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One of the most striking characteristics of 3D printing is its capability to produce multi-material objects with complex geometry. In pharmaceutics this translates to the possibility of dosage forms with multi-drug loading, tailored dosing and release. We have developed a novel dual material hot-melt inkjet 3D printing system which allows for precisely controlled multi-material solvent free inkjet printing. This reduces the need for time-consuming exchanges of printable inks and expensive post processing steps. With this printer, we show the potential for design of printed dosage forms for tailored drug release, including single and multi-material complex 3D patterns with defined localised drug loading where a drug-free ink is used as a release-retarding barrier. For this, we used Compritol HD5 ATO (matrix material) and Fenofibrate (model drug) to prepare both drug-free and drug-loaded inks with drug concentrations varying between 5% and 30% (w/w). The printed constructs demonstrated the required physical properties and displayed immediate, extended, delayed and pulsatile drug release depending on drug localisation inside of the printed formulations. For the first time, this paper demonstrates that a commonly used pharmaceutical lipid, Compritol HD5 ATO, can be printed via hot-melt inkjet printing as single ink material, or in combination with a drug, without the need for additional solvents. Concurrently, this paper demonstrates the capabilities of dual material hot-melt inkjet 3D printing system to produce multi-material personalised solid dosage forms.

Many pharmaceutics are aqueous dispersions of small or large molecules, often self-assembled in complexes from a few to hundreds of molecules. In many cases, the dispersing liquid is non-aqueous. Many pharmaceutical preparations are very viscous. The efficacy of those dispersions is in many cases a function of the nanostructure of those complexes or aggregates. To study the nanostructure of those systems, one needs electron microscopy, the only way to obtain nanostructural information by recording direct images whose interpretation is not model-dependent. However, these methodologies are complicated by the need to make liquid systems compatible with high vacuum in electron microscopes. There are also issues related to the interaction of the electron beam with the specimen such as micrograph contrast, electron beam radiation damage, and artifacts associated with specimen preparation. In this article, which is focused on the state of the art of imaging self-assembled complexes, we briefly describe cryogenic temperature transmission electron microscopy (cryo-TEM) and cryogenic temperature scanning electron microcopy (cryo-SEM). We present the principles of these methodologies, give examples of their applications as analytical tools for pharmaceutics, and list their limitations and ways to avoid pitfalls in their application.

An increasing number of clinical studies worldwide are investigating the repurposing of antiviral, immune-modulatory, and anti-inflammatory agents to face the coronavirus disease-19 (COVID-19) pandemic. Nevertheless, few effective therapies exist to prevent or treat COVID-19, which demands increased drug discovery and repurposing efforts. In fact, many currently tested drugs show unknown efficacy and unpredictable drug interactions, such that interventions are needed to guarantee access to effective and safe medicines. Anti-inflammatory therapy has proven to be effective in preventing further injury in COVID-19 patients, but the benefit comes at a cost, as targeting inflammatory pathways can imply an increased risk of infection. Thus, optimization of the risk/benefit ratio is required in the anti-inflammatory strategy against COVID-19, which accounts for drug formulations and delivery towards regionalization and personalization of treatment approaches. In this perspective, we discuss how better knowledge of endogenous immunomodulatory pathways may optimize the clinical use of novel and repurposed drugs against COVID-19 in inpatient, outpatient, and home settings through innovative drug discovery, appropriate drug delivery systems and dedicated molecular pharmaceutics.

