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Advances of Colloidal Systems in Drug Delivery and Therapeutic Application

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 25196

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Prof. Dr. Ana Fernandez-Carballido

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Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: nanomedicine; nanoparticles; microparticles; targeted treatment; breast cancer; chemotherapy
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Dr. Cristina Martín-Sabroso

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Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: chorioallantoic membrane model; cannabinoids; cannabidiol; gynaecological cancer; nanomedicines
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Dr. Juan Aparicio-Blanco

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Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: nanomedicine; brain drug delivery; brain diseases; lipid nanocapsules; glioma; cannabinoids; tailored carriers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The number of formulations of colloidal systems approved by the FDA and the EMA in recent years has been increasing, in applications as varied as in the treatment of cancer, vaccines, dry eye or fungal infections. However, it is an area undergoing continuous expansion thanks to the research of new biomaterials or polymers that improve the kinetics of drug release as well as the functionalization of these systems with the aim of achieving active targeting of the therapeutic target. In addition, in the context of challenges still lying ahead with the increasing number of marketed colloids for biomedical purposes, their characterization techniques remain to be fully established, as in the case of “macro” dosage forms.

In the present Special Issue, studies reporting original data or updated literature reviews aimed at characterization, development or therapeutic application of colloidal systems are welcome. Our aim is to compile the latest developments in the area of characterization, development or therapeutic application of colloidal systems, contributions reporting original data or updated literature reviews on this topic are welcome in this Special Issue.

Prof. Dr. Ana Fernandez-Carballido
Prof. Dr. Cristina Martín-Sabroso
Prof. Dr. Juan Aparicio-Blanco
Guest Editors

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Keywords

novel production methods
smart colloids
colloidal systems
biomaterials
novel characterization techniques
quality by design

Published Papers (10 papers)

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Research

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20 pages, 11761 KiB

Open AccessArticle

Synthesis and Characterization of Calcium Alginate-Based Microspheres Entrapped with TiO₂ Nanoparticles and Cinnamon Essential Oil Targeting Clinical Staphylococcus aureus

by Tayyaba Zaineb, Bushra Uzair, Waleed Y. Rizg, Waleed S. Alharbi, Hala M. Alkhalidi, Khaled M. Hosny, Barkat Ali Khan, Asma Bano, Mohammed Alissa and Nazia Jamil

Pharmaceutics 2022, 14(12), 2764; https://doi.org/10.3390/pharmaceutics14122764 - 09 Dec 2022

Cited by 4 | Viewed by 1911

Abstract

It is important to create new generations of materials that can destroy multidrug-resistant bacterial strains, which are a serious public health concern. This study focused on the biosynthesis of an essential oil entrapped in titanium dioxide (TiO₂) calcium alginate-based microspheres. In this research, calcium alginate-based microspheres with entrapped TiO₂ nanoparticles and cinnamon essential oil (CI-TiO₂-MSs) were synthesized, using an aqueous extract of Nigella sativa seeds for TiO₂ nanoparticle preparation, and the ionotropic gelation method for microsphere preparation. The microspheres obtained were spherical, uniformly sized, microporous, and rough surfaced, and they were fully loaded with cinnamon essential oil and TiO₂ nanoparticles. The synthesized microspheres were analyzed for antibacterial activity against the clinical multidrug-resistant strain of Staphylococcus aureus. Disc diffusion and flow cytometry analysis revealed strong antibacterial activity by CI-TiO₂-MSs. The synthesized CI-TiO₂-MSs were characterized by the SEM/EDX, X-ray diffraction, and FTIR techniques. Results showed that the TiO₂ nanoparticles were spherical and 99 to 150 nm in size, whereas the CI-TiO₂-MSs were spherical and rough surfaced. Apoptosis analysis and SEM micrography revealed that the CI-TiO₂-MSs had strong bactericidal activity against S. aureus. The in vitro antibacterial experiments proved that the encapsulated CI-TiO₂-MSs had strong potential for use as a prolonged controlled release system against multidrug-resistant clinical S. aureus. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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15 pages, 3429 KiB

