Pharmaceutics

11 pages, 3190 KiB

Open AccessArticle

Conformal Coating of Powder by Initiated Chemical Vapor Deposition on Vibrating Substrate

by Katrin Unger and Anna Maria Coclite

Pharmaceutics 2020, 12(9), 904; https://doi.org/10.3390/pharmaceutics12090904 - 22 Sep 2020

Cited by 7 | Viewed by 3261

Encapsulation of pharmaceutical powders within thin functional polymer films is a powerful and versatile method to modify drug release properties. Conformal coating over the complete surface of the particle via chemical vapor deposition techniques is a challenging task due to the compromised gas–solid [...] Read more.

Encapsulation of pharmaceutical powders within thin functional polymer films is a powerful and versatile method to modify drug release properties. Conformal coating over the complete surface of the particle via chemical vapor deposition techniques is a challenging task due to the compromised gas–solid contact. In this study, an initiated chemical vapor deposition reactor was adapted with speakers and vibration of particles was achieved by playing AC/DC’s song “Thunderstruck” to overcome the above-mentioned problem. To show the possibilities of this method, two types of powder of very different particle sizes were chosen, magnesium citrate (3–10 µm, cohesive powder) and aspirin (100–500 µm, good flowability), and coated with poly-ethylene-glycol-di-methacrylate. The release curve of coated magnesium citrate powder was retarded compared to uncoated powder. However, neither changing the thickness coating nor vibrating the powder during the deposition had influence on the release parameters, indicating, that cohesive powders cannot be coated conformally. The release of coated aspirin was as well retarded as compared to uncoated aspirin, especially in the case of the powder that vibrated during deposition. We attribute the enhancement of the retarded release to the formation of a conformal coating on the aspirin powder. Full article

(This article belongs to the Special Issue Coating Design: From Nanoparticle to Solid Dosage)

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5 pages, 199 KiB

Open AccessEditorial

PLGA Based Drug Carrier and Pharmaceutical Applications: The Most Recent Advances

by Joana Angélica Loureiro and Maria Carmo Pereira

Pharmaceutics 2020, 12(9), 903; https://doi.org/10.3390/pharmaceutics12090903 - 22 Sep 2020

Cited by 35 | Viewed by 3783

Abstract

Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful polymers that has been used to produce medicines, such as drug carriers (DC) [...] Full article

(This article belongs to the Special Issue PLGA Based Drug Carrier and Pharmaceutical Applications)

15 pages, 5261 KiB

Open AccessArticle

Composite Hydrogel of Methacrylated Hyaluronic Acid and Fragmented Polycaprolactone Nanofiber for Osteogenic Differentiation of Adipose-Derived Stem Cells

by Madhumita Patel and Won-Gun Koh

Pharmaceutics 2020, 12(9), 902; https://doi.org/10.3390/pharmaceutics12090902 - 22 Sep 2020

Cited by 29 | Viewed by 3972

Abstract

Composite hydrogels with electrospun nanofibers (NFs) have recently been used to mimic the native extracellular matrix. In this study, composite hydrogels of methacrylated hyaluronic acid containing fragmented polycaprolactone NFs were used for bone tissue engineering. The composite (NF/hydrogel) was crosslinked under ultraviolet (UV) [...] Read more.

Composite hydrogels with electrospun nanofibers (NFs) have recently been used to mimic the native extracellular matrix. In this study, composite hydrogels of methacrylated hyaluronic acid containing fragmented polycaprolactone NFs were used for bone tissue engineering. The composite (NF/hydrogel) was crosslinked under ultraviolet (UV) light. The incorporation of fragmented polycaprolactone NFs increased the compression modulus from 1762.5 to 3122.5 Pa. Subsequently, adipose-derived stem cells incorporated into the composite hydrogel exhibited a more stretched and elongated morphology and osteogenic differentiation in the absence of external factors. The mRNA expressions of osteogenic biomarkers, including collagen 1 (Col1), alkaline phosphatase, and runt-related transcription factor 2, were 3–5-fold higher in the composite hydrogel than in the hydrogel alone. In addition, results of the protein expression of Col1 and alizarin red staining confirmed osteogenic differentiation. These findings suggest that our composite hydrogel provides a suitable microenvironment for bone tissue engineering. Full article

(This article belongs to the Special Issue Advanced Nanoscience of Biomaterials for Biomedical Applications)

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16 pages, 4246 KiB

Open AccessArticle

Development of 3D Printed Drug-Eluting Scaffolds for Preventing Piercing Infection

by Emad Naseri, Christopher Cartmell, Matthew Saab, Russell G. Kerr and Ali Ahmadi

Pharmaceutics 2020, 12(9), 901; https://doi.org/10.3390/pharmaceutics12090901 - 22 Sep 2020

Cited by 20 | Viewed by 6799

Abstract

Herein, novel drug-eluting, bio-absorbable scaffold intended to cover piercing studs is introduced. This “biopierce” will stay in human tissue following piercing, and will slowly release an antimicrobial agent to prevent infection while the wound heals. Nearly 20% of all piercings lead to local [...] Read more.

Herein, novel drug-eluting, bio-absorbable scaffold intended to cover piercing studs is introduced. This “biopierce” will stay in human tissue following piercing, and will slowly release an antimicrobial agent to prevent infection while the wound heals. Nearly 20% of all piercings lead to local infection. Therefore, it is imperative to develop alternative methods of piercing aftercare to prevent infection. Biopierces were made using mupirocin loaded poly-lactic-co-glycolic acid (PLGA) biomaterial ink, and a low-temperature 3D printing technique was used to fabricate the biopierces. Proton nuclear magnetic resonance (¹H NMR) spectroscopy was used to confirm the complete removal of the solvent, and liquid chromatography high-resolution mass spectrometry (LC-HRMS) was used to confirm the structural integrity of mupirocin and to quantify the amount of the released drug over time. The efficacy of the biopierces against Staphylococcus aureus, one of the most common piercing-site pathogens, was confirmed over two weeks using in vitro antimicrobial susceptibility testing. Full article

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14 pages, 1520 KiB

Open AccessArticle

Optimisation of Mycobacterium bovis BCG Fermentation and Storage Survival

by Jordan Pascoe, Charlotte L. Hendon-Dunn, Colin P.D. Birch, Gareth A. Williams, Mark A. Chambers and Joanna Bacon

Pharmaceutics 2020, 12(9), 900; https://doi.org/10.3390/pharmaceutics12090900 - 22 Sep 2020

Cited by 5 | Viewed by 4049

Abstract

Mycobacterium bovis Bacillus Calmette–Guérin (M. bovis BCG) was generated over a century ago for protection against Mycobacterium tuberculosis (Mtb) and is one the oldest vaccines still in use. The BCG vaccine is currently produced using a pellicle growth method, which is a [...] Read more.

