Pharmaceutics

Article

20 pages, 6744 KiB

Open AccessEditor’s ChoiceArticle

Development and Use of a Residence Time Distribution (RTD) Model Control Strategy for a Continuous Manufacturing Drug Product Pharmaceutical Process

by Samantha Hurley, Anthony Tantuccio, Manuel Sebastian Escotet-Espinoza, Matthew Flamm and Matthew Metzger

Pharmaceutics 2022, 14(2), 355; https://doi.org/10.3390/pharmaceutics14020355 - 3 Feb 2022

Cited by 19 | Viewed by 6472

Abstract

Residence-time-distribution (RTD)-based models are key to understanding the mixing dynamics of continuous manufacturing systems. Such models can allow for material traceability throughout the process and can provide the ability for removal of non-conforming material from the finished product. These models have been implemented [...] Read more.

Residence-time-distribution (RTD)-based models are key to understanding the mixing dynamics of continuous manufacturing systems. Such models can allow for material traceability throughout the process and can provide the ability for removal of non-conforming material from the finished product. These models have been implemented in continuous pharmaceutical manufacturing mainly for monitoring purposes, not as an integral part of the control strategy and in-process specifications. This paper discusses the steps taken to develop an RTD model design space and how the model was statistically incorporated into the product’s control strategy. To develop the model, experiments were conducted at a range of blender impeller speeds and total system mass flow rates. RTD parameters were optimized for each condition tested using a tank-in-series-type model with a delay. Using the experimental RTD parameters, an equation was derived relating the mean residence time to the operating conditions (i.e., blender impeller speed and mass flow rate). The RTD parameters were used in combination with real-time upstream process data to predict downstream API concentration, where these predictions allowed validation across the entire operating range of the process by comparison to measured tablet assay. The standard in-process control limits for the product were statistically tightened using the validation acceptance criteria. Ultimately, this model and strategy were accepted by regulatory authorities. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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16 pages, 3935 KiB

Open AccessEditor’s ChoiceArticle

Topical Photodynamic Therapy with Different Forms of 5-Aminolevulinic Acid in the Treatment of Actinic Keratosis

by Joanna Bartosińska, Paulina Szczepanik-Kułak, Dorota Raczkiewicz, Marta Niewiedzioł, Agnieszka Gerkowicz, Dorota Kowalczuk, Mirosław Kwaśny and Dorota Krasowska

Pharmaceutics 2022, 14(2), 346; https://doi.org/10.3390/pharmaceutics14020346 - 1 Feb 2022

Cited by 11 | Viewed by 2898

Abstract

Photodynamic therapy (PDT) is safe and effective in the treatment of patients with actinic keratosis (AK). The aim of the study was to assess the efficacy, tolerability and cosmetic outcome of topical PDT in the treatment of AKs with three forms of photosensitizers: [...] Read more.

Photodynamic therapy (PDT) is safe and effective in the treatment of patients with actinic keratosis (AK). The aim of the study was to assess the efficacy, tolerability and cosmetic outcome of topical PDT in the treatment of AKs with three forms of photosensitizers: 5-Aminolevulinic acid hydrochloride (ALA-HCl), 5-Aminolevulinate methyl ester hydrochloride (MAL-HCl) and 5-Aminolevulinate phosphate (ALA-P). The formulations were applied onto selected scalp/face areas. Fluorescence was assessed with a FotoFinder Dermoscope 800 attachment. Skin areas were irradiated with Red Beam Pro+, Model APRO (MedLight GmbH, Herford, Germany). Applied treatments were assessed during the PDT as well as 7 days and 12 weeks after its completion. Ninety-four percent of patients rated obtained cosmetic effect excellent. The efficacy of applied PSs did not differ significantly. However, pain intensity during the PDT procedure was significantly lower in the area treated with ALA-P (5.8 on average) in comparison to the areas treated with ALA-HCl or MAL-HCl (7.0 on average on 0–10 scale). Obtained results show that ALA-P may undergo more selective accumulation than ALA-HCl and MAL-HCl. Our promising results suggest that PDT with the use of ALA-P in AK treatment may be an advantageous alternative to the already used ALA-HCl and MAL-HCl. Full article

(This article belongs to the Special Issue Special Issue in Honor of Dr. Michael Weber’s 70th Birthday: Photodynamic Therapy: Rising Star in Pharmaceutical Applications)

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14 pages, 25865 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Antioxidant and Wound-Healing Properties of EHO-85, a Novel Multifunctional Amorphous Hydrogel Containing Olea europaea Leaf Extract

by Antonio Casado-Diaz, José Manuel Moreno-Rojas, José Verdú-Soriano, José Luis Lázaro-Martínez, Leocadio Rodríguez-Mañas, Isaac Tunez, Manuel La Torre, Miriam Berenguer Pérez, Feliciano Priego-Capote and Gema Pereira-Caro

Pharmaceutics 2022, 14(2), 349; https://doi.org/10.3390/pharmaceutics14020349 - 1 Feb 2022

Cited by 23 | Viewed by 5079

Abstract

The excess of free radicals in the wound environment contributes to its stagnation during the inflammatory phase, favoring hard-to-heal wounds. Oxidative stress negatively affects cells and the extracellular matrix, hindering the healing process. In this study, we evaluated the antioxidant and wound-healing properties [...] Read more.

The excess of free radicals in the wound environment contributes to its stagnation during the inflammatory phase, favoring hard-to-heal wounds. Oxidative stress negatively affects cells and the extracellular matrix, hindering the healing process. In this study, we evaluated the antioxidant and wound-healing properties of a novel multifunctional amorphous hydrogel-containing Olea europaea leaf extract (OELE). Five assessments were performed: (i) phenolic compounds characterization in OELE; (ii) absolute antioxidant activity determination in OELE and hydrogel (EHO-85); (iii) antioxidant activity measurement of OELE and (iv) its protective effect on cell viability on human dermal fibroblasts (HDFs) and keratinocytes (HaCaT); and (v) EHO-85 wound-healing-capacity analysis on diabetic mice (db/db; BKS.Cg-m+/+Leprdb). The antioxidant activity of OELE was prominent: 2220, 1558, and 1969 µmol TE/g by DPPH, ABTS, and FRAP assays, respectively. Oxidative stress induced with H₂O₂ in HDFs and HaCaT was normalized, and their viability increased with OELE co-treatment, thus evidencing a protective role. EHO-85 produced an early and sustained wound-healing stimulating effect superior to controls in diabetic mice. This novel amorphous hydrogel presents an important ROS scavenger capacity due to the high phenolic content of OELE, which protects skin cells from oxidative stress and contributes to the physiological process of wound healing. Full article

(This article belongs to the Special Issue Wound Care: From Traditional Cotton Wound Dressings to Innovative Wound Dressings)

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27 pages, 5652 KiB

Open AccessEditor’s ChoiceArticle

Amphiphilic Anionic Oligomer-Stabilized Calcium Phosphate Nanoparticles with Prospects in siRNA Delivery via Convection-Enhanced Delivery

by Franziska Mitrach, Maximilian Schmid, Magali Toussaint, Sladjana Dukic-Stefanovic, Winnie Deuther-Conrad, Heike Franke, Alexander Ewe, Achim Aigner, Christian Wölk, Peter Brust, Michael C. Hacker and Michaela Schulz-Siegmund

Pharmaceutics 2022, 14(2), 326; https://doi.org/10.3390/pharmaceutics14020326 - 29 Jan 2022

Cited by 12 | Viewed by 3862

Abstract

Convection-enhanced delivery (CED) has been introduced as a concept in cancer treatment to generate high local concentrations of anticancer therapeutics and overcome the limited diffusional distribution, e.g., in the brain. RNA interference provides interesting therapeutic options to fight cancer cells but requires nanoparticulate [...] Read more.

Convection-enhanced delivery (CED) has been introduced as a concept in cancer treatment to generate high local concentrations of anticancer therapeutics and overcome the limited diffusional distribution, e.g., in the brain. RNA interference provides interesting therapeutic options to fight cancer cells but requires nanoparticulate (NP) carriers with a size below 100 nm as well as a low zeta potential for CED application. In this study, we investigated calcium phosphate NPs (CaP-NPs) as siRNA carriers for CED application. Since CaP-NPs tend to aggregate, we introduced a new terpolymer (o14PEGMA(1:1:2.5) NH₃) for stabilization of CaP-NPs intended for delivery of siRNA to brain cancer cells. This small terpolymer provides PEG chains for steric stabilization, and a fat alcohol to improve interfacial activity, as well as maleic anhydrides that allow for both labeling and high affinity to Ca(II) in the hydrolyzed state. In a systematic approach, we varied the Ca/P ratio as well as the terpolymer concentration and successfully stabilized NPs with the desired properties. Labeling of the terpolymer with the fluorescent dye Cy5 revealed the terpolymer’s high affinity to CaP. Importantly, we also determined a high efficiency of siRNA binding to the NPs that caused very effective survivin siRNA silencing in F98 rat brain cancer cells. Cytotoxicity investigations with a standard cell line resulted in minor and transient effects; no adverse effects were observed in organotypic brain slice cultures. However, more specific cytotoxicity investigations are required. This study provides a systematic and mechanistic analysis characterizing the effects of the first oligomer of a new class of stabilizers for siRNA-loaded CaP-NPs. Full article

(This article belongs to the Special Issue Non-viral Gene Delivery Systems, 2nd Edition)

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18 pages, 3144 KiB

Open AccessEditor’s ChoiceArticle

Mechanistically Coupled PK (MCPK) Model to Describe Enzyme Induction and Occupancy Dependent DDI of Dabrafenib Metabolism

by Marco Albrecht, Yuri Kogan, Dagmar Kulms and Thomas Sauter

Pharmaceutics 2022, 14(2), 310; https://doi.org/10.3390/pharmaceutics14020310 - 28 Jan 2022

Cited by 1 | Viewed by 3504

Abstract

Dabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. [...] Read more.

Dabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. To clarify whether such elevated drug concentrations could be reached by long-term drug accumulation, we mechanistically coupled the pharmacokinetics (MCPK) of dabrafenib and its metabolites. The MCPK model is qualitatively based on in vitro and quantitatively on clinical data to describe occupancy-dependent CYP3A4 enzyme induction, accumulation, and drug–drug interaction mechanisms. The prediction suggests an eight-fold increase in the steady-state concentration of potent desmethyl-dabrafenib and its inactive precursor carboxy-dabrafenib within four weeks upon 150 mg b.d. dabrafenib. While it is generally assumed that a higher dose is not critical, we found experimentally that a high physiological dabrafenib concentration fails to induce cell death in embedded 451LU melanoma spheroids. Full article

(This article belongs to the Special Issue Model-Informed Drug Discovery and Development)

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14 pages, 260 KiB

Open AccessEditor’s ChoiceArticle

Performance of Tablet Splitters, Crushers, and Grinders in Relation to Personalised Medication with Tablets

by Herman J. Woerdenbag, J. Carolina Visser, Marlyn P. A. M. Leferink op Reinink, Roël R. van Orsoy, Anko C. Eissens, Paul Hagedoorn, Hilda Dijkstra, Derk P. Allersma, Shi W. Ng, Oscar S. N. M. Smeets and Henderik W. Frijlink

Pharmaceutics 2022, 14(2), 320; https://doi.org/10.3390/pharmaceutics14020320 - 28 Jan 2022

Cited by 16 | Viewed by 5382

Abstract

Swallowing problems and the required dose adaptations needed to obtain optimal pharmacotherapy may be a hurdle in the use of tablets in daily clinical practice. Tablet splitting, crushing, or grinding is often applied to personalise medication, especially for the elderly and children. In [...] Read more.

