Pharmaceutics

22 pages, 4835 KiB

Open AccessArticle

Non-Clinical In Vitro Evaluation of Antibiotic Resistance Gene-Free Plasmids Encoding Human or Murine IL-12 Intended for First-in-Human Clinical Study

by Spela Kos, Masa Bosnjak, Tanja Jesenko, Bostjan Markelc, Urska Kamensek, Katarina Znidar, Urska Matkovic, Andrej Rencelj, Gregor Sersa, Rosana Hudej, Aneja Tuljak, Matjaz Peterka and Maja Cemazar

Pharmaceutics 2021, 13(10), 1739; https://doi.org/10.3390/pharmaceutics13101739 - 19 Oct 2021

Cited by 10 | Viewed by 3251

Abstract

Interleukin 12 (IL-12) is a key cytokine that mediates antitumor activity of immune cells. To fulfill its clinical potential, the development is focused on localized delivery systems, such as gene electrotransfer, which can provide localized delivery of IL-12 to the tumor microenvironment. Gene [...] Read more.

Interleukin 12 (IL-12) is a key cytokine that mediates antitumor activity of immune cells. To fulfill its clinical potential, the development is focused on localized delivery systems, such as gene electrotransfer, which can provide localized delivery of IL-12 to the tumor microenvironment. Gene electrotransfer of the plasmid encoding human IL-12 is already in clinical trials in USA, demonstrating positive results in the treatment of melanoma patients. To comply with EU regulatory requirements for clinical application, which recommend the use of antibiotic resistance gene-free plasmids, we constructed and developed the production process for the clinical grade quality antibiotic resistance gene-free plasmid encoding human IL-12 (p21-hIL-12-ORT) and its ortholog encoding murine IL-12 (p21-mIL-12-ORT). To demonstrate the suitability of the p21-hIL-12-ORT or p21-mIL-12-ORT plasmid for the first-in-human clinical trial, the biological activity of the expressed transgene, its level of expression and plasmid copy number were determined in vitro in the human squamous cell carcinoma cell line FaDu and the murine colon carcinoma cell line CT26. The results of the non-clinical evaluation in vitro set the basis for further in vivo testing and evaluation of antitumor activity of therapeutic molecules in murine models as well as provide crucial data for further clinical trials of the constructed antibiotic resistance gene-free plasmid in humans. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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17 pages, 5272 KiB

Open AccessArticle

Lessons Learned in Protein Precipitation Using a Membrane Emulsification Technique to Produce Reversible and Uniform Microbeads

by Sang-Koo Park, Ga Yeon Noh, Hyun Woo Yu, Eun Chae Lee, Junoh Jeong, Young-Min Park, Hyo-Kyung Han, Seong Hoon Jeong and Nam Ah Kim

Pharmaceutics 2021, 13(10), 1738; https://doi.org/10.3390/pharmaceutics13101738 - 19 Oct 2021

Cited by 5 | Viewed by 2690

Abstract

The effects of the manufacturing process and the regeneration of Shirasu porous glass (SPG) membranes were investigated on the reproducibility of protein precipitants, termed protein microbeads. Intravenous immunoglobulin (IVIG) was selected as a model protein to produce its microbeads in seven different cases. [...] Read more.

The effects of the manufacturing process and the regeneration of Shirasu porous glass (SPG) membranes were investigated on the reproducibility of protein precipitants, termed protein microbeads. Intravenous immunoglobulin (IVIG) was selected as a model protein to produce its microbeads in seven different cases. The results showed that the hydrophobically modified SPG membrane produced finer microbeads than the hydrophilic SPG membrane, but this was inconsistent when using the general regeneration method. Its reproducibility was determined to be mostly dependent on rinsing the SPG membrane prior to the modification and on the protein concentration used for emulsification. The higher concentration could foul and plug the membrane during protein release and thus the membrane must be washed thoroughly before hydrophobic modification. Moreover, the membrane regenerated by silicone resin dissolved in ethanol had better reproducibility than silicone resin dissolved in water. On the other hand, rinsing the protein precipitant with cold ethanol after the emulsification was not favorable and induced protein aggregation. With the addition of trehalose, the purity of the IVIG microbeads was almost the same as before microbeadification. Therefore, the regeneration method, protein concentration, and its stabilizer are key to the success of protein emulsification and precipitation using the SPG membrane. Full article

(This article belongs to the Special Issue Application of Supercritical Fluid and Compressed Gas in Pharmaceutical Technology)

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12 pages, 2355 KiB

Open AccessArticle

Anti-Inflammatory Effect of Tacrolimus/Hydroxypropyl-β-Cyclodextrin Eye Drops in an Endotoxin-Induced Uveitis Model

by Xurxo García-Otero, Cristina Mondelo-García, Francisco González, Roman Perez-Fernandez, Leandro Avila, Jose Ramón Antúnez-López, Miguel González-Barcia, Alfredo Adan, Pablo Aguiar, Francisco J. Otero-Espinar, Maria A. Bermúdez and Anxo Fernández-Ferreiro

Pharmaceutics 2021, 13(10), 1737; https://doi.org/10.3390/pharmaceutics13101737 - 19 Oct 2021

Cited by 10 | Viewed by 3416

Abstract

Background: Uveitis is an infrequent disease which constitutes a major cause of ocular morbidity. Correct management is essential, being corticosteroids its cornerstone. In case of contraindication to corticosteroids or treatment failure, the use of topical tacrolimus (TAC) could be an alternative which has [...] Read more.

Background: Uveitis is an infrequent disease which constitutes a major cause of ocular morbidity. Correct management is essential, being corticosteroids its cornerstone. In case of contraindication to corticosteroids or treatment failure, the use of topical tacrolimus (TAC) could be an alternative which has already demonstrated safety and effectiveness in other ocular pathologies. However, TAC eye drops are not marketed, thus their elaboration must be carried out in Hospital Pharmacy Departments (HPDs). Methods: 32 Sprague-Dawley rats were divided into 4 groups of 8 rats each: (a) untreated healthy rats (Healthy); (b) untreated Endotoxin-Induced Uveitis model-rats (EIU); (c) EIU-rats treated with standard treatment of dexamethasone ophthalmic drops (DXM) and (d) EIU-rats treated with TAC-hydroxypropyl-β-cyclodextrin eye drops previously developed by our group (TAC-HPβCD). The mRNA expression levels of IL-6, IL-8, MIP-1α and TNF-α, quantitative analysis of leucocytes in aqueous humor and histological evaluation were performed. Results: TAC-HPβCD eye drops demonstrated to reduce ocular inflammation, expression of IL-6, TNF-α, MIP-1α and leukocyte infiltration in aqueous humor. Conclusions: TAC-HPβCD eye drops showed beneficial effect in EIU model in rats, positioning as an alternative for uveitis treatment in case of corticosteroids resistance or intolerance. Full article

(This article belongs to the Special Issue Ophthalmic Drug Delivery, 2nd Edition)

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26 pages, 3313 KiB

Open AccessArticle

In Vitro Cellular and Molecular Interplay between Human Foreskin-Derived Mesenchymal Stromal/Stem Cells and the Th17 Cell Pathway

by Mehdi Najar, Makram Merimi, Wissam H. Faour, Catherine A. Lombard, Douâa Moussa Agha, Yassine Ouhaddi, Etienne M. Sokal, Laurence Lagneaux and Hassan Fahmi

Pharmaceutics 2021, 13(10), 1736; https://doi.org/10.3390/pharmaceutics13101736 - 19 Oct 2021

Cited by 9 | Viewed by 3159

Abstract

Foreskin, considered a biological waste material, has been shown to be a reservoir of therapeutic cells. The immunomodulatory properties of mesenchymal stromal/stem cells (MSCs) from the foreskin (FSK-MSCs) are being evaluated in cell-based therapy for degenerative, inflammatory and autoimmune disorders. Within the injured/inflamed [...] Read more.