Mycobacterium bovis Bacillus Calmette–Guérin (M. bovis BCG) was generated over a century ago for protection against Mycobacterium tuberculosis (Mtb) and is one the oldest vaccines still in use. The BCG vaccine is currently produced using a pellicle growth method, which is a complex and lengthy process that has been challenging to standardise. Fermentation for BCG vaccine production would reduce the complexity associated with pellicle growth and increase batch to batch reproducibility. This more standardised growth lends itself to quantification of the total number of bacilli in the BCG vaccine by alternative approaches, such as flow cytometry, which can also provide information about the metabolic status of the bacterial population. The aim of the work reported here was to determine which batch fermentation conditions and storage conditions give the most favourable outcomes in terms of the yield and stability of live M. bovis BCG Danish bacilli. We compared different media and assessed growth over time in culture, using total viable counts, total bacterial counts, and turbidity throughout culture. We applied fluorescent viability dyes and flow cytometry to measure real-time within-culture viability. Culture samples were stored in different cryoprotectants at different temperatures to assess the effect of these combined conditions on bacterial titres. Roisin’s minimal medium and Middlebrook 7H9 medium gave comparable, high titres in fermenters. Flow cytometry proved to be a useful tool for enumeration of total bacterial counts and in the assessment of within-culture cell viability and cell death. Of the cryoprotectants evaluated, 5% (v/v) DMSO showed the most significant positive effect on survival and reduced the negative effects of low temperature storage on M. bovis BCG Danish viability. In conclusion, we have shown a reproducible, more standardised approach for the production, evaluation, and storage of high titre, viable, BCG vaccine. Full article

(This article belongs to the Special Issue Tuberculosis Vaccine Research and Development)

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20 pages, 5177 KiB

Open AccessArticle

Photostability Testing of a Third-Generation Retinoid—Tazarotene in the Presence of UV Absorbers

by Agata Kryczyk-Poprawa, István Zupkó, Péter Bérdi, Paweł Żmudzki, Justyna Popiół, Bożena Muszyńska and Włodzimierz Opoka

Pharmaceutics 2020, 12(9), 899; https://doi.org/10.3390/pharmaceutics12090899 - 22 Sep 2020

Cited by 6 | Viewed by 3461

Abstract

Exposure of a drug to UV irradiation could affect its physicochemical properties. Hence, photostability testing is essential for topically administered drugs. Tazarotene, a receptor-selective, third-generation retinoid, is commonly used to treat acne vulgaris and psoriasis. In the present study, an in-depth analysis of [...] Read more.

Exposure of a drug to UV irradiation could affect its physicochemical properties. Hence, photostability testing is essential for topically administered drugs. Tazarotene, a receptor-selective, third-generation retinoid, is commonly used to treat acne vulgaris and psoriasis. In the present study, an in-depth analysis of the photostability of tazarotene in ethanolic solution in the presence of zinc oxide and/or titanium dioxide as well as benzophenone-type UV filters was performed. Eleven presumed products were derived from the photocatalytic degradation of tazarotene using ultra-performance liquid chromatography–tandem mass spectrometry, and transformation pathways were proposed. The degradation process mainly affected the 4,4-dimethyl-3,4-dihydro-2H-thiopyran moiety. The fragments most susceptible to oxidation were the methyl groups and the sulfur atom. Moreover, in the presence of sulisobenzone, under UV irradiation, tazarotene was subjected to a degradation process, which resulted in two photodecomposition products. In silico studies performed by OSIRIS Property Explorer demonstrated that five of the degradation products could be harmful in terms of the reproductive effects, which are associated with 3,4-dihydro-6-methyl-2H-1-benzothiopyran 1,1-dioxide, while one of them demonstrated potential irritant activity. The cytotoxic properties of the degradation products of tazarotene were assessed by MTT assay on a panel of human adherent cancer cells. Time- and concentration-dependent growth inhibition was evidenced in ovary (A2780) and breast (MDA-MB-231) cancer cell lines. The potential implication of the outcomes of the present research requires further studies mainly concerning the photostability of tazarotene in the topical formulations. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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7 pages, 550 KiB

Open AccessArticle

Frequency of CYP3A5 Genetic Polymorphisms and Tacrolimus Pharmacokinetics in Pediatric Liver Transplantation

by Jefferson Antonio Buendía, Esteban Halac, Andrea Bosaleh, María T. Garcia de Davila, Oscar Imvertasa and Guillermo Bramuglia

Pharmaceutics 2020, 12(9), 898; https://doi.org/10.3390/pharmaceutics12090898 - 22 Sep 2020

Cited by 12 | Viewed by 2640

Abstract

The evidence available in the pediatric population is limited for making clinical decisions regarding the optimization of tacrolimus (TAC) in pharmacotherapy. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in the [...] Read more.

The evidence available in the pediatric population is limited for making clinical decisions regarding the optimization of tacrolimus (TAC) in pharmacotherapy. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in the pediatric population. This was a longitudinal cohort study with a two-year follow-up of 77 patients under 18 years old who underwent a liver transplant during the period 2009–2012 at the J.P. Garrahan Pediatric Hospital. Tacrolimus levels from day five up to two years after the transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) was performed in liver biopsies from both the donor and the recipient. The frequency of CYP3A5*1 expression for recipients was 37.1% and 32.2% for donors. Patients who received an expresser organ showed lower Co/dose, especially following 90 days after the surgery. The role of each polymorphism is different according to the number of days after the transplant, and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phases. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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17 pages, 2037 KiB

Open AccessArticle

Liposomes Co-Encapsulating Cisplatin/Mifepristone Improve the Effect on Cervical Cancer: In Vitro and In Vivo Assessment

by Fabricio Ledezma-Gallegos, Rafael Jurado, Roser Mir, Luis Alberto Medina, Laura Mondragon-Fuentes and Patricia Garcia-Lopez

Pharmaceutics 2020, 12(9), 897; https://doi.org/10.3390/pharmaceutics12090897 - 22 Sep 2020

Cited by 22 | Viewed by 3778

Abstract

Cervical cancer is usually diagnosed in the later stages despite many campaigns for early detection and continues to be a major public health problem. The standard treatment is cisplatin-based chemotherapy plus radiotherapy, but patient response is far from ideal. In the research for [...] Read more.

