Next Issue
Previous Issue

Table of Contents

Pharmaceutics, Volume 11, Issue 7 (July 2019)

  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
Cover Story (view full-size image) A wide variety of polymeric nanocarriers with distinct architectures, sizes, and surface properties [...] Read more.
View options order results:
result details:
Displaying articles 1-63
Export citation of selected articles as:
Open AccessArticle
Effective Therapeutic Delivery and Bioavailability Enhancement of Pioglitazone Using Drug in Adhesive Transdermal Patch
Pharmaceutics 2019, 11(7), 359; https://doi.org/10.3390/pharmaceutics11070359
Received: 28 June 2019 / Revised: 18 July 2019 / Accepted: 18 July 2019 / Published: 23 July 2019
Viewed by 679 | PDF Full-text (1847 KB) | HTML Full-text | XML Full-text
Abstract
The administration of pioglitazone as an oral therapy is restricted due to various challenges. The aim of the current investigation was to evaluate the suitability of pioglitazone in adhesive transdermal patch as an alternative delivery system, in order to improve therapeutic delivery. Drug [...] Read more.
The administration of pioglitazone as an oral therapy is restricted due to various challenges. The aim of the current investigation was to evaluate the suitability of pioglitazone in adhesive transdermal patch as an alternative delivery system, in order to improve therapeutic delivery. Drug in adhesive pioglitazone (2% w/w) transdermal patch were optimized for drug release, suitable adhesive, and skin permeation enhancer. The selected patch was examined for drug-loading capacity and the patch with greater pioglitazone (6% w/w) was evaluated in rat models. The release of pioglitazone was influenced by the tested adhesive and was shown to be significantly higher (p < 0.001) with patch, prepared using Duro-Tak 87-2516. The ex vivo permeation results substantiate the release data as a greater transdermal flux (15.67 ± 2.35 µg/cm2/h) was demonstrated in patch fabricated with Duro-Tak 87-2516. Skin penetration enhancers promoted the ex vivo transdermal delivery of pioglitazone, and was ~2 folds (p < 0.0001) higher with propylene glycol, as compared to patch without enhancer. The maximum solubility of pioglitazone in Duro-Tak 87-2516 was found to be 6% w/w. Increasing the drug content in patch enhanced the transdermal flux and was highest when the pioglitazone level was 6% w/w (72.68 ± 5.76 µg/cm2/h). In vivo pharmacokinetic data demonstrate that the AUC0-α in transdermal application (13,506.51 ± 1649.92 ng·h/mL) was ~2 times higher (p < 0.0001) as compared to oral dosage form. In conclusion, the promising results observed here signifies that developed patch could be a viable alternative for oral therapy of pioglitazone. Full article
Figures

Graphical abstract

Open AccessArticle
Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer
Pharmaceutics 2019, 11(7), 358; https://doi.org/10.3390/pharmaceutics11070358
Received: 15 June 2019 / Revised: 16 July 2019 / Accepted: 20 July 2019 / Published: 23 July 2019
Viewed by 797 | PDF Full-text (4962 KB) | HTML Full-text | XML Full-text
Abstract
Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. [...] Read more.
Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)8 (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [125I]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [125I]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [125I]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%–35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [125I]I-BO530 is a promising agent for theranostics application in prostate cancer. Full article
(This article belongs to the Special Issue Targeted Radionuclide Tumor Therapy)
Figures

Graphical abstract

Open AccessArticle
Vitamin E-Loaded PLA- and PLGA-Based Core-Shell Nanoparticles: Synthesis, Structure Optimization and Controlled Drug Release
Pharmaceutics 2019, 11(7), 357; https://doi.org/10.3390/pharmaceutics11070357
Received: 27 June 2019 / Revised: 12 July 2019 / Accepted: 16 July 2019 / Published: 22 July 2019
Viewed by 513 | PDF Full-text (3525 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The (±)-α-Tocopherol (TP) with vitamin E activity has been encapsulated into biocompatible poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA) carriers, which results in the formation of well-defined nanosized (d ~200–220 nm) core-shell structured particles (NPs) with 15–19% of drug loading (DL%). The [...] Read more.
The (±)-α-Tocopherol (TP) with vitamin E activity has been encapsulated into biocompatible poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA) carriers, which results in the formation of well-defined nanosized (d ~200–220 nm) core-shell structured particles (NPs) with 15–19% of drug loading (DL%). The optimal ratios of the polymer carriers, the TP active drug as well as the applied Pluronic F127 (PLUR) non-ionic stabilizing surfactant, have been determined to obtain NPs with a TP core and a polymer shell with high encapsulation efficiency (EE%) (69%). The size and the structure of the prepared core-shell NPs as well as the interaction of the carriers and the PLUR with the TP molecules have been determined by transmission electron microscopy (TEM), dynamic light scattering (DLS), infrared spectroscopy (FT-IR) and turbidity studies, respectively. Moreover, the dissolution of the TP from the polymer NPs has been investigated by spectrophotometric measurements. It was clearly confirmed that increase in the EE% from ca. 70% (PLA/TP) to ca. 88% (PLGA65/TP) results in the controlled release of the hydrophobic TP molecules (7 h, PLA/TP: 34%; PLGA75/TP: 25%; PLGA65/TP: 18%). By replacing the PLA carrier to PLGA, ca. 15% more active substance can be encapsulated in the core (PLA/TP: 65%; PLGA65/TP: 80%). Full article
(This article belongs to the Special Issue PLGA Based Drug Carrier and Pharmaceutical Applications)
Figures

Graphical abstract

Open AccessArticle
Preparation and Characterization of Oxidized Inulin Hydrogel for Controlled Drug Delivery
Pharmaceutics 2019, 11(7), 356; https://doi.org/10.3390/pharmaceutics11070356
Received: 21 June 2019 / Revised: 15 July 2019 / Accepted: 17 July 2019 / Published: 22 July 2019
Viewed by 394 | PDF Full-text (3678 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. [...] Read more.
Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. The physicochemical properties of the obtained hydrogels were further characterized using different techniques, such as swelling experiments, in vitro drug release, degradation, and biocompatibility tests. The crosslinking was confirmed with Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC). In vitro releases of 5-fluorouracil (5FU) from the various inulin hydrogels was enhanced in acidic conditions (pH 5) compared with physiological pH (pH 7.4). In addition, blank gels did not show any appreciable cytotoxicity, whereas 5FU-loaded hydrogels demonstrated efficacy against HCT116 colon cancer cells, which further confirms the potential use of these delivery platforms for direct targeting of 5-FU to the colon. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
Figures