A new family of polyphenolic carbosilane dendrimers functionalized with ferulic, caffeic, and gallic acids has been obtained through a straightforward amidation reaction. Their antioxidant activity has been studied by different techniques such as DPPH (2,2'-diphenyl-1-picrylhydrazyl) radical scavenging assay, FRAP assay (ferric reducing antioxidant power), and cyclic voltammetry. The antioxidant analysis showed that polyphenolic dendrimers exhibited higher activities than free polyphenols in all cases. The first-generation dendrimer decorated with gallic acid stood out as the best antioxidant compound, displaying a correlation between the number of hydroxyl groups in the polyphenol structure and the antioxidant activity of the compounds. Moreover, the antibacterial capacity of these new systems has been screened against Gram-positive (+) and Gram-negative (-) bacteria, and we observed that polyphenolic dendrimers functionalized with caffeic and gallic acids were capable of decreasing bacterial growth. In contrast, ferulic carbosilane dendrimers and free polyphenols showed no effect, establishing a correlation between antioxidant activity and antibacterial capacity. Finally, a viability assay in human skin fibroblasts cells (HFF-1) allowed for corroborating the nontoxicity of the polyphenolic dendrimers at their active antibacterial concentration.

Oral tissue regeneration has received growing attention for improving the quality of life of patients. Regeneration of oral tissues such as alveolar bone and widely defected bone has been extensively investigated, including regenerative treatment of oral tissues using therapeutic cells and growth factors. Additionally, small-molecule drugs that promote bone formation have been identified and tested as new regenerative treatment. However, treatments need to progress to realize successful regeneration of oral functions. In this review, we describe recent progress in development of regenerative treatment of oral tissues. In particular, we focus on cyclodextrin (CD)-based pharmaceutics and polyelectrolyte complexation of growth factors to enhance their solubility, stability, and bioactivity. CDs can encapsulate hydrophobic small-molecule drugs into their cavities, resulting in inclusion complexes. The inclusion complexation of osteoinductive small-molecule drugs improves solubility of the drugs in aqueous solutions and increases in vitro osteogenic differentiation efficiency. Additionally, various anionic polymers such as heparin and its mimetic polymers have been developed to improve stability and bioactivity of growth factors. These polymers protect growth factors from deactivation and degradation by complex formation through electrostatic interaction, leading to potentiation of bone formation ability. These approaches using an inclusion complex and polyelectrolyte complexes have great potential in the regeneration of oral tissues.

The authors wish to make the following correction to this paper [...]

The authors wish to make the following correction to this paper [...]

Over the last few decades, Ionic Liquids (ILs) and Deep Eutectic Solvents (DES) have been studied academically throughout many fields of chemical and biological research, including pharmaceutical sciences, due to their highly tunable physical, chemical and physicochemical properties [...]

The paper entitled “Mucoadhesive Budesonide Formulation for the Treatment of Eosinophilic Esophagitis Pharmaceutics 2020, 12, 211” discusses the physicochemical and technological characterization of a formulation to treat eosinophilic esophagitis [...]

Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from diclofenac sodium hydrate with the same coformer, L-proline, which was expected to improve the pharmaceutics performance. Methods involved screening, solid phase characterization, structure determination, stability, and in vitro pharmaceutical performance tests. First, a phase diagram screen was carried out to identify the molar ratio of the multicomponent crystal formation. Next, the single crystals were prepared by slow evaporation under two conditions, which yielded two forms: one was a rod-shape and the second was a flat-square form. The characterization by infrared spectroscopy, thermal analysis, and diffractometry confirmed the formation of the new phases. Finally, structural determination using single crystal X-ray diffraction analysis solved the new salt cocrystals as a stable diclofenac&ndash, sodium&ndash, proline&ndash, water (1:1:1:4) named NDPT (natrium diclofenac proline tetrahydrate), and unstable diclofenac&ndash, water (1:1:1:1), named NDPM (natrium diclofenac proline monohydrate). The solubility and dissolution rate of these multicomponent crystals were superior to those of diclofenac sodium alone. The experimental results that this salt cocrystal is suitable for further development.

Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters were calculated with parametric and non-parametric approaches. Both methods conclude that equivalent microstructure between batches cannot be demonstrated with a reasonable sample size when the acceptance range was set at ±10%, since several physical parameters exhibit inter-batch variability10%. An acceptance range of ±10% is therefore too strict to conclude equivalence in the microstructure of semisolid dosage forms, given the inter-batch variability observed between batches of the reference product. A wider fixed acceptance range or an acceptance range widened based on the inter-batch variability of the reference product would be advisable.