Cervical cancer is usually diagnosed in the later stages despite many campaigns for early detection and continues to be a major public health problem. The standard treatment is cisplatin-based chemotherapy plus radiotherapy, but patient response is far from ideal. In the research for new drugs that enhance the activity of cisplatin, different therapeutic agents have been tested, among them the antiprogestin mifepristone. Nevertheless, the efficacy of cisplatin is limited by its low specificity for tumor tissue, which causes severe side effects. Additionally, cervical tumors often become drug resistant. These problems could possibly be addressed by the use of liposome nanoparticles to encapsulate drugs and deliver them to the target. The aim of this study was to prepare liposome nanoparticles that co-encapsulate cisplatin and mifepristone, evaluate their cytotoxicity against HeLa cells and in vivo with subcutaneous inoculations of xenografts in nu/nu mice, and examine some plausible mechanisms of action. The liposomes were elaborated by the reverse-phase method and characterized by physicochemical tests. The nanoparticles had a mean particle size of 109 ± 5.4 nm and a Zeta potential of −38.7 ± 1.2 mV, the latter parameter indicating a stable formulation. These drug-loaded liposomes significantly decreased cell viability in vitro and tumor size in vivo, without generating systemic toxicity in the animals. There was evidence of cell cycle arrest and increased apoptosis. The promising results with the co-encapsulation of cisplatin/mifepristone warrant further research. Full article

(This article belongs to the Special Issue New Formulations for Cancer Therapy)

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19 pages, 2283 KiB

Open AccessArticle

Efficient Non-Viral Gene Modification of Mesenchymal Stromal Cells from Umbilical Cord Wharton’s Jelly with Polyethylenimine

by Ana Isabel Ramos-Murillo, Elizabeth Rodríguez, Karl Beltrán, Cristian Ricaurte, Bernardo Camacho, Gustavo Salguero and Rubén Darío Godoy-Silva

Pharmaceutics 2020, 12(9), 896; https://doi.org/10.3390/pharmaceutics12090896 - 22 Sep 2020

Cited by 9 | Viewed by 4269

Abstract

Mesenchymal stromal cells (MSC) derived from human umbilical cord Wharton’s jelly (WJ) have a wide therapeutic potential in cell therapy and tissue engineering because of their multipotential capacity, which can be reinforced through gene therapy in order to modulate specific responses. However, reported [...] Read more.

Mesenchymal stromal cells (MSC) derived from human umbilical cord Wharton’s jelly (WJ) have a wide therapeutic potential in cell therapy and tissue engineering because of their multipotential capacity, which can be reinforced through gene therapy in order to modulate specific responses. However, reported methodologies to transfect WJ-MSC using cationic polymers are scarce. Here, WJ-MSC were transfected using 25 kDa branched- polyethylenimine (PEI) and a DNA plasmid encoding GFP. PEI/plasmid complexes were characterized to establish the best transfection efficiencies with lowest toxicity. Expression of MSC-related cell surface markers was evaluated. Likewise, immunomodulatory activity and multipotential capacity of transfected WJ-MSC were assessed by CD2/CD3/CD28-activated peripheral blood mononuclear cells (PBMC) cocultures and osteogenic and adipogenic differentiation assays, respectively. An association between cell number, PEI and DNA content, and transfection efficiency was observed. The highest transfection efficiency (15.3 ± 8.6%) at the lowest toxicity was achieved using 2 ng/μL DNA and 3.6 ng/μL PEI with 45,000 WJ-MSC in a 24-well plate format (200 μL). Under these conditions, there was no significant difference between the expression of MSC-identity markers, inhibitory effect on CD3+ T lymphocytes proliferation and osteogenic/adipogenic differentiation ability of transfected WJ-MSC, as compared with non-transfected cells. These results suggest that the functional properties of WJ-MSC were not altered after optimized transfection with PEI. Full article

(This article belongs to the Special Issue Gene Delivery Vectors and Physical Methods: Present and Future Trends)

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37 pages, 11998 KiB

Open AccessArticle

Determinants of Intraparenchymal Infusion Distributions: Modeling and Analyses of Human Glioblastoma Trials

by Martin Brady, Raghu Raghavan and John Sampson

Pharmaceutics 2020, 12(9), 895; https://doi.org/10.3390/pharmaceutics12090895 - 21 Sep 2020

Cited by 14 | Viewed by 3093

Abstract

Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been [...] Read more.

Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been proposed to mitigate risk for inadequate delivery through quantitative understanding of infusion characteristics. We present results from human studies and simulations of intratumoral infusions of immunotoxins in glioblastoma patients. Gd-DTPA and ¹²⁴I-labeled human serum albumin (¹²⁴I-HSA) were co-infused with the therapeutic, and their distributions measured in MRI and PET. Simulations were created by modeling tissue fluid mechanics and physiology and suggested that reduced distribution of tracer molecules within tumor is primarily related to elevated loss rates computed from DCE. PET-tracer on the other hand shows that the larger albumin molecule had longer but heterogeneous residence times within the tumor. We found over two orders of magnitude variation in distribution volumes for the same infusion volumes, with relative error ~20%, allowing understanding of even anomalous infusions. Modeling and measurement revealed that key determinants of flow include infusion-induced expansion and loss through compromised BBB. Opportunities are described to improve computer-assisted CED through iterative feedback between simulations and imaging. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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22 pages, 873 KiB

Open AccessReview

Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?

by Vladislav Suntsov, Filip Jovanovic, Emilija Knezevic, Kenneth D. Candido and Nebojsa Nick Knezevic

Pharmaceutics 2020, 12(9), 894; https://doi.org/10.3390/pharmaceutics12090894 - 21 Sep 2020

Cited by 6 | Viewed by 3431

Abstract

Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than [...] Read more.

Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than acute. The aim of this review is to compile the genes identified by numerous genetic association studies of chronic pain conditions, focusing on cLBP specifically. Higher-order neurologic processes involved in pain maintenance and generation may explain genetic contributions and functional predisposition to formation of cLBP that does not involve spine pathology. Several genes have been identified in genetic association studies of cLBP and roughly, these genes could be grouped into several categories, coding for: receptors, enzymes, cytokines and related molecules, and transcription factors. Treatment of cLBP should be multimodal. In this review, we discuss how an individual’s genotype could affect their response to therapy, as well as how genetic polymorphisms in CYP450 and other enzymes are crucial for affecting the metabolic profile of drugs used for the treatment of cLBP. Implementation of gene-focused pharmacotherapy has the potential to deliver select, more efficacious drugs and avoid unnecessary, polypharmacy-related adverse events in many painful conditions, including cLBP. Full article

(This article belongs to the Special Issue Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy)

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23 pages, 6221 KiB

Open AccessArticle

Development and Optimization of Naringenin-Loaded Chitosan-Coated Nanoemulsion for Topical Therapy in Wound Healing

by Sabah H. Akrawi, Bapi Gorain, Anroop B. Nair, Hira Choudhury, Manisha Pandey, Jigar N. Shah and Katharigatta N. Venugopala

Pharmaceutics 2020, 12(9), 893; https://doi.org/10.3390/pharmaceutics12090893 - 20 Sep 2020

Cited by 78 | Viewed by 6995

Abstract

The potential role of naringenin (NAR), a natural flavonoid, in the treatment of chronic wound has prompted the present research to deliver the drug in nanoemulsion (NE) form, where synergistic role of chitosan was achieved through development of chitosan-coated NAR NE (CNNE). The [...] Read more.