Graphical abstract

Open AccessArticle
Identification of Catalposide Metabolites in Human Liver and Intestinal Preparations and Characterization of the Relevant Sulfotransferase, UDP-glucuronosyltransferase, and Carboxylesterase Enzymes
Pharmaceutics 2019, 11(7), 355; https://doi.org/10.3390/pharmaceutics11070355
Received: 24 June 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published: 22 July 2019
Viewed by 446 | PDF Full-text (3422 KB) | HTML Full-text | XML Full-text
Abstract
Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), [...] Read more.
Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), 4-hydroxybenzoic acid (M2), 4-hydroxybenzoic acid glucuronide (M3), and catalposide glucuronide (M4) by human hepatocytes, liver S9 fractions, and intestinal microsomes. M1 formation from catalposide was catalyzed by sulfotransferases (SULTs) 1C4, SULT1A1*1, SULT1A1*2, and SULT1E1. Catalposide glucuronidation to M4 was catalyzed by gastrointestine-specific UDP-glucuronosyltransferases (UGTs) 1A8 and UGT1A10; M4 was not detected after incubation of catalposide with human liver preparations. Hydrolysis of catalposide to M2 was catalyzed by carboxylesterases (CESs) 1 and 2, and M2 was further metabolized to M3 by UGT1A6 and UGT1A9 enzymes. Catalposide was also metabolized in extrahepatic tissues; genetic polymorphisms of the carboxylesterase (CES), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for catalposide metabolism may cause inter-individual variability in terms of catalposide pharmacokinetics. Full article
(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics)
Figures

Graphical abstract

Open AccessArticle
Effect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats
Pharmaceutics 2019, 11(7), 354; https://doi.org/10.3390/pharmaceutics11070354
Received: 26 June 2019 / Revised: 15 July 2019 / Accepted: 17 July 2019 / Published: 20 July 2019
Viewed by 452 | PDF Full-text (1021 KB) | HTML Full-text | XML Full-text
Abstract
Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 [...] Read more.
Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy. Full article
(This article belongs to the Special Issue Drug–Drug Interactions)
Figures

Graphical abstract

Open AccessArticle
Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis
Pharmaceutics 2019, 11(7), 353; https://doi.org/10.3390/pharmaceutics11070353
Received: 30 June 2019 / Revised: 15 July 2019 / Accepted: 18 July 2019 / Published: 20 July 2019
Viewed by 475 | PDF Full-text (1756 KB) | HTML Full-text | XML Full-text
Abstract
Leishmaniasis is a neglected tropical disease affecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are [...] Read more.
Leishmaniasis is a neglected tropical disease affecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are not well tolerated due to severe adverse effects, need for parenteral administration and patient hospitalisation, and long duration of expensive treatments. These treatment realities justify the search for new effective drugs, repurposing existing licensed drugs towards safer and non-invasive cost-effective medicines for VL. In this work, we provide proof of concept studies of butenafine and butenafine self-nanoemulsifying drug delivery systems (B-SNEDDS) against Leishmania infantum. Liquid B-SNEDDS were optimised using design of experiments, and then were spray-dried onto porous colloidal silica carriers to produce solid-B-SNEDDS with enhanced flow properties and drug stability. Optimal liquid B-SNEDDS consisted of Butenafine:Capryol 90:Peceol:Labrasol (3:49.5:24.2:23.3 w/w), which were then sprayed-dried with Aerosil 200 with a final 1:2 (Aerosil:liquid B-SNEDDS w/w) ratio. Spray-dried particles exhibited near-maximal drug loading, while maintaining excellent powder flow properties (angle of repose <10°) and sustained release in acidic gastrointestinal media. Solid-B-SNEDDS demonstrated greater selectivity index against promastigotes and L. infantum-infected amastigotes than butenafine alone. Developed oral solid nanomedicines enable the non-invasive and safe administration of butenafine as a cost-effective and readily scalable repurposed medicine for VL. Full article
(This article belongs to the Special Issue Antifungal and Antiparasitic Drug Delivery)
Figures

Graphical abstract

Open AccessReview
Inhaled Antibiotics for Mycobacterial Lung Disease
Pharmaceutics 2019, 11(7), 352; https://doi.org/10.3390/pharmaceutics11070352
Received: 27 May 2019 / Revised: 9 July 2019 / Accepted: 15 July 2019 / Published: 19 July 2019
Viewed by 521 | PDF Full-text (346 KB) | HTML Full-text | XML Full-text
Abstract
Mycobacterial lung diseases are an increasing global health concern. Tuberculosis and nontuberculous mycobacteria differ in disease severity, epidemiology, and treatment strategies, but there are also a number of similarities. Pathophysiology and disease progression appear to be relatively similar between these two clinical diagnoses, [...] Read more.
Mycobacterial lung diseases are an increasing global health concern. Tuberculosis and nontuberculous mycobacteria differ in disease severity, epidemiology, and treatment strategies, but there are also a number of similarities. Pathophysiology and disease progression appear to be relatively similar between these two clinical diagnoses, and as a result these difficult to treat pulmonary infections often require similarly extensive treatment durations of multiple systemic drugs. In an effort to improve treatment outcomes for all mycobacterial lung diseases, a significant body of research has investigated the use of inhaled antibiotics. This review discusses previous research into inhaled development programs, as well as ongoing research of inhaled therapies for both nontuberculous mycobacterial lung disease, and tuberculosis. Due to the similarities between the causative agents, this review will also discuss the potential cross-fertilization of development programs between these similar-yet-different diseases. Finally, we will discuss some of the perceived difficulties in developing a clinically utilized inhaled antibiotic for mycobacterial diseases, and potential arguments in favor of the approach. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
Figures