Foreskin, considered a biological waste material, has been shown to be a reservoir of therapeutic cells. The immunomodulatory properties of mesenchymal stromal/stem cells (MSCs) from the foreskin (FSK-MSCs) are being evaluated in cell-based therapy for degenerative, inflammatory and autoimmune disorders. Within the injured/inflamed tissue, proinflammatory lymphocytes such as IL-17-producing T helper cells (Th17) may interact with the stromal microenvironment, including MSCs. In this context, MSCs may encounter different levels of T cells as well as specific inflammatory signals. Uncovering the cellular and molecular changes during this interplay is central for developing an efficient and safe immunotherapeutic tool. To this end, an in vitro human model of cocultures of FSK-MSCs and T cells was established. These cocultures were performed at different cell ratios in the presence of an inflammatory setting. After confirming that FSK-MSCs respond to ISCT criteria by showing a typical phenotype and multilineage potential, we evaluated by flow cytometry the expression of Th17 cell markers IL-17A, IL23 receptor and RORγt within the lymphocyte population. We also measured 15 human Th17 pathway-related cytokines. Regardless of the T cell/MSC ratio, we observed a significant increase in IL-17A expression associated with an increase in IL-23 receptor expression. Furthermore, we observed substantial modulation of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40, and TNF-α secretion. These findings suggest that FSK-MSCs are receptive to their environment and modulate the T cell response accordingly. The changes within the secretome of the stromal and immune environment are likely relevant for the therapeutic effect of MSCs. FSK-MSCs represent a valuable cellular product for immunotherapeutic purposes that needs to be further clarified and developed. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

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36 pages, 5292 KiB

Open AccessReview

Calorimetric Investigation of the Relaxation Phenomena in Amorphous Lyophilized Solids

by Sebastian Groёl, Tim Menzen and Gerhard Winter

Pharmaceutics 2021, 13(10), 1735; https://doi.org/10.3390/pharmaceutics13101735 - 19 Oct 2021

Cited by 13 | Viewed by 2926

Abstract

Studying the thermal history and relaxation of solid amorphous drug product matrices by calorimetry is a well-known approach, particularly in the context of correlating the matrix parameters with the long-term stability of freeze-dried protein drug products. Such calorimetric investigations are even more relevant [...] Read more.

Studying the thermal history and relaxation of solid amorphous drug product matrices by calorimetry is a well-known approach, particularly in the context of correlating the matrix parameters with the long-term stability of freeze-dried protein drug products. Such calorimetric investigations are even more relevant today, as the application of new process techniques in freeze-drying (which strongly influence the thermal history of the products) has recently gained more interest. To revive the application of calorimetric methods, the widely scattered knowledge on this matter is condensed into a review and completed with new experimental data. The calorimetric methods are applied to recent techniques in lyophilization, such as controlled nucleation and aggressive/collapse drying. Phenomena such as pre-T_g events in differential scanning calorimetry and aging shoulders in isothermal microcalorimetry are critically reviewed and supplemented with data of freeze-dried products that have not been characterized with these methods before. Full article

(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)

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22 pages, 5647 KiB

Open AccessArticle

A Novel Method for Predicting the Human Inherent Clearance and Its Application in the Study of the Pharmacokinetics and Drug–Drug Interaction between Azidothymidine and Fluconazole Mediated by UGT Enzyme

by Yawen Yuan, Jun Zhang, Boyu Fang, Xiaoqiang Xiang, Guo Ma, Shunguo Zhang, Bin Zhu and Weimin Cai

Pharmaceutics 2021, 13(10), 1734; https://doi.org/10.3390/pharmaceutics13101734 - 19 Oct 2021

Cited by 1 | Viewed by 2458

Abstract

In order to improve the benefit–risk ratio of pharmacokinetic (PK) research in the early development of new drugs, in silico and in vitro methods were constructed and improved. Models of intrinsic clearance rate (CL_int) were constructed based on the quantitative structure–activity [...] Read more.

In order to improve the benefit–risk ratio of pharmacokinetic (PK) research in the early development of new drugs, in silico and in vitro methods were constructed and improved. Models of intrinsic clearance rate (CL_int) were constructed based on the quantitative structure–activity relationship (QSAR) of 7882 collected compounds. Moreover, a novel in vitro metabolic method, the Bio-PK dynamic metabolic system, was constructed and combined with a physiology-based pharmacokinetic model (PBPK) model to predict the metabolism and the drug–drug interaction (DDI) of azidothymidine (AZT) and fluconazole (FCZ) mediated by the phase II metabolic enzyme UDP-glycosyltransferase (UGT) in humans. Compared with the QSAR models reported previously, the goodness of fit of our CL_int model was slightly improved (determination coefficient (R²) = 0.58 vs. 0.25–0.45). Meanwhile, compared with the predicted clearance of 61.96 L/h (fold error: 2.95–3.13) using CL_int (8 µL/min/mg) from traditional microsomal experiment, the predicted clearance using CL_int (25 μL/min/mg) from Bio-PK system was increased to 143.26 L/h (fold error: 1.27–1.36). The predicted C_max and AUC (the area under the concentration–time curve) ratio were 1.32 and 1.84 (fold error: 1.36 and 1.05) in a DDI study with an inhibition coefficient (Ki) of 13.97 μM from the Bio-PK system. The results indicate that the Bio-PK system more truly reflects the dynamic metabolism and DDI of AZT and FCZ in the body. In summary, the novel in silico and in vitro method may provide new ideas for the optimization of drug metabolism and DDI research methods in early drug development. Full article

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17 pages, 2567 KiB

Open AccessArticle

Development of Multi-Compartment 3D-Printed Tablets Loaded with Self-Nanoemulsified Formulations of Various Drugs: A New Strategy for Personalized Medicine

by Tarek A. Ahmed, Raed I. Felimban, Hossam H. Tayeb, Waleed Y. Rizg, Fuad H. Alnadwi, Hanadi A. Alotaibi, Nabil A. Alhakamy, Fathy I. Abd-Allah, Gamal A. Mohamed, Ahmed S. Zidan and Khalid M. El-Say

Pharmaceutics 2021, 13(10), 1733; https://doi.org/10.3390/pharmaceutics13101733 - 19 Oct 2021

Cited by 21 | Viewed by 4142

Abstract

This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery [...] Read more.

This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery system (SNEDDS). Screening mixture experimental design was conducted to develop SNEDDS formulation with a minimum droplet size. Five different semi-solid pastes were prepared and rheologically characterized. The prepared pastes were used to develop 3DP tablets using extrusion printing. The quality attributes of the 3DP tablets were evaluated. A non-compartmental extravascular pharmacokinetic model was implemented to investigate the in vivo behavior of the prepared tablets and the studied marketed products. The optimized SNEDDS, of a 94.43 ± 3.55 nm droplet size, was found to contain 15%, 75%, and 10% of oil, polyethylene glycol 400, and tween 80, respectively. The prepared pastes revealed a shear-thinning of pseudoplastic flow behavior. Flat-faced round tablets of 15 mm diameter and 5.6–11.2 mm thickness were successfully printed and illustrated good criteria for friability, weight variation, and content uniformity. Drug release was superior from SNEDDS-based tablets when compared to non-SNEDDS tablets. Scanning electron microscopy study of the 3DP tablets revealed a semi-porous surface that exhibited some curvature with the appearance of tortuosity and a gel porous-like structure of the inner section. GLMP and RSV demonstrated relative bioavailability of 159.50% and 245.16%, respectively. Accordingly, the developed 3DP tablets could be considered as a promising combined oral drug therapy used in treatment of metabolic disorders. However, clinical studies are needed to investigate their efficacy and safety. Full article

(This article belongs to the Special Issue Oral Drug Delivery Systems Based on Lipid-Based Carriers)

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18 pages, 2540 KiB

Open AccessArticle

On the Biocompatibility and Teat Retention of In Situ Gelling Intramammary Formulations: Cattle Mastitis Prevention and Treatment

by Sushila Bhattarai, Dhayaneethie Perumal, Michael J. Rathbone, Craig R. Bunt and Raid G. Alany

Pharmaceutics 2021, 13(10), 1732; https://doi.org/10.3390/pharmaceutics13101732 - 19 Oct 2021

Cited by 1 | Viewed by 2560

Abstract

Treatment and prevention of cattle mastitis remains a formidable challenge due to the anatomical and physiological constraints of the cow udder. In this study, we investigated polymeric excipients and solvents that can form, (when combined) novel, non-toxic and biocompatible in situ gelling formulations [...] Read more.