Open AccessArticle

Functionalization of Morin-Loaded PLGA Nanoparticles with Phenylalanine Dipeptide Targeting the Brain

by Mario Alonso, Emilia Barcia, Juan-Francisco González, Consuelo Montejo, Luis García-García, Mónica-Carolina Villa-Hermosilla, Sofía Negro, Ana-Isabel Fraguas-Sánchez and Ana Fernández-Carballido

Pharmaceutics 2022, 14(11), 2348; https://doi.org/10.3390/pharmaceutics14112348 - 31 Oct 2022

Cited by 2 | Viewed by 1671

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, with its incidence constantly increasing. To date, there is no cure for the disease, with a need for new and effective treatments. Morin hydrate (MH) is a naturally occurring flavonoid of the Moraceae family with antioxidant and anti-inflammatory properties; however, the blood–brain barrier (BBB) prevents this flavonoid from reaching the CNS when aiming to potentially treat AD. Seeking to use the LAT-1 transporter present in the BBB, a nanoparticle (NPs) formulation loaded with MH and functionalized with phenylalanine-phenylalanine dipeptide was developed (NPphe-MH) and compared to non-functionalized NPs (NP-MH). In addition, two formulations were prepared using rhodamine B (Rh-B) as a fluorescent dye (NPphe-Rh and NP-Rh) to study their biodistribution and ability to cross the BBB. Functionalization of PLGA NPs resulted in high encapsulation efficiencies for both MH and Rh-B. Studies conducted in Wistar rats showed that the presence of phenylalanine dipeptide in the NPs modified their biodistribution profiles, making them more attractive for both liver and lungs, whereas non-functionalized NPs were predominantly distributed to the spleen. Formulation NPphe-Rh remained in the brain for at least 2 h after administration. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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25 pages, 3244 KiB

Open AccessArticle

Influence of the Hydrophobicity of Pluronic Micelles Encapsulating Curcumin on the Membrane Permeability and Enhancement of Photoinduced Antibacterial Activity

by Maria Antonia Tănase, Andreia Cristina Soare, Lia Mara Diţu, Cristina Lavinia Nistor, Catalin Ionut Mihaescu, Ioana Catalina Gifu, Cristian Petcu and Ludmila Otilia Cinteza

Pharmaceutics 2022, 14(10), 2137; https://doi.org/10.3390/pharmaceutics14102137 - 08 Oct 2022

Cited by 13 | Viewed by 1687

Abstract

Apart from its well-known activity as an antimicrobial agent, Curcumin (CURC) has recently started to arouse interest as a photosensitizer in the photodynamic therapy of bacterial infections. The aim of the present study was to evidence the influence of the encapsulation of Curcumin into polymeric micelles on the efficiency of photoinduced microbial inhibition. The influence of the hydrophobicity of the selected Pluronics (P84, P123, and F127) on the encapsulation, stability, and antimicrobial efficiency of CURC-loaded micelles was investigated. In addition, the size, morphology, and drug-loading capacity of the micellar drug delivery systems have been characterized. The influence of the presence of micellar aggregates and unassociated molecules of various Pluronics on the membrane permeability was investigated on both normal and resistant microbial strains of E. coli, S. aureus, and C. albicans. The antimicrobial efficiency on the common pathogens was assessed for CURC-loaded polymeric micelles in dark conditions and activated by blue laser light (470 nm). Significant results in the reduction of the microorganism’s growth were found in cultures of C. albicans, even at very low concentrations of surfactants and Curcumin. Unlike the membrane permeabilization effect of the monomeric solution of Pluronics, reported in the case of tumoral cells, a limited permeabilization effect was found on the studied microorganisms. Encapsulation of the Curcumin in Pluronic P84 and P123 at very low, nontoxic concentrations for photosensitizer and drug-carrier, produced CURC-loaded micelles that prove to be effective in the light-activated inhibition of resistant species of Gram-positive bacteria and fungi. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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21 pages, 2814 KiB