Graphical abstract

Open AccessReview
Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled In Silico-Experimental Studies. Part I: Covalent siRNA Nanocarriers
Pharmaceutics 2019, 11(7), 351; https://doi.org/10.3390/pharmaceutics11070351
Received: 21 June 2019 / Revised: 10 July 2019 / Accepted: 16 July 2019 / Published: 18 July 2019
Cited by 1 | Viewed by 433 | PDF Full-text (6961 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the [...] Read more.
Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the clinical translation of RNA interference (RNAi) requires safe and efficient vectors for siRNA delivery into cells. Dendrimers are attractive nanovectors to serve this purpose, as they present a unique, well-defined architecture and exhibit cooperative and multivalent effects at the nanoscale. This short review presents a brief introduction to RNAi-based therapeutics, the advantages offered by dendrimers as siRNA nanocarriers, and the remarkable results we achieved with bio-inspired, structurally flexible covalent dendrimers. In the companion paper, we next report our recent efforts in designing, characterizing and testing a series of self-assembled amphiphilic dendrimers and their related structural alterations to achieve unprecedented efficient siRNA delivery both in vitro and in vivo. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
Figures

Graphical abstract

Open AccessArticle
Optimization of Aceclofenac Proniosomes by Using Different Carriers, Part 1: Development and Characterization
Pharmaceutics 2019, 11(7), 350; https://doi.org/10.3390/pharmaceutics11070350
Received: 12 June 2019 / Revised: 9 July 2019 / Accepted: 11 July 2019 / Published: 18 July 2019
Viewed by 386 | PDF Full-text (8553 KB) | HTML Full-text | XML Full-text
Abstract
In the contemporary medical model world, the proniosomal system has been serving as a new drug delivery system that is considered to significantly enhance the bioavailability of drugs with low water solubility. The application of this system can improve the bioavailability of aceclofenac [...] Read more.
In the contemporary medical model world, the proniosomal system has been serving as a new drug delivery system that is considered to significantly enhance the bioavailability of drugs with low water solubility. The application of this system can improve the bioavailability of aceclofenac that is used for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. The present study is intended to develop an optimized proniosomal aceclofenac formula by the use of different carriers. Aceclofenac proniosomes have been prepared by slurry method, and different carriers such as maltodextrin, mannitol, and glucose were tried. Prepared proniosomes characterized by differential scanning calorimetry (DSC) analysis and Fourier transform infrared (FTIR) analysis revealed the compatibility of the drug chosen with the ingredient added, powder X-ray diffractometry (XRD) confirmed the amorphous phase of the prepared proniosomes, and finally, the surfactant layer was observed by scanning electron microscopy (SEM). Aceclofenac physical state transformations were confirmed with all formulas but maltodextrin proniosomes exhibited solubility more than other formulations. HPLC method has been used to analyze the niosomes derived from proniosomes in terms of their entrapment capability and drug content. The obtained results revealed that aceclofenac proniosomes can be successfully prepared by using different carriers. Full article
Figures

Figure 1

Open AccessCommunication
Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach
Pharmaceutics 2019, 11(7), 349; https://doi.org/10.3390/pharmaceutics11070349
Received: 18 June 2019 / Revised: 14 July 2019 / Accepted: 16 July 2019 / Published: 18 July 2019
Viewed by 474 | PDF Full-text (1388 KB) | HTML Full-text | XML Full-text
Abstract
Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug [...] Read more.
Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential. Full article
(This article belongs to the Special Issue Drug Delivery to the Brain)
Figures

Figure 1

Open AccessArticle
Comparative Radioimmunotherapy of Experimental Melanoma with Novel Humanized Antibody to Melanin Labeled with 213Bismuth and 177Lutetium
Pharmaceutics 2019, 11(7), 348; https://doi.org/10.3390/pharmaceutics11070348
Received: 22 June 2019 / Revised: 11 July 2019 / Accepted: 11 July 2019 / Published: 18 July 2019
Viewed by 624 | PDF Full-text (1788 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a [...] Read more.
Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a beta emitter, 177Lu, and an alpha-emitter, 213Bi, as well as biodistribution, microSPECT/CT imaging, and mouse and human dosimetry calculations. microSPECT/CT imaging showed that a humanized antibody that targets “free” melanin in the tumor microenvironment had high tumor uptake in B16F10 murine melanoma in C57Bl/6 mice, with little to no uptake in naturally melanized tissues. Extrapolation of the mouse dosimetry data to an adult human demonstrated that doses delivered to major organs and the whole body by 177Lu-h8C3 would be approximately two times higher than those delivered by 213Bi-h8C3, while the doses to the tumor would be almost similar. RIT results indicated that 213Bi-h8C3 was more effective in slowing down the tumor growth than 177Lu-h8C3, while both radiolabeled antibodies did not produce significant hematologic or systemic side effects. We concluded that h8C3 antibody labeled with 213Bi is a promising reagent for translation into a clinical trial in patients with metastatic melanoma. Full article
(This article belongs to the Special Issue Targeted Radionuclide Tumor Therapy)
Figures

Graphical abstract

Open AccessReview
Drug Delivery Systems for Vitamin D Supplementation and Therapy
Pharmaceutics 2019, 11(7), 347; https://doi.org/10.3390/pharmaceutics11070347
Received: 13 June 2019 / Revised: 11 July 2019 / Accepted: 16 July 2019 / Published: 18 July 2019
Viewed by 583 | PDF Full-text (1483 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin D (VD) is a fat-soluble prohormone well known for its role in regulating calcium and phosphate metabolism. It has been clinically used for many years to prevent rickets in children, osteomalacia, and osteoporosis in adults. VD insufficiency is a common medical condition, [...] Read more.
Vitamin D (VD) is a fat-soluble prohormone well known for its role in regulating calcium and phosphate metabolism. It has been clinically used for many years to prevent rickets in children, osteomalacia, and osteoporosis in adults. VD insufficiency is a common medical condition, and many supplements are available in the market in order to increase serum 25-hydroxy VD levels to recommended amounts. Over the course of the last decades, it has become increasingly clear that calcitriol, an active form of VD, regulates multiple cellular processes with effects on normal and malignant cell growth and differentiation, and on the immune and cardiovascular function. Increasing evidence supports the role of the VD system in cancer prevention and therapy. Due to many pleiotropic and beneficial effects in extra-skeletal disorders, VD has gained potential and become an interesting active for encapsulation into drug delivery systems. The purpose of this review is to present the diversity of drug delivery systems that have been reported for VD or VD derivatives in an orderly manner across the following categories: Oral administration, application on the skin, cancer prevention/therapy, and other diseases or routes of administration. Full article
Figures