Treatment and prevention of cattle mastitis remains a formidable challenge due to the anatomical and physiological constraints of the cow udder. In this study, we investigated polymeric excipients and solvents that can form, (when combined) novel, non-toxic and biocompatible in situ gelling formulations in the mammary gland of bovine cattle. We also report on a new approach to screen intramammary formulations using fresh excised cow teats. Fourteen hydrophilic polymers and six solvents were evaluated for in vitro cytotoxicity and biocompatibility towards cultured bovine mammary epithelial cells (MAC-T), microscopic and macroscopic examination upon contact with excised cow teats. No significant cytotoxicity (p > 0.05) was observed with polyethylene oxides, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium alginate and xanthan gum. Polycarbophil and carbopol polymers showed significantly higher cytotoxicity (p < 0.05). Concentration-dependent cytotoxicity was observed for glycerin, propylene glycol, polyethylene glycol 400, ethanol, N-methyl-2-pyrrolidone and 2-pyrrolidone, with the 2-pyrrolidone solvents showing higher cytotoxic effects (p < 0.05). In situ gelling formulations comprising hydroxypropyl methylcellulose or carboxymethyl cellulose and solvents in specific ratios were biocompatible at higher concentrations with MAC-T cells compared to alginates. All investigated formulations could undergo in situ sol-to-gel phase transformation, forming non-toxic gels with good biocompatibility in excised cow teats hence, showing potential for use as intramammary carriers for sustained drug delivery. Full article

(This article belongs to the Special Issue Advances in Veterinary Medicines and Vaccines)

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8 pages, 870 KiB

Open AccessCommunication

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

by Karen Claesen, Lynn Roth, Joachim C. Mertens, Karlijn Hermans, Yani Sim and Dirk Hendriks

Pharmaceutics 2021, 13(10), 1731; https://doi.org/10.3390/pharmaceutics13101731 - 19 Oct 2021

Cited by 2 | Viewed by 2114

Abstract

Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 [...] Read more.

Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 gene (ApoE^−/−Fbn1^C1039G+/−), a model of advanced atherosclerosis, statins do not lower cholesterol. Consequently, studying cholesterol-independent effects of statins can be achieved more straightforwardly in these mice. Female ApoE ^−/−Fbn1C^1039G+/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided into a WD group (receiving WD only) and a WD + atorvastatin group (receiving 10 mg/kg/day atorvastatin +WD) group. After 15 weeks, blood was collected from the retro-orbital plexus, and the mice were sacrificed. Total plasma cholesterol and C-reactive protein (CRP) were measured with commercially available kits. Plasma proCPU levels were determined with an activity-based assay. Total plasma cholesterol levels were not significantly different between both groups, while proCPU levels were significantly lower in the WD + atorvastatin group. Interestingly proCPU levels correlated with CRP and circulating monocytes. In conclusion, our results confirm that atorvastatin downregulates proCPU levels in ApoE^−/−Fbn1^C1039G+/− mice on a WD, and evidence was provided that this downregulation is a pleiotropic effect of atorvastatin treatment. Full article

(This article belongs to the Special Issue Pleiotropic Effects of Statins: Developing New Therapeutic Approaches to Human Diseases)

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13 pages, 2227 KiB

Open AccessArticle

Cellular Toxicity Mechanisms and the Role of Autophagy in Pt(IV) Prodrug-Loaded Ultrasmall Iron Oxide Nanoparticles Used for Enhanced Drug Delivery

by L. Gutiérrez-Romero, L. Rivas-García, C. Sánchez-González, J. Llopis, E. Blanco and M. Montes-Bayón

Pharmaceutics 2021, 13(10), 1730; https://doi.org/10.3390/pharmaceutics13101730 - 19 Oct 2021

Cited by 5 | Viewed by 3008

Abstract

Ultrasmall iron oxide nanoparticles (<10 nm) were loaded with cis-diamminetetrachloroplatinum (IV), a cisplatin (II) prodrug, and used as an efficient nanodelivery system in cell models. To gain further insight into their behavior in ovarian cancer cells, the level of cellular incorporation as well [...] Read more.

Ultrasmall iron oxide nanoparticles (<10 nm) were loaded with cis-diamminetetrachloroplatinum (IV), a cisplatin (II) prodrug, and used as an efficient nanodelivery system in cell models. To gain further insight into their behavior in ovarian cancer cells, the level of cellular incorporation as well as the platination of mitochondrial and nuclear DNA were measured using inductively coupled plasma mass spectrometry (ICP-MS) strategies. Quantitative Pt results revealed that after 24 h exposure to 20 µM Pt in the form of the Pt(IV)-loaded nanoparticles, approximately 10% of the incorporated Pt was associated with nuclear DNA. This concentration increased up to 60% when cells were left to stand in drug-free media for 3 h. These results indicated that the intracellular reducing conditions permitted the slow release of cisplatin (II) from the cisplatin (IV)-loaded nanoparticles. Similar results were obtained for the platination of mitochondrial DNA, which reached levels up to 17,400 ± 75 ng Pt/ mg DNA when cells were left in drug-free media for 3 h, proving that this organelle was also a target for the action of the released cisplatin (II). The time-dependent formation of Pt-DNA adducts could be correlated with the time-dependent decrease in cell viability. Such a decrease in cell viability was correlated with the induction of apoptosis as the main route of cell death. The formation of autophagosomes, although observed upon exposure in treated cells, does not seem to have played an important role as a means for cells to overcome nanoparticles’ toxicity. Thus, the designed nanosystem demonstrated high cellular penetration and the “in situ” production of the intracellularly active cisplatin (II), which is able to induce cell death, in a sustained manner. Full article

(This article belongs to the Special Issue New Trends in Therapy: From Natural Products to Nanomedicine)

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15 pages, 2513 KiB

Open AccessArticle

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

by Jan Goelen, Benoni Alexander, Haren Eranga Wijesinghe, Emily Evans, Gopal Pawar, Richard D. Horniblow and Hannah K. Batchelor

Pharmaceutics 2021, 13(10), 1729; https://doi.org/10.3390/pharmaceutics13101729 - 19 Oct 2021

Cited by 5 | Viewed by 2814

Abstract

Previous studies have used magnetic resonance imaging (MRI) to quantify the fluid in the stomach and small intestine of children, and the stomach, small intestine and colon of adults. This is the first study to quantify fluid volumes and distribution using MRI in [...] Read more.