The delivery of drugs and bioactive molecules using pharmaceutical particulates and membranes are of great significance for various applications such as the treatment of secondary infections, cancer treatment, skin regeneration, orthopedic applications and others [...]

The process of 3D printing (3DP) was patented in 1986; however, the research in the field of 3DP did not become popular until the last decade. There has been an increasing research into the areas of 3DP for medical applications for fabricating prosthetics, bioprinting and pharmaceutics. This novel method allows the manufacture of dosage forms on demand, with modifications in the geometry and size resulting in changes to the release and dosage behaviour of the product. 3DP will allow wider adoption of personalised medicine due to the diversity and simplicity to change the design and dosage of the products, allowing the devices to be designed specific to the individual with the ability to alternate the drugs added to the product. Personalisation also has the potential to decrease the common side effects associated with generic dosage forms. This Special Issue Editorial outlines the current innovative research surrounding the topic of 3DP, focusing on bioprinting and various types of 3DP on applications for drug delivery as well advantages and future directions in this field of research.

Modern pharmaceutics requires novel drug loading platforms with high drug loading capacity, controlled release, high stability, and good biocompacity. Metal&ndash, organic frameworks (MOFs) show promising applications in biomedicine owing to their extraordinarily high surface area, tunable pore size, and adjustable internal surface properties. However, MOFs have low stability due to weak coordinate bonding and limited biocompatibility, limiting their bioapplication. In this study, we fabricated MOFs/polysilsesquioxane (PSQ) nanocomposites and utilized them as drug carriers. Amine-functionalized MOF (UiO-66-NH2) nanoparticles were synthesized and encapsulated with epoxy-functionalized polysilsesquioxane layer on the surface via a facile process. MOFs possessed high surface area and regular micropores, and PSQs offered stability, inertness, and functionality. The obtained UiO-66-NH2@EPSQ nanocomposites were utilized as carriers for ibuprofen, a drug with carboxylic groups on the surface, and demonstrated high drug loading capacity and well-controlled release property. The UiO-66-NH2@EPSQ nanocomposite exhibited low cytotoxicity to HeLa cells within a wide concentration range of 10&ndash, 100 &micro, g/mL, as estimated by the MTT method. The UiO-66-NH2@EPSQ drug release system could be a potential platform in the field of controlled drug delivery.

We previously reported that siRNA delivery to the brain is improved by the nose-to-brain delivery route and by conjugation with polyethylene glycol-polycaprolactone (PEG-PCL) polymer micelles and the cell-penetrating peptide, Tat (PEG-PCL-Tat). In this study, we evaluated the nose-to-brain delivery of siRNA targeting TNF-α (siTNF-α) conjugated with PEG-PCL-Tat to investigate its therapeutic effects on a transient middle cerebral artery occlusion (t-MCAO) rat model of cerebral ischemia-reperfusion injury. Intranasal treatment was provided 30 min after infarction induced via suturing. Two hours after infarction induction, the suture was removed, and blood flow was released. At 22 h post-reperfusion, we assessed the infarcted area, TNF-α production, and neurological score to determine the therapeutic effects. The infarcted area was observed over a wide range in the untreated group, whereas shrinkage of the infarcted area was observed in rats subjected to intranasal administration of siTNF-α with PEG-PCL-Tat micelles. Moreover, TNF-α production and neurological score in rats treated by intranasal administration of siTNF-α with PEG-PCL-Tat micelles were significantly lower than those in untreated and naked siTNF-α-treated rats. These results indicate that nose-to-brain delivery of siTNF-α conjugated with PEG-PCL-Tat micelles alleviated the symptoms of cerebral ischemia-reperfusion injury.