Graphical abstract

Open AccessArticle
Enhanced Intradermal Delivery of Nanosuspensions of Antifilariasis Drugs Using Dissolving Microneedles: A Proof of Concept Study
Pharmaceutics 2019, 11(7), 346; https://doi.org/10.3390/pharmaceutics11070346
Received: 25 June 2019 / Revised: 10 July 2019 / Accepted: 13 July 2019 / Published: 17 July 2019
Viewed by 558 | PDF Full-text (6021 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Conventional oral administration of antifilariasis drugs results in nonspecific targeting of the drugs and the intradermal delivery of nanoparticles with sizes of <100 nm could be used to improve lymphatic uptake. This study investigated the combination of nanosuspension and dissolving microneedles (MN-NS) as [...] Read more.
Conventional oral administration of antifilariasis drugs results in nonspecific targeting of the drugs and the intradermal delivery of nanoparticles with sizes of <100 nm could be used to improve lymphatic uptake. This study investigated the combination of nanosuspension and dissolving microneedles (MN-NS) as an alternative intradermal delivery approach for the delivery of antifilariasis drugs, namely doxycycline, albendazole, and ivermectin. NS were fabricated and optimized using a bottom-up technique. The NS were then incorporated into the MN arrays. The optimized NS were <100 nm in diameter. Furthermore, MN-NS had suitable mechanical strength and insertion capabilities. The dermatokinetic study revealed that the delivery of drugs into the dermis of excised neonatal porcine skin by MNs was significantly higher than that from a needle-free patch, with 29.29 ± 4.65%, 31.54 ± 5.35%, and 34.54 ± 4.98% of doxycycline, albendazole sulfoxide, and ivermectin retained in the dermis after 24 h. The results presented here serve as proof of concept for the significant enhancement of drug retention times in the dermis, following their formulation into NS and delivery via MN. Leading on from these studies, future work must investigate in vivo lymphatic pharmacokinetic profiling of drugs formulated into NS, in a suitable animal model. Full article
(This article belongs to the Special Issue Drug Delivery Systems Using Various Microneedle Technologies)
Figures

Graphical abstract

Open AccessArticle
Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis
Pharmaceutics 2019, 11(7), 345; https://doi.org/10.3390/pharmaceutics11070345
Received: 31 May 2019 / Revised: 10 July 2019 / Accepted: 11 July 2019 / Published: 17 July 2019
Viewed by 399 | PDF Full-text (2881 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol [...] Read more.
‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol administration would produce phospholipidosis-induced FAM that could be characterized and used in comparative inhalation toxicology. Han-Wistar rats were given amiodarone via (1) intranasal administration (6.25 mg/kg) on two days, (2) aerosol administration (3 mg/kg) on two days, (3) aerosol administration (10 mg/kg) followed by three days of 30 mg/kg or (4) oral administration (100 mg/kg) for 7 days. Alveolar macrophages in bronchoalveolar lavage were evaluated by differential cell counting and high content fluorescence imaging. Histopathology and mass-spectrometry imaging (MSI) were performed on lung slices. The higher dose aerosolised amiodarone caused transient pulmonary inflammation (p < 0.05), but only oral amiodarone resulted in FAM (p < 0.001). MSI of the lungs of orally treated rats revealed a homogenous distribution of amiodarone and a putative phospholipidosis marker, di-22:6 bis-monoacylglycerol, throughout lung tissue whereas aerosol administration resulted in localization of both compounds around the airway lumen. Thus, unlike oral administration, aerosolised amiodarone failed to produce the expected FAM responses. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
Figures

Graphical abstract

Open AccessArticle
In Vitro–In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of Its Metabolite
Pharmaceutics 2019, 11(7), 344; https://doi.org/10.3390/pharmaceutics11070344
Received: 5 June 2019 / Revised: 2 July 2019 / Accepted: 7 July 2019 / Published: 16 July 2019
Viewed by 440 | PDF Full-text (3062 KB) | HTML Full-text | XML Full-text
Abstract
In this study a novel type of in vitro–in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug’s metabolite after the oral administration of the parent drug. The pharmacokinetic [...] Read more.
In this study a novel type of in vitro–in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug’s metabolite after the oral administration of the parent drug. The pharmacokinetic data for the parent drug diltiazem (DTZ) and its desacetyl diltiazem metabolite (DTZM) were obtained from an in vivo study performed in 19 healthy volunteers. The pharmacokinetics of the parent drug and its metabolite followed a pseudomono-compartmental model and deconvolution of the DTZ or DTZM plasma concentration profiles was performed with a Wagner–Nelson-type equation. The calculated in vivo absorption fractions were correlated with the in vitro DTZ dissolution data obtained with USP 2 apparatus. A linear IVIVC was obtained for both DTZ and DTZM, with a better correlation observed for the case of the metabolite. This type of correlation of the in vitro data of the parent compound with the in vivo data of the metabolite could be useful for the development of drugs with active metabolites and prodrugs. Full article
Figures