Previous studies have used magnetic resonance imaging (MRI) to quantify the fluid in the stomach and small intestine of children, and the stomach, small intestine and colon of adults. This is the first study to quantify fluid volumes and distribution using MRI in the paediatric colon. MRI datasets from 28 fasted (aged 0–15 years) and 18 fluid-fed (aged 10–16 years) paediatric participants were acquired during routine clinical care. A series of 2D- and 3D-based software protocols were used to measure colonic fluid volume and localisation. The paediatric colon contained a mean volume of 22.5 mL ± 41.3 mL fluid, (range 0–167.5 mL, median volume 0.80 mL) in 15.5 ± 17.5 discreet fluid pockets (median 12). The proportion of the fluid pockets larger than 1 mL was 9.6%, which contributed to 94.5% of the total fluid volume observed. No correlation was detected between all-ages and colonic fluid volume, nor was a difference in colonic fluid volumes observed based on sex, fed state or age group based on ICH-classifications. This study quantified fluid volumes within the paediatric colon, and these data will aid and accelerate the development of biorelevant tools to progress paediatric drug development for colon-targeting formulations. Full article

(This article belongs to the Special Issue New Developments in Pediatric Drug Formulations)

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16 pages, 3202 KiB

Open AccessArticle

Optimization and Development of Selective Histone Deacetylase Inhibitor (MPT0B291)-Loaded Albumin Nanoparticles for Anticancer Therapy

by Athika Darumas Putri, Pai-Shan Chen, Yu-Lin Su, Jia-Pei Lin, Jing-Ping Liou and Chien-Ming Hsieh

Pharmaceutics 2021, 13(10), 1728; https://doi.org/10.3390/pharmaceutics13101728 - 19 Oct 2021

Cited by 11 | Viewed by 3531

Abstract

Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agent for various types of tumors. MPT0B291, a novel selective inhibitor of HDAC6, demonstrated significant antiproliferative activity in various human cancer cell types. However, MPT0B291 has very low water solubility, which [...] Read more.

Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agent for various types of tumors. MPT0B291, a novel selective inhibitor of HDAC6, demonstrated significant antiproliferative activity in various human cancer cell types. However, MPT0B291 has very low water solubility, which limits its clinical use for cancer therapy. In the current study, MPT0B291 was encapsulated in human serum albumin (HSA), and its anticancer activities were investigated. Nanoparticles (NPs) were prepared using two-stage emulsification resulting in 100~200-nm NPs with a fine size distribution (polydispersity index of <0.3). The in vitro drug release profiles of MPT0B291-loaded HSA NPs presented sustained-release properties. The cytotoxic effect on MIA PaCa-2 human pancreatic carcinoma cells was found to be similar to MPT0B291-loaded HSA NPs and the free-drug group. The albumin-based formulation provided a higher maximum tolerated dose than that of a drug solution with reduced toxicity toward normal cells. Furthermore, in vivo pharmacokinetic studies demonstrated an effective increase (5~8-fold) in the bioavailability of NPs containing MPT0B291 loaded in HSA compared to the free-drug solution with an extended circulation time (t_1/2) leading to significantly enhanced efficacy of anticancer treatment. Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)

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17 pages, 6160 KiB

Open AccessArticle

Development, Evaluation, and Molecular Docking of Oral Dissolving Film of Atenolol

by Karina Citra Rani, Nani Parfati, Ni Luh Dewi Aryani, Agnes Nuniek Winantari, Endang Wahyu Fitriani, Aditya Trias Pradana, Roisah Nawatila, Astridani Rizky Putranti, Florencia Irine, Florentia Angelica, Cintya Yohanes and Christina Avanti

Pharmaceutics 2021, 13(10), 1727; https://doi.org/10.3390/pharmaceutics13101727 - 19 Oct 2021

Cited by 15 | Viewed by 3894

Abstract

The development of oral dissolving film (ODF) of atenolol is an attempt to enhance convenience and compliance for geriatric patients suffering from hypertension. Film former is the most essential component in ODF that determines the physical characteristic and drug release. In this study, [...] Read more.

The development of oral dissolving film (ODF) of atenolol is an attempt to enhance convenience and compliance for geriatric patients suffering from hypertension. Film former is the most essential component in ODF that determines the physical characteristic and drug release. In this study, three different types of film former including HPMC E5 4% (w/v), 5% (w/v), CMC-Na 3% (w/v), 4% (w/v), and Na-alginate 2.5% (w/v), 3% (w/v) were optimized in Formula 1 (F1) to Formula 6 (F6), respectively. A solvent casting method was employed to develop ODF of atenolol. The films formed by HPMC E5 produced a smooth and flexible surface, whereas CMC-Na and Na-alginate produced gritty textured films. Satisfactory results were obtained from several physical parameters such as film thickness, folding endurance, swelling index, and disintegration time. The homogeneity, drug content, and dissolution properties of ODF with HPMC exhibited better characteristics than the other formulas. Formula 1 exhibited the highest drug release compared to the other ODFs. The molecular docking results showed that there was a hydrogen bonding between atenolol and film formers which was also supported by the FTIR spectrum. The findings of this study suggest that HPMC E5 is the most favorable film former for ODF of atenolol. Full article

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

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14 pages, 2177 KiB

Open AccessArticle

Gold-Decorated Platinum and Palladium Nanoparticles as Modern Nanocomplexes to Improve the Effectiveness of Simulated Anticancer Proton Therapy

by Bartosz Klebowski, Malgorzata Stec, Joanna Depciuch, Adrianna Gałuszka, Anna Pajor-Swierzy, Jarek Baran and Magdalena Parlinska-Wojtan

Pharmaceutics 2021, 13(10), 1726; https://doi.org/10.3390/pharmaceutics13101726 - 18 Oct 2021

Cited by 12 | Viewed by 2790

Abstract

Noble metal nanoparticles, such as gold (Au NPs), platinum (Pt NPs), or palladium (Pd NPs), due to their highly developed surface, stability, and radiosensitizing properties, can be applied to support proton therapy (PT) of cancer. In this paper, we investigated the potential of [...] Read more.

Noble metal nanoparticles, such as gold (Au NPs), platinum (Pt NPs), or palladium (Pd NPs), due to their highly developed surface, stability, and radiosensitizing properties, can be applied to support proton therapy (PT) of cancer. In this paper, we investigated the potential of bimetallic, c.a. 30 nm PtAu and PdAu nanocomplexes, synthesized by the green chemistry method and not used previously as radiosensitizers, to enhance the effect of colorectal cancer PT in vitro. The obtained nanomaterials were characterized by scanning transmission electron microscopy (STEM), selected area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDS), UV-Vis spectroscopy, and zeta potential measurements. The effect of PtAu and PdAu NPs in PT was investigated on colon cancer cell lines (SW480, SW620, and HCT116), as well as normal colon epithelium cell line (FHC). These cells were cultured with both types of NPs and then irradiated by proton beam with a total dose of 15 Gy. The results of the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) test showed that the NPs-assisted PT resulted in a better anticancer effect than PT used alone; however, there was no significant difference in the radiosensitizing properties between tested nanocomplexes. The MTS results were further verified by defining the cell death as apoptosis (Annexin V binding assay). Furthermore, the data showed that such a treatment was more selective for cancer cells, as normal cell viability was only slightly affected. Full article

(This article belongs to the Special Issue Metal-Based Nanoparticles: New Insights into Cancer Diagnosis and Therapy)

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23 pages, 8368 KiB

Open AccessArticle

Deaggregation and Crystallization Inhibition by Small Amount of Polymer Addition for a Co-Amorphous Curcumin-Magnolol System

by Jiawei Han, Luyuan Li, Meiling Su, Weili Heng, Yuanfeng Wei, Yuan Gao and Shuai Qian

Pharmaceutics 2021, 13(10), 1725; https://doi.org/10.3390/pharmaceutics13101725 - 18 Oct 2021

Cited by 28 | Viewed by 3125

Abstract

Different from previously reported co-amorphous systems, a co-amorphous curcumin-magnolol (CUR-MAG CM) system, as compared with its crystalline counterparts, exhibited decreased dissolution due to its aggregation during dissolution. The main purpose of the present study is to deaggregate CUR-MAG CM to optimize drug dissolution [...] Read more.