Eudragit® polymers are polymethacrylates highly used in pharmaceutics for the development of modified drug delivery systems. They are widely known due to their versatility with regards to chemical composition, solubility, and swelling properties. Moreover, Eudragit polymers are thermoplastic, and their use has been boosted in some production processes, such as hot melt extrusion (HME) and fused deposition modelling 3D printing, among other 3D printing techniques. Therefore, this review covers the studies using Eudragit polymers in the development of drug delivery systems produced by HME and 3D printing techniques over the last 10 years. Eudragit E has been the most used among them, mostly to formulate immediate release systems or as a taste-masker agent. On the other hand, Eudragit RS and Eudragit L100-55 have mainly been used to produce controlled and delayed release systems, respectively. The use of Eudragit polymers in these processes has frequently been devoted to producing solid dispersions and/or to prepare filaments to be 3D printed in different dosage forms. In this review, we highlight the countless possibilities offered by Eudragit polymers in HME and 3D printing, whether alone or in blends, discussing their prominence in the development of innovative modified drug release systems.

The authors wish to make the following corrections to this paper [...]

The authors wish to make the following corrections to the affiliation and acknowledgments part [...]

Canada has a long and rich history of ground-breaking research in drug delivery within academic institutions, pharmaceutical industry and the biotechnology community. Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect. It may involve rational site-targeting, or facilitating systemic pharmacokinetics; in any case, it is typically concerned with both quantity and duration of the presence of the drug in the body. Drug delivery is often approached through a drug's chemical formulation, medical devices or drug-device combination products. Drug delivery is a concept heavily integrated with dosage form development and selection of route of administration; the latter sometimes even being considered part of the definition. Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well as patient convenience and adherence. Over the past 30 years, numerous Canadian-based biotechnology companies have been formed stemming from the inventions conceived and developed within academic institutions. Many have led to the development of important drug delivery products that have enhanced the landscape of drug therapy in the treatment of cancer to infectious diseases. This Special Issue serves to highlight the progress of drug delivery within Canada. We invited articles on all aspects of drug delivery sciences from pre-clinical formulation development to human clinical trials that bring to light the world-class research currently undertaken in Canada for this Special Issue.

Metal-organic frameworks (MOFs) show promising application in biomedicine and pharmaceutics owing to their extraordinarily high surface area, tunable pore size, and adjustable internal surface properties. However, MOFs are prepared from non-renewable or toxic materials, which limit their real-world applications. Cyclodextrins (CDs) are a typical natural and biodegradable cyclic oligosaccharide and are primarily used to enhance the aqueous solubility, safety, and bioavailability of drugs by virtue of its low toxicity and highly flexible structure, offering a peculiar ability to form CD/drug inclusions. A sophisticated strategy where CD is deployed as a ligand to form an assembly of cyclodextrin-based MOFs (CD-MOFs) may overcome real-world application drawbacks of MOFs. CD-MOFs incorporate the porous features of MOFs and the encapsulation capability of CD for drug molecules, leading to outstanding properties when compared with traditional hybrid materials. This review focuses on the inclusion technology and drug delivery properties associated with CD-MOFs. In addition, synthetic strategies and currently developed uses of CD-MOFs are highlighted as well. Also, perspectives and future challenges in this rapidly developing research area are discussed.

The spread of antimicrobial-resistant pathogens typically existing in biofilm formation and the recent COVID-19 pandemic, although unrelated phenomena, have demonstrated the urgent need for methods to combat such increasing threats. New avenues of research for natural molecules with desirable properties to alleviate this situation have, therefore, been expanding. Biosurfactants comprise a group of unique and varied amphiphilic molecules of microbial origin capable of interacting with lipidic membranes/components of microorganisms and altering their physicochemical properties. These features have encouraged closer investigations of these microbial metabolites as new pharmaceutics with potential applications in clinical, hygiene and therapeutic fields. Mounting evidence has indicated that biosurfactants have antimicrobial, antibiofilm, antiviral, immunomodulatory and antiproliferative activities that are exploitable in new anticancer treatments and wound healing applications. Some biosurfactants have already been approved for use in clinical, food and environmental fields, while others are currently under investigation and development as antimicrobials or adjuvants to antibiotics for microbial suppression and biofilm eradication strategies. Moreover, due to the COVID-19 pandemic, biosurfactants are now being explored as an alternative to current products or procedures for effective cleaning and handwash formulations, antiviral plastic and fabric surface coating agents for shields and masks. In addition, biosurfactants have shown promise as drug delivery systems and in the medicinal relief of symptoms associated with SARS-CoV-2 acute respiratory distress syndrome.

Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on HDIs have been carried out by predictive in vitro and in vivo preclinical studies, and clinical trials. Nevertheless, the discrepancies between predictive data and the clinical significance on HDIs still exist, and different reports of HDIs add to rather than clarify the confusion regarding the use of herbal products and drug combinations. Here, we briefly review the underlying mechanisms causing PK-based HDIs, and more importantly summarize challenging issues, such as dose and treatment period effects, to be considered in study designs and interpretations of HDI evaluations.

The authors wish to make the following corrections to this paper [...]

The authors would like to make the following corrections to this paper [...]

The authors make the following correction to this paper after the final publication of the work [...]

Cancer treatment has been greatly improved by the combined use of targeted therapies and novel biotechnological methods. Regarding the former, pegylated liposomal doxorubicin (PLD) has a preferential accumulation within cancer tumors, thus having lower toxicity on healthy cells. PLD has been implemented in the targeted treatment of sarcoma, ovarian, breast, and lung cancer. In comparison with conventional doxorubicin, PLD has lower cardiotoxicity and hematotoxicity; however, PLD can induce mucositis and palmo-plantar erythrodysesthesia (PPE, hand-foot syndrome), which limits its use. Therapeutical apheresis is a clinically proven solution against early PLD toxicity without hindering the efficacy of the treatment. The present review summarizes the pharmacokinetics and pharmacodynamics of PLD and the beneficial effects of extracorporeal apheresis on the incidence of PPE during chemoradiotherapy in cancer patients.

In this study, flavonoids extracted from yellow onion skins and Lactobacillus casei were encapsulated in a combination of whey protein isolate, inulin and maltodextrin with an encapsulation efficiency of 84.82 &plusmn, 0.72% for flavonoids and 72.49 &plusmn, 0.11% for lactic acid bacteria. The obtained powder showed a flavonoid content of 89.49 &plusmn, 4.12 mg quercetin equivalents/g dry weight (DW) and an antioxidant activity of 39.27 &plusmn, 0.45 mM Trolox/g DW. The powder presented a significant antidiabetic and anti-inflammatory potential, with an inhibitory effect on &alpha, amylase, lipase and lipoxygenase of 76.40 &plusmn, 2.30%, 82.58 &plusmn, 3.36% and 49.01 &plusmn, 0.62%, respectively. The results obtained for in vitro digestion showed that the coating materials have a protective effect on the flavonoids release. Cytotoxicity results indicated that the powder was cytocompatible up to a concentration of 500 &mu, g/mL. The functional potential of the powder was tested by adding in a selected food matrix, highlighting a good stability of the phytochemicals, whereas an increase with 1 log cell forming unit (CFU)/g DW was observed after 21 days of storage. The obtained results are promising in the valorization of natural antioxidants in combination with lactic acid bacteria in order to develop multifunctional ingredients with value-added for food and pharmaceutics applications.

Three-dimensional (3D) printing offers the greatest potential to revolutionize the future of pharmaceutical manufacturing by overcoming challenges of conventional pharmaceutical operations and focusing design and production of dosage forms on the patient’s needs. Of the many technologies available, fusion deposition modelling (FDM) is considered of the lowest cost and higher reproducibility and accessibility, offering clear advantages in drug delivery. FDM requires in-house production of filaments of drug-containing thermoplastic polymers by hot-melt extrusion (HME), and the prospect of connecting the two technologies has been under investigation. The ability to integrate HME and FDM and predict and tailor the filaments’ properties will extend the range of printable polymers/formulations. Hence, this work revises the properties of the most common pharmaceutical-grade polymers used and their effect on extrudability, printability, and printing outcome, providing suitable processing windows for different raw materials. As a result, formulation selection will be more straightforward (considering the characteristics of drug and desired dosage form or release profile) and the processes setup will be more expedite (avoiding or mitigating typical processing issues), thus guaranteeing the success of both HME and FDM. Relevant techniques used to characterize filaments and 3D-printed dosage forms as an essential component for the evaluation of the quality output are also presented.