Graphical abstract

Open AccessArticle
Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents
Pharmaceutics 2019, 11(7), 343; https://doi.org/10.3390/pharmaceutics11070343
Received: 14 June 2019 / Revised: 11 July 2019 / Accepted: 12 July 2019 / Published: 16 July 2019
Viewed by 551 | PDF Full-text (6252 KB) | HTML Full-text | XML Full-text
Abstract
One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory [...] Read more.
One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory anticancer nanomedicine. In this study, we focused on one vascular mediator involved in the EPR effect, carbon monoxide (CO), and utilized two CO generating agents, one is an extrinsic CO donor (SMA/CORM2 micelle) and another is an inducer of endogenous CO generation via heme oxygenase-1 (HO-1) induction that is carried out using pegylated hemin. Both agents generated CO selectively in solid tumors, which resulted in an enhanced EPR effect and a two- to three-folds increased tumor accumulation of nanodrugs. An increase in drug accumulation in the normal tissue did not occur with the treatment of CO generators. In vivo imaging also clearly indicated a more intensified fluorescence of macromolecular nanoprobe in solid tumors when combined with these CO generators. Consequently, the combination of CO generators with anticancer nanodrugs resulted in an increased anticancer effect in the different transplanted solid tumor models. These findings strongly warrant the potential application of these CO generators as EPR enhancers in order to enhance tumor detection and therapy using nanodrugs. Full article
(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)
Figures

Graphical abstract

Open AccessArticle
Influenza Virus-Like Particles Presenting both Toxoplasma gondii ROP4 and ROP13 Enhance Protection against T. gondii Infection
Pharmaceutics 2019, 11(7), 342; https://doi.org/10.3390/pharmaceutics11070342
Received: 25 June 2019 / Revised: 10 July 2019 / Accepted: 15 July 2019 / Published: 16 July 2019
Viewed by 438 | PDF Full-text (4018 KB) | HTML Full-text | XML Full-text
Abstract
Rhoptry organelle proteins (ROPs) secreted by Toxoplasma gondii (T. gondii) play a critical role during parasite invasion into host cells. In this study, virus-like particles (VLPs) vaccines containing ROP4 and/or ROP13 together with influenza M1 were generated. ROP4+ROP13 VLPs were produced [...] Read more.
Rhoptry organelle proteins (ROPs) secreted by Toxoplasma gondii (T. gondii) play a critical role during parasite invasion into host cells. In this study, virus-like particles (VLPs) vaccines containing ROP4 and/or ROP13 together with influenza M1 were generated. ROP4+ROP13 VLPs were produced by combining ROP4 VLPs with ROP13 VLPs, and ROP(4 + 13) VLPs by co-infecting insect cells with recombinant baculovirus expressing ROP4 or ROP13. Mice intranasally immunized with ROP(4 + 13) VLPs showed significantly higher levels of IgG, IgG1, IgG2a and IgA antibody responses in sera compared to ROP4+ROP13VLPs. Upon challenge infection by oral route, mice immunized with ROP(4 + 13) VLPs elicited higher levels of IgG and IgA antibody responses in fecal, urine, intestine and vaginal samples as well as CD4+ T, CD8+ T cells, and germinal center B cell responses compared to other type of vaccines, ROP4 VLPs, ROP13 VLPs, and ROP4+ROP13 VLPs. ROP(4 + 13) VLPs vaccination showed a significant decrease in the size and number of cyst in the brain and less body weight loss compared to combination ROP4+ROP13 VLPs upon challenge infection with T. gondii ME49. These results indicated that the ROP(4 + 13) VLPs vaccination provided enhanced protection against T. gondii infection compared to ROP4+ROP13 VLPs, providing an important insight into vaccine design strategy for T. gondii VLPs vaccines. Full article
(This article belongs to the Special Issue Nanoparticles to Improve the Efficacy of Vaccines)
Figures

Figure 1

Open AccessArticle
An ImmunoPEGliposome for Targeted Antimalarial Combination Therapy at the Nanoscale
Pharmaceutics 2019, 11(7), 341; https://doi.org/10.3390/pharmaceutics11070341
Received: 3 June 2019 / Revised: 27 June 2019 / Accepted: 11 July 2019 / Published: 16 July 2019
Viewed by 584 | PDF Full-text (18581 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Combination therapies, where two drugs acting through different mechanisms are administered simultaneously, are one of the most efficient approaches currently used to treat malaria infections. However, the different pharmacokinetic profiles often exhibited by the combined drugs tend to decrease treatment efficacy as the [...] Read more.
Combination therapies, where two drugs acting through different mechanisms are administered simultaneously, are one of the most efficient approaches currently used to treat malaria infections. However, the different pharmacokinetic profiles often exhibited by the combined drugs tend to decrease treatment efficacy as the compounds are usually eliminated from the circulation at different rates. To circumvent this obstacle, we have engineered an immunoliposomal nanovector encapsulating hydrophilic and lipophilic compounds in its lumen and lipid bilayer, respectively. The antimalarial domiphen bromide has been encapsulated in the liposome membrane with good efficiency, although its high IC50 of ca. 1 µM for living parasites complicates its use as immunoliposomal therapy due to erythrocyte agglutination. The conjugation of antibodies against glycophorin A targeted the nanocarriers to Plasmodium-infected red blood cells and to gametocytes, the sole malaria parasite stage responsible for the transmission from the human to the mosquito vector. The antimalarials pyronaridine and atovaquone, which block the development of gametocytes, have been co-encapsulated in glycophorin A-targeted immunoliposomes. The co-immunoliposomized drugs have activities significantly higher than their free forms when tested in in vitro Plasmodium falciparum cultures: Pyronaridine and atovaquone concentrations that, when encapsulated in immunoliposomes, resulted in a 50% inhibition of parasite growth had no effect on the viability of the pathogen when used as free drugs. Full article
(This article belongs to the Special Issue From Drug Carriers to Vaccine Adjuvants in Malaria)
Figures