Open AccessArticle

Risk-Assessment-Based Optimization Favours the Development of Albumin Nanoparticles with Proper Characteristics Prior to Drug Loading

by Gábor Katona, Bence Sipos and Ildikó Csóka

Pharmaceutics 2022, 14(10), 2036; https://doi.org/10.3390/pharmaceutics14102036 - 24 Sep 2022

Cited by 7 | Viewed by 1667

Abstract

Albumin nanocarrier research and development is a challenging area in the field of personalized medicine and in providing advanced therapeutic solutions. Albumin as a biocompatible, nonimmunogenic, and non-toxic protein carrier that can be exploited to conjugate drugs with poor bioavailability to improve on this feature. With many different perspectives and desired target profiles, a systematic structural approach must be used in nanoparticle development. The extended Research and Development (R&D) Quality by Design thinking and methodology proved to be useful in case of specific nanoparticle development processes before. However, the coacervation method is the most frequently applied preparation method for HSA nanoparticles; there is a lack of existing research work which has directly determined the influence of process parameters, control strategy, or design space. With a quality-management-driven strategy, a knowledge space was developed for these versatile nanoparticles and an initial risk assessment was conducted on the quality-affecting factors regarding the coacervation method, followed by an optimization process via Plackett–Burman and Box–Behnken experimental design. As a result of screening the effect of process variables on the fabrication of HSA nanoparticles, an optimized colloidal drug delivery system was engineered with desired nanoparticulate properties. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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20 pages, 5774 KiB

Open AccessArticle

Gemcitabine-Loaded Nanocarrier of Essential Oil from Pulicaria crispa: Preparation, Optimization, and In Vitro Evaluation of Anticancer Activity

by Sahar M. AlMotwaa and Waad A. Al-Otaibi

Pharmaceutics 2022, 14(7), 1336; https://doi.org/10.3390/pharmaceutics14071336 - 24 Jun 2022

Cited by 2 | Viewed by 2671

Abstract

The limitations of gemcitabine (GEM) in cancer therapy are due to its poor pharmacokinetics, which cause undesired adverse effects. The current study was aimed at investigating the anticancer effect and apoptotic mechanism of synthesized nanoemulsion (NE) containing Pulicaria crispa essential oil (PC-EO) and GEM (PC-NE:GEM) on MCF-7 and Hep-G2 cancer cell lines. An optimized NE formulation was selected based on the Box–Behnken method. The droplet size of the optimized PC-NE was 9.93 ± 0.53 nm, but after GEM loading, it was increased to 11.36 ± 0.0.21 nm. Results from FTIR revealed that GEM was successfully loaded onto PC-NE. The antineoplastic effect of PC-NE:GEM on MCF-7 and Hep-G2 cancer cells was increased more than 100-fold relative to that of GEM. A combination index and isobologram based on CompuSyn software revealed the synergistic effect of the formulation produced by a 1:1 ratio combination of PC-NE and GEM. These findings were confirmed by examination of cellular morphologies. The combination formulation strongly induced about 4.48-fold and 2.95-fold increases in apoptosis in MCF-7 and Hep-G2 cells, respectively, when compared with GEM. Moreover, PC-NE:GEM produced a synergistic increase in ROS production in MCF-7 cells (15.23%) and Hep-G2 cells (31.69%), when compared with GEM. In addition, PC-NE:GEM enhanced the activation of the intrinsic apoptosis pathway through upregulation of expressions of p53 and Caspase-3, and downregulation of Bcl-2 expression in MCF-7 cells, while the expressions of Caspase-3, Bax, and p53 were upregulated in HepG2 cells. These results indicate that the GEM-loaded NE containing PC-EO may reduce the dose of GEM and eliminate the associated side effects. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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11 pages, 690 KiB