The potential role of naringenin (NAR), a natural flavonoid, in the treatment of chronic wound has prompted the present research to deliver the drug in nanoemulsion (NE) form, where synergistic role of chitosan was achieved through development of chitosan-coated NAR NE (CNNE). The NE consisted of Capryol 90, Tween 20 and Transcutol P, which was fabricated by low-energy emulsification method to encapsulate NAR within the oil core. The optimization of the formulated NEs was performed using Box–Behnken statistical design to obtain crucial variable parameters that influence globule size, size distribution and surface charge. Finally, the optimized formulation was coated with different concentrations of chitosan and subsequently characterized in vitro. The size of the CNNE was found to be increased when the drug-loaded formulation was coated with chitosan. Controlled release characteristics depicted 67–81% release of NAR from the CNNE, compared to 89% from the NE formulation. Cytotoxicity study of the formulation was performed in vitro using fibroblast cell line (NIH-3T3), where no inhibition in proliferation of the cells was observed with CNNE. Finally, the wound healing potential of the CNNE was evaluated in an abrasion-created wound model in experimental animals where the animals were treated and compared histologically at 0 and 14 days. Significant improvement in construction of the abrasion wound was observed when the animals were treated with formulated CNNE, whereas stimulation of skin regeneration was depicted in the histological examination. Therefore, it could be summarized that the chitosan coating of the developed NAR NE is a potential platform to accelerate healing of wounds. Full article

(This article belongs to the Special Issue Non-invasive Drug Delivery Systems)

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15 pages, 2332 KiB

Open AccessArticle

Selection of Cryoprotectant in Lyophilization of Progesterone-Loaded Stearic Acid Solid Lipid Nanoparticles

by Timothy M. Amis, Jwala Renukuntla, Pradeep Kumar Bolla and Bradley A. Clark

Pharmaceutics 2020, 12(9), 892; https://doi.org/10.3390/pharmaceutics12090892 - 19 Sep 2020

Cited by 40 | Viewed by 5535

Abstract

Cryoprotectants are often required in lyophilization to reduce or eliminate agglomeration of solute or suspended materials. The aim of this study was to select a cryoprotecting agent and optimize its concentration in a solid lipid nanoparticle formulation. Progesterone-loaded stearic acid solid lipid nanoparticles [...] Read more.

Cryoprotectants are often required in lyophilization to reduce or eliminate agglomeration of solute or suspended materials. The aim of this study was to select a cryoprotecting agent and optimize its concentration in a solid lipid nanoparticle formulation. Progesterone-loaded stearic acid solid lipid nanoparticles (SA-P SLNs) were prepared by hot homogenization with high speed mixing and sonication. The stearic acid content was 4.6% w/w and progesterone was 0.46% w/w of the initial formulation. Multiple surfactants were evaluated, and a lecithin and sodium taurocholate system was chosen. Three concentrations of surfactant were then evaluated, and a concentration of 2% w/w was chosen based on particle size, polydispersity, and zeta potential. Agglomeration of SA-P SLNs after lyophilization was observed as measured by increased particle size. Dextran, glycine, mannitol, polyvinylpyrrolidone (PVP), sorbitol, and trehalose were evaluated as cryoprotectants by both an initial freeze–thaw analysis and after lyophilization. Once selected as the cryoprotectant, trehalose was evaluated at 5%, 10%, 15%, and 20% for optimal concentration, with 20% trehalose being finally selected as the level of choice. Evaluation by DSC confirmed intimate interaction between stearic acid and progesterone in the SA-P SLNs, and polarized light microscopy shows successful lyophilization of the trehalose/SA-P SLN. A short term 28-day stability study suggests the need for refrigeration of the final lyophilized SA-P SLNs in moisture vapor impermeable packaging. Full article

(This article belongs to the Special Issue Pharmaceutical Freeze Drying and Spray Drying)

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20 pages, 2414 KiB

Open AccessArticle

Correlation between Elemental Composition/Mobility and Skin Cell Proliferation of Fibrous Nanoclay/Spring Water Hydrogels

by Fátima García-Villén, Rita Sánchez-Espejo, Ana Borrego-Sánchez, Pilar Cerezo, Lucia Cucca, Giuseppina Sandri and César Viseras

Pharmaceutics 2020, 12(9), 891; https://doi.org/10.3390/pharmaceutics12090891 - 18 Sep 2020

Cited by 5 | Viewed by 2918

Abstract

Inorganic hydrogels formulated with spring waters and clay minerals are used to treat musculoskeletal disorders and skin affections. Their underlying mechanism of action for skin disorders is not clear, although it is usually ascribed to the chemical composition of the formulation. The aim [...] Read more.

Inorganic hydrogels formulated with spring waters and clay minerals are used to treat musculoskeletal disorders and skin affections. Their underlying mechanism of action for skin disorders is not clear, although it is usually ascribed to the chemical composition of the formulation. The aim of this study was to assess the composition and in vitro release of elements with potential wound healing effects from hydrogels prepared with two nanoclays and natural spring water. In vitro Franz cell studies were used and the element concentration was measured by inductively coupled plasma techniques. Biocompatibility studies were used to evaluate the potential toxicity of the formulation against fibroblasts. The studied hydrogels released elements with known therapeutic interest in wound healing. The released ratios of some elements, such as Mg:Ca or Zn:Ca, played a significant role in the final therapeutic activity of the formulation. In particular, the proliferative activity of fibroblasts was ascribed to the release of Mn and the Zn:Ca ratio. Moreover, the importance of formulative studies is highlighted, since it is the optimal combination of the correct ingredients that makes a formulation effective. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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15 pages, 2313 KiB

Open AccessReview

Recent Development to Explore the Use of Biodegradable Periodic Mesoporous Organosilica (BPMO) Nanomaterials for Cancer Therapy

by Shanmugavel Chinnathambi and Fuyuhiko Tamanoi

Pharmaceutics 2020, 12(9), 890; https://doi.org/10.3390/pharmaceutics12090890 - 18 Sep 2020

Cited by 23 | Viewed by 4795

Abstract

Porous nanomaterials can be used to load various anti-cancer drugs efficiently and deliver them to a particular location in the body with minimal toxicity. Biodegradable periodic mesoporous organosilica nanoparticles (BPMOs) have recently emerged as promising candidates for disease targeting and drug delivery. They [...] Read more.

Porous nanomaterials can be used to load various anti-cancer drugs efficiently and deliver them to a particular location in the body with minimal toxicity. Biodegradable periodic mesoporous organosilica nanoparticles (BPMOs) have recently emerged as promising candidates for disease targeting and drug delivery. They have a large functional surface and well-defined pores with a biodegradable organic group framework. Multiple biodegradation methods have been explored, such as the use of redox, pH, enzymatic activity, and light. Various drug delivery systems using BPMO have been developed. This review describes recent advances in the biomedical application of BPMOs. Full article

(This article belongs to the Special Issue Biodegradable Nanoparticulate Drug Delivery Systems)

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20 pages, 10091 KiB

Open AccessArticle

Imaging of the Effect of Alcohol-Containing Media on the Performance of Hypromellose Hydrophilic Matrix Tablets: Comparison of Direct Compression and Regular Grades of Polymer

by Nihad Mawla, Sarah Hanley, Karl Walton, Waseem Kaialy, Tariq Hussain, Adam Ward, Jonathan Brown, Barbara R. Conway, Peter Timmins and Kofi Asare-Addo

Pharmaceutics 2020, 12(9), 889; https://doi.org/10.3390/pharmaceutics12090889 - 18 Sep 2020

Cited by 5 | Viewed by 3960

Abstract

As the ingestion of drug products with alcohol could have adverse effects on the release of drugs from dosage forms, it is important to understand the mechanisms underpinning the influence on drug release by evaluating the effect of alcohol-containing media on the behaviour [...] Read more.