Graphical abstract

Open AccessArticle
Supercritical Solvent Impregnation of Different Drugs in Mesoporous Nanostructured ZnO
Pharmaceutics 2019, 11(7), 340; https://doi.org/10.3390/pharmaceutics11070340
Received: 28 May 2019 / Revised: 3 July 2019 / Accepted: 12 July 2019 / Published: 15 July 2019
Viewed by 332 | PDF Full-text (3088 KB) | HTML Full-text | XML Full-text
Abstract
Supercritical solvent impregnation (SSI) is a green unconventional technique for preparing amorphous drug formulations. A mesoporous nanostructured ZnO (mesoNsZnO) carrier with 8-nm pores, spherical-nanoparticle morphology, and an SSA of 75 m2/g has been synthesized and, for the first time, subjected to [...] Read more.
Supercritical solvent impregnation (SSI) is a green unconventional technique for preparing amorphous drug formulations. A mesoporous nanostructured ZnO (mesoNsZnO) carrier with 8-nm pores, spherical-nanoparticle morphology, and an SSA of 75 m2/g has been synthesized and, for the first time, subjected to SSI with poorly water-soluble drugs. Ibuprofen (IBU), clotrimazole (CTZ), and hydrocortisone (HC) were selected as highly, moderately, and poorly CO2-soluble drugs. Powder X-ray diffraction, Fourier transform infrared spectroscopy, field emission scanning electron microscopy, nitrogen adsorption analysis, and ethanol extraction coupled with ultraviolet spectroscopy were employed to characterize the samples and quantify drug loading. Successful results were obtained with IBU and CTZ while HC loading was negligible, which could be related to different solubilities in CO2, drug size, and polarity. Successful SSI resulted in amorphous multilayer confinement of the drug. The mesoNsZnO-IBU system showed double drug loading than the mesoNsZnO-CTZ one, with a maximum uptake of 0.24 g/g. Variation of contact time during SSI of the mesoNsZnO-IBU system showed that drug loading triplicated between 3 and 8 h with an additional 30% increment between 8 h and 24 h. SSI did not affect the mesoNsZnO structure, and the presence of the adsorbed drug reduced the chemisorption of CO2 on the carrier surface. Full article
(This article belongs to the Special Issue Supercritical Fluid and Pharmaceutical Applications)
Figures

Graphical abstract

Open AccessEditorial
Transmucosal Absorption Enhancers in the Drug Delivery Field
Pharmaceutics 2019, 11(7), 339; https://doi.org/10.3390/pharmaceutics11070339
Received: 10 July 2019 / Accepted: 11 July 2019 / Published: 15 July 2019
Viewed by 501 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
Drug delivery systems that safely and consistently improve transport of poorly absorbed compounds across epithelial barriers are highly sought within the drug delivery field. The use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability [...] Read more.
Drug delivery systems that safely and consistently improve transport of poorly absorbed compounds across epithelial barriers are highly sought within the drug delivery field. The use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability via oral, nasal, buccal, ocular and pulmonary routes. To date, only a small number of permeation enhancers have progressed to clinical trials, and only one product that includes a permeation enhancer has reached the pharmaceutical market. This editorial is an introduction to the special issue entitled Transmucosal Absorption Enhancers in the Drug Delivery Field (https://www.mdpi.com/journal/pharmaceutics/special_issues/transmucosal_absorption_enhancers). The guest editors outline the scope of the issue, reflect on the results and the conclusions of the 19 articles published in the issue and provide an outlook on the use of permeation enhancers in the drug delivery field. Full article
(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)
Open AccessReview
Design of Soft Nanocarriers Combining Hyaluronic Acid with Another Functional Polymer for Cancer Therapy and Other Biomedical Applications
Pharmaceutics 2019, 11(7), 338; https://doi.org/10.3390/pharmaceutics11070338
Received: 2 June 2019 / Revised: 9 July 2019 / Accepted: 11 July 2019 / Published: 15 July 2019
Viewed by 522 | PDF Full-text (9872 KB) | HTML Full-text | XML Full-text
Abstract
The rapid advancement in medicine requires the search for new drugs, but also for new carrier systems for more efficient and targeted delivery of the bioactive molecules. Among the latter, polymeric nanocarriers have an increasingly growing potential for clinical applications due to their [...] Read more.
The rapid advancement in medicine requires the search for new drugs, but also for new carrier systems for more efficient and targeted delivery of the bioactive molecules. Among the latter, polymeric nanocarriers have an increasingly growing potential for clinical applications due to their unique physical and chemical characteristics. In this regard, nanosystems based on hyaluronic acid (HA), a polysaccharide which is ubiquitous in the body, have attracted particular interest because of the biocompatibility, biodegradability and nonimmunogenic property provided by HA. Furthermore, the fact that hyaluronic acid can be recognized by cell surface receptors in tumor cells, makes it an ideal candidate for the targeted delivery of anticancer drugs. In this review, we compile a comprehensive overview of the different types of soft nanocarriers based on HA conjugated or complexed with another polymer: micelles, nanoparticles, nanogels and polymersomes. Emphasis is made on the properties of the polymers used as well as the synthetic approaches for obtaining the different HA-polymer systems. Fabrication, characterization and potential biomedical applications of the nanocarriers will also be described. Full article
(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)
Figures

Figure 1

Open AccessReview
Ionic Polymethacrylate Based Delivery Systems: Effect of Carrier Topology and Drug Loading
Pharmaceutics 2019, 11(7), 337; https://doi.org/10.3390/pharmaceutics11070337
Received: 14 June 2019 / Revised: 5 July 2019 / Accepted: 12 July 2019 / Published: 15 July 2019
Viewed by 460 | PDF Full-text (4221 KB) | HTML Full-text | XML Full-text
Abstract
The presented drug delivery polymeric systems (DDS), i.e., conjugates and self-assemblies, based on grafted and star-shaped polymethacrylates have been studied for the last few years in our group. This minireview is focused on the relationship of polymer structure to drug conjugation/entrapment efficiency and [...] Read more.
The presented drug delivery polymeric systems (DDS), i.e., conjugates and self-assemblies, based on grafted and star-shaped polymethacrylates have been studied for the last few years in our group. This minireview is focused on the relationship of polymer structure to drug conjugation/entrapment efficiency and release capability. Both graft and linear polymers containing trimethylammonium groups showed the ability to release the pharmaceutical anions by ionic exchange, but in aqueous solution they were also self-assembled into nanoparticles with encapsulated nonionic drugs. Star-shaped polymers functionalized with ionizable amine/carboxylic groups were investigated for drug conjugation via ketimine/amide linkers. However, only the conjugates of polybases were water-soluble, giving opportunity for release studies, whereas the self-assembling polyacidic stars were encapsulated with the model drugs. Depending on the type of drug loading in the polymer matrix, their release rates were ordered as follows: Physical ≥ ionic > covalent. The studies indicated that the well-defined ionic polymethacrylates, including poly(ionic liquid)s, are advantageous for designing macromolecular carriers due to the variety of structural parameters, which are efficient for tuning of drug loading and release behavior in respect to the specific drug interactions. Full article
(This article belongs to the Special Issue Functional Polymers for Controlled Drug Release)
Figures