Open AccessArticle

Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease: Observations and Dilemmas after 10 Years of Real-Life Experience

by József Attila Szász, Viorelia Adelina Constantin, Károly Orbán-Kis, Ligia Ariana Bancu, Simona Maria Bataga, Marius Ciorba, Előd Nagy, Mircea Radu Neagoe, István Mihály, Róbert Máté Szász, Krisztina Kelemen, Mihaela Simu and Szabolcs Szatmári

Pharmaceutics 2022, 14(6), 1115; https://doi.org/10.3390/pharmaceutics14061115 - 24 May 2022

Cited by 4 | Viewed by 1971

Abstract

Advanced Parkinson’s disease (APD) cannot be treated efficiently using the classical medications however, in recent decades invasive therapeutical methods were implemented and confirmed as effective. One of these methods makes it possible to continue the levodopa (LD) supplementation as a gel administered directly into the upper intestine. However, there are a number of unanswered questions regarding this method. Therefore, we retrospectively analyzed a 10-year period of selected patients that were treated with levodopa/carbidopa intestinal gel (LCIG). We included all APD patients with motor fluctuations and dyskinesia at presentation. LCIG treatment was started in 150 patients: on average these patients received LD for 10.6 ± 4.4 years with a frequency of 5.2 ± 1.0/day until the introduction of LCIG. The estimated and the real LCIG dose differed significantly (mean: 1309 ± 321 mg vs. 1877 ± 769 mg). The mean duration of LCIG administration was 19.8 ± 3.6 h, but in a number of 62 patients we had to administer it for 24 h, to maximize the therapeutic benefit. A carefully and individually adjusted LCIG treatment improves the quality of life of APD patients, but questions remain unresolved even after treating a large number of patients. It is important to share the ideas and observations based on the real-life experience related to the optimal timing, the appropriate dose and duration of administration of the LCIG. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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12 pages, 1831 KiB

Open AccessEditor’s ChoiceArticle

Redox-Responsive Crosslinked Mixed Micelles for Controllable Release of Caffeic Acid Phenethyl Ester

by Katya Kamenova, Georgy Grancharov, Vasilena Kortenova and Petar D. Petrov

Pharmaceutics 2022, 14(3), 679; https://doi.org/10.3390/pharmaceutics14030679 - 20 Mar 2022

Cited by 6 | Viewed by 2437

Abstract

We report the elaboration of redox-responsive functional micellar nanocarriers designed for triggered release of caffeic acid phenethyl ester (CAPE) in cancer therapy. Three-layered micelles, comprising a poly(ε-caprolactone) (PCL) core, a middle poly(acrylic acid)/poly(ethylene oxide) (PAA/PEO) layer and a PEO outer corona, were prepared by co-assembly of PEO₁₁₃-b-PCL₃₅-b-PEO₁₁₃ and PAA₁₃-b-PCL₃₅-b-PAA₁₃ amphiphilic triblock copolymers in aqueous media. The preformed micelles were loaded with CAPE via hydrophobic interactions between the drug molecules and PCL core, and subsequently crosslinked by reaction of carboxyl groups from PAA and a disulfide crosslinking agent. The reaction of crosslinking took place in the middle layer of the nanocarriers without changing the encapsulation efficiency (EE~90%) of the system. The crosslinked polymeric micelles (CPMs) exhibited superior structural stability and did not release CAPE in phosphate buffer (pH 7.4). However, in weak acidic media and in the presence of 10 mM reducing agent (dithiothreitol, DTT), the payload was released at a high rate from CPMs due to the breakup of disulfide linkages. The physicochemical properties of the nanocarriers were investigated by dynamic and electrophoretic light scattering (DLS and ELS) and atomic force microscopy (AFM). The rapid release of CAPE under intracellular-like conditions and the lack of premature drug release in media resembling the blood stream (neutral pH) make the developed CPMs a promising candidate for controllable drug release in the microenvironment of tumors. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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14 pages, 3560 KiB