As the ingestion of drug products with alcohol could have adverse effects on the release of drugs from dosage forms, it is important to understand the mechanisms underpinning the influence on drug release by evaluating the effect of alcohol-containing media on the behaviour of pharmaceutical excipients. In this work, the effect of hydroalcoholic media containing up to 40% v/v absolute ethanol was evaluated, employing both the regular (CR) and direct compression grades (DC) of hypromellose. X-ray microtomography (XµT) and magnetic resonance imaging (MRI) were used as complementary techniques in determining the influence of the media composition on the ability of the CR and DC polymers to form and evolve the gel layer that controls drug release. Particle and powder properties of the polymer were characterised to determine any relationship to performance in hydroalcoholic media. Triboelectrification results showed the CR grade formulation to charge electropositively whereas the DC grade charged electronegatively. The flow properties also showed the DC grade to have a superior flow as compared to its CR counterpart. Differences in particle morphology between the grades influenced charging and flow behaviour of the powders; however, it did not seem to impact significantly either on the mechanical strength or the drug release properties of the compacted formulation using the model drug propranolol HCl. XµT and MRI imaging were successfully used as complementary techniques in determining the gel layer/hydration layer thickness measurements as the layer developed, as well as following ingress of hydroalcoholic media and its impact on the dry core. The result showed that although differences were present in the gel layer thickness potentially due to differences in particle morphology, this also did not impact significantly on the dissolution process, especially in acidic and hydroalcoholic media. Full article

(This article belongs to the Special Issue Matrix Tablets for Oral Controlled Release)

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31 pages, 3089 KiB

Open AccessReview

Non-Viral Targeted Nucleic Acid Delivery: Apply Sequences for Optimization

by Yanfang Wang and Ernst Wagner

Pharmaceutics 2020, 12(9), 888; https://doi.org/10.3390/pharmaceutics12090888 - 18 Sep 2020

Cited by 13 | Viewed by 4290

Abstract

In nature, genomes have been optimized by the evolution of their nucleic acid sequences. The design of peptide-like carriers as synthetic sequences provides a strategy for optimizing multifunctional targeted nucleic acid delivery in an iterative process. The optimization of sequence-defined nanocarriers differs for [...] Read more.

In nature, genomes have been optimized by the evolution of their nucleic acid sequences. The design of peptide-like carriers as synthetic sequences provides a strategy for optimizing multifunctional targeted nucleic acid delivery in an iterative process. The optimization of sequence-defined nanocarriers differs for different nucleic acid cargos as well as their specific applications. Supramolecular self-assembly enriched the development of a virus-inspired non-viral nucleic acid delivery system. Incorporation of DNA barcodes presents a complementary approach of applying sequences for nanocarrier optimization. This strategy may greatly help to identify nucleic acid carriers that can overcome pharmacological barriers and facilitate targeted delivery in vivo. Barcode sequences enable simultaneous evaluation of multiple nucleic acid nanocarriers in a single test organism for in vivo biodistribution as well as in vivo bioactivity. Full article

(This article belongs to the Special Issue Gene Delivery Vectors and Physical Methods: Present and Future Trends)

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12 pages, 1236 KiB

Open AccessCommunication

Franz Cell Diffusion Testing and Quantitative Confocal Raman Spectroscopy: In Vitro-In Vivo Correlation

by Fotis Iliopoulos, Peter J. Caspers, Gerwin J. Puppels and Majella E. Lane

Pharmaceutics 2020, 12(9), 887; https://doi.org/10.3390/pharmaceutics12090887 - 18 Sep 2020

Cited by 30 | Viewed by 6861

Abstract

Previously, we reported the use of Confocal Raman Spectroscopy (CRS) to investigate the topical delivery of actives and excipients. We have also correlated the results from CRS with findings from in vitro diffusion studies in human skin. However, until now CRS has only [...] Read more.

Previously, we reported the use of Confocal Raman Spectroscopy (CRS) to investigate the topical delivery of actives and excipients. We have also correlated the results from CRS with findings from in vitro diffusion studies in human skin. However, until now CRS has only been used as a semi-quantitative method of determining the skin uptake of molecules, with results expressed as arbitrary units of signal intensity. Clearly, this posed challenges for using CRS to determine skin delivery and to assess the drug bioavailability and bioequivalence of topical formulations. In the present work, the permeation of niacinamide (NIA) from various formulations in human skin was studied in vitro using conventional Franz cells and in vivo using a quantitative CRS method under finite dose conditions. The selection of NIA was based on its wide use in pharmaceutical and personal care formulations for many years. This is the first fully quantitative study to compare these methods. The vehicles investigated were neat Transcutol^® P (TC); binary combinations of propylene glycol (PG) with propylene glycol monolaurate (PGML); and ternary mixtures of PG, PGML, and isopropyl myristate (IPM). These solvents were selected to encompass a range of physicochemical properties. NIA permeation was evident from all formulations in vitro and in vivo. The vehicles PG:PGML and PG:PGML:IPM delivered comparable amounts across the skin in vitro at 24 h (100.3–106.7 µg/cm², p > 0.05) that were significantly higher compared with those of TC (1.3 µg/cm², p < 0.05). An excellent in vitro in vivo correlation (R² = 0.98) was found following the linear regression of the cumulative amounts of NIA permeated in vitro and the amounts of NIA at 2 μm in the skin measured with CRS. A very good correlation between the cumulative permeation of NIA in vitro and the total amount of NIA that penetrated the stratum corneum (SC) per unit of surface area (μg/cm²) in vivo was also observed, with a Pearson correlation coefficient (R²) of 0.94. The findings support the use of CRS for the quantitative measurement of actives delivered to the skin in vivo. Future studies will focus on exploring the reproducibility and reliability of the method by investigating the delivery of different actives from a wider range of vehicles. Additionally, quantitative CRS will be evaluated further as a method for assessing the bioequivalence of topical formulations. Full article

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14 pages, 2309 KiB

Open AccessArticle

Effect of Different Direct Compaction Grades of Mannitol on the Storage Stability of Tablet Properties Investigated Using a Kohonen Self-Organizing Map and Elastic Net Regression Model

by Atsushi Kosugi, Kok Hoong Leong, Eri Urata, Yoshihiro Hayashi, Shungo Kumada, Kotaro Okada and Yoshinori Onuki

Pharmaceutics 2020, 12(9), 886; https://doi.org/10.3390/pharmaceutics12090886 - 18 Sep 2020

Cited by 8 | Viewed by 4673

Abstract

This study tested 15 direct compaction grades to identify the contribution of different grades of mannitol to the storage stability of the resulting tablets. After preparing the model tablets with different values of hardness, they were stored at 25 °C, 75% relative humidity [...] Read more.

