrapment efficiency (%EE). A HPLC method for lidocaine quantification was optimised and validated using a mobile phase of 30%v/v PBS (0.01 m) : 70%v/v Acetonitrile at a flow rate of 1 ml/min, detected at 255 nm with retention time of 2.84 min. The release of lidocaine from selected samples was assessed in vitro. KEY FINDINGS: Transfersomes were 200 nm in size, with PDI ~ 0.3. HPLC method was valid for linearity (0.1-2 mg/ml, R2 0.9999), accuracy, intermediate precision and repeatability according to ICH guidelines. The %EE was between 44% and 56% and dependent on the formulation parameters. Taguchi DOE showed the effect of factors was in the rank order : lipid : EA ratio Ëƒ EA type Ëƒ lipid type. Optimised transfersomes sustained the release of lidocaine over 24 h. CONCLUSION: Sustained-release, lidocaine-loaded transfersomes were successfully formulated and optimised using a DOE approach, and a new HPLC method for lidocaine analysis was developed and validated.

Surfactant Effects on Lipid-Based Vesicles Properties.

Understanding the effect of surfactant properties is critical when designing vesicular delivery systems. This review evaluates previous studies to explain the influence of surfactant properties on the behavior of lipid vesicular systems, specifically their size, charge, stability, entrapment efficiency, pharmacokinetics, and pharmacodynamics. Generally, the size of vesicles decreases by increasing the surfactant concentration, carbon chain length, the hydrophilicity of the surfactant head group, and the hydrophilic-lipophilic balance. Increasing surfactant concentration can also lead to an increase in charge, which in turn reduces vesicle aggregation and enhances the stability of the system. The vesicles' entrapment efficiency not only depends on the surfactant properties but also on the encapsulated drug. For example, the encapsulation of a lipophilic drug could be enhanced by using a surfactant with a low hydrophilic-lipophilic balance value. Moreover, the membrane permeability of vesicles depends on the surfactant's carbon chain length and transition temperature. In addition, surfactants have a clear influence on pharmacokinetics and pharmacodynamics such as sustaining drug release, enhancing the circulation time of vesicles, improving targeting and cellular uptake.

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 modeling three-dimensional printing to produce single-layered FDFs (SLFDFs), or multilayered FDFs (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 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 190°C (polyvinyl alcohol) with plain or mesh designs. High-performance liquid chromatography and mass spectroscopy analysis indicated active ingredient stability during film preparation process. SLFDFs had thicknesses as small as 197 ± 21 µm, and MLFDFs had thicknesses starting from 298 ± 15 µm. Depending on the formulation and design, mesh SLFDFs presented disintegration time as short as 42 ± 7 s, and this was 48 ± 5 s 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.

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.

The application of mechanical aerosol delivery systems in an in vitro model of mechanically ventilated neonates.

Delivery of medication to the neonatal lung using current methods is inefficient. Aerosols offer one way to improve delivery to small airways. In this in vitro work, aerosol delivery by using a micropump or a rotary valve has been evaluated in a model of the neonatal setting with a pressurised metered dose inhaler plus spacer outside of the inspiratory limb. Drug depositions were assessed by spectrophotometric analyses. Drug lung deposition was increased by adjusting the rotary valve for co-ordination between the inhalation and aerosol delivery, but this intermittent mode decreased the aerosol delivery by using the micropump. Also, decreasing the volume of spacer decreased drug deposition in test lungs by using the micropump system. At the optimum conditions, the rotary valve aerosol delivery system delivered 3.68±0.91% of the Qvar nominal dose to the test lungs, and this was 2.34±0.01% for the micropump system. In conclusion, the rotary valve aerosol delivery system provided higher amounts of drug particles to the test lungs compared to the micropump system. The advantages of these methods were that the humidity in the ventilation circuit did not affect the aerosol particles in the spacer. Further optimisation is required to improve aerosol deposition in the test lungs. The article has also a short section of recent patents relevant to aerosol delivery.

Recent patents in pressurised metered dose inhalers.

In this paper recent patents in pressurised metered dose inhalers have been reviewed. The patents are related to novel valves, dose-counters, formulations, add-on devices, reduction of propellant leakage and inkjet technology. Recently patented dose-counters provide mechanisms that are less susceptible to inaccuracy, and are battery-less electronic dose-counters with the help of miniature electromechanical generators. Regarding the formulation aspect, recent patents provide methods for combinational pMDIs and more stable products. Advantages of recently patented valves are being spring-free and less subject to loss of prime. Recent developments in micromachining have allowed patents that incorporate inkjet technology to develop inhalers that are similar to pMDIs, but produce uniform aerosol droplets. Coating canisters with suitable polymers has reduced need for excipients. Recently patented add-on devices reduce aerosol deposition in the spacer by creating turbulence on the walls of the chamber. Blockage of nozzles in actuators is prevented by providing tapered nozzle channels. In conclusion, these patents show better understanding of pMDIs and provide methods to achieve products with much improved reliability, aerosol performance and stability.

The effect of spray drying on the compaction properties of hypromellose acetate succinate.

BACKGROUND: The aim of this study was to evaluate the compaction behavior of a model two-component amorphous spray-dried dispersion system compared with the unprocessed excipients, using simulated rotary tablet press production conditions. METHOD: In this study, the stabilizing polymer, hypromellose acetate succinate (HPMCAS), was solubilized and spray dried with and without sodium lauryl sulfate (SLS). The impact of compression force and speed on the tabletting process was quantified by means of tablet tensile strength, compaction energy, and Heckel analysis. RESULTS: Addition of the surfactant SLS, spray dried or as a physical mix, reduced the tablet strength. However, a lesser impact on the unprocessed excipients was observed in comparison with the spray-dried excipients. In the presence of 1% (w/w) SLS, tablets displayed a tendency to cap when compressed at higher speeds, supported by high elastic energy values indicating high uniaxial stress upon decompression. In the presence of 3% (w/w) SLS, tablets could not be produced at high speeds. Heckel analysis revealed a greater strain rate sensitivity of HPMCAS when spray dried in the presence of surfactant. Exposure of samples to a range of relative humidities before compaction had no effect on tablet strength. CONCLUSION: This study has shown that spray drying of HPMCAS in the presence of a surfactant affects the compressibility of the material, resulting in decreased tablet strength, increased elastic deformation, and capping.

Effect of device inhalational resistance on the three-dimensional configuration of the upper airway.

Entrainment and de-aggregation of aerosol particles from dry powder inhalers (DPIs) is achieved by a forceful inhalation from the device by the patient and by the airflow resistance built into the device. The aerodynamic shear stress imposed by the upper airway also plays an important role in the de-aggregation process. In this study the effect of device airflow resistance on the upper airway shape is determined. Seven healthy subjects inhaled via a test inhaler of different resistances (0.2 x 10(5) to 2.2 x 10(5) N(0.5).s.m(-4)) while the upper airway was imaged using magnetic resonance imaging. Decreasing the test inhaler resistance led to an increase in the cross-sectional areas of the upper airway at the oral cavity, oropharynx and larynx, while the cross-sectional areas of the upper trachea remained rather constant. The mean volume of the upper airway also increased from 72 (22) cm3 (mean (SD)) to 101 (25) cm3 by decreasing device airflow resistance from 2.2 x 10(5) to 0.2 x 10(5) N(0.5).s.m(-4). In conclusion, this study shows a significant variation in the shape of the upper airway during inhalation via devices with different resistances. This may aid understanding of drug deposition in the lungs from DPIs.