Figure 1

Open AccessArticle
Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)
Pharmaceutics 2019, 11(7), 336; https://doi.org/10.3390/pharmaceutics11070336
Received: 13 June 2019 / Revised: 3 July 2019 / Accepted: 9 July 2019 / Published: 15 July 2019
Viewed by 379 | PDF Full-text (3182 KB) | HTML Full-text | XML Full-text
Abstract
CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms [...] Read more.
CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were developed using mixed effect modeling analysis for exploration, and an interspecies model where allometric scaling was applied was developed based on the integrated animal PK data to predict the human PK profile. PD parameters and profile were predicted using in vitro potency and same-in-class drug information. The two-compartment first-order elimination model with Weibull-type absorption and bioavailability following the sigmoid Emax model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the Emax model of the same-in-class drug. The predicted PK/PD profile and parameters were used to simulate the human PK/PD profiles for different dose levels, and based on the simulation result, the appropriate efficacious dose was estimated as 25 mg in a 60 kg human. However, there were some discrepancies between the predicted and observed human PK/PD profiles compared to the phase I clinical data. The huge difference between the observed and predicted bioavailability suggests that there is a hurdle in predicting the absorption parameter only from animal PK data. Full article
Figures

Figure 1

Open AccessArticle
17-α Hydroxyprogesterone Nanoemulsifying Preconcentrate-Loaded Vaginal Tablet: A Novel Non-Invasive Approach for the Prevention of Preterm Birth
Pharmaceutics 2019, 11(7), 335; https://doi.org/10.3390/pharmaceutics11070335
Received: 9 May 2019 / Revised: 9 July 2019 / Accepted: 11 July 2019 / Published: 14 July 2019
Cited by 1 | Viewed by 487 | PDF Full-text (2326 KB) | HTML Full-text | XML Full-text
Abstract
Preterm birth (PTB) is a major cause of infant mortality in the United States and around the globe. Makena®—once-a-week intramuscular injection of 17-α Hydroxyprogesterone caproate (17P)—is the only FDA approved treatment for the prevention of PTB. Invasive delivery of 17P requires [...] Read more.
Preterm birth (PTB) is a major cause of infant mortality in the United States and around the globe. Makena®—once-a-week intramuscular injection of 17-α Hydroxyprogesterone caproate (17P)—is the only FDA approved treatment for the prevention of PTB. Invasive delivery of 17P requires hospitalization and expert personnel for injection. Vaginal delivery of 17P would be preferable, because of high patient compliance, reduced systemic exposure, fewer side effects, and no need for hospitalization. The objective of the present study was to prepare and evaluate a self-nanoemulsifying vaginal tablet of 17P. A solid self-nanoemulsifying preconcentrate (S-SNEDDS) of 17P and dimethylacetamide (DMA) was developed using medium chain triglycerides, a non- immunogenic surfactant, and co-processed excipient (PVA-F100). The tablet prepared was characterized for emulsification time, particle size, solid state properties, and drug release. The formulation showed >50% inhibition of TNF-α release from LPS-stimulated RAW 264.7 cells. Importantly, there were significant differences in rates of PTB and average time to delivery between control and vaginal 17P-treated groups in LPS-stimulated timed pregnant E15.5 mice. Considering the lacuna of therapeutic approaches in this area, vaginal delivery of 17P for the prevention of preterm birth has significant clinical relevance. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
Figures

Figure 1

Open AccessArticle
Towards Printed Pediatric Medicines in Hospital Pharmacies: Comparison of 2D and 3D-Printed Orodispersible Warfarin Films with Conventional Oral Powders in Unit Dose Sachets
Pharmaceutics 2019, 11(7), 334; https://doi.org/10.3390/pharmaceutics11070334
Received: 19 June 2019 / Revised: 10 July 2019 / Accepted: 11 July 2019 / Published: 14 July 2019
Cited by 1 | Viewed by 602 | PDF Full-text (3781 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
To date, the lack of age-appropriate medicines for many indications results in dose manipulation of commercially available dosage forms, commonly resulting in inaccurate doses. Various printing technologies have recently been explored in the pharmaceutical field due to the flexible and precise nature of [...] Read more.
To date, the lack of age-appropriate medicines for many indications results in dose manipulation of commercially available dosage forms, commonly resulting in inaccurate doses. Various printing technologies have recently been explored in the pharmaceutical field due to the flexible and precise nature of the techniques. The aim of this study was, therefore, to compare the currently used method to produce patient-tailored warfarin doses at HUS Pharmacy in Finland with two innovative printing techniques. Dosage forms of various strengths (0.1, 0.5, 1, and 2 mg) were prepared utilizing semisolid extrusion 3D printing, inkjet printing and the established compounding procedure for oral powders in unit dose sachets (OPSs). Orodispersible films (ODFs) drug-loaded with warfarin were prepared by means of printing using hydroxypropylcellulose as a film-forming agent. The OPSs consisted of commercially available warfarin tablets and lactose monohydrate as a filler. The ODFs resulted in thin and flexible films showing acceptable ODF properties. Moreover, the printed ODFs displayed improved drug content compared to the established OPSs. All dosage forms were found to be stable over the one-month stability study and suitable for administration through a naso-gastric tube, thus, enabling administration to all possible patient groups in a hospital ward. This work demonstrates the potential of utilizing printing technologies for the production of on-demand patient-specific doses and further discusses the advantages and limitations of each method. Full article
(This article belongs to the Special Issue 3D Printing of Pharmaceuticals and Drug Delivery Devices)
Figures