This study tested 15 direct compaction grades to identify the contribution of different grades of mannitol to the storage stability of the resulting tablets. After preparing the model tablets with different values of hardness, they were stored at 25 °C, 75% relative humidity for 1 week. Then, measurement of the tablet properties was conducted on both pre- and post-storage tablets. The tablet properties were tensile strength (TS), friability, and disintegration time (DT). The experimental data were analyzed using a Kohonen self-organizing map (SOM). The SOM analysis successfully classified the test grades into three distinct clusters having different changes in the behavior of the tablet properties accompanying storage. Cluster 1 showed an obvious rise in DT induced by storage, while cluster 3 showed a substantial change in mechanical strength of the tablet including a reduction in the TS and a rise in friability. Furthermore, the data were analyzed using an Elastic net regression technique to investigate the general relationships between the powder properties of mannitol and the change behavior of the tablet properties. Consequently, we succeeded in identifying the crucial powder properties for the storage stability of the resulting tablets. This study provides advanced technical knowledge to characterize the effect of different direct compaction grades of mannitol on the storage stability of tablet properties. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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17 pages, 2616 KiB

Open AccessArticle

Poly(Aspartic Acid) Functionalized Poly(ϵ-Caprolactone) Microspheres with Enhanced Hydroxyapatite Affinity as Bone Targeting Antibiotic Carriers

by Stijn G. Rotman, Thomas F. Moriarty, Benjamin Nottelet, Dirk W. Grijpma, David Eglin and Olivier Guillaume

Pharmaceutics 2020, 12(9), 885; https://doi.org/10.3390/pharmaceutics12090885 - 17 Sep 2020

Cited by 22 | Viewed by 3782

Abstract

Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and [...] Read more.

Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and currently available local antibiotic treatments. Targeting bacteria within the bone requires highly efficient delivery of antimicrobials to the infected bone tissue. In this work, a biodegradable microsphere carrier loaded with antibiotics and with specific affinity to bone mineral was developed. Two widely used antibiotics, i.e., Gentamicin-dioctyl sulfosuccinate (GM-AOT) and Ciprofloxacin (CF) were embedded in poly(ϵ-caprolactone) (PCL) microspheres fabricated by oil-in-water emulsion techniques with carboxylated poly(vinyl alcohol) (cPVA) as surfactant. The carboxylic acid groups present at the Poly(ϵ-caprolactone)/cPVA (PCL-cPVA) microsphere surface were functionalized with aspartic acid oligomers (ASP) granting bone targeting properties. We report on cPVA synthesis, microsphere formulation, and antibiotic loading of PCL/cPVA-ASP microspheres. Antibiotic loaded PCL/cPVA-ASP microspheres show sustained release of its antibiotic load and can inhibit bacterial growth in vitro for up to 6 days. PCL/cPVA-ASP microspheres show enhanced affinity to mineralized substrates compared to non-functionalized PCL/cPVA microspheres. These findings support further development of these bone targeting antibiotic carriers for potential treatment of persistent bone infections. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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15 pages, 6051 KiB

Open AccessArticle

Recycling of Almond By-Products for Intestinal Inflammation: Improvement of Physical-Chemical, Technological and Biological Characteristics of a Dried Almond Skins Extract

by Maria Rosaria Lauro, Stefania Marzocco, Shara Francesca Rapa, Teresa Musumeci, Virgilio Giannone, Patrizia Picerno, Rita Patrizia Aquino and Giovanni Puglisi

Pharmaceutics 2020, 12(9), 884; https://doi.org/10.3390/pharmaceutics12090884 - 17 Sep 2020

Cited by 7 | Viewed by 2859

Abstract

Background: Almond skins are rich in bioactive compounds that undergo oxidation/degradation phenomena and are poorly soluble in water, reducing in vivo absorption and bioavailability, factors that influence the pharmacological activity of an active product. We developed a dried acetonic almond skins extract/cyclodextrin complex [...] Read more.

Background: Almond skins are rich in bioactive compounds that undergo oxidation/degradation phenomena and are poorly soluble in water, reducing in vivo absorption and bioavailability, factors that influence the pharmacological activity of an active product. We developed a dried acetonic almond skins extract/cyclodextrin complex to improve extract solubility, dissolution rate and biological activity. Methods: A lyophilized acetonic almond skin extract was produced. To optimize complex formulation, phase solubility studies and complex characterization (absorption studies, differential scanning calorimetry (DSC), morphology, solubility studies) were performed. To evaluate a possible use in healthy products, tumor necrosis factor-α levels and reactive oxygen species release, as well as cicloxygenase-2 and inducible nitric oxide synthase expression in intestinal epithelial cells, were also evaluated. Results: Phase solubility studies showed a Bs-type profile. A 1:1 dried acetonic almond skins extract/cyclodextrin ratio was able to improve extract water solubility and dissolution rate (100% in 45 min). The UV-Vis spectra of complex revealed a hypsochromic and hyperchromic effect, probably due to a partial inclusion of extract in cyclodextrin cavity through weak bonds, confirmed by DSC and morphology studies. The technological improvement in the extract characteristics also led to better biological activity. In fact, the complex effectively reduces tumor necrosis factor-α levels with respect to the pure extract and significantly inhibits the reactive oxygen species release, even if only at the lower concentration of 5 μg/mL. Conclusion: The complex was able to overcome solubility problems and could be used in inflammatory disease. Full article

(This article belongs to the Special Issue Herbal Extracts and Natural Compounds: Nutraceutical and Pharmaceutical Aspects)

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18 pages, 16017 KiB

Open AccessArticle

Biodegradable Electrospun Nonwovens Releasing Propolis as a Promising Dressing Material for Burn Wound Treatment

by Mateusz Stojko, Jakub Włodarczyk, Michał Sobota, Paulina Karpeta-Jarząbek, Małgorzata Pastusiak, Henryk Janeczek, Piotr Dobrzyński, Gabriela Starczynowska, Arkadiusz Orchel, Jerzy Stojko, Olgierd Batoryna, Paweł Olczyk, Katarzyna Komosińska-Vassev, Krystyna Olczyk and Janusz Kasperczyk

Pharmaceutics 2020, 12(9), 883; https://doi.org/10.3390/pharmaceutics12090883 - 17 Sep 2020

Cited by 25 | Viewed by 4136

Abstract

The selection of dressing is crucial for the wound healing process. Traditional dressings protect against contamination and mechanical damage of an injured tissue. Alternatives for standard dressings are regenerating systems containing a polymer with an incorporated active compound. The aim of this research [...] Read more.