Swallowing problems and the required dose adaptations needed to obtain optimal pharmacotherapy may be a hurdle in the use of tablets in daily clinical practice. Tablet splitting, crushing, or grinding is often applied to personalise medication, especially for the elderly and children. In this study, the performance of different types of (commercially available) devices was studied. Included were splitters, screwcap crushers, manual grinders, and electric grinders. Unscored tablets without active ingredient were prepared, with a diameter of 9 and 13 mm and a hardness of 100–220 N. Tablets were split into two parts and the difference in weight was measured. The time needed to pulverise the tablets (crush time) was recorded. The residue remaining in the device (loss) was measured. The powder was sieved to obtain a particle fraction >600 µm and <600 µm. The median particle size and particle size distribution of the later fraction were determined using laser diffraction analysis. Splitting tablets into two equal parts appeared to be difficult with the devices tested. Most screwcap grinders yielded a coarse powder containing larger chunks. Manual and especially electric grinders produced a finer powder, making it suitable for administration via an enteral feeding tube as well as for use in individualised preparations such as capsules. In conclusion, for domestic and incidental use, a screwcap crusher may provide sufficient size reduction, while for the more demanding regular use in hospitals and nursing residences, a manual or electric grinder is preferred. Full article

(This article belongs to the Special Issue ODX Formulations for Drug Delivery and Other Approaches to Overcome Swallowing Problems)

14 pages, 2914 KiB

Open AccessEditor’s ChoiceArticle

Engineering the Surface of Ti₃C₂ MXene Nanosheets for High Stability and Multimodal Anticancer Therapy

by Chiranjeevi Korupalli, Kai-Long You, Girum Getachew, Akash S. Rasal, Worku Batu Dirersa, Mochamad Zakki Fahmi and Jia-Yaw Chang

Pharmaceutics 2022, 14(2), 304; https://doi.org/10.3390/pharmaceutics14020304 - 27 Jan 2022

Cited by 48 | Viewed by 5372

Abstract

The surface of Ti₃C₂ MXene nanosheets (TC NSs) was first modified with the antioxidants sodium ascorbate (SA) and dopamine (DA) (DSTC NS) to improve their stability in oxidative and hydration environments and thereby improve their bioapplications. This novel approach not [...] Read more.

The surface of Ti₃C₂ MXene nanosheets (TC NSs) was first modified with the antioxidants sodium ascorbate (SA) and dopamine (DA) (DSTC NS) to improve their stability in oxidative and hydration environments and thereby improve their bioapplications. This novel approach not only improved MXene stability by arresting oxidation but also increased the available functional groups for further functionalization with various biomolecules. The DSTC NSs were then sequentially conjugated with enzyme glucose oxidase (GOx) and photosensitizer Ce6 to render the obtained CGDSTC NSs with glucose starvation and photodynamic therapeutic properties and thus attain high efficiency in killing cancer cells through the cooperative effect. The as-synthesized CGDSTC NSs demonstrated tremendous photothermal effect with conversion efficiency of 45.1% and photodynamic (ROS generation) properties upon irradiation with 808 and 671 nm lasers. Furthermore, it was observed that the enzymatic activity of CGDSTC NSs increased upon laser irradiation due to enhanced solution temperature. During in vitro studies, the CGDSTC NSs exhibited cytocompatability to HePG2 and HeLa cells under nonstimulus conditions. However, they elicited more than 90% cell-killing efficiency in the presence of glucose and laser irradiation via the cooperative effect between starvation therapy and phototherapy. These results indicate that CGDSTC NSs could be used as potential therapeutic agents to eradicate cancers with no or few adverse effects. This surface modification approach is also simple and facile to adopt in MXene-based research. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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15 pages, 2454 KiB

Open AccessEditor’s ChoiceArticle

Role of Cyclodextrins and Drug Solid State Properties on Flufenamic Acid Dissolution Performance from Tablets

by Francesca Maestrelli, Marzia Cirri, Enrico De Luca, Diletta Biagi and Paola Mura

Pharmaceutics 2022, 14(2), 284; https://doi.org/10.3390/pharmaceutics14020284 - 26 Jan 2022

Cited by 7 | Viewed by 3469

Abstract

Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug characterised by a low solubility and problems of variable dissolution rate and bio-inequivalence. Different FFA batches, obtained by different suppliers, showed different powder characteristics (particle size, shape and surface properties) that may affect its dissolution [...] Read more.

Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug characterised by a low solubility and problems of variable dissolution rate and bio-inequivalence. Different FFA batches, obtained by different suppliers, showed different powder characteristics (particle size, shape and surface properties) that may affect its dissolution behaviour from solid dosage forms. Aim of this work was the improvement of FFA solubility and dissolution rate by the use of cyclodextrins (CDs) and the obtainment of an effective tablet formulation by direct compression. Several CDs have been tested, both in solution and in solid state and several binary systems drug-CDs have been obtained with different techniques, with the scope to select the most effective system. Grinding technique with randomly methylated-β-cyclodextrin (RAMEB) was the only one that allowed the complete drug amorphization, together with the highest improvement in drug dissolution rate, and was then selected for tablets formulation. Conventional and immediate release tablets were obtained and fully characterised for technological properties. In both cases an improved and well reproducible drug dissolution performance was obtained, independently from the FFA supplier and thus no more affected by the differences observed between the original FFA crystalline samples. Full article

(This article belongs to the Special Issue Impact of Physicochemical Properties of Pharmaceutical Substances on Dosage Form Performance)

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18 pages, 1931 KiB

Open AccessEditor’s ChoiceArticle

Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors

by Virginia Campani, Iris Chiara Salaroglio, Valeria Nele, Joanna Kopecka, Andreas Bernkop-Schnürch, Chiara Riganti and Giuseppe De Rosa

Pharmaceutics 2022, 14(2), 292; https://doi.org/10.3390/pharmaceutics14020292 - 26 Jan 2022

Cited by 10 | Viewed by 4115

Abstract

The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with [...] Read more.

The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with enoxaparin (Enox) are a promising strategy to deliver DTX in resistant tumors. DTX partition studies between the SEDDS pre-concentrate and the release medium (water) suggest that the drug is well retained within the SEDDS upon dilution in the release medium. All SEDDS formulations show droplets with a mean diameter between 110 and 145 nm following dilution in saline and negligible hemolytic activity; the droplet size remains unchanged upon sterilization. Enox-coated SEDDS containing DTX exhibit an enhanced inhibition of cell growth compared to the control on cells of different solid tumors characterized by high levels of FGFR, which is due to an increased DTX internalization mediated by Enox. Moreover, only Enox-coated SEDDS are able to restore the sensitivity to DTX in resistant cells expressing MRP1 and BCRP by inhibiting the activity of these two main efflux transporters for DTX. The efficacy and safety of these formulations is also confirmed in vivo in resistant non-small cell lung cancer xenografts. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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18 pages, 1478 KiB

Open AccessEditor’s ChoiceArticle

Industrial Scale Manufacturing and Downstream Processing of PLGA-Based Nanomedicines Suitable for Fully Continuous Operation

by Maria Camilla Operti, Alexander Bernhardt, Vladimir Sincari, Eliezer Jager, Silko Grimm, Andrea Engel, Martin Hruby, Carl Gustav Figdor and Oya Tagit

Pharmaceutics 2022, 14(2), 276; https://doi.org/10.3390/pharmaceutics14020276 - 25 Jan 2022

Cited by 25 | Viewed by 5768

Abstract

Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and [...] Read more.

Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and lack of product consistency in scale-up manufacturing. Therefore, a scalable and robust manufacturing technique that allows for the transfer of nanomedicine production from the benchtop to an industrial scale is highly desirable. Downstream processes for purification, concentration, and storage of the nanomedicine formulations are equally indispensable. Here, we develop an inline sonication process for the production of polymeric PLGA nanomedicines at the industrial scale. The process and formulation parameters are optimized to obtain PLGA nanoparticles with a mean diameter of 150 ± 50 nm and a small polydispersity index (PDI < 0.2). Downstream processes based on tangential flow filtration (TFF) technology and lyophilization for the washing, concentration, and storage of formulations are also established and discussed. Using the developed manufacturing and downstream processing technologies, production of two PLGA nanoformulations encasing ritonavir and celecoxib was achieved at 84 g/h rate. As a measure of actual drug content, encapsulation efficiencies of 49.5 ± 3.2% and 80.3 ± 0.9% were achieved for ritonavir and celecoxib, respectively. When operated in-series, inline sonication and TFF can be adapted for fully continuous, industrial-scale processing of PLGA-based nanomedicines. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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16 pages, 2745 KiB

Open AccessEditor’s ChoiceArticle

Simultaneous Delivery of Econazole, Terbinafine and Amorolfine with Improved Cutaneous Bioavailability: A Novel Micelle-Based Antifungal “Tri-Therapy”

by Si Gou, Michel Monod, Denis Salomon and Yogeshvar N. Kalia

Pharmaceutics 2022, 14(2), 271; https://doi.org/10.3390/pharmaceutics14020271 - 24 Jan 2022

Cited by 6 | Viewed by 3360

Abstract

Lack of accurate diagnosis and the use of formulations designed to address the poor aqueous solubility of antifungal agents, but not optimized for delivery, contribute to unsatisfactory outcomes for topical treatment of cutaneous mycoses. The objective of this study was to develop a [...] Read more.