Different from previously reported co-amorphous systems, a co-amorphous curcumin-magnolol (CUR-MAG CM) system, as compared with its crystalline counterparts, exhibited decreased dissolution due to its aggregation during dissolution. The main purpose of the present study is to deaggregate CUR-MAG CM to optimize drug dissolution and explore the deaggregation mechanism involved. Herein, a small amount of polymer (HPMC, HPC, and PVP K30) was co-formulated at 5% (w/w) with CUR-MAG CM as ternary co-amorphous systems. The polymer addition changed the surface properties of CUR-MAG CM including improved water wettability enhanced surface free energy, and hence exerted a deaggregating effect. As a result, the ternary co-amorphous systems showed faster and higher dissolution as compared with crystalline CUR/MAG and CUR-MAG CM. In addition, the nucleation and crystal growth of dissolved CUR and MAG molecules were significantly inhibited by the added polymer, maintaining a supersaturated concentration for a long time. Furthermore, polymer addition increased the T_g of CUR-MAG CM, potentially involving molecular interactions and inhibiting molecular mobility, resulting in enhanced physical stability under 25 °C/60% RH and 40 °C/75% RH conditions. Therefore, this study provides a promising strategy to optimize the dissolution and physical stability of co-amorphous systems by deaggregation and crystallization inhibition via adding small amounts of polymers. Full article

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16 pages, 2776 KiB

Open AccessArticle

Design of a Platelet-Mediated Delivery System for Drug-Incorporated Nanospheres to Enhance Anti-Tumor Therapeutic Effect

by Jun-ichiro Jo, Tsubasa Emi and Yasuhiko Tabata

Pharmaceutics 2021, 13(10), 1724; https://doi.org/10.3390/pharmaceutics13101724 - 18 Oct 2021

Cited by 3 | Viewed by 2863

Abstract

The objective of this study is to construct a platelet-mediated delivery system for drug-incorporated nanospheres. Nanospheres of poly(lactic-co-glycolic acid) (PLGA-NS) with different sizes and surface properties were prepared by changing the preparation parameters, such as the type of polymer surfactant, the concentration of [...] Read more.

The objective of this study is to construct a platelet-mediated delivery system for drug-incorporated nanospheres. Nanospheres of poly(lactic-co-glycolic acid) (PLGA-NS) with different sizes and surface properties were prepared by changing the preparation parameters, such as the type of polymer surfactant, the concentration of polymer surfactant and PLGA, and the stirring rate. When incubated with platelets, PLGA-NS prepared with poly(vinyl alcohol) suppressed the platelet activation. Scanning electron microscopic and flow cytometry examinations revealed that platelets associated with PLGA-NS (platelet hybrids, PH) had a similar appearance and biological properties to those of the original platelets. In addition, the PH with PLGA-NS specifically adhered onto the substrate pre-coated with fibrin to a significantly great extent compared with PLGA-NS alone. When applied in an in vitro model of tumor tissue which was composed of an upper chamber pre-coated with fibrin and a lower chamber culturing tumor cells, the PH with PLGA-NS incorporating an anti-tumor drug were delivered to the tumor cells through the specific adhesion onto the upper chamber and, consequently, drug release from the upper chamber took place, resulting in the growth suppression of tumor cells. It is concluded that the drug delivery system based on PH is promising for tumor treatment. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Japan)

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19 pages, 9202 KiB

Open AccessArticle

Towards a Better Understanding of Verapamil Release from Kollicoat SR:IR Coated Pellets Using Non-Invasive Analytical Tools

by Julie Fahier, Branko Vukosavljevic, Laure De Kinder, Hugues Florin, Jean-François Goossens, Maike Windbergs, Florence Siepmann, Juergen Siepmann and Susanne Muschert

Pharmaceutics 2021, 13(10), 1723; https://doi.org/10.3390/pharmaceutics13101723 - 18 Oct 2021

Cited by 5 | Viewed by 3197

Abstract

The aim of this study was to gain deeper insight into the mass transport mechanisms controlling drug release from polymer-coated pellets using non-invasive analytical tools. Pellet starter cores loaded with verapamil HCl (10% loading, 45% lactose, 45% microcrystalline cellulose) were prepared by extrusion/spheronization [...] Read more.

The aim of this study was to gain deeper insight into the mass transport mechanisms controlling drug release from polymer-coated pellets using non-invasive analytical tools. Pellet starter cores loaded with verapamil HCl (10% loading, 45% lactose, 45% microcrystalline cellulose) were prepared by extrusion/spheronization and coated with 5% Kollicoat SR:IR 95:5 or 10% Kollicoat SR:IR 90:10. Drug release was measured from ensembles of pellets as well as from single pellets upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4. The swelling of single pellets was observed by optical microscopy, while dynamic changes in the pH in the pellet cores were monitored by fluorescence spectroscopy. Also, mathematical modeling using a mechanistically realistic theory as well as SEM and Raman imaging were applied to elucidate whether drug release mainly occurs by diffusion through the intact film coatings or whether crack formation in the film coatings plays a role. Interestingly, fluorescence spectroscopy revealed that the pH within the pellet cores substantially differed upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4, resulting in significant differences in drug solubility (verapamil being a weak base) and faster drug release at lower pH: from ensembles of pellets and single pellets. The monitoring of drug release from and the swelling of single pellets indicated that crack formation in the film coatings likely plays a major role, irrespective of the Kollicoat SR:IR ratio/coating level. This was confirmed by mathematical modeling, SEM and Raman imaging. Importantly, the latter technique allowed also for non-invasive measurements, reducing the risk of artifact creation associated with sample cutting with a scalpel. Full article

(This article belongs to the Special Issue Drug Release Mechanisms Elucidated by Imaging Techniques: Visualizing the Invisible!)

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24 pages, 2033 KiB

Open AccessReview

Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

by Pia Pernille Søgaard, Marianne Lind, Chatpakorn Rassemeena Christiansen, Karsten Petersson, Adam Clauss and Ester Caffarel-Salvador

Pharmaceutics 2021, 13(10), 1722; https://doi.org/10.3390/pharmaceutics13101722 - 18 Oct 2021

Cited by 8 | Viewed by 6856

Abstract

Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent [...] Read more.

Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems. Full article

(This article belongs to the Special Issue Novel Devices for the Oral Delivery of Macromolecules)

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17 pages, 3785 KiB

Open AccessArticle

Exploring Acceptability Drivers of Oral Antibiotics in Children: Findings from an International Observational Study

by Thibault Vallet, Yahya Bensouda, Jumpei Saito, Liv Mathiesen, Varsha Pokharkar, Viviane Klingmann, Matthew Peak, Omar Elhamdaoui, Akimasa Yamatani, Ivana Ivanovic, Manjusha Sajith, Juliane Münch, Louise Bracken, Jennifer Claire Duncan, Smita Salunke, Siri Wang and Fabrice Ruiz

Pharmaceutics 2021, 13(10), 1721; https://doi.org/10.3390/pharmaceutics13101721 - 18 Oct 2021

Cited by 11 | Viewed by 3529

Abstract

Antibiotics are among the most commonly prescribed drugs in children. Adherence to the treatment with these drugs is of the utmost importance to prevent the emergence of resistant bacteria, a global health threat. In children, medicine acceptability is likely to have a significant [...] Read more.

Antibiotics are among the most commonly prescribed drugs in children. Adherence to the treatment with these drugs is of the utmost importance to prevent the emergence of resistant bacteria, a global health threat. In children, medicine acceptability is likely to have a significant impact on compliance. Herein we used a multivariate approach, considering simultaneously the many aspects of acceptability to explore the drivers of oral antibiotic acceptability in children under twelve, especially in toddlers and in preschoolers. Based on 628 real-life observer reports of the intake of 133 distinct medicines, the acceptability reference framework highlighted the influence of many factors such as age and sex of patients, previous exposure to treatment, place of administration, administration device, flavor agent in excipients and active pharmaceutical ingredient. These findings from an international observational study emphasize the multidimensional nature of acceptability. Therefore, it is crucial to consider all these different aspects for assessing this multi-faceted concept and designing or prescribing a medicine in order to reach adequate acceptability in the target population. Full article

(This article belongs to the Special Issue Advance in Development of Patient-Centric Dosage Form)

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16 pages, 2316 KiB

Open AccessArticle

Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease

by Anisha K. Nigam, Anupam A. Ojha, Julia G. Li, Da Shi, Vibha Bhatnagar, Kabir B. Nigam, Ruben Abagyan and Sanjay K. Nigam

Pharmaceutics 2021, 13(10), 1720; https://doi.org/10.3390/pharmaceutics13101720 - 18 Oct 2021

Cited by 16 | Viewed by 3690

Abstract

In patients with liver or kidney disease, it is especially important to consider the routes of metabolism and elimination of small-molecule pharmaceuticals. Once in the blood, numerous drugs are taken up by the liver for metabolism and/or biliary elimination, or by the kidney [...] Read more.