This comment is intended to discuss errors observed in the title paper, doi:10.3390/pharmaceutics12020134. When this paper was published, the authors of this commentary were excited to read it. However, the more we read, the more pitfalls were observed, which necessitated a response to revise the many errors and misleading information included in this publication.

The authors wish to make the following corrections to this paper [1]: [...]

Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening purposes. The mRNA expression of key feature membrane proteins of primary and bEnd.3 mouse brain endothelial cells were compared. Transwell

Nanotechnology is an emerging field of science that is widely used in medical sciences. However, it has limited uses in monogastric farm animal as well as fish and poultry nutrition. There are some works that have been done on curcumin and curcumin nanoparticles as pharmaceutics in animal nutrition. However, studies have shown that ingestion of curcumin or curcumin nanoparticles does not benefit the animal health much due to their lower bioavailability, which may result because of low absorption, quick metabolism and speedy elimination of curcumin from the animal body. For these reasons, advanced formulations of curcumin are needed. Curcumin nanospheres is a newly evolved field of nanobiotechnology which may have beneficial effects in terms of growth increment, anti-microbial, anti-inflammatory and neuroprotective effects on animal and fish health by means of nanosphere forms that are biodegradable and biocompatible. Thus, this review aims to highlight the potential application of curcumin, curcumin nanoparticles and curcumin nanospheres in the field of monogastric farm animal, poultry and fish nutrition. We do believe that the review provides the perceptual vision for the future development of curcumin, curcumin nanoparticles and curcumin nanospheres and their applications in monogastric farm animal, poultry and fish nutrition.

The authors wish to make the following corrections to this paper [1]: the hematoxylin and eosin-stained images of kidney in the group of healthy tissue in Figure 8 of this work [1] inadvertently duplicated the kidney results of the PBS group.[...].

Microneedle (MN) patches are promising for transcutaneous vaccination because they enable vaccine antigens to physically penetrate the stratum corneum via low-invasive skin puncturing, and to be effectively delivered to antigen-presenting cells in the skin. In second-generation MN patches, the dissolving MNs release the loaded vaccine antigen into the skin. To shorten skin application time for clinical practice, this study aims to develop novel faster-dissolving MNs. We designed two types of MNs made from a single thickening agent, carboxymethylcellulose (CMC) or hyaluronan (HN). Both CMC-MN and HN-MN completely dissolved in rat skin after a 5-min application. In pre-clinical studies, both MNs could demonstrably increase antigen-specific IgG levels after vaccination and prolong antigen deposition compared with conventional injections, and deliver antigens into resected human dermal tissue. In clinical research, we demonstrated that both MNs could reliably and safely puncture human skin without any significant skin irritation from transepidermal water loss measurements and ICDRG (International Contact Dermatitis Research Group) evaluation results.

The editors of Pharmaceutics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014:[...]

Nanovectors, such as liposomes, micelles and lipid nanoparticles, are recognized as efficient platforms for delivering therapeutic agents, especially those with low solubility in water. Besides being safe and non-toxic, drug carriers with improved performance should meet the requirements of (i) appropriate size and shape and (ii) cargo upload/release with unmodified properties. Structural issues are of primary importance to control the mechanism of action of loaded vectors. Overall properties, such as mean diameter and surface charge, can be obtained using bench instruments (Dynamic Light Scattering and Zeta potential). However, techniques with higher space and time resolution are needed for in-depth structural characterization. Small-angle X-ray (SAXS) and neutron (SANS) scattering techniques provide information at the nanoscale and have therefore been largely used to investigate nanovectors loaded with drugs or other biologically relevant molecules. Here we revise recent applications of these complementary scattering techniques in the field of drug delivery in pharmaceutics and medicine with a focus to liposomal carriers. In particular, we highlight those aspects that can be more commonly accessed by the interested users.