The selection of dressing is crucial for the wound healing process. Traditional dressings protect against contamination and mechanical damage of an injured tissue. Alternatives for standard dressings are regenerating systems containing a polymer with an incorporated active compound. The aim of this research was to obtain a biodegradable wound dressing releasing propolis in a controlled manner throughout the healing process. Dressings were obtained by electrospinning a poly(lactide-co-glycolide) copolymer (PLGA) and propolis solution. The experiment consisted of in vitro drug release studies and in vivo macroscopic treatment evaluation. In in vitro studies released active compounds, the morphology of nonwovens, chemical composition changes of polymeric material during degradation process, weight loss and water absorption were determined. For in vivo research, four domestic pigs, were used. The 21-day experiment consisted of observation of healing third-degree burn wounds supplied with PLGA 85/15 nonwovens without active compound, with 5 wt % and 10 wt % of propolis, and wounds rinsed with NaCl. The in vitro experiment showed that controlling the molar ratio of lactidyl to glycolidyl units in the PLGA copolymer gives the opportunity to change the release profile of propolis from the nonwoven. The in vivo research showed that PLGA nonwovens with propolis may be a promising dressing material in the treatment of severe burn wounds. Full article

(This article belongs to the Special Issue Design of Novel Polymeric Systems for Controlled Drug Delivery)

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20 pages, 3894 KiB

Open AccessArticle

Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation

by Mihwa Kwon, Dong Yu Lim, Chul Haeng Lee, Ji-Hyeon Jeon, Min-Koo Choi and Im-Sook Song

Pharmaceutics 2020, 12(9), 882; https://doi.org/10.3390/pharmaceutics12090882 - 17 Sep 2020

Cited by 55 | Viewed by 4337

Abstract

We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the [...] Read more.

We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 μM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs. Full article

(This article belongs to the Special Issue Novel Strategies for Enhancing Oral Bioavailability and/or Biopharmaceutics-Related Research)

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18 pages, 1661 KiB

Open AccessReview

Cellulose/Collagen Dressings for Diabetic Foot Ulcer: A Review

by Ruth Naomi and Mh Busra Fauzi

Pharmaceutics 2020, 12(9), 881; https://doi.org/10.3390/pharmaceutics12090881 - 17 Sep 2020

Cited by 31 | Viewed by 7227

Abstract

Diabetic foot ulcer (DFU) is currently a global concern and it requires urgent attention, as the cost allocation by the government for DFU increases every year. This review was performed to provide scientific evidence on the advanced biomaterials that can be utilised as [...] Read more.

Diabetic foot ulcer (DFU) is currently a global concern and it requires urgent attention, as the cost allocation by the government for DFU increases every year. This review was performed to provide scientific evidence on the advanced biomaterials that can be utilised as a first-line treatment for DFU patients. Cellulose/collagen dressings have a biological property on non-healing wounds, such as DFU. This review aims to analyse scientific-based evidence of cellulose/collagen dressing for DFU. It has been proven that the healing rate of cellulose/collagen dressing for DFU patients demonstrated a significant improvement in wound closure as compared to current standard or conventional dressings. It has been scientifically proven that cellulose/collagen dressing provides a positive effect on non-healing DFU. There is a high tendency for cellulose/collagen dressing to be used, as it highly promotes angiogenesis with a rapid re-epithelisation rate that has been proven effective in clinical trials. Full article

(This article belongs to the Special Issue Advances in Wound Dressings and Materials)

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18 pages, 2848 KiB

Open AccessReview

Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease

by Norwin Kubick, Patrick C. Henckell Flournoy, Ana-Maria Enciu, Gina Manda and Michel-Edwar Mickael

Pharmaceutics 2020, 12(9), 880; https://doi.org/10.3390/pharmaceutics12090880 - 16 Sep 2020

Cited by 29 | Viewed by 4955

Abstract

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source [...] Read more.

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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27 pages, 3307 KiB

Open AccessArticle

Uncovering New Drug Properties in Target-Based Drug–Drug Similarity Networks

by Lucreţia Udrescu, Paul Bogdan, Aimée Chiş, Ioan Ovidiu Sîrbu, Alexandru Topîrceanu, Renata-Maria Văruţ and Mihai Udrescu

Pharmaceutics 2020, 12(9), 879; https://doi.org/10.3390/pharmaceutics12090879 - 16 Sep 2020

Cited by 18 | Viewed by 4866

Abstract

Despite recent advances in bioinformatics, systems biology, and machine learning, the accurate prediction of drug properties remains an open problem. Indeed, because the biological environment is a complex system, the traditional approach—based on knowledge about the chemical structures—can not fully explain the nature [...] Read more.

Despite recent advances in bioinformatics, systems biology, and machine learning, the accurate prediction of drug properties remains an open problem. Indeed, because the biological environment is a complex system, the traditional approach—based on knowledge about the chemical structures—can not fully explain the nature of interactions between drugs and biological targets. Consequently, in this paper, we propose an unsupervised machine learning approach that uses the information we know about drug–target interactions to infer drug properties. To this end, we define drug similarity based on drug–target interactions and build a weighted Drug–Drug Similarity Network according to the drug–drug similarity relationships. Using an energy-model network layout, we generate drug communities associated with specific, dominant drug properties. DrugBank confirms the properties of 59.52% of the drugs in these communities, and 26.98% are existing drug repositioning hints we reconstruct with our DDSN approach. The remaining 13.49% of the drugs seem not to match the dominant pharmacologic property; thus, we consider them potential drug repurposing hints. The resources required to test all these repurposing hints are considerable. Therefore we introduce a mechanism of prioritization based on the betweenness/degree node centrality. Using betweenness/degree as an indicator of drug repurposing potential, we select Azelaic acid and Meprobamate as a possible antineoplastic and antifungal, respectively. Finally, we use a test procedure based on molecular docking to analyze Azelaic acid and Meprobamate’s repurposing. Full article

(This article belongs to the Section Drug Targeting and Design)

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15 pages, 5915 KiB

Open AccessArticle

Development of a Surface Coating Technique with Predictive Value for Bead Coating in the Manufacturing of Amorphous Solid Dispersions

by Eline Boel, Piyush Panini and Guy Van den Mooter

Pharmaceutics 2020, 12(9), 878; https://doi.org/10.3390/pharmaceutics12090878 - 15 Sep 2020

Cited by 6 | Viewed by 3968

Abstract

The aim of this paper was to investigate whether a surface coating technique could be developed that can predict the phase behavior of amorphous solid dispersions (ASDs) coated on beads. ASDs of miconazole (MIC) and poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in methanol (MeOH) [...] Read more.