In patients with liver or kidney disease, it is especially important to consider the routes of metabolism and elimination of small-molecule pharmaceuticals. Once in the blood, numerous drugs are taken up by the liver for metabolism and/or biliary elimination, or by the kidney for renal elimination. Many common drugs are organic anions. The major liver uptake transporters for organic anion drugs are organic anion transporter polypeptides (OATP1B1 or SLCO1B1; OATP1B3 or SLCO1B3), whereas in the kidney they are organic anion transporters (OAT1 or SLC22A6; OAT3 or SLC22A8). Since these particular OATPs are overwhelmingly found in the liver but not the kidney, and these OATs are overwhelmingly found in the kidney but not liver, it is possible to use chemoinformatics, machine learning (ML) and deep learning to analyze liver OATP-transported drugs versus kidney OAT-transported drugs. Our analysis of >30 quantitative physicochemical properties of OATP- and OAT-interacting drugs revealed eight properties that in combination, indicate a high propensity for interaction with “liver” transporters versus “kidney” ones based on machine learning (e.g., random forest, k-nearest neighbors) and deep-learning classification algorithms. Liver OATPs preferred drugs with greater hydrophobicity, higher complexity, and more ringed structures whereas kidney OATs preferred more polar drugs with more carboxyl groups. The results provide a strong molecular basis for tissue-specific targeting strategies, understanding drug–drug interactions as well as drug–metabolite interactions, and suggest a strategy for how drugs with comparable efficacy might be chosen in chronic liver or kidney disease (CKD) to minimize toxicity. Full article

(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs)

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52 pages, 4403 KiB

Open AccessReview

Green Metallic Nanoparticles for Cancer Therapy: Evaluation Models and Cancer Applications

by Ernesto Tinajero-Díaz, Daniela Salado-Leza, Carmen Gonzalez, Moisés Martínez Velázquez, Zaira López, Jorge Bravo-Madrigal, Peter Knauth, Flor Y. Flores-Hernández, Sara Elisa Herrera-Rodríguez, Rosa E. Navarro, Alejandro Cabrera-Wrooman, Edgar Krötzsch, Zaira Y. García Carvajal and Rodolfo Hernández-Gutiérrez

Pharmaceutics 2021, 13(10), 1719; https://doi.org/10.3390/pharmaceutics13101719 - 18 Oct 2021

Cited by 43 | Viewed by 6671

Abstract

Metal-based nanoparticles are widely used to deliver bioactive molecules and drugs to improve cancer therapy. Several research works have highlighted the synthesis of gold and silver nanoparticles by green chemistry, using biological entities to minimize the use of solvents and control their physicochemical [...] Read more.

Metal-based nanoparticles are widely used to deliver bioactive molecules and drugs to improve cancer therapy. Several research works have highlighted the synthesis of gold and silver nanoparticles by green chemistry, using biological entities to minimize the use of solvents and control their physicochemical and biological properties. Recent advances in evaluating the anticancer effect of green biogenic Au and Ag nanoparticles are mainly focused on the use of conventional 2D cell culture and in vivo murine models that allow determination of the half-maximal inhibitory concentration, a critical parameter to move forward clinical trials. However, the interaction between nanoparticles and the tumor microenvironment is not yet fully understood. Therefore, it is necessary to develop more human-like evaluation models or to improve the existing ones for a better understanding of the molecular bases of cancer. This review provides recent advances in biosynthesized Au and Ag nanoparticles for seven of the most common and relevant cancers and their biological assessment. In addition, it provides a general idea of the in silico, in vitro, ex vivo, and in vivo models used for the anticancer evaluation of green biogenic metal-based nanoparticles. Full article

(This article belongs to the Special Issue Nanomaterials for Smart Therapeutic Treatments)

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18 pages, 7495 KiB

Open AccessArticle

Generation of a Biomimetic Substitute of the Corneal Limbus Using Decellularized Scaffolds

by David Sánchez-Porras, Manuel Caro-Magdaleno, Carmen González-Gallardo, Óscar Darío García-García, Ingrid Garzón, Víctor Carriel, Fernando Campos and Miguel Alaminos

Pharmaceutics 2021, 13(10), 1718; https://doi.org/10.3390/pharmaceutics13101718 - 17 Oct 2021

Cited by 10 | Viewed by 3006

Abstract

Patients with severe limbal damage and limbal stem cell deficiency are a therapeutic challenge. We evaluated four decellularization protocols applied to the full-thickness and half-thickness porcine limbus, and we used two cell types to recellularize the decellularized limbi. The results demonstrated that all [...] Read more.

Patients with severe limbal damage and limbal stem cell deficiency are a therapeutic challenge. We evaluated four decellularization protocols applied to the full-thickness and half-thickness porcine limbus, and we used two cell types to recellularize the decellularized limbi. The results demonstrated that all protocols achieved efficient decellularization. However, the method that best preserved the transparency and composition of the limbus extracellular matrix was the use of 0.1% SDS applied to the half-thickness limbus. Recellularization with the limbal epithelial cell line SIRC and human adipose-derived mesenchymal stem cells (hADSCs) was able to generate a stratified epithelium able to express the limbal markers p63, pancytokeratin, and crystallin Z from day 7 in the case of SIRC and after 14–21 days of induction when hADSCs were used. Laminin and collagen IV expression was detected at the basal lamina of both cell types at days 14 and 21 of follow-up. Compared with control native limbi, tissues recellularized with SIRC showed adequate picrosirius red and alcian blue staining intensity, whereas limbi containing hADSCs showed normal collagen staining intensity. These preliminary results suggested that the limbal substitutes generated in this work share important similarities with the native limbus and could be potentially useful in the future. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products for Eye Diseases: Goals and Challenges)

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15 pages, 6394 KiB

Open AccessArticle

Hydrophilic Excipient-Independent Drug Release from SLA-Printed Pellets

by Lei Xu, Qingliang Yang, Wei Qiang, Huijie Li, Weizhen Zhong, Siying Pan and Gensheng Yang

Pharmaceutics 2021, 13(10), 1717; https://doi.org/10.3390/pharmaceutics13101717 - 17 Oct 2021

Cited by 12 | Viewed by 3067

Abstract

Three-dimensional (3D) printing technology, specifically stereolithography (SLA) technology, has recently created exciting possibilities for the design and fabrication of sophisticated dosages for oral administration, paving a practical way to precisely manufacture customized pharmaceutical dosages with both personalized properties and sustained drug release behavior. [...] Read more.