Open AccessEditor’s ChoiceArticle

Effects of Injection Volume and Route of Administration on Dolutegravir In Situ Forming Implant Pharmacokinetics

by Jordan B. Joiner, Jasmine L. King, Roopali Shrivastava, Sarah Anne Howard, Mackenzie L. Cottrell, Angela D. M. Kashuba, Paul A. Dayton and Soumya Rahima Benhabbour

Pharmaceutics 2022, 14(3), 615; https://doi.org/10.3390/pharmaceutics14030615 - 11 Mar 2022

Cited by 6 | Viewed by 2731

Abstract

Due to the versatility of the in situ forming implant (ISFI) drug delivery system, it is crucial to understand the effects of formulation parameters for clinical translation. We utilized ultrasound imaging and pharmacokinetics (PK) in mice to understand the impact of administration route, injection volume, and drug loading on ISFI formation, degradation, and drug release in mice. Placebo ISFIs injected subcutaneously (SQ) with smaller volumes (40

μ

L) exhibited complete degradation within 30–45 days, compared to larger volumes (80

μ

L), which completely degraded within 45–60 days. However, all dolutegravir (DTG)-loaded ISFIs along the range of injection volumes tested (20–80

μ

L) were present at 90 days post-injection, suggesting that DTG can prolong ISFI degradation. Ultrasound imaging showed that intramuscular (IM) ISFIs flattened rapidly post administration compared to SQ, which coincides with the earlier T_max for drug-loaded IM ISFIs. All mice exhibited DTG plasma concentrations above four times the protein-adjusted 90% inhibitory concentration (PA-IC90) throughout the entire 90 days of the study. ISFI release kinetics best fit to zero order or diffusion-controlled models. When total administered dose was held constant, there was no statistical difference in drug exposure regardless of the route of administration or number of injections. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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14 pages, 1882 KiB

Open AccessArticle

Hydroxypropyl-β-cyclodextrin Enhances Oral Absorption of Silymarin Nanoparticles Prepared Using PureNano™ Continuous Crystallizer

by Risako Onodera, Tomohiro Hayashi, Keiichi Motoyama, Kohei Tahara and Hirofumi Takeuchi

Pharmaceutics 2022, 14(2), 394; https://doi.org/10.3390/pharmaceutics14020394 - 10 Feb 2022

Cited by 4 | Viewed by 2099

Abstract

The oral bioavailability of drugs is limited by factors such as poor membrane permeability, low solubility, and low dissolution rate. Silymarin (SLM) is a health-food active ingredient that is good for immunosuppression and tumor suppression. However, obtaining a good oral bioavailability is difficult owing to its poor solubility and low dissolution ability. To overcome these concerns, we previously prepared SLM nanoparticles (NPs) using the high-pressure crystallization method (PureNano^TM) and freeze-dried them with erythritol (Ery) or hydroxypropyl-β-CyD (HP-β-CyD) as a water-soluble dispersion stabilizer. In the present study, we investigated the mechanism underlying the improved absorption of SLM/hypromellose (HPMC)/HP-β-CyD NPs after oral administration. The SLM/HPMC nano-suspension prepared using PureNano^TM exhibited a narrow size distribution. The size of the SLM/HPMC/HP-β-CyD NPs was approximately 250 nm after hydration. The SLM/HPMC/HP-β-CyD NPs were rapidly dissolved, and demonstrated a high solubility under supersaturated conditions. Additionally, they exhibited good wettability and their membrane permeability was improved compared with that of SLM original powder. These results suggest that the formulation of SLM NPs using PureNano^TM and freeze-drying with HP-β-CyD improves the absorption of SLM after oral administration by enhancing solubility, wettability, and membrane permeability. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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Review

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18 pages, 589 KiB

Open AccessEditor’s ChoiceReview

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

by Patrícia C. Pires, Márcio Rodrigues, Gilberto Alves and Adriana O. Santos

Pharmaceutics 2022, 14(3), 588; https://doi.org/10.3390/pharmaceutics14030588 - 08 Mar 2022

Cited by 25 | Viewed by 5448

Abstract

Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

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