Lack of accurate diagnosis and the use of formulations designed to address the poor aqueous solubility of antifungal agents, but not optimized for delivery, contribute to unsatisfactory outcomes for topical treatment of cutaneous mycoses. The objective of this study was to develop a micelle-based antifungal formulation containing econazole (ECZ), terbinafine (TBF) and amorolfine (AMF) using D-α-tocopheryl polyethylene glycol succinate (TPGS) for simultaneous cutaneous delivery of three agents with complementary mechanisms of action. The antifungal “tri-therapy” micelle-based formulation containing 0.1% ECZ, 0.1% TBF and 0.025% AMF had a drug loading 10-fold lower than the “reference” marketed formulations (Pevaryl^®, 1% ECZ; Lamisil^®, 1% TBF; Loceryl^®, 0.25% AMF). Finite dose application of the micelle-based formulation for 6 h resulted in a statistically equivalent deposition of ECZ (p > 0.05) and TBF (p > 0.05) from the 2 systems, and a 2-fold higher accumulation of AMF (p = 0.017). Antifungal concentrations above MIC₈₀ against Trichophyton rubrum were achieved in each skin layer with the “tri-therapy”, which also exhibited a preferential deposition of each antifungal agent in pilosebaceous unit (PSU)-containing biopsies as compared with PSU-free biopsies (p < 0.05). A planned clinical study will test whether these promising results translate to improved therapeutic outcomes in vivo. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Switzerland)

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13 pages, 3037 KiB

Open AccessEditor’s ChoiceArticle

Factors Influencing the Crystallization-Onset Time of Metastable ASDs

by Friederike Wolbert, Ineke-Katharina Fahrig, Tobias Gottschalk, Christian Luebbert, Markus Thommes and Gabriele Sadowski

Pharmaceutics 2022, 14(2), 269; https://doi.org/10.3390/pharmaceutics14020269 - 23 Jan 2022

Cited by 19 | Viewed by 4591

Abstract

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that [...] Read more.

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus^® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon–Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as “larger particles always crystallize later than smaller particles” are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Guy Van den Mooter)

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20 pages, 6930 KiB

Open AccessEditor’s ChoiceArticle

Engineered Full Thickness Electrospun Scaffold for Esophageal Tissue Regeneration: From In Vitro to In Vivo Approach

by Silvia Pisani, Stefania Croce, Simone Mauramati, Marta Marmonti, Lorenzo Cobianchi, Irene Herman, Rossella Dorati, Maria Antonietta Avanzini, Ida Genta, Marco Benazzo and Bice Conti

Pharmaceutics 2022, 14(2), 252; https://doi.org/10.3390/pharmaceutics14020252 - 21 Jan 2022

Cited by 10 | Viewed by 3444

Abstract

Acquired congenital esophageal malformations, such as malignant esophageal cancer, require esophagectomy resulting in full thickness resection, which cannot be left untreated. The proposed approach is a polymeric full-thickness scaffold engineered with mesenchymal stem cells (MSCs) to promote and speed up the regeneration process, [...] Read more.

Acquired congenital esophageal malformations, such as malignant esophageal cancer, require esophagectomy resulting in full thickness resection, which cannot be left untreated. The proposed approach is a polymeric full-thickness scaffold engineered with mesenchymal stem cells (MSCs) to promote and speed up the regeneration process, ensuring adequate support and esophageal tissue reconstruction and avoiding the use of autologous conduits. Copolymers poly-L-lactide-co-poly-ε-caprolactone (PLA-PCL) 70:30 and 85:15 ratio were chosen to prepare electrospun tubular scaffolds. Electrospinning apparatus equipped with two different types of tubular mandrels: cylindrical (∅ 10 mm) and asymmetrical (∅ 10 mm and ∅ 8 mm) were used. Tubular scaffolds underwent morphological, mechanical (uniaxial tensile stress) and biological (MTT and Dapi staining) characterization. Asymmetric tubular geometry resulted in the best properties and was selected for in vivo surgical implantation. Anesthetized pigs underwent full thickness circumferential resection of the mid-lower thoracic esophagus, followed by implantation of the asymmetric scaffold. Preliminary in vivo results demonstrated that detached stitch suture achieved better results in terms of animal welfare and scaffold integration; thus, it is to be preferred to continuous suture. Full article

(This article belongs to the Special Issue Electrospun Materials for Biomedical Applications)

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21 pages, 3852 KiB

Open AccessEditor’s ChoiceArticle

Resveratrol Encapsulation and Release from Pristine and Functionalized Mesoporous Silica Carriers

by Simona Ioniţă, Daniel Lincu, Raul-Augustin Mitran, Laila Ziko, Nada K. Sedky, Mihaela Deaconu, Ana-Maria Brezoiu, Cristian Matei and Daniela Berger

Pharmaceutics 2022, 14(1), 203; https://doi.org/10.3390/pharmaceutics14010203 - 16 Jan 2022

Cited by 27 | Viewed by 4200

Abstract

Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase [...] Read more.

Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase its dissolution rate. Pristine MCM-41, MCM-48, SBA-15, SBA-16, FDU-12 and MCF silica were obtained. The influence of SBA-15 functionalized with aminopropyl, isocyanate, phenyl, mercaptopropyl, and propionic acid moieties on resveratrol loading and release profiles was also assessed. The cytotoxic effects were evaluated for mesoporous carriers and resveratrol-loaded samples against human lung cancer (A549), breast cancer (MDA-MB-231) and human skin fibroblast (HSF) cell lines. The effect on apoptosis and cell cycle were assayed for selected resveratrol-loaded carriers. The polyphenol molecules are encapsulated only inside the mesopores, mostly in amorphous state. All materials containing either pristine or functionalized silica carriers increased polyphenol dissolution rate. The influence of the physico-chemical properties of the mesoporous carriers and resveratrol–loaded supports on the kinetic parameters was identified. Resv@SBA-15-SH and Resv@SBA-15-NCO samples exhibited the highest anticancer effect against A549 cells (IC₅₀ values were 26.06 and 36.5 µg/mL, respectively) and against MDA-MB-231 (IC₅₀ values were 35.56 and 19.30 µg/mL, respectively), which highlights their potential use against cancer. Full article

(This article belongs to the Special Issue Recent Progress in Formulation Approaches for Improving the Solubility and Bioavailability of Poorly Soluble Drugs)

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16 pages, 2848 KiB

Open AccessEditor’s ChoiceArticle

Skin Regenerative Potential of Cupuaçu Seed Extract (Theobroma grandiflorum), a Native Fruit from the Amazon: Development of a Topical Formulation Based on Chitosan-Coated Nanocapsules

by Geisa Nascimento Barbalho, Breno Noronha Matos, Gabriel Ferreira da Silva Brito, Thamires da Cunha Miranda, Thuany Alencar-Silva, Fernando Fabriz Sodré, Guilherme Martins Gelfuso, Marcilio Cunha-Filho, Juliana Lott Carvalho, Joyce Kelly do Rosário da Silva and Taís Gratieri

Pharmaceutics 2022, 14(1), 207; https://doi.org/10.3390/pharmaceutics14010207 - 16 Jan 2022

Cited by 15 | Viewed by 4074

Abstract

Scarless skin regeneration is a challenge in regenerative medicine. Herein, we explore the regenerative potential of a Cupuaçu seed extract (Theobroma grandiflorum) to develop an innovative skin regeneration formulation based on chitosan-coated nanocapsules. Cupuaçu seed extract significantly stimulated cell proliferation and [...] Read more.

Scarless skin regeneration is a challenge in regenerative medicine. Herein, we explore the regenerative potential of a Cupuaçu seed extract (Theobroma grandiflorum) to develop an innovative skin regeneration formulation based on chitosan-coated nanocapsules. Cupuaçu seed extract significantly stimulated cell proliferation and migration. A reparative gene expression profile could be verified following extract treatment, which included high levels of MKI67, a cellular proliferation marker, and extracellular matrix genes, such as ELN and HAS2, which code for elastin and hyaluronic acid synthase 2. Formulations with Cupuaçu seed extract successfully entrapped into nanocapsules (EE% > 94%) were developed. Uncoated or coated nanocapsules with low-molecular-weight chitosan presented unimodal size distribution with hydrodynamic diameters of 278.3 ± 5.0 nm (PDI = 0.18 ± 0.02) and 337.2 ± 2.1 nm (PDI = 0.27 ± 0.01), respectively. Both nanosystems were physically stable for at least 120 days and showed to be non-irritating to reconstructed human epidermis. Chitosan coating promoted active penetration into undamaged skin areas, which were still covered by the stratum corneum. In conclusion, the present study demonstrated for the first time the biotechnological potential of the frequently discarded Cupuaçu seed as a valuable pharmaceutical ingredient to be used in regenerative skin products. Full article

(This article belongs to the Special Issue Phytopharmaceutical Technology)

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25 pages, 6600 KiB

Open AccessEditor’s ChoiceArticle

Tablet Disintegration and Dispersion under In Vivo-like Hydrodynamic Conditions

by Jan Lenz, Frederik Fuest, Jan Henrik Finke, Heike Bunjes, Arno Kwade and Michael Juhnke

Pharmaceutics 2022, 14(1), 208; https://doi.org/10.3390/pharmaceutics14010208 - 16 Jan 2022

Cited by 5 | Viewed by 5562

Abstract

Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due [...] Read more.

Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due to the frequent occurrence of high hydrodynamic forces, among other reasons. In this study, 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) is applied to analyse tablet disintegration and dispersion. Disintegration time (DT) and time-resolved particle size distribution in close proximity to the tablet are determined in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets of different porosity, which are composed of pharmaceutical polymers labelled with a fluorescent dye, a filler, and disintegrants, is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeial disintegration test. Results from the 3D Tomo-LIF method proved a strong impact of fluid velocity on disintegration and dispersion. Generally, shorter DTs were determined when cross-linked sodium carboxymethly cellulose (NaCMCXL) was used as disintegrant compared to polyvinyl polypyrrolidone (PVPP). Tablets containing Kollidon VA64 were found to disintegrate by surface erosion. The novel method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We consider the 3D Tomo-LIF in vitro method to be of improved biorelevance in terms of hydrodynamic conditions in the human stomach. Full article

(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)

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19 pages, 19149 KiB

Open AccessEditor’s ChoiceArticle

DELOS Nanovesicles-Based Hydrogels: An Advanced Formulation for Topical Use

by Lídia Ballell-Hosa, Elisabet González-Mira, Hector Santana, Judit Morla-Folch, Marc Moreno-Masip, Yaima Martínez-Prieto, Albert Revuelta, Primiano Pio Di Mauro, Jaume Veciana, Santi Sala, Lidia Ferrer-Tasies and Nora Ventosa

Pharmaceutics 2022, 14(1), 199; https://doi.org/10.3390/pharmaceutics14010199 - 15 Jan 2022

Cited by 6 | Viewed by 3636

Abstract

Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. [...] Read more.

Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. Here we describe the advances on an innovative drug delivery platform called DELOS nanovesicles for topical drug delivery. Previously, the production of DELOS nanovesicles demonstrated potentiality for the topical treatment of complex wounds, achieving well-tolerated liquid dispersions by this route. Here, research efforts have been focused on designing these nanocarriers with the best skin tolerability to be applied even to damaged skin, and on exploring the feasibility of adapting the colloidal dispersions to a more suitable dosage form for topical application. Accordingly, these drug delivery systems have been efficiently evolved to a hydrogel using Methocel^TM K4M, presenting proper stability and rheological properties. Further, the integrity of these nanocarriers when being gellified has been confirmed by cryo-transmission electron microscopy and by Förster resonance energy transfer analysis with fluorescent-labeled DELOS nanovesicles, which is a crucial characterization not widely reported in the literature. Additionally, in vitro experiments have shown that recombinant human Epidermal Growth Factor (rhEGF) protein integrated into gellified DELOS nanovesicles exhibits an enhanced bioactivity compared to the liquid form. Therefore, these studies suggest that such a drug delivery system is maintained unaltered when hydrogellified, becoming the DELOS nanovesicles-based hydrogels, an advanced formulation for topical use. Full article

(This article belongs to the Special Issue Skin Performance of Drug Delivery Systems: Scope, Challenges and Future Research and Regulatory Prospects)

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14 pages, 3539 KiB

Open AccessEditor’s ChoiceArticle

Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials

by Naroa Serna, Aïda Falgàs, Annabel García-León, Ugutz Unzueta, Yáiza Núñez, Alejandro Sánchez-Chardi, Carlos Martínez-Torró, Ramón Mangues, Esther Vazquez, Isolda Casanova and Antonio Villaverde

Pharmaceutics 2022, 14(1), 192; https://doi.org/10.3390/pharmaceutics14010192 - 14 Jan 2022

Cited by 11 | Viewed by 2908

Abstract

The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots [...] Read more.

The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots and sustain a prolonged secretion of the therapeutic agent. For this, we covalently attached hydrophobic molecules (including the antitumoral drug Monomethyl Auristatin E) to a protein targeting a tumoral cell surface marker abundant in several human neoplasias, namely the cytokine receptor CXCR4. By this, a controlled aggregation of the complex is achieved, resulting in mechanically stable protein–drug microparticles. These materials, which are mimetics of bacterial inclusion bodies and of mammalian secretory granules, allow the slow leakage of fully functional conjugates at the nanoscale, both in vitro and in vivo. Upon subcutaneous administration in a mouse model of human CXCR4⁺ lymphoma, the protein–drug depots release nanoconjugates for at least 10 days, which accumulate in the tumor with a potent antitumoral effect. The modification of scaffold cell-targeted proteins by hydrophobic drug conjugation is then shown as a novel transversal platform for the design of slow releasing protein–drug depots, with potential application in a broad spectrum of clinical settings. Full article

(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)

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18 pages, 2532 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of the Mucoadhesive Properties of Chitosan-Based Microstructured Lipid Carrier (CH-MLC)

by Marta Guerini, Giorgia Condrò and Paola Perugini

Pharmaceutics 2022, 14(1), 170; https://doi.org/10.3390/pharmaceutics14010170 - 12 Jan 2022

Cited by 22 | Viewed by 4573

Abstract

Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) [...] Read more.

Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) with a new approach which requires chitosan and mucin to be compacted into a tablet and mucoadhesion to be assessed on a non-mucoadhesive substrate. This type of test showed that chitosan maintains a close bond with mucin even in the presence of a fluid and even encapsulated in microparticles. After this, using a bioreactor, the release of N-acetylcysteine (NAC) from the microparticles (NA-CH-MLC) through a layer of mucus mimicking the pathological conditions of a patient with cystic fibrosis was tested. The release of the active from NAC-CH-MLC demonstrated how the chitosan inside the microparticles acts as a penetration enhancer and how the microparticles can impart a prolonged release over time. Full article

(This article belongs to the Topic Cystic Fibrosis)

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43 pages, 7542 KiB

Open AccessEditor’s ChoiceArticle

Insights from a Box–Behnken Optimization Study of Microemulsions with Salicylic Acid for Acne Therapy

by Maria-Cristina Anicescu, Cristina-Elena Dinu-Pîrvu, Marina-Theodora Talianu, Mihaela Violeta Ghica, Valentina Anuța, Răzvan-Mihai Prisada, Anca Cecilia Nicoară and Lăcrămioara Popa

Pharmaceutics 2022, 14(1), 174; https://doi.org/10.3390/pharmaceutics14010174 - 12 Jan 2022

Cited by 12 | Viewed by 4254

Abstract

The present study brings to attention a method to develop salicylic acid-based oil in water (O/W) microemulsions using a tensioactive system based on Tween 80, lecithin, and propylene glycol (PG), enriched with a vegetable oat oil phase and hyaluronic acid. The systems were [...] Read more.

The present study brings to attention a method to develop salicylic acid-based oil in water (O/W) microemulsions using a tensioactive system based on Tween 80, lecithin, and propylene glycol (PG), enriched with a vegetable oat oil phase and hyaluronic acid. The systems were physically characterized and the Quality by design approach was applied to optimize the attributes of microemulsions using Box–Behnken modeling, combined with response surface methodology. For this purpose, a 3³ fractional factorial design was selected. The effect of independent variables namely X1: Tween 80/PG (%), X2: Lecithin (%), X3: Oil phase (%) was analyzed considering their impact upon the internal structure and evaluated parameters chosen as dependent factors: viscosity, mean droplet size, and work of adhesion. A high viscosity, a low droplet size, an adequate wettability—with a reduced mechanical work—and clarity were considered as desirable for the optimal systems. It was found that the optimal microemulsion which complied with the established conditions was based on: Tween 80/PG 40%, lecithin 0.3%, oat oil 2%, salicylic acid 0.5%, hyaluronic acid 1%, and water 56.2%. The response surface methodology was considered an appropriate tool to explain the impact of formulation factors on the physical properties of microemulsions, offering a complex pattern in the assessment of stability and quality attributes for the optimized formulation. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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20 pages, 4495 KiB

Open AccessEditor’s ChoiceArticle

Superparamagnetic Iron Oxide Nanoparticles Decorated Mesoporous Silica Nanosystem for Combined Antibiofilm Therapy

by Elena Álvarez, Manuel Estévez, Alvaro Gallo-Cordova, Blanca González, Rafael R. Castillo, María del Puerto Morales, Montserrat Colilla, Isabel Izquierdo-Barba and María Vallet-Regí

Pharmaceutics 2022, 14(1), 163; https://doi.org/10.3390/pharmaceutics14010163 - 11 Jan 2022

Cited by 28 | Viewed by 4011

Abstract

A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from [...] Read more.

A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from a unique magnetic-responsive nanocarrier for a combination therapy against biofilm. The design of the nanosystem is based on antibiotic-loaded mesoporous silica nanoparticles (MSNs) externally functionalized with a thermo-responsive polymer capping layer, and decorated in the outermost surface with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are able to generate heat upon application of an alternating magnetic field (AMF), reaching the temperature needed to induce a change in the polymer conformation from linear to globular, therefore triggering pore uncapping and the antibiotic cargo release. The microbiological assays indicated that exposure of E. coli biofilms to 200 µg/mL of the nanosystem and the application of an AMF (202 kHz, 30 mT) decreased the number of viable bacteria by 4 log₁₀ units compared with the control. The results of the present study show that combined hyperthermia and antibiotic treatment is a promising approach for the effective management of biofilm-associated infections. Full article

(This article belongs to the Topic Emerging Material-Based Approaches to Chronic and Infectious Diseases)

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22 pages, 4598 KiB

Open AccessEditor’s ChoiceArticle

Novel Nanoparticles Based on N,O-Carboxymethyl Chitosan-Dopamine Amide Conjugate for Nose-to-Brain Delivery

by Adriana Trapani, Stefania Cometa, Elvira De Giglio, Filomena Corbo, Roberta Cassano, Maria Luisa Di Gioia, Sonia Trombino, Md Niamat Hossain, Sante Di Gioia, Giuseppe Trapani and Massimo Conese

Pharmaceutics 2022, 14(1), 147; https://doi.org/10.3390/pharmaceutics14010147 - 8 Jan 2022

Cited by 24 | Viewed by 3510

Abstract

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying [...] Read more.

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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20 pages, 32370 KiB

Open AccessEditor’s ChoiceArticle

Enzyme-Responsive Amphiphilic Peptide Nanoparticles for Biocompatible and Efficient Drug Delivery

by Su Jeong Song and Joon Sig Choi

Pharmaceutics 2022, 14(1), 143; https://doi.org/10.3390/pharmaceutics14010143 - 7 Jan 2022

Cited by 24 | Viewed by 3718

Abstract

Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides [...] Read more.

Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly)₃, RH-(GFLG)₃). The self-assembled RH-(GFLG)₃ globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG)₃ nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD (^LRH-^D(GFLG)₃), DL (^DRH-L(GFLG)₃), and DD (^DRH-^D(GFLG)₃). The RH-(GFLG)₃ nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG)₃ nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG)₃ peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications. Full article

(This article belongs to the Special Issue Biodegradable, Biocompatible Carriers for Drug and Gene Delivery)

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23 pages, 8259 KiB

Open AccessEditor’s ChoiceArticle

Tailoring of Novel Azithromycin-Loaded Zinc Oxide Nanoparticles for Wound Healing

by Mohammed S. Saddik, Mahmoud M. A. Elsayed, Mohamed A. El-Mokhtar, Haitham Sedky, Jelan A. Abdel-Aleem, Ahmed M. Abu-Dief, Mostafa F. Al-Hakkani, Hazem L. Hussein, Samah A. Al-Shelkamy, Fatma Y. Meligy, Ali Khames and Heba A. Abou-Taleb

Pharmaceutics 2022, 14(1), 111; https://doi.org/10.3390/pharmaceutics14010111 - 5 Jan 2022

Cited by 108 | Viewed by 7391

Abstract

Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates [...] Read more.

Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates the healing process. So, there is an urgent need to develop a novel pharmaceutical material that promotes the healing of infected wounds. The present work aimed to prepare and evaluate the efficacy of novel azithromycin-loaded zinc oxide nanoparticles (AZM-ZnONPs) in the treatment of infected wounds. The Box–Behnken design and response surface methodology were used to evaluate loading efficiency and release characteristics of the prepared NPs. The minimum inhibitory concentration (MIC) of the formulations was determined against Staphylococcus aureus and Escherichia coli. Moreover, the anti-bacterial and wound-healing activities of the AZM-loaded ZnONPs impregnated into hydroxyl propyl methylcellulose (HPMC) gel were evaluated in an excisional wound model in rats. The prepared ZnONPs were loaded with AZM by adsorption. The prepared ZnONPs were fully characterized by XRD, EDAX, SEM, TEM, and FT-IR analysis. Particle size distribution for the prepared ZnO and AZM-ZnONPs were determined and found to be 34 and 39 nm, respectively. The mechanism by which AZM adsorbed on the surface of ZnONPs was the best fit by the Freundlich model with a maximum load capacity of 160.4 mg/g. Anti-microbial studies showed that AZM-ZnONPs were more effective than other controls. Using an experimental infection model in rats, AZM-ZnONPs impregnated into HPMC gel enhanced bacterial clearance and epidermal regeneration, and stimulated tissue formation. In conclusion, AZM -loaded ZnONPs are a promising platform for effective and rapid healing of infected wounds. Full article

(This article belongs to the Special Issue Biopolymer Materials for Wound Healing)

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11 pages, 1099 KiB

Open AccessEditor’s ChoiceArticle

Implementation and Comparison of Two Pharmacometric Tools for Model-Based Therapeutic Drug Monitoring and Precision Dosing of Daptomycin

by Justine Heitzmann, Yann Thoma, Romain Bricca, Marie-Claude Gagnieu, Vincent Leclerc, Sandrine Roux, Anne Conrad, Tristan Ferry and Sylvain Goutelle

Pharmaceutics 2022, 14(1), 114; https://doi.org/10.3390/pharmaceutics14010114 - 4 Jan 2022

Cited by 12 | Viewed by 2635

Abstract

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented [...] Read more.