Three-dimensional (3D) printing technology, specifically stereolithography (SLA) technology, has recently created exciting possibilities for the design and fabrication of sophisticated dosages for oral administration, paving a practical way to precisely manufacture customized pharmaceutical dosages with both personalized properties and sustained drug release behavior. However, the sustained drug release achieved in prior studies largely relies on the presence of hydrophilic excipients in the printing formulation, which unfortunately impedes the printability and formability of the corresponding printing formulations. The current study developed and prepared mini-sized oral pellets using the SLA technique and successfully accomplished a hydrophilic excipient-independent drug release behavior. With ibuprofen as the model drug, the customized photopolymerizable printing formulation included polyethylene glycol diacrylate (PEGDA) as a monomer and diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (TPO) as a photoinitiator. The produced mini-sized pellets were thoroughly investigated for various factors, including their printability, physical properties, microscopic features, drug content, and drug-release profiles. The drug release profiles from the printed pellets that were larger size (3 mm and 6 mm) followed the Ritger–Peppas model, demonstrating that the release was influenced by both the diffusion of the dissolved drug and by the erosion of the hydrophilic excipients (PEG400). The profiles from the smaller printed pellets (1 mm and 2 mm) followed first release kinetics, not only illustrating that the release was impacted only by drug diffusion, but also indicating that there is a size boundary between the dependent and independent hydrophilic excipients. These results could create practical benefits to the pharmaceutical industry in terms of the design and development personalized dosages using the SLA printing technique with controllable drug release by manipulating size alone. Full article

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17 pages, 3205 KiB

Open AccessArticle

Chitosan Oleate Coated PLGA Nanoparticles as siRNA Drug Delivery System

by Dalila Miele, Xin Xia, Laura Catenacci, Milena Sorrenti, Silvia Rossi, Giuseppina Sandri, Franca Ferrari, John J. Rossi and Maria Cristina Bonferoni

Pharmaceutics 2021, 13(10), 1716; https://doi.org/10.3390/pharmaceutics13101716 - 17 Oct 2021

Cited by 16 | Viewed by 3216

Abstract

Oligonucleotide therapeutics such as miRNAs and siRNAs represent a class of molecules developed to modulate gene expression by interfering with ribonucleic acids (RNAs) and protein synthesis. These molecules are characterized by strong instability and easy degradation due to nuclease enzymes. To avoid these [...] Read more.

Oligonucleotide therapeutics such as miRNAs and siRNAs represent a class of molecules developed to modulate gene expression by interfering with ribonucleic acids (RNAs) and protein synthesis. These molecules are characterized by strong instability and easy degradation due to nuclease enzymes. To avoid these drawbacks and ensure efficient delivery to target cells, viral and non-viral vectors are the two main approaches currently employed. Viral vectors are one of the major vehicles in gene therapy; however, the potent immunogenicity and the insertional mutagenesis is a potential issue for the patient. Non-viral vectors, such as polymeric nanocarriers, provide a safer and more efficient delivery of RNA-interfering molecules. The aim of this work is to employ PLGA core nanoparticles shell-coated with chitosan oleate as siRNA carriers. An siRNA targeted on HIV-1, directed against the viral Tat/Rev transcripts was employed as a model. The ionic interaction between the oligonucleotide’s moieties, negatively charged, and the positive surface charges of the chitosan shell was exploited to associate siRNA and nanoparticles. Non-covalent bonds can protect siRNA from nuclease degradation and guarantee a good cell internalization and a fast release of the siRNA into the cytosolic portion, allowing its easy activation. Full article

(This article belongs to the Special Issue Special Issue in Honor of Professor Carla Caramella)

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37 pages, 1303 KiB

Open AccessReview

Improving Curcumin Bioavailability: Current Strategies and Future Perspectives

by Rita Tabanelli, Simone Brogi and Vincenzo Calderone

Pharmaceutics 2021, 13(10), 1715; https://doi.org/10.3390/pharmaceutics13101715 - 17 Oct 2021

Cited by 146 | Viewed by 17581

Abstract

Curcumin possesses a plethora of interesting pharmacological effects. Unfortunately, it is also characterized by problematic drug delivery and scarce bioavailability, representing the main problem related to the use of this compound. Poor absorption, fast metabolism, and rapid systemic clearance are the most important [...] Read more.

Curcumin possesses a plethora of interesting pharmacological effects. Unfortunately, it is also characterized by problematic drug delivery and scarce bioavailability, representing the main problem related to the use of this compound. Poor absorption, fast metabolism, and rapid systemic clearance are the most important factors contributing to low curcumin levels in plasma and tissues. Accordingly, to overcome these issues, numerous strategies have been proposed and are investigated in this article. Due to advances in the drug delivery field, we describe here the most promising strategies for increasing curcumin bioavailability, including the use of adjuvant, complexed/encapsulated curcumin, specific curcumin formulations, and curcumin nanoparticles. We analyze current strategies, already available in the market, and the most advanced technologies that can offer a future perspective for effective curcumin formulations. We focus the attention on the effectiveness of curcumin-based formulations in clinical trials, providing a comprehensive summary. Clinical trial results, employing various delivery methods for curcumin, showed that improved bioavailability corresponds to increased therapeutic efficacy. Furthermore, advances in the field of nanoparticles hold great promise for developing curcumin-based complexes as effective therapeutic agents. Summarizing, suitable delivery methods for this polyphenol will ensure the possibility of using curcumin-derived formulations in clinical practice as preventive and disease-modifying therapeutics. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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20 pages, 4470 KiB

Open AccessArticle

Manufacturing and Examination of Vaginal Drug Delivery System by FDM 3D Printing

by Petra Arany, Ildikó Papp, Marianna Zichar, Géza Regdon, Jr., Mónika Béres, Melinda Szalóki, Renátó Kovács, Pálma Fehér, Zoltán Ujhelyi, Miklós Vecsernyés and Ildikó Bácskay

Pharmaceutics 2021, 13(10), 1714; https://doi.org/10.3390/pharmaceutics13101714 - 16 Oct 2021

Cited by 30 | Viewed by 5390

Abstract

Vaginal drug delivery systems can provide a long-term and constant liberation of the active pharmaceutical ingredient even for months. For our experiment, FDM 3D printing was used to manufacture the vaginal ring samples from thermoplastic polyurethane filament, which enables fast manufacturing of complex, [...] Read more.

Vaginal drug delivery systems can provide a long-term and constant liberation of the active pharmaceutical ingredient even for months. For our experiment, FDM 3D printing was used to manufacture the vaginal ring samples from thermoplastic polyurethane filament, which enables fast manufacturing of complex, personalized medications. 3D printing can be an excellent alternative instead of industrial manufacturing, which is complicated and time-consuming. In our work, the 3D printed vaginal rings were filled manually with jellified metronidazole or chloramphenicol for the treatment of bacterial vaginosis. The need for manual filling was certified by the thermogravimetric and heatflow assay results. The manufactured samples were analyzed by an Erweka USP type II Dissolution Apparatus, and the dissolution profile can be distinguished based on the applied jellifying agents and the API’s. All samples were considered non-similar based on the pairwise comparison. The biocompatibility properties were determined by prolonged MTT assay on HeLa cells, and the polymer could be considered non-toxic. Based on the microbiological assay on E. coli metronidazole and chitosan containing samples had bactericidal effects while just metronidazole or just chitosan containing samples bacteriostatic effect. None of these samples showed a fungistatic or fungicide effect against C. albicans. Based on our results, we successfully manufactured 3D printed vaginal rings filled with jellified metronidazole. Full article

(This article belongs to the Collection Advanced Drug Delivery Systems and Technology in Hungary)

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16 pages, 3954 KiB

Open AccessArticle

Polyelectrolytes Formulated with Primary Unconjugated Bile Acid Optimised Pharmacology of Bio-Engineered Implant

by Armin Mooranian, Corina Mihaela Ionescu, Susbin Raj Wagle, Bozica Kovacevic, Daniel Walker, Melissa Jones, Jacqueline Chester, Thomas Foster, Edan Johnston, Sanja Kojic, Goran Stojanovic, Momir Mikov and Hani Al-Salami

Pharmaceutics 2021, 13(10), 1713; https://doi.org/10.3390/pharmaceutics13101713 - 16 Oct 2021

Cited by 5 | Viewed by 2336

Abstract

Introduction. Several studies have shown that different biomaterials and hydrogels comprising various bile acids such as chenodeoxycholic acid (CDCA), as well as excipients such as poly-(styrene)-sulphonate (PSS) and poly-(allyl)-amine (PAA), exhibited positive biological effects on encapsulated viable pancreatic β-cells. Hence, this study aimed [...] Read more.