The aim of this paper was to investigate whether a surface coating technique could be developed that can predict the phase behavior of amorphous solid dispersions (ASDs) coated on beads. ASDs of miconazole (MIC) and poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in methanol (MeOH) were studied as a model system. First, the low crystallization tendency of the model drug in MeOH was evaluated and confirmed. In a next step, a drug loading screening was performed on casted films and coated beads in order to define the highest possible MIC loading that still results in a one-phase amorphous system. These results indicate that film casting is not suitable for phase behavior predictions of ASDs coated on beads. Therefore, a setup for coating a solid surface was established inside the drying chamber of a spray dryer and it was found that this surface coating technique could predict the phase behavior of MIC-PVP-VA systems coated on beads, in case an intermittent spraying procedure is applied. Finally, spray drying was also evaluated for its ability to manufacture high drug-loaded ASDs. The highest possible drug loadings that still result in a one-phase amorphous system were obtained for bead coating and its predictive intermittent surface coating technique, followed by spray drying and finally by film casting and the continuous surface coating technique, thereby underlining the importance for further research into the underexplored bead coating process. Full article

(This article belongs to the Special Issue Recent Development in the Design and Manufacture of Amorphous Drug Formulations)

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9 pages, 1845 KiB

Open AccessArticle

Image-Based Artificial Intelligence Methods for Product Control of Tablet Coating Quality

by Cosima Hirschberg, Magnus Edinger, Else Holmfred, Jukka Rantanen and Johan Boetker

Pharmaceutics 2020, 12(9), 877; https://doi.org/10.3390/pharmaceutics12090877 - 15 Sep 2020

Cited by 25 | Viewed by 5028

Abstract

Mimicking the human decision-making process is challenging. Especially, many process control situations during the manufacturing of pharmaceuticals are based on visual observations and related experience-based actions. The aim of the present work was to investigate the use of image analysis to classify the [...] Read more.

Mimicking the human decision-making process is challenging. Especially, many process control situations during the manufacturing of pharmaceuticals are based on visual observations and related experience-based actions. The aim of the present work was to investigate the use of image analysis to classify the quality of coated tablets. Tablets with an increasing amount of coating solution were imaged by fast scanning using a conventional office scanner. A segmentation routine was implemented to the images, allowing the extraction of numeric image-based information from individual tablets. The image preprocessing was performed prior to utilization of four different classification techniques for the individual tablet images. The support vector machine (SVM) technique performed superior compared to a convolutional neural network (CNN) in relation to computational time, and this approach was also slightly better at classifying the tablets correctly. The fastest multivariate method was partial least squares (PLS) regression, but this method was hampered by the inferior classification accuracy of the tablets. Finally, it was possible to create a numerical threshold classification model with an accuracy comparable to the SVM approach, so it is evident that there exist multiple valid options for classifying coated tablets. Full article

(This article belongs to the Special Issue Digital Pharmaceutics: Model-Informed Pharmaceutical Products and Process Design)

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12 pages, 4174 KiB

Open AccessArticle

Cathepsin B-Responsive Liposomes for Controlled Anticancer Drug Delivery in Hep G2 Cells

by Seulgi Lee, Su Jeong Song, Jeil Lee, Tai Hwan Ha and Joon Sig Choi

Pharmaceutics 2020, 12(9), 876; https://doi.org/10.3390/pharmaceutics12090876 - 14 Sep 2020

Cited by 30 | Viewed by 3972

Abstract

In recent decades, several types of anticancer drugs that inhibit cancer cell growth and cause cell death have been developed for chemotherapeutic application. However, these agents are usually associated with side effects resulting from nonspecific delivery, which may induce cytotoxicity in healthy cells. [...] Read more.

In recent decades, several types of anticancer drugs that inhibit cancer cell growth and cause cell death have been developed for chemotherapeutic application. However, these agents are usually associated with side effects resulting from nonspecific delivery, which may induce cytotoxicity in healthy cells. To reduce the nonspecific delivery issue, nanoparticles have been successfully used for the delivery of anticancer drugs to specific target sites. In this study, a functional polymeric lipid, PEG-GLFG-K(C₁₆)₂ (PEG-GLFG, polyethylene glycol-Gly-Leu-Phe-Gly-Lys(C₁₆)₂), was synthesized to enable controlled anticancer drug delivery using cathepsin B enzyme-responsive liposomes. The liposomes composed of PEG-GLFG/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane (chloride salt))/DPPC (dipalmitoylphosphatidylcholine)/cholesterol were prepared and characterized at various ratios. The GLFG liposomes formed were stable liposomes and were degraded when acted upon by cathepsin B enzyme. Doxorubicin (Dox) loaded GLFG liposomes (GLFG/Dox) were observed to exert an effective anticancer effect on Hep G2 cells in vitro and inhibit cancer cell proliferation in a zebrafish model. Full article

(This article belongs to the Special Issue Biomaterials-Based Drug and Gene Delivery Systems)

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19 pages, 4729 KiB

Open AccessArticle

Immunostimulating RNA Delivered by P1500 PEGylated Cationic Liposomes Limits Influenza Infection in C57Bl/6 Mice

by Elena P. Goncharova, Aleksandra V. Sen‘kova, Innokenty A. Savin, Tat‘yana O. Kabilova, Marina A. Zenkova, Valentin V. Vlassov and Elena L. Chernolovskaya

Pharmaceutics 2020, 12(9), 875; https://doi.org/10.3390/pharmaceutics12090875 - 14 Sep 2020

Cited by 6 | Viewed by 2691

Abstract

The emergence of highly pathogenic viruses and a high speed of infection spread put forward the problem of the development of novel antivirals and their delivery vehicles. In this study, we investigated the antiviral effect of the previously identified immunostimulatory 19-bp dsRNA (isRNA) [...] Read more.

The emergence of highly pathogenic viruses and a high speed of infection spread put forward the problem of the development of novel antivirals and their delivery vehicles. In this study, we investigated the antiviral effect of the previously identified immunostimulatory 19-bp dsRNA (isRNA) with 3′-nucleotide overhangs, which stimulates interferon α synthesis when delivered using cationic liposomes consisting of 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride and lipid-helper dioleoylphosphatidylethanolamine and its PEGylated formulation P1500 in vitro and in vivo. In vitro data showed that isRNA/2X3-DOPE complexes protected L929 cells from encephalomyocarditis virus infection, while isRNA/P1500 complexes were not active, which correlates with their lower transfection activity in cell culture. Comparison of the interferon-inducing activity of isRNA in BALB/c, CBA and C57Bl/6 mice showed that PEGylated liposomes significantly enhance the interferon-inducing activity of isRNA in vivo. The antiviral efficacy of the isRNA in vivo was considerably affected by the delivery system. The cationic liposomes 2X3-DOPE did not enhance the antiviral properties of isRNA in vivo. Similar liposomes equipped with a PEGylated lipoconjugate provided a pronounced anti-influenza effect of the isRNA in vivo. Administration of isRNA to C57Bl/6 led to a decrease in virus titers in the lungs and a significant decrease in the severity of the infection. Administration of a similar formulation to BALB/c mice caused only a mild antiviral effect at the initial stages of the infection. The data show that isRNA in combination with the PEGylated delivery system can be considered an effective means of suppressing influenza A infection. Full article

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

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