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented into the BestDose software. A published parametric model was imported into Tucuxi. We compared the performance of the two models in a validation dataset based on mean error (ME) and mean absolute percent error (MAPE) of individual predictions, estimated exposure and predicted doses necessary to achieve daptomycin efficacy and safety PK/PD targets. The BestDose model described the data very well in the learning dataset. In the validation dataset (94 patients, 264 concentrations), 21.3% of patients were underexposed (AUC_24h < 666 mg.h/L) and 31.9% of patients were overexposed (C_min > 24.3 mg/L) on the first TDM occasion. The BestDose model performed slightly better than the model in Tucuxi (ME = −0.13 ± 5.16 vs. −1.90 ± 6.99 mg/L, p < 0.001), but overall results were in agreement between the two models. A significant proportion of patients exhibited underexposure or overexposure to daptomycin after the initial dosage, which supports TDM. The two models may be useful for model-informed precision dosing. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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20 pages, 2457 KiB

Open AccessEditor’s ChoiceArticle

Purification Process of a Recombinant Human Follicle Stimulating Hormone Biosimilar (Primapur^®) to Yield a Pharmaceutical Product with High Batch-to-Batch Consistency

by Maria Sinegubova, Ivan Vorobiev, Anatoly Klishin, Dmitry Eremin, Nadezhda Orlova, Natalya Orlova and Mikhail Polzikov

Pharmaceutics 2022, 14(1), 96; https://doi.org/10.3390/pharmaceutics14010096 - 1 Jan 2022

Cited by 6 | Viewed by 5293

Abstract

Recombinant human follicle stimulating hormone (r-hFSH) is widely used for infertility treatment and is subject to the development of biosimilars. There are different purification strategies that can yield r-hFSH of pharmaceutical quality from Chinese hamster ovary cell culture broth. We developed a purification [...] Read more.

Recombinant human follicle stimulating hormone (r-hFSH) is widely used for infertility treatment and is subject to the development of biosimilars. There are different purification strategies that can yield r-hFSH of pharmaceutical quality from Chinese hamster ovary cell culture broth. We developed a purification process for r-hFSH centered on immunoaffinity chromatography with single-domain recombinant camelid antibodies. The resulting downstream process is simple and devoid of ultrafiltration operations. Studies on chromatography resin resource and ligand leakage showed that the immunoaffinity matrix employed was suitable for industrial use and stable for at least 40 full chromatography cycles, and the leaked single-domain antibody ligand was completely removed by subsequent purification steps. All chromatography resins employed withstood the same 40 cycles of use without significant changes in separation efficiency and product binding capacity. The resulting industrial purification process yielded batches of r-hFSH with consistent levels of purity and bioactivity. Full article

(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)

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24 pages, 6818 KiB

Open AccessEditor’s ChoiceArticle

Biodegradable Alginate Films with ZnO Nanoparticles and Citronella Essential Oil—A Novel Antimicrobial Structure

by Ludmila Motelica, Denisa Ficai, Ovidiu Oprea, Anton Ficai, Roxana-Doina Trusca, Ecaterina Andronescu and Alina Maria Holban

Pharmaceutics 2021, 13(7), 1020; https://doi.org/10.3390/pharmaceutics13071020 - 3 Jul 2021

Cited by 135 | Viewed by 8000

Abstract

The petroleum-based materials could be replaced, at least partially, by biodegradable packaging. Adding antimicrobial activity to the new packaging materials can also help improve the shelf life of food and diminish the spoilage. The objective of this research was to obtain a novel [...] Read more.

The petroleum-based materials could be replaced, at least partially, by biodegradable packaging. Adding antimicrobial activity to the new packaging materials can also help improve the shelf life of food and diminish the spoilage. The objective of this research was to obtain a novel antibacterial packaging, based on alginate as biodegradable polymer. The antibacterial activity was induced to the alginate films by adding various amounts of ZnO nanoparticles loaded with citronella (lemongrass) essential oil (CEO). The obtained films were characterized, and antibacterial activity was tested against two Gram-negative (Escherichia coli and Salmonella Typhi) and two Gram-positive (Bacillus cereus and Staphylococcus aureus) bacterial strains. The results suggest the existence of synergy between antibacterial activities of ZnO and CEO against all tested bacterial strains. The obtained films have a good antibacterial coverage, being efficient against several pathogens, the best results being obtained against Bacillus cereus. In addition, the films presented better UV light barrier properties and lower water vapor permeability (WVP) when compared with a simple alginate film. The preliminary tests indicate that the alginate films with ZnO nanoparticles and CEO can be used to successfully preserve the cheese. Therefore, our research evidences the feasibility of using alginate/ZnO/CEO films as antibacterial packaging for cheese in order to extend its shelf life. Full article

(This article belongs to the Special Issue Essential Oils in Pharmaceutical Products)

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Review

46 pages, 1601 KiB

Open AccessEditor’s ChoiceReview

Drug-Drug Interactions Between HIV Antivirals and Concomitant Drugs in HIV Patients: What We Know and What We Need to Know

by Emanuela De Bellis, Danilo Donnarumma, Adele Zarrella, Salvatore Maria Mazzeo, Annarita Pagano, Valentina Manzo, Ines Mazza, Francesco Sabbatino, Graziamaria Corbi, Pasquale Pagliano, Amelia Filippelli and Valeria Conti

Pharmaceutics 2025, 17(1), 31; https://doi.org/10.3390/pharmaceutics17010031 - 28 Dec 2024

Cited by 2 | Viewed by 2383

Abstract

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance [...] Read more.

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches. This review aims to summarize and analyze data from studies published over the last two decades on DDI-related adverse clinical outcomes involving anti-HIV drugs and those used to treat comorbidities. Several studies have examined the pharmacokinetics and tolerability of different drug combinations. Protease inhibitors, followed by nonnucleoside reverse transcriptase inhibitors and integrase inhibitors have been recognized as the main players in DDIs with antivirals used to control co-infection, such as Hepatitis C virus, or with drugs commonly used to treat HIV comorbidities, such as lipid-lowering agents, proton pump inhibitors and anticancer drugs. However, the studies do not seem to be consistent with regard to sample size and follow-up, the drugs involved, or the results obtained. It should be noted that most of the available studies were conducted in healthy volunteers without being replicated in patients. This hampered the assessment of the clinical burden of DDIs and, consequently, the optimal pharmacological management of people living with HIV. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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26 pages, 2866 KiB

Open AccessEditor’s ChoiceReview

Enhancing Patient-Centric Drug Development: Coupling Hot Melt Extrusion with Fused Deposition Modeling and Pressure-Assisted Microsyringe Additive Manufacturing Platforms with Quality by Design

by Dinesh Nyavanandi, Preethi Mandati, Nithin Vidiyala, Prashanth Parupathi, Praveen Kolimi and Hemanth Kumar Mamidi

Pharmaceutics 2025, 17(1), 14; https://doi.org/10.3390/pharmaceutics17010014 - 25 Dec 2024

Cited by 1 | Viewed by 1334

Abstract

In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is [...] Read more.

In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is well known that “one size fits all” is not true for pharmaceutical medicines. Depending on the age, sex, and disease state, each patient might need a different dose, combination of medicines, and drug release pattern from the medications. By employing traditional practices, developing patient-centric medications remains challenging and unaddressed. Over the last few years, much research has been conducted exploring various additive manufacturing techniques for developing on-demand, complex, and patient-centric medications. Among all the techniques, nozzle-based additive manufacturing platforms such as pressure-assisted microsyringe (PAM) and fused deposition modeling (FDM) have been investigated thoroughly to develop various medications. Both nozzle-based techniques involve the application of thermal energy. However, PAM can also be operated under ambient conditions to process semi-solid materials. Nozzle-based techniques can also be paired with the hot melt extrusion (HME) process for establishing a continuous manufacturing platform by employing various in-line process analytical technology (PAT) tools for monitoring critical process parameters (CPPs) and critical material attributes (CMAs) for delivering safe, efficacious, and quality medications to the patient population without compromising critical quality attributes (CQAs). This review covers an in-depth discussion of various critical parameters and their influence on product quality, along with a note on the continuous manufacturing process, quality by design, and future perspectives. Full article

(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)

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22 pages, 3006 KiB

Open AccessEditor’s ChoiceReview

How to Fabricate Hyaluronic Acid for Ocular Drug Delivery

by Martha Kim, Mi-Young Jung, Do-Yeon Lee, So Min Ahn, Gyeong Min Lee and Choul Yong Park

Pharmaceutics 2024, 16(12), 1604; https://doi.org/10.3390/pharmaceutics16121604 - 16 Dec 2024

Cited by 2 | Viewed by 2215

Abstract

This review aims to examine existing research on the development of ocular drug delivery devices utilizing hyaluronic acid (HA). Renowned for its exceptional biocompatibility, viscoelastic properties, and ability to enhance drug bioavailability, HA is a naturally occurring biopolymer. The review discussed specific mechanisms [...] Read more.

This review aims to examine existing research on the development of ocular drug delivery devices utilizing hyaluronic acid (HA). Renowned for its exceptional biocompatibility, viscoelastic properties, and ability to enhance drug bioavailability, HA is a naturally occurring biopolymer. The review discussed specific mechanisms by which HA enhances drug delivery, including prolonging drug residence time on ocular surfaces, facilitating controlled drug release, and improving drug penetration through ocular tissues. By focusing on these unique functionalities, this review highlights the potential of HA-based systems to revolutionize ocular treatment. Various fabrication techniques for HA-based ocular drug delivery systems, including hydrogels, nanoparticles, and microneedles, are discussed, highlighting their respective advantages and limitations. Additionally, this review explores the clinical applications of HA-based devices in treating a range of ocular diseases, such as dry eye syndrome, glaucoma, retinal disorders, and ocular infections. By comparing the efficacy and safety profiles of these devices with traditional ocular drug delivery methods, this review aims to provide a comprehensive understanding of the potential benefits and challenges associated with HA-based systems. Moreover, this review discusses current limitations and future directions in the field, such as the need for standardized fabrication protocols, long-term biocompatibility studies, and large-scale clinical trials. The insights and advancements presented in this review aim to guide future research and development efforts, ultimately enhancing the effectiveness of ocular drug delivery and improving patient outcomes. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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39 pages, 5518 KiB

Open AccessEditor’s ChoiceReview

Cyclodextrin Inclusion Complexes with Hydrocortisone-Type Corticosteroids

by Aleksandra Kowalska and Łukasz Szeleszczuk

Pharmaceutics 2024, 16(12), 1544; https://doi.org/10.3390/pharmaceutics16121544 - 2 Dec 2024

Viewed by 1563

Abstract

The hydrocortisone-type corticosteroid (HTC) group includes valuable active pharmaceutical ingredients (APIs) such as hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone. Unfortunately, those APIs are characterized by low solubility, which hampers their application and reduces their therapeutic efficacy. The low [...] Read more.