Introduction. Several studies have shown that different biomaterials and hydrogels comprising various bile acids such as chenodeoxycholic acid (CDCA), as well as excipients such as poly-(styrene)-sulphonate (PSS) and poly-(allyl)-amine (PAA), exhibited positive biological effects on encapsulated viable pancreatic β-cells. Hence, this study aimed to investigate whether incorporating CDCA with PSS and PAA will optimise the functions of encapsulated pancreatic islets post-transplantation in Type 1 diabetes (T1D). Methods. Mice were made T1D, divided into two equal groups, and transplanted with encapsulated islets in PSS-PAA (control) or with CDCA-PSS-PAA (treatment) microcapsules. The effects of transplanted microcapsules on blood glucose, inflammation and the bile acid profile were measured post-transplantation. Results and Conclusion. Compared with control, the treatment group showed better survival rate, improved glycaemic control, and lower inflammatory profile, illustrated by ↓ interleukin 1-β, interleukin-6, interleukin-12, and tumour-necrosis factor-α, and ↓ levels of the bile acid, as well as lithocholic acid in the plasma, liver, large intestine and faeces. The results suggest that CDCA incorporation with PSS-PAA microcapsules exerted beneficial effects on encapsulated islets and resulted in enhanced diabetes treatment, post-transplantation, at the local and systemic levels. Full article

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

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14 pages, 5719 KiB

Open AccessArticle

The Impact of Bilayer Rigidity on the Release from Magnetoliposomes Vesicles Controlled by PEMFs

by Jordan Trilli, Laura Caramazza, Patrizia Paolicelli, Maria Antonietta Casadei, Micaela Liberti, Francesca Apollonio and Stefania Petralito

Pharmaceutics 2021, 13(10), 1712; https://doi.org/10.3390/pharmaceutics13101712 - 16 Oct 2021

Cited by 8 | Viewed by 2671

Abstract

Stimuli-sensitive nanocarriers have recently been developed as a powerful tool in biomedical applications such as drug delivery, detection, and gene transfer techniques. Among the external triggers investigated, low intensity magnetic fields represent a non-invasive way to remotely control the release of compounds from [...] Read more.

Stimuli-sensitive nanocarriers have recently been developed as a powerful tool in biomedical applications such as drug delivery, detection, and gene transfer techniques. Among the external triggers investigated, low intensity magnetic fields represent a non-invasive way to remotely control the release of compounds from a magneto-sensitive carrier. Magnetoliposomes (MLs), i.e., liposomes entrapping magnetic nanoparticles (MNPs), are studied due to their capacity to transport hydrophobic and hydrophilic agents, their easy production, and due to the ability of MNPs to respond to a magnetic actuation determining the triggered release of the encapsulated compounds. Here we investigated the design and optimization of the MLs to obtain an efficient on-demand release of the transported compounds, due to the magneto-mechanical actuation induced by applying low-intensity pulsed electromagnetic fields (PEMFs). In particular we studied the effect of the bilayer packing on the ability of MLs, with oleic acid-coated MNPs encapsulated in the bilayer, to respond to PEMFs application. Three kinds of MLs are produced with an increasing rigidity of the bilayer, defined as Liquid Disorder, Liquid Order, and Gel MLs and the delivery of a hydrophilic dye (as a model drug) is investigated. Results demonstrate the efficacy of the magnetic trigger on high-ordered bilayers, which are unable to dampen the perturbation produced by MNPs motion. Full article

(This article belongs to the Special Issue Nanomedicine as a Tool to Improve the Local Delivery of Active Molecules)

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19 pages, 4791 KiB

Open AccessArticle

Curated Database and Preliminary AutoML QSAR Model for 5-HT1A Receptor

by Natalia Czub, Adam Pacławski, Jakub Szlęk and Aleksander Mendyk

Pharmaceutics 2021, 13(10), 1711; https://doi.org/10.3390/pharmaceutics13101711 - 16 Oct 2021

Cited by 8 | Viewed by 3111

Abstract

Introduction of a new drug to the market is a challenging and resource-consuming process. Predictive models developed with the use of artificial intelligence could be the solution to the growing need for an efficient tool which brings practical and knowledge benefits, but requires [...] Read more.

Introduction of a new drug to the market is a challenging and resource-consuming process. Predictive models developed with the use of artificial intelligence could be the solution to the growing need for an efficient tool which brings practical and knowledge benefits, but requires a large amount of high-quality data. The aim of our project was to develop quantitative structure–activity relationship (QSAR) model predicting serotonergic activity toward the 5-HT1A receptor on the basis of a created database. The dataset was obtained using ZINC and ChEMBL databases. It contained 9440 unique compounds, yielding the largest available database of 5-HT1A ligands with specified pKi value to date. Furthermore, the predictive model was developed using automated machine learning (AutoML) methods. According to the 10-fold cross-validation (10-CV) testing procedure, the root-mean-squared error (RMSE) was 0.5437, and the coefficient of determination (R²) was 0.74. Moreover, the Shapley Additive Explanations method (SHAP) was applied to assess a more in-depth understanding of the influence of variables on the model’s predictions. According to to the problem definition, the developed model can efficiently predict the affinity value for new molecules toward the 5-HT1A receptor on the basis of their structure encoded in the form of molecular descriptors. Usage of this model in screening processes can significantly improve the process of discovery of new drugs in the field of mental diseases and anticancer therapy. Full article

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17 pages, 5047 KiB

Open AccessArticle

Preformulation Studies and Bioavailability Enhancement of Curcumin with a ‘Two in One’ PEG-β-Cyclodextrin Polymer

by Ádám Haimhoffer, Eleftheria Dossi, Monika Béresová, Ildikó Bácskay, Judit Váradi, Ashfaq Afsar, Ágnes Rusznyák, Gábor Vasvári and Ferenc Fenyvesi

Pharmaceutics 2021, 13(10), 1710; https://doi.org/10.3390/pharmaceutics13101710 - 16 Oct 2021

Cited by 4 | Viewed by 3579

Abstract

Drug delivery systems are used to improve the biopharmaceutical properties of curcumin. Our aim was to investigate the effect of a water-soluble ‘two in one’ polymer containing covalently bonded PEG and βCD moieties (βCPCD) on the solubility and bioavailability of curcumin and compare [...] Read more.

Drug delivery systems are used to improve the biopharmaceutical properties of curcumin. Our aim was to investigate the effect of a water-soluble ‘two in one’ polymer containing covalently bonded PEG and βCD moieties (βCPCD) on the solubility and bioavailability of curcumin and compare it to a polymeric β-cyclodextrin (βCDP) cross-linked with epichlorohydrin. Phase-solubility and dynamic light scattering (DLS) experiments showed that the solubility of curcumin increased significantly in 10 m/m % βCPCD and βCDP solutions, but βCPCD–curcumin particles had higher hydrodynamic volume. The formation of the βCPCD–curcumin complex in solution and sedimented phase was confirmed by NMR spectroscopy. Biocompatibility and permeability experiments were performed on Caco-2 cells. Polymers did not show cytotoxicity up to 10 m/m % and βCPCD significantly increased the permeability of curcumin. DLS measurements revealed that among the interaction of polymers with mucin, βCPCD formed bigger aggregates compared to βCDP. Curcumin complexes were lyophilized into capsules and structurally characterized by micro-CT spectroscopy. Drug release was tested in a pH 1.2 medium. Lyophilized complexes had a solid porous matrix and both βCPCD and βCDP showed rapid drug release. βCPCD provides an opportunity to create a swellable, mucoadhesive matrix system for oral drug delivery. Full article

(This article belongs to the Special Issue Pharmaceutical and Biomedical Applications of Cyclodextrins and Derivatives)

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Pharmaceutics, Volume 13, Issue 10 (October 2021) – 212 articles

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