Graphical abstract

Open AccessArticle
Nanogels of Succinylated Glycol Chitosan-Succinyl Prednisolone Conjugate: Preparation, In Vitro Characteristics and Therapeutic Potential
Pharmaceutics 2019, 11(7), 333; https://doi.org/10.3390/pharmaceutics11070333
Received: 22 June 2019 / Revised: 10 July 2019 / Accepted: 11 July 2019 / Published: 13 July 2019
Viewed by 424 | PDF Full-text (5894 KB) | HTML Full-text | XML Full-text
Abstract
A novel anionic nanogel system was prepared using succinylated glycol chitosan-succinyl prednisolone conjugate (S-GCh-SP). The nanogel, named NG(S), was evaluated in vitro and in vivo. S-GCh-SP formed a nanogel via the aggregation of hydrophobic prednisolone (PD) moieties and the introduced succinyl groups contributed [...] Read more.
A novel anionic nanogel system was prepared using succinylated glycol chitosan-succinyl prednisolone conjugate (S-GCh-SP). The nanogel, named NG(S), was evaluated in vitro and in vivo. S-GCh-SP formed a nanogel via the aggregation of hydrophobic prednisolone (PD) moieties and the introduced succinyl groups contributed to the negative surface charge of the nanogel. The resultant NG(S) had a PD content of 13.7% (w/w), was ca. 400 nm in size and had a ζ-potential of −28 mV. NG(S) released PD very slowly at gastric pH and faster but gradually at small intestinal pH. Although NG(S) was easily taken up by the macrophage-like cell line Raw 264.7, it did not decrease cell viability, suggesting that the toxicity of the nanogel was very low. The in vivo evaluation was performed using rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. NG(S) and PD alone were not very effective at 5 mg PD eq./kg. However, NG(S) at 10 mg PD eq./kg markedly suppressed colonic damage, whereas PD alone did not. Furthermore, thymus atrophy was less with NG(S) than with PD alone. These results demonstrated that NG(S) is very safe, promotes drug effectiveness and has low toxicity. NG(S) has potential as a drug delivery system for the treatment of ulcerative colitis. Full article
Figures

Graphical abstract

Open AccessArticle
Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy
Pharmaceutics 2019, 11(7), 332; https://doi.org/10.3390/pharmaceutics11070332
Received: 25 May 2019 / Revised: 6 July 2019 / Accepted: 11 July 2019 / Published: 13 July 2019
Viewed by 388 | PDF Full-text (3374 KB) | HTML Full-text | XML Full-text
Abstract
Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was [...] Read more.
Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was first complexed ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as the permeation enhancer. This was followed by dispersion with poloxamer 188 and Labrasol to form the solid oral formulation of PMX (PMX/DCK-OP). PMX/DCK-OP exhibited a 10.6-fold increase in permeability across a Caco-2 cell monolayer compared to PMX alone. This resulted in a 70-fold increase in the oral bioavailability of PMX/DCK-OP in mice over oral PMX alone. In the A549 xenograft model, tumor volume was reduced by 51.1% in the PMX/DCK-OP treated group compared to only 32.8% in the maximum tolerated dose (MTD)-treated group. Furthermore, PMX/DCK-OP exhibited a significant anti-angiogenic effect on the A549 xenograft mice when compared to the MTD-treated group, as indicated by microvessel density quantification for CD-31. In addition, PMX/DCK-OP enhanced the release of an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), into both the blood circulation and the tumor microenvironment. Therefore, due to its oral route of administration, PMX/DCK-OP appears to be a better alternative to the conventional treatment of PMX. Full article
Figures

Graphical abstract

Open AccessArticle
Boosting Drug Discovery for Parkinson’s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles
Pharmaceutics 2019, 11(7), 331; https://doi.org/10.3390/pharmaceutics11070331
Received: 15 May 2019 / Revised: 30 June 2019 / Accepted: 9 July 2019 / Published: 12 July 2019
Viewed by 530 | PDF Full-text (2318 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely [...] Read more.
The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
Figures

Graphical abstract

Open AccessArticle
Hollow Microcapsules as Periocular Drug Depot for Sustained Release of Anti-VEGF Protein
Pharmaceutics 2019, 11(7), 330; https://doi.org/10.3390/pharmaceutics11070330
Received: 6 June 2019 / Revised: 3 July 2019 / Accepted: 6 July 2019 / Published: 11 July 2019
Viewed by 403 | PDF Full-text (12252 KB) | HTML Full-text | XML Full-text
Abstract
Diseases affecting the posterior segment of the eye such as age-related macular degeneration and diabetic retinopathy are leading causes of blindness all over the world. The current treatment regimen for such diseases involves repeated intravitreal injections of anti- Vascular Endothelial Growth Factor (VEGF) [...] Read more.
Diseases affecting the posterior segment of the eye such as age-related macular degeneration and diabetic retinopathy are leading causes of blindness all over the world. The current treatment regimen for such diseases involves repeated intravitreal injections of anti- Vascular Endothelial Growth Factor (VEGF) proteins. This method is highly invasive and can lead to severe complications. In an attempt to develop less invasive alternatives, we propose the use of a controlled release system consisting of anti-VEGF loaded hollow microcapsules that can be administered periocularly to form drug eluting depots on the episcleral surface. The microcapsules with either positive or negative surface charge were prepared by a layer by layer approach and showed pH responsive permeability switching. An ex vivo experiment using porcine sclera indicated positively charged microcapsules remained on the episcleral surface over four days while the negatively charged microcapsules were washed away. These positively charged microcapsules were then loaded with anti-VEGF protein ranibizumab using pH dependent permeability switching and protein release from the microcapsules were studied using an in vitro setup. An ex vivo experiment utilizing porcine sclera demonstrated sustained release of ranibizumab over seven days with zero-order kinetics. Full article
(This article belongs to the Special Issue Nanotechnology-Based Approaches for Chronic Diseases)
Figures

Graphical abstract

Pharmaceutics EISSN 1999-4923 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top