The hydrocortisone-type corticosteroid (HTC) group includes valuable active pharmaceutical ingredients (APIs) such as hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone. Unfortunately, those APIs are characterized by low solubility, which hampers their application and reduces their therapeutic efficacy. The low polarity of HTC molecules allows them to form inclusion complexes with various cyclodextrins (CDs); however, as shown in this review, the type of applied CDs has a major impact on the final properties of the formed complex. HTC–CD complexes have been routinely used for over 40 years to achieve various aims. Most frequently, CDs have been utilized as HTC solubilizers and absorption enhancers in pharmaceutical formulations, as well as for separation and analysis by chromatographic and electrophoretic methods. This article reviews the studies describing the synthesis as well as the biological, physiochemical, and structural properties of the inclusion complexes formed between HTC and various cyclodextrins. Full article

(This article belongs to the Special Issue Exploring the Versatility of Cyclodextrins in Pharmaceutical Formulations)

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27 pages, 2611 KiB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of the Latest Trends in Spray Freeze Drying and Comparative Insights with Conventional Technologies

by Maria Ioannou Sartzi, Dimitrios Drettas, Marina Stramarkou and Magdalini Krokida

Pharmaceutics 2024, 16(12), 1533; https://doi.org/10.3390/pharmaceutics16121533 - 29 Nov 2024

Cited by 7 | Viewed by 3812

Abstract

Spray freeze drying (SFD) represents an emerging drying technique designed to produce a wide range of pharmaceuticals, foods, and active components with high quality and enhanced stability due to their unique structural characteristics. This method combines the advantages of the well-established techniques of [...] Read more.

Spray freeze drying (SFD) represents an emerging drying technique designed to produce a wide range of pharmaceuticals, foods, and active components with high quality and enhanced stability due to their unique structural characteristics. This method combines the advantages of the well-established techniques of freeze drying (FD) and spray drying (SD) while overcoming their challenges related to high process temperatures and durations. This is why SFD has experienced steady growth in recent years regarding not only the research interest, which is reflected by the increasing number of literature articles, but most importantly, the expanded market adoption, particularly in the pharmaceutical sector. Despite its potential, the high initial investment costs and complex operational requirements may hinder its growth. This paper provides a comprehensive review of the SFD technology, highlighting its advantages over conventional drying techniques and presenting its latest applications focused on pharmaceuticals. It also offers a thorough examination of the principles and the various parameters influencing the process for a better understanding and optimization of the process according to the needs of the final product. Finally, the current limitations of SFD are discussed, and future directions for addressing the economic and technical barriers are provided so that SFD can be widely industrialized, unlocking its full potential for diverse applications. Full article

(This article belongs to the Special Issue Spray Drying in the Pharmaceutical and Nutraceutical Field)

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26 pages, 6769 KiB

Open AccessEditor’s ChoiceReview

Effect of Lipid Nanoparticle Physico-Chemical Properties and Composition on Their Interaction with the Immune System

by Laura Catenacci, Rachele Rossi, Francesca Sechi, Daniela Buonocore, Milena Sorrenti, Sara Perteghella, Marco Peviani and Maria Cristina Bonferoni

Pharmaceutics 2024, 16(12), 1521; https://doi.org/10.3390/pharmaceutics16121521 - 26 Nov 2024

Cited by 15 | Viewed by 5172

Abstract

Lipid nanoparticles (LNPs) have shown promise as a delivery system for nucleic acid-based therapeutics, including DNA, siRNA, and mRNA vaccines. The immune system plays a critical role in the response to these nanocarriers, with innate immune cells initiating an early response and adaptive [...] Read more.

Lipid nanoparticles (LNPs) have shown promise as a delivery system for nucleic acid-based therapeutics, including DNA, siRNA, and mRNA vaccines. The immune system plays a critical role in the response to these nanocarriers, with innate immune cells initiating an early response and adaptive immune cells mediating a more specific reaction, sometimes leading to potential adverse effects. Recent studies have shown that the innate immune response to LNPs is mediated by Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs), which recognize the lipid components of the nanoparticles. This recognition can trigger the activation of inflammatory pathways and the production of cytokines and chemokines, leading to potential adverse effects such as fever, inflammation, and pain at the injection site. On the other hand, the adaptive immune response to LNPs appears to be primarily directed against the protein encoded by the mRNA cargo, with little evidence of an ongoing adaptive immune response to the components of the LNP itself. Understanding the relationship between LNPs and the immune system is critical for the development of safe and effective nucleic acid-based delivery systems. In fact, targeting the immune system is essential to develop effective vaccines, as well as therapies against cancer or infections. There is a lack of research in the literature that has systematically studied the factors that influence the interaction between LNPs and the immune system and further research is needed to better elucidate the mechanisms underlying the immune response to LNPs. In this review, we discuss LNPs’ composition, physico-chemical properties, such as size, shape, and surface charge, and the protein corona formation which can affect the reactivity of the immune system, thus providing a guide for the research on new formulations that could gain a favorable efficacy/safety profile. Full article

(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)

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47 pages, 3373 KiB

Open AccessEditor’s ChoiceReview

The Application of Nano Drug Delivery Systems in Female Upper Genital Tract Disorders

by Daniélle van Staden, Minja Gerber and Hendrik J. R. Lemmer

Pharmaceutics 2024, 16(11), 1475; https://doi.org/10.3390/pharmaceutics16111475 - 19 Nov 2024

Cited by 2 | Viewed by 3136

Abstract

The prevalence of female reproductive system disorders is increasing, especially among women of reproductive age, significantly impacting their quality of life and overall health. Managing these diseases effectively is challenging due to the complex nature of the female reproductive system, characterized by dynamic [...] Read more.

The prevalence of female reproductive system disorders is increasing, especially among women of reproductive age, significantly impacting their quality of life and overall health. Managing these diseases effectively is challenging due to the complex nature of the female reproductive system, characterized by dynamic physiological environments and intricate anatomical structures. Innovative drug delivery approaches are necessary to facilitate the precise regulation and manipulation of biological tissues. Nanotechnology is increasingly considered to manage reproductive system disorders, for example, nanomaterial imaging allows for early detection and enhances diagnostic precision to determine disease severity and progression. Additionally, nano drug delivery systems are gaining attention for their ability to target the reproductive system successfully, thereby increasing therapeutic efficacy and decreasing side effects. This comprehensive review outlines the anatomy of the female upper genital tract by highlighting the complex mucosal barriers and their impact on systemic and local drug delivery. Advances in nano drug delivery are described for their sustainable therapeutic action and increased biocompatibility to highlight the potential of nano drug delivery strategies in managing female upper genital tract disorders. Full article

(This article belongs to the Special Issue Drug Delivery in the Reproductive Systems)

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28 pages, 2973 KiB

Open AccessEditor’s ChoiceReview

Peptide-Based Biomaterials for Combatting Infections and Improving Drug Delivery

by Lucia Lombardi, Jiaxu Li and Daryl R. Williams

Pharmaceutics 2024, 16(11), 1468; https://doi.org/10.3390/pharmaceutics16111468 - 18 Nov 2024

Cited by 2 | Viewed by 2361

Abstract

This review explores the potential of peptide-based biomaterials to enhance biomedical applications through self-assembly, biological responsiveness, and selective targeting. Peptides are presented as versatile agents for antimicrobial activity and drug delivery, with recent approaches incorporating antimicrobial peptides into self-assembling systems to improve effectiveness [...] Read more.

This review explores the potential of peptide-based biomaterials to enhance biomedical applications through self-assembly, biological responsiveness, and selective targeting. Peptides are presented as versatile agents for antimicrobial activity and drug delivery, with recent approaches incorporating antimicrobial peptides into self-assembling systems to improve effectiveness and reduce resistance. The review also covers peptide-based nanocarriers for cancer drug delivery, highlighting their improved stability, targeted delivery, and reduced side effects. The focus of this work is on the bioactive properties of peptides, particularly in infection control and drug delivery, rather than on their structural design or material characteristics. Additionally, it examines the role of peptidomimetics in broadening biomaterial applications and enhancing resistance to enzymatic degradation. Finally, the review discusses the commercial prospects and challenges of translating peptide biomaterials into clinical applications. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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21 pages, 1576 KiB

Open AccessEditor’s ChoiceReview

Corneal Treatment, Repair, and Regeneration: Exosomes at Rescue

by Brooke T. Robbins, Kate A. Montreuil, Neloy Kundu, Prashant Kumar and Vibhuti Agrahari

Pharmaceutics 2024, 16(11), 1424; https://doi.org/10.3390/pharmaceutics16111424 - 7 Nov 2024

Cited by 3 | Viewed by 2370

Abstract

Exosomes are extracellular vesicles within the nanosized range that play roles in intercellular communication and thus have certain biological activities. The secretory signaling communication mechanism is an efficient way of exchanging information between cells and has been investigated as nature’s therapeutic drug carriers. [...] Read more.

Exosomes are extracellular vesicles within the nanosized range that play roles in intercellular communication and thus have certain biological activities. The secretory signaling communication mechanism is an efficient way of exchanging information between cells and has been investigated as nature’s therapeutic drug carriers. This review will summarize the potential of exosomes as therapeutic tools and drug delivery vehicles for corneal pathologies. The cornea is an avascular ocular tissue, and its healing is a complex process including cell death and migration, cell proliferation and differentiation, and extracellular matrix remodeling. Here, we discussed the structure, barrier, phases, and healing cascade of cornea. We briefly reviewed the immunogenicity and toxicity of exosomes and role of exosomes in preserving cornea. Additionally, we provided combining exosome strategies with hydrogels, gene and stem cells therapy focused on corneal treatment, repair, and regeneration. Full article

(This article belongs to the Special Issue Emerging Trends and Translational Challenges in Drug and Vaccine Delivery, 2nd Edition)

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40 pages, 1184 KiB

Open AccessEditor’s ChoiceReview

Enhancing Cancer Treatment Through Combined Approaches: Photodynamic Therapy in Concert with Other Modalities

by Gyeong Hong and Ji-Eun Chang

Pharmaceutics 2024, 16(11), 1420; https://doi.org/10.3390/pharmaceutics16111420 - 6 Nov 2024

Cited by 7 | Viewed by 2903

Abstract

This review explores the role of photodynamic therapy (PDT) as an adjunctive treatment for cancers, with a focus on its potential to enhance the effects of established therapies like chemotherapy, surgery, and radiotherapy. Given the limitations of conventional cancer treatments, PDT’s ability to [...] Read more.

This review explores the role of photodynamic therapy (PDT) as an adjunctive treatment for cancers, with a focus on its potential to enhance the effects of established therapies like chemotherapy, surgery, and radiotherapy. Given the limitations of conventional cancer treatments, PDT’s ability to improve therapeutic outcomes through combination strategies is examined. In cancers such as lung, breast, cholangiocarcinoma, and cervical, PDT shows promise in enhancing response rates, reducing recurrence, and minimizing adverse effects when used alongside standard modalities. This study highlights current findings on PDT’s mechanisms in complementing chemotherapy, augmenting surgical precision, and enhancing radiotherapeutic effects, thus offering a multi-faceted approach to cancer treatment. Additionally, insights into the clinical application of PDT in these cancers emphasize its potential for reducing tumor resistance and supporting more effective, personalized care. By providing an overview of PDT’s synergistic applications across diverse cancer types, this review underscores its emerging significance in oncology as a tool to address traditional treatment limitations. Ultimately, this review aims to inform and inspire researchers and clinicians seeking to refine and innovate cancer therapy strategies through PDT integration, contributing to the advancement of more effective, synergistic cancer treatments. Full article

(This article belongs to the Special Issue Progress in Photoactive Biomaterial-Based Synergistic Combination Phototherapy)

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29 pages, 3207 KiB

Open AccessEditor’s ChoiceReview

Skin Structure, Physiology, and Pathology in Topical and Transdermal Drug Delivery

by Sofia Brito, Moonki Baek and Bum-Ho Bin

Pharmaceutics 2024, 16(11), 1403; https://doi.org/10.3390/pharmaceutics16111403 - 31 Oct 2024

Cited by 13 | Viewed by 9095

Abstract

Several industries are increasingly focused on enhancing the delivery of active ingredients through the skin to optimize therapeutic outcomes. By facilitating the penetration of active ingredients through the skin barrier, these enhancers can significantly improve the efficacy of various formulations, ranging from skincare [...] Read more.

Several industries are increasingly focused on enhancing the delivery of active ingredients through the skin to optimize therapeutic outcomes. By facilitating the penetration of active ingredients through the skin barrier, these enhancers can significantly improve the efficacy of various formulations, ranging from skincare products to therapeutic agents targeting systemic circulation. As the understanding of skin physiology and the mechanisms of drug absorption deepen, these industries are adopting permeation enhancers more widely, ultimately leading to better patient outcomes and expanded treatment options. However, the structure and physiological function of the skin can vary according to different factors, such as the area of the body and between individuals. These variations, along with external environmental exposures, aging and pathological conditions, introduce complexities that must be carefully considered when designing effective delivery systems. Considering the intricacies of skin structure and physiology, tailoring systems to account for regional differences, individual variability, and changes induced by environmental factors or disease is critical to optimizing therapeutic outcomes. This review discusses the features of skin structure, physiology, and pathologies, as well as the application of permeation enhancers in these contexts. Furthermore, it addresses the use of animal skin models in transdermal delivery and dermatological studies, along with the latest developments in this field. Full article

(This article belongs to the Special Issue Transdermal Delivery: Challenges and Opportunities)

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21 pages, 1128 KiB

Open AccessEditor’s ChoiceReview

Pharmacological Treatment of Interstitial Lung Diseases: A Novel Landscape for Inhaled Agents

by Vito D’Agnano, Fabio Perrotta, Ramona Fomez, Valerio Maria Carrozzo, Angela Schiattarella, Stefano Sanduzzi Zamparelli, Raffaella Pagliaro, Andrea Bianco and Domenica Francesca Mariniello

Pharmaceutics 2024, 16(11), 1391; https://doi.org/10.3390/pharmaceutics16111391 - 29 Oct 2024

Cited by 2 | Viewed by 2802

Abstract

Interstitial lung diseases (ILDs) encompass a heterogeneous group of over 200 disorders that require individualized treatment. Antifibrotic agents, such as nintedanib and pirfenidone, have remarkably revolutionized the treatment landscape of patients with idiopathic pulmonary fibrosis (IPF). Moreover, the approval of nintedanib has also [...] Read more.

Interstitial lung diseases (ILDs) encompass a heterogeneous group of over 200 disorders that require individualized treatment. Antifibrotic agents, such as nintedanib and pirfenidone, have remarkably revolutionized the treatment landscape of patients with idiopathic pulmonary fibrosis (IPF). Moreover, the approval of nintedanib has also expanded the therapeutic options for patients with progressive pulmonary fibrosis other than IPF. However, despite recent advances, current therapeutic strategies based on antifibrotic agents and/or immunomodulation are associated with non-negligible side effects. Therefore, several studies have explored the inhalation route aiming to spread higher local concentrations while limiting systemic toxicity. In this review, we examined the currently available literature about preclinical and clinical studies testing the efficacy and safety of inhalation-based antifibrotics, immunomodulatory agents, antioxidants, mucolytics, bronchodilators, and vasodilator agents in ILDs. Full article

(This article belongs to the Special Issue Inhalable Drugs for the Treatment of Chronic Respiratory Diseases)

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31 pages, 3958 KiB

Open AccessEditor’s ChoiceReview

Emerging Cationic Nanovaccines

by Ana Maria Carmona-Ribeiro and Yunys Pérez-Betancourt

Pharmaceutics 2024, 16(11), 1362; https://doi.org/10.3390/pharmaceutics16111362 - 25 Oct 2024

Cited by 1 | Viewed by 1990

Abstract

Cationic vaccines of nanometric sizes can directly perform the delivery of antigen(s) and immunomodulator(s) to dendritic cells in the lymph nodes. The positively charged nanovaccines are taken up by antigen-presenting cells (APCs) of the lymphatic system often originating the cellular immunological defense required [...] Read more.

Cationic vaccines of nanometric sizes can directly perform the delivery of antigen(s) and immunomodulator(s) to dendritic cells in the lymph nodes. The positively charged nanovaccines are taken up by antigen-presenting cells (APCs) of the lymphatic system often originating the cellular immunological defense required to fight intracellular microbial infections and the proliferation of cancers. Cationic molecules imparting the positive charges to nanovaccines exhibit a dose-dependent toxicity which needs to be systematically addressed. Against the coronavirus, mRNA cationic nanovaccines evolved rapidly. Nowadays cationic nanovaccines have been formulated against several infections with the advantage of cationic compounds granting protection of nucleic acids in vivo against biodegradation by nucleases. Up to the threshold concentration of cationic molecules for nanovaccine delivery, cationic nanovaccines perform well eliciting the desired Th 1 improved immune response in the absence of cytotoxicity. A second strategy in the literature involves dilution of cationic components in biocompatible polymeric matrixes. Polymeric nanoparticles incorporating cationic molecules at reduced concentrations for the cationic component often result in an absence of toxic effects. The progress in vaccinology against cancer involves in situ designs for cationic nanovaccines. The lysis of transformed cancer cells releases several tumoral antigens, which in the presence of cationic nanoadjuvants can be systemically presented for the prevention of metastatic cancer. In addition, these local cationic nanovaccines allow immunotherapeutic tumor treatment. Full article

(This article belongs to the Special Issue Applications of Nanomaterials in Immunotherapies)

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51 pages, 3047 KiB

Open AccessEditor’s ChoiceReview

The Impact of COVID-19 on RNA Therapeutics: A Surge in Lipid Nanoparticles and Alternative Delivery Systems

by Nargish Parvin, Tapas K. Mandal and Sang-Woo Joo

Pharmaceutics 2024, 16(11), 1366; https://doi.org/10.3390/pharmaceutics16111366 - 25 Oct 2024

Cited by 3 | Viewed by 3282

Abstract

The COVID-19 pandemic has significantly accelerated progress in RNA-based therapeutics, particularly through the successful development and global rollout of mRNA vaccines. This review delves into the transformative impact of the pandemic on RNA therapeutics, with a strong focus on lipid nanoparticles (LNPs) as [...] Read more.

The COVID-19 pandemic has significantly accelerated progress in RNA-based therapeutics, particularly through the successful development and global rollout of mRNA vaccines. This review delves into the transformative impact of the pandemic on RNA therapeutics, with a strong focus on lipid nanoparticles (LNPs) as a pivotal delivery platform. LNPs have proven to be critical in enhancing the stability, bioavailability, and targeted delivery of mRNA, facilitating the unprecedented success of vaccines like those developed by Pfizer-BioNTech and Moderna. Beyond vaccines, LNP technology is being explored for broader therapeutic applications, including treatments for cancer, rare genetic disorders, and infectious diseases. This review also discusses emerging RNA delivery systems, such as polymeric nanoparticles and viral vectors, which offer alternative strategies to overcome existing challenges related to stability, immune responses, and tissue-specific targeting. Additionally, we examine the pandemic’s influence on regulatory processes, including the fast-tracked approvals for RNA therapies, and the surge in research funding that has spurred further innovation in the field. Public acceptance of RNA-based treatments has also grown, laying the groundwork for future developments in personalized medicine. By providing an in-depth analysis of these advancements, this review highlights the long-term impact of COVID-19 on the evolution of RNA therapeutics and the future of precision drug delivery technologies. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)

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27 pages, 2107 KiB

Open AccessEditor’s ChoiceReview

Artificial Intelligence (AI) Applications in Drug Discovery and Drug Delivery: Revolutionizing Personalized Medicine

by Dolores R. Serrano, Francis C. Luciano, Brayan J. Anaya, Baris Ongoren, Aytug Kara, Gracia Molina, Bianca I. Ramirez, Sergio A. Sánchez-Guirales, Jesus A. Simon, Greta Tomietto, Chrysi Rapti, Helga K. Ruiz, Satyavati Rawat, Dinesh Kumar and Aikaterini Lalatsa

Pharmaceutics 2024, 16(10), 1328; https://doi.org/10.3390/pharmaceutics16101328 - 14 Oct 2024

Cited by 82 | Viewed by 30630

Abstract

Artificial intelligence (AI) encompasses a broad spectrum of techniques that have been utilized by pharmaceutical companies for decades, including machine learning, deep learning, and other advanced computational methods. These innovations have unlocked unprecedented opportunities for the acceleration of drug discovery and delivery, the [...] Read more.

Artificial intelligence (AI) encompasses a broad spectrum of techniques that have been utilized by pharmaceutical companies for decades, including machine learning, deep learning, and other advanced computational methods. These innovations have unlocked unprecedented opportunities for the acceleration of drug discovery and delivery, the optimization of treatment regimens, and the improvement of patient outcomes. AI is swiftly transforming the pharmaceutical industry, revolutionizing everything from drug development and discovery to personalized medicine, including target identification and validation, selection of excipients, prediction of the synthetic route, supply chain optimization, monitoring during continuous manufacturing processes, or predictive maintenance, among others. While the integration of AI promises to enhance efficiency, reduce costs, and improve both medicines and patient health, it also raises important questions from a regulatory point of view. In this review article, we will present a comprehensive overview of AI’s applications in the pharmaceutical industry, covering areas such as drug discovery, target optimization, personalized medicine, drug safety, and more. By analyzing current research trends and case studies, we aim to shed light on AI’s transformative impact on the pharmaceutical industry and its broader implications for healthcare. Full article

(This article belongs to the Special Issue Computational Intelligence (CI) Tools in Applications of Pharmaceutics)

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17 pages, 1313 KiB

Open AccessEditor’s ChoiceReview

Serum Albumin in Nasal Drug Delivery Systems: Exploring the Role and Application

by Sandra Aulia Mardikasari, Gábor Katona and Ildikó Csóka

Pharmaceutics 2024, 16(10), 1322; https://doi.org/10.3390/pharmaceutics16101322 - 11 Oct 2024

Cited by 5 | Viewed by 3053

Abstract

The application of serum albumin in various types of formulations has emerged as a valuable option in biomedical research, especially in the field of nasal drug delivery systems. A serum albumin-based carrier system has been employed due to several benefits, such as enhancing [...] Read more.

The application of serum albumin in various types of formulations has emerged as a valuable option in biomedical research, especially in the field of nasal drug delivery systems. A serum albumin-based carrier system has been employed due to several benefits, such as enhancing drug solubility and stability, generating the desired controlled release profile, and developing favorable properties with respect to the challenges in nasal conditions, which, in this case, involves hindering rapid elimination due to nasal mucociliary clearance. Accordingly, considering the important role of serum albumin, in-depth knowledge related to its utilization in preparing nasal drug formulation is highly encouraged. This review aimed to explore the potential application of serum albumin in fabricating nasal drug formulations and its crucial role and functionality regarding the binding interaction with nasal mucin, which significantly determines the successful administration of nasal drug formulations. Full article

(This article belongs to the Special Issue Topical Advisory Panel Members' Collection Series: Nanocarriers for Alternative Drug Delivery)

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23 pages, 2778 KiB

Open AccessEditor’s ChoiceReview

Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy

by Uri Galili

Pharmaceutics 2024, 16(10), 1263; https://doi.org/10.3390/pharmaceutics16101263 - 27 Sep 2024

Cited by 1 | Viewed by 1999

Abstract

A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in [...] Read more.

A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen “α-gal epitope” (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called “anti-Gal” (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection. Full article

(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)

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13 pages, 966 KiB

Open AccessEditor’s ChoiceReview

Topical Application of Centella asiatica in Wound Healing: Recent Insights into Mechanisms and Clinical Efficacy

by Katarzyna Witkowska, Magdalena Paczkowska-Walendowska, Ewa Garbiec and Judyta Cielecka-Piontek

Pharmaceutics 2024, 16(10), 1252; https://doi.org/10.3390/pharmaceutics16101252 - 26 Sep 2024

Cited by 10 | Viewed by 15454

Abstract

Centella asiatica, widely known as Gotu kola, is a traditional herb celebrated for its benefits in skin health and wound healing. Recent research has provided new insights into its efficacy, particularly through topical applications. This review highlights the plant’s mechanisms, focusing [...] Read more.

Centella asiatica, widely known as Gotu kola, is a traditional herb celebrated for its benefits in skin health and wound healing. Recent research has provided new insights into its efficacy, particularly through topical applications. This review highlights the plant’s mechanisms, focusing on its active compounds such as asiaticoside, madecassoside, asiatic acid, and madecassic acid, which enhance collagen synthesis, modulate inflammation, and offer antioxidant protection. Clinical trials have been collected and summarized that innovative delivery systems, such as hydrogels, nanostructures or microneedles, can accelerate wound healing, reduce wound size, and improve recovery times in various wound types, including diabetic ulcers and burns. Future research will likely refine these technologies and explore new applications, reinforcing the role of C. asiatica in contemporary wound care. Advances in formulation and delivery will continue to enhance the plant’s therapeutic potential, offering promising solutions for effective wound management. Full article

(This article belongs to the Special Issue Therapeutic Approaches for Wound-Associated Skin Diseases)

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22 pages, 6892 KiB

Open AccessEditor’s ChoiceReview

Review on Photoacoustic Monitoring after Drug Delivery: From Label-Free Biomarkers to Pharmacokinetics Agents

by Jiwoong Kim, Seongwook Choi, Chulhong Kim, Jeesu Kim and Byullee Park

Pharmaceutics 2024, 16(10), 1240; https://doi.org/10.3390/pharmaceutics16101240 - 24 Sep 2024

Cited by 5 | Viewed by 1823

Abstract

Photoacoustic imaging (PAI) is an emerging noninvasive and label-free method for capturing the vasculature, hemodynamics, and physiological responses following drug delivery. PAI combines the advantages of optical and acoustic imaging to provide high-resolution images with multiparametric information. In recent decades, PAI’s abilities have [...] Read more.

Photoacoustic imaging (PAI) is an emerging noninvasive and label-free method for capturing the vasculature, hemodynamics, and physiological responses following drug delivery. PAI combines the advantages of optical and acoustic imaging to provide high-resolution images with multiparametric information. In recent decades, PAI’s abilities have been used to determine reactivity after the administration of various drugs. This study investigates photoacoustic imaging as a label-free method of monitoring drug delivery responses by observing changes in the vascular system and oxygen saturation levels across various biological tissues. In addition, we discuss photoacoustic studies that monitor the biodistribution and pharmacokinetics of exogenous contrast agents, offering contrast-enhanced imaging of diseased regions. Finally, we demonstrate the crucial role of photoacoustic imaging in understanding drug delivery mechanisms and treatment processes. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)

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39 pages, 2469 KiB

Open AccessEditor’s ChoiceReview

Exploring the Therapeutic Implications of Co-Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer

by Mafalda Calheiros-Lobo, João P. N. Silva, Bárbara Pinto, Luís Monteiro, Patrícia M. A. Silva and Hassan Bousbaa

Pharmaceutics 2024, 16(9), 1196; https://doi.org/10.3390/pharmaceutics16091196 - 11 Sep 2024

Cited by 2 | Viewed by 1882

Abstract

Head and neck cancer (HNC), the sixth most common cancer worldwide, is increasing in incidence, with oral squamous cell carcinoma (OSCC) as the predominant subtype. OSCC mainly affects middle-aged to elderly males, often occurring on the posterior lateral border of the tongue, leading [...] Read more.

Head and neck cancer (HNC), the sixth most common cancer worldwide, is increasing in incidence, with oral squamous cell carcinoma (OSCC) as the predominant subtype. OSCC mainly affects middle-aged to elderly males, often occurring on the posterior lateral border of the tongue, leading to significant disfigurement and functional impairments, such as swallowing and speech difficulties. Despite advancements in understanding OSCC’s genetic and epigenetic variations, survival rates for advanced stages remain low, highlighting the need for new treatment options. Primary treatment includes surgery, often combined with radiotherapy (RT) and chemotherapy (CT). Cetuximab-based chemotherapy, targeting the overexpressed epidermal growth factor receptor (EGFR) in 80–90% of HNCs, is commonly used but correlates with poor prognosis. Additionally, monopolar spindle 1 (MPS1), a spindle assembly checkpoint (SAC) component, is a significant target due to its role in genomic fidelity during mitosis and its overexpression in several cancers. This review explores EGFR and MPS1 as therapeutic targets in HNC, analyzing their molecular mechanisms and the effects of their inhibition on cancer cells. It also highlights the promise of combinatorial approaches, such as microtubule-targeting agents (MTAs) and antimitotic agents, in improving HNC therapies, patient outcomes, and survival rates. Full article

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28 pages, 7409 KiB

Open AccessEditor’s ChoiceReview

Advances in Nanoparticles as Non-Viral Vectors for Efficient Delivery of CRISPR/Cas9

by Minse Kim, Youngwoo Hwang, Seongyu Lim, Hyeon-Ki Jang and Hyun-Ouk Kim

Pharmaceutics 2024, 16(9), 1197; https://doi.org/10.3390/pharmaceutics16091197 - 11 Sep 2024

Cited by 15 | Viewed by 4350

Abstract

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular [...] Read more.

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular vesicle-based systems, as non-viral vectors for CRISPR/Cas9 delivery. We discuss their advantages, limitations, and current challenges. By summarizing recent advancements and highlighting key strategies, this review aims to provide a comprehensive overview of the role of non-viral delivery systems in advancing CRISPR/Cas9 technology for clinical applications and gene therapy. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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Graphical abstract

37 pages, 5256 KiB

Open AccessEditor’s ChoiceReview

Emerging Trends in Dissolving-Microneedle Technology for Antimicrobial Skin-Infection Therapies

by Rui Luo, Huihui Xu, Qiaoni Lin, Jiaying Chi, Tingzhi Liu, Bingrui Jin, Jiayu Ou, Zejun Xu, Tingting Peng, Guilan Quan and Chao Lu

Pharmaceutics 2024, 16(9), 1188; https://doi.org/10.3390/pharmaceutics16091188 - 8 Sep 2024

Cited by 7 | Viewed by 3048

Abstract

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as [...] Read more.

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as the possibility of infection extending deep into tissues, thereby complicating drug delivery. Dissolving microneedle patches are an innovative transdermal drug-delivery system that effectively enhances drug penetration through the stratum corneum barrier, thereby increasing drug concentration at the site of infection. They offer highly efficient, safe, and patient-friendly alternatives to conventional topical formulations. This comprehensive review focuses on recent advances and emerging trends in dissolving-microneedle technology for antimicrobial skin-infection therapy. Conventional antibiotic microneedles are compared with those based on emerging antimicrobial agents, such as quorum-sensing inhibitors, antimicrobial peptides, and antimicrobial-matrix materials. The review also highlights the potential of innovative microneedles incorporating chemodynamic, nanoenzyme antimicrobial, photodynamic, and photothermal antibacterial therapies. This review explores the advantages of various antimicrobial therapies and emphasizes the potential of their combined application to improve the efficacy of microneedles. Finally, this review analyzes the druggability of different antimicrobial microneedles and discusses possible future developments. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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33 pages, 2551 KiB

Open AccessEditor’s ChoiceReview

Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer

by Ryunosuke Hoshi, Kristyna A. Gorospe, Hagar I. Labouta, Taha Azad, Warren L. Lee and Kelsie L. Thu

Pharmaceutics 2024, 16(9), 1181; https://doi.org/10.3390/pharmaceutics16091181 - 7 Sep 2024

Cited by 6 | Viewed by 3033

Abstract

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)⁺ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8⁺ T cells activates downstream signaling pathways [...] Read more.

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)⁺ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8⁺ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them. Full article

(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)

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